임상 논문

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Genitourinary syndrome of menopause (GSM) is a chronic condition that impairs quality of life and sexual function. Fractional CO2 laser therapy is a non-hormonal option, but large real-world data on symptom trajectories, durability, and ultrasonographic vulvar changes are limited. We evaluated symptom trajectories, responder rates, exposure-outcome associations, and vulvar tissue changes in a clinical cohort. We conducted a retrospective observational study at a single clinic in Japan. From 2016 to 2023, 826 women underwent fractional CO₂ vaginal and vulvar laser therapy (2,129 sessions). Symptoms were assessed using VAS (0-10) scores for six domains. Short-term outcomes were evaluated 20-59 days after the first session (n = 327), and long-term outcomes 10-14 months after the final session (n = 94). Responders were defined as a ≥2-point VAS improvement among women with baseline VAS ≥2. outcomes included ultrasonographic labia majora thickness; post-treatment imaging corresponded to the same windows when paired measurements were available. Patient satisfaction and adverse events were recorded. Mean age at first treatment was 61.9 ± 10.2 years (range, 29-87). All six symptoms improved short term, with the largest improvements typically in dyspareunia and vaginal dryness. At 10-14 months, improvements in dryness and urinary leakage attenuated, whereas dyspareunia was most durable. Labia majora thickness increased overall (16.9 ± 4.5-18.9 ± 3.1 mm), with thickening in 81.5% of women with paired measurements. Higher responder rates were observed among women receiving more sessions; however, these findings are associational and may reflect baseline severity and follow-up engagement. Satisfaction was high, and no serious adverse events were observed. In this real-world cohort, fractional CO2 vaginal and vulvar laser therapy for GSM was associated with reduced symptom severity and ultrasonographic thickening of the labia majora in a subset with paired measurements. Given the retrospective uncontrolled design, incomplete follow-up, and placebo effects in sham-controlled trials, findings should be interpreted as descriptive associations, not causal effects. Controlled studies are needed to confirm effectiveness, durability, and maintenance strategies. Energy-based devices (EBDs), including vaginal laser and radiofrequency therapies, have been proposed as minimally invasive treatments for stress urinary incontinence (SUI), but evidence remains limited and inconsistent. We hypothesised that EBDs would provide greater symptom improvement than sham, particularly in women with mild to moderate SUI. Following PRISMA guidelines, we searched Medline, Embase, the Cochrane Library, and One Search for randomised controlled trials (RCTs) comparing EBDs with sham in women with SUI, with at least 1 month of follow-up. The primary outcome was change in International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) scores. Two reviewers independently performed data extraction and RoB-2 assessment. Random-effects meta-analyses using restricted maximum likelihood estimation were conducted. Ten RCTs (11 datasets; ~ 850 women) were included. Using a random-effects model with Knapp-Hartung adjustment, the pooled EBD analysis showed a mean difference of -1.08 points (95% CI -2.08 to -0.08), indicating a statistically significant improvement with EBD. The prediction interval (-3.63 to 1.48) suggests a wide range of possible effects, including no benefit. Heterogeneity was moderate (I2 = 53%). Subgroup analysis of non-ablative Er:YAG laser showed the strongest and most homogeneous effect (MD -1.42; 95% CI -2.55 to -0.28; I2 = 29%). CO2 laser findings were inconsistent, and evidence for radiofrequency was insufficient. Adverse events were mild and transient. EBDs may improve SUI symptoms compared with sham, with the most consistent benefit observed for non-ablative Er:YAG laser. However, effects are modest and short-term. High-quality RCTs with standardised protocols and long-term follow-up are needed. Skin graft scars frequently remain hypertrophic, stiff, tethered, and dyschromic despite standard care. These scars are characterized by chronic inflammation, biomechanical rigidity, and surface irregularity, and often respond poorly to conventional fractional resurfacing or intralesional triamcinolone monotherapy due to limited penetration in thick, mature grafted tissue. Pinholxell Therapy is a standardized dual-step CO₂ laser protocol that combines deep macro-pinhole column creation (∼1 mm) with an immediate fractional CO₂ overlay, aiming to achieve simultaneous deep dermal release and surface normalization within a single session. We retrospectively analyzed 117 consecutive patients with mature graft-site scars treated with repeated sessions of the standardized dual-step Pinholxell CO₂ laser protocol at approximately 2-month intervals. Most patients underwent multiple treatments over an extended remodeling period. Scar outcomes were evaluated before and after treatment using the Vancouver Scar Scale (VSS) and the Observer Scar Assessment Scale (OSAS). Marked improvements were noted across all scar domains. The total VSS score decreased from 7.76 ± 2.22 to 1.47 ± 1.09 (p < 0.001; 81.1% reduction), with the greatest improvements in pigmentation and vascularity. The OSAS six-item total score improved from 31.78 ± 7.09 to 11.44 ± 2.59 (p < 0.001), and the overall opinion score improved from 7.15 ± 1.41 to 2.38 ± 0.48 (p < 0.001). The dual-step macro-pinhole column plus fractional CO₂ protocol produced substantial and consistent improvement in mature graft-site scars, supporting Pinholxell Therapy as a reproducible, office-based option for functional and aesthetic scar rehabilitation. In this study, we conducted a randomized controlled clinical trial to investigate the effectiveness and safety of punch excision versus manual fractional technology (MFT) in patients undergoing intralesional triamcinolone acetonide and 5-fluorouracil injection. Patients with keloid were randomly divided into two groups: One received punch excision combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (punch excision + TAC&5-FU), and the other received MFT combined with intralesional triamcinolone acetonide and 5-fluorouracil injection (MFT + TAC&5-FU). Designed treatments and regular evaluations were conducted. The significant improvement was observed in both groups. Regarding the effectiveness of different combined therapies, MFT combined with TAC&5-FU demonstrated a greater improvement of mVSS, POSAS, and DLQI without statistical differences when comparing with those of punch excision combined therapy. Likewise, the injection times and adverse events were generally similar across both groups. This study demonstrated that punch excision combined with TAC&5-FU, as well as MFT combined with TAC&5-FU, was promising therapeutic options for keloids without a notable difference in effectiveness and safety. A single-blinded randomized clinical trial. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Post-acne scarring is a prevalent dermatological concern with significant impact on quality of life. Fractional CO2 laser (FCL) and microneedling radiofrequency (MNRF) are widely used treatments, but their comparative efficacy and safety require further synthesis. This meta-analysis was conducted to compare the efficacy a

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

Facial aging involves not only soft tissue laxity but also progressive bony resorption, particularly in the maxilla and mandible. Current non-invasive aesthetic modalities primarily target soft tissues, neglecting skeletal changes that contribute to volume loss and structural descent. To propose the hypothetical role of multiwavelength diode laser (MWDL) in stimulating osteogenesis via controlled thermal delivery to the periosteum, offering a novel, non-invasive strategy for counteracting facial bone resorption. This clinical commentary discusses MWDL's mechanism-targeting the periosteal layer using 755, 808, and 1064 nm wavelengths (N.CORE 3D (previous version of Fortra), Classys Inc., Seoul) to deliver 43°C-46°C heat. A case study of a 70-year-old female receiving 16 sessions over 4 years was included. Cortical bone thickness was measured pre- and post-treatment using dental radiographs. Modest increases in cortical bone thickness were observed: from 3.4 to 3.51 mm (left) and from 3.14 to 3.37 mm (right), suggesting possible periosteal osteogenic stimulation. MWDL may represent a promising adjunct to soft tissue rejuvenation by addressing age-related skeletal decline. While early findings are encouraging, controlled trials are needed to validate efficacy, optimise protocols, and define long-term safety.

Acne scarring can impact patients negatively psychosocially. Picosecond lasers and radiofrequency microneedling may be used to improve this condition. To evaluate the efficacy and safety of combination treatment with a picosecond 755-nm Alexandrite laser (PSAL; Picosure Pro; Cynosure, Westford, MA) with diffractive lens array and a radiofrequency microneedling device (RFM; Potenza; Cynosure) for treating facial atrophic acne scars. This was a prospective, single-center, evaluator-blinded, split-face, randomized clinical trial. Twenty subjects with moderate to severe atrophic facial acne scarring were randomized to have one facial half treatment with PSAL followed by full-face treatment with RFM. Subjects received 4 treatments at 4-week intervals. The blinded Investigator's échelle d'évaluation clinique des cicatrices d'acné (ECCA) acne grading, Physician Global Aesthetic Improvement Scale (PGAIS), and Subject Global Aesthetic Improvement Scale (SGAIS) did not show a significant difference between the facial half treated with RFM only and the half treated with RFM and PSAL at interval time points. However, there was significant improvement in ECCA, PGAIS, and SGAIS for both groups over study duration. Both RFM and PSAL appear safe and may be effective for acne scarring treatment, but larger trials are required to confirm superiority or synergy. Studies using a 755 nm picosecond laser with a focus lens array have been reported to be effective for facial wrinkles and pigmentation. This study reports the safety and efficacy using a shorter interval of 2-3 weeks between treatments. Nineteen female subjects and one male subject, primarily Fitzpatrick skin types II and III (one skin type I), who had mild to moderate wrinkles and sun-induced pigmentation were enrolled and treated using the 755 nm PicoSure Laser with focus lens array. The skin was cleansed then wiped with an alcohol wipe prior to treatment. Lidocaine 30% ointment and/or forced air cooling could be used to increase subject comfort. Adjacent pulses, with minimal overlap (10% or less), were delivered to the full face. Subjects received four treatments, performed at 2-3-week intervals. The laser energy used was 0.71 J/cm2 . The physician administered 3-7 passes with an average total of 6,253 pulses per treatment. Follow-up visits occurred at 1 and 3 months post-last treatment at which the physician scored satisfaction and improvement and subjects scored satisfaction and likelihood to recommend to others. The most common side effects were mild swelling, pain, redness, and crusting, most of which subsided within hours of the treatment, with the latest resolving within 48 hours. This is similar to a previous reported study (Weiss et al. ASLMS 2015) where treatments were performed every 6 weeks with side effects resolving within 24 hours. At the 1 and 3 month follow-up visits, 94% (n = 19) and 93% (n = 15) of subjects scored themselves as satisfied or extremely satisfied with their overall results and 81% and 93% were likely to recommend the treatment based on global assessment, respectively. The treating physician was satisfied with 93% of subject's overall results. Three blinded evaluators were able to correctly identify the baseline from post-treatment photographs in 77% of the subjects at the 1 month follow-up and 69% of the subjects at the 3 month follow-up, on average. The average treatment pain score was 4.2 on a 1-10 scale. A compressed treatment interval expedites results without increasing side effects and resulted in a high physician and subject satisfaction rate. Lasers Surg. Med. 48:723-726, 2016. © 2016 Wiley Periodicals, Inc. The use of picosecond lasers to remove tattoos has greatly improved due to the long-standing outcomes of nanosecond lasers, both clinically and histologically. The first aesthetic picosecond laser available for this use was the PicoSure(®) laser system (755/532 nm). Now that a vast amount of research on its use has been conducted, we performed a comprehensive review of the literature to validate the continued application of the PicoSure(®) laser system for tattoo removal. A PubMed search was conducted using the term "picosecond" combined with "laser", "dermatology", and "laser tattoo removal". A total of 13 articles were identified, and ten of these met the inclusion criteria for this review. The majority of studies showed that picosecond lasers are an effective and safe treatment mode for the removal of tattoo pigments. Several studies also indicated potential novel applications of picosecond lasers in the removal of various tattoo pigments (eg, black, red, and yellow). Adverse effects were generally mild, such as transient hypopigmentation or blister formation, and were rarely more serious, such as scarring and/or textural change. Advancements in laser technologies and their application in cutaneous medicine have revolutionized the field of laser surgery. Computational modeling provides evidence that the optimal pulse durations for tattoo ink removal are in the picosecond domain. It is recommended that the PicoSure(®) laser system continue to be used for safe and effective tattoo removal, including for red and yellow pigments.

Optimizing oxygenation for patients necessitates a delicate balance between sufficient oxygen delivery and mitigating the potential hazards of hyperoxemia. We hypothesized that integrating Oxygen Reserve Index (ORi) monitoring would effectively reduce intraoperative hyperoxemia compared to reliance solely on pulse oximetry. This single-center randomized controlled trial included multiple trauma patients with ASA class 3 or higher undergoing general anesthesia. FiO2 adjustments to 0.5 started at T0 with arterial blood gas analysis (ABGA) every 30-minutes. Patients were randomized into Group O (ORi monitoring) and Group N (pulse oximetry). In Group O, FiO2 was reduced if ORi > 0.05; unchanged if ORi was 0-0.05. Group N decreased FiO2 if SpO2 was 100%, unchanged if SpO2 was < 99%, and increased FiO2 by 0.05 until SpO2 reached 95% or above. 54 participants were randomized, and 51 analyzed. Group O demonstrated a significantly higher percentage of normoxemia (80 ≤ PaO2 < 120 mmHg) (64.4% vs. 40.4%, P = 0.002) across 181 ABGAs. Although baseline PaO2 (T1) values were comparable within moderate hyperoxemia, at T2, only Group O achieved normoxemia, with consistently lower PaO2 values at T2, T3, and T4 compared to Group N. ORi values in Group O consistently trended lower from T1 to T4. The positive correlation between PaO2 and ORi was reaffirmed, establishing cut-off values for PaO2 ≥ 120mmHg and ≥ 150mmHg at 0.06 and 0.22, respectively. Simultaneous ORi and pulse oximetry reduce intraoperative hyperoxemia through safe and meticulous protocol adherence in patients. Previous study in human subjects has documented biomechanical and neurophysiological responses to impulsive spinal manipulative thrusts, but very little is known about the neuromechanical effects of varying thrust force-time profiles. Ten adolescent Merino sheep were anesthetized and posteroanterior mechanical thrusts were applied to the L3 spinous process using a computer-controlled, mechanical testing apparatus. Three variable pulse durations (10, 100, 200 ms, force = 80 N) and three variable force amplitudes (20, 40, 60 N, pulse duration = 100 ms) were examined for their effect on lumbar motion response (L3 displacement, L1, L2 acceleration) and normalized multifidus electromyographic response (L3, L4) using a repeated measures analysis of variance. Increasing L3 posteroanterior force amplitude resulted in a fourfold linear increase in L3 posteroanterior vertebral displacement (p < 0.001) and adjacent segment (L1, L2) posteroanterior acceleration response (p < 0.001). L3 displacement was linearly correlated (p < 0.001) to the acceleration response over the 20-80 N force range (100 ms). At constant force, 10 ms thrusts resulted in nearly fivefold lower L3 displacements and significantly increased segmental (L2) acceleration responses compared to the 100 ms (19%, p = 0.005) and 200 ms (16%, p = 0.023) thrusts. Normalized electromyographic responses increased linearly with increasing force amplitude at higher amplitudes and were appreciably affected by mechanical excitation pulse duration. Changes in the biomechanical and neuromuscular response of the ovine lumbar spine were observed in response to changes in the force-time characteristics of the spinal manipulative thrusts and may be an underlying mechanism in related clinical outcomes.

Background and Objectives: Conventional methods for removing cemented fixed prosthetic restorations (FPRs) are unreliable and lead to unsatisfactory outcomes. At their best, they allow the tooth to be saved at the expense of a laborious process that also wears down rotating tools and handpieces and occasionally results in abutment fractures. Restorations are nearly never reusable in any of these situations. Erbium-doped yttrium-aluminum-garnet (Er:YAG) and erbium-chromium yttrium-scandium-gallium-garnet (Er,Cr:YSGG) lasers casafely and effectively remove FPRs, according to scientific studiesre. This study sets out to examine the impact of Er:YAG laser radiation on the debonding of different ceramic restorations, comparing the behavior of various ceramic prosthetic restoration types under laser radiation action and evaluating the integrity of prosthetic restorations and dental surfaces exposed to laser radiation. Materials and Methods: The study included a total of 16 removed teeth, each prepared on opposite surfaces as abutments.y. Based on the previously defined groups, four types of ceramic restorations were included in the study: feldspathic (F), lithium disilicates (LD), layered zirconia (LZ), and monolithic zirconia (MZ). The thickness of the prosthetic restorations was measured at three points, and two different materials were used for cementation. The Er:YAG Fotona StarWalker MaQX laser was used to debond the ceramic FPR at a distance of 10 mm using an R14 sapphire tip with 275 mJ, 20 Hz, 5.5 W, with air cooling (setting 1 of 9) and water. After debonding, the debonded surface was visualized under electron microscopy. Results: A total of 23 ceramic FPRs were debonded, of which 12 were intact and the others fractured into two or three pieces. The electron microscopy images showed that debonding took place without causing any harm to the tooth structure. The various restoration types had the following success rates: 100% for the LZ and F groups, 87% for the LD group, and 0% for the MZ group. In terms of cement type, debonding ceramic FPRs cemented with RELYX was successful 75% of the time, compared to Variolink DC's 69% success rate. Conclusions: In summary, the majority of ceramic prosthetic restorations can be successfully and conservatively debonded with Er:YAG radiation.

Recurrent ERBB2-mutations have been recently documented in a small group of hybrid neurofibroma/schwannoma peripheral nerve sheath tumors (PNST) in patients with presumed sporadic schwannomatosis. Prompted by two cases of plexiform neurofibromas harboring Epidermal Growth Factor Receptor 2 (ERBB2) hot spot mutations, but lacking germline alterations, we sought to investigate the clinicopathologic features of PNST demonstrating this genetic alteration. ERBB2-mutant PNST cases were selected from the institutional molecular database, using a matched tumor-normal targeted DNA sequencing panel. Clinical history, radiologic findings and follow-up information were retrieved from chart review. Pathologic features, genomic and germline findings were reviewed. We identified 5 patients, all except one were females, with a median age of 34 years (range: 24-40). All revealed multiple PNSTs with a segmental distribution by imaging, including pelvis (n=2), upper limb (n=2), and stomach (n=1). None of the patients had family history or displayed clinical features of NF1, except for one patient with faded café-au-lait macules. All excised lesions were neurofibromas, including plexiform (n=4), intraneural with Schwann cell micronodules (n=2), and diffuse (n=1) subtypes. None of the cases showed features of schwannoma. All cases harbored ERBB2 kinase domain mutations (exon 19, n=3, exon 20, n=2, exon 21, n=1). One additional case had two concurrent ERBB2 mutations in exons 20 and 21. By germline testing, only one patient showed pathogenic variants (MUTYH mutation). None showed germline or somatic alterations in NF1, NF2, SMARCB1, LZTR1 or chromosome 22q loss. Patients had stable disease with no significant radiologic progression or malignant transformation; one being enrolled on a HER2-inhibitor trial for 7 years due to unresectable disease with satisfactory disease control. PNST harboring oncogenic ERBB2 mutations are multifocal, spanning various neurofibroma variants, including plexiform type, in the absence of clinical or germline evidence of syndromic disease. Our findings suggest ERBB2 mutations may represent an alternative mechanism driving neurofibroma genesis, with potential therapeutic implications. This chapter traces the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow perturbations in the genesis of hemorrhage, clinical factors that increase bleeding risk, and potential preventative strategies. In the 1970's a neuropathological study demonstrated capillary rupture within the germinal matrix as the source of hemorrhage; loss of cerebral autoregulation in the sick infant was demonstrated. In 1980's the introduction of cranial ultrasound facilitated diagnosis of hemorrhage. Experimental and clinical studies demonstrated the importance of intravascular perturbations in provoking hemorrhage. Specifically, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. Surfactant introduction was not associated with a reduction in hemorrhage. In the 1990's antenatal steroids use to accelerate lung development was recommended; this was associated with an unanticipated reduction in hemorrhage. Early indomethacin administration was associated with a reduction of severe hemorrhage. What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138+ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to <42 years, with a history of two or more first-trimester consecutive miscarriages were recruited from specialist RPL clinics. Endometrial biopsies, vaginal, ectocervical, and endometrial swabs were obtained 10 ± 4 days following a positive home ovulation test. Additional samples, including proliferative endometrium, were obtained from the Tommy's National Reproductive Health Biobank. Endometrial biopsies were processed for CD138 expression analysis and immunohistochemistry (IHC), histological dating based on Noyes' criteria, and molecular timing analysis. Metataxonomic profiling of microbiota was performed by sequencing of bacterial 16S ribosomal RNA genes alongside cytokine analysis. IHC revealed three patterns of CD138 immunoreactivity: predominantly membranous punctate staining, predominantly diffuse staining, and a mixed pattern. CD138 is constitutively expressed on the basolateral membrane of glandular epithelial cells and a subset of non-immune stromal cells. Stromal expression was very high (>200 CD138-positive stromal cells/10 mm2) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann-Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138+ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy's National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730. In recent years, interest has grown in clarifying t

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

Riehl's melanosis is a hyperpigmentation disorder that has a significant psychological and social impact on individuals. In the past 10 years, new categories have been developed, raising questions about how to classify Riehl's melanosis. The mechanism of this disease remains unclear, although the type IV hypersensitivity response caused by allergic sensitization, as well as genetic, ultraviolet radiation, and autoimmune factors, is to blame. Clinical manifestation, dermoscopy, reflectance confocal microscopy, patch/photopatch testing, histopathology, and a novel multimodality skin imaging system have been used for the diagnosis. A variety of therapies including topical skin-lightening agents, oral tranexamic acid, glycyrrhizin compound, chemical peels, and lasers and light therapies (intense pulsed light, 1064-nm Q-Switched Nd: YAG laser, 755-nm PicoWay laser, nonablative 1927-nm fractional thulium fiber laser, new pulsed-type microneedling radiofrequency), with improved effectiveness. The latest findings on possible biomarkers and their relationship to other autoimmune diseases were also summarized. Until recently, quality-switched nanosecond lasers have been the workhorse lasers in treating pigmented lesions. However, the recently commercialized picosecond lasers have provided physicians with a novel method to manage pigmented lesions. Most recently, the first picosecond laser with a 730-nm wavelength was developed to specifically target melanin and melanocytes. We report on two Asian patients with freckles, lentigines, and melasma who were successfully treated with a novel 730-nm Ti:Sapphire picosecond laser (Picoway®; Syneron Candela, Corp). The clinical outcome was measured by the global percent of clearance, which was evaluated by blinded observers by comparing the post-treatment photographs with the baseline photographs. In both patients, a significant pigmentary reduction was achieved with only one treatment session. In both patients, the treatments were well tolerated with minimal discomfort even without topical anesthesia. No post-inflammatory hyperpigmentation or repigmentation was observed until the 6-week follow-up. The pigmentary conditions treated included freckles, lentigines, and melasma. Both subjects showed clinical improvement, with the best results observed for the treatment of freckles such that 95% of the lesions achieved excellent response (75-94% lightening). The results of this case report indicate that a novel 730-nm Ti:Sapphire picosecond laser may be effective and safe in treating pigmentary disorders in darker-skinned patients. Therefore, further well-designed, prospective clinical trials are warranted to establish the potential of 730-nm picosecond lasers and determine the optimal treatment parameters in comparison to existing laser and light modalities. Lasers Surg. Med. © 2020 Wiley Periodicals LLC. Pigmentation is one of the few major characteristics according to which scars are evaluated. Data on the treatment of the hyperpigmented component of scars are sparse. The authors aimed at evaluating the efficacy of the fractional 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) picosecond laser in the treatment of the hyperpigmented component of scars. Sixteen patients with hyperpigmented scars underwent 3 to 8 treatment sessions at 3- to 6-week intervals with the 1,064-nm Nd:YAG picosecond laser (PicoWay, Candela, Resolve handpiece). The treatment response was evaluated by 2 noninvolved dermatologists on a global assessment scale (GAS) of 1 to 4. A Mexameter quantitatively evaluated the melanin content of the scar before and after laser treatments. The average GAS score of the 2 noninvolved dermatologists was 3.31 ± 0.57. The patients assessed their level of tolerance as good or excellent and their satisfaction level as moderate or high. The Mexameter showed that the melanin index decreased considerably (by 39.11 ± 11.58%) in all patients after treatment. The fractionated nonablative picosecond Nd:YAG laser was effective for the treatment of the hyperpigmented component of scars.

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

To investigate the changes of vaginal health and vulvovaginal atrophy (VVA) symptoms following CO2 laser treatment in postpartum breastfeeding women. The number of treatment sessions required to alleviate related symptoms was also determined. Postpartum healthy women who continued breastfeeding and suffered from VVA related symptoms were included in this prospective study. All the participants underwent three consecutive fractional CO2 laser treatments using Lumenis AcuPulse system with FemTouch™ handpiece at four-weeks interval. Following each laser treatment, the severity of VVA symptoms and Vaginal Health Index (VHI) score were assessed as subjective and objective outcomes. The changes in VHI score and VVA symptom severity were compared with baseline data to detect the onset of significant improvement. Thirty postpartum breastfeeding women with VVA symptoms completed the treatment courses and associated measurements. Their age ranged from 25 to 41 with an average of 34.6 years. The mean duration of breastfeeding prior to the initial laser treatment was 3.3 months. Vaginal dryness and dyspareunia were the most bothersome VVA symptoms prior to laser treatment and alleviated after two to three treatment sessions. The significant change of VHI score reaching non-atrophic level was found after the first treatment (media of score post:18 vs. pre:14, p < 0.05) and sustained stable through the following two treatments. Application of fractional CO2 vaginal laser on the management of postpartum vulvovaginal atrophy was proven effectively in our study. Objective and subjective improvements were detected after the first and second laser treatment, respectively. Two consecutive laser treatment sessions were clinically sufficient to alleviate VVA related symptoms in these young female population under postpartum breastfeeding. Background: Vaginal laxity (VL) is characterized by the relaxing of the vaginal wall that affects the quality of life and sexual function of patients. The current management of VL such as Kegel exercises and topical or systemic hormonal replacement results in unsatisfactory outcomes; thus, novel modalities are needed to improve the efficacy. Vaginal fractional carbon dioxide (CO2) laser treatment has shown growing applications for the treatment of VL, but results show nonconformities due to the lack of objective evaluations. In this study, we aimed to validate the clinical efficacy and biophysical benefits of fractional CO2 laser treatment for VL patients with the incorporation of objective approaches. Methods: This is a descriptive study without controls. A total of 29 patients were enrolled and treated with two sessions of FemTouch vaginal fractional CO2 laser, with a one-month interval between sessions. Both subjective and objective measurements, including female sexual function index (FSFI), vaginal health index score (VHIS), vaginal tactile imaging (VTI), and histology were used to validate the clinical efficacy and biophysical benefits after treatment. Results: The overall FSFI scores and VHIS scores after the first and second treatment sessions were significantly higher than the baseline scores (p < 0.01, n = 29). VTI measurements showed a significant increase in maximal pressure resistance (kPa) of both the anterior and posterior vaginal walls at a 10−12-month post-treatment visit compared with pre-treatment controls (p < 0.001; n = 16). Histological examination showed that laser treatment led to increases in the thickness of the stratified squamous epithelium layer and density of connective tissues in the lamina propria. Conclusions: Fractional CO2 vaginal laser treatment can improve both vaginal health and sexual function and restore vaginal biomechanical properties by increasing vaginal tissue tightening and improving vaginal tissue integrity in Asian women. Our data support that fractional CO2 vaginal laser is a valid treatment modality for VL.

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs. The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders. Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism. The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877. Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD. Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics. Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures. Flow cytometry is commonly used to detect cell-derived extracellular vesicles in body fluids such as blood plasma. However, continuous and simultaneous illumination of multiple particles at or below the detection limit may result in the detection of a single event. This phenomenon is called swarm detection and leads to incorrect particle concentration measurements. To prevent swarm detection, sample dilution is recommended. Since the concentration of particles differs between plasma samples, finding the optimal sample dilution requires dilution series of all samples, which is unfeasible in clinical routine. Here we developed a practical procedure to find the optimal sample dilution of plasma for extracellular vesicle flow cytometry measurements in clinical research studies. Dilution series of 5 plasma samples were measured with flow cytometry (Apogee A60-Micro), triggered on side scatter. The total particle concentration between these plasma samples ranged from 2.5 × 109 to 2.1 × 1011 mL-1. Swarm detection was absent in plasma samples when diluted ≥1.1 × 103-fold or at particle count rates <3.0 × 103 events·s-1. Application of either one of these criteria, however, resulted in insignificant particle counts in most samples. The best approach to prevent swarm detection while maintaining significant particle counts was by combining minimal dilution with maximum count rate. To prevent swarm detection in a series of clinical samples, the measurement count rate of a single diluted plasma sample can be used to determine the optimal dilution factor. For our samples, flow cytometer, and settings, the optimal dilution factor is ≥1.1 × 102-

The objectives of this study were to evaluate the safety, tolerability, and efficacy of oxymetazoline hydrochloride cream, 1% (oxymetazoline) when used as an adjunctive treatment with energy-based therapy for patients with moderate to severe facial erythema associated with rosacea. In this Phase 4, multicenter, interventional, open-label study, eligible patients received one of four energy-based therapies (potassium titanyl phosphate laser, intense pulsed light therapy, pulsed-dye laser Vbeam Perfecta, or pulsed-dye laser Cynergy) on day 1 and day 29 and once-daily application of oxymetazoline on days 3 through 27 and days 31 through 56. Improvement from baseline in Clinician Erythema Assessment (CEA) score, patient satisfaction measures, incidence of treatment-emergent adverse events (TEAEs), and worsening from baseline on dermal tolerability assessments and the Clinician Telangiectasia Assessment (CTA) were assessed. Data were summarized using descriptive statistics. A total of 46 patients (mean age, 51.1 years; 78.3% female) enrolled in this study. Similar numbers of patients received each of the energy-based therapies in addition to oxymetazoline. All patients demonstrated an improvement from baseline in CEA during the study with 39 of 43 evaluable patients (90.7%) demonstrating an improvement 6 hours posttreatment on day 56. Most patients were satisfied or very satisfied with treatment at the end of the study. All TEAEs were mild or moderate in severity. Some patients experienced worsening in dermal tolerability assessment symptoms (range: 4-21 patients; 8.7-45.7%). Worsening in CEA and CTA were each reported by three patients (6.5%) at any time during the study. Treatment with oxymetazoline as adjunctive therapy with energy-based therapy was safe, well tolerated, and reduced facial erythema in patients with moderate to severe persistent facial erythema associated with rosacea. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC. A 47-year-old white woman presented to our clinic complaining of recalcitrant warts on her trunk and extremities. She had an extensive past medical history including immunodeficiency of unknown origin, pulmonary hypertension, rheumatoid arthritis, and systemic lupus erythematosus, for which she was being treated with chronic immunosuppressive therapy with methylprednisolone and belimumab. The patient had previously failed treatments at an outside facility with liquid nitrogen, trichloroacetic acid, topical cidofovir, imiquimod, topical 5-fluorouracil, intralesional candida antigen, pulsed-dye laser (Vbeam Perfecta), surgical excision, and photodynamic therapy. (SKINmed. 2019;17:68-71). To assess the efficacy in the treatment of port wine stain in the head and neck by using (Vbeam perfecta®). Forty-two port wine stain patients were recruited at the National Hospital of Dermatology and Venereology, Hanoi, Vietnam. We reported an excellent response (43.8%) (76%-100% lightening), a good response (18.8%) (51%-75% lightening), fair improvement (18.8%) (26%-50% lightening), and no response (18.8%) (0%-25% lightening). In conclusion, pulsed dye laser is an excellent technique to remove port wine stains on the face and neck.

Riehl's melanosis is a hyperpigmentation disorder that has a significant psychological and social impact on individuals. In the past 10 years, new categories have been developed, raising questions about how to classify Riehl's melanosis. The mechanism of this disease remains unclear, although the type IV hypersensitivity response caused by allergic sensitization, as well as genetic, ultraviolet radiation, and autoimmune factors, is to blame. Clinical manifestation, dermoscopy, reflectance confocal microscopy, patch/photopatch testing, histopathology, and a novel multimodality skin imaging system have been used for the diagnosis. A variety of therapies including topical skin-lightening agents, oral tranexamic acid, glycyrrhizin compound, chemical peels, and lasers and light therapies (intense pulsed light, 1064-nm Q-Switched Nd: YAG laser, 755-nm PicoWay laser, nonablative 1927-nm fractional thulium fiber laser, new pulsed-type microneedling radiofrequency), with improved effectiveness. The latest findings on possible biomarkers and their relationship to other autoimmune diseases were also summarized. Until recently, quality-switched nanosecond lasers have been the workhorse lasers in treating pigmented lesions. However, the recently commercialized picosecond lasers have provided physicians with a novel method to manage pigmented lesions. Most recently, the first picosecond laser with a 730-nm wavelength was developed to specifically target melanin and melanocytes. We report on two Asian patients with freckles, lentigines, and melasma who were successfully treated with a novel 730-nm Ti:Sapphire picosecond laser (Picoway®; Syneron Candela, Corp). The clinical outcome was measured by the global percent of clearance, which was evaluated by blinded observers by comparing the post-treatment photographs with the baseline photographs. In both patients, a significant pigmentary reduction was achieved with only one treatment session. In both patients, the treatments were well tolerated with minimal discomfort even without topical anesthesia. No post-inflammatory hyperpigmentation or repigmentation was observed until the 6-week follow-up. The pigmentary conditions treated included freckles, lentigines, and melasma. Both subjects showed clinical improvement, with the best results observed for the treatment of freckles such that 95% of the lesions achieved excellent response (75-94% lightening). The results of this case report indicate that a novel 730-nm Ti:Sapphire picosecond laser may be effective and safe in treating pigmentary disorders in darker-skinned patients. Therefore, further well-designed, prospective clinical trials are warranted to establish the potential of 730-nm picosecond lasers and determine the optimal treatment parameters in comparison to existing laser and light modalities. Lasers Surg. Med. © 2020 Wiley Periodicals LLC. Pigmentation is one of the few major characteristics according to which scars are evaluated. Data on the treatment of the hyperpigmented component of scars are sparse. The authors aimed at evaluating the efficacy of the fractional 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) picosecond laser in the treatment of the hyperpigmented component of scars. Sixteen patients with hyperpigmented scars underwent 3 to 8 treatment sessions at 3- to 6-week intervals with the 1,064-nm Nd:YAG picosecond laser (PicoWay, Candela, Resolve handpiece). The treatment response was evaluated by 2 noninvolved dermatologists on a global assessment scale (GAS) of 1 to 4. A Mexameter quantitatively evaluated the melanin content of the scar before and after laser treatments. The average GAS score of the 2 noninvolved dermatologists was 3.31 ± 0.57. The patients assessed their level of tolerance as good or excellent and their satisfaction level as moderate or high. The Mexameter showed that the melanin index decreased considerably (by 39.11 ± 11.58%) in all patients after treatment. The fractionated nonablative picosecond Nd:YAG laser was effective for the treatment of the hyperpigmented component of scars.

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

Riehl's melanosis is a hyperpigmentation disorder that has a significant psychological and social impact on individuals. In the past 10 years, new categories have been developed, raising questions about how to classify Riehl's melanosis. The mechanism of this disease remains unclear, although the type IV hypersensitivity response caused by allergic sensitization, as well as genetic, ultraviolet radiation, and autoimmune factors, is to blame. Clinical manifestation, dermoscopy, reflectance confocal microscopy, patch/photopatch testing, histopathology, and a novel multimodality skin imaging system have been used for the diagnosis. A variety of therapies including topical skin-lightening agents, oral tranexamic acid, glycyrrhizin compound, chemical peels, and lasers and light therapies (intense pulsed light, 1064-nm Q-Switched Nd: YAG laser, 755-nm PicoWay laser, nonablative 1927-nm fractional thulium fiber laser, new pulsed-type microneedling radiofrequency), with improved effectiveness. The latest findings on possible biomarkers and their relationship to other autoimmune diseases were also summarized. Until recently, quality-switched nanosecond lasers have been the workhorse lasers in treating pigmented lesions. However, the recently commercialized picosecond lasers have provided physicians with a novel method to manage pigmented lesions. Most recently, the first picosecond laser with a 730-nm wavelength was developed to specifically target melanin and melanocytes. We report on two Asian patients with freckles, lentigines, and melasma who were successfully treated with a novel 730-nm Ti:Sapphire picosecond laser (Picoway®; Syneron Candela, Corp). The clinical outcome was measured by the global percent of clearance, which was evaluated by blinded observers by comparing the post-treatment photographs with the baseline photographs. In both patients, a significant pigmentary reduction was achieved with only one treatment session. In both patients, the treatments were well tolerated with minimal discomfort even without topical anesthesia. No post-inflammatory hyperpigmentation or repigmentation was observed until the 6-week follow-up. The pigmentary conditions treated included freckles, lentigines, and melasma. Both subjects showed clinical improvement, with the best results observed for the treatment of freckles such that 95% of the lesions achieved excellent response (75-94% lightening). The results of this case report indicate that a novel 730-nm Ti:Sapphire picosecond laser may be effective and safe in treating pigmentary disorders in darker-skinned patients. Therefore, further well-designed, prospective clinical trials are warranted to establish the potential of 730-nm picosecond lasers and determine the optimal treatment parameters in comparison to existing laser and light modalities. Lasers Surg. Med. © 2020 Wiley Periodicals LLC. Pigmentation is one of the few major characteristics according to which scars are evaluated. Data on the treatment of the hyperpigmented component of scars are sparse. The authors aimed at evaluating the efficacy of the fractional 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) picosecond laser in the treatment of the hyperpigmented component of scars. Sixteen patients with hyperpigmented scars underwent 3 to 8 treatment sessions at 3- to 6-week intervals with the 1,064-nm Nd:YAG picosecond laser (PicoWay, Candela, Resolve handpiece). The treatment response was evaluated by 2 noninvolved dermatologists on a global assessment scale (GAS) of 1 to 4. A Mexameter quantitatively evaluated the melanin content of the scar before and after laser treatments. The average GAS score of the 2 noninvolved dermatologists was 3.31 ± 0.57. The patients assessed their level of tolerance as good or excellent and their satisfaction level as moderate or high. The Mexameter showed that the melanin index decreased considerably (by 39.11 ± 11.58%) in all patients after treatment. The fractionated nonablative picosecond Nd:YAG laser was effective for the treatment of the hyperpigmented component of scars.

The objectives of this study were to evaluate the safety, tolerability, and efficacy of oxymetazoline hydrochloride cream, 1% (oxymetazoline) when used as an adjunctive treatment with energy-based therapy for patients with moderate to severe facial erythema associated with rosacea. In this Phase 4, multicenter, interventional, open-label study, eligible patients received one of four energy-based therapies (potassium titanyl phosphate laser, intense pulsed light therapy, pulsed-dye laser Vbeam Perfecta, or pulsed-dye laser Cynergy) on day 1 and day 29 and once-daily application of oxymetazoline on days 3 through 27 and days 31 through 56. Improvement from baseline in Clinician Erythema Assessment (CEA) score, patient satisfaction measures, incidence of treatment-emergent adverse events (TEAEs), and worsening from baseline on dermal tolerability assessments and the Clinician Telangiectasia Assessment (CTA) were assessed. Data were summarized using descriptive statistics. A total of 46 patients (mean age, 51.1 years; 78.3% female) enrolled in this study. Similar numbers of patients received each of the energy-based therapies in addition to oxymetazoline. All patients demonstrated an improvement from baseline in CEA during the study with 39 of 43 evaluable patients (90.7%) demonstrating an improvement 6 hours posttreatment on day 56. Most patients were satisfied or very satisfied with treatment at the end of the study. All TEAEs were mild or moderate in severity. Some patients experienced worsening in dermal tolerability assessment symptoms (range: 4-21 patients; 8.7-45.7%). Worsening in CEA and CTA were each reported by three patients (6.5%) at any time during the study. Treatment with oxymetazoline as adjunctive therapy with energy-based therapy was safe, well tolerated, and reduced facial erythema in patients with moderate to severe persistent facial erythema associated with rosacea. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC. A 47-year-old white woman presented to our clinic complaining of recalcitrant warts on her trunk and extremities. She had an extensive past medical history including immunodeficiency of unknown origin, pulmonary hypertension, rheumatoid arthritis, and systemic lupus erythematosus, for which she was being treated with chronic immunosuppressive therapy with methylprednisolone and belimumab. The patient had previously failed treatments at an outside facility with liquid nitrogen, trichloroacetic acid, topical cidofovir, imiquimod, topical 5-fluorouracil, intralesional candida antigen, pulsed-dye laser (Vbeam Perfecta), surgical excision, and photodynamic therapy. (SKINmed. 2019;17:68-71). To assess the efficacy in the treatment of port wine stain in the head and neck by using (Vbeam perfecta®). Forty-two port wine stain patients were recruited at the National Hospital of Dermatology and Venereology, Hanoi, Vietnam. We reported an excellent response (43.8%) (76%-100% lightening), a good response (18.8%) (51%-75% lightening), fair improvement (18.8%) (26%-50% lightening), and no response (18.8%) (0%-25% lightening). In conclusion, pulsed dye laser is an excellent technique to remove port wine stains on the face and neck.

Following Nonablative fractional Fraxel laser (NAFL), a well-established treatment for skin rejuvenation, immediate post-procedural care is essential to address any potential complications and accelerate the healing process. To evaluate the efficacy and patient satisfaction of a topical skincare regimen containing vitamin C, vitamin E, and ferulic acid-CE Ferulic serum (CEF) following NAFL treatment in the Chinese population. In this randomized, investigator-blinded, split-face, controlled trial, patients with mild-to-moderate facial photodamage were randomized to receive CEF treatment on one side of the face and normal saline (NS) on the other side immediately after the NAFL procedure and daily during the 7-day follow-up. The primary endpoint was the change from baseline in erythema score on Day 7, with key secondary endpoints including changes from baseline in erythema index (EI), melanin index (MI), transepidermal water loss, skin hydration, skin sebum content, scabbing, edema, overall patient satisfaction, and post-procedure pain. In total, 50 patients (female 45/50) were enrolled in this study, with a mean age of 31.6 years. The mean change from baseline in erythema score was significantly lower on the CEF side than on the NS side on Day 7 post-NAFL treatment (0.04 ± 0.40 vs. 0.18 ± 0.48, p = 0.011). The CEF side also exhibited improved changes in EI, MI, and skin hydration, as well as higher overall satisfaction and less pain compared with the NS side. Applying CEF after NAFL treatment reduced erythema progression, maintained skin hydration, and promoted the healing process compared with NS. Chinese Clinical Trial Registry: ChiCTR2300069246. Multicentric Castleman's disease (MCD) with cutaneous involvement has rarely been discussed in dermatologic literature, with few reports. Cutaneous lesions in MCD may induce deep scars, causing a significant impact in the daily life of the patients. The treatment of Castleman's disease (CD) is usually a challenge, especially in case of cutaneous involvement. We report the case of a 35-year-old Caucasian man with a 3-year-old history of MCD with cutaneous involvement that we treated with a combined therapy characterized by siltuximab and 1,927 nm fractional laser. The patient showed a therapeutic response, characterized by a reduction of systemic symptoms and cutaneous manifestations. We believe that the combination of siltuximab and 1,927 nm fractional laser might have a synergistic beneficial role in patients with cutaneous iMCD and maximize esthetic outcomes. Anyway, additional evidence is needed to validate our findings. Microbotox technique, intradermal injection of microdroplets of botulinum toxin, is a favorable rejuvenation approach in subjects who prefer more natural appearance. To determine the best injection techniques (dosage, concentration, as well as number and location of injection points), efficacy and side effects of this innovative technique for facial rejuvenation. We conducted a search in Pubmed, Embase, Web of Science, and Google Scholar databases from conception until October 2021 with keywords "microbotox" OR "mesobotox" OR "intradermal injection" AND "botulinum toxin" AND "rejuvenation" AND "wrinkle" AND "face-lift." Twenty articles were included in this review article. Different types of formulation including onabotulinum toxin A (OBA), abobotulinum toxin A (ABO), and incobotulinum toxin A (IBA) were used. The most used concentrations were 10-20 u/cc of OBA. Number of injection points varied from 4 (forehead and periorbital areas) to 999 (entire face) with 2 mm to 2 cm apart. Adjuvant treatment modalities were cross-linked hyaluronic acid, intense pulsed laser, and Fraxel laser. Most studies reported the initial results appeared after 5-14 days of procedure, lasting for nearly 3-6 months. Microbotox is an efficient and attractive method for facial rejuvenation, mid-lower face-lifting, and fine wrinkles reduction in forehead, periocular, and cheek regions, especially in younger-aged subjects. Furthermore, it is a suitable treatment for neck rejuvenation and recontouring of lower mandibular border, particularly in older subjects with marked skin laxity. The Fraxel Dual laser system (Solta Medical, Inc., Bothell, WA) contains a 1,550 and 1,927 nm wavelength single handpiece with different indications for each wavelength. To discuss treatment setting recommendations and best practices for select on-label and investigational applications of the 1,550 and 1,927 nm dual laser system. Eight board-certified dermatologists with 10 or more years of experience with the 1,550 and 1,927 nm laser system completed an online survey about their clinical experience with the system and then participated in a roundtable to share clinical perspectives and best practices for using the laser system. For all Fitzpatrick skin types, treatment recommendations were described for selected approved indications for the 1,550 and 1,927 nm laser system, including both lasers in combination. Treatment recommendations were also reached for investigational applications with the 1,550 nm laser and 1,927 nm laser. Best practices for using the lasers during the treatment session to achieve optimal outcomes and decrease the post-treatment recovery time were compiled. The 1,550 and 1,927 nm dual laser system is effective for a wide range of aesthetic and therapeutic applications, on and off the face and across all Fitzpatrick skin types. Following our survey, we can appreciate that a variety of laser platforms exist to rejuvenate the skin by resurfacing the outer layer of the skin as well as heating the lower layers of the dermis. Based on reliable clinical effectiveness and a limited side effect profile, we can confirm that nonablative fractionated technologies greatly improve the appearance of lentigines, rhytids; eliminate sun damage, attenuate scarring due to acne and other causes; and treat hyperpigmentation. The Fraxel (Solta Medical) laser system delivers pulses across a wide range of density and energy levels. We determined that when increasing the pulse energy this led to an increase in thermolysis microzone depth and width without damaging the surrounding tissue. Due to its performance and various clinical applications, Fraxel laser can be optimally considered to be the gold standard for skin rejuvenation. Sebaceous hyperplasia (SH) is a common skin presentation in adults. Due to their unwanted yellow papular appearance, patients may desire their removal. Although several treatment modalities have been reported, the full range and efficacy of options are unclear. To determine the efficacy of laser modalities in the treatment of SH. The authors will also specifically assess the efficacy, recurrence rate and side effect profile of SH treatment with Er:YAG wavelength using a variable long pulsed (VLP) Er:YAG laser (SP Dynamis Fotona laser, Ljubljana, Slovenia) Methods & Materials: A comprehensive literature search was performed through PubMed, EMBASE, and Web of Science, using the search terms [(sebaceous hyperplasia)] and [(laser[s], Er:Yag, Er:Glass, Fraxel, CO2, PDL, Pulse dye laser, Diode, Xe-Cl, Excimer, Argon, KTP, Ruby, Alexandrite or Nd:YAG)]. The search yielded a total of 119 results and 8 were identified as relevant to this reviewResults: Pulse dye laser (PDL) provides a wide range of treatment results from complete reduction to flattening of the SH without significant adverse events; recurrence rates were unreported. Short PDL showed faster treatment response than long PDL. CO2 laser can produce considerable positive cosmetic outcomes with marked clinical improvement without any recurrence, but significant adverse effects have been reported. The 1450-nm diode laser has been described to produce good (75%) clinical improvement and lesion shrinkage ranging from 50% to greater than 75% without lasting adverse effects. In

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

This study aims to shed light on the transformative potential of artificial intelligence (AI) in the early detection and risk assessment of non-communicable diseases (NCDs). Bibliometric analysis. Articles related to AI in early identification and risk evaluation of NCDs from 2000 to 2024 were retrieved from the Scopus database. This comprehensive bibliometric study focuses on a single database, Scopus and employs narrative synthesis for concise yet informative summaries. Microsoft Excel V.365 and VOSviewer software (V.1.6.20) were used to summarise bibliometric features. The study retrieved 1745 relevant articles, with a notable surge in research activity in recent years. Core journals included Scientific Reports and IEEE Access, and core institutions included the Harvard Medical School and the Ministry of Education of the People's Republic of China, while core countries comprised China, the USA, India, the UK and Saudi Arabia. Citation trends indicated substantial growth and recognition of AI's impact on NCDs management. Frequent author keywords identified key research hotspots, including specific NCDs like Alzheimer's disease and diabetes. Risk assessment studies demonstrated improved predictions for heart failure, cardiovascular risk, breast cancer, diabetes and inflammatory bowel disease. Our findings highlight the increasing role of AI in early detection and risk prediction of NCDs, emphasising its widening research impact and future clinical potential. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. The aim of this study was to identify and appraise the bibliometric properties of top 100 most-cited articles on regenerative periodontics surgery (RPS). The bibliometric research technique was conducted using a dataset comprising the 100 highly cited articles obtained from Elsevier's Scopus database on RPS. Information regarding the growth of articles by year, number of citations, citations per year, study design, study field, modalities, journals, authors, and countries were extracted for each article. Microsoft Excel (v.16) was utilized for data evaluation and tabulation. These articles on RPS were published over a span of 45 years, from 1975 to 2019, with citation metrics ranging from 144 to 820. Out of the 422 participating authors, 82% contributed to a single article. The 100 most cited articles on RPS were published in 45 years from 1975 to 2019 and number of citations ranged from 144 to 820. Out of the 422 participating authors, 82% contributed in a single article.. The study design with the highest number of cited articles was laboratory/animal studies. Others/not specified was the preferred modality, followed by infrabony modality. The Journal of Periodontology published about one-fourth of the articles, with W. V. Giannobile emerging as the most productive author. Among the 100 most-cited articles on RPS, authors from 25 different countries contributed, with the United States producing half of the articles (n = 51). Bibliometric investigation revealed that the most cited papers published before 2000 had higher citation counts due to their longer period of exposure. The ratio of authors per article increased after the year 2000. Infrabony emerges as a trending topic in RPS, with laboratory/animal studies, clinical trials, and literature reviews being the most frequently employed study designs. To study the impact of reorganization of European hospitals during the most severe phase of the SARS-CoV-2 pandemic on standards of care and early outcomes in patients with periprosthetic fractures. We reviewed available data collected from 14 hospitals in Northern Italy during the quarantine period between March 9 and May 4, 2020. The study included all patients admitted to emergency departments with periprosthetic fractures and scheduled for surgery within a 2-month period. Periprosthetic fractures were classified according to the Uniform Classification System (UCS). Distribution normality was tested using the Kolmogorov-Smirnov test. Accordingly, data were described as non-parametric. Statistical analysis was performed using the Microsoft Excel v. 16.0. In total, 1390 patients admitted to the Department of Orthopedics and Traumatology for emergency care throughout the follow-up period including 38 (2.7%) ones with periprosthetic fractures. There were 12 (31.5%) men and 26 (68.5%) women. Mean age was 81 years (range 70-96). Screening for SARS-CoV-2 by swab was performed in 23 out of 38 patients (60.5%) at admission. It was positive in 2 (5.3%) cases. Three out of thirty-eight patients (7.9%) were diagnosed with COVID-19 due to clinical signs. Of these, 2 patients were diagnosed with COVID-19 before surgery, 3 patients - after surgery. Although the study period coincided with quarantine, the number of admissions for periprosthetic fractures (3%) was similar to that in 2019 and accounted for 3% of the total number of visits to the traumatology and orthopedics departments. The study revealed no obvious changes in hospitalizations for periprosthetic fractures despite social restrictions during the first wave of the COVID-19 pandemic. In emergency, hospitals were still able to provide standard care for patients with periprosthetic fractures despite significant amount of resources redirected for the pandemic. Влияние реорганизации европейских больниц во время наиболее тяжелой фазы пандемии SARS-CoV-2 на стандарты оказания помощи и ранние результаты лечения пациентов с &#x43f

Energy-resolved photon-counting CT (PCCT) is promising for material decomposition with multi-contrast agents. However, corrections for non-idealities of PCCT detectors are required, which are still active research areas. In addition, PCCT is associated with very high cost due to lack of mass production. In this work, we proposed an alternative approach to performing multi-energy CT, which was achieved by acquiring triple or quadruple x-ray beam measurements on a dual-source CT scanner. This strategy was based on a "Twin Beam" design on a single-source scanner for dual-energy CT. Examples of beam filters and spectra for triple and quadruple x-ray beam were provided. Computer simulation studies were performed to evaluate the accuracy of material decomposition for multi-contrast mixtures using a tri-beam configuration. The proposed strategy can be readily implemented on a dual-source scanner, which may allow material decomposition of multi-contrast agents to be performed on clinical CT scanners with energy-integrating detector.

Acne scarring can impact patients negatively psychosocially. Picosecond lasers and radiofrequency microneedling may be used to improve this condition. To evaluate the efficacy and safety of combination treatment with a picosecond 755-nm Alexandrite laser (PSAL; Picosure Pro; Cynosure, Westford, MA) with diffractive lens array and a radiofrequency microneedling device (RFM; Potenza; Cynosure) for treating facial atrophic acne scars. This was a prospective, single-center, evaluator-blinded, split-face, randomized clinical trial. Twenty subjects with moderate to severe atrophic facial acne scarring were randomized to have one facial half treatment with PSAL followed by full-face treatment with RFM. Subjects received 4 treatments at 4-week intervals. The blinded Investigator's échelle d'évaluation clinique des cicatrices d'acné (ECCA) acne grading, Physician Global Aesthetic Improvement Scale (PGAIS), and Subject Global Aesthetic Improvement Scale (SGAIS) did not show a significant difference between the facial half treated with RFM only and the half treated with RFM and PSAL at interval time points. However, there was significant improvement in ECCA, PGAIS, and SGAIS for both groups over study duration. Both RFM and PSAL appear safe and may be effective for acne scarring treatment, but larger trials are required to confirm superiority or synergy. Studies using a 755 nm picosecond laser with a focus lens array have been reported to be effective for facial wrinkles and pigmentation. This study reports the safety and efficacy using a shorter interval of 2-3 weeks between treatments. Nineteen female subjects and one male subject, primarily Fitzpatrick skin types II and III (one skin type I), who had mild to moderate wrinkles and sun-induced pigmentation were enrolled and treated using the 755 nm PicoSure Laser with focus lens array. The skin was cleansed then wiped with an alcohol wipe prior to treatment. Lidocaine 30% ointment and/or forced air cooling could be used to increase subject comfort. Adjacent pulses, with minimal overlap (10% or less), were delivered to the full face. Subjects received four treatments, performed at 2-3-week intervals. The laser energy used was 0.71 J/cm2 . The physician administered 3-7 passes with an average total of 6,253 pulses per treatment. Follow-up visits occurred at 1 and 3 months post-last treatment at which the physician scored satisfaction and improvement and subjects scored satisfaction and likelihood to recommend to others. The most common side effects were mild swelling, pain, redness, and crusting, most of which subsided within hours of the treatment, with the latest resolving within 48 hours. This is similar to a previous reported study (Weiss et al. ASLMS 2015) where treatments were performed every 6 weeks with side effects resolving within 24 hours. At the 1 and 3 month follow-up visits, 94% (n = 19) and 93% (n = 15) of subjects scored themselves as satisfied or extremely satisfied with their overall results and 81% and 93% were likely to recommend the treatment based on global assessment, respectively. The treating physician was satisfied with 93% of subject's overall results. Three blinded evaluators were able to correctly identify the baseline from post-treatment photographs in 77% of the subjects at the 1 month follow-up and 69% of the subjects at the 3 month follow-up, on average. The average treatment pain score was 4.2 on a 1-10 scale. A compressed treatment interval expedites results without increasing side effects and resulted in a high physician and subject satisfaction rate. Lasers Surg. Med. 48:723-726, 2016. © 2016 Wiley Periodicals, Inc. The use of picosecond lasers to remove tattoos has greatly improved due to the long-standing outcomes of nanosecond lasers, both clinically and histologically. The first aesthetic picosecond laser available for this use was the PicoSure(®) laser system (755/532 nm). Now that a vast amount of research on its use has been conducted, we performed a comprehensive review of the literature to validate the continued application of the PicoSure(®) laser system for tattoo removal. A PubMed search was conducted using the term "picosecond" combined with "laser", "dermatology", and "laser tattoo removal". A total of 13 articles were identified, and ten of these met the inclusion criteria for this review. The majority of studies showed that picosecond lasers are an effective and safe treatment mode for the removal of tattoo pigments. Several studies also indicated potential novel applications of picosecond lasers in the removal of various tattoo pigments (eg, black, red, and yellow). Adverse effects were generally mild, such as transient hypopigmentation or blister formation, and were rarely more serious, such as scarring and/or textural change. Advancements in laser technologies and their application in cutaneous medicine have revolutionized the field of laser surgery. Computational modeling provides evidence that the optimal pulse durations for tattoo ink removal are in the picosecond domain. It is recommended that the PicoSure(®) laser system continue to be used for safe and effective tattoo removal, including for red and yellow pigments.

Acne scarring can impact patients negatively psychosocially. Picosecond lasers and radiofrequency microneedling may be used to improve this condition. To evaluate the efficacy and safety of combination treatment with a picosecond 755-nm Alexandrite laser (PSAL; Picosure Pro; Cynosure, Westford, MA) with diffractive lens array and a radiofrequency microneedling device (RFM; Potenza; Cynosure) for treating facial atrophic acne scars. This was a prospective, single-center, evaluator-blinded, split-face, randomized clinical trial. Twenty subjects with moderate to severe atrophic facial acne scarring were randomized to have one facial half treatment with PSAL followed by full-face treatment with RFM. Subjects received 4 treatments at 4-week intervals. The blinded Investigator's échelle d'évaluation clinique des cicatrices d'acné (ECCA) acne grading, Physician Global Aesthetic Improvement Scale (PGAIS), and Subject Global Aesthetic Improvement Scale (SGAIS) did not show a significant difference between the facial half treated with RFM only and the half treated with RFM and PSAL at interval time points. However, there was significant improvement in ECCA, PGAIS, and SGAIS for both groups over study duration. Both RFM and PSAL appear safe and may be effective for acne scarring treatment, but larger trials are required to confirm superiority or synergy. Studies using a 755 nm picosecond laser with a focus lens array have been reported to be effective for facial wrinkles and pigmentation. This study reports the safety and efficacy using a shorter interval of 2-3 weeks between treatments. Nineteen female subjects and one male subject, primarily Fitzpatrick skin types II and III (one skin type I), who had mild to moderate wrinkles and sun-induced pigmentation were enrolled and treated using the 755 nm PicoSure Laser with focus lens array. The skin was cleansed then wiped with an alcohol wipe prior to treatment. Lidocaine 30% ointment and/or forced air cooling could be used to increase subject comfort. Adjacent pulses, with minimal overlap (10% or less), were delivered to the full face. Subjects received four treatments, performed at 2-3-week intervals. The laser energy used was 0.71 J/cm2 . The physician administered 3-7 passes with an average total of 6,253 pulses per treatment. Follow-up visits occurred at 1 and 3 months post-last treatment at which the physician scored satisfaction and improvement and subjects scored satisfaction and likelihood to recommend to others. The most common side effects were mild swelling, pain, redness, and crusting, most of which subsided within hours of the treatment, with the latest resolving within 48 hours. This is similar to a previous reported study (Weiss et al. ASLMS 2015) where treatments were performed every 6 weeks with side effects resolving within 24 hours. At the 1 and 3 month follow-up visits, 94% (n = 19) and 93% (n = 15) of subjects scored themselves as satisfied or extremely satisfied with their overall results and 81% and 93% were likely to recommend the treatment based on global assessment, respectively. The treating physician was satisfied with 93% of subject's overall results. Three blinded evaluators were able to correctly identify the baseline from post-treatment photographs in 77% of the subjects at the 1 month follow-up and 69% of the subjects at the 3 month follow-up, on average. The average treatment pain score was 4.2 on a 1-10 scale. A compressed treatment interval expedites results without increasing side effects and resulted in a high physician and subject satisfaction rate. Lasers Surg. Med. 48:723-726, 2016. © 2016 Wiley Periodicals, Inc. The use of picosecond lasers to remove tattoos has greatly improved due to the long-standing outcomes of nanosecond lasers, both clinically and histologically. The first aesthetic picosecond laser available for this use was the PicoSure(®) laser system (755/532 nm). Now that a vast amount of research on its use has been conducted, we performed a comprehensive review of the literature to validate the continued application of the PicoSure(®) laser system for tattoo removal. A PubMed search was conducted using the term "picosecond" combined with "laser", "dermatology", and "laser tattoo removal". A total of 13 articles were identified, and ten of these met the inclusion criteria for this review. The majority of studies showed that picosecond lasers are an effective and safe treatment mode for the removal of tattoo pigments. Several studies also indicated potential novel applications of picosecond lasers in the removal of various tattoo pigments (eg, black, red, and yellow). Adverse effects were generally mild, such as transient hypopigmentation or blister formation, and were rarely more serious, such as scarring and/or textural change. Advancements in laser technologies and their application in cutaneous medicine have revolutionized the field of laser surgery. Computational modeling provides evidence that the optimal pulse durations for tattoo ink removal are in the picosecond domain. It is recommended that the PicoSure(®) laser system continue to be used for safe and effective tattoo removal, including for red and yellow pigments.

Optimizing oxygenation for patients necessitates a delicate balance between sufficient oxygen delivery and mitigating the potential hazards of hyperoxemia. We hypothesized that integrating Oxygen Reserve Index (ORi) monitoring would effectively reduce intraoperative hyperoxemia compared to reliance solely on pulse oximetry. This single-center randomized controlled trial included multiple trauma patients with ASA class 3 or higher undergoing general anesthesia. FiO2 adjustments to 0.5 started at T0 with arterial blood gas analysis (ABGA) every 30-minutes. Patients were randomized into Group O (ORi monitoring) and Group N (pulse oximetry). In Group O, FiO2 was reduced if ORi > 0.05; unchanged if ORi was 0-0.05. Group N decreased FiO2 if SpO2 was 100%, unchanged if SpO2 was < 99%, and increased FiO2 by 0.05 until SpO2 reached 95% or above. 54 participants were randomized, and 51 analyzed. Group O demonstrated a significantly higher percentage of normoxemia (80 ≤ PaO2 < 120 mmHg) (64.4% vs. 40.4%, P = 0.002) across 181 ABGAs. Although baseline PaO2 (T1) values were comparable within moderate hyperoxemia, at T2, only Group O achieved normoxemia, with consistently lower PaO2 values at T2, T3, and T4 compared to Group N. ORi values in Group O consistently trended lower from T1 to T4. The positive correlation between PaO2 and ORi was reaffirmed, establishing cut-off values for PaO2 ≥ 120mmHg and ≥ 150mmHg at 0.06 and 0.22, respectively. Simultaneous ORi and pulse oximetry reduce intraoperative hyperoxemia through safe and meticulous protocol adherence in patients. Previous study in human subjects has documented biomechanical and neurophysiological responses to impulsive spinal manipulative thrusts, but very little is known about the neuromechanical effects of varying thrust force-time profiles. Ten adolescent Merino sheep were anesthetized and posteroanterior mechanical thrusts were applied to the L3 spinous process using a computer-controlled, mechanical testing apparatus. Three variable pulse durations (10, 100, 200 ms, force = 80 N) and three variable force amplitudes (20, 40, 60 N, pulse duration = 100 ms) were examined for their effect on lumbar motion response (L3 displacement, L1, L2 acceleration) and normalized multifidus electromyographic response (L3, L4) using a repeated measures analysis of variance. Increasing L3 posteroanterior force amplitude resulted in a fourfold linear increase in L3 posteroanterior vertebral displacement (p < 0.001) and adjacent segment (L1, L2) posteroanterior acceleration response (p < 0.001). L3 displacement was linearly correlated (p < 0.001) to the acceleration response over the 20-80 N force range (100 ms). At constant force, 10 ms thrusts resulted in nearly fivefold lower L3 displacements and significantly increased segmental (L2) acceleration responses compared to the 100 ms (19%, p = 0.005) and 200 ms (16%, p = 0.023) thrusts. Normalized electromyographic responses increased linearly with increasing force amplitude at higher amplitudes and were appreciably affected by mechanical excitation pulse duration. Changes in the biomechanical and neuromuscular response of the ovine lumbar spine were observed in response to changes in the force-time characteristics of the spinal manipulative thrusts and may be an underlying mechanism in related clinical outcomes.