Communications medicine最新文献

{"title":"Multi-model assurance analysis showing large language models are highly vulnerable to adversarial hallucination attacks during clinical decision support.","authors":"Mahmud Omar, Vera Sorin, Jeremy D Collins, David Reich, Robert Freeman, Nicholas Gavin, Alexander Charney, Lisa Stump, Nicola Luigi Bragazzi, Girish N Nadkarni, Eyal Klang","doi":"10.1038/s43856-025-01021-3","DOIUrl":"10.1038/s43856-025-01021-3","url":null,"abstract":"<p><strong>Background: </strong>Large language models (LLMs) show promise in clinical contexts but can generate false facts (often referred to as \"hallucinations\"). One subset of these errors arises from adversarial attacks, in which fabricated details embedded in prompts lead the model to produce or elaborate on the false information. We embedded fabricated content in clinical prompts to elicit adversarial hallucination attacks in multiple large language models. We quantified how often they elaborated on false details and tested whether a specialized mitigation prompt or altered temperature settings reduced errors.</p><p><strong>Methods: </strong>We created 300 physician-validated simulated vignettes, each containing one fabricated detail (a laboratory test, a physical or radiological sign, or a medical condition). Each vignette was presented in short and long versions-differing only in word count but identical in medical content. We tested six LLMs under three conditions: default (standard settings), mitigating prompt (designed to reduce hallucinations), and temperature 0 (deterministic output with maximum response certainty), generating 5,400 outputs. If a model elaborated on the fabricated detail, the case was classified as a \"hallucination\".</p><p><strong>Results: </strong>Hallucination rates range from 50 % to 82 % across models and prompting methods. Prompt-based mitigation lowers the overall hallucination rate (mean across all models) from 66 % to 44 % (p < 0.001). For the best-performing model, GPT-4o, rates decline from 53 % to 23 % (p < 0.001). Temperature adjustments offer no significant improvement. Short vignettes show slightly higher odds of hallucination.</p><p><strong>Conclusions: </strong>LLMs are highly susceptible to adversarial hallucination attacks, frequently generating false clinical details that pose risks when used without safeguards. While prompt engineering reduces errors, it does not eliminate them.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"330"},"PeriodicalIF":5.4,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769410","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":"Synergistic H&E and IHC image analysis by AI predicts cancer biomarkers and survival outcomes in colorectal and breast cancer.","authors":"Yating Cheng, Norsang Lama, Ming Chen, Eghbal Amidi, Mohammadreza Ramzanpour, Md Ashequr Rahman, Joanne Xiu, Anthony Helmstetter, Lauren Dickman, Jennifer R Ribeiro, Hassan Ghani, Matthew Oberley, David Spetzler, George W Sledge","doi":"10.1038/s43856-025-01045-9","DOIUrl":"10.1038/s43856-025-01045-9","url":null,"abstract":"<p><strong>Background: </strong>Recent advancements in immunotherapy, particularly pembrolizumab, have shown promising results in treating metastatic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). Accurate detection of predictive biomarkers, such as microsatellite instability (MSI)/mismatch repair deficiency (MMRd) and programmed death-ligand 1 (PD-L1), is key to efficacy of these treatments. Traditional methods like immunohistochemistry (IHC) and next-generation sequencing are effective but are labor intensive and require subjective interpretation.</p><p><strong>Methods: </strong>We developed a dual-modality transformer-based model for predicting MSI/MMRd and PD-L1 status using hematoxylin & eosin and IHC stained whole slide images. We evaluated the model using area under the receiver operating curve (AUROC). Time-on-treatment (TOT) and overall survival (OS) were derived from insurance claims and analyzed by Kaplan-Meier method. Hazard ratios (HR) were determined using the Cox proportional hazard model.</p><p><strong>Results: </strong>Our AI framework achieves clinical-grade performance, with AUROC exceeding 0.97 for MSI/MMRd prediction in CRC and 0.96 for PD-L1 prediction in breast cancer. Patients with biomarker-positive model predictions demonstrated prolonged TOT and OS when treated with pembrolizumab. For breast cancer patients, the model's predictions were superior to PD-L1 IHC in stratifying patients with improved outcomes on pembrolizumab, suggesting a reevaluation of existing PD-L1 status thresholds.</p><p><strong>Conclusions: </strong>This study promotes the integration of advanced AI tools in clinical pathology, aiming to enhance the precision and efficiency of cancer biomarker evaluation and offering a customizable framework for varied clinical scenarios. Our model enhances predictive accuracy, integrating features from both staining methods, and exhibits superior prognostic precision compared to current biomarker assessments.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"328"},"PeriodicalIF":5.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765861","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":"Comparative ocular outcomes of tirzepatide versus other anti-obesity medications in people with obesity.","authors":"Yu-Nan Huang, Jo-Ching Chen, Pin-Hung Li, Min-Yen Hsu, Chun-Wen Cheng, Gideon Meyerowitz-Katz, Pen-Hua Su","doi":"10.1038/s43856-025-01066-4","DOIUrl":"10.1038/s43856-025-01066-4","url":null,"abstract":"<p><strong>Background: </strong>Obesity affects over one billion people worldwide and is associated with ocular complications, yet comparative effects of newer anti-obesity medications on eye health remain poorly understood. We examine ocular health outcomes among individuals with obesity receiving Tirzepatide, Semaglutide, Phentermine/Topiramate, Naltrexone/Bupropion, or Phentermine monotherapy.</p><p><strong>Methods: </strong>This propensity-score matched cohort study analyzed TriNetX US network data from November 2023 through April 2025. The study included matched pairs of obese individuals with a BMI ≥ 27 kg/m², comparing ocular outcomes between different anti-obesity medications. Primary outcomes included cataracts, oculomotor binocular dysfunction, visual disturbances, dry eye disease, ametropic accommodative dysfunction, and visual issues with blindness, assessed through Cox proportional hazards models with Bonferroni correction. Sensitivity analyses included BMI ≥ 30 kg/m² populations, subgroup stratification by clinical characteristics, and negative control outcomes to assess residual bias.</p><p><strong>Results: </strong>Here, we show that among 25,060 matched pairs comparing Tirzepatide with Semaglutide, no differences emerge across ocular outcomes. When compared with Naltrexone/Bupropion, Tirzepatide users show lower rates of cataracts (HR 0.46, 95% CI 0.23-0.92, p = 0.025) and oculomotor dysfunction (HR 0.31, 95% CI 0.16-0.60, p = 2.3 × 10^-4). Semaglutide demonstrates similar patterns. Both medications show favorable profiles for visual disturbances, with Tirzepatide demonstrating lower rates versus Phentermine (HR 0.45, 95% CI 0.31-0.68, p = 7 × 10^-5). Sensitivity analyses in the BMI ≥ 30 kg/m² population yield consistent results.</p><p><strong>Conclusions: </strong>Newer anti-obesity medications demonstrate differential associations with ocular outcomes compared to traditional agents. These findings may inform clinical decision-making regarding medication selection in obesity management, though prospective studies remain necessary to establish causal relationships.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"329"},"PeriodicalIF":5.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765860","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":"Pantethine ameliorates dilated cardiomyopathy features in PPCS deficiency disorder in patients and cell line models.","authors":"Fangfang Zhang, Tatjana Dorn, Barbara Gnutti, Yair Anikster, Sarah Kuebler, Rebecca Ahrens-Nicklas, Rachel Gosselin, Shamima Rahman, Ronen Durst, Enrica Zanuttigh, Miriam A Güra, Christine M Poch, Anna B Meier, Karl-Ludwig Laugwitz, Hans-Joachim Schüller, Ana C Messias, Ody C Sibon, Dario Finazzi, Alyssa Rippert, Dong Li, Kristen Truxal, Deipanjan Nandi, Brent C Lampert, Mildrid Yeo, Alice Gardham, Batel Nissan, Smadar Horowitz Cederboim, Alessandra Moretti, Arcangela Iuso","doi":"10.1038/s43856-025-01017-z","DOIUrl":"10.1038/s43856-025-01017-z","url":null,"abstract":"<p><strong>Background: </strong>PPCS deficiency disorder (PPCS DD) is an ultra-rare, autosomal recessive form of dilated cardiomyopathy (DCM) caused by pathogenic variants in PPCS, which encodes the enzyme catalyzing the second step in the coenzyme A (CoA) biosynthesis pathway. To date, only six patients worldwide have been identified.</p><p><strong>Methods: </strong>Whole-exome sequencing was performed to identify pathogenic PPCS variants in affected individuals. Protein stability was assessed by Western blotting. CoA levels were quantified using a microplate-based assay in patient-derived fibroblasts, cardiac progenitor cells, and cardiomyocytes. Functional evaluation of cardiac cells and engineered heart patches was conducted to investigate contractile performance and arrhythmogenicity. Pantethine was tested as a potential therapeutic agent both in vitro and through long-term clinical follow-up in patients.</p><p><strong>Results: </strong>Causative PPCS variants are identified in six individuals with DCM and variable associated features, including neuromuscular and neurological symptoms. Identified variants lead to reduced PPCS protein stability and decreased cellular CoA levels. Cardiac cells exhibit impaired contractility and arrhythmias, which are partially rescued by pantethine treatment. Clinically, patients receiving pantethine show sustained improvement over time.</p><p><strong>Conclusions: </strong>Our study expands the genetic and clinical spectrum of PPCS deficiency disorder, identifying six new cases with diverse phenotypes. Functional investigations reveal reduced CoA levels and dysfunction in patient-derived cardiac cells. Pantethine treatment shows promise in partially rescuing DCM phenotypes, both in vitro and in patients. However, complete reversal may require early intervention. These findings underscore the importance of timely diagnosis and treatment in PPCS DD. Future research should focus on optimizing pantethine supplementation and exploring additional therapies to enhance CoA levels and cardiac function in affected individuals.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"323"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762479","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":"A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding.","authors":"Chen-Yi Wang, Martin Philpott, Darragh P O'Brien, Anne Ndungu, Jessica Malzahn, Marina Maritati, Neelam Mehta, Vicki Gamble, Beatriz Martinez-Burgo, Sarah Bonham, Roman Fischer, Kurtis Garbutt, Christian M Becker, Sanjiv Manek, Adrian L Harris, Frank Sacher, Maik Obendorf, Nicole Schmidt, Jörg Müller, Thomas M Zollner, Krina T Zondervan, Benedikt M Kessler, Udo Oppermann, Adam P Cribbs","doi":"10.1038/s43856-025-01051-x","DOIUrl":"10.1038/s43856-025-01051-x","url":null,"abstract":"<p><strong>Background: </strong>Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood.</p><p><strong>Methods: </strong>To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients.</p><p><strong>Results: </strong>In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding.</p><p><strong>Conclusions: </strong>This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"318"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755201","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":"A cross-national analysis of demographic variation in self-rated mental health across 22 countries.","authors":"Chukwuemeka N Okafor, Ducel Jean-Berluche, Jason Paltzer, Elizabeth Kwon, Nikolitsa Grigoropoulou, Tyler J VanderWeele, Byron R Johnson","doi":"10.1038/s43856-025-01038-8","DOIUrl":"10.1038/s43856-025-01038-8","url":null,"abstract":"<p><strong>Background: </strong>Mental health is a critical aspect of overall well-being, encompassing not only the absence of mental disorders but also positive attributes such as stress management, and healthy relationships. Prior studies suggest that self-rated mental health varies across different cultures and sociodemographic characteristics. However, most studies on demographic variations in self-rated mental health have been conducted within specific countries or regions, leaving a gap in our understanding of how these factors influence mental health across different cultural contexts.</p><p><strong>Methods: </strong>To address this gap, we leveraged a dataset of over 200,000 individuals from 22 countries to examine the distribution of self-rated mental health among key demographic variables such as age, gender, marital status, employment, education, and religious service attendance.</p><p><strong>Results: </strong>Our findings reveal substantial country variations in self-rated mental health, measured as the mean score on a single-item Likert scale ranging from 0 (Poor) to 10 (Excellent). Participants in Tanzania, Kenya and Nigeria report the highest self-rated mental health scores, while those in Japan, Türkiye, and the United Kingdom report the lowest scores. Some demographic patterns - such as lower self-rated mental health among younger age groups and females, and higher self-rated mental health among those reporting regular religious service attendance - remain consistent across most countries. However, other patterns, such as the distribution of self-rated mental health by marital status, vary by country.</p><p><strong>Conclusions: </strong>These descriptive findings highlight the need for context-specific mental health strategies and call for future research to identify social and structural factors of self-rated mental health.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"320"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762474","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":"Advanced 4-chamber echocardiography techniques enable clinically matched precise characterization of heart disease progression in mice.","authors":"Ege Kacira, Mariam F Oueis, Nawal H Tamimi, Sarah L Sturgill, Xianyao Xu, Thomas J Hund, Mark T Ziolo, Yuchi Han, Isabelle Deschênes, Ji-Dong Fu","doi":"10.1038/s43856-025-01036-w","DOIUrl":"10.1038/s43856-025-01036-w","url":null,"abstract":"<p><strong>Background: </strong>Transthoracic echocardiography remains the primary non-invasive method for assessing cardiac function in clinical practice. However, technical challenges in acquiring accurate apical 4-chamber-long-axis (A4CLAX) views have historically limited mouse studies to left ventricle (LV) assessment using parasternal short-axis (SAX) M-mode imaging.</p><p><strong>Methods: </strong>To overcome this limitation, we developed an A4CLAX imaging approach for mice and performed a comparative analysis with established echocardiographic methods to assess cardiac function in healthy mouse hearts. To evaluate the utility of A4CLAX in detecting disease progression, we longitudinally monitored cardiac function of C57BL/6 N mice (male and female) following severe transverse aortic constriction (TAC), using both long-axis biplane (LAX-BP) and conventional SAX M-mode assays.</p><p><strong>Results: </strong>Here we show that LAX-BP echocardiography demonstrates volumetric accuracy comparable to cardiac magnetic resonance (CMR) and detects significant LV functional decline within the first week post-TAC-changes that are not clearly captured by M-mode imaging. Importantly, A4CLAX further enables clinically relevant Doppler assessments, allowing detection of mitral valve regurgitation, restrictive filling patterns, and desynchronized valve motion. It also facilitates right ventricle (RV) functional evaluation and improved atrial visualization, revealing progressive enlargement of the left atrial (LA) and left atrial appendage (LAA) associated with worsening diastolic function.</p><p><strong>Conclusions: </strong>The A4CLAX imaging approach provides clinically comparable, comprehensive echocardiographic evaluation in murine models and offers improved sensitivity for detecting subtle changes in cardiac performance during disease progression.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"325"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762477","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":"The impact of prematurity on pediatric asthma morbidity and indices with environmental pollution and genetic susceptibility.","authors":"Jelte Kelchtermans, Frank Mentch, Huiqi Qu, Sharon A McGrath-Morrow, Hakon Hakonarson","doi":"10.1038/s43856-025-01041-z","DOIUrl":"10.1038/s43856-025-01041-z","url":null,"abstract":"<p><strong>Background: </strong>Prematurity, fine particulate matter (PM_2.5), and genetic variables are linked to asthma incidence in children. However, to capture the contributions of these variables and their involvement in asthma pathogenesis, we need to understand how they interact. Here, we aim to assess the impact of prematurity on asthma exacerbations and explore interactions with PM_2.5 exposure and genetic risk.</p><p><strong>Methods: </strong>Pediatric patients with asthma and at least 5 years of follow-up data were identified from the Center for Applied Genomics biobank. Subjects were classified as full term (FT), late preterm (LPT), or extremely/very preterm (E/VPT). PM_2.5 exposure was calculated as the proportion of days between diagnosis and last recorded follow up exceeding 8 µg/m³, and a polygenic risk score (sPRS) was used to assess genetic PM_2.5 susceptibility. Regression models evaluated predictors of asthma exacerbations.</p><p><strong>Results: </strong>Among 5982 patients, 16% are LPT and 4% E/VPT. The latter patient group experiences 20.5% more exacerbations than FT patients (P = 0.04). E/VPT patients have 43.3% more exacerbations per unit increase in PM_2.5 exposure (P = 0.001) and LPT patients with a high sPRS experienced 24.0% more exacerbations (P = 0.04) compared to what would be expected from the sum of the independent effects. Additionally, LPT and E/VPT patients have 24% (P = 0.012) and 61% (P = 0.005) higher odds of exacerbations beyond 6 years of age, respectively.</p><p><strong>Conclusions: </strong>Interactions between prematurity, PM_2.5 exposure, and genetic susceptibility exacerbate asthma morbidity, underscoring the urgent need for targeted interventions in high-risk populations with overlapping vulnerabilities.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"324"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762539","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":"Sex-specific DNA methylation associations with circulating urate levels and BCG-induced urate changes.","authors":"Zhaoli Liu, Tania O Crișan, Cancan Qi, Manoj Kumar Gupta, Xuan Liu, Simone J C F M Moorlag, Valerie A C M Koeken, Xun Jiang, Mohamad Ballan, L Charlotte J de Bree, Vera P Mourits, Xu Gao, Andrea Baccarelli, Joel Schwartz, Frank Pessler, Carlos A Guzmán, Yang Li, Mihai G Netea, Leo A B Joosten, Cheng-Jian Xu","doi":"10.1038/s43856-025-01044-w","DOIUrl":"10.1038/s43856-025-01044-w","url":null,"abstract":"<p><strong>Background: </strong>Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner.</p><p><strong>Methods: </strong>We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis.</p><p><strong>Results: </strong>215 CpG sites are associated with serum urate in males, while 5 CpG sites are associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increase after BCG vaccination, and baseline DNA methylation is associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males are enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites are related to lipid and glucose metabolism.</p><p><strong>Conclusions: </strong>Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights highlight the importance of personalized and sex-specific approaches in medicine.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"321"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762538","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":"A machine learning approach to population pharmacokinetic modelling automation.","authors":"Sam Richardson, Itziar Irurzun Arana, Andrzej Nowojewski, Diansong Zhou, Jacob Leander, Weifeng Tang, Richard Dearden, Megan Gibbs","doi":"10.1038/s43856-025-01054-8","DOIUrl":"10.1038/s43856-025-01054-8","url":null,"abstract":"<p><strong>Background: </strong>Population pharmacokinetic (PopPK) models are crucial for understanding drug behaviour across populations, yet traditional development is often labour-intensive and slow. This study demonstrates an automated, out-of-the-box approach for popPK model development, leveraging optimisation algorithms implemented using pyDarwin to efficiently handle a diverse range of extravascular drugs.</p><p><strong>Methods: </strong>We proposed a generic model search space for drugs with extravascular administration and developed a penalty function to discourage over-parameterisation whilst ensuring plausible parameter values. Optimisation within the model search space was conducted using pyDarwin, employing Bayesian optimisation with a random forest surrogate combined with exhaustive local search. This approach was evaluated on one synthetic and four clinical datasets, with results compared to manually developed models.</p><p><strong>Results: </strong>Here we show that the automated approach reliably identifies model structures comparable to manually developed expert models in less than 48 h on average (40-CPU, 40 GB environment) while evaluating fewer than 2.6% of the models in the search space. Ablation experiments demonstrate the importance of our penalty function in selecting plausible models, and the benefit of global search algorithms in avoiding local minima.</p><p><strong>Conclusions: </strong>These results demonstrate that a single penalty function and model space can be used within the pyDarwin framework to automatically identify model structures for a diverse range of drugs. By reducing the configuration required at search setup, this approach simplifies the process, potentially making the technology more accessible to users. Adoption of automatic model search can accelerate popPK analysis, improve model quality, increase reproducibility, and reduce manual effort for modellers.</p>","PeriodicalId":72646,"journal":{"name":"Communications medicine","volume":"5 1","pages":"327"},"PeriodicalIF":5.4,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12314194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762476","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}