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Abstract Background We aimed to probe the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among patients with gout and hyperuricemia (HUA). Methods The study included 1169 gout patients and 7029 HUA patients from the National Health and Nutrition Examination Survey (NHANES) 2007–2018 and 2001–2018, respectively. The association between serum 25(OH)D and mortality was evaluated by Cox proportional hazard and restricted cubic spline models. Results Among participants with gout and HUA, the weighted mean concentrations of serum 25(OH)D were 71.49 ± 30.09 nmol/L and 64.81 ± 26.92 nmol/L, respectively. Vitamin D deficiency occurred in 29.68% of gout patients and 37.83% of HUA patients. During 6783 person-years of follow-up among gout patients, 248 all-cause deaths occurred, among which 76 died from cardiovascular disease (CVD) and 49 died from cancer. 1375 HUA patients were recorded for all-cause mortality during 59,859 person-years of follow-up, including 427 CVD deaths and 232 cancer deaths. After multifactorial adjustment, per one-unit increment in natural log-transformed 25(OH)D was associated with lower risk of 55% all-cause mortality and 61% CVD mortality among gout patients, and a 45% reduced risk of cancer mortality among HUA patients. Restricted cubic splines showed a U-shaped relationship with all-cause and CVD mortality among HUA patients, with inflection points of 72.7 nmol/L and 38.0 nmol/L, respectively. The results were robust in subgroup and sensitivity analyses. Conclusions Serum 25(OH)D was negatively linearly correlated with mortality among gout patients, whereas U-shaped correlated with mortality in HUA patients. These results indicate that adequate vitamin D status could prevent premature death.

Abstract Background Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not been fully known. This study aims to systematically investigate the phenotypic and genetic correlation between RA and CVD. Methods Based on UK Biobank, we conducted two cohort studies to evaluate the phenotypic relationships between RA and CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke. Next, we used linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and bivariate causal mixture model (MiXeR) methods to examine the genetic correlation and polygenic overlap between RA and CVD, using genome-wide association summary statistics. Furthermore, we explored specific shared genetic loci by conjunctional false discovery rate analysis and association analysis based on subsets. Results Compared with the general population, RA patients showed a higher incidence of CVD (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.15–1.28). We observed positive genetic correlations of RA with AF and stroke, and a mixture of negative and positive local genetic correlations underlying the global genetic correlation for CAD and HF, with 13 ~ 33% of shared genetic variants for these trait pairs. We further identified 23 pleiotropic loci associated with RA and at least one CVD, including one novel locus (rs7098414, TSPAN14, 10q23.1). Genes mapped to these shared loci were enriched in immune and inflammatory-related pathways, and modifiable risk factors, such as high diastolic blood pressure. Conclusions This study revealed the shared genetic architecture of RA and CVD, which may facilitate drug target identification and improved clinical management.

Background The training ability of community preceptors is an important factor related to the quality of standardized training for general practitioners (GPs) . In recent years, training programs for community GP preceptors have been conducted in several regions of China, but no research evaluated the implementation of these programs using a comprehensive approach so far. Objective To explore the current situation and obstacles to the implementation of training program of Graded-Supervised Ambulatory Training by the Second Affiliated Hospital of Zhejiang University School of Medicine, and provide theoretical references and strategic support for the development of problem-oriented countermeasures. Methods From October 2021 to January 2022, the implementation status of Graded-Supervised Ambulatory Training program by the Second Affiliated Hospital of Zhejiang University School of Medicine was systematically evaluated based on CIPP model from four aspects of context, input, process and product, using multiple research methods such as content analysis, expert panels, in-depth interviews, expert rating, and surveys. Results The results of policy document analysis and literature review indicated that community preceptor's training is strongly supported by national health policies, and has been widely implemented in China. The training system developed by the Second Affiliated Hospital of Zhejiang University School of Medicine basically covers the content and process of community preceptor training programme, while the assessment and incentive system developed by the community lacks of detailed instructions. From May 2021 to January 2022, ten community preceptors completed 57 times of ambulatory training, each attending four to seven times. The average score of ability of ambulatory training increased from (78.6±5.7) in the first round to (87.8±4.5) in the seventh round. The satisfaction rates of "site and equipment of training" "training forms" "content of training" and "effect of training" were over 90% among community preceptors and GP residents, yet the satisfaction rate of "proper incentives" among community preceptors was only 20%. Participants reported that the main barriers at present were "imperfect incentive system" "difficulties in recruiting appropriate patients" and "inapplicable training content" . Conclusion In the initial stage, the Graded-Supervised Ambulatory Training programme has achieved desired results in many aspects, but there is still room for improvement. In the next stage of training, countermeasures should be formulated based on the actual situation of the community practice base to continuously improve the quality of training.

Irritable bowel syndrome (IBS) patients exhibit significantly lower levels of serum selenium (Se) compared to healthy controls. This study integrates a prospective cohort analysis and animal experiments to investigate Se deficiency as a potential risk factor for IBS. Using data from the UK Biobank, a longitudinal analysis was conducted to explore the associations between dietary Se intake and the risk of incident IBS. In animal study, C57BL/6 mice were fed diets with normal (0.2 ppm) or low (0.02 ppm) Se levels to assess the impacts of Se deficiency on IBS symptoms. Furthermore, we performed 16 S rRNA sequencing, untargeted colonic fecal metabolomics analysis, and colon transcriptome profiling to uncover the regulatory mechanisms underlying Se deficiency-induced IBS. The analysis of UK Biobank data revealed a significant correlation between low dietary Se levels and an increased incidence of IBS. In the experimental study, a low Se diet induced IBS symptoms, evidenced by elevated abdominal withdrawal reflex scores, colon inflammation, and severe pathological damage to the colon. Additionally, the low Se diet caused disturbances in gut microbiota, characterized by an increase in Faecalibaculum and Helicobacter, and a decrease in Bifidobacterium and Akkermansia. Combined colonic fecal metabolomics and colon transcriptome analysis indicated that Se deficiency might trigger IBS through disruptions in pathways related to ''bile excretion'', ''steroid hormone biosynthesis'', ''arachidonic acid metabolism'', and ''drug metabolism-cytochrome P450''. These findings underscore the significant adverse effects of Se deficiency on IBS and suggest that Se supplementation should be considered for IBS patients.

BackgroundModifiable factors were found to be associated with the risk of irritable bowel syndrome (IBS) in observational studies, but whether these associations are causal is uncertain. We conducted a Mendelian randomization (MR) study to systematically explore the causal associations of modifiable factors with IBS.MethodsSummary-level statistical data for IBS was obtained from a genome-wide association study (GWAS) meta-analysis of UK Biobank (40,548 cases and 293,220 controls) and the international collaborative Bellygenes initiative (12,852 cases and 139,981 controls). Genetic instruments associated with the exposures at the genome-wide significance (p

Abstract Evidence from epidemiological literature on the association of circulating micronutrients with risk of nonalcoholic fatty liver disease (NAFLD) is inconsistent. We aimed to elucidate the causal relationships using Mendelian randomization (MR). Single-nucleotide polymorphisms associated with 14 circulating micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, B12, C, D, K1 and zinc) were employed as instrumental variables. Summary level data for NAFLD were obtained from a genome-wide association study (GWAS) meta-analysis of 8434 cases and 770,180 controls (discovery stage) and another two datasets including 1483 NAFLD cases and 17,781 controls (replication stage 1) and 2134 NAFLD cases and 33,433 controls (replication stage 2). Inverse variance-weighted method (IVW) was used as primary analysis, supplemented with a series of sensitivity analysis. Genetically predicted higher β‑carotene levels were suggestively associated with reduced NAFLD risk [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.66–0.99; P = 0.047], whereas the association did not survive the false discovery rates (FDR) correction (P FDR = 0.164). Genetically predicted circulating iron (OR 1.16, 95% CI 1.05–1.29; P = 0.006, P FDR = 0.028), selenium (OR 1.11, 95% CI 1.03–1.20; P = 0.005, P FDR = 0.028) and vitamin B12 (OR 1.08, 95% CI 1.03–1.13; P = 0.002, P FDR = 0.028) were significantly associated with increased risk of NAFLD. Moreover, the findings were consistent in individual datasets (P heterogeneity > 0.05) and confirmed in sensitivity analysis. Our study provided evidence that circulating iron, selenium and vitamin B12 might be causally linked to the risk of NAFLD, which deserves further exploration of the potential biological mechanism.

Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes S100A9 and S100A12, located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.

PurposeThis study aimed to explore the clinical characteristics of male breast cancer (MBC) patients and the factors influencing their prognosis.MethodsWe conducted a retrospective case series analysis of 117 MBC cases who were treated at Zhejiang Cancer Hospital from 2009 to 2022. Cox proportional hazard model was used to identify prognostic factors of MBC. Nomogram was constructed based on these factors, which was further evaluated by C-index and calibration curves.ResultsA total of 115 MBC cases were finally included in our analyses, with median diagnosis age of 59 years. Of these cases, 80.0% were estrogen receptor (ER) positive, 79.2% were progesterone receptor (PR) positive, 48.7% were human epidermal growth factor receptor 2 (HER2) negative, and 42.6% had Ki67 levels higher than 15%. 108 (93.9%) cases underwent radical mastectomy, while only 3 (2.6%) received breast-conserving surgery. The Logrank test suggested that lymphocyte-to-monocyte ratio (LMR) was negatively associated with both overall survival (OS) and disease-free survival (DFS) of MBC, while platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) were only positively associated with OS (all P-values < 0.05). Multivariate regression analysis showed that age (HR 1.08, 95% CI 1.03-1.13) was significant prognostic factors for OS. Meanwhile, age (HR 1.06, 95% CI 1.02-1.10), histological differentiation grade (poorly differentiated/undifferentiated vs. well-differentiated: HR 2.55, 95% CI 1.05-6.17), and TNM stage (IV vs. I: HR 31.59, 95% CI 6.01-165.93) were also significant prognostic factors for DFS. Nomograms were developed for DFS, with C-indexes of 0.782, indicating good predictive performance.ConclusionIncreased age, bigger tumor size, higher TNM stage, and lower histological differentiation grade were associated with poor MBC prognosis, and LMR, PLR, and NLR might be potential predictors for MBC prognosis.

Abstract Background Recent research has established the correlation between gut microbiota and periodontitis via oral-gut axis. Intestinal dysbiosis may play a pivotal bridging role in extra-oral inflammatory comorbidities caused by periodontitis. However, it is unclear whether the link is merely correlative or orchestrated by causative mechanistic interactions. This two-sample Mendelian randomization (MR) study was performed to evaluate the potential bidirectional causal relationships between gut microbiota and periodontitis. Materials and Methods A two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) for gut microbiota (n = 18,340) and periodontitis (cases = 12,251; controls = 22,845). The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. The PhenoScanner database was then searched for pleiotropy SNPs associated with potential confounders. In order to identify the possibly influential SNPs, we further conducted the leave-one-out analysis. Finally, a reverse MR analysis was performed to evaluate the possibility of links between periodontitis and genetically predicted gut microbiota alternation. Results 2,699 single nucleotide polymorphisms (SNPs) associated with 196 microbiota genera were selected as instrumental variables (IVs). IVW method suggested that order Enterobacteriales (OR: 1.35, 95% CI 1.10–1.66), family Bacteroidales S24.7group (OR: 1.22, 95% CI 1.05–1.41), genus Lachnospiraceae UCG008 (OR: 1.16, 95% CI 1.03–1.31), genus Prevotella 7 (OR: 1.11, 95% CI 1.01–1.23), and order Pasteurellales (OR: 1.12, 95% CI 1.00–1.26) may be associated with a higher risk of periodontitis, while genus Ruminiclostridium 6 may be linked to a lower risk (OR: 0.82, 95% CI 0.70–0.95). The sensitivity and heterogeneity analyses yielded no indication of horizontal pleiotropy or heterogeneity. Only the association between order Enterobacteriales and the likelihood of periodontitis remained consistent across all alternative MR approaches. In the reverse MR analysis, four microbiota genera were genetically predicted to be down-regulated in periodontitis, whereas two were predicted to be up-regulated. Conclusions The present MR analysis demonstrated the potential bidirectional causal relationships between gut microbiota and periodontitis. Our research provided fresh insights for the prevention and management of periodontitis. Future research is required to support the finding of our current study.

This study aimed to investigate the associations between carbohydrate intake and gout risk, along with interactions between genetic susceptibility and carbohydrates, and the mediating roles of biomarkers. We included 187,387 participants who were free of gout at baseline and completed at least one dietary assessment in the UK Biobank. Cox proportional hazard models were used to estimate the associations between carbohydrate intake and gout risk. Over a median follow-up of 11.69 years, 2548 incident cases of gout were recorded. Total carbohydrate intake was associated with a reduced gout risk (Q4 vs. Q1: HR 0.67, 95% CI 0.60–0.74), as were total sugars (0.89, 0.80–0.99), non-free sugars (0.70, 0.63–0.78), total starch (0.70, 0.63–0.78), refined grain starch (0.85, 0.76–0.95), wholegrain starch (0.73, 0.65–0.82), and fiber (0.72, 0.64–0.80), whereas free sugars (1.15, 1.04–1.28) were associated with an increased risk. Significant additive interactions were found between total carbohydrates and genetic risk, as well as between total starch and genetic risk. Serum urate was identified as a significant mediator in all associations between carbohydrate intake (total, different types, and sources) and gout risk. In conclusion, total carbohydrate and different types and sources of carbohydrate (excluding free sugars) intake were associated with a reduced risk of gout.

Abstract Context Diet is emerging as a modifiable component of lifestyle for influencing the incidence of liver cancer. Objective To investigate and quantify the potential relationship between food groups and liver cancer. Data sources PubMed and Web of Science were searched for eligible observational studies until 31st March, 2023. Data extraction The meta-analysis was conducted by pooling relative risk (RR), odds ratio (OR) or hazards ratio (HR) with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by subgroup analysis. Sensitivity analysis and publication bias test were also carried out. Data analysis Through stepwise screening, a total of 27 studies were included. The pooled estimates of liver cancer for whole grains and legumes intake were 0.66 (95% CI: 0.54–0.82; I 2 = 25.3%) and 0.86 (95% CI: 0.75–0.99; I 2 = 14.3%), respectively. However, there were null associations of nuts, poultry, egg and sweetened beverages consumption with liver cancer and the association between refined grains and liver cancer was inconclusive. In dose-response meta-analysis, the pooled estimates of liver cancer were 0.77 (95% CI: 0.65–0.91) for every 50 g/day increment in whole grains intake. Non-linear dose-response relationship (P = 0.031) was observed in the association between the intake of legumes and liver cancer, and the protective effect occurred with the dose ranging from 8 g/day to 40 g/day. Conclusions This meta-analysis shows that whole grains and legumes were inversely associated with liver cancer, whereas intake of nuts, poultry, egg and sweetened beverages may not be associated with liver cancer. Further quantitative research needs to be undertaken within a range of populations to investigate the relationship between food groups and liver cancer. Systematic review registration PROSPERO registration no. CRD42021246142

Background Observational studies have suggested the potential role of inflammatory factors in the risk of coronary artery disease (CAD). We aimed to perform 2‐sample Mendelian randomization (MR) analyses to assess the causal association between circulating cytokines/growth factors and CAD. Methods and Results The instrumental variables for 28 circulating cytokines and growth factors were identified from a genome‐wide association study of 8293 European participants. Summary‐level data on CAD were derived from a large genome‐wide association study (71 602 cases and 260 875 controls). We used the inverse‐variance‐weighted and Wald ratio methods as our main MR methods. The weighted median, simple median, maximum likelihood, MR pleiotropy residual sum and outlier, and MR‐Egger methods were performed as sensitivity analyses. Genetic colocalization analyses were conducted to validate the robustness of our MR findings. We found that genetically predicted circulating levels of macrophage migration inhibitory factor were associated with an increased risk of CAD at the Bonferroni‐adjusted level of significance (P

Existing reporting checklists lack the necessary level of detail and comprehensiveness to be used in guidelines on Chinese patent medicines (CPM). This study aims to develop a reporting guidance for CPM guidelines based on the Reporting Items of Practice Guidelines in Healthcare (RIGHT) statement. We extracted information from CPM guidelines, existing reporting standards for traditional Chinese medicine (TCM), and the RIGHT statement and its extensions to form the initial pool of reporting items for CPM guidelines. Seventeen experts from diverse disciplines participated in two rounds of Delphi process to refine and clarify the items. Finally, 18 authoritative consultants in the field of TCM and reporting guidelines reviewed and approved the RIGHT for CPM checklist. We added 16 new items and modified two items of the original RIGHT statement to form the RIGHT for CPM checklist, which contains 51 items grouped into seven sections and 23 topics. The new and revised items are distributed across four sections (Basic information, Background, Evidence, and Recommendations) and seven topics: title/subtitle (one new and one revised item), Registration information (one new item), Brief description of the health problem (four new items), Guideline development groups (one revised item), Health care questions (two new items), Recommendations (two new items), and Rationale/explanation for recommendations (six new items). The RIGHT for CPM checklist is committed to providing users with guidance for detailed, comprehensive and transparent reporting, and help practitioners better understand and implement CPM guidelines.

BackgroundPrior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research.ObjectiveWe aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach.Materials and methodsWe selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn’s disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation.ResultsGenetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn’s disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines.ConclusionOur study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.

Abstract Background Growing evidence has suggested that gut microbiota is closely related to the risk of irritable bowel syndrome (IBS), but whether there is a causal effect remains unknown. We adopted a Mendelian randomization (MR) approach to evaluate the potential causal relationships between gut microbiota and the risk of IBS. Methods Genetic instrumental variables for gut microbiota were identified from a genome-wide association study (GWAS) of 18,340 participants. Summary statistics of IBS were drawn from a GWAS including 53,400 cases and 433,201 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, reverse MR analysis was performed to evaluate the possibility of reverse causation. Results We identified suggestive associations between three bacterial traits and the risk of IBS (odds ratio (OR): 1.08; 95% confidence interval (CI): 1.02, 1.15; p = 0.011 for phylum Actinobacteria; OR: 0.95; 95% CI: 0.91, 1.00; p = 0.030 for genus Eisenbergiella and OR: 1.10; 95% CI: 1.03, 1.18; p = 0.005 for genus Flavonifractor). The results of sensitivity analyses for these bacterial traits were consistent. We did not find statistically significant associations between IBS and these three bacterial traits in the reverse MR analysis. Conclusions Our systematic analyses provide evidence to support a potential causal relationship between several gut microbiota taxa and the risk of IBS. More studies are required to show how the gut microbiota affects the development of IBS.

Abstract Frailty causes emerging global health burden due to its high prevalence and mortality. In this study, we used Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and frailty in ageing. Using inverse-variance weighted (IVW) method, genetically predicted smoking initiation was associated with an increased risk of frailty in ageing (odd ratio (OR) 1.23, 95% confidence interval (CI) 1.19–1.27, P = 3.21 × 10–39). Similarly, per year increase in age of initiation of regular smoking was associated with a 25% decrease in the risk of frailty (95% CI 7–39%, P = 7.79 × 10–3, per year), while higher number of cigarettes per day was associated with a 12% increased risk (95% CI 4–20%, P = 1.76 × 10–3). Compared with former smokers, current smokers were associated with an increased risk of frailty (OR 1.12, 95% CI 1.02–1.22, P = 0.01). Lifetime smoking was associated with a 46% higher risk of frailty (95% CI 37–56%, P = 2.63 × 10–29). Sensitivity analysis using alternative MR methods yielded similar results. Our study indicates that genetic predisposition to smoking is associated with the risk of frailty in ageing. Further studies are warranted to examine the exact role of smoking in the development of frailty.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is accompanied by muscle weakness and muscle atrophy, typically resulting in death within 3–5 years from the disease occurrence. Though the cause of ALS remains unclear, increasing evidence has suggested that inflammation is involved in the pathogenesis of ALS. Thus, we performed two-sample Mendelian randomization (MR) analyses to estimate the associations of circulating levels of cytokines and growth factors with the risk of ALS. Methods Genetic instrumental variables for circulating cytokines and growth factors were identified from a genome-wide association study (GWAS) of 8293 European participants. Summary statistics of ALS were obtained from a GWAS including 20,806 ALS cases and 59,804 controls of European ancestry. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the simple-median method, weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, a reverse MR analysis was performed to assess the possibility of reverse causation between ALS and the cytokines that we identified. Results After Bonferroni correction, genetically predicted circulating level of basic fibroblast growth factor (FGF-basic) was suggestively associated with a lower risk of ALS [odds ratio (OR): 0.74, 95% confidence interval (95% CI): 0.60–0.92, P = 0.007]. We also observed suggestive evidence that interferon gamma-induced protein 10 (IP-10) was associated with a 10% higher risk of ALS (OR: 1.10, 95% CI: 1.03–1.17, P = 0.005) in the primary study. The results of sensitivity analyses were consistent. Conclusions Our systematic MR analyses provided suggestive evidence to support causal associations of circulating FGF-basic and IP-10 with the risk of ALS. More studies are warranted to explore how these cytokines may affect the development of ALS.

BackgroundEvidence from observational studies on the association of folate and vitamin B12 with autoimmune diseases are conflicting.ObjectiveWe aimed to investigate the relationship of folate and vitamin B12 with autoimmune diseases using Mendelian randomization (MR).Materials and methodsWe selected single-nucleotide polymorphisms associated with folate and vitamin B12 at the genome-wide significance level. Summary-level data for four common autoimmune diseases (vitiligo, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus) were obtained from large-scale genome-wide association studies, with a sample size of 44,266, 86,640, 58,284, and 23,210, respectively. MR analyses were conducted using the inverse variance weighted (IVW) approach, and sensitivity analyses were further performed to test the robustness.ResultsWe found that a higher genetically determined serum folate level per one standard deviation (SD) was associated with a decreased risk of vitiligo by the IVW method [odds ratios (OR) = 0.47; 95% confidence interval (CI): 0.32–0.69; P = 1.33 × 10-4]. Sensitivity analyses using alternative methods showed similar associations, and no evidence of pleiotropy was detected by MR-Egger regression (P = 0.919). In addition, we observed that vitamin B12 per one SD was positively associated with IBD (IVW: OR = 1.14, 95% CI: 1.03–1.26, P = 0.010; maximum likelihood: OR = 1.14, 95% CI: 1.01–1.29, P = 0.035; MR-PRESSO: OR = 1.14, 95% CI:1.01–1.28, P =0.037), while the association was not significant after Bonferroni correction.ConclusionThe study provides convincing evidence for an inverse association between serum folate level and risk of vitiligo. Further studies are warranted to elucidate the possible association between vitamin B12 and risk of IBD.

Abstract The purpose of this study is to investigate the potential causal relationships between blood pressure and inflammatory bowel disease (IBD) by using the bidirectional Mendelian randomization (MR) approach. Summary‐level data for blood pressure was extracted from the hitherto largest genome‐wide study (GWAS) with 759 601 participants of European‐descent. We used 56 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for blood pressure. Summary statistics for IBD were derived from a GWAS with an overall 59 957 participants of European ancestry, of which 109 IVs were selected. Several robust analytical methods, including inverse‐variance weighted (IVW) method, weighted‐median method, MR‐Egger regression, MR‐PRESSO test, maximum likelihood method, “leave‐one‐out” and multivariable MR analysis were used to evaluate the causal associations between blood pressure and IBD. Genetically predicted higher systolic blood pressure (SBP) was associated with an increased risk of IBD (odds ratio (OR) = 1.05, 95% confidence interval (CI):1.02–1.08, P = .001 by IVW). Subgroup analysis showed that higher SBP was positively associated with Crohn's disease (CD) (OR = 1.06, 95% CI:1.03–1.09, P = 9.18 × 10−5) and ulcerative colitis (UC) (OR = 1.05, 95% CI:1.01–1.09, P = .017) risk, respectively. In reverse‐direction MR analysis, the authors observed no evidence for the causal effect of IBD on blood pressure. Our findings suggested that high SBP was associated with an increased risk of IBD (for both UC and CD). Further studies are required to clarify the underlying mechanism of this causal association.

Background: Observational studies have reported that individuals diagnosed with polycystic ovary syndrome (PCOS) face a heightened vulnerability to developing post-traumatic stress disorder (PTSD). However, it is unclear whether this relationship is causal. Consequently, we implemented a bidirectional Mendelian randomization (MR) analysis to examine the empirical causal association of PCOS and PTSD. Methods: We acquired genetic association data for PCOS through a comprehensive meta-analysis from several large-scale genome-wide association studies (GWASs), which enrolled 10,074 cases and 103,164 controls. For PTSD, we obtained data from a GWAS performed by the Psychiatric Genomics Consortium Posttraumatic Stress Disorder (PGC-PTSD) group. The study included a total of 23,212 cases of PTSD and 151,447 controls of European ancestry. For both PCOS and PTSD, we carefully selected genetic instruments that met the rigorous significance threshold (p < 5 × 10-8, r2 < 0.01). To investigate the causal association between PCOS and PTSD, we conducted bidirectional Mendelian randomization (MR) analyses. The primary analysis employed the inverse-variance weighted (IVW) method, complemented by alternative MR approaches such as the maximum-likelihood method, MR-Egger regression, Mendelian randomization-Robust Adjusted Profile Score (MR-RAPS), and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Sensitivity analyses were also carried out to verify the robustness of this association. Results: In this study, we identified and utilized 14 genetic variants as instruments for PCOS, while 2 genetic variants were selected as instruments for PTSD. Our findings demonstrated that a genetic predisposition to PCOS was significantly associated with an elevated risk of developing PTSD (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.03–1.19, p = 7.27 × 10-3 for IVW). MR-Egger regression analysis was performed, and the results did not provide evidence of directional pleiotropy (p intercept = 0.187). Sensitivity analyses utilizing alternative MR methods consistently yielded similar results, supporting the robustness of our findings. Furthermore, in the reverse MR analysis, we observed no significant association between genetic predisposition to PTSD and the risk of developing PCOS (OR = 1.15, 95% CI: 0.69–1.91, p = 0.586 for IVW). Comparable null associations were also observed when alternative MR methods were employed. Conclusions: Through a genetic epidemiological approach, we found that genetic predisposition to PCOS was associated with an increased risk of PTSD, suggesting a potential causal relationship between PCOS and PTSD. Nonetheless, further investigation is necessary to elucidate the underlying mechanism through which PCOS contributes to the development of PTSD.

BackgroundEarly weaning-induced stress impairs the intestinal barrier function and adversely affects the health of piglet. Probiotics can be used to prevent and treat various intestinal diseases. Lactobacillus rhamnosus GG (LGG) has an LuxS/AI-2 quorum sensing (QS) system that senses environmental changes through chemical signaling molecules. The aim of the study was to explore whether luxS mutant affects the protective role of LGG in the gut barrier of weaned piglets by comparing the luxS mutant (ΔluxS) with its wild-type (WT).MethodsNewborn piglets were orally administered with WT and ΔluxS at dosage of 109 CFU, respectively. Accordingly, newborn piglets in the Con group were orally administered with PBS. Piglets were weaned on day 21 and euthanized on day 24, three days following weaning.ResultsSupplementation of ΔluxS in advance significantly boosted the relative abundances of healthy microbes (including Catenibacterium, Eubacterium, Lachnospiraceae and Bifidobacterium). WT and ΔluxS maintain intestinal barrier function mainly by promoting intestinal villus to crypt ratio (VCR), occludin protein expression and mucus secretion (P

IntroductionObservational studies have reported a relationship between iron status and the risk of prostate cancer. However, it remains uncertain whether the association is causal or due to confounding or reverse causality. To further clarify the underlying causal relationship, we conducted a Mendelian randomization (MR) analysis.MethodsWe selected three genetic variants (rs1800562, rs1799945, and rs855791) closely correlated with four iron status biomarkers (serum iron, log-transformed ferritin, transferrin saturation, and transferrin) as instrumental variables. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium including 79,148 cases and 61,106 controls of European ancestry. The inverse-variance weighted (IVW) method was conducted primarily to estimate the association of genetically predicted iron status and the risk of prostate cancer, supplemented with simple-median, weighted-median and maximum-likelihood methods as sensitivity analysis. MR-Egger regression was used to detect directional pleiotropy. We also conducted a meta-analysis of observational studies to assess the associations between iron status and the risk of prostate cancer.ResultsGenetically predicted increased iron status was associated with the decreased risk of prostate cancer, with odds ratio of 0.91 [95% confidence interval (CI): 0.84, 0.99; P = 0.035] for serum iron, 0.81 (95% CI: 0.65, 1.00; P = 0.046) for log- transformed ferritin, 0.94 (95% CI: 0.88, 0.99; P = 0.029) for transferrin saturation, and 1.15 (95% CI: 0.98, 1.35; P = 0.084) for transferrin (with higher transferrin levels representing lower systemic iron status), using the inverse-variance weighted method. Sensitivity analyses produced consistent associations, and MR-Egger regression indicated no potential pleiotropy. Our replication analysis based on FinnGen research project showed compatible results with our main analysis. Results from our meta-analysis similarly showed that serum ferritin [standardized mean difference (SMD): −1.25; 95% CI: −2.34, −0.16; P = 0.024] and transferrin saturation (SMD: −1.19; 95% CI: −2.34, −0.05; P = 0.042) were lower in patients with prostate cancer compared with that in controls.DiscussionOur study suggests a protective role of iron in the risk of prostate cancer, further investigations are required to clarify the underlying mechanisms.

Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis.Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption.Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05–1.12, p = 1.51 × 10–5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27–1.52, p = 5.29 × 10–13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99–1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98–1.05, p = 0.545 by IVW).Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.

BackgroundBeef is common in daily diet, but its association with the risk of rheumatoid arthritis (RA) remains uncertain. The objective of this study is to explore the relationship between beef intake and the risk of RA.Materials and methodsWe investigated the association between beef intake and risk of RA by multivariate logistic regression, based on the National Health and Nutrition Examination Survey (NHANES) 1999–2016 involving 9,618 participants. The dose–response relationship between beef intake and RA was explored as well. Furthermore, we performed Mendelian randomization (MR) analysis to examine the causal effect of beef intake on RA. Genetic instruments for beef intake were selected from a genome-wide association study (GWAS) including 335,576 individuals from the UK Biobank study, and summary statistics relating to RA were obtained from a GWAS meta-analysis of 14,361 RA patients and 43,923 controls. The inverse-variance weighted (IVW) approach was used to estimate the causal association, and MR-Egger regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test were applied to evaluate the pleiotropy and outliers.ResultsCompared with the lowest quintile (0 to ≤33.50 g/d), beef intake was found to be significantly associated with the risk of RA [odds ratio (OR): 1.94; 95% confidence interval (CI): 1.20–3.12] in the third quintile (50.26 to ≤76.50 g/d). Moreover, a reversed “U” dose–response relationship between beef and RA (Pnon–linearity = 0.023) was found. In the MR analysis, beef intake was associated with an increased risk of RA (OR: 3.05; 95% CI: 1.11–8.35; P = 0.030) by the IVW method. The results from MR-Egger regression and MR-PRESSO test showed that there were no pleiotropic variations and outliers.ConclusionThis study indicated that there is suggestive evidence to support the causal effect of beef intake on the risk of RA, while further studies are warranted to elucidate the exact association.

BackgroundIntestinal dysbiosis is associated with inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn’s disease (CD), two subtypes of IBD, are characterized by unique microbial signatures, respectively. However, it is unclear whether UC or CD has a specific causal relationship with gut microbiota.ObjectiveTo investigate the potential causal associations between gut microbial genera and IBD, UC, or CD, two-sample Mendelian randomization (MR) analyses were conducted.Materials and MethodsWe obtained genome-wide association study (GWAS) summary statistics of gut microbiota and IBD, UC, or CD from published GWASs. Two-sample MR analyses were performed to identify potential causal gut microbial genera for IBD, UC, and CD using the inverse-variance weighted (IVW) method. Sensitivity analyses were also conducted to validate the robustness of the primary results of the MR analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation.ResultsCombining the results from the primary and sensitivity analyses, six bacterial genera were associated with the risk of IBD, UC, or CD in the IVW method. Briefly, Eubacterium ventriosum group was associated with a lower risk of IBD (P=0.011) and UC (P=1.00×10-4), whereas Coprococcus 2 was associated with a higher risk of IBD (P=0.022) and UC (P=0.007). In addition, we found a positive association between Oxalobacter with IBD (P=0.001) and CD (P=0.002), and Ruminococcaceae UCG014 with IBD (P=0.005) and CD (P=0.007). We also noticed a negative association between Enterorhabdus (P=0.044) and IBD, and between Lachnospiraceae UCG001 (P=0.023) and CD. We did not find causal effects of IBD, UC, or CD on these bacterial genera in the reverse MR analysis.ConclusionThis study expanded gut microbial genera that were causally associated with the risk of IBD, and also revealed specificity-gut microbial genera for UC or CD.

BackgroundInflammation plays a pivotal role in the pathogenesis of cancer. Though previous studies have reported a link between several inflammatory biomarkers and risk of certain types of cancer, there is a lack of systematic investigation. Therefore, we aimed to assess the role of circulating cytokines on the risk of cancer using a two-sample Mendelian randomization (MR) approach.MethodWe used genetic variants associated with circulating levels of cytokines from a meta-analysis of genome-wide association studies (GWASs) of 8,293 Finns as instrumental variables. Summary level data of 20 site-specific cancer were obtained from the UK BioBank including up to 456,348 participants of European ancestry. We performed two-sample MR analyses using inverse-variance weighted (IVW) method as the main method, followed by weighted-median and likelihood-based methods as sensitivity analysis. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.Results224 genetic variants associated with 27 circulating cytokines achieving genome-wide significance (P

Classical swine fever virus (CSFV) is a major animal pathogen threatening the global pork industry. To date, numerous anti-CSFV monoclonal antibodies (mAbs) and their recognizing epitopes have been reported. However, few mAbs were systematically characterized for the capacity to differentiate field CSFV isolates from CSF vaccine strains, and the molecular basis associated with antigenic differences between vaccines and field isolates is still largely unknown. In the present study, recombinant CSFV structural glycoproteins E2 of both virulent and vaccine strains and Erns of vaccine strain were expressed using eukaryotic cells and murine mAbs generated against E2 and Erns. After serial screening and cloning of the hybridomas, the viral spectra of mAbs were respectively determined by indirect fluorescent antibody assay (IFA) using 108 CSFVs, followed by Western blot analysis using expressed glycoproteins of all CSFV sub-genotypes including vaccine strains. The antigenic structures recognized by these mAbs were characterized by epitope mapping using truncated, chimeric, and site-directed mutated E2 and Erns proteins. We have identified two vaccine-specific, one field isolate-specific, and two universal CSFV-specific mAbs and five novel conformational epitopes with critical amino acid (aa) motifs that are associated with these five mAbs: 213EPD215, 271RXGP274, and 37LXLNDG42 on E2 and 38CKGVP42, W81, and D100/V107 on Erns. Particularly, E213 of E2 is field isolate-specific, while N40 of E2 and D100/V107 of Erns are vaccine strain-specific. Results from our study further indicate that N40D of E2 mutation in field strains was likely produced under positive selection associated with long-term mass vaccination, leading to CSFV evasion of host immune response. Taking together, this study provides new insights into the antigenic structure of CSFV E2 and Erns and the differentiating mAbs will contribute to the development of a diagnostic strategy to differentiate C-strain vaccination from natural infection (DIVA) of CSFV in terms of elimination of CSF in China.

Abstract Background The aim of this study was to quantitatively summarize the available evidence on the association of breastfeeding with the risk of childhood cancer. Methods A literature search of PubMed and Embase databases was performed to identify eligible observational studies published from inception to July 17, 2020. The categorical and dose-response meta-analysis was conducted by pooling relative risk (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression and stratification analysis. Sensitivity analysis and publication bias test were also carried out. Results Forty-five articles involving 475,579 individuals were included in the meta-analysis. Among the thirty-three studies on the association between breastfeeding and risk of childhood leukemia, the pooled risk estimates were 0.77 (95% CI, 0.65–0.91) and 0.77 (95% CI 0.63–0.94) for ever versus non/occasional breastfeeding and longest versus shortest breastfeeding duration group, respectively. There was clear indication for non-linear dose-response relationship between breastfeeding duration and the risk of childhood leukemia (P non-linear

Abstract Background The disability rate associated with rheumatoid arthritis (RA) ranks high among inflammatory joint diseases. However, the cause and potential molecular events are as yet not clear. Here, we aimed to identify differentially expressed genes (DEGs), pathways and immune infiltration involved in RA utilizing integrated bioinformatics analysis and investigating potential molecular mechanisms. Materials and methods The expression profiles of GSE55235, GSE55457, GSE55584 and GSE77298 were downloaded from the Gene Expression Omnibus database, which contained 76 synovial membrane samples, including 49 RA samples and 27 normal controls. The microarray datasets were consolidated and DEGs were acquired and further analyzed by bioinformatics techniques. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed using R (version 3.6.1) software, respectively. The protein-protein interaction (PPI) network of DEGs were developed utilizing the STRING database. Finally, the CIBERSORT was used to evaluate the infiltration of immune cells in RA. Results A total of 828 DEGs were recognized, with 758 up-regulated and 70 down-regulated. GO and KEGG pathway analyses demonstrated that these DEGs focused primarily on cytokine receptor activity and relevant signaling pathways. The 30 most firmly related genes among DEGs were identified from the PPI network. The principal component analysis showed that there was a significant difference between the two tissues in infiltration immune. Conclusion This study shows that screening for DEGs, pathways and immune infiltration utilizing integrated bioinformatics analyses could aid in the comprehension of the molecular mechanisms involved in RA development. Besides, our study provides valuable data related to DEGs, pathways and immune infiltration of RA and may provide new insight into the understanding of molecular mechanisms.

Aim: The prevalence of the use of electronic cigarettes (e-cigarettes) has grown rapidly in the past decade in the United States. While numerous studies have demonstrated combustible cigarette is closely associated with an increased risk of arthritis diseases, little is known about the effect of e-cigarette usage on inflammatory arthritis diseases. We aimed to determinate if e-cigarette usage is associated with an increased risk of inflammatory arthritis.Methods: Data were obtained from the Behavioral Risk Factor Surveillance System, which is the largest national telephone-based survey of randomly sampled adults in the United States. A total of 924,882 participants with information on e-cigarette usage and inflammatory arthritis were included. We used multivariable logistic regression to estimate the risk of arthritis associated with e-cigarette usage.Results: Of the 924,882 participants, there were 30,569 (3.3%) current e-cigarette users, and 314,190 (25.9%) reported to have inflammatory arthritis diseases. In the fully adjusted model, we observed that the odds ratio (OR) (95% confidence interval) of inflammatory arthritis diseases was 1.81 (95% CI, 1.70-1.93) for current e-cigarette users compared with never e-cigarette users. The ORs of inflammatory arthritis diseases were 1.31 (95% CI, 1.18-1.47), and 1.55 (95% CI, 1.42-1.69) among sole e-cigarette and dual users compared with never e-cigarette users, respectively.Conclusions: This is the first study to observe a cross-sectional association between e-cigarette usage and inflammatory arthritis diseases, and the findings were consistent in both sole-e-cigarette users and dual users. Our findings provide evidence that e-cigarette usage might be an important risk factor for arthritis diseases, which may have regulatory implications for e-cigarette control.

Abstract Background The early life risk factors of childhood obesity among preterm infants are unclear and little is known about the influence of the feeding practices. We aimed to identify early life risk factors for childhood overweight/obesity among preterm infants and to determine feeding practices that could modify the identified risk factors. Methods A total of 338,413 mother-child pairs were enrolled in the Jiaxing Birth Cohort (1999 to 2013), and 2125 eligible singleton preterm born children were included for analyses. We obtained data on health examination, anthropometric measurement, lifestyle, and dietary habits of each participant at their visits to clinics. An interpretable machine learning-based analytic framework was used to identify early life predictors for childhood overweight/obesity, and Poisson regression was used to examine the associations between feeding practices and the identified leading predictor. Results Of the eligible 2125 preterm infants (863 [40.6%] girls), 274 (12.9%) developed overweight/obesity at age 4–7 years. We summarized early life variables into 25 features and identified two most important features as predictors for childhood overweight/obesity: trajectory of infant BMI (body mass index) Z-score change during the first year of corrected age and maternal BMI at enrollment. According to the impacts of different BMI Z-score trajectories on the outcome, we classified this feature into the favored and unfavored trajectories. Compared with early introduction of solid foods (≤ 3 months of corrected age), introducing solid foods after 6 months of corrected age was significantly associated with 11% lower risk (risk ratio, 0.89; 95% CI, 0.82 to 0.97) of being in the unfavored trajectory. Conclusions The trajectory of BMI Z-score change within the first year of life is the most important predictor for childhood overweight/obesity among preterm infants. Introducing solid foods after 6 months of corrected age is a recommended feeding practice for mitigating the risk of being in the unfavored trajectory.

Abstract Purpose Psychological well-beings of left-behind children (LBC) in rural areas of China remain under-studied. In this cross-sectional study, we aimed to explore the subjective well-being (SWB) in LBC and its associated factors in a rural area in eastern China. Methods Stratified random cluster sampling was used to select middle school and high school students in Qingyuan County of Zhejiang Province. Relevant information including sociodemographic characteristics was collected from each participant using an organized questionnaire. SWB was measured using the modified scale developed for Chinese adolescents. Univariable and multivariable regression analyses were performed using R version 3.3.0. Results A total of 1086 children were recruited and examined in the current analysis, with 365 (33.61%) being left-behind. Compared with non-left-behind children (NLBC), LBC had significantly lower scores in family satisfaction (P = 0.003) and environment satisfaction (P = 0.020). Multivariable regression analysis uncovered that frequent parent–child communication was associated with high positive affect (P = 0.003) and life satisfaction (P

Abstract Background Although observational epidemiological studies have found that smoking is positively associated with risk of rheumatoid arthritis (RA), assessing the causality of this relationship has remained elusive because conventional observational studies are susceptible to bias such as confounding and reverse causation. Here, we applied the Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and risk of RA. Methods Summary statistics data for RA were obtained from a meta-analysis of genome-wide association studies (GWAS), including 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables (IV) and the genetic association estimates for smoking initiation and lifetime smoking were obtained from a GWAS meta-analysis including 1,232,091 individuals and a GWAS of 462,690 individuals of European ancestry, respectively. MR analyses were performed using the inverse-variance weighted (IVW) method and supplemented with the weighted-median method. Potential pleiotropy was assessed using the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test and MR-Egger regression. Sensitivity analyses were further performed to test the robustness of the association. Results We found that compared with never smokers, genetic predisposition to smoking initiation was positively associated with risk of RA (odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.15–1.52, P = 9.17 × 10−5 using the IVW method). Similarly, genetically predicted lifetime smoking was associated with an increased risk of RA (OR = 1.55, 95% CI = 1.13–2.14, P = 0.007). Sensitivity analyses using alternative MR methods and different sets of IVs produced similar results, suggesting the robustness of our findings. Conclusions These results provide support for a causal association between smoking and increased risk of RA. Further studies are warranted to explain the underlying mechanisms of smoking in the development of RA.

Although gut dysbiosis had been demonstrated to be an important factor affecting hyperuricemia (HUA) and gout, little is known for its potential mechanistic connections. In this study, Uox-KO mice model that with spontaneously developed pronounced HUA and urate nephropathy was used to explore the pathophysiologic mechanism of microbiota alterations in HUA and gout with integrated multi-omics analysis. 16S rRNA gene sequencing was performed to characterize the characteristic bacteria, and untargeted LC/MS analysis was applied to reveal the featured metabolites. Our results showed there was a significant shift in gut microbiota composition and function in Uox-KO mice compared to WT mice and apparent metabolomics differences between the two groups. Among them, amino acids metabolism appears to play a critical role. Correlation analysis further revealed that the characteristic metabolites were strongly influenced by the discrepant bacterial genera. Furthermore, impairment of intestinal integrity and profound alterations in the profile of solute carrier family resulted in dysregulation of amino acids transportation, which subsequently impacted serum uric acid level and CD4+ Th17 driven inflammation. Together, these data indicate that gut dysbiosis promotes purine metabolism disorder and inflammation in Uox-KO mice. Remodeling the gut microbiota is a promising strategy to combat HUA and gout.

Background: Accumulation of inflammatory leukocytes in articular tissues is the hallmark feature of rheumatoid arthritis (RA). Increasing evidence from observational studies has suggested that several cytokines may be involved in the development of RA. However, traditional observational studies are susceptible to bias from confounding and reverse causation; therefore, the potential causal relationships of individual cytokines with the risk of RA remain elusive.Objective: In this study, we evaluated whether genetically determined circulating levels of cytokines were associated with the risk of RA by performing Mendelian randomization (MR).Methods: We identified single nucleotide polymorphisms (SNPs) associated with circulating levels of cytokines and growth factors from a genome-wide association study (GWAS) including 8,293 participants of Finnish ancestry as instrumental variables (IVs). The association estimates of these IVs with the risk of RA were obtained from a GWAS meta-analysis including 14,361 RA cases and 43,923 controls of European ancestry. We conducted a series of MR analyses to assess the relationship between genetically determined circulating cytokines and the risk of RA, including the random-effects inverse variance-weighted, weighted-median, MR-Egger regression, and MR pleiotropy residual sum and outlier tests. For potential cytokine-RA associations supported by MR evidence, sensitivity analyses were further performed using restricted IV sets of SNPs with colocalization evidence and that excluding pleiotropic SNPs.Results: In the primary MR analysis, there was a suggestive inverse association between genetically determined circulating level of macrophage inflammatory protein-1β (MIP-1b) and the risk of RA [odds ratio (OR): 0.95, 95% confidence interval (CI) = 0.92-0.99, p = 0.016]. The effect estimates were similar in alternative MR analyses. Among SNPs used as IVs for MIP-1b, we found 92 SNPs without documented pleiotropy and three SNPs with evidence of colocalization. The association of MIP-1b with RA from sensitivity analyses using these two sets of restricted IVs remained stable.Conclusion: Our study suggests that genetically determined elevated circulating level of MIP-1b may be associated with a lower risk of RA. Further studies are warranted to determine how MIP-1b and related pathways may contribute to the development of RA.

Background: The association between circulating vitamin D levels and risk of vitiligo was inconsistent among observational studies, and whether these observed associations were causal remained unclear. Therefore, we aimed to evaluate the effect of vitamin D on the risk of vitiigo using meta-analysis and Mendelian randomization (MR).Methods: At the meta-analysis stage, literature search was performed in PubMed and Web of Science to identify eligible observational studies examining the association of circulating 25-hydroxyvitamin D [25(OH)D] or 25-hydroxyvitamin D3 [25(OH)D3] levels with risk of vitiligo up to April 30, 2021. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) of 25(OH)D and 25(OH)D3 in patients with vitiligo relative to controls were pooled. Then at the MR stage, genetic instruments for circulating 25(OH)D (N = 120,618) and 25(OH)D3 (N = 40,562) levels were selected from a meta-analysis of genome-wide association studies (GWAS) of European descent, and summary statistics of vitiligo were obtained from a meta-analysis of three GWASs including 4,680 cases and 39,586 controls. We used inverse-variance weighted (IVW) as main method, followed by weighted-median and likelihood-based methods. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.Results: In the meta-analysis, patients with vitiligo had a lower level of circulating 25(OH)D compared with controls [SMD = −1.40; 95% confidence interval (CI): −1.91, −0.89; P < 0.001], while no statistically significant difference of 25(OH)D3 between vitiligo cases and controls was found (SMD = −0.63; 95% CI: −1.29, 0.04; P = 0.064). However, in the MR analyses, genetically predicted 25(OH)D [odds ratio (OR) = 0.93, 95% CI = 0.66–1.31, P = 0.66] and 25(OH)D3 levels (OR = 0.95, 95% CI = 0.80–1.14, P = 0.60) had null associations with risk of vitiligo using the IVW method. Sensitivity analyses using alternative MR methods and instrumental variables (IV) sets obtained consistent results, and no evidence of pleiotropy or outliers was observed.Conclusion: Our study provided no convincing evidence for a causal effect of 25(OH)D or 25(OH)D3 levels on the risk of vitiligo. Further longitudinal and experimental studies, as well as functional studies are warranted to elucidate the role of vitamin D in the development of vitiligo.

Childhood is an important period for individuals’ psychological development. Due to long-term separation from the parents, left-behind children (LBC) more easily develop deviation in cognition and abnormal personality. In this study, we aimed to explore the status of psychological resilience among LBC in a rural area of eastern China. We carried out a cross-sectional survey including middle and high school students from Qingyuan County of Zhejiang Province. Psychological resilience was measured using a modified scale developed for Chinese children. Data from a total of 1086 participants were collected, and the mean ± standard deviation score of psychological resilience was 4.11 ± 0.42. Multivariable linear regression analyses revealed that being a class leader (p = 0.010) and having high self-evaluation of academic performance (p < 0.001) were related with psychological resilience. Moreover, high contact frequency between parents and children (p = 0.019) was associated with better psychological resilience among LBC. In conclusion, we found that being a class leader and having high self-evaluation of academic performance were associated with better psychological resilience among the children in this rural area and contact between parent and child was an essential factor associated with psychological resilience among LBC.

Background: The factors affecting the safety and efficacy of aminophylline use in the treatment of apnea of prematurity (AOP) in the neonatal intensive care unit (NICU) are not clear. In this study, we aimed to evaluate the potential factors affecting the efficacy and safety of aminophylline in AOP treatment at standard doses and to determine appropriate patients for this therapy. Methods: Over a 3-year period (January 2012 to December 2014), the medical records of 206 preterm infants with apnea who were admitted to the NICU of our hospital to receive aminophylline infusions were retrospectively reviewed. These infants were subjected to routine theophylline monitoring by reversed-phase high performance liquid chromatography. The primary outcome measures were the efficacy of aminophylline treatment and adverse reactions observed upon administration. Results: One-hundred and twenty-seven (61.65%) infants were considered to have undergone effective therapy and classified accordingly. Gestational age, body weight at the initiation of aminophylline, and serum theophylline concentration were identified as protective factors of therapeutic efficacy. Receiver operating characteristic (ROC) analysis indicated cutoff values of 30.36 weeks for gestational age and 1.69 kg for body weight at initiation of aminophylline administration for ensuring high efficacy of aminophylline for AOP. Fifty-three (25.73%) infants had adverse reactions. Birth weight and serum concentration of theophylline were associated with an increased risk of adverse reactions, with odds ratios of 0.167 and 1.346, respectively. The ROC curves indicated a birth weight cutoff value of 1.48 kg. Conclusion: Infants with apnea and gestational age >30.36 weeks, body weight at initiation of aminophylline treatment above 1.69 kg, and birth weight >1.48 kg are suitable for treatment with aminophylline. Monitoring of serum theophylline concentration should be implemented in the absence of clinical response or in case of suspected adverse reactions. Key Words: aminophylline, apnea of prematurity, concentration, efficacy, factor

Abstract Background The association of ABO blood groups with gastric cancer risk was proposed decades ago, but the results have been inconsistent. Methods We used two single nucleotide polymorphisms to determine ABO genotype in 4932 gastric cancer cases and 6158 controls of Chinese descent, and evaluated the associations of ABO blood groups and genotypes with risk of gastric cancer using multivariable logistic regression models. We also systematically reviewed published literature and performed a meta-analysis of all relevant studies. Results In the case-control study, compared with blood group O, both blood group A and AB were associated with increased gastric cancer risk (for group A, odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.02–1.24; for group AB, OR = 1.18, 95% CI: 1.02–1.36, respectively). Analyses of ABO genotypes revealed associations of AO and AB with risk of gastric cancer compared with OO genotype. Consistent with the case-control study, meta-analysis of 40 studies including 33,613 cases and 2,431,327 controls demonstrated that blood group A (OR = 1.19, 95% CI: 1.13–1.25) and AB (OR = 1.09, 95% CI: 1.03–1.16) were associated with increased risk of gastric cancer. Conclusions Our analyses validated the association of blood group A with risk of gastric cancer, and suggested that blood group AB was also associated with gastric cancer risk. Functional investigations are warranted to elucidate the exact mechanism of ABO blood groups in gastric carcinogenesis.

Background: Evidence from observation studies has implied an association between polycystic ovary syndrome (PCOS) and risk of depression. Nevertheless, it remains elusive if the identified correlation is causal or owing to biases in observation researches. Hence, we utilized a bidirectional two-sample Mendelian randomization (MR) method to evaluate the potential causal relationship between PCOS and depression. Methods: Genetic instruments for PCOS and depression were acquired from two large genome-wide association studies (GWASs). MR analyses were completed via the inverse-variance weighted (IVW) method and weighted median approaches. The underlying pleiotropy was tested by MR-Egger regression, and leave-one-out method was used to evaluate the stability of MR results. Results: Using the IVW analyses (odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.01–1.06, p < 0.01) and weighted median approach (OR = 1.04, 95% CI = 1.00–1.08, p < 0.05), we found that PCOS was related to an elevated risk of depression. MR-Egger regression did not identify potential horizontal pleiotropy. Sensitivity analyses using leave-one-out method also provided supportive evidence. In the reverse MR analyses, we did not observe causal effect of depression on PCOS (p > 0.05). Conclusions: The present study provides evidence to support a potential causal association between PCOS and an elevated risk of depression. Hence, early psychological intervention for PCOS might show anti-depression benefits.

BackgroundObservational studies have shown an inverse association between circulating linoleic acid (LA) and risk of ischemic stroke (IS).ObjectiveThe aim of this study was to explore whether genetic variants predicting levels of circulating LA are associated with IS and its subtypes using a two-sample Mendelian randomization (MR) analysis.MethodsLA-related single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of 8,631 participants, and summary statistics of IS and IS subtypes were obtained from the MEGASTROKE consortium. MR analysis was performed using the inverse-variance weighted (IVW) method complemented with other approaches, including weighted-median, weighted-mode, MR Pleiotropy RESidual Sum and Outlier test and MR-Egger regression, to test for the robustness of the association. Moreover, we conducted bidirectional MR analysis to assess the impact of IS-associated SNPs on circulating LA levels. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsWe found that genetically predicted circulating LA levels were inversely associated with the risk of IS by the IVW method (OR = 0.98, 95% CI: 0.97–0.99, and P = 0.003). Subgroup analyses showed a statistically significant association between LA and risk of large artery stroke (LAS; OR = 0.95, 95% CI: 0.92–0.98, and P = 0.004), but not for other IS subtypes. The results were stable in sensitivity analyses, and no evidence of reverse association between LA and risk of IS, or LAS was observed.ConclusionOur study supports a potential inverse association of genetically predicted circulating LA levels with risk of IS, particularly LAS.

Objective To quantify rheumatoid arthritis (RA) cases attributable to selected non-genetic risk factors.Design National Health and Nutrition Examination Survey (NHANES) and meta-analysis.Participants US adults.Data sources The prevalence of exposure was obtained from NHANES. Weighted analysis was performed to account for the complex sampling design in NHANES. PubMed and Web of Science up to 31 March 2019 were searched to identify epidemiological studies reported the association between non-genetic risk factors and RA in US adults. Relative risk (RR) value and the corresponding CI were pooled by meta-analysis to evaluate the associations between modifiable risk factors and RA. Population attributable fraction (PAF) was calculated based on the prevalence and RR data.Results The weighted percentages of former smokers, current smokers and overweight or obese people were 24.84%, 23.93% and 63.97%, and the average alcohol consumption was 51.34 g/week. In the meta-analysis, we found that former smokers (RR 1.22, 95% CI 1.10 to 1.36) and current smokers (RR 1.47, 95% CI 1.29 to 1.68) had higher risks of RA. Overweight and obese individuals had 1.27-fold (95% CI 1.09 to 1.48) increased risk of RA. Each per 50 g/week increment of alcohol consumption was associated with 8% (95% CI 0% to 16%) reduction in the risk of RA. Therefore, PAF value of smoking was 14.00% (95% CI 8.13% to 23.33%). Excess body mass index (BMI) was found to account for 14.73% (95% CI 5.45% to 23.50%) of RA incidence. The fraction of RA risk attributed by low alcohol intake was 8.21% (95% CI 0.31% to 16.39%). Collectively, we found that 32.69% (95% CI 13.41% to 50.96%) of RA cases were attributable to smoking, overweight or obesity and low alcohol drinking.Conclusion Nearly 33% of RA incidence was attributed to smoking, excess BMI and low alcohol drinking in USA. Our findings could provide a basis for developing guidelines of RA prevention and control in USA.

BackgroundInconsistent findings from observational studies have reported that C-reactive protein (CRP) is likely associated with risk of prostate cancer. Because conventional observational studies are susceptible to confounding and reverse causality, it remains unclear whether there is a causal relationship of CRP with risk of prostate cancer.MethodsIn this study, we applied a two-sample Mendelian randomization (MR) approach to evaluate the potential causal association of circulating CRP levels with prostate cancer risk. Instrumental variables (IVs) and corresponding genetic association estimates for circulating CRP levels were obtained from a meta-analysis of genome-wide association studies (GWASs) including 204,402 participants of European descent. The genetic association estimates of these IVs with prostate cancer were obtained from a GWAS meta-analysis including 79,148 cases and 61,106 controls of European ancestry. The inverse-variance weighted (IVW) method was used as primary MR analyses, whereas in sensitivity analyses, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used to assess the presence of pleiotropy. Odd ratio (OR) and 95% CI were calculated.ResultsOverall, 58 single-nucleotide polymorphisms were used as instruments for circulating CRP levels. MR analysis suggested that genetically determined CRP levels were not associated with prostate cancer risk (OR 1.06, 95% CI 0.96 to 1.16) using the IVW method. Sensitivity analyses using alternative MR methods produced similar results (OR 1.00, 95% CI 0.93 to 1.08 for the weighted-median method; OR 1.02, 95% CI 0.95 to 1.08 for MR-PRESSO test). MR-Egger regression did not suggest evidence of directional pleiotropy (P = 0.25).ConclusionOur study found that genetically predicted circulating CRP levels were not associated with prostate cancer risk, suggesting that CRP is unlikely to be a causal factor in the development of prostate cancer.

Esophageal cancer micro environment factor WNT2 was critical in cancer metastasis. However, very little is known about WNT2 receptors and their role in the malignant progression of ESCC. The clinical significance and underlying molecular mechanisms of FZD2, one of the receptors of WNT2, was further investigated in ESCC. We found that FZD2 expression was positively correlated with WNT2 levels in clinical ESCC specimens through database analysis. Upregulated FZD2 expression was detected in 69% (69/100) of the primary ESCC cases examined, and increased FZD2 expression was significantly correlated with poor prognosis (P < 0.05). Mechanistically, FZD2 induced the migration and invasion of ESCC cells by regulating the FZD2/STAT3 signaling. In vivo xenograft experiments further revealed the metastasis-promoting role of FZD2 in ESCC. Moreover, we found that the WNT2 ligand could stabilize and phosphorylate the FZD2 receptor by attenuating FZD2 ubiquitination, leading to the activation of STAT3 signaling and the initiation of ESCC cell metastasis. Collectively, our data revealed that a novel non-canonical WNT2/FZD2/STAT3 signaling axis is critical for ESCC progression. Strategies targeting this specific signaling axis might be developed to treat patients with ESCC.

In the face of mounting global antibiotic resistance, which has become a critical clinical problem, antimicrobial peptides (AMPs) have received considerable interest as new therapeutics with the efficacy for the treatment of multidrug-resistant (MDR) infections due to their novel mechanism. However, certain inherent shortcomings such as instability seriously limit their systemic applications in the clinic. In this study, we intend to clarify the connection between three configurations of IK8 and their stability in plasma and liver S9 of various species by confirming the metabolites. The structural information of these metabolites was scanned and identified using HPLC and Q-TOF, respectively. The results found that IK8-D exhibits superior stability, compared with IK8-2D and IK8-L in plasma and liver S9 incubation, which indicated D- type amino acids could significantly increase the stability of antimicrobial peptides.

Abstract Background Bladder cancer (BCa) is the ninth most common form of cancer in the world. There is a continuing need not only for improving the accuracy of diagnostic markers but also for the development of new treatment strategies. Recent studies have shown that the renin-angiotensin system (RAS), which include the angiotensin type 1 (AT1R), type 2(AT2R), and Mas receptors, play an important role in tumorigenesis and may guide us in meeting those needs. Results In this study, we first observed that AT1R and Mas expression levels were significantly upregulated in BCa specimens while AT2R was significantly downregulated. Viral vector mediated overexpression of AT2R induced apoptosis and dramatically suppressed BCa cell proliferation in vitro, suggesting a therapeutic effect. Investigation into the mechanism revealed that the overexpression of AT2R increases the expression levels of caspase-3, caspase-8, and p38 and decreases the expression level of pErk. AT2R overexpression also leads to upregulation of 2 apoptosis-related genes (BCL2A1, TNFSF25) and downregulation of 8 apoptosis-related genes (CASP 6, CASP 9, DFFA, IGF1R, PYCARD, TNF, TNFRSF21, TNFSF10, NAIP) in transduced EJ cells as determined by PCR Array analysis. In vivo, we observed that AT2R overexpression caused significant reduction in xenograft tumors sizes by downregulation VEGF and induction of apoptosis. Conclusions Taken together, the data suggest that AT1R, AT2R or Mas could be used as a diagnostic marker of BCa and AT2R is a promising novel target gene for BCa gene therapy.

Abstract: Thrombotic thrombocytopenic purpura (TTP), a potentially fatal blood clot disorder, is primarily caused by severe deficiency of plasma ADAMTS13 activity resulting from acquired autoantibodies. Plasma exchange is the only effective initial therapy. However, the high mortality rate and the complications associated with plasma exchange therapy remain a major concern. To address unmet clinical needs, therapeutic efficacies of anfibatide, a snake venom-derived platelet glycoprotein Ib antagonist, in murine models of spontaneous thrombocytopenia and shigatoxin-induced TTP were determined. A light scattering platelet aggregometry, microfluidic shear-based assay, and murine models of TTP were used in the study. We showed that purified anfibatide inhibits ristocetin- or botrocetin-induced human or murine platelet agglutination in the presence of von Willebrand factor in a concentration-dependent manner. Anfibatide could also dramatically inhibit the adhesion and aggregation of murine and human platelets on a collagen surface under arterial shear stress, in the presence or absence of plasma ADAMTS13 activity. Most importantly, we demonstrated that an intraperitoneal administration of anfibatide at the dose of 60 ng/g body weight twice daily mitigated spontaneous thrombocytopenia and prevented shigatoxin-induced TTP in Adamts13−/− and disease-susceptible mice (CAST/Ei strain). Thus, we conclude that anfibatide, when administered at the optimal dosage, route, and interval, is efficacious in treating spontaneous and bacterial shigatoxin-induced TTP in the murine models. Our findings may provide the basis for further development of anfibatide for the treatment of acute TTP in humans.