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{"title":"Longitudinal progression of blood biomarkers reveals a key role of reactive astrocytosis in preclinical Alzheimer's disease.","authors":"Vijay R Varma, Yang An, Przemek R Kac, Murat Bilgel, Abhay Moghekar, Tina Loeffler, David Amschl, Magdalena Daurer, Manuela Prokesch, Juan Troncoso, Kaj Blennow, Henrik Zetterberg, Nicholas J Ashton, Luigi Ferrucci, Susan M Resnick, Madhav Thambisetty","doi":"10.1016/j.medj.2025.100724","DOIUrl":"10.1016/j.medj.2025.100724","url":null,"abstract":"<p><strong>Background: </strong>Defining the progression of blood biomarkers in Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD, explored associations with AD brain pathology, and examined the relationship between reactive astrocytosis in the brain and plasma in a transgenic mouse model.</p><p><strong>Methods: </strong>We analyzed plasma blood biomarkers using the Quanterix HD-X instrument in case-control and postmortem cohorts from the Baltimore Longitudinal Study on Aging (BLSA). We assessed plasma and cortical reactive astrocytosis, measured by glial fibrillary acidic protein (GFAP), in 5xFAD transgenic and wild-type mice.</p><p><strong>Findings: </strong>In AD-converters (N = 158, 377 samples), higher plasma GFAP levels are observed 10 years prior to the onset of cognitive impairment due to AD compared with individuals who remain cognitively unimpaired (N = 160, 379 samples). Plasma GFAP levels are highest in neuropathologically confirmed AD, intermediate in asymptomatic AD, and lowest in cognitively unimpaired and associated with severity of neuritic plaques and neurofibrillary tangles. GFAP-labeled immunoreactive astrocytes in the cortex of 3- and 7-month-old 5xFAD transgenic mice increased relative to wild-type mice and higher blood GFAP concentration was associated with more GFAP-expressing astrocytes.</p><p><strong>Conclusions: </strong>Reactive astrocytosis, assessed by elevated GFAP levels, is an early event in the progression of blood biomarker changes in preclinical AD, may be an early marker of AD pathogenesis, and a promising therapeutic target.</p><p><strong>Funding: </strong>Intramural Research Program, NIA.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100724"},"PeriodicalIF":12.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267481","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":"Allogeneic CD19-targeted CAR-T therapy in refractory systemic lupus erythematosus achieved durable remission.","authors":"Dandan Wang, Xiaobing Wang, Binghe Tan, Xin Wen, Songying Ye, Yingyi Wu, Xuan Cao, Xin Zhang, Chun Wang, Linyu Geng, Huayong Zhang, Xuebing Feng, Biao Zheng, Yanran He, Mingyao Liu, Xin Wu, Bing Du, Lingyun Sun, Huji Xu","doi":"10.1016/j.medj.2025.100749","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100749","url":null,"abstract":"<p><strong>Background: </strong>Autoreactive B cells play a key role in the pathogenesis of systemic lupus erythematosus (SLE). The aim of this study is to assess the safety of allogeneic chimeric antigen receptor (CAR)-T cells for patients with lupus. This study was registered at ClinicalTrials.gov (NCT05859997).</p><p><strong>Methods: </strong>In this study, 3 patients with refractory and severe SLE with multi-organ involvement were enrolled. Genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells were infused intravenously at a dose of 1 million cells per kilogram of body weight. The safety indices, including the occurrence of graft-versus-host disease (GvHD), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS), were evaluated. The proliferation of CAR+ T cells and the number of peripheral B cells were assessed. The clinical efficacy was also assessed based on the SELENA-SLEDAI, SLEDAI-2K, BILAG, clinical SLE responder index-4 (SRI-4), and DORIS remission index.</p><p><strong>Findings: </strong>Between August 2023 and October 2023, 3 patients with SLE were enrolled and completed a 12-month follow-up. No patient underwent GvHD, CRS, or ICANS, and no severe adverse events were recorded. CAR+ T cells expanded in vivo, peaking at day 14, and then declined. The percentage of B cells in lymphocytes and the absolute circulating B cell counts were profoundly decreased. Patient 1 withdrew from the study at month 1 due to unresolved and severe thrombocytopenia and the need for the addition of an immunosuppressive drug. SELENA-SLEDAI and SLEDAI-2K scores declined, and all the patients reached SRI-4 remission at the last visit.</p><p><strong>Conclusions: </strong>In patients with severe and refractory SLE, allogeneic CAR-T cell therapy showed profound safety and clinical efficacy for disease remission.</p><p><strong>Funding: </strong>82320108010, 31821003, 81930043, 82330055, and U24A20380.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100749"},"PeriodicalIF":12.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188175","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":"Donor composition and fiber promote strain engraftment in a randomized controlled trial of fecal microbiota transplant for ulcerative colitis.","authors":"Lasha Gogokhia, Nancy Tran, Alex Grier, Manabu Nagayama, Grace Xiang, Gabriela Funez-dePagnier, Alexa Lavergne, Caroline Ericsson, Sarah Ben Maamar, Mengrui Zhang, Robert Battat, Ellen Scherl, Dana J Lukin, Randy S Longman","doi":"10.1016/j.medj.2025.100707","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100707","url":null,"abstract":"<p><strong>Background: </strong>Fecal microbiota transplantation (FMT) is an emerging treatment for ulcerative colitis (UC), but the impact of prebiotic fiber on FMT efficacy for UC is unclear. We performed a randomized, double-blind, placebo-controlled clinical trial to examine the efficacy of FMT with and without dietary fiber supplementation in patients with UC.</p><p><strong>Methods: </strong>27 patients with mild to moderate UC were randomized to receive a single FMT or placebo with or without psyllium fiber supplementation for 8 weeks. The primary outcome was clinical response at week 8, and secondary outcomes included endoscopic improvement and clinical remission. Metagenomic sequencing of fecal DNA was analyzed to determine taxonomic profiles and donor strain engraftment.</p><p><strong>Findings: </strong>The trial was terminated early due to manufacturer discontinuation of FMT product. FMT induced clinical response, remission, and endoscopic improvement in UC patients compared to placebo (p < 0.05), but fiber did not improve clinical outcomes of FMT. Recipient microbiome composition post-FMT shifted toward donor composition in responders and non-responders, but the durability of this change was stronger in responders. Clinical response and durable change in microbiome composition following FMT was donor dependent. Strain tracking analysis also demonstrated a donor-dependent variability in the rate of successful engraftment and identified a consortium of engrafted bacteria associated with treatment response or fiber supplementation.</p><p><strong>Conclusions: </strong>Single-dose FMT demonstrated clinical efficacy for mild to moderate UC compared to placebo but revealed no benefit of fiber supplementation. These results highlight proof of concept that donor selection and prebiotic fiber can shape strain-level engraftment. This study was registered at ClinicalTrials.gov: NCT03998488.</p><p><strong>Funding: </strong>National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128257, to R.S.L.).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100707"},"PeriodicalIF":12.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217118","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":"Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality.","authors":"Thanh Hoang Nhat Le, Kirsten C J van Abeelen, Edwin Ardiansyah, Julian Avila-Pacheco, Sofiati Dian, Gesa Carstens, Lara Schramke, Hoang Thanh Hai, Tran Binh Minh Nguyen, Thai Minh Triet, Amy Deik, Jesse Krejci, Jeff Pruyne, Lucas Dailey, Bachti Alisjahbana, Mihai G Netea, Riwanti Estiasari, Trinh Thi Bich Tram, Joseph Donovan, Dorothee Heemskerk, Thi Hong Chau Tran, Nguyen Duc Bang, Ahmad Rizal Ganiem, Raph L Hamers, Rovina Ruslami, Darma Imran, Kartika Maharani, Vinod Kumar, Reinout van Crevel, Guy Thwaites, Clary B Clish, Nguyen Thuy Thuong Thuong, Arjan van Laarhoven","doi":"10.1016/j.medj.2025.100703","DOIUrl":"10.1016/j.medj.2025.100703","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of cerebrospinal fluid (CSF) tryptophan metabolism contributes to the high mortality of tuberculous meningitis (TBM). We aimed to identify novel metabolic pathways associated with TBM mortality through untargeted metabolome-wide analysis.</p><p><strong>Methods: </strong>We measured 619 metabolites using untargeted liquid chromatography-mass spectrometry in pre-treatment CSF from adults with TBM from Indonesia (n = 388, 34 HIV positive) and Vietnam (n = 679, 250 HIV positive). Sixty-day mortality was modeled using Cox regression, adjusting for age and HIV status. Metabolites were ranked in a screening subset (n = 194, Indonesia) and validated in the same cohort (n = 194) and externally (n = 679, Vietnam). Secondary analysis included variable selection, clustering to classify associated metabolites into subgroups, comparison with non-infectious controls, and correlation with patient characteristics, CSF cytokines, CSF protein, and serum metabolite concentrations.</p><p><strong>Findings: </strong>Sixty-day mortality was 21.6% and was associated with the concentration of 10 CSF metabolites, including tryptophan. The strongest association was with 3-hydroxyoctanoate (FA 8:0;3OH), part of a cluster of hydroxylated fatty acids also including hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and C4-OH-carnitine. These fatty acids correlated weakly with CSF tumor necrosis factor alpha, interleukin-6 (IL-6), leukocyte counts, bacterial load, and CSF protein. Mediation analysis showed that the variation in fatty acids was linked directly to mortality rather than through disease severity.</p><p><strong>Conclusion: </strong>We identified and validated nine new metabolites associated with TBM mortality, independent of HIV status, disease severity, and tryptophan. These metabolites suggest that altered fatty acid β-oxidation is linked to TBM-associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival of TBM.</p><p><strong>Funding: </strong>National Institute of Health; Wellcome Trust, UK.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100703"},"PeriodicalIF":12.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142518","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":"Oral lamivudine in diabetic macular edema: A randomized, double-blind, placebo-controlled clinical trial.","authors":"Felipe Pereira, Joseph Magagnoli, Meenakshi Ambati, Talita Fernandes de Oliveira, Juliana Angélica Estevão de Oliveira, Vinicius Oliveira Pesquero, Lucas Zago Ribeiro, Dante Akira Kondo Kuroiwa, Fernando Korn Malerbi, Sergio Atala Dib, Nilva Bueno Moraes, Michel Eid Farah, Eduardo Buchele Rodrigues, Jayakrishna Ambati","doi":"10.1016/j.medj.2025.100747","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100747","url":null,"abstract":"<p><strong>Background: </strong>Diabetic macular edema (DME) affects millions worldwide. Intraocular injections of expensive anti-vascular endothelial growth factor (VEGF) inhibitors associated with complications are standard therapy. Lamivudine, an inexpensive oral drug, inhibits inflammasome activation, which is implicated in DME. This randomized, double-blind, placebo-controlled trial compared oral lamivudine to placebo for improving visual acuity in center-involved DME (CI-DME).</p><p><strong>Methods: </strong>Twenty-four adults enrolled between February 2022 and September 2023 with 1 or 2 eyes with CI-DME and a best-corrected visual acuity (BCVA) of less than 69 letters (Brazilian Registry of Clinical Trials RBR-87b6r5s) were randomized to lamivudine (150 mg twice daily; 10 participants; 16 eyes) or placebo (14 participants; 21 eyes) for 8 weeks. Participants were assigned intravitreous bevacizumab (1.25 mg) at week 4. Co-primary outcomes were mean changes in BCVA from baseline to weeks 4 and 8. Comparisons to anti-VEGF drugs used synthetic controls from DRCR.net Protocol T. Secondary outcomes included retinal thickness and adverse events.</p><p><strong>Findings: </strong>At 4 weeks, BCVA improved 9.8 letters with lamivudine and decreased 1.8 letters with placebo (p < 0.001). At 8 weeks, BCVA improved 16.9 letters with lamivudine and bevacizumab and 5.3 letters with placebo and bevacizumab (p < 0.001). Lamivudine was associated with greater BCVA improvement than bevacizumab or ranibizumab (p < 0.05) and was not different from aflibercept (p = 0.5). There was no significant difference in retinal thickness or adverse events between groups.</p><p><strong>Conclusions: </strong>Lamivudine, an oral inflammasome inhibitor, significantly improved vision in patients with CI-DME.</p><p><strong>Funding: </strong>This work was supported by Universidade Federal de São Paulo, Latinofarma, UVA SIF, and NIH.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100747"},"PeriodicalIF":12.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175068","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":"Epidural electrical stimulation facilitates motor recovery in spinal cord injury involving the conus medullaris: A case study.","authors":"Luigi Albano, Daniele Emedoli, Filippo Agnesi, Simone Romeni, Elena Losanno, Laura Toni, Veronica Fossati, Chiara Ciucci, Filippo Gasperotti, Leonardo Cociani, Giovanni Zucco, Edoardo Pompeo, Cinzia Mura, Jacopo Carpaneto, Andrea Tettamanti, Veronica Castelnovo, Jeffrey David Padul, Carlo Mandelli, Lina Raffaella Barzaghi, Federica Alemanno, Heike Caravati, Carla Butera, Ubaldo Del Carro, Antonella Castellano, Andrea Falini, Federica Agosta, Massimo Filippi, Sandro Iannaccone, Pietro Mortini, Silvestro Micera","doi":"10.1016/j.medj.2025.100706","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100706","url":null,"abstract":"<p><strong>Background: </strong>Emerging research increasingly supports that epidural spinal cord electrical stimulation (EES) combined with neurorehabilitation can improve motor recovery in spinal cord injury (SCI) subjects. Patients with lesions involving the medullary cone may be challenging to treat with this approach, probably due to potential peripheral nervous system damage, leaving the open question of whether this large population may benefit from EES.</p><p><strong>Methods: </strong>A T11-T12 SCI patient, with medullary cone involvement, underwent EES implant in a clinical trial (NCT05926843). During three months of testing, we determined optimal stimulation protocols for improving isolated movements and integrated them to reinstate independent walking with a walker.</p><p><strong>Findings: </strong>EES substantially boosted hip flexor, spinal erector, and abdominal muscle contraction, improving the patient's performance in isolated movements. Over three months of combining continuous subthreshold EES with personalized rehabilitation, the patient progressed from being unable to walk to overground ambulation using a two-wheeled walker and bilateral knee and foot orthoses. At the time of hospital discharge, the patient managed to cover 58 m in the 6-min walking test and completed the 10-meter walking test in 40.29 s. Six months after EES implant, the patient was able to walk independently for 1 km with a walker.</p><p><strong>Conclusions: </strong>These results underscore the potential of neurorehabilitation protocols integrating EES also for patients with medullary cone lesions and pave the way for new rehabilitation prospects.</p><p><strong>Funding: </strong>This work was funded by Università Vita-Salute San Raffaele, Boston Scientific Spa, Fondazione Cariplo, Bertarelli Foundation, and the Ministry of University and Research (MUR).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100706"},"PeriodicalIF":12.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175106","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":"Anti-BCMA CAR-T cell therapy in relapsed/refractory chronic inflammatory demyelinating polyneuropathy.","authors":"Ming-Hao Dong, Zhi-Cheng Mei, Luo-Qi Zhou, Michael Heming, Lu-Lu Xu, Yu-Xin Liu, Xiao-Wei Pang, Yun-Hui Chu, Song-Bai Cai, Huan Ye, Ke Shang, Jun Xiao, Gerd Meyer Zu Hörste, Wei Wang, Chuan Qin, Dai-Shi Tian","doi":"10.1016/j.medj.2025.100704","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100704","url":null,"abstract":"<p><strong>Background: </strong>Chronic inflammatory demyelinating polyneuropathy (CIDP) presents a significant therapeutic challenge, with up to 15% of patients being refractory to first-line treatments.</p><p><strong>Methods: </strong>Anti-B cell maturation antigen chimeric antigen receptor T (CAR-T) cell therapy was applied to two patients with highly relapsed and refractory CIDP, followed by safety and efficacy evaluation. Multi-omics analyses were performed on samples of peripheral blood mononuclear cells (PBMCs) collected before and after infusion.</p><p><strong>Findings: </strong>Both patients had no severe adverse events and achieved drug-free remission within 6 months post-CAR-T therapy. Patient 1 experienced disease recurrence 12 months post infusion following a severe infection of COVID-19, while patient 2 maintained remission over 24 months. Relapse was accompanied by reactivation of pathogenic B cells and recurrence of autoantibodies/peptides targeting axons or myelin. Metabolic reprogramming of B cells characterized by overglycolysis was linked to disease relapse, which could be modulated by regulatory factor X5.</p><p><strong>Conclusion: </strong>This study demonstrates the safety and potential of anti-BCMA CAR-T cell therapy in treating refractory CIDP and provides insights into the molecular mechanisms underlying patient responses (ClinicalTrials.gov: NCT04561557).</p><p><strong>Funding: </strong>Ministry of Science and Technology China Brain Initiative grant STI2030-Major Projects 2022ZD0204700 (to W.W.), National Natural Science Foundation of China grants 82371404 and 82071380 (to D.-S.T.) and 82471353 and 82271341 (to C.Q.), Knowledge Innovation Program of Wuhan Shuguang Project 2022020801020454 (to C.Q.), and Key Research and Development Program of Hubei Provincial Department of Science and Technology 2023BCB148 (to D.-S.T.). The clinical trial was funded by Nanjing IASO Biotechnology Co., Ltd.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100704"},"PeriodicalIF":12.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144162444","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":"DiabetesLiver score: A non-invasive algorithm for advanced liver fibrosis and liver-related outcomes in type 2 diabetes mellitus population.","authors":"Chuan Liu, Jie Shen, Jie Li, Zhihui Li, Ming-Hua Zheng, Hua Bian, Xiqiao Zhou, Wenjing Ni, Zhongji Meng, Jiaojian Lv, Yijun Tang, Xuan Liang, Min Li, Taolong Zhou, Heng Wan, Yuping Chen, Yuxia Qi, Yuli Ge, Yan Wang, Wen-Yue Liu, Mingxing Huang, Shanghao Liu, Xiaomei Wang, Mingfeng Xia, Xuefeng Li, Yuehua Wang, Xinjie Li, Xiaoxiong Hu, Yan Wu, Huimin Ying, Jing He, Fengmei Wang, Wei Yan, Huili Wu, Qingge Zhang, Weimin Jiang, Yan Huang, Yudong Zhang, Hongliang He, Xiaofeng Wu, Yuwei Zhang, Ling Li, Terry Cheuk-Fung Yip, Gao-Jun Teng, Xiaolong Qi","doi":"10.1016/j.medj.2025.100700","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100700","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to develop and validate a non-invasive model for screening advanced liver fibrosis and predicting liver-related outcomes in patients with type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>This study included patients with T2DM from five tertiary hospitals for the development and internal validation of a non-invasive model. Advanced liver fibrosis was defined as a liver stiffness measurement ≥12 kPa. An external validation cohort was obtained from the National Health and Nutrition Examination Survey (NHANES), and the model's predictive performance for hepatocellular carcinoma (HCC) and liver-related mortality was assessed in the UK Biobank.</p><p><strong>Findings: </strong>In total, 28,197 patients with T2DM were enrolled. In the derivation cohort (n = 1,129), waist circumference, alanine aminotransferase, aspartate aminotransferase, platelet count, and albumin were identified as independent risk factors for advanced fibrosis and were fit to develop the \"DiabetesLiver score.\" The area under the curve (AUC) was 0.835 (95% confidence interval [CI]: 0.781-0.890), significantly higher than the AUCs of non-invasive tests (all p < 0.01). It maintained high AUCs of 0.870 and 0.823 in the internal validation (n = 1,000), and NHANES cross-sectional (n = 1,432) cohorts, respectively. A dual cutoff of 2.39 and 3.99 with sensitivity ≥90% and specificity ≥90%, respectively, was used to classify patients into low-, middle-, and high-risk groups. In the UK Biobank cohort (n = 24,636), the high-risk group had an elevated risk of liver-related outcomes.</p><p><strong>Conclusions: </strong>The DiabetesLiver score demonstrated good performance in identifying advanced liver fibrosis and the development of liver-related events in the T2DM population.</p><p><strong>Funding: </strong>National Natural Science Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100700"},"PeriodicalIF":12.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128876","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":"HRS-5965, a small-molecule factor B inhibitor, in healthy participants and participants with renal insufficiency: A first-in-human, phase 1 trial.","authors":"Yi Xu, Fen Tian, Hong Ren, Xian Yu, Xiaoyu Chen, Kun Ye, Feifei Sun, Lin Fang, Yuan Li, Rongxin Ban, Xin Jiang, Chenjing Wang, Yaping Ma, Fu Kuang, Xin Li, Zhigao Zhang, Chaobaihui Ye, Min Hu, Feng He, Chang Shu, Yanfang Zou, Rong Huang, Kai Shen, Guangqun Xing, Yu Cao","doi":"10.1016/j.medj.2025.100698","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100698","url":null,"abstract":"<p><strong>Background: </strong>HRS-5965 is an oral selective small-molecule inhibitor of complement factor B, a key component of the alternative pathway. This study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of HRS-5965 in healthy participants and participants with renal insufficiency.</p><p><strong>Methods: </strong>The first-in-human, phase 1 study consisted of 3 parts (ClinicalTrials.gov: NCT05505955). Part 1 was a single-ascending-dose, randomized, double-blind study with 5 dose groups preset, including a food effect evaluation. Part 2 was a multiple-ascending-dose, randomized, double-blind study with 9 dose groups preset. Part 3 was an open-label, single-dose study on severe renal insufficiency. The primary endpoints were safety and tolerability.</p><p><strong>Findings: </strong>A total of 82 participants were enrolled and received either HRS-5965 or placebo (26 in part 1, 40 in part 2, and 16 in part 3). HRS-5965 was well tolerated. Treatment-emergent adverse events were comparable between the HRS-5965 groups and placebo groups in part 1 (17/20 [85.0%] vs. 6/6 [100.0%]) and part 2 (27/30 [90.0%] vs. 10/10 [100.0%]). No deaths were reported. HRS-5965 was absorbed rapidly, with a median time to reach peak concentration (T_max) ranging from 0.75 to 1.50 h in fasted states and 2.00 h in fed states. Pharmacokinetics was nonlinear, and food delayed the absorption of HRS-5965 but did not impact the exposure. Alternative pathway activity was inhibited by over 80% with HRS-5965, compared to less than 20% with placebo.</p><p><strong>Conclusion: </strong>HRS-5965 demonstrated favorable safety and robust inhibition of alternative pathway activity, supporting further clinical development.</p><p><strong>Funding: </strong>The study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100698"},"PeriodicalIF":12.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086163","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":"Advances in TIL therapy: Expanding the horizons beyond melanoma.","authors":"Pauline Wiertsema, Ya Hwee Tan, John B A G Haanen, Tom T P Seijkens, Inge Jedema","doi":"10.1016/j.medj.2025.100702","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100702","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocyte (TIL) therapy represents a breakthrough in solid tumor treatment, addressing unmet needs for patients with limited options. While its efficacy is established in advanced melanoma, TIL therapy shows early promise in non-small cell lung cancer, breast cancer, gynecological cancers, and head and neck cancers. However, challenges such as reduced T cell infiltration, lower tumor mutational burden (TMB), immunosuppressive tumor microenvironments (TME), and toxicity associated with the TIL therapy regimen hinder its broader application in these patient groups, compared with melanoma. To address these challenges, new approaches focus on the selection of tumor-reactive TIL, optimization of TIL expansion, combination of immune checkpoint inhibitors with TIL therapy to counteract immunosuppressive microenvironments, and genetic modification of TIL to enhance persistence and functionality. Larger clinical trials are essential to validate these innovations and standardize protocols. With continued advancements, TIL therapy has the potential to redefine the treatment landscape for advanced solid cancers.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100702"},"PeriodicalIF":12.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095076","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}