BMC Medicine最新文献

{"title":"Measuring individual and community capacity factors in people with multimorbidity and exploring associations with health outcomes.","authors":"Marianne McCallum, Frances S Mair, Sara Macdonald, Mary Kathleen Hannah, Kathryn Skivington, Jim Lewsey","doi":"10.1186/s12916-025-04337-y","DOIUrl":"https://doi.org/10.1186/s12916-025-04337-y","url":null,"abstract":"<p><strong>Background: </strong>People with multimorbidity work to manage their conditions (burden of treatment). Burden of Treatment Theory (BOTT) proposes poorer outcomes when this work outweighs capacity - an individual's ability to successfully undertake the work of self-management. Capacity is influenced by individual and community factors. This study aims to quantify individual and community capacity factors and explore associations, if any, with mortality and hospitalisation in people with multimorbidity.</p><p><strong>Methods: </strong>Data source is as follows: West of Scotland Twenty-07 cohort (three age-based cohorts - 15, 35 and 55 years at baseline (wave 1), followed up with four additional waves over 20 years). Participants are as follows: people with ≥ 2 chronic conditions. Variables (e.g. car access/self-esteem/neighbourliness) mapped to underlying individual and community BOTT constructs. Directed acyclic graphs (DAGs) informed analysis. Cox regression analysis using time-varying covariates explored mortality associations; multiple logistic regression explored hospitalisation associations. Both analyses were adjusted for age, sex, socioeconomic deprivation (SED), alcohol, exercise, fruit/vegetable intake, BMI, smoking, marital status, number of long-term conditions and blood pressure. Exploratory analysis of potential moderating effect of SED was also undertaken.</p><p><strong>Results: </strong>A total of 2249 people had multimorbidity across the five waves (mean age 51.5 (SD 11.6) at baseline and 61 (14.9) at wave 5; male 40.6% baseline, 41.1% wave 5; smokers 32.7% baseline, 25.3% wave 5). Living in social housing was associated with increased mortality (HR (95% CI) 1.39 (1.14, 1.68)), while registered disability was associated with increased risk of hospitalisation (OR (95% CI) 1.7 (1.27, 2.27)). Feeling fearful about walking in the dark was associated with mortality (\"try to avoid\" OR (95% CI) 0.74 (0.60, 0.92); \"feel uncomfortable\" (OR (95% CI) 0.70 (0.55, 0.89); \"no worries\" 0.69 (0.57, 0.83)). Feeling little control over one's life: disagreeing quite a bit with \"care from others helps me to get well\" OR (95% CI) 0.53 (0.33, 0.86). Initial exploratory analysis suggests high SED could act as a potential moderator, increasing associations between community factors with mortality and hospitalisations.</p><p><strong>Conclusions: </strong>Individual and community factors influencing capacity to self-manage multimorbidity are quantifiable and associated with adverse health outcomes. Our work adds to the growing body of evidence that capacity issues may be important when designing future multimorbidity interventions and services.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"566"},"PeriodicalIF":8.3,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles derived from menstrual blood-derived mesenchymal stem cells suppress inflammatory atherosclerosis by inhibiting NF-κB signaling.","authors":"Jinjin Yu, Xiaotian Liu, Lele Jin, Han Li, Suhui Wang, Yongwei Yang, Xilian Chen, Hongxia Wang, Yingke Li, Jie Lian, Chao Shi, Haihui Li, Yong Zhang, Emmanuel Jairaj Moses, Hongxing Zhang, Chunfu Zheng, Xinxing Zhu","doi":"10.1186/s12916-025-04390-7","DOIUrl":"https://doi.org/10.1186/s12916-025-04390-7","url":null,"abstract":"<p><strong>Background: </strong>Numerous studies have highlighted the beneficial effects of mesenchymal stem cells (MSCs) in various inflammatory disorders. However, the regulatory role of MSCs in inflammatory atherosclerosis and the molecular mechanisms underlying their anti-inflammatory properties have largely remained elusive.</p><p><strong>Methods: </strong>Differential ultracentrifugation was performed to isolate extracellular vesicles (EVs) released by menstrual blood-derived mesenchymal stem cells (MenSCs). An ApoE knockout atherosclerotic animal model was employed to investigate the regulatory effect of MenSC-EVs on inflammatory atherosclerosis. miRNA microarray screening analyses were conducted to identify potential effectors in MenSC-EVs that play a key role in the suppression of atherosclerosis mediated by the EVs.</p><p><strong>Results: </strong>We demonstrated the remarkable potential of MenSC-EVs in alleviating atherosclerosis through the NF-κB signaling pathway. miR-574-5p serves as a crucial effector molecule transported by MenSC-EVs, suppressing endothelial inflammation and promoting nitric oxide production. This regulation contributes to the attenuation of atherosclerosis by regulating the abundance of c-Rel. The miR-574-5p/c-Rel axis shows significant clinical relevance to atherosclerosis.</p><p><strong>Conclusions: </strong>This study reveals that the engineering of EVs derived from MenSCs holds significant promise as a strategic clinical approach for addressing inflammatory atherosclerosis.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"565"},"PeriodicalIF":8.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends in hip and knee replacement length of stay and patient demographics in England: a population-based study of 1,455,842 primary procedures.","authors":"Jonathan M R French, Kevin Deere, Adrian Sayers, Michael R Whitehouse","doi":"10.1186/s12916-025-04294-6","DOIUrl":"https://doi.org/10.1186/s12916-025-04294-6","url":null,"abstract":"<p><strong>Background: </strong>Length of stay (LOS) after hip and knee replacement has decreased steadily in the modern era with enhanced recovery protocols, enabling healthcare systems to address rising surgical demand in an ageing, comorbid population. This study examines trends in LOS, patient characteristics, and their associations for NHS-funded procedures in England, covering a period that includes the COVID-19 pandemic.</p><p><strong>Methods: </strong>Data from the National Joint Registry and Hospital Episode Statistics were linked to identify patients who underwent primary total hip replacement (THR) and total or unicompartmental (partial) knee replacement (TKR/UKR) in England between January 2010 and March 2022. LOS was analysed using flexible parametric models to estimate median values over time, with subsequent adjustment to examine associations between changing patient characteristics. Trends in 30-day readmission rates were also analysed.</p><p><strong>Results: </strong>From 2010 to 2022, median LOS decreased from 4.26 days (95% CI 4.22 to 4.30) to 2.75 days (95% CI 2.74 to 2.77) for THR, from 4.35 days (95% CI 4.32 to 4.39) to 2.91 days (95% CI 2.90 to 2.92) for TKR, and from 3.2 days (95% CI 3.16 to 3.25) to 1.91 days (95% CI 1.89 to 1.95) for UKR. Variability also decreased. There were no increases in crude 30-day readmission rates. Trends in patient demographics showed increasing comorbidity, obesity, male sex, affluence, and use of the independent sector, all of which were associated with LOS and had the overall effect of slightly attenuating its reduction. Significant changes in patient characteristics occurred around the time of the COVID-19 pandemic but have since resumed previous trends.</p><p><strong>Conclusions: </strong>Patients in England now typically stay fewer than three days for total hip or knee replacement and under two days for partial knee replacement. Despite demographic trends towards characteristics associated with longer LOS, reductions have occurred independently of these changes, suggesting potential for further shortening. However, as these diverging trends continue, ensuring equitable access to surgery will be increasingly important.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"561"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Day case hip and knee replacement in England: a population-based cohort study using linked National Joint Registry and Hospital Episode Statistics data.","authors":"Jonathan M R French, Kevin Deere, Adrian Sayers, Michael R Whitehouse","doi":"10.1186/s12916-025-04280-y","DOIUrl":"https://doi.org/10.1186/s12916-025-04280-y","url":null,"abstract":"<p><strong>Background: </strong>In response to rising demand, disruptions from the COVID-19 pandemic, and the need for improved cost-effectiveness, the way hip and knee replacements are being delivered is rapidly changing. Increasingly, they are being performed as day case procedures without an overnight stay in hospital. This study assessed the safety of this for a national cohort of NHS-funded procedures in England.</p><p><strong>Methods: </strong>Data from the National Joint Registry, Hospital Episode Statistics, and Civil Registration of Deaths databases were linked to identify patients who underwent total hip replacement (THR) and total or unicompartmental knee replacement (TKR/UKR) in England between 2010 and 2022. Outcomes including 30-day readmissions, 90-day serious adverse events, and 1-year reoperations were compared between day case and one-day stay inpatients using adjusted flexible parametric survival models.</p><p><strong>Results: </strong>The study included 7485 day case and 60,747 one-day stay inpatient procedures. Day case surgery was associated with a higher risk of 30-day readmission for THR (adjusted relative risk (RR) 1.28, 95% CI 1.07 to 1.53) and TKR (RR 1.28, 95% CI 1.10 to 1.48). A learning curve was observed where the first 6-day case THRs and the first 4-day case TKRs per unit carried significantly higher readmission risk. There were no differences in 90-day serious adverse events. However, day case TKR was associated with an increased risk of reoperation within 1 year (RR 1.50, 95% CI 1.15 to 1.96; NNTH 84), most commonly manipulation under anaesthesia (MUA). No significant differences were found for UKR.</p><p><strong>Conclusions: </strong>Day case UKR appears safe. Day case THR is generally safe, and although there is a higher risk of readmission in the first six procedures at each unit, other safety outcomes are not different. However, day case TKR carries an increased risk of reoperation, mainly for MUA which is typically performed for postoperative stiffness.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"564"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mortality and risk factors of small vulnerable newborns in 32 low- and middle-income countries.","authors":"Yizhao Huang, Hongling Zhang, Zhaoying Xiong, Yiqing Lv, Zhenxian Jia, Hongxiu Liu, Wei Xia, Shunqing Xu, Tian Chen, Yuanyuan Li","doi":"10.1186/s12916-025-04406-2","DOIUrl":"https://doi.org/10.1186/s12916-025-04406-2","url":null,"abstract":"<p><strong>Background: </strong>In 2022, 2.3 million neonatal deaths occurred globally, the majority of which were in low- and middle-income countries (LMICs). Preterm birth, small for gestational age (SGA), and low birth weight (LBW) are leading causes of neonatal mortality. The Small Vulnerable Newborn (SVN) framework was introduced to unify preterm birth, SGA, and LBW under a single concept. SVNs face significant mortality risks and are predominantly found in LMICs. Understanding the prevalence, mortality risks, and associated factors of SVNs is essential for targeted intervention efforts.</p><p><strong>Methods: </strong>This study analyzed nationally representative survey data from the Demographic and Health Surveys (DHSs) conducted between 2008 and 2022 in 32 LMICs, covering 197,405 weighted live births among mothers aged 15-49 years. SVN prevalence, neonatal mortality, infant mortality, and associated risk factors were examined using modified Poisson regression and multinomial logistic regression. Population attributable fractions (PAFs) estimated the contribution of modifiable factors.</p><p><strong>Results: </strong>The overall SVN prevalence was 23.91% across 32 LMICs. Preterm-SGA showed the highest mortality risks compared to term-nonSGA newborns (neonatal: adjusted RR = 17.51 [95% CI, 12.95-23.67]; infant: adjusted RR = 11.86 [95% CI, 9.20-15.29]). Preterm-nonSGA contributed most to overall mortality (neonatal PAF: 11.72%; infant PAF: 8.15%). Risk patterns varied by subtypes: first parity was primary for preterm-nonSGA (PAF: 14.25%), poverty for term-SGA (PAF: 7.95%), while both insufficient antenatal care (< 4 visits) and first parity were major contributors for preterm-SGA (PAF: 22.68% and 20.41%). Adolescent pregnancy showed the strongest association with overall SVNs (adjusted RR = 1.37 [95% CI, 1.33-1.40]).</p><p><strong>Conclusions: </strong>SVNs remain a significant public health challenge in LMICs, with distinct risk patterns among subtypes suggesting the importance of targeted interventions focusing on antenatal care, socioeconomic factors and adolescent pregnancy prevention.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"558"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating transthyretin with atrial morpho-functional phenotypes and atrial fibrillation risk, and the modifying role of BMI.","authors":"Nan Zhang, Ziheng Jia, Jinhua Zhao, Xuyao Han, Jie Liu, Gary Tse, Jiandong Zhou, Kang-Yin Chen, Gregory Y H Lip, Tong Liu","doi":"10.1186/s12916-025-04391-6","DOIUrl":"https://doi.org/10.1186/s12916-025-04391-6","url":null,"abstract":"<p><strong>Background: </strong>Low circulating transthyretin (TTR) concentration has been suggested as a biomarker of transthyretin tetramer instability, a prerequisite for the development of transthyretin cardiac amyloidosis. This study aimed to evaluate the associations between circulating TTR levels with incident atrial fibrillation (AF) and other arrhythmias.</p><p><strong>Methods: </strong>This study used data from the UK Biobank. Participants with available TTR data and without prior arrhythmias were included. The primary outcome was new-onset AF. The secondary outcomes were new-onset supraventricular arrhythmias (SVA), bradyarrhythmias, cardiac block, and ventricular arrhythmias (VA). Multivariable Cox regression was applied to evaluate the associations between circulating TTR levels with arrhythmia outcomes.</p><p><strong>Results: </strong>A total of 40,723 participants (mean age 56.7 ± 8.2 years; 55% women) were included. After adjusting for potential confounders, one standard deviation (SD) decrease in TTR levels was associated with an increased risk of incident AF (HR 1.06, 95% CI 1.02-1.11). Furthermore, significant associations between low TTR with atrial structural remodeling were observed, manifesting as increased left atrial volume index (β 0.51, 95% CI 0.09-0.92) and right atrial volume index (β 0.87, 95% CI 0.39-1.40). In addition, there was a significant association between lower TTR levels with higher incident SVA risk, but not for bradyarrhythmias, cardiac block, or VA. A consistently significant interaction effect was identified between TTR levels and BMI for the risk of AF, SVA, bradyarrhythmias, and cardiac block (all P_interaction < 0.05), with lower TTR levels being significantly associated with a higher risk of AF (HR 1.15, 95% CI 1.06-1.26), SVA (HR 1.15, 95% CI 1.06-1.25), bradyarrhythmias (HR 1.17, 95% CI 1.05-1.30), and cardiac block (HR 1.15, 95% CI 1.02-1.29) among individuals with a BMI < 25 kg/m². In addition, carriers of likely pathogenic or pathogenic TTR variants (LP/P) had lower levels of plasma TTR compared with noncarriers, as well as higher arrhythmia risks, especially for non-Val142Ile carriers.</p><p><strong>Conclusions: </strong>Lower circulating TTR concentrations were associated with higher risk of incident AF. Exposure to low TTR and low BMI may be associated with a higher risk of AF, SVA, bradyarrhythmias, and cardiac block.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"557"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The burden of endometriosis on quality of life in Danish women: an analysis of the Danish Blood Donor Study.","authors":"Lisette J A Kogelman, Dorte Rytter, Lone Hummelshoj, Karina Ejgaard Hansen, Ulrik Bak Kirk, Juliane Lyng Beauchamp, Jakob Thaning Bay, Mie Topholm Bruun, Nanna Brøns, Christian Erikstrup, Bitten Aagaard, Bertram Dalskov Kjerulff, Christina Mikkelsen, Susan Mikkelsen, Sisse Rye Ostrowski, Ole Birger Pedersen, Erik Sørensen, Henrik Ullum, Anne Karmisholt Grosen, Christian Lodberg Hvas, Valgerdur Steinthorsdottir, Kari Stefansson, Karina Banasik, Palle Duun Rohde, Henriette Svarre Nielsen, Mette Nyegaard","doi":"10.1186/s12916-025-04398-z","DOIUrl":"https://doi.org/10.1186/s12916-025-04398-z","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis is a complex condition with a wide range of comorbidities. It is widely underdiagnosed, with a diagnostic delay of 4 to 10 years, potentially leading to worsened disease progression and a higher burden of comorbidities affecting quality of life. Understanding the link between endometriosis and its comorbidities is essential for improving early detection of the disease.</p><p><strong>Methods: </strong>We analysed data from 953 women with a clinical diagnosis of endometriosis and 23,652 age-matched female controls enrolled in the Danish Blood Donor Study, using a case-control design. Participants completed one to four questionnaires covering a wide range of potential comorbidities; genetic data were available for a subset of participants. First, we compared the potential comorbidities between women with endometriosis and controls. Next, we investigated whether a polygenic score (PGS) for endometriosis was associated with those comorbidities. Lastly, we investigated whether women with a high genetic burden of endometriosis (highest PGS decile) experienced similar comorbidities to those diagnosed with endometriosis.</p><p><strong>Results: </strong>Women with endometriosis experienced challenges in conception, gastrointestinal symptoms, and disturbed sleep patterns, compared to age-matched controls. The endometriosis PGS showed to be a predictor for endometriosis (OR per unit PGS = 1.43, 95% CI = 1.32-1.55). Gastrointestinal symptoms were also nominally associated with the endometriosis PGS, suggesting shared genetic pathways. Women without a diagnosis of endometriosis but with a high genetic burden of endometriosis did not suffer from the same wide range of comorbidities as women diagnosed with endometriosis.</p><p><strong>Conclusions: </strong>Our findings highlight the complex genetic and clinical relationships between endometriosis and its comorbidities, emphasizing the need for future research investigating potential endometriosis subtypes.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"560"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large language models in clinical trials: applications, technical advances, and future directions.","authors":"Anqi Lin, Zhihan Wang, Aimin Jiang, Li Chen, Chang Qi, Lingxuan Zhu, Weiming Mou, Wenyi Gan, Dongqiang Zeng, Mingjia Xiao, Guangdi Chu, Shengkun Peng, Hank Z H Wong, Lin Zhang, Hengguo Zhang, Xinpei Deng, Yaxuan Wang, Jian Zhang, Quan Cheng, Bufu Tang, Peng Luo","doi":"10.1186/s12916-025-04348-9","DOIUrl":"https://doi.org/10.1186/s12916-025-04348-9","url":null,"abstract":"<p><strong>Background: </strong>As clinical trials scale up and grow more complex, researchers are facing mounting challenges, including inefficient participant recruitment, complex data management, and limited risk monitoring. These issues not only increase the workload for clinical researchers but also compromise trial reliability and safety, potentially elevating the risk of trial failure. Large language models (LLMs), as an emerging technology in natural language processing (NLP), exhibit notable advantages across various tasks, such as information extraction and relation classification.</p><p><strong>Main text: </strong>With domain-specific pre-training and fine-tuning, LLMs present promising potential in clinical trial tasks such as automated patient-trial matching and the extraction and processing of trial data, which are anticipated to reduce time and financial costs. Additionally, they offer valuable insights for scientific rationale, medical decision-making, and trial endpoint prediction. In this context, an increasing number of studies have begun to explore the applications of LLMs in the design and conduct of clinical trials.</p><p><strong>Conclusion: </strong>This paper provides a review of LLM applications in clinical trials with an emphasis on real-world integration. Comparative advantages over traditional NLP models, technical limitations, and future implementation challenges are also discussed. This narrative review aims to highlight the potential of LLMs in clinical trial workflows and clarify key challenges and future directions.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"563"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein translation dysregulation and immune cell evasion mediated by IFN and immunoproteasome downregulation define metastatic clones in HPV-related cancer of the oropharynx.","authors":"Venessa T Chin, Walter Muskovic, Rachael A McCloy, Drew R Neavin, Jose Alquicira-Hernandez, Himanshi Arora, Anne Senabouth, Kavitha Krishna Sudhakar, Patricia Keith, Eleanor Spenceley, Dominik Kaczorowski, Peter Floros, Brett Leavers, Julia A Crawford, Richard Gallagher, Joseph E Powell","doi":"10.1186/s12916-025-04392-5","DOIUrl":"https://doi.org/10.1186/s12916-025-04392-5","url":null,"abstract":"<p><strong>Background: </strong>Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is increasing in prevalence, but the drivers of metastasis remain poorly understood, which impacts the ability to personalise management decisions. Much of the genomic research to date focuses on the HPV-negative population. Here, we utilise single-cell and spatial single-cell techniques to understand the drivers of metastasis.</p><p><strong>Methods: </strong>Patients with HPV-positive OPC and cervical lymph node metastases treated with curative surgery had matched samples from the primary and lymph nodes collected for research. Single-cell RNA sequencing, single-cell spatial sequencing (Visium) and in-situ spatial platforms were performed. Cancer clones were delineated using inferred copy number variation. Expression phenotypes and interactions with the tumour microenvironment were compared between the metastasising and non-metastasising cancer clones.</p><p><strong>Results: </strong>Individual cancer clones have varied abilities to metastasise and undergo clonal expansion in the lymph node, with only a subset of clones present in the primary expanding in the lymph node. Four mechanisms were identified as defining the metastatic phenotype, including protein translation adaptation, immunoproteasome dysfunction and immune evasion, suppression of the IFN immune response and cap-independent protein translation.</p><p><strong>Conclusions: </strong>This research elucidates multiple mechanisms driving the expansion of cancer clones in HPV-positive oropharyngeal cancer. By detailing the roles of translational adaptation, immunoproteasome dysfunction, suppression of the interferon immune response and cap-independent protein translation, we provide insights into how these processes contribute to immune evasion and tumour survival.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"559"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of sitagliptin vs. placebo on bone mineralization in women with type 2 diabetes: the SLowDOWN (SitagLiptin in Diabetes for Osteoporosis in WomeN) randomized clinical trial.","authors":"Ilaria Barchetta, Tiziana Filardi, Sara Dule, Flavia Agata Cimini, Federica Sentinelli, Elisabetta Romagnoli, Giulia Passarella, Enrico Bleve, Alessandro Oldani, Vittorio Venditti, Emanuela Anastasi, Orietta Gandini, Nicola Napoli, Antonio Nicolucci, Andrea Lenzi, Marco Giorgio Baroni, Susanna Morano, Maria Gisella Cavallo","doi":"10.1186/s12916-025-04363-w","DOIUrl":"https://doi.org/10.1186/s12916-025-04363-w","url":null,"abstract":"<p><strong>Background: </strong>Women with type 2 diabetes have an increased risk of bone fragility and fractures. Experimental models suggest that dipeptidyl peptidase-4 inhibitors (DPP4-Is) may have protective effects on bone, but clinical data remain limited, and randomized trials targeting bone Outcomes are lacking. This study aimed to evaluate the efficacy and safety of 52 weeks of oral sitagliptin treatment in improving bone Outcomes in women with type 2 diabetes.</p><p><strong>Methods: </strong>This multicenter, phase III, superiority, double-blind, randomized, placebo-controlled trial enrolled 132 women with type 2 diabetes in monotherapy with metformin and stable glycemic control. Participants were recruited from diabetes Outpatient clinics at Sapienza University of Rome, Italy, and were randomly assigned to receive sitagliptin or placebo for 52 weeks. The main outcome was a change in bone mineral density (BMD) and bone turnover biomarkers. Both intention-to-treat (ITT) and per-protocol (PP) analyses were conducted.</p><p><strong>Results: </strong>Treatment with sitagliptin preserved the total proximal femur BMD T score over 52 weeks (estimated mean difference: - 0.02; 95% confidence interval: - 0.07; 0.03; p = 0.46), whereas the placebo group showed a significant reduction (estimated mean difference: - 0.13; 95% confidence interval: - 0.19; - 0.07; p < 0.0001). The between-group difference was significant in favor of sitagliptin (estimated mean difference: 0.11; 95% confidence interval: 0.03; 0.19; p = 0.0063). No significant differences were detected in other skeletal sites or bone turnover markers. PP analysis confirmed the results obtained in the ITT analysis. Compared with the placebo, sitagliptin significantly reduced the levels of inflammatory mediators involved in bone metabolism. No within- or between-group differences in glucose control at 52 weeks were reported. No serious adverse events were reported; five mild to moderate adverse events occurred and were equally distributed between the two groups.</p><p><strong>Conclusions: </strong>Sitagliptin treatment was associated with preservation of total hip T score in women with type 2 diabetes, without consistent effects on other bone sites or turnover markers. These findings suggest a potential additional benefit of sitagliptin beyond blood glucose control and warrant confirmation in longer-term studies, also including populations at higher fracture risk.</p><p><strong>Trial registration: </strong>EudraCT number: 2018-000859-40 (registered 15 March 2018); ClinicalTrials.gov identifier: NCT06770894 (retrospectively registered).</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"23 1","pages":"562"},"PeriodicalIF":8.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}