EClinicalMedicine最新文献

{"title":"Derivation of a blood count-based machine learning model to prioritise sequencing for high-risk clonal haematopoiesis: a retrospective cohort study.","authors":"Riya Nandi, Kun Zhao, Yash Pershad, Nabi Nazmoon Khondoker, Caitlyn Vlasschaert, Md Mesbah Uddin, Pradeep Natarajan, Daniel J DeAngelo, Marlise R Luskin, R Coleman Lindsley, Hajime Uno, Shai Shimony, Alexander G Bick, Lachelle D Weeks","doi":"10.1016/j.eclinm.2026.104238","DOIUrl":"10.1016/j.eclinm.2026.104238","url":null,"abstract":"<p><strong>Background: </strong>Clonal haematopoiesis is a precursor of myeloid neoplasia and common in older adults, Precursor risk stratification is critical to early cancer detection, guiding surveillance and prevention efforts to high-risk populations. Existing clonal haematopoiesis risk scores use molecular features to estimate risk of myeloid neoplasia, but only around 1% of adults with detectable clonal haematopoiesis are at high risk of myeloid neoplasia transformation. Moreover, sequencing based molecular diagnostics are expensive with limited global availability highlighting the need for pre-sequencing strategies which identify populations enriched for individuals with high-risk clonal haematopoiesis.</p><p><strong>Methods: </strong>We used blood count parameters, age, and sex as input features to and develop a multi-class machine learning model that pre-classifies individuals based on their probability of having high-risk clonal haematopoiesis or developing future myeloid neoplasia. Stratified splitting was used to divide 461,576 eligible UK Biobank participants (recruited October 1, 2006 to March 13, 2010) into a training cohort for model derivation (n = 369,260) and a test cohort for internal validation (n = 92,316). Ground truth output class assignments were defined based on documented progression to incident myeloid neoplasia and presence of clonal haematopoiesis with high-risk features defined using molecular parameters of the clonal haematopoiesis risk score. Individuals were labelled positive if they had high-risk clonal haematopoiesis and progressed to myeloid neoplasia, negative if they lacked clonal haematopoiesis with high-risk features, and equivocal if they had higher risk features but had no documented incident myeloid neoplasia event. We then compared model predictions against ground truth labels for validation in the UKB test cohort as well as in independent clinical and population cohorts from Dana-Farber Cancer Institute Hematologic Malignancy Data Repository (HMDR; n = 2233; March 26, 2010, to June 5, 2024) and the All of US database (n = 14,674; May 31, 2017 to October 1, 2023), respectively.</p><p><strong>Findings: </strong>The resulting pre-sequencing risk model (PRISM) categorises all cases of high-risk clonal haematopoiesis as positive and pre-classifies 40% (2158 of 5383) of low-risk clonal haematopoiesis and 55% (47,894 of 86,429) of clonal haematopoiesis-negative cases as negative. Validation of PRISM revealed an area under the curve of 0.89 (95% CI 0.85-0.93) in the UK Biobank test cohort, 0.74 (0.61-0.84) in HMDR, and 0.87 (0.77-0.96) in All of US. Negative predictive values for negative class assignments were 0.993 (95% CI 0.992-0.993) in the UKB test cohort, 0.968 (0.943-0.981) in HMDR, and 0.998 (0.997-0.999) in All of US.</p><p><strong>Interpretation: </strong>PRISM positive class assignment defines a population most enriched for high-risk clonal haematopoiesis, while negative class predictions, mark in","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104238"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178730","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":"Diagnostic testing for pulmonary tuberculosis in low and middle-income countries: innovations to achieve universal access-a narrative review.","authors":"Nazir A Ismail, Rebecca H Berhanu, Nina von Knorring, Marguerite Massinga Loembe, Mikashmi Kohli, Rumina Hasan, Siva K Shanmugam, Surbhi Sheokand, Achilles Katamba, Madhukar Pai, Shaheed V Omar","doi":"10.1016/j.eclinm.2026.104232","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104232","url":null,"abstract":"<p><p>Though rapid molecular diagnostics for tuberculosis (TB) have substantially improved diagnostic accuracy and turnaround times, implementation and impact has been constrained by cost, infrastructure requirements, and continued reliance on sputum. This review examines advances in diagnostic technologies and sampling strategies that could overcome these barriers and accelerate universal access to TB diagnostics. We conducted a narrative review of studies published between Jan 1, 2020, and April 30, 2026, focusing on near-point-of-care molecular (NPOC) platforms, next-generation lipoarabinomannan (LAM) assays, and non-sputum sampling approaches. Emerging NPOC molecular platforms, demonstrate high sensitivity using both sputum and tongue-swab specimens while substantially reducing equipment and testing costs compared with existing nucleic acid amplification test platforms. Next-generation urine LAM assays offer improved sensitivity and potential for use beyond people living with HIV. In addition, parallel testing approaches with multiple sample types, including sputum, tongue swab, stool for children, and urine testing, can substantially increase diagnostic yield in specific populations. Integrating low-cost technologies with non-sputum sampling strategies could provide a scalable pathway towards universal access to TB diagnostics. Realizing this potential will require streamlined regulatory pathways, sustainable financing, and integration of these tools into primary healthcare systems.</p><p><strong>Funding: </strong>None.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104232"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179040","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":"Early-onset cancer needs more than earlier screening.","authors":"eClinicalMedicine","doi":"10.1016/j.eclinm.2026.104222","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104222","url":null,"abstract":"","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"99 ","pages":"104222"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069439","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":"Effects of minocycline on health-related quality of life in patients with acute ischaemic stroke in China: a prespecified secondary analysis of the EMPHASIS trial.","authors":"Qianqian Yang, Ying Li, Luyan Wang, Tingfang Ai, Yao Lu, Meiyang Zhang, Dongyang Zhou, Chenhui Liu, Lijie Ren, Xuejiao Zhou, Yuesong Pan, Hui Qu, Xiaoling Liao, Liping Liu, Xingquan Zhao, David Wang, Yongjun Wang, Yilong Wang, Ling Guan","doi":"10.1016/j.eclinm.2026.104239","DOIUrl":"10.1016/j.eclinm.2026.104239","url":null,"abstract":"<p><strong>Background: </strong>Health-related quality of life (HRQoL) is increasingly recognised as a critical outcome after acute ischaemic stroke (AIS). Minocycline may have neuroprotective potential in AIS; however, its effects on patient-reported HRQoL remain uncertain. Therefore, we aimed to evaluate the effect of minocycline on HRQoL at 90 days.</p><p><strong>Methods: </strong>This prespecified secondary analysis was based on data from the EMPHASIS trial, a parallel randomised controlled trial of minocycline in AIS at 58 centres in China from May 19, 2023, to May 20, 2024. Eligible participants were aged 18-80 years, were enrolled within 72 h of acute ischaemic stroke onset and had a National Institutes of Health Stroke Scale score of 4-25, and a pre-stroke modified Rankin Scale score of 1 or less. Participants were randomly assigned (1:1) to receive minocycline or placebo plus standard care. HRQoL was assessed using the EuroQol five-dimension three-level questionnaire (EQ-5D-3L) at 90 days. The primary outcome was EQ-5D-3L utility score; secondary outcomes were EuroQol visual analogue scale (EQ-VAS), a favourable health state defined as EQ-5D-3L utility score ≥0.75, and EQ-5D-3L domain responses. Primary analyses were conducted in the prespecified modified intention-to-treat population using linear, log-binomial, and ordinal logistic models for continuous, binary, and ordinal outcomes. Multivariable-adjusted and per-protocol sensitivity analyses were also performed. This trial was registered with ClinicalTrials.gov (NCT05836740).</p><p><strong>Findings: </strong>Of 1724 participants, 1697 were included in the final analyses. The primary analysis showed no significant between-group difference in EQ-5D-3L utility score (p = 0.224). After multivariable adjustment, the EQ-5D-3L utility score was higher in minocycline group than in placebo group (p = 0.049). The proportion of patients achieving a favourable health state was higher in the minocycline group than in the placebo group (73.4% vs 68.9%; risk ratio 1.07, 95% confidence interval 1.003-1.13; p = 0.039), with improvements in mobility (p = 0.043), self-care (p = 0.030), and usual activities (p = 0.031). EQ-VAS did not differ significantly between two groups (p = 0.420).</p><p><strong>Interpretation: </strong>Minocycline may improve health state and EQ-5D-3L domains at 90 days, supporting further evaluation as adjunctive therapy and incorporation of patient-reported outcomes into stroke trials.</p><p><strong>Funding: </strong>National Natural Science Foundation of China, The National Key Research and Development Program of China, Beijing Health Union Cardio-cerebrovascular Disease Prevention and Treatment Foundation, Noncommunicable Chronic Diseases-National Science and Technology Major Project, New Cornerstone Science Foundation, Beijing Scholar Program, Beijing Municipal Science & Technology Commission, and Capital's Funds for Health Improvement and Research.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104239"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215200","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":"Maternal autoimmune diseases during pregnancy and mortality up to young adulthood in offspring: a register-based cohort study.","authors":"Huan Zhang, Imre Janszky, Elizabeth V Arkema, Jette Möller, Yajun Liang, Xingbo Mo, Krisztina D László","doi":"10.1016/j.eclinm.2026.104237","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104237","url":null,"abstract":"<p><strong>Background: </strong>The implications of maternal autoimmune diseases for offspring survival after infancy remain poorly understood. We aimed to examine the association between maternal autoimmune diseases during pregnancy and all-cause and cause-specific mortality in offspring from birth to early adulthood.</p><p><strong>Methods: </strong>In this nationwide population-based cohort study, we included all live births in Sweden between 2001 and 2014 and followed individuals until death, emigration, or December 31, 2023. Cox proportional hazards models were used to analyze the association between maternal autoimmune diseases during pregnancy and risk of mortality in offspring. To control for familial factors, we conducted cousin and paternal negative control analyses. Mediation analyses were performed to quantify the contribution of adverse perinatal outcomes.</p><p><strong>Findings: </strong>Among 1,455,645 offspring followed for a median of 15.3 years (interquartile range 11.9-19.0), maternal autoimmune diseases were associated with an increased risk of all-cause mortality in offspring (HR 1.22, 95% CI 1.10-1.36). Associations were evident during infancy and attenuated with higher age. No clear association was observed for paternal autoimmune diseases, and cousin analyses yielded attenuated but directionally consistent estimates. Preterm birth and small for gestational age explained a proportion of the observed associations.</p><p><strong>Interpretation: </strong>Maternal autoimmune diseases are associated with increased offspring mortality risk, with the excess risk primarily concentrated in early life and driven by deaths related to perinatal conditions and congenital malformations. These findings are consistent with a contribution of intrauterine mechanisms to the observed associations, although other maternal pathways may also contribute.</p><p><strong>Funding: </strong>The study was supported by grants from the Swedish Heart and Lung Foundation (20230493, 20241167), Karolinska Institutet Research Foundation (2024-02588) and the Swedish Research Council for Health, Working Life and Welfare (2015-00837).</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104237"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165137","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":"Upfront or deferred radiotherapy combined with chemoimmunotherapy for inoperable oesophageal squamous cell carcinoma: a target trial emulation in China.","authors":"Huiquan Liu, Jiahao Guan, Wencheng Zhang, Duojie Li, Xiaofen Fu, Lu Li, Chunbao Zang, Yuan He, Jieyong Tian, Zhuting Tong, Wei Huang, Dong Qian","doi":"10.1016/j.eclinm.2026.104236","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104236","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Radiotherapy (RT) is a curative treatment modality for inoperable oesophageal squamous cell carcinoma (ESCC). However, for patients with ESCC receiving first-line chemoimmunotherapy (CIT), the appropriate sequence of RT relative to CIT remains unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This multicentre retrospective cohort study adopted a target trial emulation framework to compare survival outcomes between groups. Time zero was defined as the start date of the initial treatment. Simulated randomisation, treatment initiation, and follow-up commenced concurrently at time zero. Patients with inoperable ESCC (including locally advanced disease and supraclavicular lymph node metastasis) who received first-line CIT between June 2018 and December 2023 were enrolled from eight large-scale hospitals across China. Stabilised inverse probability of treatment weighting was applied to minimise baseline imbalances. Prespecified grace periods were introduced to classify participants into two groups: Upfront-RT and Deferred-RT. Immortal time bias was addressed using the clone-censor-weight method. Effect sizes were estimated using the absolute rate difference (RD) in overall survival (OS) and progression-free survival (PFS), as well as the cumulative risk ratio (RR) for death or disease progression. This study was registered with the Chinese Clinical Trial Registry (Identifier: ChiCTR2500111871).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;A total of 1242 participants (median [IQR] age, 69 [62-75] years; 1004 [80.8%] male) were included in the study. With a grace period of 42 days in the primary analysis, the Deferred-RT group had improved median OS (44.1 months vs 33.4 months; adjusted HR, 0.699 [95% CI, 0.580-0.843]), and longer median PFS (21.1 months vs 16.0 months; adjusted HR, 0.760 [95% CI, 0.645-0.895]) compared with the Upfront-RT group. After correcting baseline imbalances and immortal time bias, patients in the Upfront-RT group exhibited a reduction in the 3-year OS rate (41.9% vs 57.5%; RD, -15.6%; 95% CI, -26.3% to -5.6%) and PFS rate (22.4% vs 33.8%; RD, -11.4%; 95% CI, -19.2% to -4.2%), along with an increase in 3-year cumulative risk ratios for death (RR, 1.368; 95% CI, 1.108-1.637) and disease progression (RR, 1.172; 95% CI, 1.056-1.295), compared with those in the Deferred-RT group. Sensitivity and subgroup analyses corroborated these findings. The median RT dose was 60.0 (IQR, 50.4-60.0) Gy in the Upfront-RT group and 50.4 (IQR, 0-60.0) Gy in the Deferred-RT group. The incidence of severe treatment-related oesophageal fistula was 9.0% (36 cases) and 4.8% (40 cases), respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;In this retrospective study with target trial emulation, first-line CIT plus deferred RT was associated with improved survival outcomes compared with upfront RT plus first-line CIT for patients with inoperable ESCC. However, given the inherent limitations of observational data and the lack of adjustment for ti","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104236"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164353","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":"Interdisciplinary intervention (GAIN) vs. enhanced usual care for reducing severe post-concussion symptoms in adults 2-4 months post-injury: a stepped wedge cluster randomised controlled trial.","authors":"Line Amalie Hellemose, Mille Møller Thastum, Henriette Holm Stabel, Lene Odgaard, Charlotte Ulrikka Rask, Noah D Silverberg, Toril Skandsen, Hana Malá Rytter, Charlotte Nygaard, Peter Preben Eggertsen, Carsten B Pedersen, Jørgen Feldbæk Nielsen","doi":"10.1016/j.eclinm.2026.104243","DOIUrl":"10.1016/j.eclinm.2026.104243","url":null,"abstract":"<p><strong>Background: </strong>Up to 30% of adults presenting to emergency departments develop persisting post-concussion symptoms (PPCS). Get going After concussIoN (GAIN), has previously shown promising effects in reducing PPCS in adolescents and young adults.</p><p><strong>Methods: </strong>This stepped wedge cluster randomised trial tested the effect of GAIN in reducing high levels of PPCS (i.e. a score ≥20 on the Rivermead Post-concussion Symptoms Questionnaire (RPQ)) 2-4 months post-injury in adults (18-60 years). GAIN was delivered in five clusters of municipalities in the Central Denmark Region sequentially allocated to implement the intervention, with one cluster transitioning to deliver GAIN every 3 months over six recruitment periods in the order of a computer-generated randomisation schedule. Participants were allocated to enhanced usual care (EUC) or GAIN + EUC depending on time and their place of residence. Masking of participants and therapists was not feasible. Primary outcome was change in RPQ total score from baseline to 3-month follow-up. Analyses were based on intention to treat using linear-mixed models. The trial is registered with ClinicalTrials.gov, NCT04798885.</p><p><strong>Findings: </strong>Between May 1, 2021 and November 1, 2022, 310 participants were included. The average difference in change in RPQ score between GAIN + EUC (n = 170) and EUC (n = 140) from baseline to 3-month follow-up was -2.4 points (95% CI -5.4 to 0.4, <i>p</i> = 0.09) in the adjusted model. GAIN reduced maladaptive, symptom-related perceptions and behaviours and patient satisfaction was high. GAIN + EUC was not associated with a greater improvement in psychological distress or physical and mental health than EUC. No serious adverse events were reported.</p><p><strong>Interpretation: </strong>This study could not confirm the hypothesis that GAIN added to EUC led to a larger long-term reduction in PPCS than EUC alone in adults. However, GAIN may improve long-term prognosis by reducing maladaptive, symptom-related perceptions and behaviours.</p><p><strong>Funding: </strong>The foundation Sygeforsikringen \"danmark\" and Central Denmark Region.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104243"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215169","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":"Immunogenicity and safety of an interchangeable vaccination schedule of two inactivated Japanese encephalitis vaccines: a multicentric, phase IV, open-label, randomized controlled trial.","authors":"Jeromie Wesley Vivian Thangaraj, Himabindu Reddy, Gajanan N Sapkal, Saravana Kumar Velusamy, Manish A Jain, Bhagirathi Dwibedi, Suman Kanungo, Rashmi Kundapur, Sanjay Pandey, Gururaj Rao Deshpande, Ala Saritha, Vishnunath Kadavath, Kaliaperumal Kanagasabai, Chetna Maliye, Swayam Pragyan Parida, Agniva Majumdar, Mounika Reddy, Chandramani Singh, Archana R Lade, Sandip Samanta, Arvind Kumar Singh, Sunil Kumar Chawan, Binod Kumar Pati, Rashi Srivastava, Sanjay Kumar Panda, Jayanta Saha, Bhushan Kamble, Asha Salunke, Pardeep Kumar, Sabarinathan Ramasamy, Mugunthan Narayanan Muthulakhsmi, Vijay P Bondre, Leyanna Susan George, Nivedita Gupta, Jeyashree Kathiresan, Manoj V Murhekar","doi":"10.1016/j.eclinm.2026.104235","DOIUrl":"10.1016/j.eclinm.2026.104235","url":null,"abstract":"<p><strong>Background: </strong>In India, two inactivated Japanese encephalitis (JE) vaccines, JENVAC and JEEV, are used in childhood immunization program as a two-dose schedule. Vaccine supply interruptions and population mobility can result in children receiving different products for their first and second doses. We assessed immunogenicity and safety of mixed-product vaccine schedules.</p><p><strong>Methods: </strong>In this multicentric, open-label, phase 4, non-inferiority randomized trial conducted during November 11, 2023-September 2, 2025, infants aged 9-12 months were assigned (1:1:1:1) to JENVAC-JEEV, JENVAC-JENVAC, JEEV-JENVAC, or JEEV-JEEV. Second dose was given at the age of 16-24 months. The primary outcome was seroconversion assessed by 50% plaque reduction neutralization test titer against wild-type JE virus 28 days after dose-2. The secondary outcomes included frequency of solicited and unsolicited adverse events, and serious adverse events following JE vaccine schedules. Non-inferiority was concluded if the lower bound of the 95% CI for difference in seroconversion proportion between the mixed and same-product vaccine schedule exceeded -10% and was less than 0%. Registered with Clinical Trials Registry-India (CTRI/2023/07/055155).</p><p><strong>Findings: </strong>Between November 11, 2023, and June 8, 2024, 911 infants were randomly assigned (1:1:1:1) to JENVAC-JEEV (n = 228), JENVAC-JENVAC (n = 228), JEEV-JENVAC (n = 227), and JEEV-JEEV (n = 228). In modified intention-to-treat analysis, seroconversion after second dose was 89.8% (194/216), 90.2% (184/204), 90.9% (189/208), and 89.2% (190/213) respectively. The difference in seroconversion between mixed-product and same-product vaccine schedules was -0.38% (95% CI -6.1 to 5.4) among JENVAC-primed and 1.66% (-4.1 to 7.4) among JEEV-primed infants. The corresponding estimates in per-protocol analysis were -1.11% (95% CI -6.7 to 4.5) and 0.89% (-4.9 to 6.6) respectively. Solicited adverse events occurred in 35.5-37.9% infants across the study groups. None of the serious adverse events was vaccine related.</p><p><strong>Interpretation: </strong>Mixed-product JENVAC and JEEV schedules were non-inferior to same-product schedules for short-term neutralizing antibody seroconversion and showed no safety signals. These findings support programme flexibility when children cannot complete JE vaccination with the same-product.</p><p><strong>Funding: </strong>The trial was funded by Indian Council of Medical Research, New Delhi, India.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104235"},"PeriodicalIF":12.8,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215252","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":"Association of antifungal treatment duration with 90-day mortality in critically ill adults with candidemia: a multicenter target trial emulation in France.","authors":"Florian Reizine, Juliette Henry, Luc Desmedt, Christophe Camus, Jean Marc Tadié, Valentin Coirier, François Arrive, Estelle Burban, Gabriel Eustache, Tony Belleville, Antoine Marc, Jolan Malherbe, Pierre Bouju, Paul Jaubert, Olivier Lesieur, Maxime Leclerc, Pierre Fillâtre, Aurélien Frérou, Renaud Prével, Nolwenn Mainguy, Anne Cady, Florent Morio, Solène Le Gal, Estelle Perraud, Laurence Delhaes, Sébastien Imbert, Helene Guegan, Julie Bonhomme, Marc Pihet, Clarisse Dupin, Benjamin Gaborit, Agathe Delbove, Damien Du Cheyron, Yoann Launey, Cécile Aubron, Jean-Pierre Gangneux","doi":"10.1016/j.eclinm.2026.104178","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104178","url":null,"abstract":"<p><strong>Background: </strong>The optimal duration of antifungal therapy for candidemia in intensive care unit (ICU) patients remains uncertain. We aimed to evaluate whether shorter antifungal therapy was not associated with increased mortality using a target trial emulation framework.</p><p><strong>Methods: </strong>We conducted a multicenter cohort study including adult ICU patients with candidemia from 16 ICUs in France (January 1, 2015 to January 1, 2023), emulating a target trial comparing short-course (<10 days) versus long-course (≥10 days) antifungal therapy. Patients treated for more than 21 days were excluded to minimize indication bias related to complicated candidemia. Patients who died within five days were excluded to ensure eligibility for both strategies. To account for time-dependent bias and confounding, we applied a cloning-censoring-weighting approach with inverse probability weighting. The primary outcome was all-cause mortality at day 90 after candidemia onset.</p><p><strong>Findings: </strong>Among 237 eligible patients with uncomplicated candidemia from the 492 enrolled in the CandidICU cohort, 48 (20.3%) received short-course and 189 (79.7%) long-course therapy. Overall 90-day mortality was 47.7% (113/237). Median age was 62 years [IQR 51-70], median SAPS II was 53 [40-68], and <i>Candida albicans</i> accounted for 66.7% of cases. After weighting, baseline characteristics were well balanced. Short-course therapy was not significantly associated with 90-day mortality (weighted HR 1.14, 95% CI 0.82-1.58). No differences were observed in secondary infections or organ support between groups.</p><p><strong>Interpretation: </strong>In this multicenter ICU cohort, among patients who survive the initial 5 days after candidemia onset and do not have obvious indication for prolonged therapy, short-course antifungal therapy was not associated with increased 90-day mortality after adjustment for time-dependent bias and confounders, although the confidence interval is wide and compatible with both clinically important benefit and harm. These findings are hypothesis-generating and should not alter current clinical practice. Randomized controlled trials are needed to definitively determine optimal treatment duration in critically ill patients.</p><p><strong>Funding: </strong>No funding was received for this work.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"99 ","pages":"104178"},"PeriodicalIF":12.8,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988275","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":"Short-term versus long-course neoadjuvant chemotherapy for resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): results from the second randomisation analysis of a randomised, open-label, 2 × 2 factorial phase 3 trial.","authors":"Michele Reni, Giulia Orsi, Catia Carconi, Giuseppe Malleo, Letizia Procaccio, Marina Macchini, Katia Bencardino, Barbara Merelli, Andrea Pretta, Ilario Giovanni Rapposelli, Nicolò Pecorelli, Stefano Partelli, Elisa Sperti, Stefano Crippa, Nicole Liscia, Mariacristina Di Marco, Michele Milella, Sara Lonardi, Diego Palumbo, Valter Torri, Massimo Falconi","doi":"10.1016/j.eclinm.2026.104190","DOIUrl":"10.1016/j.eclinm.2026.104190","url":null,"abstract":"<p><strong>Background: </strong>The first randomisation results from the PACT-21/CASSANDRA trial demonstrated that cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) is a standard neoadjuvant treatment option for resectable/borderline resectable (R/BR) pancreatic adenocarcinoma (PDAC). Here, we report the results of the second randomisation comparing long versus short pre-operative chemotherapy.</p><p><strong>Methods: </strong>PACT-21/CASSANDRA was a 2 × 2 factorial phase 3 trial involving 17 academic hospitals across 10 regions in Italy. Eligible patients were aged 18-75 years with pathologically confirmed R/BR PDAC and were first randomly assigned to either PAXG or fluorouracil, leucovorin, irinotecan, oxaliplatin (mFOLFIRINOX). Patients without progression or limiting toxicity after 4 months were randomised to receive 2 further months of the same chemotherapy either before (long) or after (short) surgery. The trial was designed under a two-sided superiority hypothesis (H0: HR long versus short = 1.0; H1: HR ≠ 1.0). Randomisation lists were stratified according to previous chemotherapy. The primary endpoint was event-free survival (EFS) in the intention-to-treat (ITT) population. Secondary endpoints were radiological, CA19.9 and complete pathological response, R0 and N0 resections, chemotherapy dose-density, and overall survival (OS). Analyses were performed using SAS version 9.4. This trial is registered with ClinicalTrials.gov (NCT04793932) and EudraCT (2020-003080-26 and 2024-519031-42-00).</p><p><strong>Findings: </strong>Between Feb 23, 2021, and Sept 03, 2024, 86 patients were assigned to long and 79 to short preoperative chemotherapy. No difference in EFS was observed between the two groups in the intention-to-treat population (unadjusted HR 0.98; 95% CI; 0.68-1.41; <i>P</i> = 0.90). CA19-9 response (58 [97%] of 60 versus 41 [84%] of 49 patients; <i>P =</i> 0.02), pathological complete response (4 [5%] of 86 versus 0 of 79 patients; <i>P</i> = 0.05), N0 resection rate (39 [45%] of 86 versus 21 [27%] of 79 patients; <i>P =</i> 0.01), and chemotherapy dose-density were improved by longer chemotherapy. OS data are not yet mature.</p><p><strong>Interpretation: </strong>Long and short preoperative chemotherapy obtains similar EFS in R/BR PDAC. Future research should focus on more effective treatment regimens and explore the optimal post-operative therapy.</p><p><strong>Funding: </strong>MyEverest and Codice Viola (patients' associations).</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"99 ","pages":"104190"},"PeriodicalIF":12.8,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13571558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963129","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}