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{"title":"Body ownership alterations in stroke emerge from reduced proprioceptive precision and damage to the frontoparietal network.","authors":"Giulio Mastria, Tommaso Bertoni, Henri Perrin, Nikita Akulenko, Gaia Risso, Michel Akselrod, Eleonora Guanziroli, Franco Molteni, Patric Hagmann, Michela Bassolino, Andrea Serino","doi":"10.1016/j.medj.2024.10.013","DOIUrl":"10.1016/j.medj.2024.10.013","url":null,"abstract":"<p><strong>Background: </strong>Stroke patients often experience alterations in their subjective feeling of ownership for the affected limb, which can hinder motor function and interfere with rehabilitation. In this study, we aimed at disentangling the complex relationship between sensory impairment, body ownership (BO), and motor control in stroke patients.</p><p><strong>Methods: </strong>We recruited 20 stroke patients with unilateral upper limb sensory deficits and 35 age-matched controls. Participants performed a virtual reality reaching task with a varying displacement between their real unseen hand and a visible virtual hand. We measured reaching errors and subjective ownership ratings as indicators of hand ownership. Reaching errors were modeled using a probabilistic causal inference model, in which ownership for the virtual hand is inferred from the level of congruency between visual and proprioceptive inputs and used to weigh the amount of visual adjustment to reaching movements.</p><p><strong>Findings: </strong>Stroke patients were more likely to experience ownership over an incongruent virtual hand and integrate it into their motor plans. The model explained this tendency in terms of a decreased capability of detecting visuo-proprioceptive incongruences, proportionally to the amount of proprioceptive deficit. Lesion analysis further revealed that BO alterations, not fully explained by the proprioceptive deficit, are linked to frontoparietal network damage, suggesting a disruption in higher-level multisensory integration functions.</p><p><strong>Conclusions: </strong>Collectively, our results show that BO alterations in stroke patients can be quantitatively predicted and explained in a computational framework as the result of sensory loss and higher-level multisensory integration deficits.</p><p><strong>Funding: </strong>Swiss National Science Foundation (163951).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100536"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629099","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":"Diagnosing recipient- vs. donor-derived posttransplant myelodysplastic neoplasm via targeted single-cell mutational profiling.","authors":"Jana Ihlow, Livius Penter, Lam Giang Vuong, Philip Bischoff, Benedikt Obermayer, Alexandra Trinks, Olga Blau, Anke Behnke, Thomas Conrad, Markus Morkel, Catherine J Wu, Jörg Westermann, Lars Bullinger, Ann-Christin von Brünneck, Nils Blüthgen, David Horst, Samantha D Praktiknjo","doi":"10.1016/j.medj.2024.11.001","DOIUrl":"10.1016/j.medj.2024.11.001","url":null,"abstract":"<p><strong>Background: </strong>Distinguishing donor- vs. recipient-derived myelodysplastic neoplasm (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is challenging and has direct therapeutical implications.</p><p><strong>Methods: </strong>Here, we took a translational approach that we used in addition to conventional diagnostic techniques to resolve the origin of MDS in a 38-year-old patient with acquired aplastic anemia and evolving MDS after first allo-HSCT. Specifically, we used single-cell transcriptional profiling to differentiate between donor- and recipient-derived bone marrow cells and established a strategy that additionally allows identification of cells carrying the MDS-associated U2AF1^S34Y variant.</p><p><strong>Results: </strong>The patient exhibited mixed donor chimerism combined with severely reduced erythropoiesis and dysplastic morphology within the granulocytic and megakaryocytic lineage along with the MDS-associated U2AF1^S34Y mutation in the bone marrow. Single-cell transcriptional profiling together with targeted enrichment of the U2AF1^S34Y-specific locus further revealed that, while the immune compartment was mainly populated by donor-derived cells, myelopoiesis was predominantly driven by the recipient. Additionally, concordant with recipient-derived MDS, we found that U2AF1^S34Y-mutated cells were exclusively recipient derived with X but not Y chromosome-specific gene expression.</p><p><strong>Conclusion: </strong>Our study highlights the clinical potential of integrating high-resolution single-cell techniques to resolve complex cases for personalized treatment decisions.</p><p><strong>Funding: </strong>The study was funded by intramural resources of the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100548"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792447","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":"BilT03: Phase 1b/2 multicenter trial of nivolumab with 5-fluorouracil and liposomal irinotecan for previously treated advanced biliary tract cancer.","authors":"Vaibhav Sahai, Kent A Griffith, Bruce S Lin, Heloisa P Soares, Sreenivasa R Chandana, Oxana Crysler, Chandan Kumar-Sinha, Thomas Enzler, Dominique Dippman, Valerie Gunchick, Mark M Zalupski","doi":"10.1016/j.medj.2024.10.024","DOIUrl":"10.1016/j.medj.2024.10.024","url":null,"abstract":"<p><strong>Background: </strong>Second-line chemotherapy with 5-fluorouracil/leucovorin (5FULV) and liposomal irinotecan improves survival in advanced biliary tract cancer (BTC). In this phase 1b/2 trial, we investigated the combination of 5FULV and liposomal irinotecan with nivolumab following progression on first-line chemotherapy for advanced BTC.</p><p><strong>Methods: </strong>Patients received 2,400 mg/m² 5-fluorouracil, leucovorin (dose level: 0:400 or -1:200 mg/m²), 70 mg/m² liposomal irinotecan, and 240 mg nivolumab every 2 weeks (ClinicalTrials.gov: NCT03785873). The phase 1b and 2 primary objectives included recommended phase 2 dose (RP2D) and median progression-free survival (PFS; null and alternative hypotheses of 2.9 and 5.0 months) with a two-sided alpha of 0.05 and >80% power. Secondary objectives were safety, objective response rate (ORR), and overall survival (OS).</p><p><strong>Findings: </strong>Of 30 patients with a median age of 63.5 years, 18 (60%) were men, 25 (83%) were White, 16 (53%) had an ECOG performance status of 0, and 19 (63.3%) had intrahepatic cholangiocarcinoma. In phase 1b, the RP2D was dose level 0 after a dose-limiting toxicity event of enterocolitis (n = 1). Median PFS was 4.1 months (95% confidence interval [CI], 1.9-9.9). The ORR was 16.7% (5 partial responses) per irRECIST, the median OS was 7.4 months (95% CI, 5.7-15.9), and the 24-month survival rate was 23.3%. The most common grade ≥3 treatment-related adverse events were diarrhea (5; 16.7%), fatigue (4; 13.3%), and neutropenia (3; 10%).</p><p><strong>Conclusions: </strong>Treatment was well tolerated, but the primary endpoint was not met. The median OS was similar to prior trials with this drug combination, but the 24-month survival rate was higher than expected.</p><p><strong>Funding: </strong>This work was funded by Ipsen Biopharmaceuticals, Bristol-Myers Squibb (CA209-8LF), and the University of Michigan Rogel Cancer Center (P30CA046592).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100547"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865599","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":"GLP-1 agonists to slow down Parkinson's progression? The quest continues.","authors":"Bastiaan R Bloem, Eric A Macklin, Michael A Schwarzschild","doi":"10.1016/j.medj.2025.100645","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100645","url":null,"abstract":"<p><p>A much-anticipated phase 3 clinical trial (EXENATIDE-PD3) tested whether exenatide, a GLP-1 receptor agonist used to treat type 2 diabetes, might be neuroprotective in persons with Parkinson's disease.¹ There was no difference between exenatide and matched placebo for the primary outcome or any secondary or exploratory outcomes. We discuss the implications for future attempts to modify the course of Parkinson's disease.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 4","pages":"100645"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022291","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 cluster randomized trial of xylitol chewing gum for prevention of preterm birth: The PPaX trial.","authors":"Gregory C Valentine, Kathleen M Antony, Haleh Sangi-Haghpeykar, Alexis C Wood, Rose Chirwa, Saukani Petro, Mary Dumba, Deborah Nanthuru, Cynthia Shope, Jesse Mlotha-Namarika, Jeffrey Wilkinson, Joshua Aagaard, Ellen J Aagaard, Maxim D Seferovic, Judy Levison, Peter Kazembe, Kjersti M Aagaard","doi":"10.1016/j.medj.2024.10.016","DOIUrl":"10.1016/j.medj.2024.10.016","url":null,"abstract":"<p><strong>Background: </strong>Maternal periodontal disease is associated with preterm and low-birthweight deliveries, but randomized trials of likely efficacious treatments (e.g., dental scaling and root planing) during pregnancy have not reduced these adverse outcomes. As an alternative, we hypothesized that periconception initiation of xylitol chewing gum would reduce the occurrence of preterm or low-birthweight deliveries among a historical high-prevalence population in Malawi.</p><p><strong>Methods: </strong>We conducted an open-label, parallel-enrollment, matched-pair, cluster-randomized, controlled clinical trial across eight health centers (sites) in and around Lilongwe, Malawi. Sites were paired by anticipated delivery volume and randomized to prenatal and oral health education alone (active control) or with twice-daily xylitol chewing gum (intervention) throughout the periconception and antenatal periods. For the primary prevention of preterm (<37 weeks) and low-birthweight (<2,500 g) deliveries (co-primary outcomes), comparison by allocation group was performed using generalized linear mixed models for each outcome as a fixed factor and the site(s) as a random factor.</p><p><strong>Findings: </strong>10,069 participants were enrolled (n = 4,549 at intervention sites, n = 5,520 at active control sites), with >95% available for analyses. Initiation of xylitol chewing gum resulted in significant reductions in the co-primary outcomes: preterm birth (12.6% [549/4,349] vs. 16.5% [878/5,321]; relative risk [RR] 0.76, 95% confidence interval [CI] 0.57-0.99) and <2,500-g neonates (8.9% [385/4,305] vs. 12.9% [679/5,260]; RR 0.70, 95% CI 0.49-0.99). Xylitol chewing gum use also led to fewer neonatal demises (0.2% [8/4,305] vs. 0.4% [22/5,260]; RR 0.41, 95% CI 0.19-0.89).</p><p><strong>Conclusions: </strong>Periconception initiation and ongoing use of xylitol chewing gum significantly reduced the occurrence of preterm and low-birthweight deliveries in Malawi.</p><p><strong>Funding: </strong>E.W. Al Thrasher Foundation (to K.A.) and USAID Saving Lives at Birth Grand Challenges Grant AID-OAA-G-11-00062 (to K.A.). Additional financial and in-kind support was graciously provided by Texas Children's Hospital and Baylor Foundation Malawi.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100539"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629076","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":"Organoids and organs-on-chips: Recent advances, applications in drug development, and regulatory challenges.","authors":"Liangbin Zhou, Jingjing Huang, Cun Li, Qi Gu, Gang Li, Zhong Alan Li, Jiankun Xu, Jie Zhou, Rocky S Tuan","doi":"10.1016/j.medj.2025.100667","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100667","url":null,"abstract":"<p><p>Organoids and organs-on-chips (OoCs) are rapidly evolving technologies for creating miniature human tissue models. They can mimic complex physiological functions and pathological conditions, offering more realistic platforms for disease modeling, drug screening, precision medicine, and regenerative therapies. The passing of the FDA Modernization Act 2.0 has reduced animal testing requirements for drug trials, marking a significant milestone in using advanced in vitro models such as organoids and OoCs for therapeutic discovery. Apart from technical and ethical challenges, regulatory issues persist in ensuring the reliability, scientificity, and applicability of these models in drug development. This perspective explores the concept, advancements, pros and cons, and applications of organoids and OoCs, particularly in drug research and development. It also examines global regulatory agencies' policies and actions on using these models in drug evaluation, aiming to guide industry standard setting and advance regulatory science.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 4","pages":"100667"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045540","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 role of wild birds in pathogen dynamics: Ecological hotspots, surveillance strategies, and global health implications.","authors":"Mohamed A Bakheet, Justin Bahl","doi":"10.1016/j.medj.2025.100606","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100606","url":null,"abstract":"<p><p>Wild birds spread pathogens that threaten animals and humans, acting as reservoirs and vectors. Qiu et al.¹ analyzed 1,834 studies, identifying 760 pathogens in 1,438 bird species, including zoonotic and emerging threats. Their research highlights global hotspots, showing that migratory birds aid dispersal while resident birds drive local transmission, emphasizing the need for enhanced surveillance to mitigate zoonotic and pandemic risks.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 4","pages":"100606"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015301","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":"AAV gene therapy for mucopolysaccharidoses.","authors":"Shaukat Khan, Yasuhiko Ago, Shunji Tomatsu","doi":"10.1016/j.medj.2025.100609","DOIUrl":"https://doi.org/10.1016/j.medj.2025.100609","url":null,"abstract":"<p><p>Adeno-associated viral (AAV) vectors emerge as a promising treatment option for genetic diseases. They are recognized as the most effective in vivo gene therapy due to their safety, efficacy, and ability to provide long-term therapeutic transgene expression.¹^,²^,³ Rossi et al.¹ have demonstrated that AAV gene therapy is effective and safe for treating patients with mucopolysaccharidosis VI, paving the way for potential treatments for mucopolysaccharidoses.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"6 4","pages":"100609"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031359","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":"No association between the early-life gut microbiota and childhood body mass index and body composition.","authors":"Christina Egeø Poulsen, Rebecca Vinding, Morten A Rasmussen, Shiraz Shah, Urvish Trivedi, Cristina Leal Rodriguez, Michael L Widdowson, Jie Jiang, Casper S Poulsen, Anders Eliasen, Bo Chawes, Klaus Bønnelykke, Camilla H F Hansen, Søren J Sørensen, Jonathan Thorsen, Jakob Stokholm","doi":"10.1016/j.medj.2024.10.015","DOIUrl":"10.1016/j.medj.2024.10.015","url":null,"abstract":"<p><strong>Background: </strong>The gut microbiota has been implicated in adult obesity, but the causality is still unclear. It has been hypothesized that an obesity-prone gut microbiota can be established in infancy, but only few studies have examined the early-life gut microbiota in relation to obesity in childhood, and no consistent associations have been reported. Here, we examine the association between the early-life gut microbiota and body mass index (BMI) development and body composition throughout childhood.</p><p><strong>Methods: </strong>Gut microbiota from stool were collected from 700 children in the Copenhagen Prospective Studies on Asthma in Childhood₂₀₁₀ (COPSAC₂₀₁₀) cohort at ages of 1 week, 1month, 1 year, 4 years, and 6 years and analyzed by 16S rRNA gene sequencing. Outcomes included BMI World Health Organization (WHO) Z scores (zBMI), overweight (zBMI > 1.04) and obesity (zBMI > 1.64) (0-10 years), and adiposity rebound and body composition from dual-energy X-ray absorptiometry at 6 years.</p><p><strong>Findings: </strong>The early-life gut microbiota diversity, overall composition, and individual taxon abundances in unsupervised and supervised models were not consistently associated with either current or later BMI Z scores, overweight, obesity, adiposity rebound, or body composition in childhood.</p><p><strong>Conclusions: </strong>In a deeply characterized longitudinal birth cohort, we did not observe any consistent associations between the early-life gut microbiota and BMI or risk of obesity in later childhood. While this does not conclusively rule out a relationship, it suggests that if such associations exist, they may be more complex and potentially influenced by factors emerging later in life, including lifestyle changes.</p><p><strong>Funding: </strong>COPSAC is funded by private and public research funds (all listed on www.copsac.com).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100538"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629140","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":"Hb Monza: A novel extensive HBB duplication with preserved α-β subunit interaction and unstable hemoglobin phenotype.","authors":"Ivan Civettini, Arianna Zappaterra, Paola Corti, Amedeo Messina, Andrea Aroldi, Andrea Biondi, Fabrizio Cavalca, Valentina Crippa, Francesca Crosti, Giulia Maria Ferrari, Federica Malighetti, Luca Mologni, Alberto Piperno, Daniele Ramazzotti, Chiara Scollo, Alfonso Zambon, Fabio Rossi, Carlo Gambacorti-Passerini","doi":"10.1016/j.medj.2024.11.007","DOIUrl":"10.1016/j.medj.2024.11.007","url":null,"abstract":"<p><strong>Background: </strong>Unstable hemoglobins are caused by single amino acid substitutions in the HBB gene, often affecting key histidine residues, leading to protein destabilization and hemolytic crises. In contrast, long HBB variants, exceeding 20 bp, are rare and associated with a β-thalassemia phenotype due to disrupted α-β chain interactions. We describe a family wherein four of six members carry a novel 23-amino-acid in-frame duplication of HBB (c.176_244dup), named hemoglobin (Hb) Monza. Despite its length, this duplication manifests as an unstable hemoglobin variant rather than a β-thalassemia phenotype.</p><p><strong>Methods: </strong>A static 3D model of the Hb Monza β chain was generated using AlphaFold and SWISS-MODEL. Molecular dynamics (MD) simulations were performed with the Generalized Born implicit solvent model. After energy minimization and heating to 311 K (38°C), a 40 ns production run was conducted.</p><p><strong>Findings: </strong>3D modeling of Hb Monza revealed minimal structural changes in the Hb β chain, particularly in the key histidine residues and their interaction with the iron atom. Additionally, the static 3D model showed a preserved α-β interaction, explaining the absence of a β-thalassemia clinical phenotype. MD simulations under thermal stress revealed a notable increase in root-mean-square deviation compared to the wild-type β subunit, along with a loss of contacts with the heme, explaining the hemolytic crises during febrile episodes.</p><p><strong>Conclusion: </strong>Despite the long duplication in HBB, Hb Monza retains functional α-β interaction while demonstrating instability under stressful conditions. This unique variant presents with an unstable Hb phenotype rather than a β-thalassemia phenotype.</p><p><strong>Funding: </strong>No financial funding was received.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100554"},"PeriodicalIF":12.8,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865602","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}