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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.

Background: In Bangladesh, cholera treatment focuses on acute watery diarrhea in symptomatic cases at health facilities, though asymptomatic infections are common. Understanding the role of asymptomatic infections in transmission is crucial for designing appropriate control strategies in this setting.

Methods: We utilized data from household studies conducted in Dhaka, Bangladesh during 2006-2018 where a symptomatic confirmed cholera case and their household contacts were followed for thirty days. Vibriocidal antibodies, bacteriological culture, and symptom histories were collected at multiple times points. We used a hidden Markov model to estimate risk of infection from intra-household and extra-household (i.e., community and environmental) sources and to quantify relative risk of transmission from symptomatic and asymptomatic infected household contacts.

Results: Estimated daily risk of intra-household infection from a symptomatic individual to another household member was 2.6% (95% CI: 0.4% - 5.6%) and from an asymptomatic infected individual to another household member was 1.6% (95% CI: 0.2% - 4.5%). We found no significant differences in probability of infection from asymptomatic compared to symptomatic individuals (OR: 0.60; 95% CI: 0.11 - 3.23). We estimated that daily risk of infection from extra-household sources during follow-up was 1.0% (95% CI: 0.7% - 1.4%).

Conclusion: Mitigation measures focused solely on treatment of symptomatic cholera cases may be insufficient to prevent transmission in a household. This supports use of interventions that reduce risk of transmission irrespective of symptoms, such as prophylactic antibiotic treatment for household members and/or providing safe water and hygiene kits following a confirmed household or community case.

Background: Early identification of risk for hospitalisation is crucial to reducing public health burden. Immune and endocrine-related markers are robust indicators of disease in epidemiological studies, but their value has not been consistently established with severe disorders requiring hospitalisation. Patterning of biomarker expression through latent profile analysis (LPA), may improve predictive accuracy for clinical outcomes above individual biomarkers alone.

Method: Four biomarkers (C-reactive protein; fibrinogen; leukocytes; insulin growth-factor-1) measured in the English Longitudinal Study of Ageing (ELSA) in 2008 were linked to administrative data on hospitalisations obtained from Hospital Episode Statistics (HES). Hospitalisation for 12 disease classes was monitored from 2008-2018 (n=4,940). Analyses were adjusted for genetic predisposition and a wide set of confounders.

Findings: There were 9,419 cases of hospitalisation over the 10-year follow-up period. LPA of the four biomarkers indicated a three-profile solution offered greatest parsimony, categorised as low-risk [52.43%]; moderate-risk [35.89%]; and high-risk [11.68%] inflammatory status. Profiles offered greater specificity than individual biomarkers with a risk gradient in hospitalisation for sleep, circulatory, endocrine, and genitourinary disorders, where the magnitude of associations was notably higher in the high-risk group. Profiles also identified risk for infection-related hospitalisation not identified by individual biomarkers alone (HR: high-versus-low-risk=1.38; 95%CI=1.08-1.78, p=0.011). No associations emerged in hospitalisation for digestive, nervous, or skin disorders.

Interpretation: LPA enabled more precise risk-stratification and subgroup-specific analyses, with profiles better characterising health outcomes requiring hospitalisation than individual biomarkers.

Funding: Biotechnology and Biological Sciences Research Council (BBSRC); Economic and Social Research Council (ESRC); National Institute on Aging.

Background: Persons with HIV (PWH) have an increased risk of heart failure compared with the general population despite effective viral suppression. No methods currently exist to predict heart failure risk in PWH. We sought to develop a proteomics-based risk model of incident heart failure in a longitudinal cohort of PWH in the Veterans Aging Cohort Study Biomarker Cohort.

Methods: We characterized the baseline plasma proteome of 1,398 PWH using the SomaScan 4.0 aptamer-based platform. We incorporated traditional risk factors, HIV-specific variables, and inflammatory/coagulation markers into Cox proportional hazards models of incident heart failure. For protein risk models, we used least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation to identify the optimal set of predictors. Model performance was evaluated using Harrell's Concordance Index (C-index).

Results: Among 1,398 PWH, 240 (17.1%) developed incident heart failure over 13.1 years of median follow-up. The sample was randomly divided 2:1 into training (n = 932) and test (n = 466) sets. In the training set, 4,248 proteins were screened, identifying 227 significant markers (Bonferroni-corrected p-value <1E-5); 108 of these were validated in the test set (Bonferroni-corrected p <2E-4) and included as candidate predictors in downstream LASSO models. Using LASSO-Cox regression, we identified a subset of predictor proteins alone and in combination with clinical and laboratory risk factors. Among the clinical risk factor models, individual traditional risk factors in combination with HIV disease markers (CD4⁺ T-cell count, viral load) exhibited the best predictive performance (C-index 0.656 [95% confidence interval 0.591 - 0.720]). Addition of circulating inflammatory and coagulation markers (soluble CD-14, interleukin-6, D-dimer) did not substantially improve performance (C-index 0.657 [0.594 - 0.720]). By contrast, a protein-only model incorporating 8 markers achieved an improved C-index of 0.725 [0.597 - 0.825]; proteins vs clinical model, p = 0.033), while the addition of CD4⁺ count and viral load performed similarly (C-index 0.715 [0.587 - 0.816]).

Conclusion: An 8-protein signature demonstrated superior predictive performance for long-term incident heart failure risk among PWH compared with baseline traditional risk factors and inflammatory markers. These findings highlight the potential of a proteomics-based approach for risk stratification in this population, which provides additive value beyond traditional or HIV-specific clinical risk factors.

Background: Adolescence is a period of rapid neurobiological and behavioural change, yet it remains unclear how deviations from normative brain maturation relate to the development of internalising and externalising symptoms.

Methods: Using data from the Adolescent Brain Cognitive Development (ABCD) Study, we combined brain age prediction with bivariate latent growth curve (BLGC) models to test whether deviations in brain maturation - indexed by the brain age gap (BAG) - relate to mental health development across late childhood and adolescence. Brain age was estimated using T1-weighted, diffusion (dMRI), resting-state fMRI, and multimodal MRI data across four waves (ages ~8.3-17.5). Internalising and externalising symptoms were assessed across ten waves with the self-report Brief Problem Monitor (BPM).

Results: Across T1, dMRI, and multimodal models, deviations from age-expected brain maturation and internalising and externalising symptoms showed coordinated nonlinear development across adolescence. Adolescents whose brains increasingly diverged from age-expected maturation over time also showed increasing symptom trajectories. These associations were small to moderate in magnitude and were most consistent for internalising symptoms in females (r = .15-.23), whereas externalising symptoms showed broader but less selective nonlinear associations across modalities in both males and females (r = .15-.23). Intercept-level associations were weaker and modality-specific (r = .06-.11). Formal tests provided no evidence for robust sex differences in these associations after correction for multiple comparisons.

Conclusion: These results indicate that adolescent development of mental health problems is more strongly linked to nonlinear changes in how individuals diverge from age-expected brain trajectories, rather than to fixed differences in brain age. Shifts in brain maturational tempo may therefore be a key feature underlying vulnerability to psychopathology in youth.

Background: Cardiovascular health (CVH) and genetic susceptibility to adverse left ventricular (LV) remodeling are each linked to cardiovascular diseases (CVD); however, their combined role remains unclear.

Methods: Framingham Heart Study participants [n=1,255 Offspring-Exam 8 (2005-2008), n=2,835 Generation 3-Exam 1 (2002-2005)] had assessment of modifiable risk factors comprising the American Heart Association's Life's Essential 8 (LE8) score with higher scores indicating better CVH health. A Polygenic Risk Score (PRS) for LV mass index (LVMI) was also calculated based on published PRS(PGS003427). We created 9 groups combining LE8 and PRS tertiles (high LE8+low PRS served as referent group reflecting optimal risk) and related these groups to presence of LVMI, LV ejection fraction (LVEF), and the ratio of the peak early diastolic mitral inflow velocity (E wave) to the peak early diastolic mitral annular velocity (e' wave; E/e'; separate model for each outcome), and incident cardiovascular disease (CVD; a composite of coronary heart disease [CHD], heart failure, stroke, peripheral arterial disease). We applied linear mixed regression and Cox regression models to evaluate the relation of LE8-PRS groups with all outcomes mentioned above.

Results: Participants (56% women, mean age 47 years) had mean LE8 score 70 (SD=13), indicating intermediate CV health and normal LVMI and systolic function (LVMI 76±13 g/m², LVEF 65±5%, E/e' 6 ±1.8 cm/s). Over 19 years of follow-up, composite CV events and CHD occurred in n=188 and n=99, respectively, of Offspring and n=83 and n=49 respectively, of Gen 3 participants. Compared to the referent group, individuals in the low LE8-high PRS group had high LVMI, E/e', and over three-fold higher risks for CVD and CHD, with incidence rates of approximately 1.84 versus 4.06 per 1,000 person-year, respectively.

Conclusion: Lower LE8 scores (indicating worse CVH) combined with high genetic risk confer higher conjoint risks for adverse LV structure, function, and CVD development.

Obsessive-compulsive disorder (OCD) is a chronic, serious psychiatric disorder that affects 2-3% of the population and is associated with high personal and societal costs. Genetic factors are estimated to explain roughly half the risk of developing OCD, and genomic studies are just beginning to identify common and rare genetic variants mediating this risk. A major goal of genomic studies is to yield insights into the etiology of OCD and identify molecular targets for the development of novel therapeutics. However, the overwhelming majority of subjects in existing genetic studies are of European ancestry, limiting the generalizability of these findings. To address this gap in understanding, we established the Black EquaLity in OCD NeuroGenomics (BELONG) study ( https://belongocd.com/ ). BELONG aims to collect DNA and clinical data from 1,250 richly phenotyped OCD cases of African ancestry in a culturally sensitive manner. In addition, BELONG includes the collection of parental DNA samples for trio-based analyses and unrelated matched controls for case-control analysis. DNA samples will be sequenced using optimized approaches that will allow us to examine both rare and common genome-wide variation to identify OCD risk genes. We will also meta-analyze these data with other existing OCD genomic data. Overall, BELONG will increase the representation of Black Americans in OCD genetic research, which is necessary to generalize precision medicine discoveries in psychiatric genetics.

Aggressive variant prostate cancer (AVPC) is a lethal subtype of prostate cancer characterized by its androgen independence, resistance to chemotherapy, and display of neuroendocrine features which can emerge either de novo or via transformation after a prior diagnosis of adenocarcinoma. The poor clinical outcomes in patients with AVPC are associated with its profound molecular heterogeneity. In this study, we analyzed 23 consecutive AVPC cases treated at a dedicated small-cell clinic (2017-2025) using clinicogenomic and transcriptomic profiling. Transformed AVPC exhibited significantly shorter overall survival times than de novo AVPC (11.8 vs 26.0 months, P < 0.001). Integrative genomic analyses identified residual androgen signaling in subsets of cases harboring neuroendocrine lineage programs, highlighting a decoupling of lineage identity and morphology. To facilitate mechanistic and pharmacologic studies, we established NCI-LYM-1, a patient-derived organoid/PDX from an AR-negative, ASCL1+/SYP+ lymph node metastasis, which faithfully recapitulates the donor tumor's molecular and phenotypic features. Short- and long-read whole-genome sequencing combined with optical genome mapping identified biallelic inactivation of PTEN, TP53, RB1 and BRCA2 as potential drivers, demonstrating clonal concordance with circulating tumor DNA from the original patient donor. Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by in vitro organoid testing with the BCL-2/BCL-xL inhibitor navitoclax (IC₅₀: 0.27 μM) and the MCL-1 inhibitor AZD-5991 (IC₅₀: 0.060 μM). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies.

Background: Epstein-Barr virus (EBV) establishes latency in most adults and can be reactivated under conditions of co-infection and immune dysregulation. COVID-19 has been associated with EBV reactivation, primarily in hospitalized cohorts, but EBV shedding in the oral cavity and the extent to which these dynamics trigger a systemic anti-EBV antibody response during acute COVID-19 remain poorly understood.

Methods: We conducted a nested cohort study of 69 community-based participants including 56 SARS-CoV-2-positive individuals and 13 uninfected household contacts, enrolled as part of a prospective cohort within 5 days of COVID-19 symptom onset. Participants self-collected saliva and nasal samples daily through day 14, then every 3 days until day 21, and once more at day 28. Blood samples were collected on day 28. SARS-CoV-2 RNA in the saliva and nares and EBV DNA in the saliva were quantified by RT-qPCR and qPCR, respectively. EBV antibody responses against viral capsid antigen IgM and IgG, early (D) antigen IgG, and nuclear antigen IgG were quantified in serum by ELISA.

Results: SARS-CoV-2-positive participants tended to be more likely to experience consecutive days of EBV shedding in saliva (p = 0.10) and contributed a higher mean number of EBV DNA-positive specimens compared with uninfected controls (5 vs. 1 per participant in EBV+ participants; p = 0.018). Among SARS-CoV-2-positive participants with EBV reactivation, a positive correlation was observed between maximum EBV DNA in saliva and SARS-CoV-2 RNA levels in saliva (r = 0.49, p = 0.047) but not with SARS-CoV-2 RNA levels in nasal samples (r = -0.12, p = 0.67). EBV reactivation in saliva was not associated with induction of serological responses to systemic EBV reactivation.

Conclusions: This cohort study provides evidence that SARS-CoV-2 infection is associated with prolonged salivary EBV shedding, that concurrent high levels of EBV and SARS-CoV-2 in saliva are correlated, but these salivary EBV shedding dynamics do not drive systemic EBV antibody responses. Further research with larger cohorts and mechanistic assays would be helpful to elucidate the biological pathway triggering systemic EBV antibody responses.

Angioedema is a life-threatening adverse drug reaction associated with renin-angiotensin-aldosterone system (RAAS) inhibitors, characterized by localized swelling in the deep layers of the skin. Well-established evidence indicates an up to fivefold higher incidence of RAAS inhibitor-induced angioedema in self-identified Black patients compared to White patients. The mechanisms underlying this health disparity remain poorly understood and are often attributed to race, a poor proxy for interindividual genetic similarity and social stressors. Here, we investigate the genetic and social determinants of RAAS inhibitor-induced angioedema as well as the etiology of this racial difference. In particular, we (1) discovered OTULINL and CRABP1 as novel loci for RAAS inhibitor-induced angioedema, (2) confirmed the importance of bradykinin for this adverse drug reaction, (3) reported the first significant genome-wide association in self-identified Black participants, (4) identified alcohol use as an important social determinant, (5) demonstrated the strong role of variants enriched in 1000 Genomes African superpopulation-like genomes as the driver of racially differential angioedema risk, and (6) demonstrated the combined role of polygenic effect size and allele frequency differences in explaining these racial differences. Our results suggest that a clinical precision medicine tool may more precisely predict for whom RAAS inhibitors should be avoided (to prevent angioedema) compared to using race. These findings ultimately underscore the value of an evidence-based approach to removing race from treatment guidelines, which carries less potential harm than other removal strategies.