Causal analysis between gastro-oesophageal reflux disease and obstructive sleep apnoea.

Background: Based on evidence from existing observational research, clarifying the causal relationship between gastro-oesophageal reflux disease (GORD) and obstructive sleep apnoea (OSA) is challenging. Here, Mendelian randomisation, a method based on genetics, was used to provide new evidence for causality. Methods: Summary statistics from two publicly available genome-wide association studies were used to evaluate the causal relationship between GORD and OSA (the GORD database was used as an exposure variable and the OSA database as an outcome). Inverse variance weighting was used as the main analytical tool in Mendelian randomisation to estimate causal effects. The robustness of the results was evaluated by sensitivity analysis. Possible mediators were evaluated using multivariate Mendelian randomisation. Results: A statistically significant causal relationship was observed between GORD and OSA (OR 1.597, 95% CI 1.401-1.821, p<0.001), and similar results were observed in weighted median and Mendelian randomisation-Egger regression analyses. No bias was found in the sensitivity analysis of Mendelian randomisation estimation. Multivariate Mendelian randomisation showed that GORD significantly increased the risk of developing OSA, even when the possible mediator was excluded (OR 1.107, 95% CI 1.101-1.212, p<0.001). Conclusion: Our study confirmed a causal relationship between GORD and OSA and suggests that intervention measures should be taken for patients with GORD to prevent the occurrence of OSA.

Causal effects of education attainment on oral and oropharyngeal cancer: New evidence from a meta-analysis and Mendelian randomization study.

Objectives: Higher educational attainment (EA) has proven to be beneficial for preventing and treating various types of cancers. Currently, there is little evidence on the association between EA and prevention of oral cavity and pharyngeal cancer (OCPC). Methods: Several databases were searched until October 1, 2022, and a meta-analysis was performed. A Mendelian randomization (MR) study was conducted with EA (i.e., the exposure) data derived from the Social Science Genetic Association Consortium and 6,034 cases of OCPC (i.e., outcome) selected from the Integrative Epidemiology Unit genome-wide association study. Five methods were used to evaluate the causality between EA and OCPC. The leave-one-out sensitivity test, MR-Egger regression, and multivariable MR (MVMR) analysis were applied to evaluate the MR results. Results: The meta-analysis included 36 eligible studies. EA was significantly and negatively associated with OCPC risk (odds ratio [OR]: 0.439, 95% confidence interval [CI]: 0.383-0.503, P < 0.001). MR analysis revealed that the risk of OCPC, oropharyngeal cancer, and oral cavity cancer decreased with an increase in education (OR: 0.349, 95% CI: 0.222-0.548, P < 0.001; OR: 0.343, 95% CI: 0.198-0.597; P < 0.001; OR: 0.342, 95% CI: 0.195-0.601, P < 0.001, respectively). Even after correcting for mediators, high EA still significantly reduced the risk of OCPC (OR: 0.361, 95% CI: 0.281-0.463, P < 0.001). Conclusion: Both the meta-analysis and MR results demonstrated that high levels of EA can reduce the risk of OCPC in the general population.

Exploring the causality between educational attainment and gastroesophageal reflux disease: A Mendelian randomization study.

BACKGROUND AND OBJECTIVES: Observational studies suggest that higher educational attainment (EA) contributes to the prevention and treatment of gastroesophageal reflux disease (GERD). However, the causality of this relationship is not supported by strong evidence. We used publicly available genetic summary data, including that on EA, GERD, and the common risk of GERD, to prove this causality. METHODS: Multiple methods in Mendelian randomization (MR) were employed to evaluate the causality. The leave-one-out sensitivity test, MR-Egger regression, and multivariable MR (MVMR) analysis were applied to evaluate the MR results. RESULTS: Higher EA was significantly associated with lower GERD risk (inverse variance weighted method, odds ratio [OR]: 0.979, 95% confidence interval [CI]: 0.975-0.984, P <0.001). Similar results were obtained when the weighted median and weighted mode were used for causal estimation. After adjusting for potential mediators, the MVMR analysis showed that body mass index (BMI) and EA were still significantly correlated and negatively correlated with GERD (OR: 0.997, 95% CI: 0.996-0.998, P =0.008 and OR: 0.981, 95% CI: 0.977-0.984, P <0.001), respectively. CONCLUSIONS: Higher levels of EA may have a protective effect against GERD by having a negative causal relationship. Additionally, BMI may be a crucial factor in the EA-GERD pathway.

Depression Promotes Gastroesophageal Reflux Disease: New Evidence Based on Mendelian Randomization.

BACKGROUND: Although observational studies have reported that depression is a risk factor for gastroesophageal reflux disease, it is difficult to determine the potential causal correlation. Thus, this study investigated the causal relevance of depression for gastroesophageal reflux disease using Mendelian randomization and provided new evidence for their association. METHODS: Based on data from the UK Biobank, we assessed the causality of the 2 diseases by analyzing 135 458 severe depressive disorder cases and 41 024 gastroesophageal reflux disease cases. The causal inference was assessed using inverse-variance weighting, weighted median, Mendelian randomization-Egger, and weighted median methods. Simultaneously, pleiotropy and sensitivity analyses were used for quality control. Finally, we also explored whether depression affects gastroesophageal reflux disease through other risk factors. RESULTS: A positive causal relationship between depression and gastroesophageal reflux disease was found in the inverse-variance weighted and weighted median methods, both of which were statistically significant [odds ratio = 1.011, 95% CI: 1.004-1.017, P =.001; odds ratio = 1.011, 95% CI: 1.004-1.020, P =.002)]. Sensitivity analyses were consistent with a causal interpretation, and the main deviation of genetic pleiotropy was not found (Intercept ß = 0.0005; SE = 0.005, P =.908). The genetic susceptibility to depression was also associated with smoking, insomnia, and sleep apnea (odds ratio = 1.166, 95% CI: 1.033-1.316, P =.013; odds ratio = 1.089, 95% CI: 1.045-1.134; and odds ratio = 1.004, 95% CI: 1.001-1.006, P =.001, respectively). CONCLUSION: Our results verified a causal correlation that depression could slightly increase the risk of gastroesophageal reflux disease.

Childhood asthma and type 1 diabetes mellitus: A meta-analysis and bidirectional Mendelian randomization study.

BACKGROUND: Worldwide incidence and prevalence of both asthma and type 1 diabetes mellitus (T1DM) in children have been increasing in past decades. Association between the two diseases has been found in some but not in other studies. OBJECTIVE: We conducted a meta-analysis to verify such an association, and bidirectional Mendelian randomization analysis to examine the potential cause-effect relationships. METHODS: Three databases (PubMed, Embase, and Web of Science) were searched from their inception to February 1, 2021. Pooled hazard ratios (HR) or odds ratios (OR), and 95% confidence intervals, were calculated. Associations between single-nucleotide polymorphisms with childhood asthma and T1DM were selected based on genome-wide association studies. The outcome datasets were obtained from FinnGen study. We used the inverse-variance-weighted (IVW), weighted median and MR-Egger methods to estimate causal effects. To assess robustness and horizontal pleiotropy, MR-Egger regression and MR pleiotropy residual sum and outlier test were conducted. RESULTS: In meta-analysis, childhood asthma was associated with an increased risk of T1DM (HR = 1.30, 95% CI 1.05-1.61, P = .014), whereas T1DM was not associated with the risk of asthma (HR = 0.98, 95% CI 0.64-1.51, P = .941; OR = 0.84, 95% CI 0.65-1.08, P = .168). MR analysis indicated increased genetic risk of T1DM in children with asthma (OR = 1.308; 95% CI 1.030-1.661; P = .028). Analysis using the IVW method indicated no association between T1DM and genetic risk of asthma (OR = 1.027, 95%CI 0.970-1.089, P = .358). CONCLUSION: Both meta-analysis and MR study suggested that childhood asthma was a risk factor for T1DM. No epidemiological or genetic evidence was found for an association of T1DM with asthma incidence. Further studies could be carried out to leverage this newfound insight into better clinical and experimental research in asthma and T1DM.

Au-Stabilized Nanoporous PdCuAu Alloys Exhibiting Outstanding Catalytic Activity and Durability for the Formic Acid Oxidation Reaction.

Metallic Pd is widely recognized as an efficient electrocatalyst for the formic acid oxidation reaction (FAOR), which unfortunately suffers from poor durability owing to Pd dissolution and CO poisoning. The present work describes an effective method to enhance Pd durability by alloying with Cu and Au. Cu could provide surface OH at low potentials to remove poisonous CO for improved CO resistance. Au, the most inert metal, was added to reduce Pd and Cu dissolution. Moreover, alloying with Cu and Au could also modulate the electronic structure of Pd which is just profitable for the FAOR. The constructed PdCuAu with a nanoporous structure exhibits a specific activity of 14.9 mA cm-2 and a Pd mass activity of 6012 A g-1, which is ∼15 times and ∼14 times higher than those of commercial Pd/C. While these two electrocatalysts were used as fuel cell anodes, the maximum power density of the PdCuAu anode (Pd loading 10 µg cm-2) is 93.2 mW cm-2 and the value of the Pd/C anode (Pd loading 1.2 mg cm-2) is 60.3 mW cm-2. The power efficiency of Pd has been notably increased by 185 times in this home-made nanoporous PdCuAu ternary alloy electrocatalyst.

Causal Association between Whole-Body Water Mass and Sleep Apnea: A Mendelian Randomization Study.

Rationale: Growing evidence has suggested that body water content plays a critical role in sleep apnea. However, the causal relationship has not been established. Objectives: This study aimed to investigate whether increased whole-body water mass is causally associated with a higher risk of sleep apnea using two-sample Mendelian randomization (MR) analysis. Methods: Body water mass (BWM)-associated genetic instruments were extracted from a genome-wide association study conducted by Neale Lab, which incorporates 331,315 individuals of European ancestry. Genetic variants for sleep apnea were derived from the FinnGen dataset. MR analysis was performed using inverse variance-weighted and weight median methods, respectively. MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier tests were applied to evaluate the directional pleiotropy. In addition, we performed a multivariable MR analysis that includes body mass index, snoring, and waist-to-hip ratio as covariate exposures to address their confounding effects. To elucidate mechanisms of the association between BWM and sleep apnea, we further conducted MR analysis on common edematous diseases. Results: MR estimates showed that per standard deviation increase in BWM led to an increase in the risk of sleep apnea by 49% (odds ratio [OR], 1.490; 95% confidence interval [CI], 1.308-1.696; P = 1.75 × 10-9). The result after MR-Pleiotropy Residual Sum and Outlier correction further supports their causal association (OR, 1.414; 95% CI, 1.253-1.595; P = 1.76 × 10-8). In addition, the multivariable MR analysis indicates a significant causal association between a higher BWM and increased risk of sleep apnea (OR, 1.204; 95% CI, 1.031-1.377; P = 0.036). Genetic predisposition to a higher BWM was also causally related to increased risk of edematous diseases. Conclusions: Our results suggested that increased BWM is a potential risk factor for sleep apnea. Pathologic edema is a possible intermediate factor mediating this causal association.

Plasma Proteins as Occupational Hazard Risk Monitors for Populations Working in Harsh Environments: A Mendelian Randomization Study.

Harsh work environments can include very cold, hot, dusty, and noisy workplaces, as well as exposure in the workplace with chemicals and other fumes, cigarette smoke, and diesel exhaust. Although working in these harsh environments can have a negative effect on health, there are no effective biomarkers for monitoring health conditions until workers develop disease symptoms. Plasma protein concentrations, which reflect metabolism and immune status, have great potential as biomarkers for various health conditions. Using a Mendelian-randomization (MR) design, this study analyzed the effects of these harsh environments on plasma proteins to identify proteins that can be used as biomarkers of health status. Preliminary analysis using inverse variance weighted (IVW) method with a p-value cutoff of 0.05 showed that workplace environments could affect the concentrations of hundreds of plasma proteins. After filtering for sensitivity via MR-Egger, and Weighted Median MR approaches, 28 plasma proteins altered by workplace environments were identified. Further MR analysis showed that 20 of these plasma proteins, including UNC5D, IGFBP1, SCG3, ST3GAL6, and ST3GAL2 are affected by noisy workplace environments; TFF1, RBM39, ACYP2, STAT3, GRB2, CXCL1, EIF1AD, CSNK1G2, and CRKL that are affected by chemical fumes; ADCYAP1, NRSN1, TMEM132A, and CA10 that are affected by passive smoking; LILRB2, and TENM4 that are affected by diesel exhaust, are associated with the risk of at least one disease. These proteins have the potential to serve as biomarkers to monitor the occupational hazards risk of workers working in corresponding environments. These findings also provide clues to study the biological mechanisms of occupational hazards.

Higher basophil count decreases narcolepsy risk: a Mendelian randomization study.

BACKGROUND: Blood cell properties effectively reflect immune status. Basophil and CD8+ CD27+ T cell levels are correlated with narcolepsy, but their causal association is unclear. This study aims to evaluate the causality between blood cell count and narcolepsy risk at the genetic level. METHODS: Two-sample Mendelian randomization (MR) analyses were performed on 35 published blood cell properties, using genome-wide association study (GWAS) datasets and one published GWAS dataset of narcolepsy, to explore causality between blood cell count and narcolepsy risk. Inverse variance weighted, MR-Egger, and weighted median approaches were employed for the MR analysis, odds ratio (OR) calculations, and heterogeneity tests of single nucleotide polymorphisms were conducted with the TwoSampleMR package in R. Multivariable Mendelian randomization (MVMR) was used to adjust the analysis further and eliminate the mediation effect between exposures. RESULTS: Basophil counts, total basophil neutrophil counts, total neutrophil eosinophil counts, granulocyte counts, and myeloid white cell counts showed inverse associations with narcolepsy risk based on the two-sample MR analysis. MVMR confirmed that only basophil counts were significantly associated with narcolepsy risk for the blood cell properties tested (OR = 0.23, 95% confidence interval 0.08-0.62; p = 0.004, power = 99.99%). Each standard deviation increase in basophil count (0.03 per nL), compared to the median level (0.04 per nL), decreased narcolepsy risk by 77%. CONCLUSION: Higher white blood cell counts, especially basophil counts, are protective factors for narcolepsy. Basophil counts has great potential to be used as a new biomarker to shorten diagnostic delay and to monitor the therapeutic effects of treatments for narcolepsy.

Educational attainment could be a protective factor against obstructive sleep apnea: a study based on Mendelian randomization.

BACKGROUND: Causality between education and obstructive sleep apnea (OSA) is not known. METHODS: Genetic variants, as instrumental variables for years of education, were derived from the Social Science Genetic Association Consortium. The outcome datasets related to OSA were from the FinnGen research project (www.finngen.fi/en/). Inverse variance-weighted, weighted-median, and Mendelian randomization-Egger analysis were used to estimate causal effects. To assess the robustness and horizontal pleiotropy of significant results, leave-one-out sensitivity analysis and Mendelian randomization-Egger regression analysis were conducted. The inverse variance-weighted method was undertaken to estimate the association between years of education and other known risk factors for OSA. Analyses were conducted using the Two Sample Mendelian Randomization package of R 4·0·3. RESULTS: Genetic predisposition towards 4.2 years of additional education was associated with a 27.8% lower risk of OSA [odds ratio (OR) =0.722, 95% confidence interval (CI): 0.566-0.921; P=0.009]. Sensitivity analyses were consistent with a causal interpretation in which a major bias from genetic pleiotropy was unlikely. The Mendelian randomization assumptions did not seem to be violated. Genetic predisposition towards longer education was associated with a lower body mass index, fewer cigarettes smoked per day, and greater alcohol intake per week. CONCLUSIONS: Our data indicated that education could be a protective factor against OSA. Potential mechanisms could include body mass index, tobacco smoking, and alcohol intake.

Association between depression and sleep apnoea: a Mendelian randomisation study.

BACKGROUND: Studies have reported a close relationship between depression and sleep apnoea, yet it is unknown whether these are causally related. Thus, we aimed to determine whether depression is associated with the aetiology of sleep apnoea. METHODS: We used publicly available genetic summary data from two large consortia: the Psychiatric Genomics Consortium, with data from 36 single-nucleotide polymorphisms (SNPs) closely associated with major depressive disorder (MDD), and the UK Biobank, including 456 736 patients with sleep apnoea and 766 964 controls. For Mendelian randomisation (MR) analysis, we used the inverse-variance weighted method, weighted median method, MR-Egger regression, MR pleiotropy residual sum and outlier test to retrieve summary data. Analyses were performed using the "TwoSampleMR" package in R. RESULTS: Out of the 36 SNPs associated with MDD, we found statistically significant evidence of a potential causal effect of MDD on the risk of sleep apnoea (OR 1.004, 95% CI 1.001-1.006; p=0.001). Similar results were obtained using the MR-Egger and weighted median methods. Additionally, we found no heterogeneity or pleiotropy. CONCLUSIONS: Our findings suggest that depression slightly increases the risk of sleep apnoea. Further investigation of the potential biological mechanisms is necessary.

Inflammatory Bowel disease promote oral cancer and pharyngeal cancer: new evidence of Mendelian randomization.

BACKGROUND: Evidence from observational studies shows that inflammatory bowel disease (IBD) [comprising ulcerative colitis (UC) and Crohn's disease (CD)] is a risk factor to Oral cavity and pharyngeal cancer (OC&PC) [comprising Oral cavity cancer (OCC) and Oropharyngeal cancer (OPC)], but it is unclear whether these diseases have potential causality. OBJECTIVES: We aimed to explore the causal relationship between IBD and OC&PC. MATERIALS AND METHODS: A mendelian randomized (MR) study was performed to estimate the causal relationship between IBD and OC&PC. RESULTS: The potential causal relationship was statistically significant between IBD and OCC (OR = 1.14, 95% confidence interval (CI): 1.02-1.27, p = .02), UC and OCC (OR = 1.13, 95% CI: 1.01-1.27, p = .03), respectively. There was a universal null effect of IBD on OC&PC (IBD: OR = 1.01, 95%CI: 0.93-1.10, p = .74; UC: OR = 1.00, 95%CI: 0.92-1.10, p = .94; CD: OR = 1.02, 95%CI: 0.94-1.09, p = .69), and IBD on OPC (IBD: OR = 0.93, 95%CI: 0.81-1.06, p = 0.26; UC: OR = 0.90, 95%CI: 0.79-1.03, p = .12; CD: OR = 1.04, 95%CI: 0.94-1.15, p = .44). CONCLUSIONS AND SIGNIFICANCE: MR analyses support new evidence indicating there may be a positive causal effect of IBD (including UC) on OCC. Further investigation of the potential biological mechanisms is necessary.

Prognostic significance of tumor-infiltrating lymphocytes and macrophages in nasopharyngeal carcinoma: a systematic review and meta-analysis.

PURPOSE: Many studies have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating macrophages (TIMs) in patients with nasopharyngeal carcinoma (NPC), but the results remain controversial. Here, we performed a meta-analysis to evaluate the prognostic significance of TILs/TIMs in patients with NPC METHODS: The study was registered with PROSPERO (CRD42021234078). PubMed, Embase, and Web of Science databases were searched up to Dec 30, 2020. We reviewed studies that evaluated the relationship between TILs/TIMs and overall survival (OS), disease-free survival (DFS), or progression-free survival (PFS) in NPC. For TILs, CD3, CD4, CD8, and FOXP3 were searched as T-cell markers, CD19 and CD20 as B-cell markers, and CD56 as a natural killer cell marker. For TIMs, CD68 and CD163 were searched as total and M2 macrophage markers, respectively. RESULTS: In total, 19 studies with 3708 NPC were included in this meta-analysis. We found that high total numbers of TILs were significantly associated with favorable OS [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.38-0.57 and PFS (HR 0.48, 95% CI 0.38-0.62)]. In contrast, tumor infiltration by CD3+ T cells (HR 0.55, 95% CI 0.39-0.76), CD4+ T cells (HR 0.40, 95% CI 0.18-0.85), and CD8+ T cells (HR 0.56, 95% CI 0.34-0.93) correlated positively with OS. No significant relationship was found between survival and tumor infiltration by FOXP3+ T cells, CD68+ macrophages, or CD163+ macrophages. CONCLUSION: Our findings revealed that tumor infiltration by CD3+ , CD4+ , and CD8+ T cells could be prognostic biomarkers in NPC.

Serum EA-IgA and D-dimer, but not VCA-IgA, are associated with prognosis in patients with nasopharyngeal carcinoma: a meta-analysis.

BACKGROUND: Patients with nasopharyngeal cancer (NPC) differ in prognosis, even at the same stage; therefore, new biomarkers are urgently required to identify early-stage NPC patients at high risk of poor prognosis. Although Epstein-Barr virus (EBV) DNA has been used for prognosis, the value of many other biomarkers expressed during the infection cycle of EBV remains unclarified. This study aimed to evaluate the prognostic potential of EA-IgA, VCA-IgA and D-dimer in patients with NPC. METHODS: Electronic databases, including PubMed, Embase and Web of Science, were searched up to February 1, 2021. Pooled data were extracted from studies that evaluated the relationship between NPC and overall survival (OS), distant metastasis-free survival (DMFS) or disease-free survival (DFS) and then were subjected to a meta-analysis. RESULTS: Nine studies with 5729 patients were included in this meta-analysis. In patients with NPC, EA-IgA levels significantly predicted OS (HR = 1.63, 95% CI 1.07-2.48). D-Dimer levels significantly predicted OS (HR = 1.75, 95% CI 1.24-2.47) and DMFS (HR = 1.91, 95% CI 1.31-2.79). However, high levels of VCA-IgA were not associated with OS (HR = 1.24, 95% CI 0.95-1.60), DMFS (HR = 1.41, 95% CI 0.92-2.17) or DFS (HR = 2.39, 95% CI 0.78-7.26). CONCLUSIONS: The present findings reveal that EA-IgA and D-dimer, but not VCA-IgA, can be used as prognostic biomarkers in NPC.

A New Coordinate System for Magnetic Resonance Imaging of the Vestibular System.

Objectives: To develop and evaluate a new coordinate system for MRI of the vestibular system. Methods: In this study, 53 internal auditory canal MRI and 78 temporal bone CT datasets were analyzed. Mimics Medical software version 21.0 was used to visualize and three-dimensionally reconstruct the image data. We established a new coordinate system, named W-X, based on the center of the bilateral eyeballs and vertex of the bilateral superior semicircular canals. Using the W-X coordinate system and Reid's coordinate system, we measured the orientations of the planes of the anterior semicircular canal (ASCC), the lateral semicircular canal (LSCC), and the posterior semicircular canal (PSCC). Results: No significant differences between the angles measured using CT and MRI were found for any of the semicircular canal planes (p > 0.05). No statistical differences were found between the angles measured using Reid's coordinate system (CT) and the W-X coordinate system (MRI). The mean values of ∠ASCC & LSCC, ∠ASCC & PSCC, and ∠LSCC & PSCC were 84.67 ± 5.76, 94.21 ± 3.81, and 91.79 ± 5.22 degrees, respectively. The angle between the LSCC plane and the horizontal imaging plane was 15.64 ± 3.92 degrees, and the angle between the PSCC plane and the sagittal imaging plane was 48.79 ± 4.46 degrees. Conclusion: A new W-X coordinate system was developed for MRI studies of the vestibular system and can be used to measure the orientations of the semicircular canals.