medRxiv : the preprint server for health sciences最新文献

{"title":"Predicting Nonsense-mediated mRNA Decay from Splicing Events in Sepsis using RNA-Sequencing Data.","authors":"Jaewook Shin, Alger M Fredericks, Brandon E Armstead, Alfred Ayala, Maya Cohen, William G Fairbrother, Mitchell M Levy, Kwesi K Lillard, Emanuele Raggi, Gerard J Nau, Sean F Monaghan","doi":"10.1101/2025.03.31.25324958","DOIUrl":"https://doi.org/10.1101/2025.03.31.25324958","url":null,"abstract":"<p><p>Alternative splicing (AS) and nonsense-mediated mRNA decay (NMD) are highly conserved cellular mechanisms that modulate gene expression. Here we introduce NMD pipeline that computes how splicing events introduce premature termination codons to mRNA transcripts via frameshift, then predicts the rate of PTC-dependent NMD. We utilize whole blood, deep RNA-sequencing data from critically ill patients to study gene expression in sepsis. Statistical significance was determined as adjusted p value < 0.05 and |log2foldchange| > 2 for differential gene expression and probability >= 0.9 and |DeltaPsi| > 0.1 for AS. NMD pipeline was developed based on AS data from Whippet. We demonstrate that the rate of NMD is higher in sepsis and deceased groups compared to control and survived groups, which signify purposeful downregulation of transcripts by AS-NMD or aberrant splicing due to altered physiology. Predominance of non-exon skipping events was associated with disease and mortality states. The NMD pipeline also revealed proteins with potential novel roles in sepsis. Together, these results emphasize the utility of NMD pipeline in studying AS-NMD along with differential gene expression and discovering potential protein targets in sepsis.</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/PMC11996588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061058","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":"Continuous Infusion of the CXCR4 Antagonist Plerixafor for WHIM Syndrome.","authors":"David H McDermott, Shamik Majumdar, Daniel Velez, Elena Cho, Zhanzhou Li, Ji-Liang Gao, Megan C Grieco, Monica G Lawrence, Susana L Silva, Leslie A Castelo-Soccio, Dean Follmann, Philip M Murphy","doi":"10.1101/2025.04.19.25325865","DOIUrl":"https://doi.org/10.1101/2025.04.19.25325865","url":null,"abstract":"<p><p>WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis) syndrome is an ultrarare inborn error of immunity caused by heterozygous, gain-of-function <i>CXCR4</i> mutations that impede leukocyte egress from bone marrow, resulting in panleukopenia. The CXCR4 antagonist plerixafor (AMD3100, Mozobil) durably reverses panleukopenia and in most WHIM patients induces wart regression; however, its short half-life requires twice daily injection. To develop a simpler, cheaper and potentially more effective method of drug delivery, we conducted a Phase 1 study of WHIM patients given plerixafor 0.02-0.08 mg/kg/d by continuous subcutaneous infusion using an OmniPod insulin pump, and assessed compliance as well as effects on blood leukocyte counts, infections, chronic skin conditions and adverse events. Six patients were treated for a total of 6.3 patient-years; one patient dropped out early for personal reasons. The drug infusion rate was adjusted to achieve a normal absolute lymphocyte count and an absolute neutrophil count >500 cells/μl in all patients. An average of 2.1 infections/patient-year occurred (range 0-4). Treatment of two infections involved brief hospitalization. On plerixafor, partial wart regression occurred in 3 of 4 patients, a single molluscum contagiosum infection regressed and a chronic post-Mohs surgical wound epithelialized. There were 3 serious adverse events, but none was attributable to the treatment. All patients preferred pump administration over syringe injection. Thus, in WHIM patients a continuous infusion pump may be a convenient, safe and potentially cost-effective means of delivering plerixafor chronically to correct panleukopenia and to improve chronic skin conditions. Clinicaltrials.gov NCT00967785.</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/PMC12051493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061779","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":"Population-weighted Image-on-scalar Regression Analyses of Large Scale Neuroimaging Data.","authors":"Zikai Lin, M Fiona Molloy, Chandra Sripada, Jian Kang, Yajuan Si","doi":"10.1101/2025.04.21.25326171","DOIUrl":"https://doi.org/10.1101/2025.04.21.25326171","url":null,"abstract":"<p><p>Recent advances in neuroimaging modeling highlight the importance of accounting for subgroup heterogeneity in population-based neuroscience research through various investigations in large scale neuroimaging data collection. To integrate survey methodology with neuroscience research, we present an imaging data analysis and yield population generalizability with screened subsets of data. The Adolescent Brain Cognitive Development (ABCD) Study has enrolled a large cohort of participants to reflect the individual variation of the U.S. population in adolescent development. To ensure population representation, the ABCD Study has released the base weights. We estimated the associations between brain activities and cognitive performance using the functional Magnetic Resonance Imaging (fMRI) data from the ABCD Study's N-Back working memory task. Notably, the imaging subsample exhibits differences from the baseline cohort in key child characteristics and such discrepancies cannot be addressed simply by applying the ABCD base weights. We developed new population weights specific to the subsample and included the adjusted weights in the image-on-scalar regression model. We validated the approach through synthetic simulations and applications to fMRI data from the ABCD Study. Our findings demonstrate that population weighting adjustments effectively capture active brain areas associated with cognition, enhancing the validity and generalizability of population neuroscience research.</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/PMC12045411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060148","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":"Utilization of a Psychosis Consultation Service: Early Lessons from a Statewide Initiative.","authors":"Sümeyra N Tayfur, Laura A Yoviene Sykes, Cenk Tek, Vinod H Srihari","doi":"10.1101/2025.04.21.25324324","DOIUrl":"https://doi.org/10.1101/2025.04.21.25324324","url":null,"abstract":"<p><p>In February 2024, the Program for Specialized Treatment Early in Psychosis (STEP) in Connecticut launched the STEP Learning Collaborative (STEP-LC), a statewide learning health system. As part of this initiative, STEP-LC introduced a free consultation service to support clinicians, administrators, and healthcare leaders in the continuing care of young people with recent-onset psychosis (ages 16-35). As the only coordinated specialty care (CSC) clinic in the state offering this provider-to-provider service, STEP aims to address clinical and systemic challenges by providing expert guidance on medication management, psychotherapy, family engagement, and program development. Consultations are requested through a brief online form publicly available on the STEP-LC website (link). Experts at STEP aim to respond within one business day to initiate discussions regarding the identified case. The service is designed to be flexible, offering one-on-one meetings, integrating consultations into existing team meetings at the requesters' agencies, and allowing outside organizations to observe STEP operations. To date, 26 consultations have been completed: 24 within the state and 2 from out-of-state. Within-state requests primarily involved direct clinical issues, such as treatment planning, transitions of care, and family support strategies. Out-of-state consultations focused on broader systemic needs, including the development of new early psychosis programs and collaborative networks. Feedback from consultees highlights the value of the service in enhancing the quality and accessibility of psychosis care. This initiative underscores the importance of leveraging specialized expertise to support both individual and systemic efforts in early psychosis intervention.</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/PMC12045390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060789","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 Assessment of Pleiotropy Across >1000 Traits from Global Biobanks.","authors":"Michael G Levin, Satoshi Koyama, Jakob Woerner, David Y Zhang, Alexis Rodriguez, Tarak Nandi, Buu Truong, Sarah A Abramowitz, Hritvik Gupta, Himani Kamineni, Whitney Hornsby, Zilinghan Li, Taylor Cohron, Jennifer E Huffman, Patrick Ellinor, Dokyoon Kim, Katherine P Liao, Ravi K Madduri, Benjamin F Voight, Anurag Verma, Scott M Damrauer, Pradeep Natarajan","doi":"10.1101/2025.04.18.25326074","DOIUrl":"https://doi.org/10.1101/2025.04.18.25326074","url":null,"abstract":"<p><p>Large-scale genetic association studies have identified thousands of trait-associated risk loci, establishing the polygenic basis for common complex traits and diseases. Although prior studies suggest that many trait-associated loci are pleiotropic, the extent to which this pleiotropy reflects shared causal variants or confounding by linkage disequilibrium remains poorly characterized. To define a set of candidate loci with potentially pleiotropic associations, we performed genome-wide association study (GWAS) meta-analyses of up to 1,167 clinically relevant traits and diseases across 1,789,365 diverse individuals genetically similar to Admixed American (AMR, N_Max = 60,756), African (AFR, N_Max = 128,361), East Asian (EAS, N_Max = 307,465), European (EUR, N_Max = 1,283,907), and South Asian (SAS, N_Max = 8,876) reference populations from the VA Million Veteran Program (MVP), UK Biobank (UKB), FinnGen, Biobank Japan (BBJ), Tohoku Medical Megabank (ToMMO), and Korean Genome and Epidemiology Study (KoGES). We identified 27,193 genome-wide significant locus-trait pairs (1MB region with P_GWAMA < 5 × 10^-8) in within-population analysis and 29,139 in multi-population analysis (P_MR-MEGA < 5 × 10^-8). Among these, 11.5% (n = 3,149) of locus-trait pairs in population-wise and 6.4% (n = 1,875) in multi-population analyses did not reach genome-wide significance in previously published GWAS. In aggregate, the genome-wide significant loci fell within 2,624 non-overlapping autosomal genomic windows on average ~600kb in size. Each locus contained genome-wide significant signals for a median of 6 traits (IQR 2 to 18), including 2,110 (80%) pleiotropic loci associated with >1 trait. Multi-trait colocalization identified 1,902 (72%) loci with high-confidence (posterior probability > 0.9) evidence of a shared causal variant across two or more traits. Variants in pleiotropic loci were significantly enriched for a broad spectrum of functional annotations compared to non-pleiotropic counterparts. Polygenic scores (PGS) developed from these data generally improved prediction compared to existing PGS and were broadly associated with both on- and off-target phenotypes. These results provide a contemporary map of genetic pleiotropy across the spectrum of human traits/diseases and genetic backgrounds.</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/PMC12045404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035524","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":"Large language models for extracting histopathologic diagnoses of colorectal cancer and dysplasia from electronic health records.","authors":"Brian Johnson, Tyler Bath, Xinyi Huang, Mark Lamm, Ashley Earles, Hyrum Eddington, Anna M Dornisch, Lily J Jih, Samir Gupta, Shailja C Shah, Kit Curtius","doi":"10.1101/2024.11.27.24318083","DOIUrl":"https://doi.org/10.1101/2024.11.27.24318083","url":null,"abstract":"<p><strong>Background: </strong>Accurate data resources are essential for impactful medical research, but available structured datasets are often incomplete or inaccurate. Recent advances in open-weight large language models (LLMs) enable more accurate data extraction from unstructured text in electronic health records (EHRs) but have not yet been thoroughly validated for challenging diagnoses such as inflammatory bowel disease (IBD)-related neoplasia.</p><p><strong>Objective: </strong>Create a validated approach using LLMs for identifying histopathologic diagnoses in pathology reports from the nationwide Veterans Health Administration database, including patients with genotype data within the Million Veteran Program (MVP) biobank.</p><p><strong>Design: </strong>Our approach utilizes simple 'yes/no' question prompts for following phenotypes of interest: any colorectal dysplasia, high-grade dysplasia and/or colorectal adenocarcinoma (HGD/CRC), and invasive CRC. We validated the method on diagnostic tasks by applying prompts to reports from patients with IBD (and validated separately in non-IBD) and calculated F-1 scores as a balanced accuracy measure.</p><p><strong>Results: </strong>In patients with IBD in MVP, we achieved F1-scores of 96.1% (95% CI 92.5-99.4%) for identifying dysplasia, 93.7% (88.2-98.4%) for identifying HGD/CRC, and 98% (96.3-99.4%) for identifying CRC. In patients without IBD in MVP, we achieved F1-scores of 99.2% (98.2-100%) for identifying any colorectal dysplasia, 96.5% (93.0-99.2%) for identifying HGD/CRC, and 95% (92.8-97.2%) for identifying CRC using LLM Gemma-2.</p><p><strong>Conclusion: </strong>LLMs provided excellent accuracy in extracting the diagnoses of interest from EHRs. Our validated methods generalized to unstructured pathology notes, even withstanding challenges of resource-limited computing environments. This may therefore be a promising approach for other clinical phenotypes given the minimal human-led development required.</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/PMC12045448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002666","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":"Effectiveness of the Ticket to Work program in supporting employment among adults with disabilities.","authors":"Pei-Shu Ho, Joshua C Chang, Rebecca A Parks, Kathleen Coale, Chunxiao Zhou, Rafael Jiménez Silva, Julia Porcino, Elizabeth Marfeo, Elizabeth K Rasch","doi":"10.1101/2025.04.22.25325884","DOIUrl":"10.1101/2025.04.22.25325884","url":null,"abstract":"<p><strong>Background: </strong>Returning to work benefits many people with disabilities, as it supports personal financial independence and provides opportunities for greater societal contributions. The U.S. Social Security Administration's Ticket to Work (TTW) program offers expanded support services to help disability beneficiaries achieve financial independence through gainful employment. SSA has continuously sought new ways to identify those who would most benefit from using a Ticket.</p><p><strong>Objective: </strong>To identify factors contributing to TTW participation and assess its impact on benefits forgone for work.</p><p><strong>Methods: </strong>We conducted a cohort study using SSA administrative data to predict TTW participation and its impact on benefit cessation. The study sample included beneficiaries with a physical or mental residual functional capacity assessment from 2016. We applied a frequentist propensity score matching estimate and a doubly robust Bayesian hierarchical model-based estimate.</p><p><strong>Results: </strong>The study included 172,640 beneficiaries (52.7% male, average age 52 years) with a range of qualifying conditions: musculoskeletal disorders (45.04%), mental disorders (29.10%), neurological disorders (9.82%). Both analytic methods yielded consistent results, showing that TTW participation is effective even after controlling for confounding factors. Personal characteristics (e.g., sex, age, education, race/ethnicity), health and functional status (e.g., work cessation due to health issues, need for alternate sitting arrangements, and limitations in understanding and memory) and environmental factors (e.g., region of residence) influenced Ticket participation.</p><p><strong>Conclusions: </strong>Our findings offer valuable insights for identifying potential TTW participants and estimating benefit savings for SSDI/SSI programs. Future research should explore available support services and barriers to access to improve TTW outcomes.</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/PMC12045388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047274","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":"Differentiating Hyperkinetic and Hypokinetic Motor Features in the Progression of Huntington's Disease.","authors":"Nabil Halabi, Annie Killoran, Peg C Nopoulos, Jordan L Schultz","doi":"10.1101/2025.04.17.25325819","DOIUrl":"https://doi.org/10.1101/2025.04.17.25325819","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a monogenic neurodegenerative disorder typically characterized by chorea, a hyperkinetic motor feature. Historical data suggest that hypokinetic features, like rigidity and bradykinesia, become more prominent in later stages of HD. No evidence-based analysis has confirmed this observation. Additionally, several motor features of the disease are not clearly defined as hypokinetic or hyperkinetic.</p><p><strong>Objectives: </strong>This study aimed to 1) elucidate the trajectory of hyperkinetic and hypokinetic features across the disease course and 2) to classify vague motor features as following a hyperkinetic or hypokinetic trajectory.</p><p><strong>Methods: </strong>Data from 13,475 motor-manifest HD patients from the Enroll-HD platform were analyzed. Linear mixed-effects models were constructed for each of the 31 Unified Huntington's Disease Rating Scale (UHDRS) motor subscales, with disease burden as the primary predictor. The models were used to generate the trajectories of features known to represent hyperkinesis and hypokinesis, with the same being done for vague subscales. Dynamic time warping (DTW) was then used to classify said subscales as having a hyperkinetic or hypokinetic trajectory.</p><p><strong>Results: </strong>Hyperkinetic features rise initially and diminish in middle disease, while hypokinetic features continually increase across the disease course. All non-choreiform features demonstrated a hypokinetic-like trajectory.</p><p><strong>Conclusions: </strong>HD is generally considered a hyperkinetic movement disorder, but the middle and late stages of the disease are predominated by hypokinesis. These findings suggest that hypokinetic features may be a larger contributor to the overall motor burden of HD. This has significant implications for clinical trial design, motor phenotype clustering, and pharmacotherapy.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multivariate cell-based assay for blood-based diagnostics enhances lung cancer risk stratification.","authors":"Jason D Berndt, Fergal J Duffy, Mark D D'Ascenzo, Leslie R Miller, Yijun Qi, G Adam Whitney, Samuel A Danziger, Anil Vachani, Pierre P Massion, Stephen A Deppen, Robert J Lipshutz, John D Aitchison, Jennifer J Smith","doi":"10.1101/2024.11.04.24316585","DOIUrl":"https://doi.org/10.1101/2024.11.04.24316585","url":null,"abstract":"<p><p>The indicator cell assay platform (iCAP) is a tool for blood-based diagnostics that addresses the low signal-to-noise ratio of blood biomarkers by using cells as biosensors. The assay exposes small volumes of patient serum to standardized cells in culture and classifies disease by machine learning analysis of the gene expression readout from the cells. We developed the lung cancer iCAP (LC-iCAP) as a rule-out test for nodule management in computed tomography (CT)-based lung-cancer screening. We performed analytical optimization, rigorous reproducibility testing, and assessed performance in a study with prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design. LC-iCAP achieved an AUC of 0.64 (95% CI, 0.51-0.76) on the ROC curve in validation. Post-validation integration of the assay readout with CT-based features showed improved clinical utility compared to the Mayo Clinic model, with 90% sensitivity, 64% specificity, and 95% negative predictive value at 25% prevalence. The lung-cancer specific readout was enriched for hypoxia-responsive genes and was reproducible across different indicator cell lineages. This is the first validation study of an iCAP and the first application for early cancer detection. The LC-iCAP uses immortalized cells, is scalable and cost-effective and has a multivariate readout. This study supports its potential as a next-generation multivalent platform for precision medicine applications in multi-cancer screening and drug development.</p><p><strong>Key points: </strong>We developed the LC-iCAP, novel approach for liquid biopsies that uses cultured cells as biosensors. The cells detect cancer signals in serum and transduce them into standardized gene expression profiles, which are analyzed by machine learning for disease classification. The assay is inexpensive and scalable and has a multivariate readout with potential utility for precision medicine and multi-cancer early detection.A LC-iCAP-based lung cancer risk classifier demonstrated improved specificity compared to existing tests, suggesting meaningful clinical utility for managing indeterminate pulmonary nodules.We identified a lung-cancer specific transcriptional response to hypoxia in the assay readout, implicating HIF1A and HIF2A activity in the response consistent with known lung cancer biology and highlighting the platform's mechanistic relevance.Standardized controls and validation studies demonstrated assay reproducibility, lineage stability, and detection of technical errors-supporting the platform's readiness for clinical deployment.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015911","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":"Stereo-encephalography-guided multi-lead deep brain stimulation for treatment-refractory obsessive compulsive disorder - study design and individualized surgical targeting approach.","authors":"Robert L Seilheimer, Liming Qiu, Giovanna Rocchio, Young-Hoon Nho, Gustavo Campos, Bijan Pesaran, Nolan R Williams, Camarin E Rolle, Vivek P Buch, T Mindy Ganguly, Kai J Miller, Mario Cristancho, Desmond J Oathes, Lily Brown, Katherine W Scangos, Daniel A N Barbosa, Casey H Halpern","doi":"10.1101/2025.04.17.25325961","DOIUrl":"https://doi.org/10.1101/2025.04.17.25325961","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Treatment-refractory obsessive-compulsive disorder (trOCD) is a complex brain network disorder that remains partially understood and may require personalized treatment strategies due to disease heterogeneity. While stereo-electroencephalography (sEEG) is standard of care for surgical epilepsy workups, its use in refractory neuropsychiatric disorders remains investigational. A multi-site, multi-stage, double-blinded, randomized crossover clinical trial is currently underway, using sEEG to guide selection of multi-nodal targets for subsequent deep brain stimulation (DBS) in the treatment of trOCD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;To describe the study design of this ongoing clinical trial, with an emphasis on personalized surgical targeting strategies that ensure both the feasibility and precision of sEEG electrode placement, and enable adequate sampling of relevant targets in trOCD for network evaluation and modulation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Adult patients with severe trOCD (Yale-Brown Obsessive Compulsive Scale ≥ 28) who meet eligibility criteria will be enrolled in this study. The clinical trial ( NCT05623306 ) involves three stages. In stage 1, up to 20 sEEG electrodes will be implanted in cortical and subcortical regions implicated in trOCD. Individualized probabilistic-tractography-guided target refinement will be performed for surgical planning. To ensure surgical feasibility of non-conventional surgical trajectories, patient-specific three-dimensional (3D) printed head models may be used for surgical rehearsal. Continuous and synchronous audiovisual and intracranial electroencephalographic (iEEG) recordings will be performed in the psychiatric monitoring unit. Participants undergo psychologist-led symptom provocations, brain stimulation evoked potential mapping, acute stimulation testing and cognitive tasks over a 12-day inpatient evaluation. In stage 2, up to four permanent DBS electrodes will be implanted followed by stimulation optimization for up to 52 weeks. Stage 3 involves a randomized, double-blinded cross-over phase.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Expected outcomes: &lt;/strong&gt;Safety, feasibility and preliminary efficacy will be assessed in this ongoing study. Primary safety endpoints include the number and type of serious adverse events. Feasibility endpoints include percentage of patients in whom OCD-relevant network or stimulation target can be identified. Treatment response will be determined by change in Y-BOCS II score between active and sham stimulation conditions. We anticipate that sEEG to guide selection of multi-nodal targets for DBS will be safe, feasible and result in clinically meaningful improvements in symptom severity and functional impairment in trOCD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;We present the clinical protocol of sEEG-guided investigation of brain networks involved in trOCD and describe our tractography-guided surgical targeting strategy designed to optimize individualized netwo","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061557","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}