medRxiv : the preprint server for health sciences最新文献

The Biorepository and Integrative Genomics (BIG) Initiative in Tennessee has developed a pioneering resource to address gaps in genomic research by linking genomic, phenotypic, and environmental data from a diverse Mid-South population, including underrepresented groups. We analyzed 13,152 exomes from BIG and found significant genetic diversity, with 50% of participants inferred to have non-European or several types of admixed ancestry. Ancestry within the BIG cohort is stratified, with distinct geographic and demographic patterns, as African ancestry is more common in urban areas, while European ancestry is more common in suburban regions. We observe ancestry-specific rates of novel genetic variants, which are enriched for functional or clinical relevance. Disease prevalence analysis linked ancestry and environmental factors, showing higher odds ratios for asthma and obesity in minority groups, particularly in the urban area. Finally, we observe discrepancies between self-reported race and genetic ancestry, with related individuals self-identifying in differing racial categories. These findings underscore the limitations of race as a biomedical variable. BIG has proven to be an effective model for community-centered precision medicine. We integrated genomics education, and fostered great trust among the contributing communities. Future goals include cohort expansion, and enhanced genomic analysis, to ensure equitable healthcare outcomes.

Pain and distress are frequently reported by people with HIV. Although pain is widely acknowledged to contribute to distress, distress may also contribute to pain and its persistence. Given the evidence supporting a relationship between distress and clinical pain, the current study investigated the relationships between distress, secondary hyperalgesia (SH), and persistent pain in people with HIV, reporting pain (n=19) or being pain free (n=26). We anticipated that SH is an important link between distress and persistent pain, with distress potentially exacerbating pain by increasing the responsiveness of neurons in the central nervous system to nociceptive signalling. Our primary hypothesis was that self-reported distress would be positively associated with the induced surface area (primary measure) and magnitude (secondary measure) of SH. The secondary hypothesis was that individuals with persistent pain would display greater induced SH compared to those who reported being pain-free. The results showed that distress was positively associated with the surface area (p=0.02) and the magnitude (p=0.01) of induced SH. However, participants with persistent pain showed no difference in the surface area of SH compared to pain-free participants (p=0.87), and those with pain displayed a marginally lower magnitude of SH (p=0.05). These findings suggest that distress may be a worthy target of interventions in people exposed to acutely painful events. While this relationship may not be specific to people with HIV, further research is needed to establish its relevance to people without HIV.

Background: People with Alzheimer's disease (AD) now have access to disease-modifying treatment with anti-amyloid monoclonal antibodies (mAbs). Their perception of risks and benefits and approach to treatment decisions remain unknown.

Objective: We aimed to understand how people with AD weigh the benefits and costs of anti-amyloid mAbs and incorporate these into decisions about treatment.

Methods: We conducted semi-structured interviews with people with biomarker- or imaging-confirmed AD and mild or moderate cognitive impairment who were seen at memory care clinics and discussed lecanemab with a clinician. Interviews were recorded, transcribed, and deidentified. Thematic analysis identified themes and subthemes.

Results: Among 22 participants (mean age 70, 8 [36%] women, 22 [100%] White), analysis revealed 3 major themes and associated subthemes: 1) People with AD sought and obtained information from different sources-advocacy organizations, the Internet, and clinicians; 2) Hopes, expected benefits, and the existential threat of dementia drove willingness and readiness to start lecanemab; 3) Individual traits, family factors, and degree of trust in expertise influenced how people balanced risks and benefits. Some would accept treatment at any cost; others carefully weighed risks and burdens, but were motivated by supportive families, insurance coverage, and trust in expertise; for a few, costs decidedly outweighed their personal benefits. People with AD desired more individualized information and to hear more from patients who took the medication.

Conclusion: Results from this first qualitative study of people with AD considering treatment with anti-amyloid mAbs can inform clinician, health system and policy efforts to individualize decisions.

Background: Differentiating Bipolar (BD) and depressive (DD) disorders remains challenging in clinical practice due to overlapping symptoms. Our study employs fixel-based analysis (FBA) to examine fiber-specific white matter differences in BD and DD and gain insights into the ability of FBA metrics to predict future spectrum mood symptoms.

Methods: 163 individuals between 18 and 45 years with BD, DD, and healthy controls (HC) underwent Diffusion Magnetic Resonance Imaging. FBA was used to assess fiber density (FD), fiber cross-section (FC), and fiber density cross-section (FDC) in major white matter tracts. A longitudinal follow-up evaluated whether FBA measures predicted future spectrum depressive and hypomanic symptom trajectories over six months.

Results: Direct comparisons between BD and DD indicated lower FD in the right superior longitudinal and uncinate fasciculi and left thalamo-occipital tract in BD versus DD. Individuals with DD exhibited lower FD in the left arcuate fasciculus than those with BD. Compared to HC, both groups showed lower FD in the splenium of the corpus callosum and left striato-occipital and optic radiation tracts. FD in these tracts predicted future spectrum symptom severity. Exploratory analyses revealed associations between FD, medication use, and marijuana exposure.

Conclusions: Our findings highlight distinct and overlapping white matter alterations in BD and DD. Furthermore, FD in key tracts may serve as a predictor of future symptom trajectories, supporting the potential clinical utility of FD as a biomarker for mood disorder prognosis. Future longitudinal studies are needed to explore the impact of treatment and disease progression on white matter microstructure.

Background: Bones and muscles are connected anatomically, and functionally. Preliminary evidence has shown the gut microbiome influences the aging process of bone and muscle in animal studies. However, such evidence in humans is still scarce. This study aimed to assess the microbiome-bone and microbiome-muscle associations in two cohorts of community-dwelling older adults.

Methods: We leveraged information from two large population-based cohorts, i.e., the Rotterdam Study (mean age 62.7 ± 5.6 years; n=1,249) and the Framingham Heart Study (mean age 55.2 ± 9.1 years; n=1,227). For individuals included in this study, gut microbiome 16S rRNA sequencing, musculoskeletal phenotyping derived from DXA images, lifestyle and socioeconomic data, and medication records were available. Per cohort, the 16S rRNA sequencing data, derived from stool, were processed with the DADA2 pipeline and taxonomies were assigned using the SILVA reference database. In addition, the microbiome functional potential was obtained with PICRUSt2. Further, we investigated the association between the human gut microbiome (alpha diversity, genera and predicted functional pathways) and appendicular lean mass (ALM), femoral neck bone mineral density (FN-BMD) and trabecular bone score (TBS) using multilinear regression models controlling for multiple confounders, and performed a joint analysis from both cohorts. Sex-stratified analyses were also conducted.

Results: The gut microbiome alpha diversity was not associated with either tested phenotype after accounting for multiple-testing (P>1.67e-02). In the joint analysis, lower abundance of Oscillibacter (beta= -.51, 95%CI [-0.74, -.29]), Anaerotruncus (beta=-0.41, 95%CI [-0.61, - 0.21]), Eisenbergiella (beta=-0.39, 95%CI [-0.59, -.19]) and higher abundance of Agathobacter (beta=0.40, 95%CI [0.20, 0.60]) were associated with higher ALM (P<2.0e-04). Lower abundance of Anaerotruncus (beta=-0.32, 95%CI [-0.45, -.19]), Hungatella (beta=-0.26, 95%CI [-0.38, -.15]) and Clostridiales bacterium DTU089 (beta=-0.37, 95%CI [-0.55, -.19]) was associated with higher ALM only in females (P< 2.0e-04). Moreover, the biotin biosynthesis II pathway was positively associated with ALM (beta=0.44, 95% CI [0.24, 0.64]) (P<1.90e-04) in females while no associations were observed in males. We did not observe any robust association of bone traits with gut microbiome features.

Conclusion: Our results indicate that specific genera are associated with ALM in middle-aged and older adults and these associations can present in a sex-specific manner. Overall, our study suggests that the gut microbiome is linked to muscle aging in middle-aged and older adults. However, larger sample sizes are still needed to underpin the specific microbiome features involved.

Head and neck cancer (HNC) is the sixth most common cancer globally. Incidence and survival rates vary significantly across geographic regions and tumor subsites. This is partly due to differences in risk factor exposure, which includes tobacco smoking, alcohol consumption and human papillomavirus (HPV) infection, alongside detection and treatment strategies. The VOYAGER (human papillomaVirus, Oral and oropharYngeal cAncer GEnomic Research) consortium is a collaboration between five large North American and European studies which generated data on 10,530 participants (7,233 cases and 3,297 controls). The primary goal of the collaboration was to improve understanding of the role of HPV and genetic factors in oral cavity and oropharyngeal cancer risk and outcome. Demographic and clinical data collected by the five studies were harmonized, and HPV status was determined for the majority of cases. In addition, 999 tumors were sequenced to define somatic mutations. These activities generated a comprehensive biomedical resource that can be utilized to answer critical outstanding research questions to help improve HNC prevention, early detection, treatment, and surveillance.

Growing evidence suggests abnormalities of brain structural connectome in psychiatric disorders, but the causal relationships remain underexplored. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causal links between 206 white-matter connectivity phenotypes (n = 26,333, UK Biobank) and 13 major psychiatric disorders (n = 14,307 to 1,222,882). Forward MR analyses identified causal effects of genetically predicted five white-matter structural connectivity phenotypes on six psychiatric disorders, with associations being significant or suggestive. For instance, structural connectivity between the left-hemisphere frontoparietal control network and right-hemisphere default mode network was significantly negatively associated with autism spectrum disorder risk, while increased structural connectivity between the right-hemisphere frontoparietal control network and hippocampus was significantly linked to decreased anorexia nervosa and cannabis use disorder risk. Reverse MR analyses revealed significantly or suggestively causal relationships between the risk of two psychiatric disorders and four different white-matter structural connectivity phenotypes. For example, the susceptibility of anorexia nervosa was found to be significantly negatively associated with structural connectivity between the left-hemisphere visual network and pallidum. These findings offer new insights into the etiology of psychiatric disorders and highlight potential biomarkers for early detection and prevention at the brain structural connectome level.

Infection by Trypanosoma cruzi , the agent of Chagas disease, can irreparably damage the cardiac and gastrointestinal systems during decades of parasite persistence and related inflammation in these tissues. Diagnosis of chronic disease requires confirmation by multiple serological assays due to the imperfect performance of existing clinical tests. Current serology tests utilize antigens discovered over three decades ago with small specimen sets predominantly from South America, and lower test performance has been observed in patients who acquired T. cruzi infection in Central America and Mexico. Here, we attempt to address this gap by evaluating antibody responses against the entire T. cruzi proteome with phage display immunoprecipitation sequencing comprised of 228,127 47-amino acid peptides. We utilized diverse specimen sets from Mexico, Central America and South America, as well as different stages of cardiac disease severity, from 185 cases and 143 controls. We identified over 1,300 antigenic T. cruzi peptides derived from 961 proteins between specimen sets. A total of 67 peptides were reactive in 70% of samples across all regions, and 3 peptide epitopes were enriched in ≥90% of seropositive samples. Of these three, only one antigen, belonging to the trans-sialidase family, has not previously been described as a diagnostic target. Orthogonal validation of this peptide demonstrated increased antibody reactivity for infections originating from Central America. Overall, this study provides proteome-wide identification of seroreactive T. cruzi peptides across a large cohort spanning multiple endemic areas and identified a novel trans-sialidase peptide antigen (TS-2.23) with significant potential for translation into diagnostic serological assays.

Background: Clinical outcomes of acute myocardial infarction (AMI) are known to vary between females and males; however, the nature of this sex dimorphism remains controversial. Most AMI transcriptomic studies have not considered differences between females and males, and combined sexes in their analysis to increase sample size and gain power (canonical approach). Our objective was to (1) use a sex-specific differentially expressed gene meta-analysis (ss-DEGma) in blood and (2) identify sex-specific pathways related to the early phase of AMI.

Methods: Gene expression data (7 sets) for sex-combined (canonical) and sex-specific analysis (ss-DEGma) were obtained from the publicly-available GEO database. Datasets from whole blood and peripheral blood cells sampled within 3 days post-AMI were analyzed using GEO2R. The massiR tool identified sex in 72% of samples. The top-ranking DEGs were used to identify significant sex-specific biological pathways in the KEGG database (FDR <0.05).

Results: We performed this meta-analysis in 291 women and 452 men and > 20,000 genes (see Table for identified DEGs). Sex-combined DEGs yielded 100 significant KEGG pathways. Sex-specific DEGs yielded 8/61 (13%) additional new pathways not identified by the sex-combined analysis. Sex-combined pathways were predominantly immunological (35%), while male- and female-specific pathways were 43% and 18% immunological, respectively. Proliferative and metabolic pathways were the next most represented pathways in females, which were not present in males at all.

Conclusion: We present 8 new sex-specific AMI-related transcriptional pathways not identified in the canonical sex-combined analysis. Furthermore, we find that 53% of pathways identified in the canonical sex-combined analysis are not shared between sexes. This data underscores an urgent need for prospective sex-specific transcriptomic analysis to define the sex-specific biological difference post-AMI.