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{"title":"GLP-1 receptor agonist exposure in the periconceptional period and adverse obstetric outcomes: A systematic review and meta-analysis.","authors":"Francesco D'Antonio, Maria Elena Flacco, Lamberto Manzoli, Athina Samara, Asma Khalil","doi":"10.1016/j.medj.2026.101267","DOIUrl":"10.1016/j.medj.2026.101267","url":null,"abstract":"<p><strong>Background: </strong>This systematic review and meta-analysis assesses whether exposure to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) during pregnancy or the periconceptional period is associated with adverse maternal and perinatal outcomes.</p><p><strong>Methods: </strong>Medline, Embase, and the Cochrane Library were searched for observational studies comparing pregnancies exposed and unexposed to GLP-1 RAs within 6 months before a positive pregnancy test. Outcomes included miscarriage, intrauterine death, congenital anomalies, preterm birth (PTB), hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), fetal growth restriction (FGR), small for gestational age (SGA), large for gestational age (LGA), and excess gestational weight gain. Random-effects meta-analyses and subgroup analyses by indication were performed.</p><p><strong>Findings: </strong>Ten studies included 2,118,215 women, of whom 8,325 were exposed and 2,109,890 were unexposed. Pooled estimates did not show a clearly detectable increase in miscarriage or intrauterine death, congenital anomalies, preterm birth, HDP, gestational diabetes, abnormal fetal growth, or excess gestational weight gain. A lower pooled estimate for preeclampsia was observed (odds ratio [OR]: 0.87, 95% confidence interval [CI]: 0.78-0.98; p = 0.02), but this was based on two datasets and should be interpreted cautiously. Subgroup analyses showed no clearly detectable differences by indication. The exposure-window sensitivity analysis, covering 90 days before conception through the end of the first trimester, used the same four studies as the primary congenital-malformation analysis and therefore was not independent.</p><p><strong>Conclusion: </strong>Available observational evidence did not identify a clearly detectable increase in adverse maternal or perinatal outcomes following periconceptional exposure to GLP-1 RAs. However, these findings do not establish safety because of heterogeneity, residual confounding, and limited datasets.</p><p><strong>Funding: </strong>None.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101267"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149082101","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":"MAIT cells show promise as an immunotherapy tool with both adaptive and innate characteristics.","authors":"Johan K Sandberg","doi":"10.1016/j.medj.2026.101299","DOIUrl":"https://doi.org/10.1016/j.medj.2026.101299","url":null,"abstract":"<p><p>May unconventional MAIT cells be an effective innovative immunotherapy tool against liver cancer? This question is addressed by Yang and colleagues in this issue of Med.¹ Their findings with adoptive transfer of expanded human MAIT cells to cancer xenograft mouse models suggest that these cells may hold greater promise in the cancer field than previously thought.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 10","pages":"101299"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149469","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":"Genome editing for hereditary angioedema: A landmark trial and important unanswered questions.","authors":"Mauro Cancian, Maurizio Margaglione","doi":"10.1016/j.medj.2026.101324","DOIUrl":"https://doi.org/10.1016/j.medj.2026.101324","url":null,"abstract":"<p><p>Hereditary angioedema is a bradykinin-mediated genetic disorder increasingly controlled with effective long-term prophylaxis. In a phase 3 trial, a single dose of lonvoguran ziclumeran, an in vivo CRISPR-Cas9 therapy targeting KLKB1, significantly reduced attack rates. This approach represents a highly promising therapeutic strategy for HAE. However, it also raises important questions that require further investigation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 10","pages":"101324"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149739","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":"Prenatal exposure to the plasticizer DEHP increases the likelihood of early-life autism and ADHD symptoms through epigenetic programming.","authors":"Samuel Tanner, Alex Eisner, Boris Novakovic, Lada Holland, Toby Mansell, Gillian England-Mason, Sarah Merrill, Deborah Dewey, Martin O'Hely, Christos Symeonides, Richard Saffery, Mimi L K Tang, Peter D Sly, Peter Vuillermin, Chol-Hee Jung, Daniel Park, Anne-Louise Ponsonby","doi":"10.1016/j.medj.2026.101291","DOIUrl":"10.1016/j.medj.2026.101291","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence implicates prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting plasticizer, in the development of autism and attention-deficit/hyperactivity disorder (ADHD). Yet underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Here, we examined whether cord blood DNA methylation, a key epigenetic marker, mediates the association between prenatal DEHP exposure and autism and ADHD symptoms in 847 children from the Barwon Infant Study. Autism and ADHD are complex phenotypes driven by alterations in higher-level gene networks and neuronal circuits, where diverse genetic and environmental risk factors converge. Accordingly, rather than a gene-by-gene approach, we employed a data-driven strategy to elucidate broader functional epigenetic signatures of autism and ADHD elicited by DEHP exposure. This included (1) a methylation profile score for DEHP exposure (MPS_DEHP), and (2) a targeted analysis of DEHP-associated co-methylated gene networks.</p><p><strong>Findings: </strong>Causal mediation analysis showed that both MPS_DEHP and a network of 531 co-methylated genes mediated the effect of DEHP on increased autism and ADHD symptoms at ages 2 and 4 years (proportion mediated: 0.21-0.80). The co-methylation network was enriched for neural cell-type markers, autism and ADHD risk genes (including FOXP1, SHANK2, and PLXNB1), and targets of endocrine receptors previously linked to DEHP (including estrogen and glucocorticoid receptors), providing biological plausibility. We validated key results in independent blood (n = 66) and postmortem brain (n = 40) DNA methylation datasets.</p><p><strong>Conclusion: </strong>These findings provide mechanistic evidence linking DEHP to adverse neurodevelopment and reinforce mounting concerns regarding the risks of prenatal exposure.</p><p><strong>Funding: </strong>Funding was obtained from the NHMRC, the Minderoo Foundation, and additional sources (detailed in acknowledgments).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101291"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945485","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":"Cardiovascular-kidney-metabolic syndrome and the risk of liver-related and cardiovascular events across the steatotic liver disease spectrum.","authors":"Qiong-Yue Fan, Li-You Lian, Tian-Yi Xia, Nicholas W S Chew, Qin-Fen Chen, Yu-Xing Dong, Giovanni Targher, Christopher D Byrne, Xu Jiang, Xiao-Dong Wang, Laurence S Sperling, Gregory Y H Lip, Jun-Kang Chen, Yi-Jia Huang, Sheng-Hong Ju, Xiao-Dong Zhou, Ming-Hua Zheng","doi":"10.1016/j.medj.2026.101294","DOIUrl":"10.1016/j.medj.2026.101294","url":null,"abstract":"<p><strong>Background: </strong>Steatotic liver disease (SLD) is closely associated with cardiometabolic factors, but whether the cardiovascular-kidney-metabolic (CKM) stage stratifies risk for major adverse cardiovascular events (MACEs) and liver-related events (LREs) across SLD subtypes remains unclear.</p><p><strong>Methods: </strong>In the UK Biobank study, participants with SLD were classified into subtypes of metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-related liver disease (ALD). The primary outcomes were incident MACEs and LREs, assessed overall and by subtype. Associations were evaluated using Cox models, Kaplan-Meier curves, and population-attributable risks (PARs).</p><p><strong>Findings: </strong>Over 14.7 years of follow-up, 17,973 MACEs (14.0%) and 2,742 LREs (2.0%) occurred among 142,564 individuals with SLD. Higher CKM stage was associated with graded increases in both outcomes (CKM stages 2-4 vs. 0-1: adjusted HRs 1.51 [95% CI 1.43-1.59] to 3.62 [3.31-3.97] for MACEs and 1.28 [1.11-1.48] to 2.32 [1.95-2.75] for LREs), with similar trends across subtypes. Obesity and hypertension were the leading contributors to both outcomes (PARs of up to 19.0% and 22.8% for LREs), whereas diabetes contributed more prominently to LREs than to MACEs (17.5% vs. 7.9%).</p><p><strong>Conclusions: </strong>A higher CKM stage is associated with an increased long-term risk of MACEs and LREs across the SLD spectrum. Obesity and hypertension are the primary contributors to both outcomes, and diabetes additionally contributes to LREs.</p><p><strong>Funding: </strong>Supported by the National Science and Technology Major Project, the National Key R&D Program of China, and the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101294"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921123","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":"Adoptive MAIT cell therapy for liver cancer enhanced by multimodal modulation of immune receptors and checkpoints.","authors":"Yan-Ruide Li, Xinyuan Shen, Yichen Zhu, Yuning Chen, Jie Huang, Shelby Yeh, Thomas Yuen, Coral L Clune, Paulina Dominguez-Vela, Shreya Gumate, Vatche G Agopian, Lili Yang","doi":"10.1016/j.medj.2026.101272","DOIUrl":"10.1016/j.medj.2026.101272","url":null,"abstract":"<p><strong>Background: </strong>Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that recognize riboflavin-derived metabolites presented by the monomorphic major histocompatibility complex (MHC)-class I-related molecule MR1. MAIT cells are highly enriched in the human liver and are increasingly implicated in liver cancer immunity, yet their antitumor potential and therapeutic applicability remain incompletely defined.</p><p><strong>Methods: </strong>Here, we profiled MAIT cells derived from peripheral blood of healthy donors and patients with hepatocellular carcinoma, revealing disease-associated phenotypic alterations marked by immune checkpoint dysregulation. To address current therapeutic limitations, we developed a robust ex vivo expansion platform capable of generating MAIT cells with high yield, purity, and potent cytotoxic function. Using multiple human liver cancer subcutaneous and orthotopic xenograft mouse models, we demonstrate that adoptively transferred MAIT cells mediate effective tumor targeting and killing in vivo.</p><p><strong>Findings: </strong>Mechanistically, MAIT cell antitumor activity is driven by both T cell receptor (TCR)-dependent recognition and natural killer receptor (NKR)-mediated cytotoxicity and is further enhanced by antigen stimulation; cytokine receptor signaling, particularly via interleukin (IL)-15; and immune checkpoint modulation involving programmed cell death protein 1 (PD-1) and T cell immunoglobulin and ITIM domain (TIGIT). In addition, MAIT cells demonstrated a favorable safety profile, with no evidence of liver toxicity observed in xenograft mouse models.</p><p><strong>Conclusions: </strong>Together, these findings establish MAIT cells as functional antitumor effectors in liver cancer and provide a mechanistic and translational framework for adoptive MAIT cell therapy enhanced by multimodal modulation of immune receptors and checkpoints.</p><p><strong>Funding: </strong>Major funding was provided by the California Institute for Regenerative Medicine (CIRM).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101272"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881933","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":"ASTRUM-006 and the changing landscape of perioperative therapy for gastric cancer.","authors":"Hyung-Don Kim, Ian Chau, Raghav Sundar","doi":"10.1016/j.medj.2026.101302","DOIUrl":"https://doi.org/10.1016/j.medj.2026.101302","url":null,"abstract":"<p><p>ASTRUM-006 provides phase 3 evidence that perioperative immune checkpoint inhibition improves event-free survival with Asian SOX-based chemotherapy in PD-L1-positive gastric cancer. Its postoperative chemotherapy-sparing strategy is attractive, although unmasking, event adjudication, and non-R0 or occult metastatic disease warrant consideration. The study nevertheless broadens the perioperative treatment framework and provides an important platform for refining patient selection and postoperative treatment intensity.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 10","pages":"101302"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148576","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":"Renal rescue in myeloma: How deep does the hematologic response need to be?","authors":"Friederike Bachmann, Stefan Knop","doi":"10.1016/j.medj.2026.101303","DOIUrl":"https://doi.org/10.1016/j.medj.2026.101303","url":null,"abstract":"<p><p>The choice of first-line therapy is exceptionally challenging when multiple myeloma is associated with advanced renal failure. In this issue of Med, Xiao and colleagues report on results from a randomized phase 2 study¹ indicating that the pomalidomide, bortezomib, and dexamethasone triplet leads to better myeloma disease control, thereby increasing renal function after four cycles.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"7 10","pages":"101303"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149056","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":"The human oral and airway viral genome catalog from metagenomes enables virome characterization informing respiratory health.","authors":"Xiaohui Zou, Yawen Ni, Qing Zhang, Kang Chang, Shenghui Li, Yue Zhang, Hailong Yu, Chun Wang, Xiaoxuan Yao, Shibin Chen, Xiaolu Nie, Jiankang Zhao, Binghuai Lu, Yanqin Li, Ning Gan, Zhong Wang, Qiulong Yan, Bin Cao","doi":"10.1016/j.medj.2026.101269","DOIUrl":"10.1016/j.medj.2026.101269","url":null,"abstract":"<p><strong>Background: </strong>Viral communities of the upper aerodigestive tract represent an important component of the human microbial ecosystem but remain poorly characterized due to the limited availability of habitat-specific reference resources.</p><p><strong>Methods: </strong>We integrated 19,997 public and 2,673 newly sequenced oral and airway metagenomes to establish the Oral and Airway Viral Genome Catalogue (OAVGC). Viral genomes were reconstructed and characterized through taxonomic assignment, prokaryotic host prediction, functional annotation, and assessment of putative antibacterial activity. Our prospective longitudinal aging cohort, alongside 5 in-house datasets and publicly cohorts, were analyzed to investigate associations between airway virome profiles and respiratory health.</p><p><strong>Findings: </strong>The OAVGC comprised 141,459 high-quality viral genomes (completeness ≥90%) clustered into 68,708 viral operational taxonomic units (vOTUs). Approximately half of these viruses and families are previously undescribed, with independent cross-cohort detection and PCR assays providing additional support for their occurrence. Across multiple respiratory infection cohorts, the virome exhibited convergent diversity reductions and compositional signatures. In the prospective cohort, the baseline airway virome was correlated with host lung function and geriatric health scores. Virome-based machine learning classifiers demonstrated potential for predicting the future occurrence of upper respiratory tract infections up to 12 months in advance, outperforming bacteriome-based models in our prediction analyses.</p><p><strong>Conclusions: </strong>The OAVGC provides an unprecedented genomic and functional resource for investigating the ecological and clinical associations of the oral-airway virome, revealing its potential impact on respiratory health and capacity to predict future infections.</p><p><strong>Funding: </strong>National Natural Science Foundation of China (82341113) and National Key R&D Program of China (2022YFA1304303).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101269"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881937","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":"N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.","authors":"Margot A Cousin, Aditi I Dagli, Laurence Mignon, Jaimin S Shah, Mercedes Prudencio, Tania F Gendron, Angita Jain, Evan Udine, Marka van Blitterswijk, Erik H Middlebrooks, Megan H Donahue, Jany E Dagher, Jens O Watzlawik, Wolfdieter Springer, Tejal Parekh, Zachary T McEachin, Leonard Petrucelli, Björn Oskarsson","doi":"10.1016/j.medj.2026.101295","DOIUrl":"10.1016/j.medj.2026.101295","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic CHCHD10 variants cause a rare, dominantly inherited form of amyotrophic lateral sclerosis (ALS). Non-allele-selective CHCHD10 knockdown may mitigate a toxic gain-of-function mechanism. We evaluated nL-CHCHD-001 in one participant with the p.Arg15Leu variant.</p><p><strong>Methods: </strong>In this open-label N-of-1 study, 320-gapmer antisense oligonucleotides (ASOs) were screened, and a lead candidate was selected according to specificity and non-clinical safety criteria. Six intrathecal doses were administered over 12 months (three 50-mg doses followed by three 75-mg doses). Prespecified primary outcomes were 12-month changes in functional, cognitive, quality-of-life, respiratory, neurofilament light (NfL), and survival measures; secondary outcomes assessed were safety and tolerability. Analyses were descriptive.</p><p><strong>Findings: </strong>No serious adverse events occurred. Post-dose headache and fatigue were mild to moderate, and cerebrospinal fluid safety results were unremarkable. Plasma NfL decreased by approximately 50% from a mildly elevated pretreatment baseline and entered the laboratory reference range. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score increased from 33 to 36, vital capacity increased from 48% to 55% (as predicted), cognitive and quality-of-life scores remained stable, and the participant was alive at 12 months.</p><p><strong>Conclusions: </strong>Individualized CHCHD10-directed treatment was feasible and well tolerated and was temporally associated with biomarker and clinical stability or improvement. This N-of-1 study demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit. These findings support further evaluation of nL-CHCHD-001 and highlight NfL as a practical treatment-response biomarker for personalized therapeutics in ALS.</p><p><strong>Clinicaltrials: </strong>gov: NCT06392126.</p><p><strong>Funding: </strong>This study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"101295"},"PeriodicalIF":13.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}