EClinicalMedicinePub Date : 2025-08-20eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103433
Thomas J C Ward, Lorna Latimer, Enya Daynes, Suzanne C Freeman, Sarah Ward, Jiaqing Xu, Muhammed Haris, Majda Bakali, Sophie Reap, Mamoon Iqbal, Lin Wang, Akash Mavilakandy, Aarinola Olaiya, Hnin Aung, Theresa C Harvey-Dunstan, Sally J Singh, Neil J Greening, Rachael A Evans, Michael C Steiner, Alex J Sutton
{"title":"Impact of pulmonary rehabilitation programme design on effectiveness in COPD: a systematic review and component network meta-analysis.","authors":"Thomas J C Ward, Lorna Latimer, Enya Daynes, Suzanne C Freeman, Sarah Ward, Jiaqing Xu, Muhammed Haris, Majda Bakali, Sophie Reap, Mamoon Iqbal, Lin Wang, Akash Mavilakandy, Aarinola Olaiya, Hnin Aung, Theresa C Harvey-Dunstan, Sally J Singh, Neil J Greening, Rachael A Evans, Michael C Steiner, Alex J Sutton","doi":"10.1016/j.eclinm.2025.103433","DOIUrl":"10.1016/j.eclinm.2025.103433","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary rehabilitation (PR) is a key treatment for chronic obstructive pulmonary disease (COPD) recommended by all guidelines. However, programmes vary widely and the optimal combination of components to maximise benefits and efficiency remains unknown. We aimed to use the novel technique of component network meta-analysis (cNMA) to investigate the relative contribution of 1) exercise modality and intensity, 2) non-exercise components, 3) type of supervision, and 4) programme duration of PR for people with COPD.</p><p><strong>Methods: </strong>MEDLINE, EMBASE, CINAHL, and Cochrane databases searched in October 2023 with no date or language restrictions. We included randomised controlled trials (RCTs) which included an intervention involving exercise for people with COPD. We present outcomes of exercise capacity, breathlessness and health related quality of life (HRQoL). Screening and eligibility were assessed by two independent reviewers. cNMA, a technique developed to investigate complex interventions such as PR, was conducted to examine the contribution of single components within diverse multicomponent interventions controlling for cohort demographics. PROSPERO: CRD42022322058.</p><p><strong>Findings: </strong>We included 337 RCTs with 18,911 participants and 227 intervention components. In-person supervision enhanced gains in exercise capacity (Standardised mean difference (SMD) 0.41, 95% CrI 0.20; 0.63), HRQoL (0.43 95% CrI 0.19; 0.68) and breathlessness (0.31 95% CrI 0.04; 0.58) over exercise training alone with moderate to high certainty. Remote supervision increased gains in exercise capacity (0.40 95% CrI 0.08; 0.73) with trends towards improvements in HRQoL and breathlessness, with low certainty. Aerobic training appeared to be most effective for all outcomes at high or very high intensity but with low certainty. Addition of structured education did not improve any outcome. Psychological interventions led improvements in exercise capacity (0.37 95% CrI 0.01; 0.73, low certainty) and HRQoL (0.54 95% CrI 0.18; 0.91, moderate certainty). There was trend towards improvements in breathlessness with addition of breathing exercises (0.26 95% CrI -0.04; 0.56, low certainty). Programme duration did not impact outcomes. For outcomes of exercise capacity, HRQoL and breathlessness there were 60%, 63% and 59% studies at high risk of bias respectively.</p><p><strong>Interpretation: </strong>This large-scale analysis of over 300 randomised PR trials found the strongest effects for in-person supervised and prescribed aerobic exercise training with less certainty for the benefit of other commonly used PR components and delivery methods.</p><p><strong>Funding: </strong>This research was funded through a National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands grant (2.12) and carried out at the NIHR Leicester Biomedical Research Centre (BRC).</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103433"},"PeriodicalIF":10.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946966","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}
{"title":"Efficacy and safety of tazemetostat, an EZH2 inhibitor, in Chinese patients with relapsed/refractory follicular lymphoma: a multicentre, single-arm, phase 2 study.","authors":"Junning Cao, Guangliang Chen, Lihua Qiu, Liling Zhang, Ming Jiang, Ying Cheng, Qiaohua Zhang, Lihong Liu, Ping Li, Yuerong Shuang, Huaqing Wang, Hongwei Xue, Huijing Wu, Meifang Zheng, Keshu Zhou, Zhiming Li, Hongmei Jing, Wei Yang, Zunmin Zhu, Wenyu Li, Jiaxuan Wangwu, Heyu Huang, Qiantao Jia, Dongmei Chen, Songhua Fan, M Ming Shi, Weiguo Su","doi":"10.1016/j.eclinm.2025.103399","DOIUrl":"10.1016/j.eclinm.2025.103399","url":null,"abstract":"<p><strong>Background: </strong>Tazemetostat, the first enhancer of zeste homolog 2 (EZH2) inhibitor approved by the U.S. Food and Drug Administration, has shown efficacy in a global population with relapsed or refractory (R/R) follicular lymphoma (FL). This phase 2 study was primarily designed as a registration-intent bridging trial of tazemetostat in Chinese patients with <i>EZH2-</i>mutant (<i>EZH2</i> <sup>mut</sup>) R/R FL; the study also included evaluation in the <i>EZH2</i> wild-type (<i>EZH2</i> <sup>wt</sup>) population.</p><p><strong>Methods: </strong>This multicentre, single-arm, phase 2 study was conducted at 19 sites in China. Eligible patients (aged ≥18 years) with histologically confirmed grade 1-3a FL were categorised by <i>EZH2</i> status: mutant (<i>EZH2</i> <sup>mut</sup>, bridging cohort) and wild-type (<i>EZH2</i> <sup>wt</sup>), and received oral tazemetostat 800 mg twice daily in continuous 28-day cycles until investigator-assessed disease progression, intolerable toxicity, withdrawal of consent, or other protocol-specified criteria. The <i>EZH2</i> <sup>mut</sup> cohort primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Efficacy in the <i>EZH2</i> <sup>mut</sup> cohort was assessed in patients who received at least one dose of tazemetostat and had centrally confirmed FL. Efficacy in the <i>EZH2</i> <sup>wt</sup> cohort and safety in both cohorts were assessed in all patients who received at least one dose of tazemetostat. This study is registered with ClinicalTrials.gov, NCT05467943.</p><p><strong>Findings: </strong>Between July 29, 2022, and Aug 31, 2023, 22 patients with <i>EZH2</i> <sup>mut</sup> R/R FL were enrolled (three lines [3L] of prior therapy, 31.8%; four lines [4L] of prior therapy or more, 27.3%). As of Aug 31, 2024 (median follow-up 14.4 months), IRC-assessed ORR was 63.6% (95% confidence interval [CI], 40.7%-82.8%), clinical benefit rate (CBR) was 90.9% (70.8%-98.9%), median duration of response (DoR) was not reached (18-month DoR rate, 51.6% [18.2%-77.3%]), and median progression-free survival was 15.4 (8.2-not estimable) months. All patients experienced treatment-related adverse events (TRAEs), and 13.6% had grade ≥3 TRAEs; most common TRAEs were haematological toxicities. For the <i>EZH2</i> <sup>wt</sup> cohort, 20 patients were enrolled (3L, 35.0%; ≥4L, 45.0%). Tazemetostat also demonstrated efficacy benefit and a manageable safety profile in the <i>EZH2</i> <sup>wt</sup> cohort, with an investigator-assessed ORR of 35.0% (95% CI, 15.4%-59.2%), CBR of 85.0% (62.1%-96.8%), and median DoR of 8.4 (1.9-15.7) months.</p><p><strong>Interpretation: </strong>These results suggest that tazemetostat has a clinically meaningful efficacy and was well tolerated in Chinese patients with R/R FL. Larger trials are warranted. A multicentre, randomised, phase 3 trial of tazemetostat combined with lenalidomide plus rituximab vs. lenalidomide plus rituximab in patients with R/","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103399"},"PeriodicalIF":10.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946942","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}
EClinicalMedicinePub Date : 2025-08-14eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103434
Abdulazeez Imam, Michuki Maina, Jalemba Aluvaala, Vincent Kagonya, Onesmus Onyango, Fredrick Were, Sebastian Fuller, Kenneth Karumba, Mike English, David Gathara
{"title":"Delivery of care in high mortality hospital settings: a direct observational study examining 1848 h of neonatal nursing in Kenya.","authors":"Abdulazeez Imam, Michuki Maina, Jalemba Aluvaala, Vincent Kagonya, Onesmus Onyango, Fredrick Were, Sebastian Fuller, Kenneth Karumba, Mike English, David Gathara","doi":"10.1016/j.eclinm.2025.103434","DOIUrl":"10.1016/j.eclinm.2025.103434","url":null,"abstract":"<p><strong>Background: </strong>In resource-constrained countries, deploying better technologies is expected to improve neonatal care but little attention has been paid to the critical role of nurse staffing. We investigate nursing workloads and their relationship with care provision in recently upgraded Kenyan neonatal units.</p><p><strong>Methods: </strong>We conducted a cross-sectional analysis using data from direct bedside observations across 8 intermediate-level neonatal units (defined by the World Health organization (WHO) as neonatal units capable of providing specialised but not intensive neonatal care) in Kenya over a 6-week period between February and March 2022. We excluded babies who were so severely ill that they were at risk of imminent death or transfer to a critical care facility and babies with congenital anomalies and surgical conditions. We used a structured observation checklist that had undergone content and face-validity testing in Kenya to collect workload and nursing care provision data. We determined nursing hours per patient per 12-h shift to measure nursing workload (primary exposure variable) and used a composite measure, the nursing care index (NCI), to score the nursing care delivered to a baby (primary outcome variable). The relationship between nursing workload and nursing care provision was assessed using multilevel models.</p><p><strong>Findings: </strong>Across 8 hospitals spanning 1848 h of observation of 597 sick newborns, the median nursing time available for each newborn ranged from 19.2 to 72.0 min on a 12-h shift. Nurses delivered 32% of expected care, completely missed 32%, and informally delegated 36% of tasks. Unsupervised nursing students and mothers played prominent roles in the care of clinically unstable babies. An exploratory model combining qualified nurse and nursing student hours, that considerably expanded the range of the nursing workload metric, demonstrated a 3.1% increase in nurse-delivered care per additional 60 min of nursing time per baby per shift (β: 0.031, 95% CI: 0.019-0.043).</p><p><strong>Interpretation: </strong>The nursing time available to care for sick newborns in Kenya is inadequate resulting in suboptimal care quality. Improving care quality, reducing of newborn mortality and making effective use of new technologies may not be possible without increasing nurse staffing in resource-constrained countries.</p><p><strong>Funding: </strong>National Institute for Health and Care Research.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103434"},"PeriodicalIF":10.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946885","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}
EClinicalMedicinePub Date : 2025-08-14eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103430
Byron L Lam, Vitaliy Zak, Victor H Gonzalez, Ninel Z Gregori, Sai H Chavala, Subrata Batabyal, Michael Carlson, Sanghoon Kim, Ananta Ayyagari, Jean Chang, Hayley Lane, Nozhat Choudry, John Koester, Mark Von Tress, Jody Piltz-Seymour, Najam A Sharif, Stephen H Tsang, Vinit B Mahajan, David S Boyer, Allen C Ho, Samuel B Barone, Samarendra K Mohanty
{"title":"Safety and efficacy of MCO-010 optogenetic therapy in patients with Stargardt disease in USA (STARLIGHT): an open-label multi-center Ph2 trial.","authors":"Byron L Lam, Vitaliy Zak, Victor H Gonzalez, Ninel Z Gregori, Sai H Chavala, Subrata Batabyal, Michael Carlson, Sanghoon Kim, Ananta Ayyagari, Jean Chang, Hayley Lane, Nozhat Choudry, John Koester, Mark Von Tress, Jody Piltz-Seymour, Najam A Sharif, Stephen H Tsang, Vinit B Mahajan, David S Boyer, Allen C Ho, Samuel B Barone, Samarendra K Mohanty","doi":"10.1016/j.eclinm.2025.103430","DOIUrl":"10.1016/j.eclinm.2025.103430","url":null,"abstract":"<p><strong>Background: </strong>Stargardt disease (SD) is an inherited degenerative retinal disease affecting rod and cone photoreceptors and retinal pigment epithelial (RPE) cells, leading to severe and irreversible vision loss. Optogenetics is a promising approach to restoring vision by photosensitizing spared healthy retinal neurons.</p><p><strong>Methods: </strong>The STARLIGHT phase 2 open-label study (NCT05417126) was conducted over 48-weeks at two US sites to assess the safety and efficacy of MCO-010 administered via a single intravitreal injection in the worse-seeing eye of SD patients. The study began on July 5, 2022, and was completed on September 28, 2023. MCO-010 targets bipolar cells rather than retinal ganglion cells (RGCs) to utilize more abundant cells that respond to ambient light while preserving natural visual processing pathways after treatment. Six adults (mean age 50 years, range 32-71 years, four males and two females) received 1.2E11 genome copies (gc)/eye of MCO-010. The primary outcome was the incidence, nature, severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), intraocular inflammation, retinal thickness, best-corrected visual acuity (BCVA), and lesion size. Secondary endpoints included change in BCVA, vision-guided mobility, and shape determination accuracy. Visual field perimetry and Michigan Retinal Degeneration Questionnaire (MRDQ) were exploratory endpoints.</p><p><strong>Findings: </strong>All six participants had at least one ocular TEAE; non-ocular TEAEs occurred in three participants. The most common TEAEs were conjunctival hemorrhage, ocular hypertension, and vitreous cells (two subjects). There were no deaths, hospitalization, loss of eye, retinal detachment, endophthalmitis, or TEAEs leading to study discontinuation. The BCVA (mean ± SD) of the six treated eyes at baseline and 48-week follow-up was 22.8 ± 9.87 (range 9-35), and 28.3 ± 13.28 (range 4-42) ETDRS letters, respectively. The BCVA change from baseline was 7.2 ± 11.74, 4.2 ± 14.81, and 5.5 ± 12.29 at 12, 24, and 48 weeks, respectively. With a wearable magnifier (low-vision glasses), the BCVA change was 17.8 ± 13.35, 15.7 ± 17.37, 13.3 ± 21.37 at 12, 24, and 48 weeks, respectively. The improvement in mean defect in visual field perimetry was 1.02 ± 3.54, 2.47 ± 5.00, and 2.63 ± 5.26 dB at 12, 24, and 48 weeks, respectively. Specific improvements were noted in reading, and color, and contrast domains of the MRDQ.</p><p><strong>Interpretation: </strong>MCO-010 optogenetic phase 2 results support further investigation for treatment SD. To our knowledge, this is the first report of improving on(eye)-chart vision of SD participants utilizing optogenetics.</p><p><strong>Funding: </strong>Nanoscope Therapeutics Inc.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103430"},"PeriodicalIF":10.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946920","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}
EClinicalMedicinePub Date : 2025-08-14eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103429
Stephen J Freedland, Ugo De Giorgi, Antti Rannikko, Fred Saad, Miguel Ramirez-Backhaus, Anchen F Nasr, Jasmina I Ivanova, Arijit Ganguli, Pavol Kral, Arlene L Reisman, Neal D Shore
{"title":"Impact of treatment suspension on health-related quality of life in the EMBARK trial: a post hoc analysis.","authors":"Stephen J Freedland, Ugo De Giorgi, Antti Rannikko, Fred Saad, Miguel Ramirez-Backhaus, Anchen F Nasr, Jasmina I Ivanova, Arijit Ganguli, Pavol Kral, Arlene L Reisman, Neal D Shore","doi":"10.1016/j.eclinm.2025.103429","DOIUrl":"10.1016/j.eclinm.2025.103429","url":null,"abstract":"<p><strong>Background: </strong>Enzalutamide was approved for high-risk biochemically recurrent (hrBCR) prostate cancer based on the EMBARK trial (NCT02319837; 17 December 2014-31 January 2023). In EMBARK, treatment was suspended at week 37 if prostate-specific antigen (PSA) was <0.2 ng/mL and reinstated if PSA rose to ≥2.0 ng/mL with radical prostatectomy or ≥5.0 ng/mL without. This post hoc analysis assessed the impact of treatment suspension on health-related quality of life (HRQoL) to address overtreatment concerns.</p><p><strong>Methods: </strong>Longitudinal change in HRQoL from treatment suspension at week 37 to subsequent assessments until week 109 was analyzed with mixed models for repeated measures (MMRM) and descriptively among these patients. Separate models were used to assess four patient-reported outcome (PRO) instruments-Brief Pain Inventory - short form, Functional Assessment of Cancer Therapy - Prostate, QoL Questionnaire - Prostate 25, and European QoL 5-Dimensions 5-Levels health questionnaire-with predefined clinically meaningful thresholds. Intention-to-treat analysis was used.</p><p><strong>Findings: </strong>Treatment was suspended in 90% (321/355), 86% (304/355), and 67% (240/358) of participants treated with enzalutamide + leuprolide, enzalutamide monotherapy, and leuprolide alone, respectively. MMRM showed no meaningful change in any treatment arm after treatment suspension across all assessed PRO measures, except hormonal treatment-related symptoms, for which clinically meaningful improvement was observed after treatment suspension at week 61 for enzalutamide monotherapy, week 73 for leuprolide alone, and week 85 for enzalutamide + leuprolide. The descriptive analysis showed similar findings.</p><p><strong>Interpretation: </strong>Enzalutamide ± leuprolide in patients with hrBCR improves metastasis-free survival versus leuprolide alone with no clinically meaningful changes in the measured HRQoL domains during treatment or after treatment suspension, with gradual improvement in hormonal treatment-related symptoms after treatment suspension in this selective clinical trial population. Further real-world studies are warranted to better explore the benefits of treatment suspension.</p><p><strong>Funding: </strong>This study was funded by Pfizer Inc. and Astellas Pharma Inc.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103429"},"PeriodicalIF":10.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946908","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}
EClinicalMedicinePub Date : 2025-08-13eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103432
Yang-Hong Dai, Po-Huang Chen, Yi-Jhih Huang, Ding-Jie Lee, Po-Chien Shen, Cheng-Hsiang Lo, Yu-Guang Chen, Yu-Fu Su, Jen-Fu Yang, Ying-Fu Wang, Wen-Yen Huang, Chun-Shu Lin, Chih-Cheng Tsao, Katherine A Vallis
{"title":"Radiation dose escalation in locally advanced oesophageal cancer: a systematic review and hierarchical Bayesian meta-analysis.","authors":"Yang-Hong Dai, Po-Huang Chen, Yi-Jhih Huang, Ding-Jie Lee, Po-Chien Shen, Cheng-Hsiang Lo, Yu-Guang Chen, Yu-Fu Su, Jen-Fu Yang, Ying-Fu Wang, Wen-Yen Huang, Chun-Shu Lin, Chih-Cheng Tsao, Katherine A Vallis","doi":"10.1016/j.eclinm.2025.103432","DOIUrl":"10.1016/j.eclinm.2025.103432","url":null,"abstract":"<p><strong>Background: </strong>The impact of radiation dose escalation in locally advanced oesophageal cancer remains controversial. While higher doses may improve locoregional control, their effect on overall survival (OS) and progression-free survival (PFS) remains uncertain. The aim of this study was to thoroughly evaluate the impact of dose escalation on survival.</p><p><strong>Methods: </strong>A systematic search on Jan 4, 2025, identified studies evaluating definitive chemoradiotherapy (CRTx) for locally advanced oesophageal cancer stratified by radiation dose. Bayesian and frequentist meta-analyses assessed OS, PFS, and locoregional PFS (LRPFS). Meta-regression examined the influence of histology, tumour location, chemotherapy, and radiation techniques. Additional analyses included gene set enrichment analysis and immune infiltration estimation. This study is registered with PROSPERO, CRD42024538961.</p><p><strong>Findings: </strong>A total of 42 studies involving 8379 patients were included. High-dose radiotherapy significantly improved LRPFS, with the largest benefit observed at 1-year (median difference: 18.6%; 95% credible interval [CrI]: 10.7-26.1%). A modest improvement in OS was noted at 3-year (7.0%; 95% CrI: 0.01-13.9%), particularly in squamous cell carcinoma (SqCC). Meta-regression identified SqCC and taxane-based chemotherapy as key moderators, with high-dose conferring greater benefits in Asian populations. Genomic analysis revealed higher radiosensitivity and significant immune activation in Asian SqCC. Taxane-based chemotherapy regimens were the strongest predictors of 1-/2-year OS and PFS but diminished at 5-year. Any-grade pneumonitis was more common in high-dose, but frequencies of grade 3 or higher pneumonitis were similar. Modern techniques like intensity-modulated or volumetric-modulated radiotherapy were associated with higher complete response rate and a trend toward reduced toxicity. The study heterogeneity was moderate to high across pooled estimates but addressed through hierarchical modeling and subgroup/sensitivity analyses. Most included studies were retrospective with moderate risk of bias, and the certainty of evidence for primary outcomes was rated as low to high.</p><p><strong>Interpretation: </strong>Radiation dose escalation improves locoregional control and may enhance OS in SqCC, particularly in Asian populations, highlighting the need for histology- and region-specific therapeutic strategies. The choice of chemotherapy regimen may affect the interpretation of survival effects associated with high-dose. Furthermore, the genomic correlates of radiosensitivity and immune activation suggest potential for biologically guided dose personalization and combination with immunotherapy.</p><p><strong>Funding: </strong>None.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103432"},"PeriodicalIF":10.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946957","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}
EClinicalMedicinePub Date : 2025-08-13eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103426
Luciana Teofili, Patrizia Papacci, Claudio Pellegrino, Carlo Dani, Francesco Cresi, Giulia Remaschi, Giulia Ansaldi, Carmen Giannantonio, Maria Francesca Campagnoli, Barbara Vania, Marco Fabbri, Roberta Penta de Vera d' Aragona, Anna Molisso, Enrico Beccastrini, Antonella Dragonetti, Tina Pasciuto, Sabrina Gabbriellini, Silvia Baroni, Francesca Serrao, Velia Purcaro, Genny Raffaeli, Stefania Villa, Daniele Prati, Isabella Mondello, Alessandra Falcone, Maria Letizia Patti, Tiziana Boggini, Paola Bergamaschi, Domenico Lepore, Fabrizio Gaetano Saverio Franco, Lorenzo Orazi, Iolanda Mozzetta, Antonio Baldascino, Caterina Giovanna Valentini, Emanuela Locatelli, Roberto Albiani, Federico Genzano Besso, Giulia Vanina Cantone, Alessandra Coscia, Alfonso Trimarchi, Giacomo Cavallaro, Stefano Ghirardello, Giovanni Vento
{"title":"Cord red blood cell transfusions for severe retinopathy in preterm neonates in Italy: a multicenter randomized controlled trial.","authors":"Luciana Teofili, Patrizia Papacci, Claudio Pellegrino, Carlo Dani, Francesco Cresi, Giulia Remaschi, Giulia Ansaldi, Carmen Giannantonio, Maria Francesca Campagnoli, Barbara Vania, Marco Fabbri, Roberta Penta de Vera d' Aragona, Anna Molisso, Enrico Beccastrini, Antonella Dragonetti, Tina Pasciuto, Sabrina Gabbriellini, Silvia Baroni, Francesca Serrao, Velia Purcaro, Genny Raffaeli, Stefania Villa, Daniele Prati, Isabella Mondello, Alessandra Falcone, Maria Letizia Patti, Tiziana Boggini, Paola Bergamaschi, Domenico Lepore, Fabrizio Gaetano Saverio Franco, Lorenzo Orazi, Iolanda Mozzetta, Antonio Baldascino, Caterina Giovanna Valentini, Emanuela Locatelli, Roberto Albiani, Federico Genzano Besso, Giulia Vanina Cantone, Alessandra Coscia, Alfonso Trimarchi, Giacomo Cavallaro, Stefano Ghirardello, Giovanni Vento","doi":"10.1016/j.eclinm.2025.103426","DOIUrl":"10.1016/j.eclinm.2025.103426","url":null,"abstract":"<p><strong>Background: </strong>Red blood cell (RBC) transfusions in preterm neonates are associated with retinopathy of prematurity (ROP).</p><p><strong>Methods: </strong>BORN is a multicenter randomized trial investigating whether RBC transfusions from cord blood (CB-RBCs) instead of adult donors (A-RBCs) reduce ROP severity (NCT05100212). The study was conducted between December 2021 and November 2024 in 8 hospitals sited in 8 different Italian regions. Extremely low gestational age neonates (ELGANs) were randomized 1:1 to receive A-RBCs (control) or CB-RBCs (intervention) from birth to postmenstrual age (PMA) of 29 + 6 weeks. The main outcome was severe-ROP rate at 40 weeks PMA or discharge.</p><p><strong>Findings: </strong>By intention-to-treat-analysis, 56 patients per arm were evaluated: 16 in the control arm and 14 in the intervention arm developed severe ROP (28·6% versus 25·0%, risk difference [RD] -0·03 [95% CI -0·21% to 0·14%]; <i>P</i> = 0·831). Twenty-four (42·8%) patients in the intervention arm received also A-RBCs. Per-protocol-analysis included those patients receiving exclusively the assigned treatment, consisting of 38 ELGANs in the control arm and 17 in the intervention arm, with comparable characteristics. Thirteen ELGANs in the control arm developed severe ROP, and 10 required ROP treatment whilst no patients in the intervention arm developed severe ROP or treatment-requiring ROP (34·2% versus 0%, RD -0·34 [95% CI -0·51% to -0·07%] for severe ROP, <i>P</i> = 0·005, and 26·3% versus 0%, RD -0·28 [95% CI -0·46% to -0·02%] for treatment-requiring ROP, <i>P</i> = 0·022). Twenty-four patients in the control arm and 5 in the intervention arm developed moderate/severe BPD (63·2% versus 29·4%, RD -0·33 [95% CI -0·56% to -0·02%], <i>P</i> = 0·039).</p><p><strong>Interpretation: </strong>CB-RBCs may protect ELGANs from severe forms of ROP and BPD.</p><p><strong>Funding: </strong>Funded by Fresenius HemoCare Italia SRL (Prot. N 0038762/21-04/11/2021; grant number 5800134-FPG).</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103426"},"PeriodicalIF":10.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946977","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}
EClinicalMedicinePub Date : 2025-08-12eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103415
Peng Peng Xu, Bin Hu, Fan Zhou, Zhi Han Xu, Qian Chen, Tong Yuan Liu, Bang Jun Guo, Chang Sheng Zhou, Xin Wei Tao, Hong Yan Qiao, Jia Ni Zou, Xiang Ming Fang, Wen Cai Huang, Long Jiang Zhang
{"title":"An artificial intelligence model integrating culprit lesion diagnosis and risk assessment for acute coronary syndrome.","authors":"Peng Peng Xu, Bin Hu, Fan Zhou, Zhi Han Xu, Qian Chen, Tong Yuan Liu, Bang Jun Guo, Chang Sheng Zhou, Xin Wei Tao, Hong Yan Qiao, Jia Ni Zou, Xiang Ming Fang, Wen Cai Huang, Long Jiang Zhang","doi":"10.1016/j.eclinm.2025.103415","DOIUrl":"10.1016/j.eclinm.2025.103415","url":null,"abstract":"<p><strong>Background: </strong>An integrated machine learning (ML) approach capable of both diagnosing acute coronary syndrome (ACS, encompassing myocardial infarction and unstable angina) and predicting future ACS risk within defined optimal timeframes remains an unmet need in cardiovascular risk stratification.</p><p><strong>Methods: </strong>We conducted a multicentre cohort study in China between January 2012 and December 2021. The derivation cohort (cohort 1+ cohort 2), consisting of a training, validation, and independent external test set, retrospectively included 1854 patients from four hospitals who underwent coronary computed tomography angiography (CCTA) and received a definitive diagnosis of ACS or chronic coronary syndromes (CCS) within 7 days. The diagnostic performance of five commonly used ML algorithms for identifying ACS culprit lesions was developed and compared within this cohort. After selecting the optimal ML model, its performance was further validated in a single-center prospective cohort (cohort 3) and a nested case-control cohort (cohort 4) from two multicenter prospective cohorts to assess its ability to predict future ACS risk stratification (≥30 days).</p><p><strong>Findings: </strong>The derivation cohort comprised 1854 participants, among whom 281 experienced new-onset ACS within 7 day. The single-centre prospective cohort included 563 participants, of whom 23 developed ACS during follow-up (median 60.0 months). The nested case-control cohort included 202 participants, of whom 43 developed ACS during follow-up (median 28.0 months). In the derivation cohort, the random forest (RF) model demonstrated the best diagnostic performance and robustness among the five ML algorithms for detecting ACS culprit lesions, achieving an area under the receiver operating characteristic curve (AUC) of 0.85 across the training (95% confidence interval [Cl]: 0.82-0.89), validation (95% Cl: 0.80-0.90), and test sets (95% Cl: 0.78-0.92). In two prospective cohorts, Kaplan-Meier curves showed that the RF model successfully stratified the risk of future ACS events (both log-rank <i>P</i> < 0.001). The time-dependent AUC curve further indicated that the optimal validity period for the RF model derived from the culprit lesion was 2 years. The model's ability to distinguish ACS events within this period was superior to that of the stenosis severity model (AUC: Cohort 3: 0.79 [95% Cl: 0.66-0.93] vs. 0.67 [95% Cl: 0.52-0.82], <i>P</i> = 0.02; Cohort 4: 0.67 [95% Cl: 0.56-0.77] vs. 0.60 [95% Cl: 0.52-0.68], <i>P</i> = 0.05). Additionally, the RF model showed a significant improvement in performance compared to the stenosis severity model in both Cohorts 3 and 4 (all net reclassification improvement [NRI] values > 0).</p><p><strong>Interpretation: </strong>The ACS culprit lesion model developed using RF algorithms demonstrated superior diagnostic performance and was effective for short-term (2-year) ACS risk stratification.</p><p><strong>Funding:","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103415"},"PeriodicalIF":10.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882442","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}
EClinicalMedicinePub Date : 2025-08-12eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103414
Elisa Landin Basterra, Ugo Gentilini, Daniella Medeiros Cavalcanti, Andrea Ferreira da Silva, Lucas de Oliveira Ferreira de Sales, Natanael J Silva, Davide Rasella
{"title":"Impact of social protection on child malnutrition and mortality across 46 LMICs: a longitudinal study over two decades with insights from the COVID-19 pandemic.","authors":"Elisa Landin Basterra, Ugo Gentilini, Daniella Medeiros Cavalcanti, Andrea Ferreira da Silva, Lucas de Oliveira Ferreira de Sales, Natanael J Silva, Davide Rasella","doi":"10.1016/j.eclinm.2025.103414","DOIUrl":"10.1016/j.eclinm.2025.103414","url":null,"abstract":"<p><strong>Background: </strong>Under-5 mortality and malnutrition are major public health challenges in low- and middle-income countries (LMICs), worsened by crises like the COVID-19 pandemic. Evidence on social protection reducing under-5 mortality in LMICs is limited. We examined the impact of social protection coverage, defined as the proportion of the population covered by any form of social protection, on under-5 mortality, stunting, and wasting across 46 LMICs from 2000 to 2021.</p><p><strong>Methods: </strong>Our study analyzed 1012 country-year observations. Outcomes included under-5 mortality (deaths per 1000 live births), prevalence of wasting (weight-for-height Z-scores < -2 SD), and stunting (height-for-age Z-scores < -2 SD). Coverage of social protection was defined as the proportion of the population receiving at least one social protection benefit. We used fixed-effects Poisson models with robust standard errors to estimate associations, adjusting for socioeconomic, healthcare, and gender-related variables. Interaction terms captured social protection mitigation effects during COVID-19, and counterfactual scenarios estimated averted deaths. Analyses were disaggregated by sex and age groups.</p><p><strong>Findings: </strong>Social protection coverage prevented an estimated 3.05 million under-5 deaths overall, including 583,590 during the pandemic. Higher coverage was significantly associated with reductions in under-5 mortality (IRR:0.71,95%CI:0.54-0.96), stunting (IRR:0.75,95%CI:0.60-0.94), and wasting (IRR:0.87,95%CI:0.78-0.98). During the COVID-19 pandemic years, social protection led to additional reductions in under-5 mortality (IRR:0.68,95%CI:0.59-0.79) and stunting (IRR:0.74,95%CI:0.57-0.95). Toddler mortality (1-2 years) showed the greatest reduction effects (IRR:0.62,95%CI:0.41-0.95). Females showed slightly stronger effects. Sensitivity and triangulation analyses validated all results.</p><p><strong>Interpretation: </strong>Social protection coverage strongly reduced child mortality, stunting, and wasting in LMICs, with heightened impact during the pandemic years. Scaling up social protection programs can be crucial for reducing health inequities, building child resilience, and advancing child health targets in the future.</p><p><strong>Funding: </strong>This study was funded by the Rapid Social Response (RSR) Multidonor Trust Fund at the World Bank.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103414"},"PeriodicalIF":10.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882461","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}
EClinicalMedicinePub Date : 2025-08-12eCollection Date: 2025-09-01DOI: 10.1016/j.eclinm.2025.103408
Sivesh K Kamarajah, Nadia Gudiozzi, John M Findlay, Matthew J Lee, Thomas Pinkney, Sheraz R Markar
{"title":"Evaluation of safety of preoperative GLP-1 receptor agonists in patients undergoing elective surgery: a systematic review, meta-analysis and meta-regression.","authors":"Sivesh K Kamarajah, Nadia Gudiozzi, John M Findlay, Matthew J Lee, Thomas Pinkney, Sheraz R Markar","doi":"10.1016/j.eclinm.2025.103408","DOIUrl":"10.1016/j.eclinm.2025.103408","url":null,"abstract":"<p><strong>Background: </strong>Obesity remains a major global public health challenge, particularly among surgical patients, where it can be associated with increased perioperative and longer-term risk. While preoperative weight management strategies are often used to mitigate these risks, scalable interventions remain limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are an emerging pharmacological approach for weight loss, but their perioperative safety remains uncertain. This study aimed to assess the safety and efficacy of preoperative GLP-1 therapy in elective surgical systems.</p><p><strong>Methods: </strong>In this systematic review and meta-analysis, we systematically searched PubMed, MEDLINE, Embase, and the Cochrane Library from database inception to March 31, 2025, for studies evaluating preoperative GLP-1 RA use in adults undergoing elective surgery, with no language restriction. The primary outcome was perioperative safety, defined as any complication within 90 days after surgery. The secondary outcome was preoperative weight loss. Both frequentist and Bayesian random-effects meta-analyses were conducted. A Bayesian hierarchical meta-regression was used to explore effect modifiers on the primary outcome. A risk-of-bias and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessment were done to determine the certainty of the evidence. Final GRADE judgements were made by two independent reviewers, with consensus reached through discussion. Between-study heterogeneity was quantified using the <i>I</i> <sup><i>2</i></sup> statistic and visualised using a standard forest plot. Potential publication bias and small study effects were assessed using visual inspection of funnel plots and Egger's test. This study is registered with PROSPERO, CRD420251027809.</p><p><strong>Findings: </strong>A total of 21 studies, comprising 97,059 patients, met inclusion criteria; 31.9% (n = 30,981) received preoperative GLP-1 RA therapy. Most studies were single-centre observational cohorts from high-income countries, with no randomised trials identified. Postoperative complications were reported in 12 studies, with no evidence of increased risk in GLP-1 users (pooled odds ratio: 0.78, 95% confidence interval: 0.59-1.05). The pooled estimate shows high heterogeneity (<i>I</i> <sup><i>2</i></sup> = 73%). Bayesian meta-analysis yielded consistent findings (posterior mean OR: 0.78; 95% credible interval: 0.57-1.12). Meta-regression identified no statistically significant modifiers of treatment effect to explain the heterogeneity. The overall GRADE assessment for certainty of evidence was very low. In studies reporting weight loss, preoperative GLP-1 RA use was associated with weight loss of up to 16.7 kg or 6.0 kg/m<sup>2</sup> over six months, though reporting varied across studies.</p><p><strong>Interpretation: </strong>Preoperative GLP-1 RA therapy may support clinically meaningful weight loss without a clear signal of","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103408"},"PeriodicalIF":10.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12496209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238269","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}