medRxiv : the preprint server for health sciences最新文献

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.

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.

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.

Genome-wide association studies (GWAS) identified multiple loci for cardiovascular disease, but their relevance to individuals with chronic kidney disease (CKD), who are at higher risk of cardiovascular disease, is unknown. In this study, we performed GWAS analyses of coronary heart disease (CHD) or all-cause stroke in African (AFR) and European (EUR) American participants with CKD of the Chronic Renal Insufficiency Cohort (CRIC). Mixed- effect logistic regression models were race-stratified and adjusted for age, sex, site of recruitment, estimated glomerular filtration rate (eGFR), and principal components, followed by meta-analysis. We attempted replication in participants from two biobanks with biomarker or ICD-10 (International Classification of Diseases, 10th Revision) diagnostic codes for CKD. We assessed the association of single nucleotide variants (SNVs) at known CHD and stroke loci in CRIC and tested the genetic correlation among CRIC, a biobank-based cohort and published GWAS of cardiovascular disease. Among 3,588 CRIC participants, 1,203 had CHD and 535 had all-cause stroke. We identified six SNVs across three loci ( LINC02744 , AZIN1- AS1 , and ATP6V0A4 ) associated with all-cause stroke, and two intronic SNVs at the PPARG locus associated with CHD. However, SNV associations were not significant in replication studies. Published SNVs for CHD or stroke were not associated with cardiovascular outcomes in CRIC. When testing the genetic correlations between published GWAS and CRIC GWAS, they were significant for CHD (genetic correlations (rg) range of 0.39 to 0.51, p-value< 0.007). These findings suggest some differences in the genetic architecture of CHD and stroke among individuals with CKD compared to those from the general population, although large numbers of CKD participants are needed to assess if findings are related to participant selection and CKD severity, or non-traditional risk factors in people with CKD.

Mycobacterium tuberculosis (Mtb) is a major threat to global health and is responsible for over one million deaths each year. To stem the tide of cases and maximize opportunities for early interventions, there is an urgent need for affordable and simple means of tuberculosis diagnosis in under-resourced areas. We sought to develop a CRISPR-based isothermal assay coupled with a compatible, straightforward sample processing technique for point-of-care use. Here, we combine Recombinase Polymerase Amplification (RPA) with Cas13a and Cas12a, to create two parallelised one-pot assays that detect two conserved elements of Mtb (IS6110 and IS1081) and an internal control targeting human DNA. These assays were shown to be compatible with lateral flow and can be readily lyophilized. Our finalized assay exhibited sensitivity over a wide range of bacterial loads (10⁵ to 10² CFU/mL) in sputum. The limit of detection (LoD) of the assay was determined to be 69.0 (51.0 - 86.9) CFU/mL for Mtb strain H37Rv spiked in sputum and 80.5 (59.4 - 101.6) CFU/mL for M. bovis BCG. Our assay showed no cross reactivity against a wide range of bacterial/fungal isolates. Clinical tests on 13 blinded sputum samples revealed 100% (6/6) sensitivity and 100% (7/7) specificity compared to culture. Our assay exhibited comparable sensitivity in clinical samples to the microbiological gold standard, TB culture, and to the nucleic acid state-of-the-art, GeneXpert MTB/RIF Ultra. This technology streamlines TB diagnosis from sample extraction to assay readout in a rapid and robust format, making it the first test to combine amplification and detection while being compatible with both lateral flow and lyophilization.

Objective: Sedentary behavior significantly increases the risk for chronic diseases and cognitive decline in aging, underscoring the need for effective interventions. Older adults exhibit a 'positivity effect', whereby processing of positive information is prioritized over negative information. In addition, self-affirmation was shown to reduce sedentary behavior in younger adults, but its effects in older adults remain unknown. This study tested a novel, technology-based intervention combining daily self-affirmation and gain-framed health messages to reduce sedentary behavior in older adults.

Methods: In a 6-week randomized controlled trial (NCT0431536), 48 cognitively unimpaired, sedentary older adults were randomized into two groups: The intervention group (mean age=70.0±5.4years) completed daily self-affirmation based on their highest-ranked value, followed by gain-framed health messages. The active control group (mean age=68.4±5.0years) performed self-affirmation on their lowest-ranked value, followed by loss-framed messages. This was a single-blinded clinical trial that incorporated a hybrid efficacy and implementation design. Thus, information about intervention feasibility was examined. In addition, baseline motivational traits, including reward sensitivity, were assessed as moderators of behavior change. The neural basis of self-affirmation and gain-framed health messaging was examined at baseline using a task-based, event-related fMRI paradigm across groups, after randomization at the outset of the intervention.

Results: The intervention showed high adherence (0.92±0.08) and positive ease-of-use ratings. While the intervention did not significantly reduce sedentary behavior compared to the active control condition, increased reward sensitivity predicted reduced sedentary behavior across all participants. FMRI results showed increased ventral striatal activation in the intervention group, compared to the active control group during reading of gain-framed compared to neutral messages.

Conclusions: This study supports the feasibility of technology-based sedentary beahvior reduction interventions for older adults. While self-affirmation combined with gain-framed messaging did not significantly reduce sedentary behavior, gain-framed messages engaged the reward network, and reward sensitivity predicted future reduction in sedentary behavior.

Rapid health outcome data acquisition using existing questionnaires can greatly facilitate time-sensitive research during or after a wildfire event. We aimed to develop a readily available library of questionnaires for self-reported health outcomes to serve as a centralized platform for wildfire researchers seeking to quickly design instruments tailored to their research aims. In this paper, we describe the methodology used to identify relevant health questionnaires and compile them into a structured library. We first followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 checklist and performed a systematic literature review of prior research on wildfire exposure and health and used this to 1) identify health outcome categories associated with wildfire and smoke exposure and 2) extract questionnaires used for self-report of health outcomes related to wildfire exposure. We also performed a secondary search of existing questionnaire repositories to identify additional instruments relevant to health impacts of wildfire exposure. All questionnaires (n=100) were organized by eight health outcome categories (mental health = 60, respiratory health = 19, overall health = 17, sleep = 10, cardiovascular health = 4, allergy = 1, irritation (eye, throat, skin) = 2, and metabolic health = 1). The library (see supplementary information) will be accompanied by a decision-tree framework in development, which will assist future users in building new questionnaires that best fit their study population and research aims. Both the questionnaire library and the forthcoming decision-support framework will be publicly accessible to researchers, public health agencies, and other groups interested in rapid response data collection to characterize the impacts of wildfires. Additionally, this method of creating a wildfire exposure health questionnaire library may serve as a template for rapid collection of questionnaire-based data following other disasters.

Blood-based protein biomarkers may provide important insights into the long-term neuropathology of traumatic brain injury (TBI). This is urgently required to identify mechanistic processes underlying post-traumatic neurodegeneration (PTND); a progressive post-recovery clinical decline experienced by a portion of TBI survivors. The aim of this study was to examine change over time in protein levels in a chronic TBI cohort. We selected six markers (Aβ ₄₂ /Aβ ₄₀ , GFAP, NfL, BD-tau, p-tau231, and p-tau181) with known importance in acute TBI and/or other neurodegenerative conditions. We used a longitudinal design with two time points approximately 3.5 years apart on average (SD 1.34). Proteins were measured in plasma using the ultrasensitive Single molecule array technology for 63 participants with mild to severe chronic TBI (sustained ≥ 1 year ago; M 28 years; SD 16.3 since their first blow to the head) from the Late Effects of TBI study (48% female; current age M 52 years; SD 13.4). Multivariate linear mixed effect models with adjustments for multiple comparisons were performed to examine trajectories in proteins over time with age and age squared as covariates. A series of sensitivity analyses were conducted to account for outliers and to explore effects of key covariates: sex, APOE ε4 carrier status, medical comorbidities, age at first blow to the head, time since first blow to the head, and injury severity. Over an average of 3.5 years, there were significant reductions in plasma Aβ ₄₂ /Aβ ₄₀ (β = -0.004, SE = 0.001, t = -3.75, q = .001) and significant increases in plasma GFAP (β = 12.96, SE = 4.41, t = 2.94, q = .01). There were no significant changes in NFL, BD-tau, p-tau231, or p-tau181. Both plasma Aβ ₄₂ /Aβ ₄₀ and GFAP have been associated with brain amyloidosis, suggesting a role for Aβ mis-metabolism and aggregation in the long-term neuropathological consequences of TBI. These findings are hypothesis generating for future studies exploring the diverse biological mechanisms of PTND.