medRxiv : the preprint server for health sciences最新文献

{"title":"Combinatorial effects of gene dosage, polygenic background and environment on complex traits.","authors":"Molly F Sacks, Marieke Klein, Tim B Bigdeli, Mart Kals, Matthew T Oetjens, Florian Bénitière, Jacquelyn Johnson, Adam Maihofer, Margit Nõukas, Michael Francis, Bryan Gorman, Iskander Said, Giulio Genovese, Georgios Voloudakis, Kyriacos Markianos, Murray Stein, Joel Gelernter, David H Ledbetter, Caroline M Nievergelt, Christa Lese Martin, Vincent-Raphaël Bourque, Omar Shanta, Jeffrey R MacDonald, Bhooma Thiruvahindrapuram, Mamad Ahangari, Anjali Srinivasan, James Guevara, Jessica H Hall, Josephine E Haddon, Claudia Vingerhoets, David Linden, Mieke M van Haelst, Marianne B M van den Bree, Carrie E Bearden, Raquel E Gur, T Blaine Crowley, Daniel E McGinn, Beverly S Emanuel, Elaine H Zackai, Ann Swillen, Thérèse van Amelsvoort, Jacob Vorstman, Anne S Bassett, Donna M McDonald-McGinn, Panos Roussos, Mihaela Aslan, Philip D Harvey, Sébastien Jacquemont, Saiju Pyarajan, Kelli Lehto, Peter M Visscher, Jonathan Sebat","doi":"10.64898/2026.04.30.26352063","DOIUrl":"https://doi.org/10.64898/2026.04.30.26352063","url":null,"abstract":"<p><p>Complex traits arise from the combined effects of rare and common genetic variation, development and environment, but resolving their joint contributions has been limited by statistical power. Here, we meta-analyze effects of recurrent copy number variants (CNVs), polygenic scores, sex, age and medications on height and body mass index in 1,447,001 individuals across 6 biobanks and clinical cohorts. CNVs show largely mirror dose-dependent effects of deletions and duplications on both traits, but a subset of loci exhibit asymmetric dose-responses on adult height, consistent with buffering of one allele but not the other. Polygenic background and medications combine with CNVs in ways broadly consistent with additivity. However, detailed analyses of loci at 16p11.2 and 22q11.2 reveal context-dependent effects that vary across development, physiology and sex. At 22q11.2, the net effect of a CNV reflects opposing and reinforcing contributions of multiple genes, providing a potential mechanism for buffering of dosage effects. These results indicate that genetic effects follow additive patterns in aggregate, while context-dependent deviations are widespread for specific loci.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848330","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":"Early-life dentine-based elemental biodynamics and cord blood telomere length.","authors":"Bhargavi Srinath, Rohitha Ravisekar, Kshitij Sachdev, Joseph Eggers, Libni Avib Torres Olascoaga, Nia McRae, Inessa Lopez, Chelsea A DeBolt, Aderonke Akinkugbe, Romana Ranchadiya, Martha M Téllez-Rojo, Chris Gennings, Robert B Wallace, Robert Wright, Rosalind J Wright, Manish Arora, Cecilia S Alcala, Manasi Agrawal, Jamil M Lane, Maria J Rosa, Shoshannah I Eggers, Vishal Midya","doi":"10.64898/2026.04.30.26351974","DOIUrl":"https://doi.org/10.64898/2026.04.30.26351974","url":null,"abstract":"<p><strong>Background: </strong>Leukocyte telomere length (LTL) from cord blood is a marker of biological aging and long-term systemic health. Exposure to essential and toxic metals has been shown to influence LTL in a sexually dimorphic manner. However, little is known about the interplay between early-life longitudinal biodynamic patterns of these elements and cord blood LTL, as well as potential sex differences.</p><p><strong>Methods: </strong>From an ongoing longitudinal birth cohort study in Mexico City, we used available tooth samples from 231 children (129 males and 102 females) to generate 16 elemental weekly time series of direct fetal intensities from the second trimester through four to five months after birth. We analyzed the dentine growth rings using Inductively Coupled Plasma Mass Spectrometry to generate time-resolved elemental intensities. The elements included were Li, Mg, Ca, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Cd, Sn, Ba, Pb, and Bi. LTL was measured in cord blood using qPCR. We used cross-recurrence quantification analysis and entropy-complexity-based measures to generate time-resolved features that quantify the synchronization of elemental biodynamics. A stability-selection approach using five-fold cross-validation of regularized ridge regression was used for feature selection, and covariate-adjusted linear models were used to estimate associations with LTL.</p><p><strong>Findings: </strong>The biodynamic interaction of Mg-Co and Mn-Sn was identified as the most stable feature among male and female children, respectively. In males, higher vertical entropy (i.e., a measure of higher variability) of Mg-Co temporal biodynamics was associated with shorter LTL (β[95%CI]: -0.9[-0.14,-0.03]; p-value<0.01), but not in females (β[95%CI]:-0.02[-0.10,0.06]; p-value=0.60); whereas higher recurrence rate (i.e., a measure of higher synchronicity) of Mn-Sn temporal biodynamics was associated with longer LTL (β[95%CI]: 0.09[0.02,0.16]; p-value=0.01), in females but not in males (β[95%CI], 0.03[-0.04, 0.09]; p-value=0.39).</p><p><strong>Interpretation: </strong>We demonstrate that time-varying multi-elemental synchronization of early-life elemental biodynamics, a potential marker of homeostatic balance, may be associated with cord blood-based telomere length in a sexual dimorphic manner.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848285","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":"Utilizing Intraindividual Cognitive Variability to Predict Early Neuronal Synuclein Disease Progression.","authors":"Hannah L Combs, Ryan Kurth, Anuprita Nair, Michele K York, Daniel Weintraub, David-Erick Lafontant, Chelsea Caspell-Garcia","doi":"10.1101/2025.10.21.25338482","DOIUrl":"https://doi.org/10.1101/2025.10.21.25338482","url":null,"abstract":"<p><strong>Background: </strong>Neuronal synuclein disease (NSD) involves pathological α-synuclein presence and often dopaminergic dysfunction, initially preceding overt clinical symptoms. NSD-ISS identifies Stage 2A (no dopaminergic dysfunction) and 2B (dopaminergic dysfunction) as prodromal phases marked by subtle clinical signs without functional impairment. Intraindividual variability/ dispersion (IIV-D), reflecting within-person inconsistency across cognitive tasks, has emerged as a potential marker of early neurodegenerative changes.</p><p><strong>Objectives: </strong>This study examined whether IIV-D differentiates NSD Stage 2 participants from healthy controls and predicts progression to more advanced NSD stages.</p><p><strong>Methods: </strong>Data from the Parkinson's Progression Markers Initiative were used to assess performance across 11 neuropsychological tests in 934 participants (832 Stage 2; 102 controls). IIV-D was quantified using the total coefficient of variation (CoV) and a domain-specific attention/executive CoV. Group comparisons and logistic regression assessed associations between IIV-D, clinical characteristics, and disease progression.</p><p><strong>Results: </strong>Stage 2 participants exhibited significantly greater CoV than controls ( <i>p</i> = .003). Higher IIV-D was associated with worse motor symptoms, non-motor burden, and functional impairment. Among Stage 2 participants, subsequent converters to Stage 3+ (n = 100) had significantly higher total CoV ( <i>p</i> = .008) and attention/executive CoV ( <i>p</i> = .020) at baseline. CoV independently predicted conversion after one year (OR = 1.44, <i>p</i> = .008), controlling for baseline motor severity.</p><p><strong>Conclusions: </strong>IIV-D, particularly CoV, may be a sensitive cognitive marker of early NSD and predict short-term disease progression. Findings support integrating cognitive dispersion metrics into early detection strategies for prodromal synucleinopathies, though replication is needed to confirm generalizability and clinical utility.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848326","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":"Cortical Lesions Form Predominantly in Early Multiple Sclerosis.","authors":"Batuhan Ayci, Emma Dereskewicz, Jonadab Dos Santos Silva, Julia Galasso, Phoebe Rust, Francesco La Rosa, Jiaen Liu, Daniel S Reich, James F Sumowski, Erin S Beck","doi":"10.64898/2026.04.30.26352141","DOIUrl":"https://doi.org/10.64898/2026.04.30.26352141","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cortical lesions are common in multiple sclerosis (MS) and associated with disability, but their characterization in early MS has been limited. Here, we aimed to characterize cortical lesions in newly diagnosed MS with 7 tesla (T) brain MRI.</p><p><strong>Methods: </strong>Adults within 14 months of relapsing-remitting MS diagnosis underwent 7T brain MRI and clinical evaluation at Mount Sinai. Cortical lesions were identified using T1-weighted (w) (median of three acquisitions) and T2*w images (both at 0.5mm ³ ). Non-cortical brain lesions were segmented on 0.7mm ³ T1w images. Lesion burden in newly diagnosed MS was compared with a previously analyzed NIH cohort with longer time since diagnosis, imaged using a similar protocol.</p><p><strong>Results: </strong>61 individuals were included in the newly diagnosed MS cohort (mean age 34 ± 4 years; 72% female; median time since diagnosis 5 months, interquartile range [IQR] 6). Cortical lesions were identified in 50/61 (81%) individuals, and subpial cortical lesions were identified in 46 (75%). Median cortical lesion number was 5 (IQR 11), median volume 319 μl (IQR 1049). Cortical lesions constituted a median of 14% of total brain lesion volume (IQR 43%), and in 21% of individuals, cortical lesions constituted >50% of total brain lesion volume. Cortical lesion number was associated with worse 9-hole peg test (ρ=0.33, p=0.008) and Symbol Digit Modalities Test performance (ρ=-0.29, p=0.02). When pooled with the NIH cohort (n=60, median time since diagnosis 12 years, IQR 17), non-cortical lesion volume was ∼3.5 times higher in people with time since diagnosis >36 months (median 4.7 ml, IQR 8.7) vs ≤36 months (median 1.2 ml, IQR 2.4, p<0.001). In contrast, cortical lesion volume was only ∼1.3 times higher in people with time since diagnosis >36 months (median 416 μl, IQR 1013) vs ≤36 months (median 318 μl, IQR 925, p=0.04). Non-cortical lesion volume was moderately associated with time since diagnosis (ρ=0.54, p<0.001) vs ρ=0.27 (p<0.001) for cortical lesions.</p><p><strong>Discussion: </strong>Cortical lesions are prevalent in newly diagnosed MS and constitute a substantial portion of total lesion burden. Cortical lesion volume is similar in early vs established MS, suggesting most cortical lesions form early in disease.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848339","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":"Disease Risk Prediction Using Structured EHR Data: Can Generalist Large Language Models Match Specialized Clinical Foundation Models? A Comparative Evaluation with Fine-Tuning.","authors":"Bingyu Mao, Made K Prasadha, Ziqian Xie, Jianping He, Michael Ghebranious, Hua Xu, Degui Zhi, Laila Rasmy","doi":"10.64898/2026.04.24.26351503","DOIUrl":"https://doi.org/10.64898/2026.04.24.26351503","url":null,"abstract":"<p><strong>Background: </strong>Electronic health records (EHRs) with clinical decision support tools are now ubiquitous in healthcare organizations. Clinical foundation models (CFMs) pretrained on large-scale, heterogeneous structured EHR data have emerged as a powerful approach to improve predictive performance and generalizability. Meanwhile, large language models (LLMs) pretrained on broad data sources are being applied to an expanding range of healthcare tasks. However, it remains unclear whether generalist LLMs can match specialized CFMs for disease risk prediction using structured clinical data.</p><p><strong>Methods: </strong>We compared CFMs (Med-BERT, CLMBR) against fine-tuned generalist LLMs (Mistral, LLaMA-2/3/3.1), a clinical LLM (Me-LLaMA), and LLM-generated embeddings paired with simple classifiers (using DeepSeek, Qwen3, and GPT-OSS) on two disease risk prediction tasks: heart failure risk among diabetic patients (DHF) and pancreatic cancer diagnosis (PaCa). Evaluations spanned multi-site EHR data, claims data, and an open-source single-institution benchmark (EHRSHOT). Performance was assessed using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC).</p><p><strong>Results: </strong>On larger EHR and claims cohorts (>30,000 patients), fine-tuned CFMs outperformed fine-tuned LLMs by a small but statistically significant margin (<1% AUROC). The clinical LLM performed comparably to generalist LLMs despite being smaller. On the open-source PaCa cohort (3,810 patients, 199 cases), LLMs achieved slightly higher AUROCs that were not statistically significant (LLaMA-3.1-70B 86.1% vs. Med-BERT 85.3%, p=0.27), but CFMs achieved significantly higher AUPRC (Med-BERT 55.9% vs. LLaMA-3.1-70B 41.1%, p=0.001). Notably, LLM-generated trajectory embeddings paired with logistic regression or a simple MLP, without any LLM fine-tuning, achieved the best overall performance, with AUROC exceeding 90% (Qwen3) and AUPRC reaching 66% (GPT-OSS 20B).</p><p><strong>Conclusion: </strong>LLM-generated embeddings with lightweight classifiers outperformed both fine-tuned CFMs and fine-tuned LLMs on AUROC and AUPRC. While these results demonstrate the potential of generalist models to match or surpass specialized CFMs, their substantially greater computational cost and variable AUPRC performance in the fine-tuning setting warrant caution. We provide a reproducible evaluation framework and codebase to support continued benchmarking.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848280","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":"Proteomic Signatures of Protected <i>APOE</i> -ε4 Carriers Reveal Causal Pathways Associated with Delayed Alzheimer's Disease Onset.","authors":"Yann Le Guen, Junyoung Park, Andrés Peña-Tauber, Michael D Greicius","doi":"10.64898/2026.04.30.26352191","DOIUrl":"https://doi.org/10.64898/2026.04.30.26352191","url":null,"abstract":"<p><strong>Introduction: </strong><i>APOE</i> -ε4 is the strongest common genetic risk factor for Alzheimer's disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether a protected-ε4-first proteomic approach could identify plasma proteins associated with delayed clinical onset among ε4 carriers.</p><p><strong>Methods: </strong>We analyzed harmonized plasma proteomics from the Global Neurodegeneration Proteomics Consortium. Protected ε4 carriers (ε3/ε4 aged ≥75 years; ε4/ε4 aged ≥65 years; CDR=0; n=456) were compared with ε4 carriers with AD (n=1,096). Protein-wise linear models adjusted for age, sex, ε4 dosage, and plasma proteomic principal components. Top signals were integrated with high-confidence loss-of-function burden testing and plasma/CSF Mendelian randomization.</p><p><strong>Results: </strong>ε4 protected was associated with 721 protein levels. Integrated analyses prioritized proteins linked to ε4-modified disease biology, including LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10, and proteins aligned with broader AD-related change, including OMG, SELENOW, VAT1, and TPPP3. TREM2 and ACE were also identified, providing internal biological validation of the approach.</p><p><strong>Discussion: </strong>A protected-ε4-first plasma proteomic strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset and helps prioritize candidate ε4-specific modifiers for prevention-focused therapeutics.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848333","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":"Effects of Controlled Diets High in and Free of Ultraprocessed Food on the Brain of Emerging Adults.","authors":"Emma H Leslie, Maria Rego, Monica Ahrens, Wenjing Yu, Mary Elizabeth Baugh, Anastasia Groccia, Rhianna Sullivan, Han Lee, Ryann Kolb, Delbert L Herald, Valisa E Hedrick, Kevin P Davy, Benjamin Katz, Brenda M Davy, Alexandra G DiFeliceantonio","doi":"10.64898/2026.04.30.26352056","DOIUrl":"https://doi.org/10.64898/2026.04.30.26352056","url":null,"abstract":"<p><strong>Objective: </strong>The average American consumes 55% of their daily energy from ultraprocessed foods (UPF) created through industrial processes and additives not used at home. We investigated if a high-UPF diet alters brain response to milkshake compared with a diet free-from UPF (NonUPF) in emerging adults, who are in a critical period for brain development and typically consume high amounts of UPF.</p><p><strong>Methods: </strong>In a randomized controlled crossover trial participants aged 18-25 completed two, 2-week controlled feeding periods including a UPF (81% UPF) and nonUPF (0% UPF) diet. Before and after each diet intervention participants consumed milkshake concomitant with functional magnetic resonance imaging.</p><p><strong>Results: </strong>In the entire cohort, there were no differences between diet conditions in brain response. An exploratory analysis revealed orbitofrontal cortex (OFC) response to milkshake decreased after the UPF diet and increased following the NonUPF diet in adolescents (18-21 years) but not young adults (22-25 years). Habitual UPF intake (gs) was positively associated with OFC response to milkshake independent of diet intervention in all participants.</p><p><strong>Conclusions: </strong>An acute UPF dietary intervention may only alter brain response in adolescents. Further work is needed to determine potential vulnerability of adolescents to changes in dietary UPF on brain response to rewards.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848287","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":"Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing.","authors":"Sophia B Gibson, Nikhita Damaraju, J Gus Gustafson, Elsa V Balton, Sirisak Chanprasert, Ian A Glass, Martha Horike-Pyne, Runjun D Kumar, Kathleen A Leppig, Chris Lundberg, Jane Ranchalis, Elisabeth A Rosenthal, Andrew K Solomon, Andrew B Stergachis, Mark Wener, Gail P Jarvik, Elizabeth E Blue, Katrina M Dipple, Harriet Dashnow, Lea M Starita, Danny E Miller","doi":"10.64898/2026.04.30.26352103","DOIUrl":"https://doi.org/10.64898/2026.04.30.26352103","url":null,"abstract":"<p><strong>Background: </strong>Tandem repeat expansions (TREs) cause over 60 known neurological, neuromuscular, and developmental disorders. Detecting these expansions genome-wide is challenging due to their size, sequence complexity (including interruptions), and population variation. While long-read sequencing is an emerging technology that can fully resolve many TREs, no methods have been described for genome-wide identification and prioritization of candidate pathogenic TREs with this technology.</p><p><strong>Methods: </strong>Using a newly developed pipeline called TRoLR (Tandem Repeat outliers identified with Long Reads), we analyzed haplotype-resolved long-read genome assemblies from 471 ancestrally diverse individuals to define population distributions for over three million tandem repeat loci, capturing clinically relevant interruptions. Outlier expansions were identified relative to these distributions and prioritized by genomic location and comparison to known pathogenic loci. The framework was applied to 47 cases from the Undiagnosed Diseases Network.</p><p><strong>Results: </strong>Population stratification of repeat metrics was observed at 7% of loci, with highest variability among individuals of African ancestry. Outlier analysis confirmed known pathogenic <i>CNBP</i> and <i>ATXN8OS</i> expansions, detected carrier-range alleles at <i>RFC1</i> , <i>CSTB</i> , and <i>FXN</i> , and revealed a novel CGG expansion in the 5' UTR of <i>PCMTD2</i> exhibiting hypermethylation and intergenerational instability. Genome-wide screening also identified intronic pentanucleotide expansions at <i>IQCB1</i> and <i>MAP3K15</i> in controls composed of motifs that have been associated with pathogenicity at other disease loci.</p><p><strong>Conclusions: </strong>Quantifying the longest uninterrupted repeat segment in long-read assemblies enables detection of clinically relevant repeat expansions and loss of stabilizing interruptions. This approach enhances both diagnostic confirmation and discovery of candidate pathogenic expansions, with implications for clinical interpretation and research into complex repeat-mediated disorders.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848345","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":"PATIENT PATHWAYS TO UGANDA'S FIRST SPECIALISED EARLY INTERVENTION IN PSYCHOSIS SERVICE AND RELATION TO THEIR CLINICAL OUTCOMES.","authors":"Emmanuel Kiiza Mwesiga, Wilber Ssembajjwe, Rossette Immy Ndigamanya, Sophia Balinga, Blessed Tabitha Aujo, Mary Ampaire, Andrea Kaggwa Kaddu, Andrew Sentoogo Ssemata, Allan Kalungi, Ronald Kiguba, Johesephat Byamugisha, Mark Kaddumukasa, Martha Sajatovic, Noeline Nakasujja","doi":"10.64898/2026.04.30.26352152","DOIUrl":"https://doi.org/10.64898/2026.04.30.26352152","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Early Intervention for Psychosis Services (EIPS) enhance outcomes for individuals experiencing their first episode of psychosis (FEP). However, in low-resource settings, there is limited knowledge about i) the pathways patients take to access EIPS, ii) the proportion and factors associated with acceptance of referral to EIPS, and iii) if different pathways to EIPS services affect clinical outcomes. Uganda's first EIPS, the Specialised Treatment Early in Psychosis Service at Makerere University Hospital (STEP_MaKH), presents a unique opportunity to explore these important questions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Aims: &lt;/strong&gt;We aimed to examine the pathways to EIPS, the factors associated with referral to specialised psychosis care and the impact of initial treatment-seeking behaviour on long-term symptom remission and quality of life.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a multiple-method study. Pathways to care were assessed retrospectively using the WHO Encounter Form among adults with FEP eligible for referral to STEP_MaKH. Among those who completed referral and enrolled in STEP_MaKH. Symptom severity and quality of life were followed prospectively for 12 months. Modified Poisson regression identified predictors of referral completion. Kaplan-Meier methods and Cox proportional hazards models examined time to symptom remission and time to achieving a good quality of life.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of the 187 adults with first-episode psychosis eligible for referral to STEP_MaKH, Native/religious healers (n = 86) were the predominant first point of contact. Only 56 (29.9%) accepted referral to STEP_MaKH. Participants referred from Mulago National Referral Hospital more likely to enrol than those referred from Butabika (RR = 4.7; 95% CI: 2.90-7.87). Longer delays from first treatment contact were associated with reduced likelihood of reaching STEP_MaKH (RR = 0.99 per month; p = 0.041). After enrolment, symptoms improved rapidly with 60% achieving PANSS remission by Month 1, and fewer than 10% remained non-remitted by Months 2-3. In adjusted Cox models, participants initially seen by mental health workers achieved remission more quickly than those initially seen by non-medical personnel (HR = 1.48; 95% CI: 1.05-2.10). Older age was associated with slower remission (HR = 0.94; p = 0.023). Quality of life improved over the follow-up period, with earlier attainment of good quality of life among those initially managed by mental health workers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Pathways to care for FEP in Uganda are complex and culturally mediated, with substantial attrition before specialised early psychosis care is reached. Referral completion is strongly shaped by referral site and by delays in the care pathway. Once in specialised care, clinical outcomes improve rapidly, and initial contact with mental health workers is associated with faster symptom remission and earlier gains in quality of life. Strengthening re","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848506","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":"Adapting, piloting, and evaluating a pediatric lead screening and risk-reduction intervention in Nairobi: A hybrid implementation-effectiveness trial protocol.","authors":"Ikenna Onoh, Cyrus Mugo, Anne Riederer, Elizabeth Maleche-Obimbo, Faridah Hussein Were, Christine Loftus, Ferdinand Mukumbang, Edith Lumumba, Barbra Richardson, Priscilla Wanini Edemba, Beatrice C Mutai, Catherine Karr, Sarah Benki-Nugent","doi":"10.64898/2026.04.28.26351918","DOIUrl":"https://doi.org/10.64898/2026.04.28.26351918","url":null,"abstract":"<p><strong>Background: </strong>Childhood lead exposure is prevalent worldwide including low- and middle-income countries (LMICs). Structured screening and prevention programs to address pediatric lead exposure are largely absent in these settings. Adapted interventions are needed to close this implementation gap in an urban African context. This paper describes the protocol for the Lead Exposure Intervention Program (LEIP), which aims to adapt, pilot, and evaluate a pediatric lead exposure screening and risk-reduction protocol in Nairobi, Kenya.</p><p><strong>Methods: </strong>LEIP is a multi-phase, hybrid type 3 implementation-effectiveness study. Phase 1 is a formative one-arm study leveraging an existing mother-child cohort and stakeholder-led tools adaptation to pilot a program comprising blood lead level (BLL) screening with a lead risk survey and tailored caregiver risk reduction messaging. Phase 2 is a randomized trial in public sector clinics. In this phase, approximately 1,500 children will be screened to identify 100 with elevated BLL (≥5 µg/dL) for enrollment, who will then be randomized 1:1 to receive either clinic-only risk-reduction messaging or the same clinic-based messaging plus a home visit for environmental assessment and additional tailored messaging. Follow-up at 3 and 9 months will assess caregiver recall of key messages and adoption of recommended exposure-reduction behaviors, as well as changes in child BLL. Phase 3 involves qualitative interviews with caregivers and key stakeholders to identify multi-level barriers and facilitators to intervention uptake. Quantitative and qualitative findings will be integrated to inform refinements for scale-up.</p><p><strong>Discussion: </strong>This study represents a critical opportunity to develop and evaluate an adaptive, screening-based lead exposure intervention tailored to the urban LMIC context. By incorporating implementation science principles and stakeholder-driven design, LEIP is well-positioned to inform scalable national and regional approaches. The inclusion of both quantitative and qualitative components enhances the protocol's ability to capture multilevel dynamics of uptake, fidelity, and sustainability, and generate actionable insights for future large-scale implementations.</p><p><strong>Trial registration: </strong>Registered on ClinicalTrials.gov ( NCT07401251 ).</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848311","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}