medRxiv : the preprint server for health sciences最新文献

Objective: Much medical data is only available in unstructured electronic health records (EHR). These data can be obtained through manual (human) extraction or programmatic natural language processing (NLP) methods. We estimate that NLP only becomes economically competitive with manual extraction when there are ~6500 EHRs records. We have found that there is interest from clinicians and researchers in using NLP on projects with fewer records. We examine whether a large language model (LLM) can be used to reduce the cost of NLP to make it economically competitive for such projects, and study the feasibility of such framework for accuracy.

Materials and methods: We developed an NLP pipeline using an off-the-shelf open LLM to extract breast cancer ER, PR, and HER2 biomarker data. Pipeline development stopped when the prompts performances were competitive with manual extraction. The development time and extraction performance were compared to those for an existing rule-based (RB) NLP pipeline. The code for the extraction portion of the LLM pipeline is available at https://github.com/sehagler/llm_biomarker_extraction .

Results: The LLM pipeline produced performance competitive with manual data extraction with a hands-on development time that was ~38% that of the RB pipeline.

Discussion: LLMs exhibit lower hands-on development costs compared to standard NLP techniques, but require significant and potentially costly computation resources.

Conclusion: LLMs may potentially allow the economically competitive application of NLP to smaller projects if computation costs can be managed.

Alcohol use disorder (AUD) is a chronic, relapsing condition and a major public health problem. However, few medications are approved to treat AUD, and those available show limited efficacy. Drug repurposing is a cost-effective strategy to identify novel therapeutic uses for existing medications. Here, we describe a pipeline that integrates genetic and electronic health record (EHR) data to identify and evaluate drugs to be repurposed for treating AUD. Our approach comprises 1) alcohol-associated gene identification and biological network generation; 2) mapping drugs to target proteins; 3) filtering promising repurposing candidates; and 4) an exemplar pharmacoepidemiologic analysis of the effect of an identified drug (i.e., baclofen) on alcohol consumption. Linking loci to genes from a genome-wide association study (GWAS) of problematic alcohol use identified 94 genes, which we expanded to 327 alcohol-related genes through network-based analyses. Across these analyses, 52 genes were linked to 195 FDA-approved drugs, including four already approved or used off-label to treat AUD. After filtering for safety, relevance, and data availability, 26 candidate drugs, including baclofen, were selected for further evaluation. An evaluation of the real-world effectiveness of baclofen using national EHR data from the United States Department of Veterans Affairs provided evidence that baclofen-exposed patients reduced alcohol consumption more than propensity-score-matched unexposed patients. This approach, which aligns genomic findings with real-world clinical data, provides an efficient method for identifying promising drug repurposing candidates and prioritizing those that merit evaluation in randomized trials to ultimately advance pharmacotherapies for AUD.

Introduction: Engaging individuals with lived experience enhances the rigor and real-world relevance of clinical research. In adolescent idiopathic scoliosis (AIS), where non-surgical evidence remains limited, involving patients and caregivers informs design, recruitment, and retention for future trials.

Methods: Using the Community Engagement (CE) Studio model, we conducted a 1.5-hour virtual session with children aged 10-16 years with AIS and their caregivers residing in North America. Participants (no spinal surgery; with/without brace) were recruited through engagement databases, advocacy organizations, and social media. A trained facilitator led structured discussions. Responses were thematically synthesized, including summaries related to recruitment, retention, study protocol, meaningful outcomes and treatment success. Participants received compensation and a follow-up Qualtrics survey. The CE Studio, based on the Vanderbilt model is advisory, and IRB- exempt.

Results: Of 81 respondents, 31 were eligible and 18 participated (nine girls, nine caregivers) representing seven ethnicities across nine U.S. states. All participants valued the proposed multicenter RCT on scoliosis exercise rehabilitation and expressed willingness to enroll; 78% would accept randomization to either the active or 6-month waitlist control arm. Reported barriers included limited access to physiotherapy (43%), physician skepticism (57%), and bracing preference (43%). The most bothersome symptoms were pain (50%) and brace discomfort (17%). Prioritized outcomes included preventing curve progression, avoiding surgery, pain reduction, and improved appearance.

Conclusions: Participants expressed strong willingness to enroll, emphasizing pain, progression, and access to care as key barriers. Improved communication with providers about non-surgical options was viewed as essential to support shared decision-making.

Aging is the strongest known risk factor for Alzheimer's disease (AD), and elevated plasma amyloid-β (Aβ) levels in healthy adults are associated with increased AD risk. Aging is also associated with autonomic imbalance, characterized by increased sympathetic and decreased parasympathetic activity. In our previous randomized clinical trial, we found that four weeks of daily slow-paced breathing designed to enhance parasympathetic activity reduced plasma Aβ42 and Aβ40 levels in younger and older adults and showed a trend toward increasing Aβ42/Aβ40 ratio only in older adults. The primary goal of the current study was to extend these findings in 62 adults aged 50 to 70 years using randomized assignment to 10 weeks of slow-paced breathing or a random-paced breathing control with three assessment time points. Secondary objectives included examining the effects of slow-paced breathing on brain structure (i.e., perivascular space and hippocampal volumes) and cognitive performance. Consistent with prior findings, the slow-paced breathing group showed greater decreases in plasma Aβ42 than the control group. However, group differences were not significant for Aβ40 or Aβ42/Aβ40 ratios, and no significant effects were observed for the secondary outcomes. The non-significant findings may be due to changes we made to both intervention and control condition methods relative to our previous trial. Further research is needed to explore the underlying mechanisms and potential effects of slow-paced breathing on Aβ accumulation in the brain.

Highlights: Participants were randomly assigned to slow-placed breathing or a breathing controlIndividualized protocols determined breathing pacesTen weeks of daily slow-paced breathing practice reduced plasma Aβ42 levels.

Réunion island just experienced a massive chikungunya virus outbreak in 2024-2025, with more than 54,000 confirmed cases. This is the second major chikungunya outbreak on the island, following the first one that peaked 20 years ago. It has been assessed that this new outbreak finds its origin in a single introduction event into the island, offering a unique opportunity to exploit viral genomic data to understand the epidemiological and dispersal dynamics of the introduced transmission chain. We sequenced >3,000 near-full viral genomes collected during the course of the epidemic. Harnessing this genomic dataset, we used a set of phylodynamic and phylogeographic approaches to unravel the paths taken by the transmission chain and the external factors having impacted its dynamics on the island. Our analyses highlight a dispersal pattern in line with a gravity-model dynamic with viral transition events being more frequent from and toward more populated areas. While we find that dispersal events were on average more likely between geographically close locations, our analyses also reveal that the transmission chain was overall spatially intermixed, with frequent exchanges among distant residential areas. In addition, we show that the decrease in transmission rate leading to the end of the epidemic can, at least to a large extent, be attributed to the population immunity resulting from both the current and the 2005-2006 epidemic. While a short-term resurgence of viral transmission cannot be excluded, the impact of herd immunity constitutes an encouraging outcome that should at least contribute to limiting the spread of the virus in the upcoming seasons.

Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Importance: Traumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI.

Objective: Since TBI facilitates infiltration of circulating natural anti-NMDAR1 autoantibodies into the brain, we tested the hypothesis that natural anti-NMDAR1 autoantibody levels in plasma may modify risk for development of psychiatric symptoms after TBI.

Design settings and participants: Data were analyzed from 1025 Marine Resiliency Study-II participants, a longitudinal study that included plasma collection and assessments for TBI, PTSD (Clinician Administered PTSD Scale-IV), depression (Beck Depression Inventory-2) and anxiety symptoms (Beck Anxiety Inventory) before and after a combat deployment to Afghanistan (2010-2013). Plasma anti-NMDAR1 autoantibody levels were quantified using a luciferase-based immunnoassay. Outcomes were post-deployment symptoms and the predictor was a continuous or dichotomous measure of anti-NMDAR1 autoantibody level. Covariates included pre-deployment symptoms, deployment history and experiences.

Results: TBI (606 with TBI, 419 without TBI) was associated with significantly greater depression, PTSD and anxiety symptoms post-deployment. In individuals with no TBI history, anti-NMDAR1 autoantibody levels were not associated with symptoms. In individuals that endorsed a TBI however, higher pre-deployment plasma levels of natural anti-NMDAR1 autoantibodies were significantly associated with lower predicted post-deployment depression and PTSD symptoms, but not anxiety. In the TBI group, high autoantibody group membership lowered predicted post-deployment CAPS-IV and BDI-2 scores by 22 and 25% respectively (Cohen's d=0.25-0.32). After deployment, prevalence of moderate-severe depression was significantly lower in participants with high anti-NMDAR1 autoantibodies (.8% [2/256 participants]) compared with participants with low anti-NMDAR1 autoantibodies (3.5% [27/763 participants]), as was prevalence of taking psychotropic medications.

Conclusions and relevance: Natural anti-NMDAR1 autoantibodies may be a "resilience" factor for TBI-associated increases in depression and PTSD symptoms, supporting the hypothesis that natural anti-NMDAR1 autoantibodies could have neuroprotective effects. Mechanistic studies are warranted to understand if plasma natural anti-NMDAR1 autoantibodies reach the CNS to suppress glutamate excitotoxicity associated with TBI.

Importance: General responders of the World Trade Center (WTC) Health Program (WTCHP), who were uniquely exposed to chemical toxicants and extreme psychological stress during the 2001 terrorist attack, now experience a wide range of unusually prevalent health outcomes for a mid-aged population, including frailty, Post Traumatic Stress Disorder (PTSD), and depression.

Objective: We investigated whether these outcomes are associated with urban environmental exposures experienced in the two decades post 9/11.

Design: Prospective cohort study.

Setting: WTCHP general responders' cohort.

Participants: We included 18,861 WTCHP general responders between the years 2003 to 2023 who took part in rescue, recovery, and clean-up tasks following the 9/11/2001 attack on the WTC.

Exposures: We evaluated the distinct and combined associations with annual fine particulate matter (PM _2.5 ), temperature, and Green View Index (GVI) and assessed interactions with WTC-exposures.

Outcomes: We assessed frailty using a validated index developed specifically for the WTCHP. We determined PTSD and depression status based on repeated test scores from validated tools administered during the monitoring visits.

Results: We included 18,861 responders, 81.89% were males, and the mean age at entry was 47. Interquartile range increases in PM _2.5 and temperature were significantly associated with increased frailty, PTSD, and depression scores, while greenness (GVI) was protective. A decile increase in the overall exposure mixture was associated with a 0.50% (95% confidence interval 0.08; 0.94) increase in frailty and a 0.10 unit (0.02; 0.18) increase in PTSD scores, primarily driven by temperature. Importantly, the exposure-mixture was associated with an increased risk of reaching a clinical threshold for PTSD (odds ratio: 1.013[1.001,1.024]). Finally, the associations between the exposure-mixture and mental health were significantly amplified among responders with high WTC-exposures, though no such modification was observed for frailty.

Conclusion and relevance: Exposures to heat and PM _2.5 were associated with increased frailty, PTSD, and depression, while greenness exposure was protective. Responders who experienced more intense WTC exposures were more vulnerable to later-life environmental exposure-mixture effects on mental health. These findings may help explain the elevated burden of these conditions among WTCHP responders and suggest avenues for public health interventions including education on risk mitigation strategies.

Opioid use disorder (OUD) has been linked to cardiometabolic diseases in adults through reductions in adiponectin-an adipocytokine with insulin-sensitizing effects. Opioid use during pregnancy dysregulates neonatal growth and may predispose to adult-onset diseases, but the impact of maternal OUD on neonatal adiponectin has not been studied. We hypothesize that maternal OUD also reduces adiponectin level in offspring (primary outcome) and alters growth (secondary outcome). To test our hypothesis, we conducted a prospective, observational pilot study and compared the expression of salivary adiponectin receptor 1/ ADIPOR1 and anthropometric and body composition (fat and fat-free mass) measurements between opioid-exposed and age-matched non-exposed neonates born at ≥34 weeks' gestation. Data were stratified by exposure and sex using a Student's t-test. Significance was set at p<0.05. A total of 67 neonates (35 opioid-exposed, 32 non-exposed neonates) were enrolled. Compared to healthy, non-exposed neonates, the expression of ADIPOR1 was reduced in opioid-exposed neonates (0.27-fold, p<0.01), with the lowest expression in those requiring pharmacotherapy (0.048-fold, p<0.001). Despite the smaller anthropometric measurements in the exposed than non-exposed neonates (2915±625 grams vs. 3209±345 grams, p=0.02), opioid-exposed neonates had comparable adiposity to non-exposed neonates (8.60±4.52% vs. 8.53±4.00%, p=0.95). Less breast milk was used in the exposed than non-exposed group (25.7% vs. 71.9%, p<0.01). Maternal OUD may be associated with aberrant growth and excess adiposity in offspring through its effect on adiponectin signaling, predisposing these neonates to cardiometabolic risks.