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