Summary Of Data Research Articles

Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis

In advanced pancreatic ductal adenocarcinoma (PDAC), first-line chemotherapy is the standard of care. Due to the absence of head-to-head comparisons in clinical trials, we performed this systematic review and network meta-analysis to compare treatment options for PDAC in terms of their efficacy and toxicity. PubMed, the Cochrane Central Register of Controlled Trials, Embase, and oncological meetings websites were searched until Nov 15, 2023. We included phase 2-3 randomised controlled trials published after Jan 1, 2000, evaluating first-line treatments in patients with previously untreated, unresectable, locally advanced or metastatic PDAC. Primary endpoints assessed were progression-free survival and overall survival. Summary data were extracted from published reports. The deviance information criterion was used to choose between a random-effects or fixed-effects model. Hazard ratios (HRs) with 95% credible intervals were estimated using a Bayesian approach. The risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool and studies were graded as low, some concerns, or high risk of bias. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. This systematic review and network meta-analysis is registered with PROSPERO, CRD42023450330. 6050 records were screened and 79 randomised controlled trials (22 168 patients) were included in the analysis. Gemcitabine was the most frequent comparator (in 50 [63%] of 79 trials) and was considered as the reference treatment. A fixed-effect model was used to analyse the primary outcomes. Regarding progression-free survival (71 trials, 19 479 patients), the most effective treatments were gemcitabine plus nab-paclitaxel alternating folinic acid, fluorouracil, and oxaliplatin ([FOLFOX] HR 0·32, 95% credible interval 0·22-0·47), cisplatin, nab-paclitaxel, capecitabine, and gemcitabine ([PAXG] 0·35, 0·22-0·55), and liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin ([NALIRIFOX] 0·43, 0·34-0·54), followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin ([FOLFIRINOX] 0·55, 0·47-0·65) and gemcitabine plus nab-paclitaxel (0·62, 0·54-0·72). Similar results were observed for overall survival (79 trials, 22 104 patients): PAXG (HR 0·40, 95% credible interval 0·25-0·65), gemcitabine plus nab-paclitaxel alternating FOLFOX (0·46, 0·32-0·66), and NALIRIFOX (0·56, 0·45-0·70) had the highest benefit, followed by FOLFIRINOX (0·66, 0·56-0·78) and gemcitabine plus nab-paclitaxel (0·67, 0·59-0·77). The overall risk of bias was low to some concerns. Certainty of evidence was low. Our findings suggest that NALIRIFOX and FOLFIRINOX should be the preferred options for patients who can tolerate these regimens, with gemcitabine plus nab-paclitaxel remaining a viable alternative, particularly in patients unfit for triplet therapy. Phase 3 randomised controlled trials investigating concomitant or sequential quadruplets are warranted. None.

Genetically Predicted Sleep Traits and Sensorineural Hearing Loss: A Mendelian Randomization Study.

Observational studies suggest a potential association between sleep characteristics, sensorineural hearing loss (SNHL), and sudden SNHL (SSNHL), but causal evidence is scarce. We sought to clarify this issue using two-sample Mendelian randomization analysis. The inverse-variance weighted (IVW) method was performed as primary analysis to assess bidirectional causal associations between sleep traits (chronotype, sleep duration, insomnia, daytime sleepiness, and snoring) and SNHL/SSNHL using publicly available Genome-Wide Association Studies summary data from two large consortia (UK Biobank and FinnGen). Sensitivity analyses, including Mendelian randomization (MR)-Egger, Mendelian randomization pleiotropy residual sum and outlier, weight median, Cochran's Q test, leave-one-out analysis, and potential pleiotropy analysis, were conducted to ensure robustness. IVW analysis found suggestive associations of morning chronotype (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.01-1.16, p = 0.031) and daytime sleepiness (OR = 1.88, 95% CI = 1.24-2.87, p = 0.003) with SNHL onset. Additionally, morning chronotype was nominally associated with SSNHL onset using IVW method (OR = 1.37, 95% CI = 1.10-1.71, p = 0.006). However, there was no evidence for the causal effect of SNHL and SSNHL on different sleep traits (all p > 0.05). Sensitivity analysis showed that the results were stable. Within the MR limitations, morning chronotype and daytime sleepiness were underlying causal contributors to the burden of SNHL, indicating that optimal sleep might facilitate the prevention and development of SNHL. 3 Laryngoscope, 134:4723-4729, 2024.

Can early gut microbiota screening reduce the incidence of cognitive impairment? A Mendelian randomization study.

Background: Gastrointestinal symptoms are now detected early in the clinical course of many dementia patients, and studies of the microbiome-gut-brain axis have confirmed bidirectional interactions between the gut and the brain. However, the causal relationship between gut microbiota and cognitive impairment has not been fully established. Therefore, this study conducted a bidirectional Mendelian randomization study to elucidate the potential causal relationship of gut microbiota to cognitive impairment. Objective: Using Mendelian randomization to identify gut flora with a genetic causal effect on the development of cognitive impairment. Methods: This study utilized publicly available genome-wide association study summary data to perform MR analysis, with gut microbiota as the exposure and various cognitive function indicators as well as scores for Alzheimer's disease as outcomes. This study selected single nucleotide polymorphisms as instrumental variables based on p-values, F-statistics, and r2. Bidirectional Mendelian randomization was conducted using methods such as inverse variance weighted, MR-Egger, simple mode, and weighted mode to assess the causal relationship. Concurrently, this study carried out Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to identify potential heterogeneity and horizontal pleiotropy. Results: This study identified a total of 31 gut microbes that have a causal relationship with cognitive impairment, which include 1 phylum, 4 classes, 3 orders, 2 families, and 21 genera. Conclusions: This study unveiled specific gut microbiota associated with cognitive impairment, offering new insights and approaches for the prevention and treatment of cognitive impairment through gut microbiota such as Bifidobacterium and Ruminococcus gnavus group.

Associations between T-cell traits and narcolepsy type 1: new insights from a Mendelian randomization study.

Narcolepsy type 1 (NT1) is primarily caused by a malfunctioning immune system in which T-cells damage the hypothalamus. To elucidate the causal relationships between biomarkers in T-cells and NT1, we employed Mendelian randomization (MR) analysis. We conducted a two-sample MR analysis utilizing genetically predicted T-cell traits to examine their effects on NT1. Genome-wide association study summary data were extracted from studies by Valeria (3,757 participants) for 211 T-cell traits, Ollila (6,073 cases and 84,856 controls) for NT1. The MR analysis was executed at two threshold levels. Inverse variance weighted, Wald ratio, weighted median, and MR-Egger regression methods were used for the MR analysis. Odds ratios (ORs) were calculated, and heterogeneity tests, as well as pleiotropy tests, were conducted. After Bonferroni correction at the significant level (p < 1.18 × 10-4), a higher ratio of naive CD4- CD8- T-cells was identified as a risk factor for NT1 (OR = 10.50; 95% CI: 6.98, 15.90, p = 3.89 ×10-29). Conversely, CD4 on HLA DR+ CD4+ T cells (mean fluorescence intensity, MFI) exhibited a negative correlation with NT1. At nominally significant levels (p < 0.05) for both threshold levels, HVEM (herpesvirus entry mediator) on naive CD8+ T cells (MFI) was suggested as a protective factor for NT1. Additionally, a higher ratio of CD25++ CD45RA- CD4 not regulatory T cells, CD127 on CD45RA- CD4 not regulatory T cells (MFI), CD127 on CD28+ CD4+ T cells (MFI), CD3 on HLA DR+ T cells (MFI), and CD3 on HLA DR+ CD4+ T cells (MFI) were suggested as risk factors for NT1. This study confirmed the causal effects of CD4+ and CD8+ T-cells on NT1 and found several novel T-cell-related characteristics.

Cost-effectiveness analysis of emergency department-based hepatitis C screening and linkage-to-care program

BackgroundIn the United States (US), hepatitis C virus (HCV) screening is not covered by payers in settings outside of primary care. A non-traditional, emergency department (ED)-based HCV screening program can be cost-effective and identify infection in vulnerable populations with a high HCV risk. This study examined the long-term cost-effectiveness of routine HCV screening and linkage-to-care for high-risk patients in the ED from the payer’s perspective.MethodsThe University of Illinois Hospital and Health Sciences System (UIH) implemented Project HEAL (HIV & HCV Screening, Education, Awareness, Linkage-to-Care). Under this initiative, patients who presented to the ED received opt-out HCV screening if they were at high risk for HCV infection (birth cohort between 1945 and 1964, persons who inject drugs, and HIV infection) with subsequent linkage-to-care if infected. Using the summary data from Project HEAL, a hybrid decision-analytic Markov model was developed based on the HCV screening procedure in the ED and the natural history of HCV. A 30-year time horizon and 1-year cycle length were used. All patients who received the ED-based HCV screening were referred for treatment with direct-acting antiviral (DAA) regardless of their fibrosis stage.ResultsWhen unscreened/untreated patients received DAA treatment at F1, F2, F3, and compensated cirrhosis stages, the incremental cost-effectiveness ratio (ICER) ranged from $6,084 to $77,063 per quality-adjusted life year (QALY) gained. When unscreened/untreated patients received DAA treatment at the decompensated cirrhosis stage, no HCV screening was dominated.ConclusionED-based HCV screening and linkage-to-care was cost-effective at the willingness-to-pay (WTP) threshold of $100,000/QALY in all scenarios. A reduction in infected persons in the community may provide additional benefits not evaluated in this study.

Causal Associations Between the Gut Microbiota and Hypertension-Related Traits Through Mendelian Randomization: A Cross-Sectional Cohort Study.

Previous studies have suggested a link between the gut microbiome and hypertension-related traits like blood pressure. However, these reports are often limited by weak causal evidence. This study investigates the potential causal association between gut microbiota and hypertension-related traits using Mendelian randomization with summary data from genome-wide association studies. The inverse-variance weighted method revealed that the Clostridium innocuum group (Odds ratio [OR]: 1.0047, 95% confidence interval [CI]: 1.0004-1.0090, p=0.0336), Eubacterium fissicatena group (OR: 1.0047, 95% CI: 1.0005-1.0088, p=0.0266), Lachnospiraceae FCS020 group (OR: 1.0063, 95% CI: 1.0004-1.0122, p=0.0361), and Olsenella (OR: 1.0044, 95% CI: 1.0001-1.0088, p=0.0430) were associated with an increased risk of hypertension. Conversely, Flavonifractor (OR: 0.9901, 95% CI: 0.9821-0.9982, p=0.0166), Parabacteroides (OR: 0.9874, 95% CI: 0.9776-0.9972, p=0.0121), and Senegalimassilia (OR: 0.9907, 95% CI: 0.9842-0.9974, p=0.0063) were associated with a decreased risk of hypertension. External validation with the Guangdong Gut Microbiome Project confirmed a negative correlation between Parabacteroides and hypertension, potentially through metabolic pathways. These findings provide further evidence supporting the hypothesis that microbes and their metabolites play a role in blood pressure regulation.

Narrowing socioeconomic inequalities in coronary heart disease: insight from Mendelian randomization

Abstract Background Socioeconomic inequalities in coronary heart disease (CHD) represent a pressing global public health concern. However, which dimensions of socioeconomic status (SES) affect CHD and the potential modifiable mediators remain elusive. Methods We performed two-sample Mendelian randomization (MR) analyses based on summary data from large-scale genome-wide association studies in populations of European ancestry. Specifically, by applying bidirectional univariable MR (UVMR) and multivariable MR (MVMR), we investigated the causal relationships of education, occupation, income, Townsend deprivation index (TDI) with CHD and the independent effects of these SES indicators. We further employed a two-step MR to comprehensively profile the mediating effects of 23 behavioral, 3 psychological and 5 biological factors in the relationships. Results An independent causal association was observed between genetically predicated education and CHD, with a 30% lower risk of CHD (OR: 0.70; 95% CI: 0.53-0.93) for each 4.2-year of schooling. Each one-s.d. higher household income was causally, but not independently, associated with a 39% lower risk of CHD (OR: 0.61; 95% CI: 0.49-0.77). No significant causal association was suggested for occupation and TDI with CHD, and no reverse causal effect was observed for CHD on the SES indicators. Of 31 candidate mediators, nine factors mediated the effect of education on CHD significantly, with an individual mediation proportion of 33.5% for smoking, 29.2% for sedentary behaviour, 14.4% for blood lipids, 13.4% for BMI, 11.7% for systolic blood pressure, 9.5% for diastolic blood pressure, 7.8% for well-being spectrum, 6.4% for depression and 2.8% for blood glucose. Conclusions This study highlights that education was the primary SES indicator affecting CHD with considerable mediation by a number of modifiable risk factors. These findings inform policies to mitigate disparities of CHD risk attributable to socioeconomic inequalities. Key messages • Education can be prioritized over other common SES indicators as an essential strategy to reduce the burden of CHD. • Interventions for narrowing socioeconomic inequalities in CHD could focus on more easily modifiable mediating factors.

Statistical methods leveraging the hierarchical structure of adverse events for signal detection in clinical trials: a scoping review of the methodological literature

BackgroundIn randomised controlled trials with efficacy-related primary outcomes, adverse events are collected to monitor potential intervention harms. The analysis of adverse event data is challenging, due to the complex nature of the data and the large number of unprespecified outcomes. This is compounded by a lack of guidance on best analysis approaches, resulting in widespread inadequate practices and the use of overly simplistic methods; leading to sub-optimal exploitation of these rich datasets. To address the complexities of adverse events analysis, statistical methods are proposed that leverage existing structures within the data, for instance by considering groupings of adverse events based on biological or clinical relationships.MethodsWe conducted a methodological scoping review of the literature to identify all existing methods using structures within the data to detect signals for adverse reactions in a trial. Embase, MEDLINE, Scopus and Web of Science databases were systematically searched. We reviewed the analysis approaches of each method, extracted methodological characteristics and constructed a narrative summary of the findings.ResultsWe identified 18 different methods from 14 sources. These were categorised as either Bayesian approaches (n=11), which flagged events based on posterior estimates of treatment effects, or error controlling procedures (n=7), which flagged events based on adjusted p-values while controlling for some type of error rate. We identified 5 defining methodological characteristics: the type of outcomes considered (e.g. binary outcomes), the nature of the data (e.g. summary data), the timing of the analysis (e.g. final analysis), the restrictions on the events considered (e.g. rare events) and the grouping systems used.ConclusionsWe found a large number of analysis methods that use the group structures of adverse events. Continuous methodological developments in this area highlight the growing awareness that better practices are needed. The use of more adequate analysis methods could help trialists obtain a better picture of the safety-risk profile of an intervention. The results of this review can be used by statisticians to better understand the current methodological landscape and identify suitable methods for data analysis - although further research is needed to determine which methods are best suited and create adequate recommendations.

Causal associations of insulin and Lp(a) levels: a Mendelian randomization study

Abstract Background Numerous observational studies have demonstrated circulating lipoprotein(a) [Lp(a)] to be inversely related to occurrence of type 2 diabetes [T2D]. However, this is not consistently supported by Mendelian randomization [MR] studies. In vitro studies have shown insulin to downregulate Lp(a) expression, which might be another mechanism behind the correlation observed between Lp(a) and T2D. Purpose In this MR study, we investigated the influence of genetically predicted levels of insulin on genetically predicted Lp(a) levels to elucidate the potential causal links between Lp(a) and diabetes. Methods Independent genetic variants associated with insulin levels were acquired from a meta-analysis of genome-wide association studies (GWAS, N=151,013). Summary data for Lp(a) were acquired from a GWAS study in the UK Biobank (N=361,194). Inverse-variance-weighted (IVM) method was used to perform a two sample MR study. Sensitivity analysis was conducted via MR Egger, weighted median (WME), as well as leave-one-out analysis. Results Genetically predicted insulin levels were negatively associated with Lp(a) levels according to IVM estimate (p=0.003). In sensitivity analysis, WME supported this result (p=0.0002), while MR-Egger was not statistically significant (p=0.11). Leave-one-out analysis did not show the results to depend on any single variant. Conclusion This MR study provides robust evidence supporting the association between plasma insulin levels and decreased Lp(a) concentration. These findings suggest that hyperinsulinemia triggered by insulin resistance can be in part responsible for the observed negative correlation between low Lp(a) and T2D risk. Figure 1. Genetic associations between insulin levels and Lp(a). Each genetic variant included in the analysis is represented as a point + 95% CI. Localization on the horizontal axis represents the correlation of the variant with exposure (plasma fasting insulin, inverse variance normal transformed values). Localization on the vertical axis represents the correlation of the variant with outcome (Lp(a), natural log transformed values). Lines represent estimates of different MR methods.Figure 1.

Study on the Correlation between SLC39A8 Gene and Body Constitution-related Phenotypes and Hearing loss: Based on a Mendelian Randomization analysis

IntroductionWe examined the role of hearing functions as potential mediators in relationships between noise exposures and abnormal body constitution-related results. Additionally, we employed Mendelian randomization (MR) to explore the causative connections between hearing problems and bodily composition.Material and methodsGene connections pertaining to phenotypes of hearing loss and body constitution were obtained from publically available summary data collected from adult population genome-wide association studies. Colocalization analysis was utilized to scrutinize the genetic associations pertaining to age-related hearing impairment (ARHI) liability and BMI within the SLC39A8 locus. For a comprehensive examination, we employed bi-directional MR encompassing both the 'forward' direction (from the composition of the body to hearing) and the 'reverse' direction.ResultsA common causative variable (rs13107325) for BMI and ARHI at the SLC39A8 locus was supported by colocalization analysis, which revealed that the two diseases shared the variant at the SLC39A8 gene. The forward analyses showed that body fat percentage (BFP) was significantly linked with the risk of ARHI [OR =0.95 (95% CI:0.93 to 0.98)] and that waist circumference (WC) was favorably associated with sensorineural hearing loss (SNHL) [OR=0.83 (95% CI:0.72 to 0.97)].ConclusionsWe couldn't find any proof to back up a causal relationship between constitution and HL in the reverse MR Analysis. Colocalization analysis recommended that SLC39A8 variant was often the source of high ARHI and BMI risk. In prospective MR, we discovered causal associations between WC and BFP with SNHL and ARHI, respectively. Therefore, our results suggest lipid metabolic abnormalities leading to adverse health outcome may lead to HL.

Research on Dynamic Evaluation Method of Tourist Destination Accessibility Based on Interpretive Structure Model

Because of its core role in the process of tourism, tourism destination has always been the focus of discussion among the industry, but the comprehensive evaluation of tourism destination is rarely mentioned. This paper selects tourism destination as the focus of investigation, gives the evaluation method of tourism destination, adapts to the trend of tourism modernization, and discusses the quantifiable model of tourism destination evaluation. This paper first selects several tourism destinations as samples, collects and combs the information related to spatial equity of tourism destinations, and determines the main problem categories of spatial equity of tourism destinations. Then, through the summary of relevant data and case analysis, a framework of tourism target accessibility risk factors is formed. At the same time, considering the interaction between risk factors, we then give a method to determine the weight that can improve granular computing. First, we use this method to obtain the quotient space family with hierarchical characteristics through the similarity relationship between data, and then we can calculate the importance of each feature in the quotient space family, so as to obtain the corresponding weight between different influence indexes. Finally, the paper takes the tourism destination spatial equity problem as the main research goal, and through the dynamic evaluation of the tourism destination spatial equity risk impact structure using the interpretive structure model, and describes the schematic diagram of its impact structure, so as to find out the direct, source, process and other factors that cause the problem.

Matching-Adjusted Indirect Comparison of Risankizumab Versus Deucravacitinib in Patients with Moderate-to-Severe Plaque Psoriasis.

Despite advancements in the treatment of psoriasis (PsO), there are few head-to-head studies assessing comparative effectiveness of the newest therapies approved to treat PsO. Our objective was to assess the comparative clinical effectiveness of risankizumab and deucravacitinib in patients with moderate-to-severe PsO. This placebo-anchored matching-adjusted indirect comparison (MAIC) analysis utilized data from UltIMMa-1/2 risankizumab and POETYK PSO-1/2 deucravacitinib trials. Individual patient data from UltiMMA-1/2 were weighted via propensity score to match POETYK PSO-1/2 published summary data. Rate differences between risankizumab and deucravacitinib were assessed for Psoriasis Area and Severity Index (PASI) 75/90/100, the Static Physician Global Assessment (sPGA = 0 or 0/1), and the Dermatology Life Quality Index (DLQI) 0/1. At 16weeks, risankizumab-treated patients demonstrated statistically significantly higher rates of skin clearance and greater improvement in quality of life (QoL) compared to those treated with deucravacitinib. Across all outcomes, risankizumab demonstrated a lower number needed to treat compared to deucravacitinib. Limitations are potential bias due to unobserved/unmeasurable differences and limited generalizability of the results. This indirect comparison demonstrates that risankizumab has higher rates of skin clearance and greater improvements in QoL than deucravacitinib. This study will help inform healthcare providers in their treatment and management strategy of PsO.

Trends in Medicare Utilization and Reimbursement for Traumatic Brain Injury: 2003–2021

Traumatic brain injury (TBI) is a significant public health issue among Medicare beneficiaries, with many specialties reporting consistent annual decreases in utilization and reimbursement. This study investigates the trends in Medicare utilization and rates of reimbursement for neurosurgical procedures related to TBI from 2003 to 2021, aiming to provide insights into the economic aspects of TBI care. Utilizing the Medicare Part B National Summary Data files, we analyzed 14 neurosurgical procedures over the 18-year period, assessing the changes in procedural volume and mean reimbursement per procedure, adjusted for inflation to the 2021 USD using the Consumer Price Index. From 2003 to 2021, TBI-related neurosurgical interventions showed a total percent change of −15.39% in procedural volume and −3.11% in inflation-adjusted mean reimbursement per procedure. Linear regression analyses indicated a significant downward trend in the overall procedural volume (p &lt; 0.001) but no significant trend in the inflation-adjusted mean reimbursement rates (p = 0.585). Subgroup analyses did not reveal significant changes in the reimbursement rates for decompressive craniotomy/craniectomy, cranioplasty, intracranial pressure management, and traumatic fracture/penetration procedures. Our study indicates a significant decrease in neurosurgical TBI procedural volumes, while reimbursement rates remained stable when adjusted for inflation, highlighting the need for policy adjustments to ensure adequate resources for TBI care.

Trends in Phototherapy Utilization, Payments, and Geographic Distribution: An Analysis of United States Medicare Part B From 2000 to 2021.

Trends in phototherapy utilization in the context of new therapeutics have not been evaluated. This study aimed to evaluate phototherapy utilization, payments, and geographic distribution for Medicare beneficiaries from 2000 to 2021. A longitudinal analysis of the Medicare Part B National Summary Data Files was conducted to obtain phototherapy utilization and payment amounts. Medicare Physician & Other Practitioners by Provider and Service datasets were used to determine provider type and geographic distribution. Between 2000 and 2021, total Medicare phototherapy volume increased from 335,152 to 621,850, correlating with a 3.0% annual growth rate (5.0% between 2000 and 2015, -3.1% between 2016 and 2021). Ultraviolet B phototherapy represented the majority of use, rising from 68.1% in 2000 to 78.0% in 2021. Psoralens plus ultraviolet A decreased by 11.3% annually, while laser treatments increased by 17.3%. Between 2013 and 2021, the number of clinics offering phototherapy declined; facilities were available in only 9.9% of counties, mainly clustered along both coasts and east of the Mississippi. Overall, phototherapy continues to be an important therapeutic option. Limited access in non-urban areas remains a significant challenge, and further work is necessary to both evaluate this impact and reduce disparities.

Interactions Between Eleven Sleep-Related Characteristics and Diabetic Nephropathy: A Bidirectional Mendelian Randomization Study in European Population.

Observational studies often report disturbed sleep patterns in individuals with diabetic nephropathy (DN). The possible causal relationship behind these connections remains unknown. This research assessed the possible cause-and-effect relationship between eleven sleep-related characteristics and the risk of developing DN using a two-sample Mendelian randomization (MR) study. This study employed a two-sample bidirectional MR analytical approach. Genetic data for eleven sleep-related characteristics were acquired from the genome-wide association studies (GWAS) database of individuals of European ancestry which involve scanning complete sets of DNA, or genomes. GWAS summary data for DN included 4,111 DN cases and 308,539 controls. Instrumental variables were single nucleotide polymorphisms strongly linked to sleep-related characteristics. The main analysis used the random-effects inverse variance weighted (IVW) approach, with validation through sensitivity testing. MR analysis revealed that a higher genetic predisposition for sleep efficiency reduced the chance of developing DN (odds ratio [OR]: 0.384; 95% confidence interval [CI] 0.205-0.717; p=0.003). Genetic susceptibility to DN was associated with a higher likelihood of experiencing more sleep episodes (OR: 1.015; 95% CI 1.003-1.028; p=0.016). Sensitivity analysis confirmed the robustness of these correlations. No significant connections were found between other genetically predicted sleep characteristics and the likelihood of developing DN. Our research indicates that a genetic predisposition for better sleep efficiency is linked to a lower risk of developing DN. There is also evidence suggesting that genetic predisposition to DN may directly impact sleep episodes. Further research is needed to explore the molecular mechanisms underlying these findings.

Efficacy of Gonadotropin Treatment for Induction of Spermatogenesis in Men With Pathologic Gonadotropin Deficiency: A Meta-Analysis.

Hypogonadotropic hypogonadism (HH) is a treatable cause of nonobstructive azoospermic male infertility. Gonadotropin treatment can successfully induce spermatogenesis in most patients, although comprehensive quantitative summary data on spermatogenic outcomes like those required to induce pregnancy is lacking in the literature. Systematic review and meta-analysis of outcomes related to male reproductive function following gonadotropin treatment. Our search strategy identified 41 studies encompassing 1673 patients with a mean age of 25 (± 5) years. Average sperm concentration achieved after a median of 18 months of gonadotropin treatment was 11.6 M/mL of ejaculate (95% CI 8.4-14.9). Sperm concentrations > 0, > 1, > 5, > 10 and > 20 M/mL were achieved by 78%, 55%, 36%, 24% and 15% of patients, respectively. Mean sperm output and the proportion of patients achieving all sperm thresholds were significantly greater following combined hCG/FSH treatment compared with hCG monotherapy. When compared by diagnosis, patients with congenital HH (CHH) had significantly lower mean sperm output compared with patients with hypopituitarism or mixed patient cohorts that did not differentiate between CHH and hypopituitarism. Treatment-related increases in testosterone and testicular volume (TV) were not different between hCG and combined hCG/FSH treated patients, although increases in TV were lower in men with CHH compared with those with hypopituitarism. Gonadotropin treatment successfully induced spermatogenesis in most men with pathological gonadotropin deficiency. Sperm outputs more consistent with those typically needed to induce a natural pregnancy were less commonly achieved. Despite similar effects on serum testosterone and TV, combined hCG/FSH appeared more efficacious than hCG alone at inducing spermatogenesis.

Association between venous leg ulcers and knee osteoarthritis: A Mendelian randomization study.

To gain a clearer understanding of the relationship between venous leg ulcers (VLUs) and knee osteoarthritis (KOA), we performed a two-sample, bidirectional Mendelian randomization (MR) analysis in this study. The present MR was carried out using summary data from publicly available genome-wide association studies. After filtering single-nucleotide polymorphism (SNP), we applied a variety of MR methods including inverse variance weighted (IVW), MR egger, weighted mode, and weighted median. IVW analysis revealed that the genetic association between VLUs and KOA was not significant (β = -0.017; SE 0.039; p = 0.658). In agreement with the IVW analysis, the findings of the weighted median estimator (β = -0.017; SE 0.052, p = 0.751), MR egger (β = 0.057; SE 0.084; p = 0.513), and weighted mode (β = 0.060; SE 0.078; p = 0.456) indicated the absence of a significant genetic association between VLUs and KOA. Furthermore, reverse causality analysis suggested a lack of genetic relationship between KOA and VLUs. In conclusion, the present MR study does not suggest a causal relationship or reverse causal relationship between VLUs and KOA.

A comprehensive framework for trans-ancestry pathway analysis using GWAS summary data from diverse populations.

As more multi-ancestry GWAS summary data become available, we have developed a comprehensive trans-ancestry pathway analysis framework that effectively utilizes this diverse genetic information. Within this framework, we evaluated various strategies for integrating genetic data at different levels-SNP, gene, and pathway-from multiple ancestry groups. Through extensive simulation studies, we have identified robust strategies that demonstrate superior performance across diverse scenarios. Applying these methods, we analyzed 6,970 pathways for their association with schizophrenia, incorporating data from African, East Asian, and European populations. Our analysis identified over 200 pathways significantly associated with schizophrenia, even after excluding genes near genome-wide significant loci. This approach substantially enhances detection efficiency compared to traditional single-ancestry pathway analysis and the conventional approach that amalgamates single-ancestry pathway analysis results across different ancestry groups. Our framework provides a flexible and effective tool for leveraging the expanding pool of multi-ancestry GWAS summary data, thereby improving our ability to identify biologically relevant pathways that contribute to disease susceptibility.

Aberrant Mitochondrial tRNA Genes Appear Frequently in Animal Evolution.

Mitochondrial tRNAs have acquired a diverse portfolio of aberrant structures throughout metazoan evolution. With the availability of more than 12,500 mitogenome sequences, it is essential to compile a comprehensive overview of the pattern changes with regard to mt-tRNA repertoire and structural variations. This, of course, requires reanalysis of the sequence data of more than 250,000 mt-tRNAs with a uniform workflow. Here, we report our results on the complete reannotation of all mitogenomes available in the RefSeq database by September 2022 using mitos2. Based on the individual cases of mt-tRNA variants reported throughout the literature, our data pinpoint the respective hotspots of change, i.e. Acanthocephala (Lophotrochozoa), Nematoda, Acariformes and Araneae (Arthropoda). Less dramatic deviations of mt-tRNAs from the norm are observed throughout many other clades. Loss of arms in animal mt-tRNA clearly is a phenomenon that occurred independently many times, not limited to a small number of specific clades. The summary data here provide a starting point for systematic investigations into the detailed evolutionary processes of structural reduction and and loss of mt-tRNAs as well as a resource for further improvements of annotation workflows for mt-tRNA annotation.

Binding profiles for 961 Drosophila and C. elegans transcription factors reveal tissue-specific regulatory relationships.

A catalog of transcription factor (TF) binding sites in the genome is critical for deciphering regulatory relationships. Here we present the culmination of the efforts of the Model Organism ENCyclopedia Of DNA Elements (modENCODE) and the model organism Encyclopedia of Regulatory Networks (modERN) consortia to systematically assay TF binding events in vivo in two major model organisms, Drosophila melanogaster (fly) and Caenorhabditis elegans (worm). These datasets comprise 605 TFs identifying 3.6M sites in the fly and 356 TFs identifying 0.9 M sites in the worm and represent the majority of the regulatory space in each genome. We demonstrate that TFs associate with chromatin in clusters termed "metapeaks", that larger metapeaks have characteristics of high occupancy target (HOT) regions, and that the importance of consensus sequence motifs bound by TFs depends on metapeak size and complexity. Combining ChIP-seq data with single cell RNA-seq data in a machine learning model identifies TFs with a prominent role in promoting target gene expression in specific cell types, even differentiating between parent-daughter cells during embryogenesis. These data are a rich resource for the community that should fuel and guide future investigations into TF function. To facilitate data accessibility and utility, all strains expressing GFP-tagged TFs are available at the stock centers for each organism. The chromatin immunoprecipitation sequencing data are available through the ENCODE Data Coordinating Center, GEO, and through a direct interface that provides rapid access to processed data sets and summary analyses, as well as widgets to probe the cell type-specific TF-target relationships.