Search Results (1,014)

Background and Objectives: Emerging evidence indicates that individuals exposed to adverse childhood experiences (ACEs) face elevated risks for various chronic illnesses. However, the association between ACEs and osteoporosis risk remains underexplored, particularly regarding potential modifications by genetic susceptibility. This prospective cohort study aims to examine the relationship of ACEs with incident osteoporosis and investigate interactions with polygenic risk score (PRS). Materials and Methods: This study analyzed 124,789 UK Biobank participants initially free of osteoporosis. Cumulative ACE burden (emotional neglect, emotional abuse, physical neglect, physical abuse, sexual abuse) was ascertained through validated questionnaires. Multivariable-adjusted Cox proportional hazards models assessed osteoporosis risk during a median follow-up of 12.8 years. Moderation analysis examined genetic susceptibility interactions using a standardized PRS incorporating osteoporosis-related SNPs. Results: Among 2474 incident osteoporosis cases, cumulative ACEs showed dose–response associations with osteoporosis risk (adjusted hazard ratio [HR]_{per one-unit increase} = 1.07, 95% confidence interval [CI] 1.04–1.11; high ACEs [≥3 types] vs. none: HR = 1.26, 1.10–1.43). Specifically, emotional neglect (HR = 1.14, 1.04–1.25), emotional abuse (HR = 1.14, 1.03–1.27), physical abuse (HR = 1.17, 1.05–1.30), and sexual abuse (HR = 1.15, 1.01–1.31) demonstrated comparable effect sizes. Sex-stratified analysis revealed stronger associations in women. Joint exposure to high ACEs/high PRS tripled osteoporosis risk (HR = 3.04, 2.46–3.76 vs. low ACEs/low PRS) although G × E interaction was nonsignificant (P-interaction = 0.10). Conclusions: These results suggest that ACEs conferred incremental osteoporosis risk independent of genetic predisposition. These findings support the inclusion of ACE screening in osteoporosis prevention strategies and highlight the need for targeted bone health interventions for youth exposed to ACEs. Full article

Background/Objectives: Latinos, particularly those of Mexican ancestry, experience high rates of type 2 diabetes and sleep disturbances, exacerbating adverse health outcomes. This study aimed to examine the prevalence of excessive daytime sleepiness and its associations with diet, cardiometabolic risk factors, and glycemic control in this population. Methods: This cross-sectional study utilized data from the El Banco por Salud biobank, including 1685 participants (aged 52.6 ± 14.5 years, BMI: 32.4 ± 7.0 kg/m²) recruited from Federally Qualified Community Health Centers. Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale, while dietary information was obtained via the Brief Dietary Assessment Tool for Hispanics. Primary outcomes included cardiometabolic risk factors and glycated hemoglobin (HbA1c) levels. Results: Excessive daytime sleepiness (Epworth Sleepiness Scale > 10) was present in 22.0% of participants and was associated with higher BMI (p < 0.001), larger waist circumference (p = 0.002), poorer diet quality, increased dyslipidemia (p = 0.036), and elevated HbA1c (p = 0.007). Linear regression analyses confirmed that excessive daytime sleepiness was significantly associated with higher HbA1c levels, both in unadjusted (R² = 0.011; p < 0.001) and adjusted for demographic, anthropometric, and socioeconomic factors (R² = 0.107; p = 0.004) models. Conclusions: Excessive daytime sleepiness among Latinos of Mexican ancestry is associated with unhealthy dietary patterns and poor glycemic control, highlighting the need for targeted interventions addressing sleep and dietary habits in this vulnerable population. Full article

Background/Objectives: Guillain–Barré syndrome (GBS) is a rare autoimmune peripheral neuropathy that affects both the myelin sheaths and axons of the peripheral nervous system. It is the leading cause of acute neuromuscular paralysis worldwide, with an annual incidence of less than two cases per 100,000 people. Although most patients recover, a small proportion do not regain mobility and even remain dependent on mechanical ventilation. In this study, we refer to the analysis of samples collected from GBS patients at different defined time points during hospital recovery and performed by a medical or research group. Methods: The conditions for whole blood collection, peripheral blood mononuclear cell isolation, and serum collection from GBS patients and volunteer donors are explained. Aliquots of these human samples have been used for red blood cell phenotyping, transcriptomic and proteomic analyses, and serum biochemical parameter studies. Results: The initial sporadic preservation of human samples from GBS patients and control volunteers enabled the creation of a biobank collection for current and future studies related to the diagnosis and treatment of GBS. Conclusions: In this article, we describe the laboratory procedures and the integration of a GBS biobank collection, local medical services, and academic institutions collaborating in its respective field. The report establishes the intra-disciplinary and inter-institutional network to conduct long-term longitudinal studies on GBS. Full article

Brain morphological abnormalities are common in patients with neurodevelopmental disorders (NDDs) and other neuropsychiatric disorders, often reflecting abnormal brain development and function. Genetic studies have found common genetic factors in NDDs and other neuropsychiatric disorders, although the etiology of brain structural changes in these disorders remains poorly understood. In this study, we analyzed magnetic resonance imaging (MRI) and genetic data from more than 30K individuals from the UK Biobank to evaluate whether NDD-risk copy number variants (CNVs) are also associated with neuroanatomical changes in both patients and neurotypical individuals. We found that the size differences in brain regions such as corpus callosum and cerebellum were associated with the deletions of specific areas of the human genome, and that specific neuroanatomical changes confer a risk of neuropsychiatric disorders. Furthermore, we observed that gene sets located in these genomic regions were enriched for pathways crucial for brain development and for phenotypes commonly observed in patients with NDDs. These findings highlight the link between CNVs, brain structure abnormalities, and the shared pathophysiology of NDDs and other neuropsychiatric disorders, providing new insights into the underlying mechanisms of these disorders and the identification of potential biomarkers for better diagnosis. Full article

Background/Objectives: Biomarkers such as lens agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin, as well as biomarker- and/or clinical-parameter-derived composite models (GALAD, GAAP, ASAP, aMAP, Doylestown), may improve detection in addition to alpha-fetoprotein, yet comparative data across diverse populations remain limited. Methods: In this biobank-based case–control study, we evaluated 562 adults (120 healthy controls, 277 chronic liver disease, 165 hepatocellular carcinoma) from January 2019 to 2024. Diagnostic performance for any-stage and early-stage hepatocellular carcinoma was assessed across three thresholds: Youden-index-derived optimal cut-offs, research-established cut-offs, and cut-offs ensuring 90% specificity. Receiver operating characteristic analysis was performed. Subgroup analyses were stratified by etiology and alpha-fetoprotein status. Results: At optimal cut-offs, GALAD showed the highest sensitivity for any-stage (90.3%) and early-stage (89.1%) hepatocellular carcinoma, with 70–80% specificity. Using established cut-offs, GALAD retained the highest sensitivity for any-stage (75.8%) and early-stage (57.8%) hepatocellular carcinoma, with 93.5% specificity. GALAD demonstrated the best performance in non-viral hepatocellular carcinomas (area under the curve 0.872), whereas GAAP and ASAP showed similarly high area under the curve values in viral etiology (area under the curve 0.955–0.960). Conclusions: Our results demonstrate the consistent performance of the GALAD score across diverse populations and underscore its superiority over individual biomarkers and other composite models. Notably, the GAAP and ASAP scores—which use one less biomarker (AFP-L3)—exhibited comparable performance, particularly in viral etiology. These findings support the integration of the composite biomarker models into tailored hepatocellular carcinoma surveillance strategies. Full article

Objectives: Observational studies have shown that chronic obstructive pulmonary disease (COPD) is associated with an increased risk of hearing impairment. However, causality remains unclear, including with respect to lung function. This study aimed to investigate the associations of lung function and COPD with hearing impairment in the UK Biobank and confirm potential causalities using Mendelian randomization (MR). Methods: Cross-sectional analyses were performed using logistic regression models in a subsample of the UK Biobank. Two-sample MR analyses were performed on summary statistics for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), COPD, and sensorineural hearing loss. Results: FEV1 and FVC were negatively associated with hearing impairment, with odds ratios (95% confidence intervals) of 0.80 (0.77, 0.84) and 0.80 (0.76, 0.83), respectively. COPD was positively associated with hearing impairment, with an odds ratio (95% confidence interval) of 1.10 (1.02, 1.18). In the MR analyses, a negative association was found between FVC and sensorineural hearing loss, with an odds ratio (95% confidence interval) of 0.91 (0.83, 0.99). For FVE1 and COPD, no significant associations were found. Conclusions: The results of this study showed that FVC was causally associated with hearing impairment, suggesting a potential protective effect of FVC on hearing impairment. Full article

Background/Objectives: Epilepsy and sleep disturbances frequently co-occur, yet the causal nature of this relationship remains uncertain, particularly in relation to epilepsy subtypes and status epilepticus. We investigated potential bidirectional causal associations between sleep-related traits and epilepsy, including subtypes and status epilepticus, using Mendelian randomization (MR). Methods: We conducted two-sample MR using genome-wide association study (GWAS) summary statistics from European ancestry cohorts. Epilepsy, its subtypes, and status epilepticus were analyzed using data from the International League Against Epilepsy Consortium on Complex Epilepsies (ILAE) and the FinnGen study. Nine self-reported sleep-related traits were derived from the UK Biobank-based GWAS. Causal estimates were primarily obtained using inverse variance weighted models with additional MR analysis methods. Pleiotropy and heterogeneity were assessed to enhance the robustness of the finding. Results: Several subtype-specific associations were identified, with direction and statistical significance varying across cohorts and subtypes. After correction for multiple testing and filtering for tests with ≥10 instrumental variables to ensure robust and reliable MR estimates, several consistent and potentially mutually reinforcing associations emerged. In the ILAE cohort, focal epilepsy with hippocampal sclerosis was associated with an increased risk of insomnia, and juvenile myoclonic epilepsy with reduced sleep duration. In the FinnGen cohort, overall epilepsy was associated with increased risk of both insomnia and daytime sleepiness. In reverse MR, daytime sleepiness and napping were associated with increased risk of epilepsy, while daytime napping and frequent insomnia symptoms were linked to elevated risk of status epilepticus. Conclusions: Our findings reveal subtype-specific and bidirectional causal links between epilepsy and sleep-related traits. These results highlight the biological interplay between epileptic networks and sleep regulation and underscore the need for further clinical and mechanistic studies. Full article

To assess the association between known (PlGF, sFlt-1, betaHCG, PAPPA) and novel (cell-free DNA, cfDNA, and total endothelial and platelet microvesicles, MVs) maternal blood biomarkers measured at the first trimester with the later development of preeclampsia (PE) and PE-related severe adverse events (SAE), we conducted a retrospective case–control study including women with an established diagnosis of preeclampsia (cases) and healthy pregnant women (controls). Biomarkers were measured from first-trimester blood samples stored in a hospital biobank. A total of 89 women, 54 women with PE and 35 controls were included. PlGF showed good performance for diagnosing overall preeclampsia (AUC: 0.71; 95% CI 0.59–0.82), early-onset preeclampsia (AUC 0.80; 95% CI 0.68–0.9) and fetal-neonatal SAEs (AUC: 0.73; 95% CI 0.63–0.84). Multivariate models including clinical variables, PlGF and other biomarkers showed good to very good discrimination for the development of PE, early-onset PE and fetal-neonatal SAEs (AUCs of 0.87, 0.89 and 0.79, respectively). Platelet-derived MVs were the best isolated biomarker for late-onset PE and, combined with systolic blood pressure, showed good discrimination (AUC: 0.81; 95% CI 0.71–0.92). For maternal SAEs, a model incorporating cfDNA and sFlt-1 provided excellent discrimination (AUC 0.92; 95% CI 0.82–1.00). Our findings suggest that multivariate models incorporating both clinical variables and first-trimester biomarkers may improve risk stratification for PE, especially for late-onset PE and for identifying women at risk of severe maternal or fetal complications. Notably, the inclusion of novel biomarkers such as cfDNA and MVs added value in clinical scenarios where the predictive performance of existing tools remains suboptimal. Full article

Background/Objectives: The increased use of antibiotics is raising concerns about environmental contamination and antibiotic resistance, exemplified by the case of cotrimoxazole, a widely prescribed combination of sulfamethoxazole and trimethoprim. After oral administration and absorption, both drugs are excreted in their parent and metabolized forms, which is a factor that is commonly considered in environmental studies. Many studies, however, rely on pharmacokinetic data from drug developers, who mostly investigate drug metabolism in healthy male volunteers rather than in actual patient populations. Methods: We investigated the real-world metabolism and urinary excretion of cotrimoxazole in an LC-SWATH/MS-based pharmacometabolomics study of 149 kidney transplant recipients who took part in the TransplantLines Biobank and Cohort Study (NCT0327284). Results: Our study confirmed (as “putatively characterized compound classes”) the presence of all the expected metabolites, and we (putatively) identified several previously unreported metabolites, including glucuronide conjugates of both drugs and two isoxazole ring-opened variants of sulfamethoxazole. The relative metabolite profiles furthermore indicated that the active drug trimethoprim accounted for 75% of the total signal intensity. For sulfamethoxazole, its acetylated metabolite was the main metabolite (59%), followed by the active parent drug (17%) and its glucuronide (7%). Alongside trimethoprim, these substances could serve as analytical targets for environmental cotrimoxazole monitoring, given their abundance (all three substances), activity (parent drug), and/or back-transformation potential (both conjugated metabolites). The isoxazole ring-opened variants (2–3%) may also warrant attention, considering their (presumed) absolute excreted quantities and potential pharmacological activity. Conclusions: This study underscores the value of pharmacometabolomics in elucidating real-world metabolite profiles, and it provides novel insights into cotrimoxazole metabolism and excretion, with implications for environmental and clinical monitoring. Full article

Background: Obesity is a global health challenge associated with metabolic and cardiovascular diseases. Traditional Chinese Medicine (TCM) body constitution theory offers a unique perspective on individual susceptibility to obesity; however, its integration into public health strategies remains underexplored. Objective: To examine the associations between vegetarian dietary patterns, TCM body constitution types (Phlegm stasis, Yang deficiency, and Yin deficiency), and overweight/obesity in a large-scale national cohort. Methods: Data were obtained from 3597 participants enrolled in the Taiwan Biobank. Socio-demographic variables, lifestyle behaviors (diet, smoking, physical activity), and anthropometric indicators (BMI and waist circumference) were assessed. Participants were categorized by weight status and TCM body constitution. Polytomous logistic regression models were used to evaluate associations between vegetarian dietary patterns, constitution types, and overweight/obesity, adjusting for potential confounders. Results: Among participants (mean age, 50.1 ± 9.4 years), 55.6% had normal BMI, 27.3% were overweight, and 17.1% were obese. Vegetarian dietary patterns were significantly associated with lower odds of Phlegm stasis (OR: 0.96; p < 0.001), Yang deficiency (OR: 0.97; p < 0.001), and Yin deficiency (OR: 0.97; p < 0.001), as well as with lower odds of overweight (OR: 0.72; p < 0.05) and obesity (OR: 0.67; p < 0.05). Physical activity was also associated with lower odds of all three constitution types and obesity. Phlegm stasis constitution was associated with higher odds of obesity (range of ORs: 1.18–1.58; p < 0.001). Conclusions: Vegetarian dietary patterns and regular physical activity were associated with lower odds of obesity and TCM constitution imbalances, particularly Phlegm stasis. These findings suggest a potential role for constitution-informed strategies in obesity-related public health approaches. Longitudinal studies are warranted to clarify temporal relationships and mechanisms. Clinical Trials Registration: ClinicalTrials.gov NCT03938207 (Study Start: 1 October 2022). Full article

The coronavirus disease 2019 (COVID-19) pandemic has led to substantial health and financial burdens worldwide, and vaccines provide hope for reducing the burden of this pandemic. However, vaccinated people remain at risk for SARS-CoV-2 infection. Genome-wide association studies (GWASs) may identify potential genetic factors involved in the development of COVID-19 breakthrough infections (BIs); however, very few or no GWASs have been conducted for COVID-19 BI thus far. We conducted a GWAS and detailed bioinformatics analysis on COVID-19 BIs in a European population via the UK Biobank (UKBB). We conducted a series of analyses at different levels, including SNP-based, gene-based, pathway, and transcriptome-wide association analyses, to investigate genetic factors associated with COVID-19 BIs and hospitalized infections. The polygenic risk score (PRS) and Hoeffding’s test were performed to reveal the genetic relationships between BIs and other medical conditions. Two independent loci (LD-clumped at r² = 0.01) reached genome-wide significance (p < 5 × 10⁻⁸), including rs36170929, which mapped to LOC102725191/VWDE, and rs28645263, which mapped to RETREG1. A pathway enrichment analysis highlighted pathways such as viral myocarditis, Rho-selective guanine exchange factor AKAP13 signaling, and lipid metabolism. The PRS analyses revealed significant genetic overlap between COVID-19 BIs and heart failure and between HbA1c and type 1 diabetes. Genetic dependence was also observed between COVID-19 BIs and asthma, lung abnormalities, schizophrenia, and type 1 diabetes on the basis of Hoeffding’s test. This GWAS revealed two significant loci that may be associated with COVID-19 BIs and a number of genes and pathways that may be involved in BIs. Genetic overlap with other diseases was identified. Further studies are warranted to replicate these findings and elucidate the mechanisms involved. Full article

The nicotine metabolite ratio (NMR) has been informative in selecting treatment choices for nicotine dependence and increasing treatment efficacy in Western settings; however, the clinical utility of the NMR among smokers in low-resource settings remains unclear. Prospective analysis was conducted using data from a randomized controlled trial of smoking cessation among adults living with HIV, to examine the association between the NMR and response to smoking cessation treatment. NMR was assessed using bio-banked urine samples collected at baseline. Self-reported smoking at 6 months was verified using a urine cotinine test and exhaled breath carbon monoxide (CO). We found no associations between the NMR and smoking abstinence (adjusted risk ratio (aRR) = 0.82; 95% CI: 0.45, 1.49; p = 0.53). No evidence of effect modification by treatment conditions was observed on the multiplicative scale (aRR = 1.17; 95% CI: 0.32, 4.30; p = 0.81) or additive scale (adjusted relative excess risk due to interaction (aRERI) = 0.10; 95% CI: −1.16, 1.36; p = 0.44). Our results suggest that the NMR may not be a viable approach for selecting smoking cessation treatment in this setting, given the minimal variability in our sample and racial/ethnic makeup of this population. Full article

Background/Objectives: Tramadol is an opioid frequently prescribed for moderate to severe pain and has seen a global increase in use. This presents numerous challenges in clinical management. This study aims to elucidate metabolic signatures associated with tramadol consumption, enhancing predictive capabilities for therapeutic outcomes and optimizing patient-specific treatment plans. Methods: Data were obtained from the Qatar Biobank (QBB), focusing on pharmacogenomic variants associated with tramadol use and prescription trends. A cohort of 27 individuals who were administered daily tramadol doses between 100 and 400 mg with available metabolomic profiles were selected. The pharmacokinetics of tramadol were evaluated in relation to specific CYP2D6 genetic variants. Comparative pharmacometabolomic profiles were generated for tramadol users versus a control group of 54 non-users. Additionally, prescription data encompassing tramadol formulations were collected from the electronic medical records (EMR) system of the major public hospital network in Qatar (Hamad Medical Corporation) to discern prescribing patterns. Results: From January 2019 to December 2022, tramadol prescriptions varied, with chronic pain as the primary indication, followed by acute pain. Pharmacogenomic analysis indicated that CYP2D6 allele variations significantly impacted tramadol and O-desmethyltramadol glucuronide levels, notably in ‘normal metabolizers’. Metabolomic analysis revealed distinct metabolic profiles in tramadol users, with significant variations in phosphatidylcholine, histidine, and lysine pathways compared to controls, highlighting tramadol’s unique biochemical impacts. Conclusions: This study underscores the importance of integrating genetic and omics-based approaches to enhance tramadol’s efficacy and safety. These findings support personalized pain management strategies, enhancing treatment outcomes for both chronic and acute pain. Full article

Glioblastoma is a highly aggressive, infiltrative brain tumor of the central nervous system (CNS). Its extensive molecular and biochemical heterogenicity hinders the identification of reliable biomarkers and therapeutic targets, thereby making prognosis and existing therapy ineffective. In recent years, breakthroughs in the use of proteomics on a range of biological samples, such as plasma, cerebrospinal fluid (CSF), tissues, brain cells, and exosomes, represent a potential improvement to GBM investigations. Mass spectrometry-based approaches represent an important technique in the characterization of the tumoral proteome, for the identification of differentially expressed proteins, and for studying altered molecular pathways involved in tumor stages. Proteomics studies advance our knowledge about GBM pathogenesis, the discovery of reliable diagnostic and prognostic markers, and therapeutic approaches, also. In this context, for the effective application of proteomics on GBM, it is mandatory to develop a translational network by integrating hospitals, biobanks, and research institutions into a single network, to enable a collaborative approach across disciplines, thereby enabling rapid translation to clinical application of new proteomic insights. Today, high-quality biobanks play a key role in enabling collaborative, ethically compliant research, supporting the effective application of proteomics in glioblastoma studies and the translation of discoveries into clinical practice. This review explores current trends in proteomics and GBM research, highlighting how leveraging biobank infrastructure and fostering institutional cooperation can drive the development of targeted pilot projects to enhance the impact and effectiveness of glioblastoma research. Full article

Background: The associations between physical activity (PA) and all-cause mortality remain under-investigated among individuals with impaired lung function. Methods: With 201,596 participants from the UK Biobank cohort, baseline pre-bronchodilation lung function tests and a modified International Physical Activity Questionnaire were used to assess lung function status (normal, restricted, obstructed) and PA attributes (volume, intensity, duration). All-cause mortality was determined through linkage to the National Health Services Register. Cox proportional hazard regression was applied to characterize the associations between PA metrics and all-cause mortality among people with different lung function statuses. Dose–response relationships between PA metrics and all-cause mortality risks were examined using restricted cubic splines (number of knots = 4). Results: Over a 11.81-year median follow-up, 5.24% of participants died. All-cause mortality risk declined with increasing total PA volume, plateauing at 1800 MET-min/week without further reduction in individuals with and without impaired lung function. Similar trends were observed for PA intensity and duration, with both factors demonstrating reduced mortality risk that plateaued after reaching a specific threshold. Notably, 24.1% (95% CI: 16.7%, 30.8%) and 43.1% (95% CI: 36.1%, 49.7%) lower mortality risk was observed among individuals with and without impaired lung function for PA with 1201–1800 MET-min/wk. Conclusions: PA was associated with a decreased risk of all-cause mortality among individuals with and without impaired lung function, suggesting that those with impaired lung function might also benefit from PA. Full article