Med最新文献

{"title":"Twice-yearly lenacapavir: A milestone for HIV prevention in young African women.","authors":"Silvia Nozza, Antonella Castagna","doi":"10.1016/j.medj.2024.08.008","DOIUrl":"https://doi.org/10.1016/j.medj.2024.08.008","url":null,"abstract":"<p><p>The PURPOSE 1 trial¹ demonstrated that after 52 weeks, no cisgender women acquired HIV infection after receiving subcutaneous twice-yearly lenacapavir. HIV incidence with lenacapavir was significantly lower than HIV incidence with daily oral emtricitabine/tenofovir alafenamide (F/TAF) or daily oral emtricitabine/tenofovir disoproxil fumarate (F/TDF). It is the first pre-exposure prophylaxis regimen with 100% efficacy in young women.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":"5 10","pages":"1200-1202"},"PeriodicalIF":12.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476411","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 randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer.","authors":"Ning Li, Meng Qiu, Yanqiao Zhang, Mudan Yang, Linzhi Lu, Wei Li, Yuntao Ma, Xiaoming Hou, Guoping Sun, Mingquan Cai, Jingran Wang, Jianwei Lu, Diansheng Zhong, Zhibin Huo, Jingdong Zhang, Xianli Yin, Jun Deng, Zimin Liu, Hongming Pan, Ye Chen, Futang Yang, Haoyu Yu, Jing Li, Qingyu Wang, Jun Zhu, Jin Li","doi":"10.1016/j.medj.2024.06.004","DOIUrl":"10.1016/j.medj.2024.06.004","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer is the fifth most common cancer and the fourth most common cause of cancer death worldwide, yet the prognosis of advanced disease remains poor.</p><p><strong>Methods: </strong>This was a randomized, double-blinded, phase 2 trial (ClinicalTrials.gov: NCT04908813). Patients with locally advanced/metastatic HER2-positive gastric/gastroesophageal junction cancer and no prior systemic antitumor therapy were randomized 1:1:1 to 25 mg/kg HLX22 (a novel anti-HER2 antibody) + HLX02 (trastuzumab biosimilar) + oxaliplatin and capecitabine (XELOX) (group A), 15 mg/kg HLX22 + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were progression-free survival (PFS) and objective response rate (ORR) assessed by independent radiological review committee (IRRC).</p><p><strong>Findings: </strong>Between November 29, 2021, and June 6, 2022, 82 patients were screened; 53 were randomized to group A (n = 18), B (n = 17), and C (n = 18). With 14.3 months of median follow-up, IRRC-assessed median PFS was prolonged with the addition of HLX22 (A vs. C, 15.1 vs. 8.2 months, hazard ratio [HR] 0.5 [95% confidence interval (CI) 0.17-1.27]; B vs. C, not reached vs. 8.2 months, HR 0.1 [95% CI 0.04-0.52]). Confirmed ORR was comparable among groups (A vs. B vs. C, 77.8% vs. 82.4% vs. 88.9%). Treatment-related adverse events (TRAEs) were observed in 18 (100%), 16 (94.1%), and 17 (94.4%) patients, respectively. One (5.6%) patient in group C reported a grade 5 TRAE.</p><p><strong>Conclusions: </strong>Adding HLX22 to HLX02 and XELOX prolonged PFS and enhanced antitumor response in the first-line treatment of HER2-positive gastric cancer, with manageable safety.</p><p><strong>Funding: </strong>Shanghai Henlius Biotech, Inc.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1255-1265.e2"},"PeriodicalIF":12.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580968","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":"Preclinical assessment for translation to humans: The PATH approach for assessing supporting evidence for early-phase trials and innovative care.","authors":"Jonathan Kimmelman, Patrick Bodilly Kane, Selin Bicer, Benjamin Gregory Carlisle","doi":"10.1016/j.medj.2024.07.014","DOIUrl":"10.1016/j.medj.2024.07.014","url":null,"abstract":"<p><p>Early-phase trials and innovative care draw support from basic science, preclinical studies, and clinical research. Such evidential diversity presents a challenge for traditional ways of synthesizing evidence. In what follows, we review the limitations of existing approaches for communicating supporting evidence for early-phase trials. We then offer a structured approach, PATH (preclinical assessment for translation to humans). PATH is grounded in the premise that the case for administering novel strategies to patients requires connecting the dots between nine mechanistic steps supporting a clinical claim. Using PATH entails first parsing supporting evidence, assessing the strength of evidence at each step, and then assessing the strength of a chain of evidence linking drug administration to clinical effect. While PATH requires further refinement, the approach reduces some of the opacity, arbitrariness, and biases in current ways of presenting and assessing scientific support for early-phase trials and innovative care.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"1227-1236"},"PeriodicalIF":12.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907820","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}

{"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":" ","pages":""},"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":" ","pages":""},"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":" ","pages":""},"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":"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":" ","pages":""},"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":"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":" ","pages":""},"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":"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":" ","pages":""},"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":" ","pages":""},"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}