medRxiv : the preprint server for health sciences最新文献

{"title":"Interstitial Cystitis: a phenotype and rare variant exome sequencing study.","authors":"Joshua E Motelow, Ayan Malakar, Sarath Babu Krishna Murthy, Miguel Verbitsky, Atlas Kahn, Elicia Estrella, Louis Kunkel, Madelyn Wiesenhahn, Jaimee Becket, Natasha Harris, Richard Lee, Rosalyn Adam, Krzysztof Kiryluk, Ali G Gharavi, Catherine A Brownstein","doi":"10.1101/2025.02.16.25322147","DOIUrl":"https://doi.org/10.1101/2025.02.16.25322147","url":null,"abstract":"<p><p>Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood and underdiagnosed syndrome of chronic bladder/pelvic pain with urinary frequency and urgency. Though IC/BPS can be hereditary, little is known of its genetic etiology. Using the eMERGE data, we confirmed known phenotypic associations such as gastroesophageal reflux disease and irritable bowel syndrome and detected new associations, including osteoarthrosis/osteoarthritis and Barrett's esophagus. An exome wide ultra-rare variants analysis in 348 IC/BPS and 11,981 controls extended the previously reported association with <i>ATP2C1</i> and <i>ATP2A2,</i> implicated in Mendelian desquamating skin disorders, but did not provide evidence for other previously proposed pathogenic pathways such as bladder development, nociception or inflammation. Pathway analysis detected new associations with \"anaphase-promoting complex-dependent catabolic process\", the \"regulation of MAPK cascade\" and \"integrin binding\". These findings suggest perturbations in biological networks for epithelial integrity and cell cycle progression in IC/BPS pathogenesis, and provide a roadmap for its future investigation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545534","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":"Alterations in the hepatic microenvironment following direct-acting antiviral therapy for chronic hepatitis C.","authors":"Daniel E Millian, Esteban Arroyave, Timothy G Wanninger, Santhoshi Krishnan, Daniel Bao, Jared R Zhang, Arvind Rao, Heidi Spratt, Monique Ferguson, Vincent Chen, Heather L Stevenson, Omar A Saldarriaga","doi":"10.1101/2025.02.17.25321289","DOIUrl":"https://doi.org/10.1101/2025.02.17.25321289","url":null,"abstract":"<p><p><b>Background and aims.</b> The first direct-acting antivirals (DAAs) to treat the viral hepatitis C (HCV) became available in 2011. Despite numerous clinical studies of patient outcomes after treatment, few have evaluated changes in the liver microenvironment. Despite achieving sustained virologic response (SVR), patients may still experience adverse outcomes like cirrhosis and hepatocellular carcinoma. By comparing gene and protein expression in liver biopsies collected before and after treatment, we sought to determine whether specific signatures correlated with disease progression and adverse clinical outcomes. <b>Methods.</b> Biopsies were collected from 22 patients before and after DAA treatment. We measured ∼770 genes and used multispectral imaging with custom machine learning algorithms to analyze phenotypes of intrahepatic macrophages (CD68, CD14, CD16, MAC387, CD163) and T cells (CD3, CD4, CD8, CD45, FoxP3). <b>Results.</b> Before DAA treatment, patients showed two distinct gene expression patterns: one with high pro-inflammatory and antiviral gene expression and another with weaker expression. Patients with adverse outcomes exhibited significantly (p<0.05) more inflammatory activity and had more advanced fibrosis stages in their baseline biopsies than those with liver disease resolution. Patients who achieved SVR had significantly decreased liver enzymes, reduced inflammatory scores, and restored type 1 interferon pathways similar to controls. However, after DAA treatment, patients with persistently high gene expression (67%, pre-hot) still had significantly worse outcomes (p<0.049) despite achieving SVR. A persistent lymphocytic infiltrate was observed in a subset of these patients (76.5%). After therapy, anti-inflammatory macrophages (CD16+, CD16+CD163+, CD16+CD68+) increased, and T cell heterogeneity was more pronounced, showing a predominance of helper and memory T cells (CD3+CD45RO+, CD4+CD45RO+, CD3+CD4+CD45RO+). <b>Conclusions.</b> Patients who have more inflamed livers and more advanced fibrosis before DAA treatment should be closely followed for the development of adverse outcomes, even after achieving SVR. We can enhance patient risk stratification by integrating gene and protein expression profiles with clinical data. This could identify those who may benefit from more intensive monitoring or alternative therapeutic approaches, inspiring a new era of personalized patient care.</p><p><strong>Lay summary: </strong>Direct-acting antiviral (DAA) therapy has dramatically improved the treatment of chronic HCV, making it curable for most people. This study determined gene and protein expression differences in the liver before and after treatment of HCV. These results will lead to a deeper understanding of the changes in the hepatic immune microenvironment with and without the virus present in the liver in hopes of improving patient surveillance, prognosis, and outcome in the future.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545538","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":"Mitochondrial DNA-Mediated Immune Activation After Resuscitation from Cardiac Arrest.","authors":"Tyler J Rolland, Emily R Hudson, Luke A Graser, Sumbule Zahra, Daniel Cucinotta, Swati D Sonkawade, Umesh C Sharma, Brian R Weil","doi":"10.1101/2025.02.14.25322318","DOIUrl":"https://doi.org/10.1101/2025.02.14.25322318","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Post-cardiac arrest syndrome (PCAS) is characterized by a robust inflammatory response that contributes to significant morbidity and mortality among patients resuscitated from sudden cardiac arrest (SCA). Mitochondrial DNA (mtDNA), with its bacterial-like genomic motifs, has been implicated as a damage-associated molecular pattern in other inflammatory contexts, but its role as a pro-inflammatory stimulus in PCAS has not been studied. Accordingly, the present study was designed to determine if PCAS is characterized by a rise in circulating mtDNA and, if so, whether mtDNA is selectively released, how it activates immune cells, and if targeting mtDNA-sensing pathways attenuates leukocyte activation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Plasma mtDNA and nuclear DNA (nucDNA) levels were measured in peripheral blood samples collected ∼4-hours post-ROSC from swine with PCAS (n=8) and patients hospitalized after resuscitation from out-of-hospital cardiac arrest (OHCA; n= 57). Additionally, &lt;i&gt;in vitro&lt;/i&gt; studies were performed where porcine peripheral blood mononuclear cells (PBMCs) were treated with mtDNA or extracellular vesicles (EVs) isolated from post-ROSC plasma. Pharmacological inhibitors were utilized to inhibit toll-like receptor 9 (TLR9)- and cyclic GMP-AMP synthase (cGAS)-mediated mtDNA sensing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A significant ∼250-fold elevation in circulating mtDNA was observed shortly after ROSC in swine despite negligible changes in circulating nucDNA, suggesting selective release of mtDNA in PCAS. This finding was corroborated in human OHCA survivors, in which circulating mtDNA was similarly elevated during the early post-ROSC period. Circulating mtDNA was largely encapsulated within EVs in swine and humans, suggesting a conserved mechanism of release across species. &lt;i&gt;In vitro&lt;/i&gt; studies demonstrated that PBMC internalization of mtDNA-containing-EVs was required for immune activation and promoted development of a pro-inflammatory leukocyte phenotype characterized by altered surface marker expression and increased release of TNFα, IL-1β, and IL-6. Disrupting EVs or degrading enclosed DNA attenuated these responses, which were partially restored upon reintroduction of mtDNA. Pharmacological blockade of TLR9 or cGAS pathways significantly reduced mtDNA-induced inflammation, providing insight regarding signaling pathways that may be targeted to modulate mtDNA-mediated immune activation in PCAS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;These novel findings demonstrate that brief whole-body ischemia and reperfusion in the context of resuscitation from SCA triggers selective mtDNA release, primarily within EVs, that acts as a potent driver of immune activation in PCAS. By linking EV-encapsulated mtDNA to TLR9 and cGAS activation, this study provides a foundation for the development of novel therapeutic interventions aimed at limiting mtDNA release or disrupting its downstream sensing pathways to enhance s","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545578","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":"Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations.","authors":"Xiaoyuan Zhong, Robert Mitchell, Christine Billstrand, Emma Thompson, Noboru J Sakabe, Ivy Aneas, Isabella M Salamone, Jing Gu, Anne I Sperling, Nathan Schoettler, Marcelo A Nóbrega, Xin He, Carole Ober","doi":"10.1101/2025.02.11.25322088","DOIUrl":"https://doi.org/10.1101/2025.02.11.25322088","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset asthma (COA). However, the causal variants, regulatory elements, and effector genes at these loci are largely unknown.</p><p><strong>Methods: </strong>We performed heritability enrichment analysis to determine relevant cell types for AOA and COA, respectively. Next, we fine-mapped putative causal variants at AOA and COA loci. To improve the resolution of fine-mapping, we integrated ATAC-seq data in blood and lung cell types to annotate variants in candidate <i>cis</i> -regulatory elements (CREs). We then computationally prioritized candidate CREs underlying asthma risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) in bronchial epithelial cells (BECs) and further validated a subset by luciferase assays. Combining chromatin interaction data and expression quantitative trait loci, we nominated genes targeted by candidate CREs and prioritized effector genes for AOA and COA.</p><p><strong>Results: </strong>Heritability enrichment analysis suggested a shared role of immune cells in the development of both AOA and COA while highlighting the distinct contribution of lung structural cells in COA. Functional fine-mapping uncovered 21 and 67 credible sets for AOA and COA, respectively, with only 16% shared between the two. Notably, one-third of the loci contained multiple credible sets. Our CRE prioritization strategy nominated 62 and 169 candidate CREs for AOA and COA, respectively. Over 60% of these candidate CREs showed open chromatin in multiple cell lineages, suggesting their potential pleiotropic effects in different cell types. Furthermore, COA candidate CREs were enriched for enhancers experimentally validated by MPRA in BECs. The prioritized effector genes included many genes involved in immune and inflammatory responses. Notably, multiple genes, including <i>TNFSF4</i> , a drug target undergoing clinical trials, were supported by two independent GWAS signals, indicating widespread allelic heterogeneity. Four out of six selected candidate CREs demonstrated allele-specific regulatory properties in luciferase assays in BECs.</p><p><strong>Conclusions: </strong>We present a comprehensive characterization of causal variants, regulatory elements, and effector genes underlying AOA and COA genetics. Our results supported a distinct genetic basis between AOA and COA and highlighted regulatory complexity at many GWAS loci marked by both extensive pleiotropy and allelic heterogeneity.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545531","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":"Intraoperative nerve imaging with sodium fluorescein.","authors":"Roy K Park, Bernardo A Arús, Jennifer Y Lee, Merle M Weitzenberg, Melissa C Lee, Mark S Nyaeme, Julia Barthel, Giuseppe Balsamo, Fred M Baik, Katie Speirs, Berit Blume, Metar Heller-Algazi, Andriy Chmyrov, Oliver Plettenburg, Uchechukwu C Megwalu, Jürgen Weitz, Marius Distler, Oliver T Bruns, Tulio A Valdez","doi":"10.1101/2025.02.08.25321923","DOIUrl":"https://doi.org/10.1101/2025.02.08.25321923","url":null,"abstract":"<p><p>Nerve damage during surgery is a common and serious complication, often leading to chronic pain, functional impairments, and diminished quality of life. However, existing methods for intraoperative nerve identification remain insufficient, especially for detecting small or hidden nerve branches. Here we present a new application of a clinically approved fluorescent agent, sodium fluorescein, to enhance nerve visualization during surgery. Utilizing both clinical and customized imaging systems, fluorescein remarkably improved nerve contrast, revealing structures undetectable with white light, including small branches embedded within tissues. With its established safety profile, low cost, and immediate clinical applicability, sodium fluorescein offers the potential to revolutionize surgical practice by minimizing nerve injuries and improving patient outcomes. Clinical Trial Registration: NCT06054178 .</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545558","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":"Change targets, messaging, and content delivery for a community-engaged social media campaign addressing HIV-related stigma in Peru: a qualitative study.","authors":"Alyson Nunez, Marguerite Curtis, Milagros Wong, Kristin A Kosyluk, Jerome T Galea, Molly F Franke, Renato A Errea","doi":"10.1101/2025.02.12.25321801","DOIUrl":"https://doi.org/10.1101/2025.02.12.25321801","url":null,"abstract":"<p><p>Mitigating HIV-related stigma is critical to improving HIV outcomes and reaching global HIV targets. We conducted formative community-engaged research to identify key characteristics of a social media campaign to address HIV-related stigma among youth in Lima, Peru. Focus groups and in-depth interviews with young people living with HIV (men who have sex with men, transgender women, sex workers, persons with perinatally-acquired HIV, cisgender women, and Venezuelan migrants), HIV advocates, and healthcare providers were carried out from November 2022 to July 2023. Audio recordings were transcribed verbatim and analysed for emergent themes using framework analysis. Two change targets were identified for campaign messaging: 1) changing how HIV and people living with HIV (PLWH) are perceived, and 2) changing attitudes and actions towards PLWH. Messages aligning with the first change target included education to raise awareness that HIV does not discriminate; HIV is a chronic, treatable condition; and \"undetectable equals untransmittable\" (U=U). Messages aligning with the second target included normalizing open conversations about HIV, encouraging support versus pity for PLWH, fostering unity among HIV-affected communities, and promoting inclusion of PLWH. Participants provided recommendations to achieve these messaging objectives, including how, to whom and by whom messages are delivered.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485138","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":"OMKar: optical map based automated karyotyping of genomes to identify constitutional abnormalities.","authors":"Siavash Raeisi Dehkordi, Zhaoyang Jia, Joey Estabrook, Jen Hauenstein, Neil Miller, Naz Güleray-Lafci, Jürgen Neesen, Alex Hastie, Alka Chaubey, Andy Wing Chun Pang, Paul Dremsek, Vineet Bafna","doi":"10.1101/2025.02.13.25322211","DOIUrl":"https://doi.org/10.1101/2025.02.13.25322211","url":null,"abstract":"<p><p>The whole genome karyotype refers to the sequence of large chromosomal segments that make up an individual's genotype. karyotype analysis, which includes descriptions of aneuploidies and other rearrangements is crucial for understanding genetic risk factors, for diagnosis, treatment decisions, and genetic counseling linked to constitutional disorders. The current karyotyping standard is based on microscopic examination of chromosomes, a complex process that requires high expertise and offers Mb scale resolution. Optical Genome Mapping (OGM) technology can identify large DNA lesions in a cost-effective manner. In this paper, we developed OMKar, a method that uses OGM data to create a virtual karyotype. OMKar processes Structural (SV) and Copy Number (CN) Variants as inputs and encodes them into a compact breakpoint graph. It recomputes copy numbers using Integer Linear Programming to maintain CN balance and then identifies constrained Eulerian paths representing entire donor chromosomes. In tests using 38 whole genome simulations of constitutional disorders, OMKar reconstructed the karyotype with 88% precision and 95% recall on SV concordance and 95% Jaccard score on CN concordance. We applied OMKar to 50 prenatal, 41 postnatal, and 63 parental samples from ten different sites. OMKar reconstructed the correct karyotype in 144 out of 154 samples, covering 25 of 25 aneuploidies, 32 of 32 balanced translocations, and 72 of 82 unbalanced variations. Detected constitutional disorders included Cri-du-chat, Wolf-Hirschhorn, Prader-Willi deletions, Down, and Turner syndromes. Importantly, it identified a plausible genetic mechanism for five cases of constitutional disorder that were not detected by other technologies. Together, these results demonstrate the robustness of OMKar for OGM-based karyotyping. OMKar is publicly available at https://github.com/siavashre/OMKar .</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485346","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":"Hematologic dynamics during pregnancy and their association with obstetric complications: a retrospective cohort study.","authors":"Veronica Tozzo, Rachel Petherbridge, Kaitlyn James, Sarah Hsu, Chloe Michalopoulos, Brody H Foy, Tanayott Thaweethai, Christopher Mow, Jacqueline Maya, Carolina Batlle Camero, Lydia Shook, Kathryn J Gray, Logan Mauney, John M Higgins, Camille E Powe","doi":"10.1101/2025.02.13.25322250","DOIUrl":"https://doi.org/10.1101/2025.02.13.25322250","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;Pregnancy alters hematologic state as measured by complete blood counts (CBC), but the longitudinal changes in CBC indices that define healthy pregnancies are not well established. Our objectives were (1) to define gestational age-specific reference intervals for CBCs and their longitudinal changes in a large United States-based cohort and (2) to use these reference intervals to examine associations between extreme CBC values and changes and risk of obstetric complications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design: &lt;/strong&gt;Retrospective cohort study including electronic health record-based discovery and validation cohorts.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Setting: &lt;/strong&gt;Academic medical center and affiliated health system in the United States between 1998 and 2022.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants: &lt;/strong&gt;Individuals with singleton pregnancies delivering after 30 weeks' gestation who presented for prenatal care prior to 20 weeks'. There were 45,992 pregnancies in the discovery cohort, 18% of whom had complications, and 50,603 in the validation cohort, 22% with complications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcome measures: &lt;/strong&gt;Composite outcome (hypertensive disorder of pregnancy, small for gestational age birthweight or preterm birth) and its individual components. We analyzed associations between CBC results and outcomes using generalized estimating equations for logistic regression with Bonferroni correction for multiple hypothesis testing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Hematocrit, hemoglobin, and red cell count values above their reference intervals were associated with increased risk of the composite obstetric complication: OR [95% CI] of 1.4 [1.2, 1.6] p=1.8 &lt;i&gt;x&lt;/i&gt; 10 &lt;sup&gt;-5&lt;/sup&gt; for hematocrit; 1.7[1.4, 1.9] p=1.4 &lt;i&gt;x&lt;/i&gt; 10 &lt;sup&gt;-10&lt;/sup&gt; for hemoglobin; and 1.6[1.4, 1.9] p=3.9×10 &lt;sup&gt;-9&lt;/sup&gt; for red cell count. Extreme increase in hemoglobin (&gt;0.67 g/dL) or red cell count (&gt;0.07 10 &lt;sup&gt;6&lt;/sup&gt; /mm &lt;sup&gt;3&lt;/sup&gt; ) between 7-14 weeks' and 26-29 weeks' gestation was associated with increased risk for preterm birth (OR [95% CI] for hemoglobin 2.0[1.6, 2.6] p=2 &lt;i&gt;x&lt;/i&gt; 10 &lt;sup&gt;-8&lt;/sup&gt; and red cell count: 2.1[1.7, 2.6] p=9 &lt;i&gt;x&lt;/i&gt; 10 &lt;sup&gt;-14&lt;/sup&gt; ). Reference intervals in this cohort were often wider than those previously published for mean red cell volume, mean red cell hemoglobin, red cell count, and mean red cell hemoglobin concentration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Elevated measures of red blood cell count and large intra-pregnancy increases in those measures are associated with subsequent obstetric complications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary box: &lt;/strong&gt;&lt;b&gt;What is already known on this topic:&lt;/b&gt; Pregnancy causes significant changes in hematologic state as measured by routine complete blood counts (CBCs).&lt;b&gt;What this study adds:&lt;/b&gt; We studied more than 95,000 pregnancies and found that elevations (both absolute and relative to baseline 1 &lt;sup&gt;st&lt;/sup&gt; trimester values) in hematocrit, hemoglobin, and red cell count are associated with ","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485257","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":"Explainable artificial intelligence for neuroimaging-based dementia diagnosis and prognosis.","authors":"Sophie A Martin, An Zhao, Jiongqi Qu, Phoebe Imms, Andrei Irimia, Frederik Barkhof, James H Cole","doi":"10.1101/2025.01.13.25320382","DOIUrl":"10.1101/2025.01.13.25320382","url":null,"abstract":"<p><strong>Introduction: </strong>Artificial intelligence and neuroimaging enable accurate dementia prediction, but 'black box' models can be difficult to trust. Explainable artificial intelligence (XAI) describes techniques to understand model behaviour and the influence of features, however deciding which method is most appropriate is non-trivial. Vision transformers (ViT) have also gained popularity, providing a self-explainable, alternative to traditional convolutional neural networks (CNN).</p><p><strong>Methods: </strong>We used T1-weighted MRI to train models on two tasks: Alzheimer's disease (AD) classification (diagnosis) and predicting conversion from mild-cognitive impairment (MCI) to AD (prognosis). We compared ten XAI methods across CNN and ViT architectures.</p><p><strong>Results: </strong>Models achieved balanced accuracies of 81% and 67% for diagnosis and prognosis. XAI outputs highlighted brain regions relevant to AD and contained useful information for MCI prognosis.</p><p><strong>Discussion: </strong>XAI can be used to verify that models are utilising relevant features and to generate valuable measures for further analysis.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049097","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":"Neoadjuvant chemotherapy response and genetic susceptibility in recently parous women with breast cancer.","authors":"Saya Dennis, Takahiro Tsukioki, Masha Kocherginsky, Andrea Keya Qi, Sarah DeHorn, Michael Gurley, Erica Wrubel, Yuan Luo, Seema Ahsan Khan","doi":"10.1101/2025.02.13.25322229","DOIUrl":"10.1101/2025.02.13.25322229","url":null,"abstract":"<p><strong>Introduction: </strong>Women with recent parity are at increased short-term breast cancer (BC) risk and face a worse prognosis. The effect of parity on response to neoadjuvant chemotherapy (NAC) is unstudied, and the influence of inherited susceptibility on parity-related short-term risk remains unclear.</p><p><strong>Methods: </strong>We conducted a retrospective case-cohort study among women aged ≤50 with non-metastatic BC diagnosed between 2010 and 2020 who underwent genetic testing and were treated at Northwestern Medicine. Associations between NAC response and recency of parity were evaluated using multivariate logistic regression, stratified by tumor biologic subtypes. Relationships between germline mutations, recency of parity, and BC were explored via multi-state modeling and linear regression.</p><p><strong>Results: </strong>Among 1,080 eligible women, 231 received NAC. Treatment response was poorer in parous women with triple negative tumors compared to nullipara, regardless of the recency of parity ( <i>P</i> <0.03). Among 122 women (11.3%) with detectable pathogenic mutations, adjusted analyses with both modeling approaches revealed no indications that <i>BRCA1/2</i> carriers had an increased hazard of BC diagnosis in the decade following recent parity, compared to nulliparous mutation carriers. For <i>BRCA2</i> and <i>PALB2</i> carriers, breast cancer diagnosis occurred less frequently in the post-partum intervals.</p><p><strong>Conclusion: </strong>We observed a poor response to NAC in parous TNBC patients compared to nullipara; effects of immunotherapy-based regimens deserve evaluation in the context of parity. Post-partum BC occurrence is not increased in <i>BRCA1/2</i> carriers; effects of rarer susceptibility genes may differ. These important effects of parity on BC in young women and those at genetic risk warrant larger prospective studies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485289","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}