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{"title":"Gene therapy and cost-effectiveness analysis: Current issues and future research.","authors":"Scott Johnson, Marric Buessing, Thomas O'Connell, Abena Otu-Adum, Thomas A Ciulla","doi":"10.1016/j.medj.2026.101151","DOIUrl":"10.1016/j.medj.2026.101151","url":null,"abstract":"<p><p>Gene therapies represent a paradigm shift in healthcare, offering the potential for one-time treatment of genetic diseases that require chronic, burdensome management. However, these transformative therapies pose distinctive challenges for traditional cost-effectiveness analysis (CEA). This review examines how CEA of gene therapies is complicated by five distinguishing attributes: rarity, one-time administration, high durable efficacy, substantial upfront costs, and potential financing challenges. We analyze approved gene therapies, ranging in price from $60,000 to over $4 million per treatment, and review US CEAs that assess long-term value, which often find list prices above thresholds but are comparable to other recent therapies. Key methodological challenges include limited data on rare diseases, inappropriate health utility sources, uncertainty about treatment durability, and potential undervaluation of transformative health improvements. Emerging solutions include innovative financing mechanisms, methodological advances, and evolving value frameworks. Developing appropriate economic assessment methods for gene therapies is crucial for ensuring patient access while maintaining innovation incentives.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101151"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148164806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A unified multi-task framework enables interpretable chest radiograph analysis.","authors":"Lijian Xu, Ziyu Ni, Xinglong Liu, Xiaosong Wang, Hongsheng Li, Shaoting Zhang","doi":"10.1016/j.medj.2026.101223","DOIUrl":"10.1016/j.medj.2026.101223","url":null,"abstract":"<p><strong>Background: </strong>While multimodal deep learning has advanced medical imaging analysis, existing black-box systems may remain confined to isolated tasks, often overlooking the trust-sensitive nature of clinical diagnosis as a multi-task process.</p><p><strong>Methods: </strong>We propose IMT-CXR (interpretable multi-task transformer for chest X-ray analysis), a framework that emulates radiologists' diagnostic workflow through three evidence-driven stages: (1) disease recognition, (2) attribute characterization (e.g., size, location, and severity quantification), and (3) evidence-integrated report generation with traceable decision pathways. The framework employs a unified transformer architecture optimized via medical-domain instruction tuning, which sequentially executes four clinical tasks: multi-label disease classification, lesion localization, anatomical segmentation, and radiology report generation.</p><p><strong>Findings: </strong>Experimental validation demonstrates competitive performance on ten CXR benchmarks under direct inference and fine-tuning settings. In a blinded evaluation of 160 historical reports from four medical centers, three radiologists rated 66% of artificial intelligence (AI)-generated reports as comparable to or surpassing original clinical reports in diagnostic clarity, highlighting the framework's translational potential.</p><p><strong>Conclusions: </strong>By establishing traceable diagnostic pathways from anatomical findings to conclusions, this work bridges the gap between AI technical metrics and clinical utility, advancing trustworthy AI systems in medical imaging.</p><p><strong>Funding: </strong>This research was partially supported by the Centre for Perceptual and Interactive Intelligence (CPII) Ltd. under the Innovation and Technology Commission (ITC)'s InnoHK.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101223"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148424869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma proteomics linking primary and secondary diseases: Insights into molecular mediation from UK Biobank data.","authors":"Hanyu Qian, Chao Wu, Bo Li, Anthony Rosenzweig, Meng Wang","doi":"10.1016/j.medj.2026.101232","DOIUrl":"10.1016/j.medj.2026.101232","url":null,"abstract":"<p><strong>Background: </strong>Diabetes, hypertension, and dyslipidemia are major risk factors for cardiovascular, neurological, renal, and pulmonary diseases, yet clinically accessible molecular mediators linking these cardiometabolic conditions to downstream complications remain unclear.</p><p><strong>Methods: </strong>We analyzed plasma proteomic data from 53,030 UK Biobank participants with longitudinal follow-up. Mediation analysis evaluated circulating proteins linking three primary cardiometabolic diseases to 18 secondary outcomes. Mendelian randomization assessed potential causal relationships, and machine learning evaluated the predictive value of identified mediators.</p><p><strong>Findings: </strong>We identified 998 significant mediation pathways involving 337 unique plasma proteins. GDF15 consistently mediated associations between diabetes and cardiovascular diseases, and ACE2 linked poorly controlled diabetes to increased risk of nerve root and plexus disorders. Mediators were enriched in receptor-mediated signaling and molecular-interaction pathways. Mendelian randomization supported potential causal roles for 44 proteins. Incorporating mediator proteins into machine-learning models improved prediction of secondary disease risk beyond traditional clinical factors and other plasma proteins.</p><p><strong>Conclusions: </strong>Plasma proteins help mediate progression from cardiometabolic diseases to downstream complications. These findings provide a molecular map of disease mediation pathways, nominate biomarkers and therapeutic targets, and support improved risk stratification and targeted intervention.</p><p><strong>Funding: </strong>This this study was supported by the National Institutes of Health, the American Heart Association, and institutional funding.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101232"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Burden of 10 mental disorders in low- and middle-income countries, 1990-2023, with forecasts to 2050: a Global Burden of Disease Study.","authors":"","doi":"10.1016/j.medj.2026.101224","DOIUrl":"10.1016/j.medj.2026.101224","url":null,"abstract":"<p><strong>Background: </strong>Mental disorders impose a disproportionate burden on populations in low- to middle-income countries (LMICs) and low-income countries (LICs), yet longitudinal assessments across these settings remain limited.</p><p><strong>Methods: </strong>Using the Global Burden of Disease Study 2023, we investigated prevalence and disability-adjusted life years (DALYs) for 10 mental disorder subcategories across 76 LMICs and LICs from 1990 to 2023 and projected trends through 2050 via a generalized ensemble modeling approach.</p><p><strong>Findings: </strong>Age-standardized prevalence rose markedly between 1990 and 2023, from 10,759.9 (95% uncertainty interval, 9,560.1-12,088.6) to 13,929.3 (12,512.5-15,829.0) per 100,000 in LMICs and from 11,723.6 (10,577.7-12,987.5) to 14,979.1 (13,512.9-16,770.7) in LICs, accompanied by corresponding increases in age-standardized DALY rates. The most pronounced increases in both age-standardized prevalence and DALYs were observed during the COVID-19 pandemic. Anxiety disorders (total percentage change: 102.3% in LMICs; 67.3% in LICs), eating disorders (40.7% in LMICs; 4.8% in LICs), depressive disorders (28.6% in LMICs; 29.8% in LICs), and autism spectrum disorders (14.9% in LMICs; 22.5% in LICs) showed the largest increases in prevalence. Under a reference scenario where past trends persist, age-standardized prevalence is projected to reach 17,155.8 (14,449.5-20,212.5) per 100,000 in LMICs and 17,968.4 (15,109.8-21,090.9) in LICs by 2050.</p><p><strong>Conclusions: </strong>These findings reveal persistent and widening disparities in mental health burden across resource-limited settings, substantially exacerbated by the pandemic. Without targeted, scalable, and sustained policy interventions, the burden in LMICs and LICs will continue to worsen, underscoring the critical need for context-specific public health action.</p><p><strong>Funding: </strong>This study was funded by the Gates Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101224"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daraxonrasib in refractory PDAC: A one-eyed king in the land of the blind?","authors":"Giulia Orsi, Michele Reni","doi":"10.1016/j.medj.2026.101227","DOIUrl":"10.1016/j.medj.2026.101227","url":null,"abstract":"<p><p>The phase 3 RASolute 302 trial demonstrated significant overall and progression-free survival benefits with daraxonrasib over investigator's choice chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma harboring RAS G12 mutations after progression on prior chemotherapy.¹ The benefit in patients with non-G12 RAS mutations or RAS wild-type tumors remains unclear.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 8","pages":"101227"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy for hypertrophic cardiomyopathy: From feasibility to a fieldwide framework.","authors":"Milind Y Desai, Susan K Keen, Eugene Braunwald","doi":"10.1016/j.medj.2026.101229","DOIUrl":"10.1016/j.medj.2026.101229","url":null,"abstract":"<p><p>The emergence of gene-based therapies for hypertrophic cardiomyopathy (HCM) represents a pivotal inflection point in cardiovascular medicine, but their successful translation will depend on coordinated advances beyond vector design alone. Here, we propose a fieldwide framework for HCM gene therapy development, encompassing core evaluation, safety and immunosuppression management, endpoint definition, long-term surveillance, and considerations of equity and scalability. We argue that harmonization across these domains is essential to ensure that early clinical signals are interpretable, comparable, and translatable into durable patient benefit. This framework provides a roadmap to guide the transition from early feasibility to broad, equitable implementation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101229"},"PeriodicalIF":13.3,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced cholangiocarcinoma in 2025: Therapeutic sequencing and global implementation.","authors":"Fausto Petrelli, Chiara Pesenti, Fulvia Milena Cribiù, Marcella Arru, Alessandro Russo, Matteo Viti, Andrea Celotti, Gianluca Tomasello, Antonio Ghidini, Alberto Zaniboni, Gianluca Baiocchi, Ornella Garrone, Michele Ghidini","doi":"10.1016/j.medj.2026.101189","DOIUrl":"10.1016/j.medj.2026.101189","url":null,"abstract":"<p><strong>Background: </strong>Cholangiocarcinoma is an aggressive biliary tract cancer with a median overall survival of approximately 1 year with first-line gemcitabine plus cisplatin. Actionable genomic alterations are frequent in intrahepatic disease and provide a rationale for genotype-directed therapy.</p><p><strong>Methods: </strong>We searched PubMed (MEDLINE), Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from January 1, 2010, through June 30, 2025, for randomized trials, large prospective cohorts, and pivotal phase 2 studies evaluating chemotherapy, targeted therapy, or immunotherapy in cholangiocarcinoma. Two reviewers independently screened records and extracted data. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Evidence was synthesized qualitatively.</p><p><strong>Findings: </strong>Seven phase 3 trials define contemporary first-line management. Gemcitabine plus cisplatin with durvalumab improved overall survival compared with chemotherapy alone (12.9 vs. 11.3 months; hazard ratio, 0.76) without increasing grade 3 or higher toxicity. In biomarker-selected populations, fibroblast growth factor receptor inhibitors achieved objective response rates of 35%-42% and median progression-free survival of 6.9-9.0 months after platinum therapy; ivosidenib improved progression-free survival in isocitrate dehydrogenase 1-mutant disease (2.7 vs. 1.4 months; hazard ratio, 0.37). Dual B-Raf proto-oncogene, serine/threonine kinase (BRAF) and MEK inhibition, trastuzumab deruxtecan in human epidermal growth factor receptor 2 (HER2)-positive disease, and pembrolizumab in microsatellite instability-high tumors also demonstrated clinically meaningful activity. In a 32-trial network meta-analysis, genotype-matched therapy reduced the risk of progression vs. fluorouracil, leucovorin, and oxaliplatin (hazard ratio, 0.44).</p><p><strong>Conclusions: </strong>Chemoimmunotherapy is the reference first-line regimen for biomarker-unselected advanced cholangiocarcinoma. Early comprehensive genomic profiling is essential to enable timely, matched targeted therapy and maximize population-level benefit.</p><p><strong>Funding: </strong>This study has no funding to declare.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101189"},"PeriodicalIF":13.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148353804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic lupus erythematosus: Phase 2 trials to watch in 2026.","authors":"Eric F Morand, Sarah A Jones","doi":"10.1016/j.medj.2026.101187","DOIUrl":"https://doi.org/10.1016/j.medj.2026.101187","url":null,"abstract":"<p><p>In 2026, a large number of clinical trials are underway for patients with systemic lupus erythematosus (SLE). In addition to multiple registration trials, several others, which we highlight here, target novel mechanisms that may yield insights into disease pathogenesis.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 7","pages":"101187"},"PeriodicalIF":13.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148424804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-drug conjugates and the need for third-modality regulatory science.","authors":"Ning Jiang, Jun-Jie Mao, Xing-Yu Zhou, Pei-Wen Ma, Jia-Wei Zhou, Gang Qin, Shu-Hang Wang, Ning Li","doi":"10.1016/j.medj.2026.101184","DOIUrl":"https://doi.org/10.1016/j.medj.2026.101184","url":null,"abstract":"<p><p>ADCs challenge conventional biologic and small-molecule framework regulation because their performance emerges from integrated antibody, linker, payload, and manufacturing attributes. This commentary proposes a risk-based third-modality science combining product-level assessment, component-specific scrutiny, platform evidence, and life cycle comparability to support ADC innovation, manufacturing flexibility, patient access, and regulatory rigor.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 7","pages":"101184"},"PeriodicalIF":13.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148424832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose macrophage heterogeneity: A potential immunometabolic target for preventing weight regain.","authors":"Meng Yao Li, Zi Xuan Hua, Chun Li Ban, Qing Yun Li","doi":"10.1016/j.medj.2026.101188","DOIUrl":"10.1016/j.medj.2026.101188","url":null,"abstract":"<p><p>Obesity represents a critical public health challenge. As of 2021, over two billion adults were overweight or living with obesity,¹ conditions that increase the risk of multiple chronic diseases and premature mortality. Although effective weight-loss strategies exist, post-intervention weight regain remains the central obstacle to long-term management.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 7","pages":"101188"},"PeriodicalIF":13.3,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148424894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}