Randomized Study Research Articles

Impact of non-alcoholic fatty liver disease and fibrosis on mortality and kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A multi-cohort longitudinal study.

To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease. Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events. In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events. In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events.

The causal relationship between plasma protein-to-protein ratios and type 2 diabetes and its complications: Proteomics mendelian randomization study.

In recent years, proteomics research has surged, with numerous observational studies identifying associations between plasma proteins and type 2 diabetes. However, research specifically focusing on the ratios of plasma proteins in type 2 diabetes remains relatively scarce. This study primarily employed a two-sample, two-step Mendelian randomization (MR) approach, leveraging genetic data from several large, publicly accessible genome-wide association studies, wherein single nucleotide polymorphisms served as proxies for exposures and diseases. Within this framework, we applied two-sample MR to assess the associations between the 2821 plasma protein-to-protein ratios and type 2 diabetes along with its complications and utilized reverse MR to confirm the unidirectionality of these causal relationships. In addition, we employed two-step MR to investigate the potential mediating role of body mass index in these associations. To augment the robustness of our findings, we systematically implemented a series of sensitivity analyses. The results gleaned from the inverse-variance weighted method elucidated that a cumulative sum of 23 protein-to-protein ratios bore a causal nexus with type 2 diabetes across both sample cohorts. With each incremental elevation of 1 standard deviation in the genetically anticipated protein-to-protein ratio, the susceptibility to type 2 diabetes oscillated from 0.93 (95% confidence interval: 0.87, 1.00) for the CNTN3/NCSS1 protein level ratio to 1.13 (1.06, 1.22) for the DBNL/NCK2 protein level ratio. Moreover, a tally of eight protein-to-protein ratios correlated with a minimum of one complication linked to type 2 diabetes. Diverse sensitivity analyses corroborated the robustness of these observations. The outcomes of our investigation unveiled correlations between 23 plasma protein-to-protein ratios and type 2 diabetes, with eight of these ratios entwined with complications of type 2 diabetes. These discoveries offer novel perspectives on the diagnosis and management of type 2 diabetes and its associated complications.

COVID-19 and Parkinson’s disease: a single-center study and Mendelian randomization study

To investigate the association between COVID-19 and Parkinson’s disease (PD) via a single-center study and a Mendelian randomization (MR) study. A questionnaire-based survey was conducted among PD patients at a single center from December 7, 2022, to March 10, 2023. Logistic regression analysis was performed to identify the infection-related risk factors. Subsequently, bidirectional two-sample Mendelian randomization was employed to explore the association between COVID-19 and PD. In the cross-sectional analysis, it was found that the prevalence of COVID-19 infection in PD patients was 65.7%. Forty-eight (35.3%) PD patients experienced exacerbation of motor symptoms following COVID-19 infection. Long PD disease duration (≥ 10 years) (OR: 3.327, P = 0.045) and long time since last vaccination (> 12 m) (OR: 4.916, P = 0.035) were identified as significant risk factors related to infection. The MR analysis results supported that PD increases the COVID-19 susceptibility (β = 0.081, OR = 1.084, P = 0.006). However, the MR analysis showed that PD did not increases the COVID-19 severity and hospitalization, and no significant association of COVID-19 on PD was observed. The findings from this cross-sectional study suggest that individuals with PD may experience worsened motor symptoms following COVID-19 infection. Long disease duration (≥10 years) and long time since last vaccination (> 12 m) are identified as important risk factors for infection in these patients. Furthermore, our MR study provides evidence supporting an association between PD and COVID-19 susceptibility.

Causal association between skin cancer and immune cells: mendelian randomization (MR) study

BackgroundNumerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR.MethodsThis study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results.ResultsWe discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results.ConclusionThis study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

Insights into inflammation and implications for the pathogenesis and long-term outcomes of endometrial cancer: genome-wide surveys and a clinical cohort study

BackgroundDespite evidence showing a connection between inflammation and endometrial cancer (EC) risk, the surveys on genetic correlation and cohort studies investigating the impact on long-term outcomes have yet to be refined. We aimed to address the impact of inflammation factors on the pathogenesis, progression and consequences of EC.MethodsFor the genetic correlation analyses, a two-sample of Mendelian randomization (MR) study was applied to investigate inflammation-related single-nucleotide polymorphisms involved with endometrial cancer from GWAS databases. The observational retrospective study included consecutive patients diagnosed with EC (stage I to IV) with surgeries between January 2010 and October 2020 at the Cancer Hospital of Shantou University Medical College.ResultsThe 2-sample MR surveys indicated no causal relationship between inflammatory cytokines and endometrial cancer. 780 cases (median age, 55.0 years ) diagnosed with EC were included in the cohort and followed up for an average of 6.8 years. Increased inflammatory parameters at baseline were associated with a higher FIGO stage and invasive EC risk (odds ratios [OR] 1.01 to 4.20). Multivariate-cox regression suggested that multiple inflammatory indicators were significantly associated with overall survival (OS) and progression-free survival (PFS) (P < 0.05). Nomogram models based on inflammatory risk and clinical factors were developed for OS and PFS with C-index of 0.811 and 0.789, respectively. LASSO regression for the validation supported the predictive efficacy of inflammatory and clinical factors on the long-term outcomes of EC.ConclusionsDespite the fact that the genetic surveys did not show a detrimental impact of inflammatory cytokines on the endometrial cancer risk, our cohort study suggested that inflammatory level was associated with the progression and long-term outcomes of EC. This evidence may contribute to new strategies targeted at decreasing inflammation levels during EC therapy.

Causal benefits of 25 dietary intakes on epigenetic ageing: a Mendelian randomisation study.

DNA methylation GrimAge acceleration (DMGA) and intrinsic epigenetic age acceleration (IEAA) are important physiological markers for assessing the ageing process. Evidence from cross-sectional studies suggests that some dietary intake is associated with DMGA and IEAA. However, the causal relationship between them has yet to be elucidated. This Mendelian randomisation study uses genetic variants associated with different dietary intakes as instrumental variables to explore the causal benefits of multiple dietary intakes on DMGA and IEAA. Cheese intake, dark chocolate intake, average weekly red wine intake, dried fruit intake, fresh fruit intake, porridge intake, cereal intake, and liver intake had a negative causal association with DMGA, and poultry intake and doughnut intake had a positive causal association with DMGA (p < 0.05). Muesli and bran cereal intake had a negative causal association with IEAA, and pineapple intake had a positive causal association with IEAA (p < 0.05). Dietary intake positively causally associated with IEAA or DMGA may have accelerated biological ageing; conversely, dietary intake negatively causally associated with IEAA or DMGA may have contributed to delaying biological ageing. Based on genetic evidence, this study demonstrated some significant causal benefits of dietary intake on DMGA and IEAA, suggesting the possibility of intervening in DNA methylation acceleration and epigenetic age acceleration by adjusting these food intakes, thereby promoting health and delaying ageing. However, the findings of this study are exploratory and preliminary and need to be supported and validated by evidence from further clinical studies and mechanistic studies.

Causal relationship between multiple sclerosis and primary Sjögren's syndrome: a two-sample mendelian randomization study.

This study aims to investigate the causal relationship between primary Sjögren's syndrome (SS) and multiple sclerosis (MS) using a two-sample Mendelian randomization (MR) analysis to provide insights into their common mechanisms and implications for therapeutic strategies.We utilized data from Genome-Wide Association Studies (GWAS) for primary SS (1,290 cases and 213,145 controls) and MS (4,888 cases and 10,395 controls), restricted to European ancestry. Instrumental variables (IVs) were selected based on genetic variants associated with primary SS. The primary MR method was Inverse Variance Weighted (IVW), supplemented by MR Egger, Weighted Median, Simple Mode, and Weighted Mode algorithms to assess the bidirectional causal relationships between MS and primary SS. Sensitivity analyses, including MR-PRESSO and leave-one-out analysis, were conducted to ensure the robustness of our findings.After excluding SNPs with pleiotropic effects, 42 and 5 SNPs were identified as robust IVs for primary SS and MS, respectively. Our analysis revealed a significant protective effect of MS on primary SS, with IVW showing an OR of 0.896 (95% CI: 0.841-0.954, P = 0.001). No significant heterogeneity or horizontal pleiotropy was detected, supporting the reliability of the results.Our findings suggest a potential protective effect of MS against primary SS, indicating a negative causal association between these two autoimmune diseases. This adds valuable genetic evidence to the understanding of the complex interplay between primary SS and MS, offering new avenues for research and therapeutic interventions.

Causality between multiple autoimmune disorders and migraine and its subtypes: a two-sample Mendelian randomization study

Causality between multiple autoimmune disorders and migraine and its subtypes: a two-sample Mendelian randomization study

Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study

Causal relationship between mitochondrial-associated proteins and cerebral aneurysms: a Mendelian randomization study

Wearable Devices, Health Care Use, and Psychological Well-Being in Patients With Atrial Fibrillation.

Wearables are increasingly used by patients with atrial fibrillation (AF) for symptom monitoring and health management, but their impact on patient health care use and psychological well-being is not well understood. In this retrospective, propensity-matched study of patients with AF, survey and electronic health record data were merged to compare AF-specific health care use (outpatient/inpatient visits, rhythm-related testing, and procedures) and informal health care use (telephone calls and patient portal messages) over a 9-month period between wearable users and nonusers. We also examined the effects of wearable cardiac monitoring features (eg, heart rate alerts, irregular rhythm notification, and ECG) on patient behavior and well-being. Of 172 patients with AF in this analysis (age, 72.6±9.0 years; 42% women), 83 used a wearable. Compared with nonusers, wearable users reported higher rates of symptom monitoring and preoccupation (P=0.03) and more AF treatment concerns (P=0.02). Moreover, 20% of wearable users experienced anxiety and always contacted their doctors in response to irregular rhythm notifications. After matching, AF-specific health care use was significantly greater among wearable users compared with nonusers (P=0.04), including significantly higher rates of ECGs, echocardiograms/transesophageal echocardiogram, and ablation. Wearable users were also significantly more likely to use informal health care resources compared with nonusers (P=0.05). Wearables were associated with higher rates of symptom monitoring and preoccupation, AF treatment concerns, AF-specific health care use, and use of informal health care resources. Prospective, randomized studies are needed to understand the net effects of wearables and their alerts on patients, providers, and the health care system.

Bioequivalence and Food Effect Assessment of Eltrombopag Olamine Tablets in Healthy Chinese Subjects: An Open, Randomized, Single-Dose, and Two-Period Crossover Study.

Eltrombopag, a nonpeptide thrombopoietin receptor agonist, is primarily used for treating immune thrombocytopenic purpura. The aim of this study was to investigate the pharmacokinetic profile and food-drug interaction of test and reference eltrombopag olamine tablets among healthy Chinese volunteers. An open, randomized, single-dose, 2-period crossover design was employed, involving fasting and fed conditions with a 10-day washout period. Ninety-six healthy volunteers received a single oral dose of 25mg of the 2 eltrombopag formulations, with 48 participants in each group: fasting volunteers and those consuming a high-fat, low-calcium meal. Plasma eltrombopag concentrations were analyzed using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were derived from the concentration-time profiles. The geometric mean ratios, with 90% confidence intervals, for the maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence acceptance criteria (80%-125%) under both fasting and fed conditions, indicating bioequivalence between the test and reference formulations. Administration of eltrombopag with a high-fat, low-calcium diet reduced the net systemic exposure by approximately 40%. Adverse events were recorded, and no serious adverse events were observed in either fasting or fed conditions. In conclusion, eltrombopag is well tolerated and exhibits a favorable safety profile in the Chinese population. The achievement of bioequivalence under fasting and fed conditions supports the demonstration of biosimilarity between the test and reference formulations.

No increased complication rate with the use of soft tissue quadriceps tendon autograft for primary ACL reconstruction – a systematic review

BackgroundThe autograft of choice for anterior cruciate ligament reconstruction (ACLR) remains debateable. Recently there has been increased popularity of soft tissue quadriceps tendon (s-QT) autograft due to less donor site morbidity, reduced anterior knee pain and comparable re-operation and complication rates. The aim of this review was to analyse functional outcomes of primary ACLR using s-QT in adult population without the bone plug and to report its complication profile against other autografts. Patient and methodsThis systematic review was performed in accordance with PRISMA guidelines and a review of literature was conducted on four online databases (Medline, EMBASE, Cochrane and Google Scholar). Clinical studies reporting on patients undergoing primary ACLR with s-QT autograft or in comparison to BPTB or HS autografts with a minimum of 6 months follow-up were included. The studies were inclusive of only all soft tissue QT autograft regardless of the implants or fixation method used. Critical appraisal of studies was conducted using the Methodological Index for Non-Randomized Studies (MINORS) tool. ResultsFourteen studies were eligible. There were three randomised control studies (RCT) and 11 non-randomised comparative studies with 1543 patients who underwent ACLR. 682 underwent s-QT, 498 had hamstring tendon (HT) and 174 had bone-patellar tendon-bone (BPTB). 60% (n = 930) were males and mean follow up was 23.6 months (6–65). Eight studies reported post-operative patient reported outcome measures (PROMs). The mean International Knee Documentation Committee (IKDC) score was 91.5 ± 15.1 whereas mean Lysholm score was 90 ± 3.9. Five studies reported on laxity with mean anterior tibial translation (ATT) of 1.28 ± 1.09 mm. Overall complication rate of s-QT ACLR was 6% with 3% graft failure, 0.52% arthrofibrosis, 0.2% infection, 0.75% revision ACLR. There was no significant difference in functional outcome scores, knee stability and range of motion (ROM) between s-QT, HT and BPTB. Conclusions-QT for ACLR has a comparable functional outcome, laxity, failure and with overall graft failure rate of 3%. Level of evidenceIII; Systematic review and meta-analysis.

Causal role of immune cells in chronic periodontitis: a bidirectional Mendelian randomization study

BackgroundThis study aims to explore the bidirectional causal relationship between immune cell phenotypes and chronic periodontitis using a Mendelian randomization framework. Materials and methodsThrough a two-sample Mendelian randomization analysis, this research examined genetic data related to 731 immune cell traits and chronic periodontitis. Instrumental variables were chosen based on their genetic links to either immune traits or periodontitis. Various statistical techniques, including MR-Egger regression, weighted median, and inverse-variance weighted (IVW) analysis, were employed to determine the causal connections.ResultsPredominantly using the IVW method, 26 distinct immune phenotypes were identified as potentially influencing periodontitis (P < 0.05). Conversely, periodontitis potentially affected 33 different immune phenotypes (P < 0.05). The results for pleiotropy and sensitivity tests were stable. However, these associations lost significance after adjusting for the False Discovery Rate.ConclusionThis study uncovers a complex bidirectional causal relationship between certain immune cell phenotypes and chronic periodontitis, underscoring the intricate interaction between the immune system and the pathogenesis of periodontal disease.

Causality of genetically determined blood metabolites on inflammatory bowel disease: a two-sample Mendelian randomization study

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease of the gastrointestinal tract, including two subtypes: Crohn’s disease (CD) and ulcerative colitis (UC). Metabolic disorders are important factors in the development of IBD. However, the evidence for the causal relationship between blood metabolites and IBD remains limited. A two-sample MR analysis was applied to evaluate relationships between 486 blood metabolites and IBD. The inverse variance weighted method was chosen as the primary MR analysis method. False discovery rate correction was used to control for false positives in multiple testing. Following complementary and sensitivity analyses were conducted using methods such as weight median, MR-egger, weighted mode, simple mode, Cochran Q test, and MR-PRESSO. Moreover, we performed replication, meta-analysis, Steiger test, and linkage disequilibrium score regression to enhance the robustness of the results. Additionally, we performed metabolic pathway analysis to identify potential metabolic pathways. As a result, we identified four significant causal associations between four blood metabolites and two IBD subtypes. Specifically, one metabolite was identified as being associated with the development of CD (mannose: odds ratio (OR) = 0.19, 95% confidence interval (CI) 0.08–0.43, P = 8.54 × 10–5). Three metabolites were identified as being associated with the development of UC (arachidonate (20:4n6): OR = 0.18, 95% CI 0.11–0.30, P = 2.09 × 10–11; 1, 5-anhydroglucitol: OR = 2.21, 95% CI 1.47–3.34, P = 1.50 × 10–4; 2-stearoylglycerophosphocholine: OR = 2.66, 95% CI 1.53–4.63, P = 5.30 × 10–4). The findings of our study suggested that the identified metabolites and metabolic pathways can be considered as useful circulating metabolic biomarkers for the screening and prevention of IBD in clinical practice, as well as candidate molecules for future mechanism exploration and drug target selection.

Overexpression of REC8 induces aberrant gamete meiotic division and contributes to AML pathogenesis - a multiplexed microarray analysis and mendelian randomization study.

Acute myeloid leukemia (AML) is a notably lethal disease, characterized by malignant clonal proliferation of hematopoietic stem cells in the bone marrow. This study seeks to unveil potential therapeutic targets for AML, using a combined approach of microarray analysis and Mendelian randomization (MR). We collected data samples from the Gene Expression Omnibus (GEO) database and extracted pQTL data from genome-wide association studies (GWAS) to identify overlapping genes between the DEGs and GWAS data. Gene enrichment and pathway annotation analyses were performed on these genes. Furthermore, we validated gene expression levels and assessed their clinical relevance. By taking the intersection of these gene sets, we obtained a list of co-expressed genes, including four upregulated genes (REC8, TPM2, ZMIZ1, CD82) and two downregulated genes (IFNAR1, TMCO3). MR analysis demonstrated that genetically predicted protein levels of CD82, REC8, ZMIZ1, and TPM2 were significantly associated with increased odds of AML, while IFNAR1 and TMCO3 showed a protective effect. Gene ontology and KEGG pathway analyses revealed significant enrichment in functions related to female gamete generation, meiosis, p53 signaling pathway, and cardiac muscle contraction. Differences in immune cell profiles were observed between AML survivors and those with poor prognosis, including lower levels of neutrophils and higher levels of follicular helper T cells in the latter group. This study identifies a causal relationship between gene expression and AML and highlights the potential role of REC8 in leukemogenesis, possibly through its impact on gametocyte meiotic abnormalities. The findings provide new insights into the prevention and treatment of leukemia.

Association of education with cholelithiasis and mediating effects of cardiometabolic factors: A Mendelian randomization study.

Education, cognition, and intelligence are associated with cholelithiasis occurrence, yet which one has a prominent effect on cholelithiasis and which cardiometabolic risk factors mediate the causal relationship remain unelucidated. To explore the causal associations between education, cognition, and intelligence and cholelithiasis, and the cardiometabolic risk factors that mediate the associations. Applying genome-wide association study summary statistics of primarily European individuals, we utilized two-sample multivariable Mendelian randomization to estimate the independent effects of education, intelligence, and cognition on cholelithiasis and cholecystitis (FinnGen study, 37041 and 11632 patients, respectively; n = 486484 participants) and performed two-step Mendelian randomization to evaluate 21 potential mediators and their mediating effects on the relationships between each exposure and cholelithiasis. Inverse variance weighted Mendelian randomization results from the FinnGen consortium showed that genetically higher education, cognition, or intelligence were not independently associated with cholelithiasis and cholecystitis; when adjusted for cholelithiasis, higher education still presented an inverse effect on cholecystitis [odds ratio: 0.292 (95%CI: 0.171-0.501)], which could not be induced by cognition or intelligence. Five out of 21 cardiometabolic risk factors were perceived as mediators of the association between education and cholelithiasis, including body mass index (20.84%), body fat percentage (40.3%), waist circumference (44.4%), waist-to-hip ratio (32.9%), and time spent watching television (41.6%), while time spent watching television was also a mediator from cognition (20.4%) and intelligence to cholelithiasis (28.4%). All results were robust to sensitivity analyses. Education, cognition, and intelligence all play crucial roles in the development of cholelithiasis, and several cardiometabolic mediators have been identified for prevention of cholelithiasis due to defects in each exposure.

Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease.

Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

Random Dynamic Responses of Two Parallel Interfacial Cracks Between A Functionally Graded Material Strip And Two Dissimilar Elastic Strips

Abstract An analytical approach is presented in this article for the random dynamic study of two parallel interfacial cracks in a functionally graded material (FGM) strip that is bonded between two distinct elastic strips. One of the parallel cracks is placed at the interface of the elastic strip I and the FGM strip, and another is at the interface of the FGM strip and elastic strip II. A stationary stochastic process of time is used to model the dynamic loadings that are applied to the crack faces. To find the solution, the FGM strip is splited into a number of sub-strips, and using an average method, the material properties of each sub-strip are reduced to random variables. A fundamental problem is formulated to find the solution. The boundary conditions are reduced to a set of singular integral equations employing the Fourier sine, Fourier cosine, and Laplace transforms, which are solved by using the Collocation method. Further, the analytical expressions of dynamic stress intensity factors (DSIFs) about the crack tips in the time domain are obtained with the help of the Improved Dubner and Abate's method. Finally, the Monte Carlo method is used to obtain the mathematical expectation and standard deviation of DSIFs. The outcomes of the present study are also verified. The unique aspect of this study is the pictorial illustration of mathematical expectation and standard deviation as functions of the number of sub-strips, functionally graded parameter, thickness of the strips, and length of parallel interfacial cracks.

Causal association between air pollution and allergic rhinitis, asthma: a Mendelian randomization study

BackgroundsObservational studies suggest that air pollutants, including particulate matter and nitrogen compounds, could elevate asthma and allergic rhinitis health risks. Nevertheless, the exact nature of the causal relationship between air pollution and asthma and allergic rhinitis remains unknown. This study utilizes the Mendelian randomization (MR) technique to explore the potential causal links between air pollution components (PM2.5, PM2.5–10, PM10, NO₂, and nitrogen dioxide) and the incidence of allergic rhinitis and asthma.MethodsA MR study utilized summary statistics from GWAS that are publicly accessible. The inverse variance weighting (IVW) approach served as the foundational analysis technique. To ensure robustness, supplementary methodologies such as the weighted median, MR-Egger regression, simple mode, and weighted model were also applied. Heterogeneity was evaluated using Cochran’s Q test, and the presence of pleiotropy was determined through MR-Egger regression. The MR-PRESSO test was employed for outlier detection, and the analysis’s sensitivity was scrutinized via a leave-one-out strategy.ResultsThe IVW technique showed a strong correlation between PM10 and asthma (OR = 0.625, 95% CI = 0.396–0.988, p = 0.044). No significant associations were found between asthma and other air pollutants such as PM2.5, PM2.5–10, NO₂, or nitrogen dioxide. Similarly, allergic rhinitis showed no causal relationships with any studied air pollution metrics. Pleiotropy was absent in the findings. Sensitivity analyses, employing the leave-one-out method, confirmed the stability of these results, unaffected by individual single nucleotide polymorphisms (SNPs).ConclusionThis Mendelian randomization study establishes a causal link between PM10 exposure and asthma, suggesting that interventions to reduce air pollution may decelerate the adverse progression of asthma.

Causal effects of genetic birth weight and gestational age on adult esophageal diseases: Mendelian randomization study

Causal effects of genetic birth weight and gestational age on adult esophageal diseases: Mendelian randomization study