medRxiv : the preprint server for health sciences最新文献

{"title":"Representation of Older Adults and Women in Randomized Trials of Non-Invasive Imaging for Chest Pain.","authors":"Phillip Lim, Tansu Eris, Leslee J Shaw, Laura Gelfman, Annetine Gelijns, Alan Moskowitz, Emilia Bagiella, Fay A Lin, Deepak L Bhatt, Gregg Stone, R Sean Morrison, David Cohen, Michael Nanna, Karen Alexander, Krishna K Patel","doi":"10.1101/2025.04.23.25326261","DOIUrl":"https://doi.org/10.1101/2025.04.23.25326261","url":null,"abstract":"<p><strong>Background: </strong>Non-invasive imaging is widely used both for initial diagnosis and to guide management of ischemic heart disease (IHD). Older adults and women with IHD may have different responses to imaging as well as to treatments and outcomes that follow compared with younger adults and men. We aimed to study the representation of older adults and women in randomized controlled trials (RCT) of non-invasive imaging among patients with acute and stable chest pain.</p><p><strong>Methods: </strong>We conducted a systematic search to identify RCTs evaluating non-invasive, imaging-guided diagnosis and management for IHD that were published before September 1, 2023. Participation-to-Prevalence Ratio (PPR) was estimated for women and age subgroups of <65, 65-74, ≥75 years. PPR of <0.8, 0.8-1.2, and >1.2 indicated underrepresentation, appropriate representation, and overrepresentation, respectively.</p><p><strong>Results: </strong>Among 53 RCTs, sex and age breakdown were available in 53 (n=55,893) and 21 trials (n=35,503), respectively. The median age across all trials was 57.4 years [IQR: 55.0- 60.2]. Participants aged <65 years were overrepresented with a median PPR 2.13 [IQR: 1.73- 2.43], while those aged 65-74 years and ≥75 years were underrepresented with median PPRs of 0.74 [IQR: 0.56-0.83] and 0.21 [IQR: 0.11-0.33], respectively. Women were adequately represented with a median PPR of 1.2 [1.06-1.32].</p><p><strong>Conclusion: </strong>While women were appropriately represented, adults 65 years or older, especially those ≥75 years, were under-represented in these trials. Future RCTs on non-invasive imaging should target enrollment of older adults to ensure generalizability of results to this growing population.</p><p><strong>Clinical perspective: </strong>In a systematic review of 53 randomized controlled trials of non-invasive imaging for chest pain published before September 1, 2023 (n=55,893 participants), adults aged 65 years and older, especially those aged 75 years and above, were significantly underrepresented, whereas women had representation proportional to prevalence estimates. These findings highlight an urgent need to increase enrollment of older adults in future imaging trials to ensure broader applicability and relevance of study results.</p><p><strong>Abstract figure: </strong></p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056589","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":"Advance Warning and Response Systems in Kenya: A Scoping Review.","authors":"Lisa M Were, Jenifer A Otieno, Moriasi Nyanchoka, Perpetua W Karanja, Dalmas Omia, Philip Ngere, Eric Osoro, M Kariuki Njenga, Mercy Mulaku, Isaac Ngere","doi":"10.1101/2025.04.23.25326250","DOIUrl":"https://doi.org/10.1101/2025.04.23.25326250","url":null,"abstract":"<p><strong>Introduction: </strong>Infectious diseases (IDs) cause approximately 13.7 million deaths globally. The Kenyan Advance Warning and Response Systems (AW&RS) against ID outbreaks is a core capacity of the 2005 International Health Regulations and a key indicator of health security. We mapped evidence on Kenya's AW&RS and their enablers, and barriers for successfully detecting IDs, including climate-sensitive IDs.</p><p><strong>Methods: </strong>We searched Cochrane Library, MEDLINE, EMBASE, Web of Science, Africa Index Medicus, and SCOPUS before August 26th, 2024. We also searched for grey literature on the Google Scholar search engine alongside the main repositories of Kenyan Universities. Two independent reviewers conducted study selection, while one reviewer extracted data. Discrepancies were resolved through discussion. Results were synthesised narratively and thematically.</p><p><strong>Results: </strong>The search yielded 4,379 records from databases and 1,363 articles from websites, university repositories, and citations; we included 166 articles in the analysis. Integrated Disease Surveillance and Response (IDSR) and cohort surveillance systems were the most common (37.2%). Most studies were concentrated in Nairobi County (25.7%) and reported on malaria (23.6%). Most systems (82.4%) monitored the disease burden and outbreaks using hospital-based data (35.1%) and automated alert mechanisms (27.7%). National bulletins report a temporal association between environmental factors and disease prevalence. Malaria, Rift Valley Fever (RVF), and cholera cases increased with higher precipitation, lower temperatures and increased vegetative index. AW&RS used the accuracy and reliability of the model prediction to measure the system's performance. Effectiveness was evaluated based on system acceptability and timeliness. Health system factors were predominant, with 121 enablers and 127 barriers. Key enablers included skilled personnel (13 studies), whereas inadequate finances were a major barrier (21 studies).</p><p><strong>Conclusion: </strong>Most AW&RS were IDSR and cohort-based surveillance. Climate changes have resulted in observed trends in diseases such as malaria and RVF, but further studies are needed to determine causal links. Insufficient funding hinders the effective implementation of AW&RS. Future research should assess the cost drivers influencing system effectiveness.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996109","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":"Histology-Based Virtual RNA Inference Identifies Pathways Associated with Metastasis Risk in Colorectal Cancer.","authors":"Gokul Srinivasan, Minh-Khang Le, Zarif Azher, Xiaoying Liu, Louis Vaickus, Harsimran Kaur, Fred Kolling, Scott Palisoul, Laurent Perreard, Ken S Lau, Keluo Yao, Joshua Levy","doi":"10.1101/2025.04.22.25326170","DOIUrl":"https://doi.org/10.1101/2025.04.22.25326170","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a major health concern, with over 150,000 new diagnoses and more than 50,000 deaths annually in the United States, underscoring an urgent need for improved screening, prognostication, disease management, and therapeutic approaches. The tumor microenvironment (TME)-comprising cancerous and immune cells interacting within the tumor's spatial architecture-plays a critical role in disease progression and treatment outcomes, reinforcing its importance as a prognostic marker for metastasis and recurrence risk. However, traditional methods for TME characterization, such as bulk transcriptomics and multiplex protein assays, lack sufficient spatial resolution. Although spatial transcriptomics (ST) allows for the high-resolution mapping of whole transcriptomes at near-cellular resolution, current ST technologies (e.g., Visium, Xenium) are limited by high costs, low throughput, and issues with reproducibility, preventing their widespread application in large-scale molecular epidemiology studies. In this study, we refined and implemented Virtual RNA Inference (VRI) to derive ST-level molecular information directly from hematoxylin and eosin (H&E)-stained tissue images. Our VRI models were trained on the largest matched CRC ST dataset to date, comprising 45 patients and more than 300,000 Visium spots from primary tumors. Using state-of-the-art architectures (UNI, ResNet-50, ViT, and VMamba), we achieved a median Spearman's correlation coefficient of 0.546 between predicted and measured spot-level expression. As validation, VRI-derived gene signatures linked to specific tissue regions (tumor, interface, submucosa, stroma, serosa, muscularis, inflammation) showed strong concordance with signatures generated via direct ST, and VRI performed accurately in estimating cell-type proportions spatially from H&E slides. In an expanded CRC cohort controlling for tumor invasiveness and clinical factors, we further identified VRI-derived gene signatures significantly associated with key prognostic outcomes, including metastasis status. Although certain tumor-related pathways are not fully captured by histology alone, our findings highlight the ability of VRI to infer a wide range of \"histology-associated\" biological pathways at near-cellular resolution without requiring ST profiling. Future efforts will extend this framework to expand TME phenotyping from standard H&E tissue images, with the potential to accelerate translational CRC research at scale.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056298","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":"Leveraging electronic health records to examine differential clinical outcomes in people with Alzheimer's Disease.","authors":"Shruthi Venkatesh, Linshanshan Wang, Michele Morris, Mohammed Moro, Ratnam Srivastava, Yunqing Han, Riddhi Patira, Sarah Berman, Oscar Lopez, Shyam Visweswaran, Tianrun Cai, Tianxi Cai, Zongqi Xia","doi":"10.1101/2025.04.22.25326230","DOIUrl":"https://doi.org/10.1101/2025.04.22.25326230","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) carries a high societal burden inequitably distributed across demographic groups.</p><p><strong>Objective: </strong>To examine differences in readily ascertainable clinical outcomes of AD decline among demographic groups.</p><p><strong>Methods: </strong>Leveraging the electronic health record (EHR) data (1994-2022) of patients with ≥1 diagnosis code for AD or related dementia from two large healthcare systems, we applied a knowledge graph-guided unsupervised phenotyping algorithm to predict AD diagnosis status and validated using gold-standard chart-reviewed and registry-derived diagnosis labels. After excluding patients with <24 months of data or who were admitted to nursing homes prior to AD diagnosis, we performed survival analyses at each healthcare system to assess the time to two readily ascertainable clinical outcomes of AD decline ( <i>i.e.,</i> nursing home admission, death), stratified by demographic groups and accounting for baseline covariates ( <i>e.g.,</i> age, gender, race, ethnicity, healthcare utilization, and comorbidities). We then performed a fixed-effects meta-analysis of the survival analysis data from both healthcare systems.</p><p><strong>Results: </strong>The AD diagnosis phenotyping algorithm demonstrated high accuracy in identifying AD patients across both healthcare systems (AUROC score range: 0.835-0.923). Of the 34,181 AD patients in both healthcare systems (62% women, 90% non-Hispanic White, 80.39±9.28 years of age at AD diagnosis), 32% were admitted to nursing homes and 50% died during follow- up. In the fixed-effect meta-analysis, non-Hispanic White patients had a lower risk of nursing home admission (HR[95% CI]=0.825[0.776-0.877], <i>p</i> <0.001) and higher risk of death (HR[95% CI]=1.381[1.283-1.487], <i>p</i> <.0001) than racial and ethnic minorities. There was no difference between women and men in their risk of nursing home admission (HR[95% CI]=1.008[0.967-1.050], <i>p</i> =.762), but women had a lower risk of death (HR[95% CI]=0.873[0.837-0.910], <i>p</i> <.0001) than men.</p><p><strong>Conclusion: </strong>This study creates two large EHR-based AD cohorts and adds to the real-world evidence of demographic differences in clinical AD decline, which could potentially inform individual clinical management and future public health policies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036572","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":"Heterozygous and Homozygous <i>RFC1 AAGGG</i> Repeat Expansions are Common in Idiopathic Peripheral Neuropathy.","authors":"Zitian Tang, Sinem S Ovunc, Elle Mehinovic, Simone Thomas, Jenna Ulibarri, Zefan Li, Dustin Baldridge, Carlos Cruchaga, Matt Johnson, Jeffrey Milbrandt, Brian Callaghan, Ahmet Höke, Peter K Todd, Sheng Chih Jin","doi":"10.1101/2025.04.18.25325809","DOIUrl":"https://doi.org/10.1101/2025.04.18.25325809","url":null,"abstract":"<p><strong>Objective: </strong>Biallelic intronic AAGGG repeat expansions in <i>RFC1</i> cause Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome and may also contribute to isolated sensory neuropathy. The clinical significance of both heterozygous and biallelic <i>RFC1</i> expansions in more diverse patient populations remains unclear-partly due to the absence of accurate, user-friendly computational tools specifically tailored for tandem repeat analysis.</p><p><strong>Methods: </strong>To discern the relationship between <i>RFC1</i> expansions and idiopathic peripheral neuropathy (iPN), we performed whole-genome sequencing (WGS) followed by PCR-based confirmation in a large, well-characterized U.S. cohort consisting of 788 iPN patients (369 pure small fiber neuropathy (SFN), 266 sensorimotor, 144 pure sensory, and 9 pure motor). We developed an integrative pipeline combining ExpansionHunter Denovo and Expansion Hunter coupled with unsupervised clustering to reliably detect and genotype <i>RFC1</i> expansions from short-read WGS data, achieving 98.2% concordance with repeat-primed PCR based validation.</p><p><strong>Results: </strong>Biallelic <i>RFC1</i> expansions were absent in 879 controls but present in 2.8% of iPN patients (Fisher's exact <i>p</i> = 5.9×10 ^-8 ), including 6.2% of pure sensory, 2.2% of SFN, and 1.5% of sensorimotor neuropathy, indicating that motor nerve involvement should not exclude patients from <i>RFC1</i> repeat screening. We also observed a markedly increased frequency of monoallelic expansions in iPN compared to controls (13.2% versus 2.5%; Fisher's exact <i>p</i> = 3.4×10 ^-17 ), without evidence of secondary mutations or expansions on the other allele.</p><p><strong>Interpretation: </strong>Our approach provides a robust, cost-effective method for detecting <i>RFC1</i> expansions from WGS data. Our findings indicate that both heterozygous and homozygous AAGGG repeat expansions in <i>RFC1</i> can contribute to development of iPN.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065530","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":"Artificial Intelligence-based Diagnosis of Kaposi Sarcoma using Photographs in Dark-skinned Patients.","authors":"Sarah J Coates, Feng Yang, Cody Hill, Zhiyun Xue, Sivaramakrishnan Rajaraman, Aggrey Semeere, Racheal Ayanga, Miriam Laker-Oketta, Helen Byakwaga, Robert Lukande, Matthew Semakadde, Micheal Kanyesigye, Megan Wenger, Philip LeBoit, Timothy McCalmont, Ethel Cesarman, David Erickson, Toby Maurer, Sameer Antani, Jeffrey Martin","doi":"10.1101/2025.04.21.25326060","DOIUrl":"https://doi.org/10.1101/2025.04.21.25326060","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Advanced-stage disease at the time of diagnosis, with resultant high mortality, is among the most urgent issues for HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa. Lack of access to skilled clinical personnel and histopathologic technology in the region contribute to diagnostic delays and advanced stage at diagnosis. Accordingly, new paradigms for KS diagnosis are needed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To evaluate the accuracy of artificial intelligence (AI)-based interpretation of digital surface images of skin lesions to diagnose KS among dark-skinned patients in Uganda.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Cross-sectional study of consecutive participants referred to skin biopsy services in Uganda because of clinical suspicion of KS. Lesions were photographed using a digital camera, and punch biopsies were obtained. Histopathologic interpretation was considered the gold standard. Using training (∼70% of images) and validation (∼10% of images) sets, we developed a prediction model using a rule-based combination of YOLO (You Only Look Once) version 5 and 8 object detection classifiers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;Free-of-charge skin biopsy services.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;Consecutive sample of 482 individuals were evaluated due to clinical suspicion of KS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes: &lt;/strong&gt;Sensitivity, specificity, positive and negative predictive value (with accompanying 95% confidence intervals) of the AI-based prediction model in a test set (∼20% of images). The accuracy of a dermatologist's visual interpretation of images was also described.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;472 participants (1385 images) were evaluable. Of these, 36% were female, median age was 34 years, and 94% had HIV; 332 had KS, and 140 had no KS by histopathology. In the test set, the AI-derived prediction model achieved 89% sensitivity (85%-94%) and 51% specificity (40%-61%) for diagnosing KS; positive predictive value was 81% (75%-86%) and negative predictive value was 67% (55%-78%). A dermatologist evaluating the same images, with emphasis on sensitivity, achieved sensitivity of 93% (89%-96%) and specificity of 19% (11%-28%).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;Among dark-skinned patients in Uganda with skin lesions suspicious for KS, evaluation of digital surface images by an AI-based prediction model produced moderate accuracy for diagnosing KS. While currently inadequate for clinical use, this inaugural assessment is sufficiently promising to justify evaluation of larger datasets and evolving technologies to determine if accuracy can be improved.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;&lt;b&gt;Question:&lt;/b&gt; Can an artificial intelligence (AI)-based prediction model be developed from digital images to accurately distinguish Kaposi sarcoma (KS) from non-KS in dark-skinned patients?&lt;b&gt;Findings:&lt;/b&gt; Evaluation of digital images of skin lesions from patients in Uganda by an AI-based prediction model produced ","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063567","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":"Phenome-wide comorbidity network analysis reveals clinical risk patterns in enthesopathy and enthesitis.","authors":"Yonghyun Nam, Dong-Gi Lee, Jakob Woerner, Se-Hwan Lee, Min Ji Lee, Sung-Han Jo, Jaeun Jung, Su Chin Heo, Chris Hyunchul Jo, Dokyoon Kim","doi":"10.1101/2025.04.21.25326169","DOIUrl":"https://doi.org/10.1101/2025.04.21.25326169","url":null,"abstract":"<p><strong>Background: </strong>Enthesopathy and enthesitis, including rotator cuff disease and other tendon disorders, represent a heterogeneous group of musculoskeletal conditions with complex etiologies. Understanding how systemic health profiles influence their onset remains a critical challenge in musculoskeletal medicine.</p><p><strong>Methods: </strong>We conducted a large-scale, phenome-wide comorbidity analysis using longitudinal electronic health records (EHR) from 432,757 UK Biobank participants. Incident cases of peripheral enthesopathies were compared to controls across 434 baseline disease phenotypes. A directed ego network was constructed to link significantly associated comorbidities to the target condition using odds ratio-based associations. Unsupervised clustering via UMAP and DBSCAN identified data-driven comorbidity clusters, which were consolidated into unified endotypes-interpreted as distinct systemic profiles contributing to disease risk. Additionally, metapath-based trajectory analysis was applied to uncover temporally structured multimorbidity chains leading to disease onset.</p><p><strong>Results: </strong>We identified 183 baseline conditions significantly associated with the future development of enthesopathy (FDR < 0.05). Network clustering revealed eight comorbidity clusters, which were consolidated into four unified endotypes: Metabolic-Psychosomatic, Inflammatory-Multisystem, Mechanical-Injury-driven, and Aging-Intervention-related. Metapath analysis uncovered common three-step disease trajectories, such as metabolic-infectious-musculoskeletal and inflammatory skin-to-joint progressions, highlighting potential mechanistic pathways. These endotypes showed diverse clinical features but shared biological coherence, suggesting that different systemic health profiles can converge to drive tendon-related disease.</p><p><strong>Conclusions: </strong>This study introduces a scalable framework for identifying systemic multimorbidity patterns underlying enthesopathy and enthesitis using phenome-wide comorbidity networks. By integrating network clustering and metapath analysis, we uncover interpretable, data-driven endotypes that may inform individualized risk assessment and targeted care strategies. These findings contribute to the growing field of biobank-scale disease modeling and offer a foundation for precision approaches in musculoskeletal medicine.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004472","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":"Homelessness, type of homelessness, and risk of cause-specific mortality: a systematic review and meta-analysis of 116 studies comprising 2,563,633 homeless people and 129,292,553 population controls.","authors":"J White, Y Moriarty, M Lau, R Cannings-John, A Palmer, A L Weightman, M Kiseleva, G D Batty","doi":"10.1101/2025.04.22.25326193","DOIUrl":"https://doi.org/10.1101/2025.04.22.25326193","url":null,"abstract":"<p><strong>Background: </strong>Homelessness might increase the risk of premature mortality, but evidence is scarce, imprecise, and is mostly limited to rough sleepers as opposed to more common types of homelessness.</p><p><strong>Methods: </strong>Published studies were retrieved through a systematic search of MEDLINE, Embase PsycINFO and Scopus from inception to December 2024. Unpublished data were identified from open-access data archives. We used random-effects meta-analysis to combine effect estimates from published and unpublished data. This review is registered at PROSPERO (CRD42023430984).</p><p><strong>Findings: </strong>We included 116 studies from Europe, the USA, South America, Africa, Asia, and Australia. The meta-analysis of all-cause mortality comprised 110,892,271 people (1,618,049 exposed to homelessness). The risk of all-cause mortality was significantly increased in people exposed to homelessness (Relative risk [RR] 2·12 [95% CI 1·91-2·57], p<0·001, I²=99·7%), with risks similar in men (3·88, 2·69-5·06) and women (3·46, 2·17-4·70). This risk was most elevated in people who had slept rough (7·63, 3·29-11·97), followed by those who used low-cost hotels (5·18, 1·14-9·23), then hostels (3·44, 2·10-4·77). In analyses of cause-specific mortality (26,291,900 people, 1,202,205 homeless), summary RR estimates were elevated for 33 of the 36 (92%) causes of death and highest for deaths due to psychoactive substance use disorder (21·36, 14·44-31·67), accidental injuries (13·15, 5·46-31·69), drug-overdose (10·80, 6·37-18·31), and those that are alcohol-related (5·93, 1·10-22·04). No evidence of publication bias was detected.</p><p><strong>Interpretation: </strong>Homeless people experience an increased risk of premature mortality across an array of health outcomes. That the most extreme inequities have an interrelated aetiology suggests a cross-sectoral medical, housing, and social care response is required.</p><p><strong>Funding: </strong>The Centre for Homelessness Impact, Health and Care Research Wales, UK Medical Research Council (MR/P023444/1) and the US National Institute on Aging.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048929","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":"Phase Ib Study of Enzalutamide with Venetoclax in Patients with Metastatic Castration-Resistant Prostate Cancer.","authors":"Stuthi Perimbeti, Anmbreen Jamroze, Dharmesh Gopalakrishnan, Rohit Jain, Changchuan Jiang, Julianne L Holleran, Robert A Parise, Robert Bies, David Quinn, Kristopher Attwood, Xiaozhuo Liu, Jason S Kirk, Jan H Beumer, Dean G Tang, Gurkamal Chatta","doi":"10.1101/2025.04.22.25326208","DOIUrl":"https://doi.org/10.1101/2025.04.22.25326208","url":null,"abstract":"<p><strong>Purpose: </strong>Castration and enzalutamide induce BCL-2 to drive therapy resistance in prostate cancer (PCa). We conducted a phase Ib trial to test that metastatic castration-resistant PCa (mCRPC) can be effectively targeted by combining enzalutamide with the BCL-2 inhibitor venetoclax.</p><p><strong>Experimental design: </strong>This phase Ib single-arm trial of enzalutamide (160 mg/d) with venetoclax in patients with progressive mCRPC assessed dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Three dose levels (DL) of venetoclax (DL1 400 mg/d; DL2 600 mg/d; and DL3 800 mg) were evaluated using a 3+3 design. We also analyzed enzalutamide and venetoclax pharmacokinetics and conducted pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) to determine the impact of venetoclax on BCL-2 expression.</p><p><strong>Results: </strong>A total of 10 patients were enrolled across 3 DL and no DLT was observed. Mean duration on treatment was 29 weeks (range: 8-140 weeks). Treatment-related adverse events (TRAEs) were mostly grade 1-2, and Grade 3 TRAEs included hypertension (20%), fatigue (10%), and thrombocytopenia (10%). 1/10 (10%) attained PSA50 response and 4/10 (40%) had stable disease. Estimated median overall survival (OS) was 19 months (95% CI 5-28 months) and median time to next systemic therapy (TNST) was 5 months (95% CI 1-35 months). Pharmacokinetic results revealed sub-therapeutic plasma levels of venetoclax. Pharmacodynamic studies demonstrated that venetoclax enhanced BCL-2β generation and promoted BCL-2 degradation.</p><p><strong>Conclusions: </strong>Enzalutamide with venetoclax has an acceptable toxicity profile in patients with mCRPC. Despite sub-therapeutic venetoclax levels, the treatment elicited pharmacodynamic and clinical response in a subset of patients.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061549","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":"Quantification of Modifiable Risk Factors in Monoclonal Gammopathy of Undetermined Significance Progression to Multiple Myeloma.","authors":"Mei Wang, Byron Sigel, Lawrence Liu, John H Huber, Mengmeng Ji, Martin W Schoen, Kristen M Sanfilippo, Theodore S Thomas, Graham A Colditz, Shi-Yi Wang, Su-Hsin Chang","doi":"10.1101/2025.04.21.25326164","DOIUrl":"https://doi.org/10.1101/2025.04.21.25326164","url":null,"abstract":"<p><strong>Purpose: </strong>Multiple myeloma (MM) is the most common plasma cell dyscrasia in the United States with notably significant health disparities. MM is preceded by an asymptomatic precursor monoclonal gammopathy of undetermined significance (MGUS). Studies have identified several risk factors for the progression of MGUS to MM; however, the relative contributions of these remain unknown. Particularly, understanding the contribution among those modifiable factors may inform MM prevention.</p><p><strong>Methods: </strong>This study quantified these contributions by estimating the adjusted population attributable fractions (aPAF) of modifiable risk factors for MM among the Veteran population with MGUS.</p><p><strong>Results: </strong>Among all evaluated risk factors, excess body mass index (BMI ≥25 kg/m ² ) was the leading factor (Black: aPAF=27.0%, 95% CI 19.3-33.9%; White: 27.1%, 95% CI 20.3-33.4%; All: aPAF=27.1%, 95% CI: 22.0-31.8%).</p><p><strong>Conclusion: </strong>Our study highlights the potential for weight management as a key strategy in reducing the risk of progression to MM in Black and White patients diagnosed with MGUS.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060044","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}