Pub Date : 2025-11-28eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103665
Martin Meuli, Clemens Schiestl, Fabienne Hartmann-Fritsch, Esther Middelkoop, Bong-Sung Kim, Kathrin Neuhaus, Jan A Plock, Daniel Rittirsch, Cornelis H van der Vlies, Bruno Azzena, Daniela Marino, Kathi Mujynya, Melinda Farkas, Jenny Bressan, Ernst Reichmann, Sophie Böttcher-Haberzeth
Background: For burn surgery, major therapeutic challenges are shortage of autologous donor sites for split-thickness skin, and massive devastating scarring. We investigated the therapeutic role of denovoSkin™, a bio-engineered autologous skin, in a prospective, randomized, controlled phase IIb clinical trial compared to the gold standard the split thickness skin graft (STSG).
Methods: Patients, ≥12 years, with deep partial and/or full-thickness burns requiring surgical wound coverage were enrolled at four sites in Switzerland, the Netherlands, and Italy. Two comparable skin defects (max. 98 cm2 each) per patient were intra-patient randomized to denovoSkin™ (experimental) or autologous STSG (control) treatment. Safety assessments were performed in all patients. Primary efficacy endpoint was the ratio of biopsy size to grafted area with take 4 weeks post-grafting. The analyses of the primary efficacy variable were performed on the modified Full Analysis Set (mFAS) and the per protocol set (PPS) with the analysis on the mFAS as the primary analysis. Other efficacy endpoints included wound closure and scar quality. Efficacy and safety follow-ups were conducted up to 12 months post-grafting. The trial started in March 2018 and completed recruitment in July 2022 and is registered at clinicaltrials.gov (NCT03227146).
Findings: 21 patients were enrolled between March 26, 2018, and July 26 2022. 13 patients were included in the PPS. There were no significant safety differences between denovoSkin™ and STSG. 164 serious adverse events were observed (81%). Only two (hematoma and partial skin necrosis) could be related to denovoSkin™. They rapidly healed spontaneously. The expansion ratio for denovoSkin™ versus STSG was 7·0 times larger for denovoSkin™ (p < 0·001). In the mFAS the mean expansion ratio for denovoSkin™ was 10·76 (SD 6·03), and for STSG it was 1·70 (SD 0·68). The mean ratio of the two expansion ratios (denovoSkin™/STSG) was 7·41 (SD 4·87). By month 3, experimental and control areas were fully epithelialized. Scar evaluation up to 12 months post-grafting revealed no clinically relevant scarring for denovoSkin™, but mostly hypertrophic scarring for STSG.
Interpretation: DenovoSkin™ is a novel and safe treatment option for deep burns. It lessens the need for conventional grafting and so spares donor sites. In sharp contrast to STSG, denovoSkin™ grafting showed minimal scarring, a finding never evidenced before in a randomized trial.
Funding: This study was financed by Wyss Zurich Translational Center (project "denovoSkin") and CUTISS AG.
{"title":"Safety and efficacy of bio-engineered, autologous dermo-epidermal skin grafts in adolescent and adult burn patients: 1-year results of a prospective, randomized, controlled, multicenter phase IIB clinical trial.","authors":"Martin Meuli, Clemens Schiestl, Fabienne Hartmann-Fritsch, Esther Middelkoop, Bong-Sung Kim, Kathrin Neuhaus, Jan A Plock, Daniel Rittirsch, Cornelis H van der Vlies, Bruno Azzena, Daniela Marino, Kathi Mujynya, Melinda Farkas, Jenny Bressan, Ernst Reichmann, Sophie Böttcher-Haberzeth","doi":"10.1016/j.eclinm.2025.103665","DOIUrl":"10.1016/j.eclinm.2025.103665","url":null,"abstract":"<p><strong>Background: </strong>For burn surgery, major therapeutic challenges are shortage of autologous donor sites for split-thickness skin, and massive devastating scarring. We investigated the therapeutic role of denovoSkin™, a bio-engineered autologous skin, in a prospective, randomized, controlled phase IIb clinical trial compared to the gold standard the split thickness skin graft (STSG).</p><p><strong>Methods: </strong>Patients, ≥12 years, with deep partial and/or full-thickness burns requiring surgical wound coverage were enrolled at four sites in Switzerland, the Netherlands, and Italy. Two comparable skin defects (max. 98 cm<sup>2</sup> each) per patient were intra-patient randomized to denovoSkin™ (experimental) or autologous STSG (control) treatment. Safety assessments were performed in all patients. Primary efficacy endpoint was the ratio of biopsy size to grafted area with take 4 weeks post-grafting. The analyses of the primary efficacy variable were performed on the modified Full Analysis Set (mFAS) and the per protocol set (PPS) with the analysis on the mFAS as the primary analysis. Other efficacy endpoints included wound closure and scar quality. Efficacy and safety follow-ups were conducted up to 12 months post-grafting. The trial started in March 2018 and completed recruitment in July 2022 and is registered at clinicaltrials.gov (NCT03227146).</p><p><strong>Findings: </strong>21 patients were enrolled between March 26, 2018, and July 26 2022. 13 patients were included in the PPS. There were no significant safety differences between denovoSkin™ and STSG. 164 serious adverse events were observed (81%). Only two (hematoma and partial skin necrosis) could be related to denovoSkin™. They rapidly healed spontaneously. The expansion ratio for denovoSkin™ versus STSG was 7·0 times larger for denovoSkin™ (p < 0·001). In the mFAS the mean expansion ratio for denovoSkin™ was 10·76 (SD 6·03), and for STSG it was 1·70 (SD 0·68). The mean ratio of the two expansion ratios (denovoSkin™/STSG) was 7·41 (SD 4·87). By month 3, experimental and control areas were fully epithelialized. Scar evaluation up to 12 months post-grafting revealed no clinically relevant scarring for denovoSkin™, but mostly hypertrophic scarring for STSG.</p><p><strong>Interpretation: </strong>DenovoSkin™ is a novel and safe treatment option for deep burns. It lessens the need for conventional grafting and so spares donor sites. In sharp contrast to STSG, denovoSkin™ grafting showed minimal scarring, a finding never evidenced before in a randomized trial.</p><p><strong>Funding: </strong>This study was financed by Wyss Zurich Translational Center (project \"denovoSkin\") and CUTISS AG.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103665"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103661
Hao Shen, Tao Yuan, Anfeng Si, Yihang Shen, Jinhuan Liu, Lv Jin, Zhihao Xie, Huayi Zhang, Wenxin Wei, Yizhe Dai, Tao Jiang, Chenxiang He, Shichao Zhang, Yuheng Hu, Shengyu Huang, Zhishi Yang, Yao Chen, Xiaofeng Zhang, Feng Shen, Xiaolong Qi, Jun Li
Background: Post-hepatectomy liver failure (PHLF) is the leading cause of morbidity and mortality following major hepatectomy. Existing prediction models inadequately capture the dynamic liver regeneration and perioperative changes, limiting their predictive accuracy. We aimed to develop a machine learning (ML) modelling system (PILOT architecture) integrating liver regeneration-associated biomarkers with time-phased perioperative data for PHLF prediction.
Methods: This retrospective multicentre study included 1071 patients undergoing major hepatectomy at three centres (2019-2024), divided into training (n = 623) and two external validation cohorts (n = 206 and 242). Fifty-five perioperative variables, including novel liver regeneration-associated biomarkers (GATA3, RAMP2, VEGFA, PEDF), were categorised into three time-phased datasets (preoperative, intraoperative, postoperative). Thirteen ML algorithms were evaluated across these datasets, with gradient-based feature reduction strategies applied to optimise the PILOT models. This study is registered with ClinicalTrials.gov (NCT05779098).
Findings: PILOT-Pre, PILOT-Intra (LightGBM with 10 and 15 features, respectively), and PILOT-Post (XGBoost with 20 features) models showed superior discrimination in training (AUCs: 0.754 [95% CI: 0.717-0.790], 0.787 [0.728-0.846], 0.904 [0.883-0.924]) and validation cohorts (AUCs: 0.740-0.895) compared to traditional models (AUCs: 0.502-0.644; all P < 0.050). A risk-stratification framework integrating PILOT-Pre and PILOT-Intra predictions achieved a class-specific precision of 94.4%-96.6% for PHLF events in the consensus high-risk group and 92.1%-95.5% for non-PHLF events in the consensus low-risk populations. SHAP analysis revealed that serum phosphorus levels >2.4 mg/dL on postoperative day 3, liver RAMP2-GATA3 ratios <10.1, and serum PEDF-VEGFA indices >4.9 were associated with an increased predicted PHLF risk.
Interpretation: The PILOT architecture integrates liver regeneration-associated biomarkers with time-phased data to accurately predict PHLF within the first 6 h postoperatively. Based on consistency analysis of predictions of PILOT-Pre and PILOT-Intra models, this framework enables early risk stratification, thereby providing a practical tool for personalised perioperative management.
Funding: This research was funded by the projects from National Natural Science Foundation of China (82403243), Program for National Postdoctoral Researchers Funding of China (GZC20231943), and Shanghai Municipal Commission of Science and Technology (23Y11905900).
{"title":"Liver regeneration-associated machine learning architecture integrating time-phased predictions for post-hepatectomy liver failure.","authors":"Hao Shen, Tao Yuan, Anfeng Si, Yihang Shen, Jinhuan Liu, Lv Jin, Zhihao Xie, Huayi Zhang, Wenxin Wei, Yizhe Dai, Tao Jiang, Chenxiang He, Shichao Zhang, Yuheng Hu, Shengyu Huang, Zhishi Yang, Yao Chen, Xiaofeng Zhang, Feng Shen, Xiaolong Qi, Jun Li","doi":"10.1016/j.eclinm.2025.103661","DOIUrl":"10.1016/j.eclinm.2025.103661","url":null,"abstract":"<p><strong>Background: </strong>Post-hepatectomy liver failure (PHLF) is the leading cause of morbidity and mortality following major hepatectomy. Existing prediction models inadequately capture the dynamic liver regeneration and perioperative changes, limiting their predictive accuracy. We aimed to develop a machine learning (ML) modelling system (PILOT architecture) integrating liver regeneration-associated biomarkers with time-phased perioperative data for PHLF prediction.</p><p><strong>Methods: </strong>This retrospective multicentre study included 1071 patients undergoing major hepatectomy at three centres (2019-2024), divided into training (n = 623) and two external validation cohorts (n = 206 and 242). Fifty-five perioperative variables, including novel liver regeneration-associated biomarkers (GATA3, RAMP2, VEGFA, PEDF), were categorised into three time-phased datasets (preoperative, intraoperative, postoperative). Thirteen ML algorithms were evaluated across these datasets, with gradient-based feature reduction strategies applied to optimise the PILOT models. This study is registered with ClinicalTrials.gov (NCT05779098).</p><p><strong>Findings: </strong>PILOT-Pre, PILOT-Intra (LightGBM with 10 and 15 features, respectively), and PILOT-Post (XGBoost with 20 features) models showed superior discrimination in training (AUCs: 0.754 [95% CI: 0.717-0.790], 0.787 [0.728-0.846], 0.904 [0.883-0.924]) and validation cohorts (AUCs: 0.740-0.895) compared to traditional models (AUCs: 0.502-0.644; all <i>P</i> < 0.050). A risk-stratification framework integrating PILOT-Pre and PILOT-Intra predictions achieved a class-specific precision of 94.4%-96.6% for PHLF events in the consensus high-risk group and 92.1%-95.5% for non-PHLF events in the consensus low-risk populations. SHAP analysis revealed that serum phosphorus levels >2.4 mg/dL on postoperative day 3, liver RAMP2-GATA3 ratios <10.1, and serum PEDF-VEGFA indices >4.9 were associated with an increased predicted PHLF risk.</p><p><strong>Interpretation: </strong>The PILOT architecture integrates liver regeneration-associated biomarkers with time-phased data to accurately predict PHLF within the first 6 h postoperatively. Based on consistency analysis of predictions of PILOT-Pre and PILOT-Intra models, this framework enables early risk stratification, thereby providing a practical tool for personalised perioperative management.</p><p><strong>Funding: </strong>This research was funded by the projects from National Natural Science Foundation of China (82403243), Program for National Postdoctoral Researchers Funding of China (GZC20231943), and Shanghai Municipal Commission of Science and Technology (23Y11905900).</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103661"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103670
Sebastian Bogner, Corinna Seliger-Behme, Michael F Leitzmann, Patricia Bohmann
<p><strong>Background: </strong>Receiving a cancer diagnosis is strongly associated with a higher risk of suicide. However, studies examining suicidality in patients with colorectal cancer show some inconsistencies, particularly concerning factors such as disease stage or specific diagnosis.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis to investigate the association between colorectal cancer and suicide or suicidal ideation. EMBASE, MEDLINE, PsycINFO, Science Citation Index Expanded & Social Sciences Citation Index, CINAHL, and Google Scholar were searched from database inception to May 31, 2025. Eligible studies included longitudinal cohort or case-control designs involving patients with colorectal cancer aged ≥14 years. Control groups comprised individuals from the same population without cancer. Data were independently extracted by two researchers from published reports available in English or German. The primary outcome was suicide, defined as death from intentional self-harm; the secondary outcome was suicidal ideation, defined as non-fatal thoughts of suicide. We performed random-effects meta-analyses, assessing heterogeneity with Q and I<sup>2</sup> statistics and publication bias with funnel plots, Begg's, and Egger's tests. The study was registered (PROSPERO: CRD420251051277).</p><p><strong>Findings: </strong>Among 4,700 records screened, 44 studies met the inclusion criteria, encompassing at least 9,385,472 patients with colorectal cancer and 13,308 suicides. Of these, 34 studies reported Standardised Mortality Ratios (SMR; colorectal cancer patients: n = 8,251,924; suicides: n = 12,081) and were included in the meta-analysis. After excluding studies with potential overlap in patient populations, the primary analysis was based on nine independent studies including at least 1,204,072 individuals with colorectal cancer, of whom 2,731 died by suicide. For suicidal ideation, we report the results of five individual studies. All included studies met methodological quality criteria, with a Newcastle-Ottawa Scale score of ≥7. The findings indicate a significantly increased suicide risk for patients with colorectal cancer, with a pooled SMR of 1.40 (95% CI: 1.33-1.49, I<sup>2</sup> = 28.17%, no evidence for publication bias) compared to the general population. Subgroup analyses revealed notably higher suicide risks among patients with metastatic disease (SMR = 3.63, 95% CI: 2.99-4.41), those under 40 years of age (SMR = 2.15, 95% CI: 1.60-2.88), and individuals diagnosed within the past six months (SMR = 2.69, 95% CI: 1.29-5.61). For suicidal ideation, primary studies did not observe differences between patients with colorectal cancer and their reference groups, such as cancer-free individuals (SMR = 1.70, 95% CI: 0.65-4.42) or patients with hepatic cancer (SMR = 1.14, 95% CI: 0.94-1.38).</p><p><strong>Interpretation: </strong>Our results indicate the need for comprehensive psychological screening in patien
{"title":"Suicide mortality and suicidal ideation among patients with colorectal cancer: a systematic review and meta-analysis.","authors":"Sebastian Bogner, Corinna Seliger-Behme, Michael F Leitzmann, Patricia Bohmann","doi":"10.1016/j.eclinm.2025.103670","DOIUrl":"10.1016/j.eclinm.2025.103670","url":null,"abstract":"<p><strong>Background: </strong>Receiving a cancer diagnosis is strongly associated with a higher risk of suicide. However, studies examining suicidality in patients with colorectal cancer show some inconsistencies, particularly concerning factors such as disease stage or specific diagnosis.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis to investigate the association between colorectal cancer and suicide or suicidal ideation. EMBASE, MEDLINE, PsycINFO, Science Citation Index Expanded & Social Sciences Citation Index, CINAHL, and Google Scholar were searched from database inception to May 31, 2025. Eligible studies included longitudinal cohort or case-control designs involving patients with colorectal cancer aged ≥14 years. Control groups comprised individuals from the same population without cancer. Data were independently extracted by two researchers from published reports available in English or German. The primary outcome was suicide, defined as death from intentional self-harm; the secondary outcome was suicidal ideation, defined as non-fatal thoughts of suicide. We performed random-effects meta-analyses, assessing heterogeneity with Q and I<sup>2</sup> statistics and publication bias with funnel plots, Begg's, and Egger's tests. The study was registered (PROSPERO: CRD420251051277).</p><p><strong>Findings: </strong>Among 4,700 records screened, 44 studies met the inclusion criteria, encompassing at least 9,385,472 patients with colorectal cancer and 13,308 suicides. Of these, 34 studies reported Standardised Mortality Ratios (SMR; colorectal cancer patients: n = 8,251,924; suicides: n = 12,081) and were included in the meta-analysis. After excluding studies with potential overlap in patient populations, the primary analysis was based on nine independent studies including at least 1,204,072 individuals with colorectal cancer, of whom 2,731 died by suicide. For suicidal ideation, we report the results of five individual studies. All included studies met methodological quality criteria, with a Newcastle-Ottawa Scale score of ≥7. The findings indicate a significantly increased suicide risk for patients with colorectal cancer, with a pooled SMR of 1.40 (95% CI: 1.33-1.49, I<sup>2</sup> = 28.17%, no evidence for publication bias) compared to the general population. Subgroup analyses revealed notably higher suicide risks among patients with metastatic disease (SMR = 3.63, 95% CI: 2.99-4.41), those under 40 years of age (SMR = 2.15, 95% CI: 1.60-2.88), and individuals diagnosed within the past six months (SMR = 2.69, 95% CI: 1.29-5.61). For suicidal ideation, primary studies did not observe differences between patients with colorectal cancer and their reference groups, such as cancer-free individuals (SMR = 1.70, 95% CI: 0.65-4.42) or patients with hepatic cancer (SMR = 1.14, 95% CI: 0.94-1.38).</p><p><strong>Interpretation: </strong>Our results indicate the need for comprehensive psychological screening in patien","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103670"},"PeriodicalIF":10.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12704310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103668
Tony Butler, Emaediong I Akpanekpo, Lee Knight, Kristy Robledo, David Greenberg, Andrew Ellis, Stephen Allnutt, Kay Wilhelm, Alison Jones, Rodney Scott, Bianca Ton, Luke Grant, Philip Mitchell, Ross Tynan, Jocelyn Jones, Dominic Villa, Duncan Chappell, Carolynn Dixon, Alison Churchill, Val Gebski, Tony Keech, Peter W Schofield
Background: Biological studies suggest serotonin modulation via selective serotonin reuptake inhibitors (SSRIs) might reduce impulsive violence, however, robust evidence in offender populations is limited. We aimed to determine whether sertraline reduces violent reoffending compared with placebo in highly impulsive men with recurrent violent offending.
Methods: We conducted a double-blind, placebo-controlled, randomised clinical trial in community settings in New South Wales, Australia. Eligible participants were men aged 18 years or older with ≥2 prior violent convictions and a Barratt Impulsiveness Scale score ≥70. Following a 4-week single-blind active run-in phase with sertraline, participants were randomly assigned (1:1, minimization stratified by key factors) to receive oral sertraline (100 mg daily) or matching placebo for 12 months. The primary outcome was the first convicted violent offence within 12 months, assessed via linkage to the state Reoffending Database. The primary analysis followed the intention-to-treat principle. The trial is registered with ANZCTR (ACTRN12613000442707) and is closed to new participants.
Findings: Between October 28, 2013, and July 13, 2021, 630 eligible men were randomly assigned: 319 to sertraline and 311 to placebo. By 12 months, only 204 participants remained engaged with the study. All participants were included in the primary analysis. A primary outcome event (violent offence within 12 months) occurred in 72 (22.6%) of 319 participants assigned sertraline and 70 (22.5%) of 311 assigned placebo (Relative Risk 1.00, 95% CI 0.75-1.34; p = 0.99). Serious adverse events occurred in 22 (6.9%) participants receiving sertraline and 29 (9.3%) receiving placebo.
Interpretation: Sertraline did not significantly reduce the risk of violent reoffending compared with placebo. Post-hoc analyses suggested a possible selective effect on domestic violence offending.
Funding: Initial funding for the ReINVEST trial was provided from an Australian National Health and Medical Research Council partnership grant No. 533559. From 2018, subsequent funding was provided by the NSW Department of Communities and Justice.
背景：生物学研究表明，通过选择性5 -羟色胺再摄取抑制剂（SSRIs）调节5 -羟色胺可能会减少冲动暴力，然而，在罪犯群体中的有力证据有限。我们的目的是确定与安慰剂相比，舍曲林是否能减少反复发生暴力犯罪的高度冲动男性的暴力再犯。方法：我们在澳大利亚新南威尔士州的社区环境中进行了一项双盲、安慰剂对照、随机临床试验。符合条件的参与者为年龄在18岁或以上、有2次或以上暴力前科且Barratt冲动量表得分≥70分的男性。在4周的单盲主动使用舍曲林后，参与者被随机分配（1:1，按关键因素分层最小化），接受口服舍曲林（每天100毫克）或匹配的安慰剂，为期12个月。主要结果是12个月内第一次被定罪的暴力犯罪，通过与国家再犯罪数据库的联系进行评估。初步分析遵循意向治疗原则。该试验已在ANZCTR注册（ACTRN12613000442707），并对新参与者关闭。研究结果：在2013年10月28日至2021年7月13日期间，630名符合条件的男性被随机分配：319名服用舍曲林，311名服用安慰剂。12个月后，只有204名参与者继续参与这项研究。所有参与者均纳入初步分析。319名服用舍曲林的受试者中有72名（22.6%）发生了主要结局事件（12个月内的暴力犯罪），311名服用安慰剂的受试者中有70名（22.5%）发生了主要结局事件（相对风险1.00,95% CI 0.75-1.34; p = 0.99）。严重不良事件发生在接受舍曲林治疗的22名（6.9%）和接受安慰剂治疗的29名（9.3%）。解释：与安慰剂相比，舍曲林没有显著降低暴力再犯的风险。事后分析表明，对家庭暴力犯罪可能有选择性影响。资金：ReINVEST试验的初始资金由澳大利亚国家卫生和医学研究委员会伙伴关系赠款第533559号提供。从2018年起，后续资金由新南威尔士州社区和司法部提供。
{"title":"Sertraline to reduce recidivism in impulsive violent offenders (ReINVEST): a randomised double blind clinical trial.","authors":"Tony Butler, Emaediong I Akpanekpo, Lee Knight, Kristy Robledo, David Greenberg, Andrew Ellis, Stephen Allnutt, Kay Wilhelm, Alison Jones, Rodney Scott, Bianca Ton, Luke Grant, Philip Mitchell, Ross Tynan, Jocelyn Jones, Dominic Villa, Duncan Chappell, Carolynn Dixon, Alison Churchill, Val Gebski, Tony Keech, Peter W Schofield","doi":"10.1016/j.eclinm.2025.103668","DOIUrl":"10.1016/j.eclinm.2025.103668","url":null,"abstract":"<p><strong>Background: </strong>Biological studies suggest serotonin modulation via selective serotonin reuptake inhibitors (SSRIs) might reduce impulsive violence, however, robust evidence in offender populations is limited. We aimed to determine whether sertraline reduces violent reoffending compared with placebo in highly impulsive men with recurrent violent offending.</p><p><strong>Methods: </strong>We conducted a double-blind, placebo-controlled, randomised clinical trial in community settings in New South Wales, Australia. Eligible participants were men aged 18 years or older with ≥2 prior violent convictions and a Barratt Impulsiveness Scale score ≥70. Following a 4-week single-blind active run-in phase with sertraline, participants were randomly assigned (1:1, minimization stratified by key factors) to receive oral sertraline (100 mg daily) or matching placebo for 12 months. The primary outcome was the first convicted violent offence within 12 months, assessed via linkage to the state Reoffending Database. The primary analysis followed the intention-to-treat principle. The trial is registered with ANZCTR (ACTRN12613000442707) and is closed to new participants.</p><p><strong>Findings: </strong>Between October 28, 2013, and July 13, 2021, 630 eligible men were randomly assigned: 319 to sertraline and 311 to placebo. By 12 months, only 204 participants remained engaged with the study. All participants were included in the primary analysis. A primary outcome event (violent offence within 12 months) occurred in 72 (22.6%) of 319 participants assigned sertraline and 70 (22.5%) of 311 assigned placebo (Relative Risk 1.00, 95% CI 0.75-1.34; p = 0.99). Serious adverse events occurred in 22 (6.9%) participants receiving sertraline and 29 (9.3%) receiving placebo.</p><p><strong>Interpretation: </strong>Sertraline did not significantly reduce the risk of violent reoffending compared with placebo. Post-hoc analyses suggested a possible selective effect on domestic violence offending.</p><p><strong>Funding: </strong>Initial funding for the ReINVEST trial was provided from an Australian National Health and Medical Research Council partnership grant No. 533559. From 2018, subsequent funding was provided by the NSW Department of Communities and Justice.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103668"},"PeriodicalIF":10.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103664
Eugene Yee Hing Tang, Jacob Brain, Rhiannon De Ivey, Serena Sabatini, Felicity Mills, Emma Jackson, Linda Errington, Claire Burley, Jennifer Dunne, Leanne Greene, Ram Bajpai, Christopher Price, Louise Robinson, Nele Demeyere, Blossom Christa Maree Stephan, Maree Stephan, Terry Quinn
<p><strong>Background: </strong>Survivors of stroke are at a higher risk of cognitive syndromes, including dementia and delirium. Timely identification of those at-risk for cognitive syndromes could ensure better clinical management and implementation of risk reduction strategies. This study updates and appraises current evidence on prognostic accuracy of multicomponent risk models for post-stroke cognitive syndromes.</p><p><strong>Methods: </strong>In this updated systematic review, we searched multidisciplinary electronic databases between November 2019 and October 2024 for relevant studies. An updated search was conducted on May 30, 2025. Studies were included if they described a multicomponent risk prediction tool developed in a stroke population (aged ≥18 years), free of cognitive impairment/dementia at baseline, with no exclusions on language. All study designs of primary research were eligible provided the study reported a multicomponent model at any point to predict participant cognitive outcomes i.e., incident cognitive impairment, dementia or delirium. Multicomponent refers to having more than one feature in the model e.g. if the study only reported the discriminatory accuracy of a cognitive score this was not eligible. All studies had to report sufficient discriminative performance metrics to assess model performance. Data were extracted from selected studies using a pre-specified proforma. Risk of bias was assessed using the Prediction model Risk of Bias Assessment Tool (PROBAST), certainty of evidence by GRADE, and between-study heterogeneity via <i>I</i>-squared (<i>I</i> <sup><i>2</i></sup> ) statistics. Our study was preregistered with PROSPERO (CRD42024601845).</p><p><strong>Findings: </strong>From 16,259 articles, 20 new studies contributed 31 models for post-stroke cognitive impairment and/or dementia and six models for post-stroke delirium with most developed in Asia (n = 12). Most models (n = 10) used logistic regression, with some using machine learning methods (n = 5). Development cohorts were small (mean n = 677). The pooled c-statistic for post-stroke cognitive impairment and delirium were 0.81 (95% CI 0.77-0.85, <i>I</i> <sup><i>2</i></sup> 95.7%) and 0.85 (95% CI 0.77-0.93, <i>I</i> <sup><i>2</i></sup> 52.7%), respectively. Three models externally validated (C-statistic: 0.72-0.91); and two models underwent temporal validation (AUC 0.81-0.82). Eight studies included measures of calibration which all demonstrated good calibration. Most studies (n = 17) were deemed to have low risk of bias and applicability concerns but overall certainty of evidence by GRADE was low.</p><p><strong>Interpretation: </strong>Development of risk models to predict cognitive syndromes post-stroke has increased. Development cohorts remain small, largely developed in Asia with very few assessing model transportability. Future studies should pool data and utilise the potential of routinely collected large datasets. Stakeholder engagement and cost-
{"title":"Clinical prediction rules for cognitive outcomes post-stroke: an updated systematic review and meta-analysis.","authors":"Eugene Yee Hing Tang, Jacob Brain, Rhiannon De Ivey, Serena Sabatini, Felicity Mills, Emma Jackson, Linda Errington, Claire Burley, Jennifer Dunne, Leanne Greene, Ram Bajpai, Christopher Price, Louise Robinson, Nele Demeyere, Blossom Christa Maree Stephan, Maree Stephan, Terry Quinn","doi":"10.1016/j.eclinm.2025.103664","DOIUrl":"10.1016/j.eclinm.2025.103664","url":null,"abstract":"<p><strong>Background: </strong>Survivors of stroke are at a higher risk of cognitive syndromes, including dementia and delirium. Timely identification of those at-risk for cognitive syndromes could ensure better clinical management and implementation of risk reduction strategies. This study updates and appraises current evidence on prognostic accuracy of multicomponent risk models for post-stroke cognitive syndromes.</p><p><strong>Methods: </strong>In this updated systematic review, we searched multidisciplinary electronic databases between November 2019 and October 2024 for relevant studies. An updated search was conducted on May 30, 2025. Studies were included if they described a multicomponent risk prediction tool developed in a stroke population (aged ≥18 years), free of cognitive impairment/dementia at baseline, with no exclusions on language. All study designs of primary research were eligible provided the study reported a multicomponent model at any point to predict participant cognitive outcomes i.e., incident cognitive impairment, dementia or delirium. Multicomponent refers to having more than one feature in the model e.g. if the study only reported the discriminatory accuracy of a cognitive score this was not eligible. All studies had to report sufficient discriminative performance metrics to assess model performance. Data were extracted from selected studies using a pre-specified proforma. Risk of bias was assessed using the Prediction model Risk of Bias Assessment Tool (PROBAST), certainty of evidence by GRADE, and between-study heterogeneity via <i>I</i>-squared (<i>I</i> <sup><i>2</i></sup> ) statistics. Our study was preregistered with PROSPERO (CRD42024601845).</p><p><strong>Findings: </strong>From 16,259 articles, 20 new studies contributed 31 models for post-stroke cognitive impairment and/or dementia and six models for post-stroke delirium with most developed in Asia (n = 12). Most models (n = 10) used logistic regression, with some using machine learning methods (n = 5). Development cohorts were small (mean n = 677). The pooled c-statistic for post-stroke cognitive impairment and delirium were 0.81 (95% CI 0.77-0.85, <i>I</i> <sup><i>2</i></sup> 95.7%) and 0.85 (95% CI 0.77-0.93, <i>I</i> <sup><i>2</i></sup> 52.7%), respectively. Three models externally validated (C-statistic: 0.72-0.91); and two models underwent temporal validation (AUC 0.81-0.82). Eight studies included measures of calibration which all demonstrated good calibration. Most studies (n = 17) were deemed to have low risk of bias and applicability concerns but overall certainty of evidence by GRADE was low.</p><p><strong>Interpretation: </strong>Development of risk models to predict cognitive syndromes post-stroke has increased. Development cohorts remain small, largely developed in Asia with very few assessing model transportability. Future studies should pool data and utilise the potential of routinely collected large datasets. Stakeholder engagement and cost-","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103664"},"PeriodicalIF":10.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103658
Marietta Iacucci, Valentina Vadori, Pablo Meseguer, Irene Zammarchi, Giovanni Santacroce, Rocio Del Amor, Davide Zardo, Brian Hayes, Rory Crotty, Louise Burke, Bisi Bode Kolawole, Ujwala Chaudhuri, Silvio Danese, Subrata Ghosh, Valery Naranjo, Enrico Grisan
Background: Histological remission (HR) is a key treatment goal in ulcerative colitis (UC), suggesting better disease management and treatment response. Absence of mucosal neutrophils is crucial to defining HR. However, the role of neutrophil quantity and localisation remains unclear. We aimed to develop a novel AI-driven pipeline to automate neutrophil detection, localisation, and quantification, supporting assessment of HR and treatment response.
Methods: We developed an AI-driven pipeline by integrating and combining the outputs of two deep learning models to segment whole-slide images (WSIs) into epithelium, crypts and lamina propria and detect and quantify neutrophils. Optimal neutrophil density cut-offs to assess disease activity in UC patients from the AMAC phase 2 Mirikizumab trial (NCT02589665; 2015-2019) were identified and validated in the multicentre prospective PICaSSO cohort (2016-2019). Cut-offs to determine treatment response at weeks 12 and 52 were also evaluated.
Findings: 303 WSIs of UC patients from the multicentre, randomised, double-blind, parallel-arm, placebo-controlled phase 2 clinical trial of Mirikizumab were analysed. The models yielded a 65.0% DICE Sørensen for region segmentation on average and 82.3% precision for neutrophil detection. A density cut-off 21.7 cells/mm2 assessed disease activity with 86% (95% CI: 79%-92%) accuracy, 94% (88%-99%) sensitivity, 74% (54%-89%) specificity, as validated in the PICaSSO cohort. Moreover, a cut-off <21.7 cells/mm2 demonstrated 79% (95% CI: 67%-92%) and 85% (95% CI: 70%-96%) accuracy in assessing treatment response at weeks 12 and 52, respectively.
Interpretation: This novel AI-based pipeline demonstrates strong potential to detect, localise, and quantify neutrophils to assess histological activity in clinical trials and real-world settings. Furthermore, it effectively stratifies treatment response, offering a reliable and objective framework for personalised UC management.
Funding: This paper has been supported by research grants from Eli Lilly and Company.
{"title":"Detection, localisation, and quantification of neutrophils to assess disease activity and early response to therapy in ulcerative colitis: a novel AI-driven model.","authors":"Marietta Iacucci, Valentina Vadori, Pablo Meseguer, Irene Zammarchi, Giovanni Santacroce, Rocio Del Amor, Davide Zardo, Brian Hayes, Rory Crotty, Louise Burke, Bisi Bode Kolawole, Ujwala Chaudhuri, Silvio Danese, Subrata Ghosh, Valery Naranjo, Enrico Grisan","doi":"10.1016/j.eclinm.2025.103658","DOIUrl":"10.1016/j.eclinm.2025.103658","url":null,"abstract":"<p><strong>Background: </strong>Histological remission (HR) is a key treatment goal in ulcerative colitis (UC), suggesting better disease management and treatment response. Absence of mucosal neutrophils is crucial to defining HR. However, the role of neutrophil quantity and localisation remains unclear. We aimed to develop a novel AI-driven pipeline to automate neutrophil detection, localisation, and quantification, supporting assessment of HR and treatment response.</p><p><strong>Methods: </strong>We developed an AI-driven pipeline by integrating and combining the outputs of two deep learning models to segment whole-slide images (WSIs) into epithelium, crypts and lamina propria and detect and quantify neutrophils. Optimal neutrophil density cut-offs to assess disease activity in UC patients from the AMAC phase 2 Mirikizumab trial (NCT02589665; 2015-2019) were identified and validated in the multicentre prospective PICaSSO cohort (2016-2019). Cut-offs to determine treatment response at weeks 12 and 52 were also evaluated.</p><p><strong>Findings: </strong>303 WSIs of UC patients from the multicentre, randomised, double-blind, parallel-arm, placebo-controlled phase 2 clinical trial of Mirikizumab were analysed. The models yielded a 65.0% DICE Sørensen for region segmentation on average and 82.3% precision for neutrophil detection. A density cut-off <math><mrow><mo>≥</mo></mrow> </math> 21.7 cells/mm<sup>2</sup> assessed disease activity with 86% (95% CI: 79%-92%) accuracy, 94% (88%-99%) sensitivity, 74% (54%-89%) specificity, as validated in the PICaSSO cohort. Moreover, a cut-off <21.7 cells/mm<sup>2</sup> demonstrated 79% (95% CI: 67%-92%) and 85% (95% CI: 70%-96%) accuracy in assessing treatment response at weeks 12 and 52, respectively.</p><p><strong>Interpretation: </strong>This novel AI-based pipeline demonstrates strong potential to detect, localise, and quantify neutrophils to assess histological activity in clinical trials and real-world settings. Furthermore, it effectively stratifies treatment response, offering a reliable and objective framework for personalised UC management.</p><p><strong>Funding: </strong>This paper has been supported by research grants from Eli Lilly and Company.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103658"},"PeriodicalIF":10.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12702044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Background: </strong>Inappropriate antibiotic use is a key driver of antimicrobial resistance (AMR), a growing global threat that disproportionately affects children in low and lower-middle-income countries (LLMICs). In response, the WHO Global Research Agenda for Antimicrobial Resistance in Human Health prioritises research on antimicrobial stewardship programs (ASPs, formally introduced in 2007) and feasible point-of-care testing (POCT) in paediatric populations, where evidence on implementation and effectiveness remains limited. We aimed to address this gap and inform the design and scale-up of paediatric-focused strategies via a systematic review and meta-analysis on the impact of ASPs and POCTs in children in LLMICs.</p><p><strong>Methods: </strong>For this systematic review and meta-analysis, we searched MEDLINE, Embase, Cochrane Library, Scopus, Global Health, CINAHL, African Journals Online (AJOL), and Latin American and Caribbean Health Sciences Literature (LILACS) for relevant studies published between January 1, 2007, and December 31, 2024. A search update was conducted on September 1, 2025. The search strategy included a combination of Medical Subject Heading (MeSH) and free text terms for 'children', 'antibiotic', 'stewardship program', and 'point-of-care', without any language restrictions. Eligible studies included children (aged <18 years) and were conducted in healthcare settings (inpatient or outpatient) within LLMICs, as per 2024 World Bank classification. Randomised controlled trials, before-and-after, and cohort studies were eligible for inclusion. Outcomes were antibiotic use, guideline adherence, costs, antimicrobial resistance, and clinical outcomes. When three or more reports assessed the same intervention and outcome, a random-effects meta-analysis was performed, and odds ratios (ORs) with 95% confidence intervals (CIs) were reported. This work is registered with PROSPERO, CRD42024491248.</p><p><strong>Findings: </strong>Of the 11,191 records identified, 78 reports from 13 countries in Africa and 12 countries in Asia were included in the evidence synthesis. These studies evaluated 68 ASPs and 30 POCTs, either alone or in combination. Most reported improvements in antibiotic prescribing (77%) and adherence to guidelines (80%). Success rates were higher when ASPs were combined with POCTs (85%) compared to ASPs (73%) or POCTs alone (80%). Bundled interventions were more effective (81%) than single ones (70%). No increase in adverse clinical outcomes was observed, supporting the safety of ASPs. Meta-analysis showed that clinical decision support systems reduced antibiotic prescribing in primary care (overall OR 0.17, 95% CI 0.07-0.45, I<sup>2</sup> 99.7).</p><p><strong>Interpretation: </strong>Evidence shows that ASPs and POCTs are feasible and effective in children in LLMICs, supporting the development of adaptable, paediatric-focused strategies. Future research should focus on large-scale implementation studies
背景：抗生素使用不当是导致抗菌素耐药性（AMR）的一个关键因素，这是一种日益严重的全球威胁，对低收入和中低收入国家（LLMICs）儿童的影响尤为严重。为此，世卫组织《人类健康中抗菌素耐药性全球研究议程》重点研究2007年正式推出的抗菌素管理规划（asp）和儿科人群中可行的护理点检测（POCT），因为关于实施和有效性的证据仍然有限。我们旨在解决这一差距，并通过对低收入中低收入国家儿童的asp和poct影响的系统评价和荟萃分析，为儿科重点战略的设计和扩大提供信息。方法：通过MEDLINE、Embase、Cochrane Library、Scopus、Global Health、CINAHL、African Journals Online （AJOL）和Latin American and Caribbean Health Sciences Literature （LILACS）检索2007年1月1日至2024年12月31日期间发表的相关研究，进行系统评价和meta分析。在2025年9月1日进行了一次搜索更新。搜索策略包括医学主题标题（MeSH）和“儿童”、“抗生素”、“管理计划”和“护理点”等免费文本术语的组合，没有任何语言限制。结果：在确定的11191份记录中，来自13个非洲国家和12个亚洲国家的78份报告被纳入证据综合。这些研究评估了68个asp和30个poct，无论是单独的还是联合的。大多数报告在抗生素处方（77%）和遵守指南（80%）方面有所改善。asp联合POCTs的成功率（85%）高于asp（73%）或单独POCTs（80%）。捆绑干预措施（81%）比单一干预措施（70%）更有效。未观察到不良临床结果的增加，支持asp的安全性。荟萃分析显示，临床决策支持系统减少了初级保健的抗生素处方（总体OR 0.17, 95% CI 0.07-0.45, I2 99.7）。解释：证据表明，在低收入中低收入国家的儿童中，asp和poct是可行和有效的，支持制定适应性强、以儿科为重点的战略。未来的研究应侧重于大规模实施研究和针对具体情况的评估，以优化低收入中等收入国家的儿科asp和poct。资助：这项工作是在意大利国家恢复和复原力计划（任务4，组成部分2）的支持下，作为解决新发传染病未满足需求的INF-ACT-One卫生基础和转化研究行动的一部分进行的。
{"title":"Antibiotic stewardship and point-of-care testing for children in 25 low-income and lower-middle-income countries: a systematic review and meta-analysis.","authors":"Emelyne Gres, Giulia Brigadoi, Elita Zamperetti, Angela Dramowski, Désiré Dahourou, Hypolite Muhindo Mavoko, Trésor Zola Matuvanga, Raph L Hamers, Valériane Leroy, Daniele Dona', Elisa Barbieri","doi":"10.1016/j.eclinm.2025.103667","DOIUrl":"10.1016/j.eclinm.2025.103667","url":null,"abstract":"<p><strong>Background: </strong>Inappropriate antibiotic use is a key driver of antimicrobial resistance (AMR), a growing global threat that disproportionately affects children in low and lower-middle-income countries (LLMICs). In response, the WHO Global Research Agenda for Antimicrobial Resistance in Human Health prioritises research on antimicrobial stewardship programs (ASPs, formally introduced in 2007) and feasible point-of-care testing (POCT) in paediatric populations, where evidence on implementation and effectiveness remains limited. We aimed to address this gap and inform the design and scale-up of paediatric-focused strategies via a systematic review and meta-analysis on the impact of ASPs and POCTs in children in LLMICs.</p><p><strong>Methods: </strong>For this systematic review and meta-analysis, we searched MEDLINE, Embase, Cochrane Library, Scopus, Global Health, CINAHL, African Journals Online (AJOL), and Latin American and Caribbean Health Sciences Literature (LILACS) for relevant studies published between January 1, 2007, and December 31, 2024. A search update was conducted on September 1, 2025. The search strategy included a combination of Medical Subject Heading (MeSH) and free text terms for 'children', 'antibiotic', 'stewardship program', and 'point-of-care', without any language restrictions. Eligible studies included children (aged <18 years) and were conducted in healthcare settings (inpatient or outpatient) within LLMICs, as per 2024 World Bank classification. Randomised controlled trials, before-and-after, and cohort studies were eligible for inclusion. Outcomes were antibiotic use, guideline adherence, costs, antimicrobial resistance, and clinical outcomes. When three or more reports assessed the same intervention and outcome, a random-effects meta-analysis was performed, and odds ratios (ORs) with 95% confidence intervals (CIs) were reported. This work is registered with PROSPERO, CRD42024491248.</p><p><strong>Findings: </strong>Of the 11,191 records identified, 78 reports from 13 countries in Africa and 12 countries in Asia were included in the evidence synthesis. These studies evaluated 68 ASPs and 30 POCTs, either alone or in combination. Most reported improvements in antibiotic prescribing (77%) and adherence to guidelines (80%). Success rates were higher when ASPs were combined with POCTs (85%) compared to ASPs (73%) or POCTs alone (80%). Bundled interventions were more effective (81%) than single ones (70%). No increase in adverse clinical outcomes was observed, supporting the safety of ASPs. Meta-analysis showed that clinical decision support systems reduced antibiotic prescribing in primary care (overall OR 0.17, 95% CI 0.07-0.45, I<sup>2</sup> 99.7).</p><p><strong>Interpretation: </strong>Evidence shows that ASPs and POCTs are feasible and effective in children in LLMICs, supporting the development of adaptable, paediatric-focused strategies. Future research should focus on large-scale implementation studies ","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103667"},"PeriodicalIF":10.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103655
Mohammed Safeer V S, Simran Behl, Pankaj C Vaidya, Pawan Tiwari, Saroj Kundan Bharti, Najiya Nahan, Jitendra Kumar Sahu, Dipika Bansal
<p><strong>Background: </strong>The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (correctors and potentiators) emerged as a promising approach, aiming to restore CFTR protein function. A lack of head-to-head trials comparing CFTR modulators leaves uncertainty about the optimal treatment. We aimed to evaluate the comparative efficacy and safety of CFTR modulators for people with cystic fibrosis who have a phe508del mutation.</p><p><strong>Methods: </strong>We conducted an extensive literature search for both published and unpublished randomized controlled trials in databases such as PubMed, EMBASE, Scopus, Ovid, Cochrane Central Register of Controlled Trials, and international trial registers from inception until May 21, 2025. We included studies that used any CFTR modulators (monotherapy or combination) for the treatment of children and adults with a confirmed diagnosis of cystic fibrosis with phe508del CFTR mutation. Two reviewers independently and in duplicate performed study selection, data extraction, and quality assessment. Our primary outcomes were efficacy (change in percent predicted forced expiratory volume (ppFEV<sub>1</sub>), sweat chloride) and safety (frequency of serious adverse events). We performed a random effect bayesian network meta-analysis for each outcome using the gemtc and BUGSnet package in R. The confidence in the network meta-analysis framework was utilized to determine the certainty of evidence. The study protocol was registered with Prospective Register of Systematic Reviews (CRD42024505081).</p><p><strong>Findings: </strong>Of the 3473 studies identified through our literature search, 29 studies involving 6450 patients examining 34 treatment combinations were included. For adults treated over 4-8 weeks, vanzacaftor 10 mg-tezacaftor 100 mg-deutivacaftor 150 mg combination therapy had a significant improvement over placebo in improving ppFEV<sub>1</sub> (MD: 15.9; 95% CrI: 7.2-24.2 [high certainty]) with a SUCRA of 92% suggesting the highest probability of effectiveness. Moreover, the vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 150 mg showed a significant reduction in sweat chloride levels (MD: -49.3 mmol/L; 95% CrI: -67.2 to -31.7 [high certainty]) and improved the CFQ-R scores (MD: 39; 95% CrI: 21.2-56.9; [high certainty]) when compared to placebo after 4-8 weeks of treatment. Our findings also highlighted that the triple combination therapies of vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 250 mg and elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg provided clinically meaningful improvements across all measured outcomes in adults treated for more than 8 weeks. Confidence in the estimates ranged from high to low, and safety analyses were limited by the low serious adverse event rates.</p><p><strong>Interpretation: </strong>Our findings indicate that vanzacaftor-tezacaftor-deutivacaftor and elexacaftor-tezacaftor-deutivacaftor emerged as the most effective treatm
{"title":"Comparative efficacy and safety of CFTR modulators for people with cystic fibrosis with phe508del mutation: a systematic review and bayesian network meta-analysis.","authors":"Mohammed Safeer V S, Simran Behl, Pankaj C Vaidya, Pawan Tiwari, Saroj Kundan Bharti, Najiya Nahan, Jitendra Kumar Sahu, Dipika Bansal","doi":"10.1016/j.eclinm.2025.103655","DOIUrl":"10.1016/j.eclinm.2025.103655","url":null,"abstract":"<p><strong>Background: </strong>The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (correctors and potentiators) emerged as a promising approach, aiming to restore CFTR protein function. A lack of head-to-head trials comparing CFTR modulators leaves uncertainty about the optimal treatment. We aimed to evaluate the comparative efficacy and safety of CFTR modulators for people with cystic fibrosis who have a phe508del mutation.</p><p><strong>Methods: </strong>We conducted an extensive literature search for both published and unpublished randomized controlled trials in databases such as PubMed, EMBASE, Scopus, Ovid, Cochrane Central Register of Controlled Trials, and international trial registers from inception until May 21, 2025. We included studies that used any CFTR modulators (monotherapy or combination) for the treatment of children and adults with a confirmed diagnosis of cystic fibrosis with phe508del CFTR mutation. Two reviewers independently and in duplicate performed study selection, data extraction, and quality assessment. Our primary outcomes were efficacy (change in percent predicted forced expiratory volume (ppFEV<sub>1</sub>), sweat chloride) and safety (frequency of serious adverse events). We performed a random effect bayesian network meta-analysis for each outcome using the gemtc and BUGSnet package in R. The confidence in the network meta-analysis framework was utilized to determine the certainty of evidence. The study protocol was registered with Prospective Register of Systematic Reviews (CRD42024505081).</p><p><strong>Findings: </strong>Of the 3473 studies identified through our literature search, 29 studies involving 6450 patients examining 34 treatment combinations were included. For adults treated over 4-8 weeks, vanzacaftor 10 mg-tezacaftor 100 mg-deutivacaftor 150 mg combination therapy had a significant improvement over placebo in improving ppFEV<sub>1</sub> (MD: 15.9; 95% CrI: 7.2-24.2 [high certainty]) with a SUCRA of 92% suggesting the highest probability of effectiveness. Moreover, the vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 150 mg showed a significant reduction in sweat chloride levels (MD: -49.3 mmol/L; 95% CrI: -67.2 to -31.7 [high certainty]) and improved the CFQ-R scores (MD: 39; 95% CrI: 21.2-56.9; [high certainty]) when compared to placebo after 4-8 weeks of treatment. Our findings also highlighted that the triple combination therapies of vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 250 mg and elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg provided clinically meaningful improvements across all measured outcomes in adults treated for more than 8 weeks. Confidence in the estimates ranged from high to low, and safety analyses were limited by the low serious adverse event rates.</p><p><strong>Interpretation: </strong>Our findings indicate that vanzacaftor-tezacaftor-deutivacaftor and elexacaftor-tezacaftor-deutivacaftor emerged as the most effective treatm","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"90 ","pages":"103655"},"PeriodicalIF":10.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103673
Ruslan Akhmedullin, Abduzhappar Gaipov
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Pub Date : 2025-11-24eCollection Date: 2025-12-01DOI: 10.1016/j.eclinm.2025.103647
Curdin Brugger, Bassam Abu Hamad, Jan Hattendorf, Mirko S Winkler, Nicole Probst-Hensch
<p><strong>Background: </strong>The Gaza Strip has experienced prolonged conflict and blockade, straining infrastructure, basic services, and daily life. These chronic stressors pose a severe threat to mental health. The escalation to war in October 2023 led to widespread displacement, destruction, and loss of life. While cross-sectional studies before the war suggest high psychological distress, longitudinal data documenting the temporal course of mental health during conflict escalation are lacking.</p><p><strong>Methods: </strong>This study uses longitudinal data from 677 adults (aged at least 40 years) who participated in three self-report household surveys (2020, 2023, 2025) in the Gaza Strip. The three surveys were carried out in the governorates of Gaza, North Gaza, and Rafah, and responses were gathered from March 18 to July 15, 2020; January 24 to March 7, 2023; and January 12-28, 2025, respectively. The primary endpoint, mental health status, was assessed in all three survey rounds using the 12-item General Health Questionnaire (GHQ-12). Items were scored dichotomously (0/1), resulting in a total GHQ-12 score ranging from 0 to 12, with higher scores indicating greater psychological distress. We applied a conservative threshold of GHQ-12 score >6 for defining high psychological distress, consistent with previous studies in the Gaza Strip. Descriptive analyses documented temporal changes in GHQ-12 scores and items. A mixed-effects logistic regression model estimated the association between survey year and high psychological distress, adjusting for socio-demographic variables.</p><p><strong>Findings: </strong>A total of 677 participants took part in all three surveys (from 2980 in 2020 and 1547 in 2023). In 2020, 49%, 31%, and 20% of the 677 retained participants lived in Gaza, North Gaza, and Rafah governorates, respectively. 51% (n = 347) of the participants were women, and the majority (70%) were aged 40-59 years. High psychological distress (GHQ-12 score >6) increased from 19.5% in 2020 and 17.4% in 2023 to 67.2% in 2025. Adjusted models showed 12 times higher odds of psychological distress in 2025 compared with 2020 (OR = 12.45; 95% CI: 9.01-17.20). This increase did not differ across socio-demographic subgroups, although older adults and those with secondary or higher education were less likely to exhibit high psychological distress.</p><p><strong>Interpretation: </strong>While our study cannot establish causality, the recent tripling of severe psychological distress evolved from a background of an exceedingly high mental health burden before October 2023. Our findings underscore the relevance of providing long-term psychosocial and mental health services, including strengthening resilience, to prevent long-term consequences for the current and next generations in Gaza and other conflict-affected populations. Future research should examine the long-term mental health trajectories and resilience, including intergenerational impacts.</
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