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{"title":"Host genetic and immune factors drive evasion of HIV-1 pathogenesis in viremic non-progressors.","authors":"Ángel Bayón-Gil, Inmaculada Hernández, Judith Dalmau, Juan C Nieto, Víctor Urrea, Lidia Garrido-Sanz, Ginevra Caratú, Maria C García-Guerrero, Cristina Gálvez, María Salgado, Itziar Erkizia, Fernando Laguía, Patricia Resa-Infante, Marta Massanella, Raúl Tonda, Jordi Morata, Kai Ying Hong, Jane Koshy, Aaron R Goldman, Leila Giron, Mohamed Abdel-Mohsen, Holger Heyn, Javier Martinez-Picado, Maria C Puertas","doi":"10.1016/j.medj.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.007","url":null,"abstract":"<p><strong>Background: </strong>Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4⁺ T cell counts despite uncontrolled viral replication-a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies.</p><p><strong>Methods: </strong>We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors.</p><p><strong>Findings: </strong>Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4⁺ T cell apoptosis.</p><p><strong>Conclusions: </strong>In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis.</p><p><strong>Funding: </strong>The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476406","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":"Maternal exercise during pregnancy is associated with reduced risk of asthma in the child: A prospective birth cohort study.","authors":"Emma-Reetta Musakka, Maija Paula Tuulia Ylilauri, Jonna Jalanka, Anne Maarit Karvonen, Martin Täubel, Sari Hantunen, Soili Marianne Lehto, Juha Pekkanen, Katri Backman, Leea Keski-Nisula, Pirkka Viljami Kirjavainen","doi":"10.1016/j.medj.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.003","url":null,"abstract":"<p><strong>Background: </strong>The means of primary prevention of asthma are limited. Maternal physical activity during pregnancy promotes fetal lung development and the newborn's lung function; thus, it could lower asthma risk and aid in asthma prevention. The objective of this study is to determine whether maternal physical activity during pregnancy is associated with asthma development in the child.</p><p><strong>Methods: </strong>The study population included 963 mother-infant pairs from the prospective Kuopio Birth Cohort study. Data on maternal physical activity during pregnancy, confounding factors, and children's asthma at 5 to 7 years of age were obtained from the Kuopio University Hospital birth registry and questionnaires.</p><p><strong>Findings: </strong>Maternal physical activity during pregnancy, when practiced three or more times per week, was associated with a reduced risk of asthma in the child, with an adjusted odds ratio of 0.54 (95% confidence interval 0.33-0.89; p = 0.02). The association was stable across a comprehensive set of adjustments, including length of gestation, mode of delivery, and maternal health indicators (e.g., asthma, smoking, pre-pregnancy body mass index and weight gain during pregnancy, infections, medication, healthy diet, stress), as well as various family environment variables.</p><p><strong>Conclusions: </strong>Maternal physical activity during pregnancy may be associated with marked protection of asthma in childhood and should be studied further as an applicable measure for asthma prevention.</p><p><strong>Funding: </strong>The study has been financially supported by grants from the Academy of Finland (no. 349427), the Emil Aaltonen Foundation, the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Juho Vainio Foundation (no. 202200461), the Kuopio Area Respiratory Foundation, and the Ida Montini Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401505","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":"Humoral signatures of Caspr2-antibody spectrum disorder track with clinical phenotypes and outcomes.","authors":"Paula Terroba-Navajas, Marianna Spatola, Omar Chuquisana, Bastien Joubert, Juna M de Vries, Andre Dik, Laura Marmolejo, Friederike Jönsson, Gordan Lauc, Stjepana Kovac, Harald Prüss, Heinz Wiendl, Maarten J Titulaer, Jérôme Honnorat, Jan D Lünemann","doi":"10.1016/j.medj.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.004","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood.</p><p><strong>Methods: </strong>We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes.</p><p><strong>Findings: </strong>We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up.</p><p><strong>Conclusions: </strong>The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes.</p><p><strong>Funding: </strong>This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406970","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":"First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.","authors":"Qing Zhou, Yan Yu, Ligang Xing, Ying Cheng, Ying Wang, Yueyin Pan, Yun Fan, Jianhua Shi, Guojun Zhang, Jiuwei Cui, Jianying Zhou, Yong Song, Wu Zhuang, Zhiyong Ma, Yanping Hu, Gaofeng Li, Xiaorong Dong, Jifeng Feng, Shun Lu, Jingxun Wu, Juan Li, Longzhen Zhang, Dong Wang, Xinhua Xu, Tsung-Ying Yang, Nong Yang, Yubiao Guo, Jun Zhao, Yu Yao, Diansheng Zhong, Bing Xia, Cheng-Ta Yang, Bo Zhu, Ping Sun, Byoung Yong Shim, Yuan Chen, Zhen Wang, Myung-Ju Ahn, Jie Wang, Yi-Long Wu","doi":"10.1016/j.medj.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.002","url":null,"abstract":"<p><strong>Background: </strong>Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients.</p><p><strong>Methods: </strong>In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1.</p><p><strong>Findings: </strong>Overall, 439 patients were randomized (zorifertinib n = 220; control n = 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9 months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3 months with zorifertinib and 31.8 months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib.</p><p><strong>Conclusions: </strong>Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC.</p><p><strong>Funding: </strong>This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401504","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":"Identification of distinct stool metabolites in women with endometriosis for non-invasive diagnosis and potential for microbiota-based therapies.","authors":"Chandni Talwar, Goutham Venkata Naga Davuluri, Abu Hena Mostafa Kamal, Cristian Coarfa, Sang Jun Han, Surabi Veeraragavan, Krishna Parsawar, Nagireddy Putluri, Kristi Hoffman, Patricia Jimenez, Scott Biest, Ramakrishna Kommagani","doi":"10.1016/j.medj.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.medj.2024.09.006","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis, a poorly studied gynecological condition, is characterized by the presence of ectopic endometrial lesions resulting in pelvic pain, inflammation, and infertility. These associated symptoms contribute to a significant burden, often exacerbated by delayed diagnosis. Current diagnostic methods involve invasive procedures, and existing treatments provide no cure.</p><p><strong>Methods: </strong>Microbiome-metabolome signatures in stool samples from individuals with and without endometriosis were determined using unbiased metabolomics and 16S bacteria sequencing. Functional studies for selected microbiota-derived metabolites were conducted in vitro using patient-derived cells and in vivo by employing murine and human xenograft pre-clinical disease models.</p><p><strong>Findings: </strong>We discovered a unique bacteria-derived metabolite signature intricately linked to endometriosis. The altered fecal metabolite profile exhibits a strong correlation with that observed in inflammatory bowel disease (IBD), revealing intriguing connections between these two conditions. Notably, we validated 4-hydroxyindole, a gut-bacteria-derived metabolite that is lower in stool samples of endometriosis. Extensive in vivo studies found that 4-hydroxyindole suppressed the initiation and progression of endometriosis-associated inflammation and hyperalgesia in heterologous mouse and in pre-clinical models of the disease.</p><p><strong>Conclusions: </strong>Our findings are the first to provide a distinct stool metabolite signature in women with endometriosis, which could serve as stool-based non-invasive diagnostics. Further, the gut-microbiota-derived 4-hydroxyindole poses as a therapeutic candidate for ameliorating endometriosis.</p><p><strong>Funding: </strong>This work was funded by the NIH/NICHD grants (R01HD102680, R01HD104813) and a Research Scholar Grant from the American Cancer Society to R.K.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476407","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":"Responsiveness of different disease activity indices in moderate-to-severe ulcerative colitis.","authors":"Virginia Solitano, Remo Panaccione, Bruce E Sands, Zhongya Wang, Malcolm Hogan, Guangyong Zou, Laurent Peyrin-Biroulet, Silvio Danese, Linda J Cornfield, Brian G Feagan, Siddharth Singh, Vipul Jairath, Christopher Ma","doi":"10.1016/j.medj.2024.09.001","DOIUrl":"10.1016/j.medj.2024.09.001","url":null,"abstract":"<p><strong>Background: </strong>Clinical, endoscopic, histological, and composite instruments are currently used to measure disease activity in patients with ulcerative colitis (UC). We compared the responsiveness of the Mayo Clinic score (MCS), modified MCS (mMS; excluding physician global assessment), partial MCS (pMS; MCS without endoscopic subscore), Robart's Histopathology Index (RHI), and UC-100 score to change after ustekinumab treatment in patients with moderately to severely active UC.</p><p><strong>Methods: </strong>Post hoc analysis of the phase 3 UNIFI induction trial (ClinicalTrials.gov: NCT02407236) was conducted. Participants with moderately to severely active UC were randomized to receive ustekinumab or placebo. Treatment assignment was the criterion to assess responsiveness, which was quantified using the probability of a treated participant having a larger change in score than a placebo participant, termed the win probability (WinP), and estimated using nonparametric methods.</p><p><strong>Findings: </strong>The UC-100 score demonstrated large responsiveness (WinP 0.72 [95% confidence interval: 0.66-0.78]), and the MCS (0.68 [0.62-0.73]), mMS (0.69 [0.63-0.75]), and pMS (0.65 [0.59-0.71]) demonstrated similar effect sizes. Of the component items of the Mayo score, the endoscopic subscore (WinP 0.76 [0.69-0.82]) and the stool frequency subscore (WinP 0.74 [0.69-0.79]) were the most responsive. The Inflammatory Bowel Disease Questionnaire (IBDQ) quality-of-life questionnaire was also responsive (WinP 0.78 [0.72-0.82]).</p><p><strong>Conclusions: </strong>UC disease activity indices are similarly responsive. Depending on the treatment setting, time point of evaluation, and feasibility of measurement, different scores may be used to demonstrate response. These results support the use of mMS as a composite primary endpoint, incorporating both patient-reported and endoscopic outcome measures. The UC-100 score may be more appropriate in settings that also routinely incorporate histological evaluation.</p><p><strong>Funding: </strong>There is no funding for this study.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378394","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":"Heterozygous cis HYDIN mutations cause primary ciliary dyskinesia.","authors":"Randy Suryadinata, Paul Martinello, Vicki Bennett-Wood, Phil Robinson","doi":"10.1016/j.medj.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.medj.2024.08.007","url":null,"abstract":"<p><strong>Background: </strong>The product of ciliary gene HYDIN is an integral component for c2b projection within the motile cilia central pair (CP) apparatus. Biallelic mutations of this gene cause primary ciliary dyskinesia (PCD), an uncommon heterogeneous recessive disorder affecting motile cilia, resulting in defective mucociliary clearance that leads to chronic suppurative lung disease.</p><p><strong>Methods: </strong>Nasal brushing samples were collected from two siblings attending the Victorian Diagnostic service for PCD. Nasal airway epithelial cells (NAECs) were cultured before cilia structure and function studies using high-speed video microscopy (HSVM), transmission electron microscopy, and immunofluorescence.</p><p><strong>Findings: </strong>Cultured NAECs from both siblings showed defective cilia beating patterns under HSVM. A confirmatory PCD diagnosis was achieved through immunofluorescence, which showed the loss of HYDIN and the associated protein SPEF2 from the cilia axoneme.</p><p><strong>Conclusions: </strong>This case report details the diagnosis of two siblings who displayed similar defective cilia beating phenotypes seen in patients with PCD bearing recessive HYDIN mutations. Uniquely, both siblings carry two previously unreported HYDIN mutations, which are in the cis position, demonstrating the possibility for disease manifestation without biallelic mutations of ciliary genes.</p><p><strong>Funding: </strong>The authors declare no funding support for this study.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355446","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":"Patient-derived organoids in precision cancer medicine.","authors":"Le Tong, Weiyingqi Cui, Boya Zhang, Pedro Fonseca, Qian Zhao, Ping Zhang, Beibei Xu, Qisi Zhang, Zhen Li, Brinton Seashore-Ludlow, Ying Yang, Longlong Si, Andreas Lundqvist","doi":"10.1016/j.medj.2024.08.010","DOIUrl":"https://doi.org/10.1016/j.medj.2024.08.010","url":null,"abstract":"<p><p>Organoids are three-dimensional (3D) cultures, normally derived from stem cells, that replicate the complex structure and function of human tissues. They offer a physiologically relevant model to address important questions in cancer research. The generation of patient-derived organoids (PDOs) from various human cancers allows for deeper insights into tumor heterogeneity and spatial organization. Additionally, interrogating non-tumor stromal cells increases the relevance in studying the tumor microenvironment, thereby enhancing the relevance of PDOs in personalized medicine. PDOs mark a significant advancement in cancer research and patient care, signifying a shift toward more innovative and patient-centric approaches. This review covers aspects of PDO cultures to address the modeling of the tumor microenvironment, including extracellular matrices, air-liquid interface and microfluidic cultures, and organ-on-chip. Specifically, the role of PDOs as preclinical models in gene editing, molecular profiling, drug testing, and biomarker discovery and their potential for guiding personalized treatment in clinical practice are discussed.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355447","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":"Gut microbiome pattern impacts treatment response in primary biliary cholangitis.","authors":"Qiaoyan Liu, Bingyuan Huang, Yijun Zhou, Yiran Wei, Yikang Li, Bo Li, You Li, Jun Zhang, Qiwei Qian, Ruiling Chen, Zhuwan Lyu, Rui Wang, Qin Cao, Qun Xu, Qixia Wang, Qi Miao, Zhengrui You, Min Lian, Merrill Eric Gershwin, Qiaofei Jin, Xiao Xiao, Xiong Ma, Ruqi Tang","doi":"10.1016/j.medj.2024.08.003","DOIUrl":"https://doi.org/10.1016/j.medj.2024.08.003","url":null,"abstract":"<p><strong>Background: </strong>Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC.</p><p><strong>Methods: </strong>We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts.</p><p><strong>Findings: </strong>PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridia^low microbiomes, Clostridia^high microbiomes were more similar to healthy controls. Notably, patients in the Clostridia^low subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridia^high subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridia^low subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridia^high group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts.</p><p><strong>Conclusions: </strong>Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies.</p><p><strong>Funding: </strong>This research was mainly supported by the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297064","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":"Exceptional, naturally occurring HIV-1 control: Insight into a functional cure.","authors":"María Salgado, Stephen A Migueles, Xu G Yu, Javier Martinez-Picado","doi":"10.1016/j.medj.2024.06.008","DOIUrl":"10.1016/j.medj.2024.06.008","url":null,"abstract":"<p><p>Exceptional elite controllers represent an extremely rare group of people with HIV-1 (PWH) who exhibit spontaneous, high-level control of viral replication below the limits of detection in sensitive clinical monitoring assays and without disease progression in the absence of antiretroviral therapy for prolonged periods, frequently exceeding 25 years. Here, we discuss the different cases that have been reported in the scientific literature, their unique genetic, virological, and immunological characteristics, and their relevance as the best model for the functional cure of HIV-1.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11411266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141627890","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}