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Summary Objective There is considerable evidence for relationship between gut microbiota and osteoarthritis (OA), but no studies have investigated their causal relationship. Method This study utilized large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and OA risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for OA. Comprehensively sensitive analyses were performed to validate the robustness of results and novel multivariable MR analyses were further conducted to ensure the independence of causal association. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations. Finally, enrichment analyses were used to investigate the biofunction. Results After correction, three microbial taxa were identified to be causally associated with diverse joint OA (PFDR Conclusions This study found that several microbial taxa were causally associated with diverse joint OA. The results enhanced our understanding of gut microbiota in the pathology of OA.

Objective: Observational studies have shown the association between iron status and osteoarthritis (OA). However, due to difficulties of determining sequential temporality, their causal association is still elusive. Based on the summary data of genome-wide association studies (GWASs) of a large-scale population, this study explored the genetic causal association between iron status and OA. Methods: First, we took a series of quality control steps to select eligible instrumental SNPs which were strongly associated with exposure. The genetic causal association between iron status and OA was analyzed using the two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for analysis. The results were mainly based on IVW (random effects), followed by sensitivity analysis. IVW and MR-Egger were used for heterogeneity testing. MR-Egger was also used for pleiotropy testing. Leave-one-SNP-out analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Maximum likelihood, penalized weighted median, and IVW (fixed effects) were performed to further validate the reliability of results. Results: IVW results showed that transferrin saturation had a positive causal association with knee osteoarthritis (KOA), hip osteoarthritis (HOA) and KOA or HOA (p < 0.05, OR > 1), and there was a negative causal association between transferrin and HOA and KOA or HOA (p < 0.05, OR < 1). The results of heterogeneity test showed that our IVW analysis results were basically free of heterogeneity (p > 0.05). The results of the pleiotropy test showed that there was no pleiotropy in our IVW analysis (p > 0.05). The analysis results of maximum likelihood, penalized weighted median and IVW (fixed effects) were consistent with our IVW results. No genetic causal association was found between serum iron and ferritin and OA. Conclusions: This study provides evidence of the causal association between iron status and OA, which provides novel insights to the genetic research of OA.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative movement disorder. Observational studies suggest higher levels of plasma urate may protect against Parkinson's risk and progression; however, causality cannot be established. OBJECTIVES: This study set out to determine whether there is a true causal association between urate levels and PD age at onset (AAO) and progression severity using recently released PD AAO and progression genome-wide association study (GWAS) data. METHODS: A large two-sample Mendelian randomization design was employed, using genetic variants underlying urate levels and the latest GWAS data for PD outcomes. RESULTS: This study found no causal association between urate levels and Parkinson's risk, AAO, or progression severity. CONCLUSIONS: Our results predict increasing urate levels as a therapeutic strategy is unlikely to benefit PD patients. © 2021 International Parkinson and Movement Disorder Society

Atrial fibrillation (AF) patients have enlarged left atria (LA), but prior studies suggested enlarged atria as both cause and consequence of AF. The aim of this study is to investigate the causal association between AF and LA size and function. In the UK Biobank, all individuals with contoured cardiovascular magnetic resonance data were selected. LA maximal volume (LA max), LA minimal volume (LA min), LA stroke volume and LA ejection fraction were measured and indexed to body surface area (BSA). Two-sample Mendelian randomization analyses were performed using 84 of the known genetic variants associated with AF to assess the association with all LA size and function in individuals without prevalent AF. A total of 4274 individuals (mean age 62.0 ± 7.5 years, 53.2% women) were included. Mendelian randomization analyses estimated a causal effect between genetically determined AF and BSA-indexed LA max, LA min, and LA ejection fraction, but not between AF and LA stroke volume. Leave-one-out analyses showed that the causal associations were attenuated after exclusion of rs67249485, located near PITX2 gene. Our results suggest that AF causally increases LA size and decreases LA ejection fraction. The AF risk allele of rs67249485, located near the PITX2 gene, contributes strongly to these associations.

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25–1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15–1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24–1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14–1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24–1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12–1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

AIM This study aimed to determine the causal association between salt added to food and body mass index (BMI) by integrating a summary-level genome-wide association study (GWAS) data. METHODS We performed two-sample Mendelian randomisation (MR) analyses using summary statistics of GWAS. Inverse-variance weighted (IVW), maximum likelihood estimation, and random effect model were used to analyse the effect of salt added to food on BMI. A bidirectional MR analysis with BMI as the exposure and salt added to food as the outcome was also performed. RESULTS The single nucleotide polymorphisms (SNPs) were selected from the UK Biobank (n = 462 630) and a meta-analysis of 322 154 European-descent individuals. The IVW method estimate indicated that salt added to food was positively associated with BMI (β = 0.1416, SE = 0.0576, P = .0139). Results from maximum likelihood estimation (β = 0.1476, SE = 0.0363, P

Prostate cancer affects a significant proportion of men worldwide. Evidence from genetic and clinical studies suggests that there may be a causal association between prostate cancer and the human papilloma virus (HPV). As HPV is a vaccine-preventable pathogen, the possibility of a role in prostate cancer causation may reinforce the importance of effective HPV vaccination campaigns. This is of particular relevance in light of the COVID-19 pandemic, which may have considerable effects on HPV vaccine uptake and distribution.

Background Previous studies conducted in high altitude regions showed that maternal altitude was associated with low birth weight. The effect size of birth weight reduction is inclusive with unknown effects due to preterm birth. We systematically reviewed the literature and synthesize evidence on associations between altitude elevation from sea level and birth weight. Method We searched MEDLINE/PubMed, Embase, Scopus, Web of Science, and Cochrane database, from inception to May 5, 2020 for studies that reported maternal altitude and birth weight. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude. Bayesian multilevel effect models were employed to estimate the effect size on birth weight (and gestational age) associated with altitude. Results The systematic search identified 1020 articles, with 52 articles meeting the inclusion criteria providing 207 estimates for the association of altitude and birth weight (n = 4,428,563), and with 22 articles providing 71 estimates for gestational age (n = 2,149,627). A reduction in mean birth weight of 96.98 g was associated with every 1000 m increase in altitude across 52 studies. A statistically significant but numerically minimal effect of maternal altitude elevation was observed on the gestational age (0.3 days), corresponding to a negligible estimation of 5 g lower birth weight. A relatively high heterogeneity of between-study association (I2>84.1%) and small study effect was found. Conclusion A clinically meaningful birth weight reduction was associated with maternal altitude elevation beginning from sea level. Future longitudinal studies are needed to elucidate the causal association and to understand the late effect of maternal altitude.

Aims Observational studies have reported that homocysteine (Hcy) is associated with an increased risk of coronary artery disease (CAD) in individuals with diabetes, though controversy remains. The present study aimed to investigate the causal association between Hcy and CAD in individuals with diabetes. Methods A 2-sample Mendelian randomization (MR) study was designed to infer causality. Genetic summary data on the association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) of up to 44,147 individuals of European ancestry. SNP-CAD data were obtained from another recently published GWAS which included 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The fixed-effects inverse variance-weighted method was employed to calculate the effect estimates. Other robust methods and leave-one-out analyses were used in the follow-up sensitivity analyses. Potential pleiotropy was assessed with the MR-Egger intercept test. Results The 2-sample MR analysis suggested no evidence of an association between genetically predicted plasma Hcy levels and CAD risk in individuals with diabetes (odds ratio = 1.14, 95% confidence interval: 0.82–1.58, p = 0.43) using 9 SNPs as instrumental variables. Similar results were observed in the follow-up sensitivity analyses. The MR-Egger intercept test indicated no evidence of directional pleiotropy (intercept = 0.03, 95% confidence interval: − 0.08–0.03, p = 0.35). Conclusion This 2-sample MR analysis found no evidence of a causal association between plasma Hcy levels and CAD risk in individuals with diabetes.

Isolated pleural effusion is a rare manifestation of filariasis that mimics tuberculosis, especially in endemic regions. We describe a case of lymphocytic and exudative pleural effusion showing microfilaria on pleural fluid cytology. A retrospective review of all cases of filarial pleural effusion reported after 2000 was conducted to evaluate the association between filariasis and pleural effusion as well as to screen the features that can help in accurate detection of these patients. The analysis suggested a causal association between the parasite and the development of pleural effusion with a high sensitivity of pleural fluid cytology for diagnosis.

Introduction Radiopharmaceuticals may cause adverse events. Knowledge about adverse events from a patient’s perspective could help healthcare professionals to detect, understand, and manage adverse events more efficiently when using radiopharmaceuticals. Researchers need a validated questionnaire that can be used in patients to assess adverse events with radiopharmaceuticals. Objective The aim of this study was to develop, validate the content of, and perform initial testing of a questionnaire assessing patient-reported adverse events of radiopharmaceuticals. Methods Based on existing literature, six professionals drafted and evaluated a first version of the questionnaire. Further content validation was performed using cognitive interviews with six patients undergoing a nuclear medicine examination. After adaptations, the questionnaire was developed into a web-based questionnaire. One hundred patients undergoing nuclear examination tested this version, and the results were used to assess its acceptability and evaluate reported adverse events. Results Questions and answer options were revised in the initial questionnaire to improve clarity. In addition, some questions were removed. The final version consisted of 18 questions. In the test phase, the acceptability of the questionnaire was demonstrated (e.g. 79% of the patients who received the questionnaire completed it, and the median time to complete the questionnaire was 12 min for patients who reported an adverse event). Of the 100 patients (53% men, median age 64 years), 12 reported a total of 22 adverse events. One of these adverse events had a high causal association. Conclusion After validation and testing, the developed questionnaire to study patient-reported adverse events of radiopharmaceuticals is a suitable and valid instrument which can be used in future research. Electronic supplementary material The online version of this article (10.1007/s40264-019-00895-2) contains supplementary material, which is available to authorized users.

Patient: — Final Diagnosis: Pituitary apoplexy with hypothyroidism Symptoms: — Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic Objective: Educational purpose Background: Standard translations of Hippocratic works are sometimes misleading because the translators knew less about their subject than did the ancient authors. Case Report: A new translation and explication of a chapter from a Hippocratic work of the fifth century before the Common Era (BCE), Diseases II, describes patients with pituitary apoplexy and subsequent myxedema, the 2 events separated by as much as 14 years. Conclusions: The association of myxedema with an intracranial event that occurred years earlier predates by 2400 years the causal association of a pituitary adenoma with hormonal deficiency.

Background Obstructive sleep apnea (OSA) has shown to be associated with an increased risk of atrial fibrillation in observational studies. Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causal effect of OSA on atrial fibrillation. Methods and Results We used a 2‐sample Mendelian randomization (MR) method to evaluate the causal effect of OSA on atrial fibrillation. Summary data on genetic variant‐OSA association were obtained from a recently published genome‐wide association studies with up to 217 955 individuals and data on variant‐atrial fibrillation association from another genome‐wide association study with up to 1 030 836 individuals. Effect estimates were evaluated using inverse‐variance weighted method. Other MR analyses, including penalized inverse‐variance weighted, penalized robust inverse‐variance weighted, MR‐Egger, simple median, weighted median, weighted mode‐based estimate and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods were performed in sensitivity analyses. The MR analyses in both the fixed‐effect and random‐effect inverse‐variance weighted models showed that genetically predicted OSA was associated with an increased risk of atrial fibrillation (odds ratio [OR], 1.21; 95% CI, 1.12–1.31, P P P =0.14). Results were robust using other MR methods in sensitivity analyses. Conclusions This MR analysis found that genetically predicted OSA had causal effect on an increased risk of atrial fibrillation.

Our study looks at the effects of burnout and stress levels of nurses, behaviour regarding medical waste, and other effective risk factors on the first time and recurrent diagnosis of nosocomial infection (NI) in neonatal intensive care units in Hargeisa, Somaliland. This multicentric follow-up study was conducted and repeated measurements were taken from 72 neonates and 45 nurses working in three hospitals for a period of five months. Nurses with high burnout levels had 3.7 times higher risk of neonates under their care being diagnosed with an NI (odds ratio: 3.743; 95% CI: 1.498–9.356). By controlling other variables, the stress level of nurses increased the incidence rate of neonates being diagnosed more than once with NI by 3.2 times. Statistically, the direction of causal association was from the high burnout among nurses to the diagnosis of NI, and high stress was associated with the recurrent diagnosis of infections in neonates.

BackgroundThe causal association between coffee consumption and the risk of OA is limited. This study was conducted to identify the potential causal effects of coffee consumption on total, knee, hip, and self-reported OA.MethodsGenome-wide association studies (GWAS) of OA were derived from the UK Biobank, comprising 50,508 participants of European ancestry (10,083 with cases and 40,425 controls), and genetic data for specific diagnosed knee OA (4462 cases and 17,885 controls), hip OA (12,625 cases and 50,898 controls), and self-reported OA (12,658 cases and 50,898 controls). Primary and secondary genetic instruments (11 SNPs and 8 SNPs) were selected as instrumental variants from GWAS among 375,833 and 91,462 participants. Two-sample Mendelian randomization (MR) analyses were performed to test the effects of the selected single nucleotide polymorphisms (SNPs) and the OA risk. The causal effects were primarily estimated using weighted median and inverse-variance weighted method with several sensitivity analyses.ResultsThe MR analyses suggested that genetically predicted 1% increase of coffee consumption was associated with an increased risk of overall OA (OR:1.009, 95% CI:1.003-1.016), knee OA (OR:1.023, 95% CI:1.009-1.038), self-reported OA (OR:1.007, 95% CI:1.003-1.011), but not hip OA (OR: 1.012, 95%CI:0.999-1.024) using primary genetic instruments. Similar results were found when using secondary genetic instruments that genetically predicted coffee consumption (cups/day). Additionally, the sensitivity analyses for leave-one-out methods supported a robust association between exposure traits and OA.ConclusionOur findings indicate that genetically predicted coffee consumption exerts a causal effect on total, knee, and self-reported OA risk, but not at the hip. Further research is required to unravel the role of coffee consumption in OA prevention.

A 44-year-old previously healthy woman developed acute myelitis in close temporal relationship with ChAdOx1 nCoV-19 vaccine first-dose administration. The neurological involvement was mainly sensory with neuroimaging showing two mono-metameric lesions involving the posterior and lateral cord at dorsal level. Significant improvement was promptly recorded with high-dose intravenous steroids, with complete recovery within one month. The strict temporal relationship between vaccination and myelitis, together with the absence of clues pointing to alternative diagnoses, might suggest a conceivable role for anti-SARS-CoV-2 vaccine as immunological trigger, although a causal relationship has yet to be established and our preliminary observation suggests caution., Graphical abstract Unlabelled Image

Background: IBS and Migraine are two diseases featuring high prevalence. Previous studies have suggested a relationship between Irritable Bowel Syndrome (IBS) and migraine, although the causal association remains unclear. We sought to explore the causal association between IBS and migraine, and to prove the importance of migraine prevention in IBS patients.Methods: This study used a two-sample Mendelian-randomization analysis to explore the association of IBS with migraine. Genetic association with migraine were acquired from the UK Biobank (UKB) genetic databases (cases: 1,072; controls: 360,122). We performed estimation using Inverse Variance Weighting (IVW), along with Maximum Likelihood, MR-RAPS, MR-Egger and Weighted Median for sensitivity analysis. Considering possible bias, we also conducted polymorphism, heterogeneity, and directional analysis.Results: The IVW estimation genetically predicted the causal association between IBS and migraine (OR=1.09, 95%CI 1.01 to 1.17, p=0.03). Neither statistical horizontal pleiotropy (MR Egger p=0.42; MR-PRESSO p=0.78) nor possible heterogeneity (IVW Q = 26.15, p=0.80) was found. Reverse causation was also not detected (p steigerConclusion: Mendelian randomization analysis supported a positive-going causal association of IBS with migraine, providing enlightenment for disease prevention and control.

Background In low- and middle-income countries, such as Brazil, studies on the causes of death in asbestos-exposed workers are scarce. Methods A cohort study was performed involving 988 males who had worked in the asbestos-cement industry in the state of Sao Paulo, with a total of 12,217 person-years of observation between 1995 and 2016. The standardized mortality ratio (SMR) stratified by age was calculated as the ratio between the observed rate and the expected rate in the state of Sao Paulo. Results Increased SMRs were observed for overall mortality (SMR 1.1, 95% confidence interval [CI], 0.98-1.23) and mortality due to pleural malignant neoplasms (MN) (SMR, 69.4; 95% CI, 22.55-162.1), asbestosis (SMR, 975.7; 95% CI, 396.4-2031), peritoneal MN (SMR, 5.0; 95% CI, 0.13-27.78), laryngeal MN (SMR, 1.4; 95% CI, 0.30-4.20), and pulmonary MN (SMR, 1.5; 95% CI, 0.82-2.64). Conclusion The present study highlights the damage caused by asbestos exposure and reinforces the existing evidence of a causal association between exposure and increased mortality due to pleural MN, pulmonary MN, and asbestosis.

Emerging data increasingly point towards the duodenum as a key region underlying the pathophysiology of functional dyspepsia (FD), one of the most prevalent functional GI disorders. The duodenum plays a major role in the control and coordination of gastroduodenal function. Impaired duodenal mucosal integrity and low-grade inflammation have been associated with altered neuronal signalling and systemic immune activation, and these alterations may ultimately lead to dyspeptic symptoms. Likely luminal candidates inducing the duodenal barrier defect include acid, bile, the microbiota and food antigens although no causal association with symptoms has been convincingly demonstrated. Recognition of duodenal pathology in FD will hopefully lead to the discovery of new biomarkers and therapeutic targets, allowing biologically targeted rather than symptom-based therapy. In this review, we summarise the recent advances in the diagnosis and treatment of FD with a focus on the duodenum.

Purpose Research into causality assessment tools enabling patients to assess suspected adverse drug reactions (ADRs) is limited. Supporting patients with tools could improve their confidence in discussions with health professionals and encourage reporting of suspected ADRs to regulators. This study describes development and preliminary validation of an instrument: Side Effect Patient ASsessment Tool (SE-PAST). Methods SE-PAST was developed from survey and interview data involving patients experiencing suspected ADRs. It included 10 statements enabling causality assessment, covering timing, additional information sources, and experiences, with four options: yes/no/don't know/not applicable. Scoring and weighting resulted in four categories of causal association: highly probable, probable, possible, unlikely. Validation involved obtaining feedback from 31 individuals experiencing an ADR. Further validation involved online distribution through patient support groups and comparison of reported symptoms to known ADRs. Results Validators found SE-PAST easy to read (31), to understand (27), and to complete (29). A total of 294 respondents completed SE-PAST online, with 98% completing eight or more causality assessment statements. Symptoms were categorised as highly probable (46; 16%), probable (80; 62%), possible (44; 15%), and unlikely (21; 7%). A total of 221 respondents identified one suspected medicine, with 95% of these reporting at least one symptom known to be an ADR. Of 227 providing feedback, 139 (61%) found SE-PAST useful, 160 (71%) felt motivated to discuss their experience with a health professional, and 136 (60%) were encouraged to report to the regulator. Conclusion SE-PAST was easily completed and understood by people experiencing suspected ADRs and could be useful in encouraging patient reporting to health professionals and agencies.

Although observational studies have shown that abnormal systemic iron status is associated with an increased risk of heart failure (HF), it remains unclear whether this relationship represents true causality. We aimed to explore the causal relationship between iron status and HF risk. Two-sample Mendelian randomisation (MR) was applied to obtain a causal estimate. Genetic summary statistical data for the associations (p < 5 × 10−8) between single nucleotide polymorphisms (SNPs) and four iron status parameters were obtained from the Genetics of Iron Status Consortium in genome-wide association studies involving 48,972 subjects. Statistical data on the association of SNPs with HF were extracted from the UK biobank consortium (including 1088 HF cases and 360,106 controls). The results were further tested using MR based on the Bayesian model averaging (MR-BMA) and multivariate MR (MVMR). Of the twelve SNPs considered to be valid instrumental variables, three SNPs (rs1800562, rs855791, and rs1799945) were associated with all four iron biomarkers. Genetically predicted iron status biomarkers were not causally associated with HF risk (all p > 0.05). Sensitivity analysis did not show evidence of potential heterogeneity and horizontal pleiotropy. Convincing evidence to support a causal relationship between iron status and HF risk was not found. The strong relationship between abnormal iron status and HF risk may be explained by an indirect mechanism.

Background: A growing number of cohort studies revealed an inverse association between cheese intake and cardiovascular diseases, yet the causal relationship is unclear. Objective: To assess the causal relationship between cheese intake, and cardiovascular diseases and cardiovascular biomarkers. Methods: A two-sample Mendelian randomization (MR) analysis based on publicly available genome-wide association studies was employed to infer the causal relationship. The effect estimates were calculated using the random-effects inverse-variance-weighted method. Results: Cheese intake per standard deviation increase causally reduced the risks of type 2 diabetes (odds ratio (OR) = 0.46; 95% confidence interval (CI), 0.34–0.63; p = 1.02 × 10−6), heart failure (OR = 0.62; 95% CI, 0.49–0.79; p = 0.0001), coronary heart disease (OR = 0.65; 95% CI, 0.53–0.79; p = 2.01 × 10−5), hypertension (OR = 0.67; 95% CI, 0.53–0.84; p = 0.001), and ischemic stroke (OR = 0.76; 95% CI, 0.63–0.91; p = 0.003). Suggestive evidence of an inverse association between cheese intake and peripheral artery disease was also observed. No associations were observed for atrial fibrillation, cardiac death, pulmonary embolism, or transient ischemic attack. The better prognosis associated with cheese intake may be explained by lower body mass index (BMI; effect estimate = −0.58; 95% CI, from −0.88 to −0.27; p = 0.0002), waist circumference (effect estimate = −0.49; 95% CI, from −0.76 to −0.23; p = 0.0003), triglycerides (effect estimate = −0.33; 95% CI, from −0.50 to −0.17; p = 4.91 × 10−5), and fasting glucose (effect estimate = −0.20; 95% CI, from −0.33 to −0.07; p = 0.0003). There was suggestive evidence of a positive association between cheese intake and high-density lipoprotein. No influences were observed for blood pressure or inflammation biomarkers. Conclusions: This two-sample MR analysis found causally inverse associations between cheese intake and type 2 diabetes, heart failure, coronary heart disease, hypertension, and ischemic stroke.

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

BackgroundUntil now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson’s disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention.MethodsWe selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test.ResultsWe did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = − 1.134, 95% CI: [− 2.515, 0.248],P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = − 1.750, 95% CI: [− 3.396, − 0.105],P = 0.037) and MR-Egger (beta = − 2.592, 95% CI: [− 4.623, − 0.560],P = 0.012).ConclusionsWe demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.

In recent months genomic characterization of pandemic SARS-CoV-2 isolates identified viral variants that are less susceptible to neutralization by convalescent plasma (CP), vaccine-elicited plasma/sera, or SARS-CoV-2 monoclonal antibodies than earlier SARS-CoV-2 strains. In this Viewpoint, Casadevall et al. argue against the causal association made in some press articles between the emergence of SARS-CoV-2 variants and convalescent plasma use.

Background The mycobiome is the fungal component of the gut microbiome and is implicated in several autoimmune diseases. However, its role in MS has not been studied. Methods In this case-control observational study, we performed ITS sequencing and characterised the gut mycobiome in people with MS (pwMS) and healthy controls at baseline and after six months. Findings The mycobiome had significantly higher alpha diversity and inter-subject variation in pwMS than controls. Saccharomyces and Aspergillus were over-represented in pwMS. Saccharomyces was positively correlated with circulating basophils and negatively correlated with regulatory B cells, while Aspergillus was positively correlated with activated CD16+ dendritic cells in pwMS. Different mycobiome profiles, defined as mycotypes, were associated with different bacterial microbiome and immune cell subsets in the blood. Initial treatment with dimethyl fumarate, a common immunomodulatory therapy which also has fungicidal activity, did not cause uniform gut mycobiome changes across all pwMS. Interpretation There is an alteration of the gut mycobiome in pwMS, compared to healthy controls. Further study is required to assess any causal association of the mycobiome with MS and its direct or indirect interactions with bacteria and autoimmunity. Funding This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS102633-04 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-1805-31003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG- 1907-34474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Editor, Acro-ischaemic lesions have been observed both in adults withsevere forms of COVID-19 and in younger patients with no ormild symptoms of COVID-19 [...]

We read with great interest the letter from Perez Naranjo et al. (1) regarding the case we recently published in this journal (2). We believe that the case presented by the authors is undoubtedly useful as it contributes to the scarce existing casuistry on the relationship between COVID-19 and the development of pneumatosis/pneumoperitoneum. We would like to emphasize the difficulty of determining the causality of this association due to the frequent co-occurrence of other causes that could justify the presence of pneumatosis/pneumoperitoneum.

We aim to characterize the association between education and incident stroke (including total stroke, ischemic stroke, and hemorrhagic stroke) and assess whether there is a causal relationship between them. The final sample size was 11,509 in this study from the Atherosclerosis Risk in Communities (ARIC) study. Cox hazard regression models were used to explore the association between education level and incident stroke. Two-sample Mendelian randomization (MR) was used to estimate the causality. During a median follow-up of 25.3 years, 915 cases (8.0%) of stroke occurred. Participants with advanced education level were associated with 25% (HR 0.75; 95% CI 0.62, 0.91) decreased the rate of incident total stroke. Hazard ratio of intermediate and advanced education level for ischemic stroke were 0.82 (0.69, 0.98) and 0.73 (0.60, 0.90) separately. In the MR analysis, we observed evidence that education was likely a negetive causal risk factor for ischemic stroke (OR 0.764, 95% CI 0.585–0.998, P = 0.048). Higher education level was associated with a decreased rate of total stroke and ischemic stroke incident, but not hemorrhagic stroke incident. There might be a protective causal association between education and ischemic stroke (but not total stroke nor hemorrhagic stroke).

Background To investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach. Methods Genetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses. Results Six, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 – 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 – 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses. Conclusions/interpretation Serum 25OHD, Ca and PTH levels may not be causally associated with the risk of CAD in patients with diabetes.

OBJECTIVE There is sparse evidence for the association of suitable food substitutions for red and processed meat on the risk of type 2 diabetes. We modeled the association between replacing red and processed meat with other protein sources and the risk of type 2 diabetes and estimated its population impact. RESEARCH DESIGN AND METHODS The European Prospective Investigation into Cancer (EPIC)-InterAct case cohort included 11,741 individuals with type 2 diabetes and a subcohort of 15,450 participants in eight countries. We modeled the replacement of self-reported red and processed meat with poultry, fish, eggs, legumes, cheese, cereals, yogurt, milk, and nuts. Country-specific hazard ratios (HRs) for incident type 2 diabetes were estimated by Prentice-weighted Cox regression and pooled using random-effects meta-analysis. RESULTS There was a lower hazard for type 2 diabetes for the modeled replacement of red and processed meat (50 g/day) with cheese (HR 0.90, 95% CI 0.83–0.97) (30 g/day), yogurt (0.90, 0.86–0.95) (70 g/day), nuts (0.90, 0.84–0.96) (10 g/day), or cereals (0.92, 0.88–0.96) (30 g/day) but not for replacements with poultry, fish, eggs, legumes, or milk. If a causal association is assumed, replacing red and processed meat with cheese, yogurt, or nuts could prevent 8.8%, 8.3%, or 7.5%, respectively, of new cases of type 2 diabetes. CONCLUSIONS Replacement of red and processed meat with cheese, yogurt, nuts, or cereals was associated with a lower rate of type 2 diabetes. Substituting red and processed meat by other protein sources may contribute to the prevention of incident type 2 diabetes in European populations.

The causal association of LDL-cholesterol (LDL-C) with atherosclerotic cardiovascular disease (ASCVD) has been demonstrated in robust experimental, epidemiological, genetic, and interventional randomized controlled trials (RCTs). The goal of this review is to show how the knowledge acquired from statin RCTs influenced and was recommended on guidelines for prevention of ASCVD during the last three decades. Guideline recommendations have evolved with accruing information derived mostly from statin RCTs, and as decades passed, more intensive LDL-C lowering was recommended according to a given ASCVD risk. Recent guidelines are unanimous in recommending intensive LDL-C lowering for the highest-risk individuals; however, they differ regarding risk stratification tools, use of specific LDL-C targets, management of primary prevention individuals, and thresholds to start non-statin lipid-lowering therapies. Even considering the advent of non-statin therapies like ezetimibe and PCSK9 inhibitors, due to their efficacy, safety, and low cost, guidelines state that statins persist as the main component of ASCVD preventive strategies and should be prescribed in adequate doses to attain evidence-based LDL-C lowering.

The association between perineal talc use and ovarian cancer has been evaluated in several epidemiology studies. Some case-control studies reported weak positive associations, while other case-control and three large prospective cohort investigations found this association to be null. A weight-of-evidence evaluation was conducted of the epidemiology, toxicity, exposure, transport, in vitro, and mechanistic evidence to determine whether, collectively, these data support a causal association. Our review of the literature indicated that, while both case-control and cohort studies may be impacted by bias, the possibility of recall and other biases from the low participation rates and retrospective self-reporting of talc exposure cannot be ruled out for any of the case-control studies. The hypothesis that talc exposure induces ovarian cancer is only supported if one discounts the null results of the cohort studies and the fact that significant bias and/or confounding are likely reasons for the associations reported in some case-control investigations. In addition, one would need to ignore the evidence from animal experiments that show no marked association with cancer, in vitro and genotoxicity studies that did not indicate a carcinogenic mechanism of action for talc, and mechanistic and transport investigations that did not support the retrograde transport of talc to the ovaries. An alternative hypothesis that talc does not produce ovarian cancer, and that bias and confounding contribute the reported positive associations in case-control studies, is better supported by the evidence across all scientific disciplines. It is concluded that the evidence does not support a causal association between perineal talc use and ovarian cancer.

Prospective studies have shown that abnormally circulating cholesterol is associated with the risk of dementia. However, whether the association is causal or not remains unclear. We attempt to infer the causal association in a MR meta-analysis by using ApoE gene polymorphisms as instrument variables. Studies with dementia risk (27 studies) or circulating lipid levels (7 studies) were included, with totally 3136 dementia patients and 3103 healthy controls. The analyses showed that carriers of ε2 allele significantly were of decreased risk of AD (OR = 0.70; 95% CI: 0.58–0.84; P P P P P P P P

Background Exposures to perfluoroalkyl substances (PFAS) have shown positive associations with serum lipids in previous studies. While many studies on lipids investigated associations with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), there are only a few studies regarding other PFAS, such as perfluorohexane sulfonic acid (PFHxS). The purpose of the current study is to investigate if associations with serum lipids were present, not only for serum PFOS and PFOA, but also for PFHxS, and if the associations with PFAS remained also in a comparison based only on residency in areas with contrasting exposure to PFAS. Methods 1945 adults aged 20–60 were included from Ronneby, Sweden, a municipality where one out of two waterworks had been heavily contaminated from aqueous fire-fighting foams, and from a nearby control area. The exposure was categorized based on either been living in areas with contrasting PFAS exposure or based on the actual serum PFAS measurements. Regression analyses of serum lipids were fitted against serum PFAS levels, percentile groups, smooth splines and between exposed and reference areas, adjusting for age, sex and BMI. Results Drinking water contamination caused high serum levels of PFOS (median 157 ng/ml) and PFHxS (median 136 ng/ml) and PFOA (median 8.6 ng/ml). These serum PFAS levels in the exposed groups were 5 to 100-fold higher than in the controls. In this population with mixed PFAS exposure, predominantly PFOS and PFHxS, PFAS exposure were positively associated with serum lipids. This was observed both when quantifying exposure as contrast between exposed and controls, and in terms of serum PFAS. Due to high correlations between each PFAS, we cannot separate them. Conclusions In conclusion, the present study provides further evidence of a causal association between PFAS and serum lipids, especially for PFHxS.

Background The pathologies of the posterior teeth in the first and second quadrant and their treatments can be associated with pathology of the maxillary sinus in up to 30% of the cases. Sinus lift surgery in order to place dental implants have increased their incidence. It is necessary, therefore, to address sinonasal pathology (SN) related to dental pathology (DP) or dental treatments (DT) from an interdisciplinary point of view by establishing collaborative working groups between Dentistry (DEN) and Otolaryngology (ENT), as well as by developing registries and establishing coordinated diagnosis and treatment protocols of sinonasal pathology. The aim of this study was to present a brand new and useful classification that relates dental pathology and dental treatments performed on antral teeth with sinonasal pathology to facilitate communication between dentists and otolaryngologists. Methods A review of the literature was performed and a classification which related dental pathology and treatments to sinonasal pathology was developed. Results Six categories are described in our system: absence of sinonasal or dental pathology (0); patients with dental pathology associated (1) or not (4) with sinonasal pathology; 2 and 5- patients with dental treatment not associated (2) or associated (5) with sinonasal pathology; and patients with sinonasal pathology without dental pathology (3). The classification has applications in diagnosis (association and possible causal relationship between the sinonasal and dental pathology) and in the treatment of these pathologies simultaneously or sequentially. Conclusions This classification integrates the presence or absence of dental pathology or dental treatment, and its association or not it with sinonasal pathology. Moreover, it facilitates the communication between dentists and otolaringologists and eases the registration of information and the planning of dental, implant and sinus lift treatments.

Background and aims Although several studies have shown an association between plasma homocysteine (Hcy) levels and atrial fibrillation (AF), the causality remains unclear. We undertook a Mendelian randomization (MR) study to investigate the causal association between Hcy and AF. Methods and results Single-nucleotide polymorphisms (SNPs) which genome-wide significantly associated with plasma Hcy levels were obtained from a genome-wide meta-analysis (N = 44 147). MR analyses including the random-effect inverse variance-weighted (IVW) meta-analysis, weighted median analysis, and MR-Egger regression were used to estimate the associations between the selected SNPs and AF based on a meta-analysis of genome-wide association study for AF (N = 588 190). The MR analyses revealed no causal role of genetically elevated plasma Hcy levels with AF risk (random-effect IVW, odds ratio per 1 SD increase in Hcy levels = 0.972, 95% confidence interval = 0.919 to 1.027, P = 0.308). The results were consistent with the weighted median method, MR-Egger and the analysis after excluding the pleiotropic SNPs. No heterogeneity and directional pleiotropy were observed in sensitivity analyses. Conclusion The findings suggested that plasma Hcy levels were not causally associated with AF.

To investigate whether periodontitis is causally associated with risk of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). We performed two-sample Mendelian randomization (MR) analysis using the inverse variance-weighted (IVW), weighted median, and MR-Egger regression methods on publicly available summary statistics datasets using a periodontitis genome-wide association study (GWAS) as an exposure and RA and SLE GWASs on individuals of European descent as outcomes. We selected 7 or 20 single-nucleotide polymorphisms from a periodontitis GWAS as instrumental variables for RA or SLE. The IVW method results support a causal association between periodontitis and RA (beta = 0.168, SE = 0.080, p = 0.035) and SLE (beta = 0.0001, SE = 0.0001, p = 0.046) risk; however, the weighted median approach did not indicate a significant causal association. MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the RA (intercept = −0.115, p = 0.078) or SLE results (intercept = 4.68E-05, p = 0.394); no significant causal association was found between periodontitis and RA and SLE. The MR estimates from the IVW, weighted median, and MR-Egger regression analyses were not consistent. Only the results of MR analysis by the IVW method indicated that periodontitis is likely causally associated with an increased risk of RA and SLE incidence. Our MR showed weak causal association between periodontitis and RA or SLE. These findings may assist in elucidating the underlying mechanisms of the effects of periodontitis on RA and SLE incidence.

Background Atrial fibrillation ( AF ) has been shown to be associated with an increased risk of dementia as well as Alzheimer disease in observational studies. Whether this association reflects causal association is still unclear. The purpose of this study was to examine the causal association of AF with Alzheimer disease. Methods and Results We used a 2‐sample Mendelian randomization approach to evaluate the causal effect of AF on Alzheimer disease. Summary data on the association of single nucleotide polymorphisms with AF were obtained from a recently published genome‐wide association study with up to 1 030 836 individuals and data on single nucleotide polymorphism‐Alzheimer disease association from another genome‐wide association study with up to 455 258 individuals. AF was mainly diagnosed according to International Classification of Diseases, Ninth Revision ( ICD ‐9 or ICD ‐10 ) and Alzheimer disease was mainly diagnosed according to clinical criteria (eg, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association [ NINCDS ‐ ADRDA ] criteria). Effect estimates were calculated using the inverse‐variance weighted method. The Mendelian randomization analysis showed nonsignificant association of genetically predicted AF with risk of Alzheimer disease (odds ratio=1.002, 95% CI: 0.996–1.009, P =0.47) using 93 single nucleotide polymorphisms as the instruments. Mendelian randomization‐Egger indicated no evidence of genetic pleiotropy (intercept=0.0002, 95% CI : −0.001 to 0.001, P =0.70). Conclusions This Mendelian randomization analysis found no evidence to support causal association between AF and Alzheimer disease.

International audience; Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (β = − 0.76, 95% CI − 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (β = − 0.06, 95% CI − 0.93 to 0.87 mmHg), or pulse pressure (β = − 0.65, 95% CI − 1.38 to 0.69 mmHg, all p > 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

Esophageal cancers comprise about 1% of all cancers diagnosed in the US but are more prevalent in other regions of the world. Several regulatory agencies have classified asbestos as a known human carcinogen, and it is linked to multiple diseases and malignancies, including lung cancer and mesothelioma. In a 2006 review of the epidemiological literature, the Institute of Medicine (IOM) did not find sufficient evidence to demonstrate a causal relationship between asbestos exposure and esophageal cancer. To reevaluate this conclusion, we performed a critical review of the animal toxicological, epidemiological, and mechanism of action literature on esophageal cancer and asbestos, incorporating studies published since 2006. Although there is some evidence in the epidemiological literature for an increased risk of esophageal cancer in asbestos-exposed occupational cohorts, these studies generally did not control for critical esophageal cancer risk factors (e.g. smoking, alcohol consumption). Furthermore, data from animal toxicological studies do not indicate that asbestos exposure increases esophageal cancer risk. Based on our evaluation of the literature, and reaffirming the IOM’s findings, we conclude that there is insufficient evidence to demonstrate a causal link between asbestos exposure and esophageal cancer.

ContextNonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa.ObjectiveTo test the hypothesis that NAFLD is causally related to IR.Design and MethodsWe performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR). We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD).ResultsNonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (β-coefficient = 0.20, P < 0.001), and NAFLD was associated with ln-HOMA-IR (β-coefficient = 0.28, P < 0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected β-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (β-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR. The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD.ConclusionsOur study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not “captured” by our MR design might underpin the association between NAFLD and HOMA-IR.

The aim of this study was to examine whether the vitamin D level is causally associated with risk of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). We performed two-sample Mendelian randomization (MR) analyses using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods on publicly available summary statistics datasets using two vitamin D level genome-wide association studies (GWASs) as exposure and SLE and RA GWASs on people of European descent as outcomes. We selected three independent single-nucleotide polymorphisms located at SSTR4 (rs2207173), GC (rs2282679), and NADSYN1 (3829251) with genome-wide significance from two GWASs on vitamin D levels as instrumental variables. The IVW, weighted median, and MR-Egger regression methods yielded no evidence of a causal association between vitamin D level and risk of SLE (beta = 0.032, SE = 0.119, p = 0.789; beta = 0.233, SE = 0.274, p = 0.552; beta = 0.054, SE = 0.125, p = 0.665; respectively) or RA (beta = 0.026, SE = 0.061, p = 0.664; beta = 0.025, SE = 0.065, p = 0.695; beta = 0.025, SE = 0.065, p = 0.695; respectively). In addition, MR-Egger regression revealed directional pleiotropy was unlikely to be biasing the result for SLE (intercept = - 0.058, p = 0.545) or RA (intercept = - 0.027, p = 0.558). The MR estimates from IVW, weighted median, and MR-Egger regression analyses were consistent. MR analysis did not support a causal association between the vitamin D level and SLE or RA.

A longstanding hypothesis is that some alcohol use problems (AUP) develop and are maintained through the "self-medication" of internalizing (INT; depression and anxiety) problems. However, their high rate of co-occurrence with one another and with externalizing (EXT; antisocial behavior and impulse control) problems obscures any causal association because EXT may account for the INT-AUP link. Using a large community sample, we estimated prospective effects of INT and EXT on AUP via latent cross-lagged mediation panel spanning 14 years from childhood (ages 9-11) to young adulthood (ages 21-23). After adjusting for the cross-lagged, concurrent, and stability effects across factors, INT decreased AUP risk through its direct and indirect effects and increased AUP risk through shared variance with EXT. Between childhood and young adulthood, unique aspects of INT reduced risk for AUP while aspects of INT shared with EXT increased risk for AUP. (PsycINFO Database Record