medRxiv : the preprint server for health sciences最新文献

{"title":"A precision health approach to medication management in neurodivergence: a model development and validation study using four international cohorts.","authors":"Marlee M Vandewouw, Kamran Niroomand, Harshit Bokadia, Sophia Lenz, Jesiqua Rapley, Alfredo Arias, Jennifer Crosbie, Elisabetta Trinari, Elizabeth Kelley, Robert Nicolson, Russell J Schachar, Paul D Arnold, Alana Iaboni, Jason P Lerch, Melanie Penner, Danielle Baribeau, Evdokia Anagnostou, Azadeh Kushki","doi":"10.1101/2025.03.12.25323683","DOIUrl":"10.1101/2025.03.12.25323683","url":null,"abstract":"<p><strong>Background: </strong>Psychotropic medications are commonly used for neurodivergent children, but their effectiveness varies, making prescribing challenging and potentially exposing individuals to multiple medication trials. We developed artificial intelligence (AI) models to predict medication success for stimulants, anti-depressants, and anti-psychotics. We first demonstrate feasibility using cross-sectional data from three research cohorts, then use a cohort of patients from a pharmacology clinic to predict medication choice by class, longitudinally, from electronic medical records (EMRs).</p><p><strong>Methods: </strong>Models were built to predict cross-sectional medication usage from the Child Behaviour Checklist. Data from the Province of Ontario Neurodevelopmental (POND) network (<i>N</i>=598) trained and tested the models, while data from the Healthy Brain Network (HBN; <i>N</i>=1,764) and Adolescent Brain Cognitive Development (ABCD; <i>N</i>=2,396) studies were used for external validation. For the EMR cohort, data from the Psychopharmacology Program (PPP; <i>N</i>=312) at Holland Bloorview Kids Rehabilitation Hospital were used to predict longitudinal success. Stacked ensemble models were built separately for each medication class, and area under the receiving operating characteristic curve (AU-ROC) evaluated performance.</p><p><strong>Findings: </strong>The research cohorts demonstrated feasibility, with internal testing (POND) achieving an AU-ROC (mean [95% CI]) of 0.72 [0.71,0.74] for stimulants, 0.83 [0.80,0.85] for anti-depressants, and 0.79 [0.76,0.82] for anti-psychotics. Performance in external testing sets (HBN and ABCD) confirmed generalizability. In the EMR cohort (PPP), AU-ROC were high: 0.90 [0.88,0.91] for anti-psychotics, 0.82 [0.92,0.83] for stimulants and 0.82 [0.80,0.84] for anti-depressants.</p><p><strong>Interpretation: </strong>This study demonstrates the feasibility of using AI to enhance medication management for neurodivergent children, with expert clinician decisions learned with high accuracy. These findings support the potential for AI decision aids in community settings, promoting faster access to personalized care while highlighting the complexity of clinical and sociodemographic factors influencing medication decisions.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757118","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":"NICU Voices: Understanding Parent Perspectives of Research in the Neonatal Intensive Care Unit.","authors":"Melissa Coloma, Brandon Nguyen, William Cody Bartrug, Louie M Swander, Karla Luna Silva, Egbert Villegas, Adam Numis, Patrick McQuillen, Shabnam Peyvandi, Elizabeth E Rogers, Elizabeth E Crouch, Mercedes Paredes","doi":"10.1101/2025.03.12.25322895","DOIUrl":"https://doi.org/10.1101/2025.03.12.25322895","url":null,"abstract":"<p><strong>Importance: </strong>Neonatal intensive care units (NICUs) care for a vulnerable population with suboptimal research recruitment rates. Understanding NICU parents' motivations and recommendations may improve recruitment efforts.</p><p><strong>Objective: </strong>Identify key factors influencing NICU parents' decisions to enroll their newborns in research and gather recommendations to enhance engagement.</p><p><strong>Design: </strong>Semi-structured interviews were conducted with 24 parents from three NICU study populations: NSR-RISE, TRANSIT-CHD, and PROMPT. Using a grounded theory approach, data was analyzed prior to developing hypotheses, allowing themes to emerge organically during data analysis. Transcripts were coded through multiple rounds of data analysis until thematic saturation was reached.</p><p><strong>Setting: </strong>Interviews occurred virtually with previous research participants at UCSF hospitals.</p><p><strong>Participants: </strong>65 parents of NICU patients were invited; 24 participated. Inclusion criteria included 1) parent age older than 18 years, 2) NICU admission history, 3) prior participation in NSR-RISE, TRANSIT-CHD, or PROMPT, and 4) child aged 18-36 months at time of interview.</p><p><strong>Main outcomes and measures: </strong>Using a grounded theory approach, data was analyzed prior to developing hypotheses, allowing themes to emerge organically during data analysis.</p><p><strong>Results: </strong>Parents of 8 NSR-RISE, 8 TRANSIT-CHD, and 8 PROMPT-enrolled neonates participated. Three primary themes emerged: 1) parents' lived experiences during an emotionally intense NICU period fostered parental resilience and newfound support systems, 2) decision-making regarding NICU research participation included factors such as prognosis, emotional state, desire to aid future families, and perceived risks versus benefits, and 3) recommendations for improving NICU research recruitment, such as timely, empathic communication from trusted researchers, sensitivity to emotions, concise language, and early emphasis of altruistic goals.</p><p><strong>Conclusions and relevance: </strong>Altruism is a key motivator for NICU parents' research participation. Recruitment strategies should emphasize empathetic, well-timed communication from trusted persons, clearly addressing risks and altruistic outcomes. Sensitivity to the emotionally charged NICU environment is essential for improving engagement and enhancing the NICU experience.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757148","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":"Commercial Cannabis Product Testing: Fidelity to Labels and Regulations.","authors":"Sarah Limbacher, Suneeta Godbole, Julia Wrobel, Duncan I Mackie, Stephen Goldman, Ashley Brooks-Russell","doi":"10.1101/2025.03.14.25323943","DOIUrl":"10.1101/2025.03.14.25323943","url":null,"abstract":"<p><strong>Background: </strong>In Colorado, regulations for recreational and medical cannabis sales require Tetrahydrocannabinol (THC) concentration is printed on all products. Labeled THC concentrations can vary by +/-15% of what is in the product. Studies show THC concentrations recorded on product labels are not always reflective of the THC concentration in the cannabis product and there is evidence consumers make purchasing decisions based on label claims.</p><p><strong>Aims: </strong>Explore the accuracy of cannabis product labels and differences between THC label accuracy and product type.</p><p><strong>Design: </strong>Data for this analysis come from a larger observational study of cannabis impairment. N=74 flower, concentrate, and edible product samples from licensed Colorado dispensaries were collected and independently tested for THC concentration.</p><p><strong>Setting: </strong>This study was conducted in Colorado, in the Denver Metro Area.</p><p><strong>Participants: </strong>Participants in the study voluntarily enrolled and provided one-gram samples of the cannabis they consumed during the study to be independently tested. The cannabis tested for this analysis was donated on a voluntary basis, not all participants chose to donate.</p><p><strong>Measurement: </strong>The main outcomes of interest for this analysis are accuracy of cannabis product labels compared to observed THC content, accuracy in the context of legally allowable variation, and difference between accuracy by product.</p><p><strong>Findings: </strong>Overall, label values were higher than observed values in flower and edible products (p < 0.001) but was not significant for concentrates (p = 0.85). Flower products were observed to be significantly lower on labels versus the 15% legally allowable range (p = 0.04). Concentrate and edible products were not significantly different (p = 0.9 and p = 0.5, respectively).</p><p><strong>Conclusions: </strong>There is tension between legally allowable THC concentration claims on cannabis product labels and how consumers purchase cannabis. As cannabis policy evolves, standards and regulations that ensure accurate THC concentrations are reported on product labels are urgently needed.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757123","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":"Combining evidence from human genetic and functional screens to identify pathways altering obesity and fat distribution.","authors":"Nikolas A Baya, Ilknur Sur Erdem, Samvida S Venkatesh, Saskia Reibe, Philip D Charles, Elena Navarro-Guerrero, Barney Hill, Frederik Heymann Lassen, Melina Claussnitzer, Duncan S Palmer, Cecilia M Lindgren","doi":"10.1101/2024.09.19.24313913","DOIUrl":"10.1101/2024.09.19.24313913","url":null,"abstract":"<p><p>Overall adiposity and body fat distribution are heritable traits associated with altered risk of cardiometabolic disease and mortality. Performing rare variant (minor allele frequency<1%) association testing using exome-sequencing data from 402,375 participants in the UK Biobank (UKB) for nine overall and tissue-specific fat distribution traits, we identified 19 genes where putatively damaging rare variation associated with at least one trait (Bonferroni-adjusted <i>P</i> <1.58×10 ^-7 ) and 50 additional genes at FDR≤1% ( <i>P</i> ≤4.37×10 ^-5 ). These 69 genes exhibited significantly higher (one-sided <i>t</i> -test <i>P</i> =3.58×10 ^-18 ) common variant prioritisation scores than genes not significantly enriched for rare putatively damaging variation, with evidence of monotonic allelic series (dose-response relationships) among ultra-rare variants (minor allele count≤10) in 22 genes. Combining rare and common variation evidence, allelic series and longitudinal analysis, we selected 14 genes for CRISPR knockdown in human white adipose tissue cell lines. In three previously uncharacterised target genes, knockdown increased (two-sided <i>t</i> -test <i>P</i> <0.05) lipid accumulation, a cellular phenotype relevant for fat mass traits, compared to Cas9-empty negative controls: <i>COL5A3</i> (fold change [FC]=1.72, <i>P</i> =0.0028), <i>EXOC7</i> (FC=1.35, <i>P</i> =0.0096), and <i>TRIP10</i> (FC=1.39, <i>P</i> =0.0157); furthermore, knockdown of <i>PPARG</i> (FC=0.25, <i>P</i> =5.52×10 ^-7 ) and <i>SLTM</i> (FC=0.51, <i>P</i> =1.91×10 ^-4 ) resulted in reduced lipid accumulation. Integrating across population-based genetic and <i>in vitro</i> functional evidence, we highlight therapeutic avenues for altering obesity and body fat distribution by modulating lipid accumulation.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383121","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":"Childhood adversity is associated with longitudinal white matter changes after adulthood trauma.","authors":"Tianyi Li, Megan E Huibregtse, Timothy D Ely, Sanne J H van Rooij, Lauren A M Lebois, E Kate Webb, Tanja Jovanovic, Stacey L House, Steven E Bruce, Vishnu P Murty, Francesca L Beaudoin, Xinming An, Thomas C Neylan, Gari D Clifford, Sarah D Linnstaedt, Kenneth A Bollen, Scott L Rauch, John P Haran, Alan B Storrow, Christopher Lewandowski, Paul I Musey, Phyllis L Hendry, Sophia Sheikh, Christopher W Jones, Brittany E Punches, Lauren A Hudak, Jose L Pascual, Mark J Seamon, Elizabeth M Datner, Claire Pearson, David A Peak, Roland C Merchant, Robert M Domeier, Niels K Rathlev, Brian J O'Neil, Paulina Sergot, Leon D Sanchez, John F Sheridan, Ronald C Kessler, Karestan C Koenen, Kerry J Ressler, Samuel A McLean, Jennifer S Stevens, Nathaniel G Harnett","doi":"10.1101/2025.03.08.25323425","DOIUrl":"https://doi.org/10.1101/2025.03.08.25323425","url":null,"abstract":"<p><strong>Background: </strong>Childhood adversity is associated with susceptibility to posttraumatic stress disorder (PTSD) in adulthood. Both PTSD and adverse experiences in childhood are linked to disrupted white matter microstructure, yet the role of white matter as a potential neural mechanism connecting childhood adversity to PTSD remains unclear. The present study investigated the potential moderating role of previous childhood adversity on longitudinal changes in white matter microstructures and posttraumatic stress symptoms following a recent traumatic event in adulthood.</p><p><strong>Methods: </strong>As part of the AURORA Study, 114 recent trauma survivors completed diffusion weighted imaging at 2-weeks and 6-months after exposure. Participants reported on prior childhood adversity and PTSD symptoms at 2-weeks, 6-months, and 12-months post-trauma. We performed both region-of-interest (ROI) and whole-brain correlational tractography analyses to index associations between white matter microstructure changes and prior adversity.</p><p><strong>Results: </strong>Whole-brain correlational tractography revealed that greater childhood adversity moderated the changes in quantitative anisotropy (QA) over time across threat and visual processing tracts including the cingulum bundle and inferior fronto-occipital fasciculus (IFOF). Further, QA changes within cingulum bundle, IFOF, and inferior longitudinal fasciculus were associated with changes in PTSD symptoms between 2-weeks and 6-months.</p><p><strong>Conclusions: </strong>Our findings suggest temporal variability in threat and visual white matter tracts may be a potential neural pathway through which childhood adversity confers risk to PTSD symptoms after adulthood trauma. Future studies should take the temporal properties of white matter into consideration to better understand the neurobiology of childhood adversity and PTSD.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757000","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":"Risk factors for lung cancer in never-smokers: Multi-cohort study.","authors":"G David Batty, Frederick K Ho, Steven Bell","doi":"10.1101/2025.03.11.25323738","DOIUrl":"10.1101/2025.03.11.25323738","url":null,"abstract":"<p><strong>Background: </strong>If lung cancer in never-smokers was a single disease entity, it would be the sixth most commonly occurring malignancy. Despite the population impact, its risk factors are poorly understood owing to a dearth of larger-scale, well-characterised studies.</p><p><strong>Methods: </strong>We pooled individual-participant data from 18 prospective cohort studies comprising 91,588 never smokers (55,452 women) aged 16-102 years at study induction. Participants were linked to national death registries.</p><p><strong>Results: </strong>A maximum of 17 years follow-up (mean 9.7) gave rise to 85 lung cancer deaths. Of the 19 potential determinants captured at baseline, only being older age (hazard ratio; 95% confidence interval per 10 year increase: 2.45; 2.11, 2.85), male (2.25; 1.46, 3.48), and having a high fruit and vegetable intake (2.29; 1.25, 4.17) were associated with elevated rates of lung cancer in this never-smoking group. No other substantial relationships were detected.</p><p><strong>Conclusions: </strong>Despite the number and breadth of potential risk factors featured in this multi-cohort study, there was no clear suggestion of new determinants of lung cancer in never-smokers.</p><p><strong>Impact: </strong>Our findings point to the need to explore the influence of risk factors additional to those included herein, particular in the field of genetics. Our unlikely finding for fruit and vegetable consumption warrants further testing.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757104","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":"Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study.","authors":"Joshua Harvey, Jennifer Imm, Morteza Kouhsar, Adam R Smith, Byron Creese, Rebecca G Smith, Gregory Wheildon, Leonidas Chouliaras, Gemma Shireby, Zane Jaunmuktane, Eduardo De Pablo-Fernández, Thomas Warner, Debbie Lett, Djordje Gveric, Hannah Brooks, Johannes Attems, Alan Thomas, Emma Dempster, Clive Ballard, John T O'Brien, Dag Aarsland, Jonathan Mill, Lasse Pihlstrøm, Ehsan Pishva, Katie Lunnon","doi":"10.1101/2025.03.13.25323837","DOIUrl":"10.1101/2025.03.13.25323837","url":null,"abstract":"<p><p>Lewy body (LB) diseases are an umbrella term encompassing a range of neurodegenerative conditions all characterized by the hallmark of intra-neuronal α-synuclein associated with the development of motor and cognitive dysfunction. In this study, we have conducted a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of LB pathology. Utilizing a combined dataset of 1239 samples across 855 unique donors, we identified a set of 30 false discovery rate (FDR) significant loci that are differentially methylated in association with LB pathology, the most significant of which were located in <i>UBASH3B</i> and <i>PTAFR</i>, as well as an intergenic locus. Ontological enrichment analysis of our meta-analysis results highlights several neurologically relevant traits, including synaptic, inflammatory and vascular alterations. We leverage our summary statistics to compare DNA methylation signatures between different neurodegenerative pathologies and highlight a shared epigenetic profile across LB diseases, Alzheimer's disease and Huntington's disease, although the top-ranked loci show disease specificity. Finally, utilizing summary statistics from previous large-scale genome-wide association studies we report FDR significant enrichment of DNA methylation differences with respect to increasing LB pathology in the <i>SNCA</i> genomic region, a gene previously associated with Parkinson's disease and dementia with Lewy bodies.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756987","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 association study in Brazil identifies risk factor-adjusted genetic susceptibility to pulmonary tuberculosis with cell-specific gene expression effects.","authors":"Kimberly A Dill-McFarland, Bruno B Andrade, Marina C Figueiredo, Alice M S Andrade, Francys Avendaño-Rangel, Marcelo Cordeiro-Santos, Afrânio L Kritski, Valeria C Rolla, Juan M Cubillos-Angulo, Spyros A Kalams, Josh D Simmons, Jared M Oakes, Jonathan Peña Avila, Helder I Nakaya, Rama D Gangula, Peter F Rebeiro, Gustavo Amorim, Simon A Mallal, Timothy R Sterling, Thomas R Hawn","doi":"10.1101/2025.03.13.25323932","DOIUrl":"https://doi.org/10.1101/2025.03.13.25323932","url":null,"abstract":"<p><p>Although genetic factors contribute to tuberculosis (TB) risk, no cross-population causal variants have been identified by genome-wide association studies (GWAS). Here, we utilized low-pass whole genome sequencing (lpWGS) with imputation plus detailed epidemiologic risk factors and single-cell expression quantitative loci (sceQTL) to address prior GWAS limitations. Using 947 pulmonary tuberculosis (PTB) cases and 1807 close contact controls in the Regional Prospective Observational Research in TB (RePORT) study in Brazil, we estimated PTB heritability to be 47.7%. We identified 19 SNPs associated with PTB (P<5E-8) after adjustment for major risk factors (HIV, diabetes, smoking). Seven of these SNPs were associated with peripheral blood cell-specific sceQTLs in controls. Specifically, SNPs cis to transcription factors ZNF717 and MAML3 were associated with PTB disease and gene expression in monocytes, T cells, or B cells. Overall, this study utilized lpWGS, in-depth epidemiology, and single-cell analyses to detect population-specific genetic risk factors for PTB in Brazil.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757063","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":"High-grade B-cell lymphoma, not otherwise specified: an LLMPP study.","authors":"Brett Collinge, Laura K Hilton, Jasper Wong, Waleed Alduaij, Susana Ben-Neriah, Graham W Slack, Pedro Farinha, Merrill Boyle, Barbara Meissner, James R Cook, German Ott, Andreas Rosenwald, Elias Campo, Catalina Amador, Timothy C Greiner, Philipp W Raess, Joo Y Song, Giorgio Inghirami, Sarah L Ondrejka, Elaine S Jaffe, Dennis D Weisenburger, Wing C Chan, Harald Holte, Klaus Beiske, Kai Fu, Jan Delabie, Stefania Pittaluga, Javeed Iqbal, George Wright, Kerry J Savage, Andrew J Mungall, Louis M Staudt, Christian Steidl, Andrew L Feldman, Ryan D Morin, Lisa M Rimsza, David W Scott","doi":"10.1101/2025.03.11.25323696","DOIUrl":"https://doi.org/10.1101/2025.03.11.25323696","url":null,"abstract":"<p><p>Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin, 59% were germinal center B-cell-like (GCB), and 25% were activated B-cell-like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included <i>MYC</i> -rearrangement (47% vs. 6%), dark zone signature (DZsig) expression (45% vs. 7%), and more frequent mutation of <i>ID3</i> , <i>MYC</i> , <i>CCND3</i> , and <i>TP53</i> - all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, with those classified as DLBCL-like frequently <i>BCL2</i> -rearranged. Among DZsig-GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.</p><p><strong>Key points: </strong>Molecular analyses reveal that HGBCL-NOS encompasses a heterogeneous collection of tumors.A subset of HGBCL-NOS can be assigned to established molecular groups, while others remain unclassified.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756848","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":"Associations between Cardiovascular Risk Factors and Neurofilament Light Levels Among U.S. Mexican American Adults.","authors":"Monica M Diaz, Eran Dayan","doi":"10.1101/2025.03.13.25323894","DOIUrl":"https://doi.org/10.1101/2025.03.13.25323894","url":null,"abstract":"<p><strong>Background: </strong>The pathophysiological mechanisms that may differentially impact brain health and cognitive aging outcomes among Latino compared with non-Latino White (NLW) adults in the U.S remain incompletely understood. Recent evidence suggests that neurofilament light (NfL) levels, a biomarker of neuronal injury predictive of dementia risk, is associated with cardiovascular risk factors in both Latino and NLW populations. The current study examines whether associations between plasma NfL levels and markers for cardiovascular health differ among U.S. Mexican American (MA) and NLW adults enrolled in the Health and Aging Brain Study: Health Disparities (HABS-HD).</p><p><strong>Methods: </strong>Data from 1317 participants (648 MA and 669 NLW) were analyzed, including phenotypic, neuroimaging, and plasma NfL data. Cardiovascular health factors included total volume of white matter hyperintensities (WMH), and diagnoses of hypertension, diabetes, and CVD.</p><p><strong>Results: </strong>We found that NfL burden levels among MA and NLW participants differed as a function of diabetes and CVD diagnosis, with steeper differences observed in the MA group. Additionally, the association between WMH volume and NfL varied between the two groups, with a steeper association observed in the MA group.</p><p><strong>Conclusions: </strong>These findings highlight the potential utility of NfL as a prognostic biomarker for CVD and neurodegeneration, particularly among MA adults. Further research is needed to clarify the mechanisms underlying these associations and to develop targeted neurodegenerative prevention strategies that address disparities in brain aging.</p>","PeriodicalId":94281,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756560","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}