EClinicalMedicine最新文献

{"title":"Vitamin B12 replacement strategies: a Brazilian delphi consensus.","authors":"Ricardo V Cohen, Randy Levinson, Otavio Baiocchi, João Eduardo N Salles, Marcondes Cavalcante França, Tomas Navarro, Fabio Trujilho, José Maria Soares, Daniel Nakagawa, Marcelo Valente, Ricardo Barbuti, Raphael Ribeiro Spera, Fabio Moura, Cynthia Valerio, Carlos A Schiavon, Fania Cristina Dos Santos, Anna Carolina Batista Dantas, Andre Abdo, Marcelo Luis Steiner, Henri Augusto Korkes, Julianne Tannous Cordenonssi, Philip Bachour","doi":"10.1016/j.eclinm.2026.104205","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104205","url":null,"abstract":"<p><strong>Background: </strong>Vitamin B12 deficiency is common in older adults, atrophic gastritis, and after bariatric surgery, and can cause irreversible neurological injury. Oral, sublingual, and intramuscular routes all correct serum concentrations, yet whether any route is superior for clinically meaningful outcomes is unclear, and international guidelines diverge. This consensus was convened to define where evidence is adequate, where it is lacking, and the priority research questions.</p><p><strong>Methods: </strong>This was a modified Delphi consensus study. The RAND/UCLA Appropriateness Method was applied through a two-stage process of 2 electronic rounds and an in-person meeting in São Paulo, Brazil. Panellists were recruited between 1 July 2025 and 15 July 2025. Thirty statements were voted on, presented as 31 graded items, using a binary (agree or disagree) format with a priori percentage-agreement grades (A+, 100%; A, 90%-99.9%; B, 80%-89.9%; C, 70%-79.9%; and D, 66%-69.9%). Draft statements, informed by a systematic review, were rated anonymously by a Brazilian multidisciplinary panel of 20 experts across haematology, gastroenterology, endocrinology, bariatric surgery, and geriatric medicine/neurology. Of 20 experts invited, all 20 agreed to participate and completed the electronic rounds (100%); 16 (80%) attended the in-person meeting. Patient representatives (n = 2) participated as non-voting observers. Grade A (at least 90% agreement) was the stopping rule. This consensus was not registered.</p><p><strong>Findings: </strong>In total, 30 statements across 6 modules were agreed, comprising 31 separately graded items as statement 1 was presented in two parts (1a and 1b); 22 of 31 items (71%) reached grade A+ (100% agreement) and 9 of 31 (29%) reached grade A (90%-99.9%). All routes were judged capable of normalising serum vitamin B12, but none showed proven superiority for symptom resolution, neurological recovery, functional status, or quality of life. Evidence gaps were greatest after bariatric surgery, in older adults with cognitive impairment or frailty, and in pernicious anaemia. Dosing, monitoring, and response definitions varied substantially.</p><p><strong>Interpretation: </strong>Vitamin B12 replacement across all routes remains guided primarily by biochemical rather than clinical evidence. Treatment should be individualised by aetiology, patient preference, feasibility, and access, with functional biomarkers and clinical assessment complementing serum levels. Adequately powered, long-term comparative trials using standardised, patient-centred outcomes are the priority.</p><p><strong>Funding: </strong>This work was funded by Myralis Indústria Farmacêutica Ltda, São Paulo, Brazil.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104205"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105802","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":"Effect of a wearable-based individualised multidomain lifestyle intervention on cognitive and physical function in older adults at risk of decline (INSPIOR): a single-centre, open-label, randomised controlled trial.","authors":"Keisuke Sakurai, Ryo Tanaka, Joseph Ledsam, Izumi Shiraishi, Hiroyasu Kasahara, Saya Anzai, Miwa Watanabe, Momoko Funakawa, Saori Shimada, Tatsuya Goto, Riki Kawabata, Keiko Murasakino, Tomoko Kawaura, Noriko Inamura, Ko Kaneta, Satoru Kobayashi, Toshiyuki Nomura, Nori Karasawa, Takashi Matsumoto, Tomoki Taira, Toshihiro Ishiguro, Kazuyuki Kudo, Matthew J Thompson, Hiroki Kayama, Yukihiro Sugawara, Shin'ichi Warisawa, Tatsuhiro Hisatsune","doi":"10.1016/j.eclinm.2026.104212","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104212","url":null,"abstract":"<p><strong>Background: </strong>Multidomain lifestyle programmes are the leading preventive approach to cognitive decline, but they rely on intensive face-to-face delivery that is hard to scale. We assessed whether an automated, wearable-based multidomain programme of activity, sleep, and optional nutrition prompts changed cognitive and physical function in at-risk older adults.</p><p><strong>Methods: </strong>INSPIOR was a 6-month, single-centre, open-label, randomised controlled trial in Kashiwa, Japan. Adults aged 65-92 years with low body-mass index, pre-frailty, frailty, or sarcopenia-related decline were randomly assigned 1:1, in permuted blocks of four and without stratification, to the Fitbit-based intervention or an assessment-only control; allocation was not concealed and outcome assessors were not masked. Co-primary outcomes were the Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT), and skeletal muscle mass index (SMI), with no pre-specified hierarchy or multiplicity adjustment; analyses used intention-to-treat analysis of covariance with multiple imputation. This trial was registered with UMIN-CTR, UMIN000052707, and ClinicalTrials.gov, NCT06135740.</p><p><strong>Findings: </strong>Between Nov 8, 2023, and Jul 31, 2024, 355 participants were randomly assigned to the intervention group (n = 178) or control group (n = 177); all were analysed. Adjusted between-group differences were 0·58 MoCA points (95% CI 0·03-1·13; p = 0·039; Holm-adjusted p = 0·12), 0·16 s (-5·07 to 5·40; p = 0·95) for TMT-A, 5·59 s (-3·88 to 15·05; p = 0·25) for TMT-B, and -0·01 kg/m² (-0·09 to 0·07; p = 0·88) for SMI. Mild skin irritation and dietary-recording stress occurred; no serious adverse event was intervention-related.</p><p><strong>Interpretation: </strong>The intervention was associated with a small difference in a global cognitive screening score that did not survive multiplicity adjustment and is of uncertain clinical significance; the other two showed none. Larger, longer, masked trials are needed.</p><p><strong>Funding: </strong>University of Tokyo-NH Foods Collaborative Research Programme, Google, Mitsui Fudosan.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104212"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105736","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":"The effect of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors on stroke risk in type 2 diabetes: a nationwide longitudinal cohort study in Sweden with contextualisation analysis.","authors":"Anastasios Mavridis, Tamar Abzhandadze, Dongni Buvarp, Koen Simons, Björn Eliasson, Mia von Euler, Adam Viktorisson, Katharina S Sunnerhagen","doi":"10.1016/j.eclinm.2026.104220","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104220","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The impact of SGLT2 inhibitors (SGLT2i), GLP-1 receptor agonists (GLP-1RA), and DPP-4 inhibitors (DPP-4i) on stroke risk in individuals with type 2 diabetes remains uncertain. Meta-analyses of randomised controlled trials (RCTs) show a protective effect for GLP-1RA but neutral findings for SGLT2i and DPP-4i, whereas observational studies often suggest broader stroke risk reductions. This study aimed to estimate the associations of SGLT2i, GLP-1RA, and DPP-4i with stroke risk in nationwide longitudinal data, and to contextualize these results within existing meta-analyses of RCTs and observational studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This was a nationwide longitudinal study including individuals with type 2 diabetes first registered in the Swedish National Diabetes Register between January 1, 2013, and December 31, 2019. Individuals with a prior stroke or insufficient data for multiple imputation were excluded. The primary outcome was ischemic stroke. Treatments, comorbidities, and laboratory values were updated over time. Marginal structural models with inverse probability of treatment weighting and weighted Cox regression were used to estimate hazard ratios (HRs) for ischemic, hemorrhagic and total stroke pooled across five multiply imputed datasets. To contextualise the findings, PubMed was searched from inception to June 23, 2026, for meta-analyses of randomised controlled trials and observational studies reporting stroke outcomes for the three drug classes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We included 171,917 individuals with type 2 diabetes [59.2% males, baseline mean (SD) age 62.7 (11.6), mean (SD) follow-up 3.0 (1.9) years] contributing 1,617,462 clinical registrations. During follow-up, 2734 (1.59%) ischemic and 428 (0.25%) hemorrhagic strokes occurred. GLP-1RA use was associated with a lower risk of ischemic (HR 0.46, 95% CI 0.29-0.72) and total stroke (HR 0.51, 95% CI 0.33-0.79), whereas no clear associations were observed for hemorrhagic stroke. SGLT2i and DPP-4i showed no clear associations with any stroke outcome. The contextualisation identified 91 meta-analyses. RCT meta-analyses generally showed a protective effect for GLP-1RA and neutral effects for SGLT2i and DPP-4i, while observational meta-analyses suggested protective associations for GLP-1RA and SGLT2i.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;In this nationwide study, GLP-1RA were associated with reduced stroke risk, while SGLT2i and DPP-4i showed neutral effects. The overall direction of findings was consistent with evidence from RCT meta-analyses. Future research should investigate how these therapies can be optimally incorporated into treatment strategies for stroke prevention in individuals with type 2 diabetes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;Sahlgrenska University Hospital's funds, the Swedish National Stroke Association, the Swedish Brain Foundation, the Swedish Heart Lung Foundation, the Bygg-Göta Foundation for scientific research,","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104220"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105759","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":"Corrigendum to \"Circadian and behavioural timing in MASLD: a systematic review of human observational studies\".","authors":"Arunkumar Subramanian, Raja Affendi Raja Ali, Gavin Stewart Dawe, Vetriselvan Subramaniyan","doi":"10.1016/j.eclinm.2026.104229","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104229","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1016/j.eclinm.2026.104187.].</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104229"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105796","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":"Comparative efficacy of vitamin B12 supplementation routes in adults with replacement indication: a systematic review.","authors":"Daniela Debone, André Ferreira Azeredo da Silva, Julianne Tannous Cordenonssi, Ricardo V Cohen","doi":"10.1016/j.eclinm.2026.104214","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104214","url":null,"abstract":"<p><strong>Background: </strong>Vitamin B12 deficiency is common and often requires long-term supplementation to prevent serious complications, yet the comparative efficacy of the oral, sublingual, and intramuscular routes remains uncertain. This systematic review evaluated the efficacy of different vitamin B12 supplementation routes in adults with an indication for replacement.</p><p><strong>Methods: </strong>PubMed, Embase, and Cochrane CENTRAL were searched without language or date restrictions, from inception to July 18, 2025, updated July 13, 2026, following PRISMA 2020 reporting. Eligible studies were randomized trials and observational cohorts comparing oral, sublingual, or intramuscular vitamin B12 supplementation in adults with an indication for replacement; pediatric and non-comparative studies were excluded. Risk of bias was assessed with RoB 2.0 (trials) and ROBINS-I (cohorts). The primary outcome was serum vitamin B12 or clinical response. This systematic review was registered with PROSPERO, number CRD420251126832.</p><p><strong>Findings: </strong>13 studies met the inclusion criteria: 7 randomized controlled trials, 3 observational cohorts, 2 conference abstracts, and 1 research letter Included studies were conducted across 10 countries spanning Asia, Europe, North and South America, and Oceania, in both single-center and multicenter settings. Comparisons of oral vs. intramuscular supplementation were most frequent (8 studies), several suggesting comparable or superior biochemical responses with oral administration. Sublingual supplementation was underrepresented (5 studies) but showed short-term biochemical efficacy similar or superior to the other routes. All three routes increased serum vitamin B12 levels. All seven randomized controlled trials were judged to have some concerns regarding risk of bias, mainly due to limitations in randomization procedures and selective outcome reporting; all three observational studies were judged to be at serious risk of bias, primarily due to inadequate confounding adjustment. The remaining three studies (2 conference abstracts, 1 research letter) were not assessed.</p><p><strong>Interpretation: </strong>Route selection should consider patient preference, tolerability, and access. Evidence for sublingual supplementation remains particularly limited, although the available studies suggest that it may represent a potential non-invasive alternative for selected patients. Future research should include adequately powered comparative studies assessing patient-centered outcomes, such as symptom improvement, treatment adherence, and preference.</p><p><strong>Funding: </strong>Myralis Industria Farmacêutica Ltda.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104214"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105758","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":"Tumour-agnostic immunotherapy: aligning biological rationale, biomarker precision, and real-world implementation.","authors":"Jia Liu, Juliana Beal, Niamh Coleman, James Lynam, Vivek Subbiah","doi":"10.1016/j.eclinm.2026.104211","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104211","url":null,"abstract":"<p><p>Tumour-agnostic immunotherapy has reshaped precision oncology by showing that treatment benefit can, in selected settings, be predicted by a shared biological state rather than anatomical origin. Microsatellite instability-high or mismatch repair-deficient cancer is the clearest example, with durable responses across diverse malignancies. By contrast, broader biomarkers show that pan-cancer applicability cannot be inferred from a measurable molecular feature alone. Tumour lineage, antigen presentation, immune microenvironment, prior therapy, and health-system context all influence whether a tumour-agnostic indication translates into real-world benefit. We examine the biological principles that distinguish robust from context-dependent immunotherapy biomarkers, the uncertainty created by rare cancers and incomplete evidence, and the implementation challenges that arise when therapeutic access outpaces biomarker infrastructure. Using Australia's broad reimbursement of immune checkpoint inhibitors for immunotherapy-sensitive advanced cancers as a case study, we consider implications for emerging pan-tumour platforms. We argue for biologically informed access embedded within learning health systems.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104211"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105739","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":"Booster dose of COVID-19 vaccine and its effectiveness against post COVID-19 condition in individuals with pre-existing immunity: a sequential propensity score-matched cohort study.","authors":"Lisa Morris, Erik Bülow, Huiqi Li, Yiyi Xu, Magnus Gisslén, Fredrik Nyberg, Maria Bygdell","doi":"10.1016/j.eclinm.2026.104215","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104215","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;COVID-19 vaccination before primary infection is associated with decreased risk for post COVID-19 condition, but its effectiveness in populations with pre-existing immunity against SARS-CoV-2 is unknown. Our aim was to assess the COVID-19 vaccine effectiveness against post COVID-19 condition of four doses compared with three doses, both in the general population and in subpopulations with and without risk factors for severe acute COVID-19.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this, sequential, propensity score-matched cohort study conducted between 27 December 2020 and 29 February 2024, we included adults (≥18 years) who had received their third dose of COVID-19 vaccine, had no previous diagnosis of post COVID-19 condition, and who were successfully matched. At each index date (the date of the fourth dose for the exposed), an individual who had not yet received a fourth dose was included as unexposed, using exact matching followed by propensity score matching. Propensity scores were estimated based on socioeconomic factors, comorbidities, health-seeking behaviours, previous COVID-19, and prescribed medications. Individuals were followed from index date until diagnosis of post COVID-19 condition, moving out of study counties, death, new vaccination, six months after index date, or end of follow-up. The primary outcome was a clinical diagnosis of post COVID-19 condition from primary or specialist care.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;In total, 801,869 exposed individuals who received a fourth dose were successfully matched with 801,869 individuals with three doses. The incidence rate of post COVID-19 condition in the group with three doses was 1.67 per 1000 person-years (95% CI 1.52-1.83), compared with 1.14 per 1000 person-years (95% CI 1.02-1.28) in the four-dose group. In Cox regression analyses, a fourth vaccine dose was associated with a decreased risk of being diagnosed with post COVID-19 condition, with a vaccine effectiveness of 31% (95% CI 22-38). Among those with risk factors for severe acute COVID-19, the incidence rates of post COVID-19 condition were 2.14 per 1000 person-years (95% CI 1.91-2.39) for three doses and 1.32 per 1000 person-years (95% CI 1.07-1.54) for four doses, with a vaccine effectiveness of 38% (95% CI 29-47) for the fourth dose against post COVID-19 condition.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;Receiving a fourth dose of COVID-19 vaccine was associated with a lower risk of being diagnosed with post COVID-19 condition compared with three doses, although the absolute risk reduction was small. Due to the observational design of the study, residual confounding cannot be excluded.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;Swedish state under the agreement between the Swedish government and the county councils (the ALF-agreement), the Swedish Research Council, King Gustaf V's and Queen Victoria's Foundation, the SciLifeLab from the Knut and Alice Wallenberg Foundation, the Swedish Research Council f","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104215"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105771","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":"Regional inequality in infant RSV morbidity and mortality burden in the era of expanded RSV passive immunisation: a global projection modelling study.","authors":"Shaolong Ren, Bingbing Cong, Jing Zou, Ling Guo, Harish Nair, Erin Sparrow, Daniel R Feikin, You Li","doi":"10.1016/j.eclinm.2026.104219","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104219","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection (ALRI) in infants, with low- and middle-income countries (LMICs) bearing a disproportionately high burden. While novel RSV prophylactic products including long-acting monoclonal antibodies and a maternal vaccine are being rolled out for protecting the general infant population in high-income countries, implementation in LMICs is only expected by 2028, potentially exacerbating health inequities. We aimed to assess regional inequality in infant RSV disease burden with and without the implementation of these interventions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We re-analysed the previous global RSV disease burden dataset in infants by WHO regions and World Bank Income Classification for the year of 2019 as a baseline, using generalised linear mixed-effects models. We developed a static deterministic model that explicitly accounted for the varied risks for RSV admission by birth month and chronological age in month and projected the annual RSV-associated ALRI hospital admissions and RSV-attributable deaths under two scenarios: a no-implementation scenario that assumed the same hospital admission and mortality rates to the 2019 baseline, and a June-2025 product use scenario that was based on country-level implementation status of novel RSV prophylactic products as of June 2025; the two scenarios were then compared to estimate the impact of the current implementation of novel prophylactic products. We further calculated the ratio of RSV-attributable deaths between the highest and lowest burden quintiles (Q5-Q1 ratio) to assess inequality under the two scenarios.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;At baseline, the African Region had the highest incidence of RSV-associated ALRI (117.4 per 1000 person-years, 95% uncertainty range, UR: 60.0-229.8) and highest RSV-attributable mortality rate (0.97 per 1000 person-years, 95% UR: 0.76-1.31) while having the lowest RSV-associated ALRI hospital admission rate (12.6 per 1000 person-years; 95% UR: 7.5-21.3); the Eastern Mediterranean Region had the highest hospital admission rate (29.9 per 1000 person-years, 95% UR: 14.2-63.2). The regional variations in incidence, hospital admission, and mortality rates persisted when further stratifying the above estimates by country income level. As of June 2025, nirsevimab and maternal RSVpreF had been licensed in 54 and 64 countries, respectively, with 16 and 12 countries introducing them into their national immunisation programmes. A total of 4,641,000 doses of nirsevimab and 1,955,000 doses of RSVPreF were estimated to be administered annually under the June-2025 product use scenario globally. Administration of both products was projected to jointly avert 91,000 (95% UR: 75,000-118,000) RSV-associated ALRI hospital admissions and 300 (95% UR: 210-470) RSV-attributable deaths in infants annually, corresponding to 3.7% (95% UR: 2.7-4.9) and 0.4% (95% UR: 0.3-0.7) o","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104219"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105720","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":"E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort.","authors":"Jung-Yun Lee, Kosei Hasegawa, Byoung-Gie Kim, Barry Berman, Shiro Suzuki, Bradley Corr, Mayu Yunokawa, Douglas Orr, Noboru Yamamoto, Pamela T Soliman, David S Miller, Alka A Potdar, Takatoshi Sahara, Takayuki Kimura, Lea Dutta, Jincao Wu, Jodi McKenzie, Chrisann Kyi","doi":"10.1016/j.eclinm.2026.104206","DOIUrl":"https://doi.org/10.1016/j.eclinm.2026.104206","url":null,"abstract":"<p><strong>Background: </strong>Novel therapies are needed for advanced endometrial cancer (aEC) that recurs after chemotherapy + immunotherapy. Lenvatinib has antitumour activity in patients with aEC after platinum-based chemotherapy and is approved in combination with pembrolizumab for aEC following prior systemic therapy. E7386, an oral anticancer agent, inhibits the interaction between β-catenin and CREB-binding protein (CBP). Preliminary results of a dose expansion cohort of Study 102 (n = 16) showed manageable safety and promising antitumour activity of E7386 + lenvatinib in aEC that progressed after platinum-based chemotherapy and anti-programmed cell death (ligand) 1, including responses in patients with prior lenvatinib. We report safety and antitumour activity for this complete dose expansion cohort.</p><p><strong>Methods: </strong>In a dose expansion cohort of Study 102 (NCT04008797), patients with aEC that progressed after platinum-based chemotherapy and immunotherapy received E7386 120 mg twice daily plus lenvatinib 14 mg once daily (amended from 20 mg during enrolment). The primary endpoint was safety; secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate, and progression-free survival by investigator per RECIST v1·1).</p><p><strong>Findings: </strong>Thirty patients were enrolled; 16 (53·3%) previously received lenvatinib. By data cut-off (4 June, 2025), five (16·7%) patients had treatment ongoing. All patients experienced treatment-emergent adverse events (TEAEs), most commonly vomiting (n = 22, 73·3%). Nineteen (63·3%) patients had grade 3 TEAEs, most frequently diarrhoea (n = 4). No grade 4-5 AEs were observed. TEAEs led to withdrawal of lenvatinib and/or E7386 in two patients. Overall, 11 patients (three with prior lenvatinib) had a confirmed response (one complete, ten partial) for an ORR of 36·7% (95% CI: 19·9-56·1). In patients without prior lenvatinib (n = 14), the ORR was 57·1% (95% CI: 28·9-82·3).</p><p><strong>Interpretation: </strong>E7386 + lenvatinib showed promising antitumour activity with a manageable safety profile in heavily pretreated patients with aEC following platinum-based chemotherapy + immunotherapy. The dose-optimisation phase of Study 102 (E7386 + lenvatinib in patients with advanced endometrial carcinoma) is currently enrolling (NCT04008797).</p><p><strong>Funding: </strong>Eisai Inc., Nutley, NJ, USA.</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"100 ","pages":"104206"},"PeriodicalIF":12.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105751","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":"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":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;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}