Reverse Causation Bias Research Articles

How Does Politics Affect Quality of Public Transport Infrastructure?

While prior studies have investigated the impacts of political factors such as the ideological stance on quality of public infrastructure, there is a paucity of research on the political effects of re-election success, party fragmentation (political power), and the formation of new electoral consistency on quality of public transport infrastructure, which is represented in this paper by road maintenance efficiency. We employ an instrumental variable approach to mitigate a potential reverse causality bias inherent in literature. Our empirical results show that local governments whose political representatives were re-elected give rise to lower road maintenance efficiency. Local governments with new electoral constituencies report a higher road maintenance efficiency.

Association between dried fruit intake and kidney function: research from univariate and multivariate Mendelian randomized studies.

Observational studies have identified an association between dried fruit intake and kidney function. However, these studies have limitations such as vulnerability to confounders and reverse causality bias. Therefore, this study aimed to explore the potential causal relationship between dried fruit intake and kidney function. A two-sample Mendelian randomization (MR) study was conducted using a large-scale genome-wide association study dataset to investigate the causal relationship between dried fruit intake and kidney function markers (blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), cystatin C (CyC), hematuria, microalbuminuria). The main analytical method was inverse variance weighting. In addition, we applied the MR Egger and weighted median to assess the robustness of the results. Finally, Multivariate Mendelian randomization (MVMR) was used to estimate the direct effect of dried fruit intake on kidney function markers. The univariate MR analysis showed that increased dried fruit intake was associated with lower kidney function markers, including BUN (β: -0.171, 95% confidence interval (CI): -0.239 to -0.102, p = 1.063 × 10-6), CR (β: -0.205, 95% CI: -0.311 to -0.099, p = 1.455 × 10-4), UA (β = -0.317, 95% CI: -0.384 to -0.249, p = 4.439 × 10-20), and CysC (β = -0.323, 95% CI: -0.384 to -0.249, p = 1.074 × 10-11); however, it was unrelated to hematuria and microalbuminuria. Causality persisted after performing MVMR analysis; however, with the addition of alcohol consumption and smoking as exposure factors, the causality for UA (β = -0.296, 95% CI: -0.523 to -0.068, p = 1.094 × 10-2) and CysC (β = -0.238, 95% CI: -0.465 to -0.011, p = 4.024× 10-2) weakened, while the causality for BUN (β = -0.038, 95% CI: -0.215 to 0.138, p = 6.698 × 10-1) and CR (β = -0.038, 95% CI: -0.431 to 0.046, p = 1.347 × 10-1) disappeared. Increased dried fruit intake was associated with lower kidney function markers (BUN, CR, UA, and CysC) in the absence of smoking and alcohol consumption; however, the causal relationship between dried fruit intake and BUN and CR disappeared in the presence of smoking and alcohol consumption. These results provide a promising avenue for delaying the course of chronic kidney disease.

Staff engagement, co‐workers' complementarity and employee retention: evidence from English NHS hospitals

AbstractRetention of skilled workers is essential for labour‐intensive organizations like hospitals, where an excessive turnover of doctors and nurses can reduce the quality and quantity of services provided to patients. Exploiting a unique and rich panel dataset based on employee‐level payroll and staff survey records from the universe of English NHS hospitals, we investigate empirically the role played by two non‐pecuniary job factors, staff engagement and the retention of complementary co‐workers, in affecting employee retention within the public hospital sector. We estimate dynamic panel data models to deal with reverse causality bias, and validate these estimates through unconditional quantile regressions with hospital‐level fixed effects. Our findings show that a one standard deviation increase in nurse engagement is associated with a 16% standard deviation increase in their retention; and also that a 10% increase in nurse retention is associated with a 1.6% increase in doctor retention, with this co‐workers' complementarity spillover effect driven by the retention of more experienced nurses. Nurse and doctor engagement is positively associated with managers who have effective communication, involve staff in the decision‐making process, and act on staff feedback; in particular, older nurse engagement is responsive to managers caring for staff health and wellbeing.

Associations between daytime napping, sleep duration, and depression and 15 cardiovascular diseases: a Mendelian randomization study.

Numerous studies have documented the effects of daytime napping, sleep duration, and depression on cardiovascular diseases (CVDs). However, the evidence has been gleaned from observational studies that might be riddled with confounding variables and the possibility of reverse causation bias. Therefore, the present study employed a Mendelian randomization (MR) methodology to meticulously explore the relationships between daytime napping, sleep duration, and depression, and the risk profiles of CVDs. Genome-wide significant genetic variants associated with daytime napping, sleep duration, and depression were used as the instrumental variables (IVs). Data on the genetic correlations between these IVs and 15 CVDs were derived from the United Kingdom (UK) Biobank, Finnish Genome Studies, and other large-scale collaborations. We conducted both univariate and multivariate MR analyses to assess the overall effects and mediated relationships after adjusting for potential confounders, including body mass index (BMI), smoking status, and type 2 diabetes. The effect sizes were estimated using inverse variance-weighted (IVW) regression. The MR analysis revealed that an increased risk of heart failure (HF) [odds ratio (OR): 1.366; 95% confidence interval (CI): 1.013-1.842; P=0.04], coronary atherosclerosis (OR: 1.918; 95% CI: 1.257-2.927; P=0.003), myocardial infarction (MI) (OR: 1.505; 95% CI: 1.025-2.211; P=0.04), and coronary artery disease (CAD) (OR: 1.519; 95% CI: 1.130-2.043; P=0.006) was significantly associated with genetically predicted daytime napping. Prolonged sleep duration was found to be related to a reduced risk of HF (OR: 0.995; 95% CI: 0.993-0.998; P=2.69E-04), peripheral vascular disease (PVD) (OR: 0.984; 95% CI: 0.971-0.997; P=0.02), and CAD (OR: 0.997; 95% CI: 0.994-0.999; P=0.006). Additionally, a statistically significant positive relationship was observed between depressive disorders and the occurrence of atrial fibrillation (AF) (OR: 1.298, 95% CI: 1.065-1.583, P=0.01), indicating a heightened susceptibility. The multivariable MR analyses substantiated the reliability of the observed associations between daytime napping and the incidence of HF and CAD, following adjustments for genetically predicted BMI and smoking. The sensitivity analysis did not reveal any evidence of horizontal pleiotropy or heterogeneity, thus supporting the validity of the study's results. This MR investigation posits a potential causal nexus between daytime napping, sleep duration, and depression, and the genesis of CVDs, offering new perspectives on the prevention and management of CVDs.

Restriction of salt, alcohol and coffee intake and Ménière's disease: insight from Mendelian randomization study.

Restricting salt, caffeine, and alcohol intake is commonly recommended as a first-line treatment for patients with Ménière's disease (MD). However, it remains unclear whether these interventions effectively improve symptoms of MD. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis to evaluate the relationship between these dietary modifications and MD. Summary statistics for salt added to food, alcohol consumption, coffee consumption, and MD were sourced from the United Kingdom Biobank, GSCAN, and the FinnGen study, involving up to 941,280 participants. The main analyses were performed using the random-effects inverse-variance weighted (IVW) approach and were complemented by four additional methods. Multiple sensitivity analyses were performed to validate the findings, and both forward and reverse MR analyses were employed to address potential reverse causality bias. The primary MR results using the IVW method revealed that salt added to food (OR = 0.719, 95% CI: 0.429-1.206; p = 0.211), alcohol consumption (OR = 0.834, 95% CI: 0.427-1.628; p = 0.595), and coffee consumption (OR = 0.852, 95% CI: 0.555-1.306; p = 0.461) were not significantly correlated with MD. In reverse analysis, no evidence of significant effect was found from MD to salt added to food (OR = 1.000, 95% CI: 0.993-1.007; p = 0.957), alcohol consumption (OR = 0.998, 95% CI: 0.987-1.008; p = 0.682), and coffee consumption (OR = 0.998, 95% CI: 0.985-1.011; p = 0.72). This MR analysis did not identify convincing evidence to support the idea that restricting salt, caffeine, and alcohol intake is beneficial for the treatment of MD.

IL6 receptor inhibitors: exploring the therapeutic potential across multiple diseases through drug target Mendelian randomization.

High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects. To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible. IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP. IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.

Consumption of Total and Specific Alcoholic Beverages and Long-Term Risk of Gout Among Men and Women

Previous studies on alcohol consumption and incident gout have mostly included men or combined both sexes, and the sex-specific associations between alcohol consumption and gout are poorly understood. To evaluate the consumption of total and specific alcoholic beverages in association with incident gout in men and women. This prospective cohort study included 401 128 participants in the UK Biobank aged 37 to 73 years who were free of gout at baseline (2006-2010). Participants were followed up through December 31, 2021, and data were analyzed between August 2023 and June 2024. Questionnaire-based consumption of total alcohol and specific alcoholic beverages. The outcome was incident gout, identified using hospital records. Multivariable Cox proportional hazards regression models were used to estimate sex-specific hazard ratios (HRs) and 95% CIs of incident gout associated with alcohol consumption, with a particular consideration of reverse causation bias. The main analysis included 179 828 men (mean [SD] age, 56.0 [8.2] years) and 221 300 women (mean [SD] age, 56.0 [8.0] years). Current drinkers showed a higher risk of gout than never drinkers among men (HR, 1.69; 95% CI, 1.30-2.18) but not among women (HR, 0.83; 95% CI, 0.67-1.03). Among current drinkers, higher total alcohol consumption was associated with a higher risk of gout among both sexes and more strongly among men than women (men: HR, 2.05 [95% CI, 1.84-2.30]; women: HR, 1.34 [95% CI, 1.12-1.61]). The most evident sex difference in the consumption of specific alcoholic beverages was observed for beer or cider (men: mean [SD], 4.2 [4.8] pints per week; women: mean [SD], 0.4 [1.1] pints per week). Consumption of champagne or white wine, beer or cider, and spirits each was associated with a higher risk of gout among both sexes, with beer or cider showing the strongest association per 1 pint per day (men: HR, 1.60 [95% CI, 1.53-1.67]; women: HR, 1.62 [95% CI, 1.02-2.57]). Some inverse associations between light to moderate consumption of specific alcoholic beverages and gout were eliminated after adjusting for other alcoholic beverages and excluding individuals who had reduced alcohol consumption for health reasons, self-reported poor health, or had cardiovascular disease, cancer, or kidney failure at baseline, or developed gout within the first 2 years of follow-up. In this cohort study, higher consumption of several specific alcoholic beverages was associated with a higher risk of gout among both sexes. The sex-specific associations for total alcohol consumption may be associated with differences between men and women in the types of alcohol consumed.

Causal relationship between serum uric acid and cardiovascular disease: A Mendelian randomization study

BackgroundObservational studies have established an association between serum uric acid and cardiovascular disease (CVD). However, these studies are susceptible to uncontrolled confounders and reverse causality bias. To overcome these challenges, we employed a two-sample Mendelian randomization (MR) approach to investigate the causal link between serum uric acid and CVD. MethodsWe utilized Genome-wide association study (GWAS) data for serum uric acid and six CVD: coronary artery disease (CAD), hypertension, myocardial infarction (MI), heart failure (HF), angina, and coronary heart disease (CHD). MR analyses employed inverse variance weighting (IVW), MR-Egger, weighted median, and weighted model. Sensitivity analyses were conducted to assess result reliability, including Cochrane’s Q test, MR-Egger intercept, MR-PRESSO, and the leave-one-out approach. ResultsIVW analysis revealed that a genetic predisposition to elevated serum uric acid levels significantly increases the risk of CVD, with higher odds ratios (ORs) observed for CAD (OR: 1.227; 95 % CI: 1.107–1.360, P = 0.0002), hypertension (OR: 1.318, 95 %CI: 1.184–1.466, P = 2.13E-06), MI (OR: 1.184, 95 %CI: 1.108–1.266, P = 2.13E-06), HF (OR: 1.158, 95 %CI: 1.066–1.258, P = 2.13E-06), angina (OR: 1.150, 95 %CI: 1.074–1.231, P = 0.0002) and CHD (OR: 1.170, 95 %CI: 1.072–1.276, P = 0.0005). Sensitivity analysis research results have robustness. ConclusionThis MR study robustly demonstrates a significant causal relationship between genetically elevated serum uric acid and various cardiovascular diseases, suggesting that higher levels may enhance the risk of cardiovascular events. Consequently, patients with elevated uric acid levels warrant early and aggressive interventions to mitigate cardiovascular risks.

Causal effects of sedentary behaviours on the risk of migraine: A univariable and multivariable Mendelian randomization study.

Migraine is a common and burdensome neurological disorder. The causal relationship between sedentary behaviours (SBs) and migraine remains instinct. We aimed to evaluate the roles of SBs including watching TV, using computer and driving in the risk of migraine. We conducted a univariable and multivariable Mendelian randomization (MR) study based on summary datasets of large genome-wide association studies. The inverse variance weighted method was utilized as the primary analytical tool. Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier and leave-one-out were conducted as sensitivity analysis. Additionally, we performed a meta-analysis to combine the causal estimates. In the discovery analysis, we identified causal associations between time spent watching TV and an increased risk of migraine (p = 0.015) and migraine without aura (MO) (p = 0.002). Such causalities with increasing risk of migraine (p = 0.005), and MO (p = 0.006) were further verified using summary datasets from another study in the replication analysis. There was no significant causal association found between time spent using computer, driving and migraine or its two subtypes. The meta-analysis and multivariable MR analysis also strongly supported the causal relationships between time spent watching TV and an increased risk of migraine (p = 0.0003 and p = 0.034), as well as MO (p < 0.0001 and p = 0.0004), respectively. These findings were robust under all sensitivity analysis. Our study suggested that time spent watching TV may be causally associated with an increased risk of migraine, particularly MO. Large-scale and well-designed cohort studies may be warranted for further validation. This study represents the first attempt to investigate whether a causal relationship exists between SBs and migraine. Utilizing MR analysis helps mitigate reverse causation bias and confounding factors commonly encountered in observational cohorts, thereby enhancing the robustness of derived causal associations. Our MR analysis revealed that time spent watching TV may serve as a potential risk factor for migraine, particularly MO.

Genetically determined dietary habits and risk of Alzheimer's disease: a Mendelian randomization study.

Emerging evidence have suggested that dietary habits have potential implication on the development of Alzheimer's disease (AD). However, elucidating the causal relationship between specific dietary factors and AD risk remains a challenge. Therefore, our study endeavors to investigate the causal association between dietary habits and the risk of AD. We analyzed data on 231 dietary habits sourced from the UK Biobank and MRC-IEU, and AD data obtained from the FinnGen database. Employing a framework based on the classic two-sample Mendelian randomization (MR) study, we utilized the inverse-variance weighted (IVW) method as the primary analysis. Additionally, we conducted Steiger filtering and other methods to mitigate horizontal pleiotropy. The robustness of our overall findings was confirmed through multiple sensitivity analysis methods, and forward MR and reverse MR to address potential reverse causality bias. Our study evaluated the causal effect between 231 dietary habits involving over 500,000 participants of European ancestry, and 10,520 AD cases. Only oily fish intake demonstrated a significant protective causal relationship with AD following FDR correction (raw p-value = 1.28e-4, FDR p-value = 0.011, OR = 0.60, 95%CI: 0.47-0.78). Additionally, six dietary habits potentially influenced AD risk, with protective causal effects observed for average monthly intake of other alcoholic drinks (raw p-value = 0.024, FDR p-value = 0.574, OR = 0.57, 95%CI: 0.35-0.93) and tea intake (raw p-value = 0.047, FDR p-value = 0.581, OR = 0.78, 95%CI: 0.603-1.00). Conversely, detrimental causal effects were observed for the average weekly champagne plus white wine intake (raw p-value = 0.006, FDR p-value = 0.243, OR = 2.96, 95%CI: 1.37-6.38), Danish pastry intake (raw p-value = 0.036, FDR p-value = 0.574, OR = 13.33, 95%CI: 1.19-149.69), and doughnut intake (raw p-value = 0.039, FDR p-value = 0.574, OR = 7.41, 95%CI: 1.11-49.57). Moreover, the protective effect of goat's cheese intake phenotype exhibited statistical significance only in the IVW method (raw p-value<0.05). Our results provide genetic support for a protective causal effect of oily fish intake on AD risk. Additionally, average monthly intake of other alcoholic drinks and tea consumption were also related with a lower risk of AD. Conversely, average weekly champagne plus white wine intake, Danish pastry intake, and doughnut intake were causally associated with increased risk of AD.

Hometown religiosity and financial reporting quality: evidence from chairpersons

PurposeThis study aims to investigate whether there is a relationship between the religiosity levels of chairpersons’ hometowns and the financial reporting quality of companies.Design/methodology/approachUsing a unique hand-collected data set obtained from various sources, the authors use ordinary least squares and logistic regressions to test the hypotheses and further implement various methods to address potential issues such as omitted variables, reverse causality and selection bias problems. In addition, the authors control for the religiosity level of chief executive officers’ (CEOs) hometowns. Finally, the authors divide the sample into two subsamples – companies with strong corporate governance and companies with weak corporate governance – to investigate the effect of chairpersons’ hometown religiosity on financial reporting quality under strong or weak corporate governance.FindingsThe findings demonstrate that companies with chairpersons from religious hometowns produce high-quality financial reports. Additional tests, such as the Heckman selection model and instrument variable regression, confirm the robustness of the main results. Controlling for the religiosity level of the CEO’s hometown yields consistent findings with the main results. Finally, additional results indicate that the religiosity levels of chairpersons’ hometowns play a significant role in enhancing financial reporting quality in companies with weak corporate governance.Practical implicationsCompanies should consider appointing board members or chairpersons from more religious hometowns, as the empirical results of this study support the positive effects of chairpersons’ hometown religiosity on financial reporting quality.Originality/valueTo the best of the authors’ knowledge, the current study is among the first to demonstrate the relationship between the religiosity level of the chairpersons’ hometown and the financial reporting quality of companies. The study introduces unique hometown religiosity proxies and controls for various variables related to corporate governance, chairperson attributes, company characteristics, and audit firm characteristics.

Associations between varicose veins and heart failure: A genetic correlation and mendelian randomization study.

Varicose veins and heart failure (HF) are increasingly prevalent. Although numbers of observational studies have indicated that varicose veins might contribute to the risk of HF, the causal relationship between them remains unclear due to the uncontrolled confounding factors and reverse causation bias. Therefore, this study aimed to explore the potential causal relationship between varicose veins and HF. Based on publicly released genome-wide association studies (GWAS), gene correlation was assessed using linkage disequilibrium score (LDSC) regression, and we conducted a two-sample Mendelian randomization (TSMR) analysis to infer the causal relationship. We performed the Inverse variance weighted (IVW) method as the primary analysis, and used Weighted median, MR-Egger, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to detect and correct for horizontal pleiotropy. LDSC revealed there was a positive genetic correlation between varicose veins and HF (rg = 0.1726184, Se = 0.04511803, P = .0001). The results of the IVW method indicated that genetically predicted varicose veins were associated with an increased risk of HF (odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.01-1.06; P = .009). Our findings illustrated the significant causal effect of varicose veins on HF, suggesting that people with varicose veins might have a higher risk of HF. The results provided a novel and important perspective into the development mechanism of HF.

Action-Based Fiscal Consolidations and Economic Growth

This paper tests the hypothesis that action-based fiscal consolidations have a negative effect on GDP growth. Using the IMF’s dataset on action-based fiscal consolidations, instrumental variables’ regressions show that action-based fiscal consolidations have a significant positive effect on GDP growth. The instrumental variables’ regressions also show that action-based fiscal consolidations significantly increase investment and productivity. The findings presented in this paper thus strongly reject the hypothesis that action-based fiscal consolidations reduce growth. The paper argues that least squares estimates presented in previous literature suffer from negative reverse causality bias: GDP growth has a significant positive effect on both the likelihood and the magnitude of action-based fiscal consolidations. To uncover causal effects of action-based fiscal consolidations, researchers need to use an instrumental variables approach.

Housing Market and Household Consumption in Urban China: A Debt Perspective

Urbanization precipitates substantial economic transformations, with housing markets playing a pivotal role. The expansion of cities escalates housing demand, subsequently increasing housing debt, which is a crucial factor influencing household consumption. This study utilizes data from six rounds of the China Family Panel Studies (CFPS) spanning 2010 to 2020 to investigate the impact of housing debt on household consumption in urban China. Given the dynamics changes in housing debt status, as well as the endogeneity problems caused by reverse causality and selection bias between households’ debt decisions and consumption behavior, this study employs both the difference-in differences with multiple periods and groups (DIDM) model and the two-way fixed effects model. The results show that the average consumption expenditure of households with housing debt is 14% higher than those without. A 1% increase in housing debt size correlates with a 0.011% rise in consumption. Moreover, this positive effect is more pronounced among low-income households and those with older household heads, as well as those owning multiple properties. Compared to non-durable consumption, the impact of housing debt is more substantial on durable consumption. Further mechanism analysis reveals that the effect of housing debt on household consumption is primarily driven by an increase in housing assets, spurred by the rising housing prices. This study underscores the importance of integrating housing debt management within the framework of sustainable urban development, which not only ensures equitable access to housing but also fosters the promotion of sustainable consumption.

Association of tooth location, occlusal support and chewing ability with cognitive decline and incident dementia.

Emerging evidence suggests association of tooth loss with impaired cognition. However, the differential effects of anterior versus posterior tooth loss, occlusal support loss and chewing ability are not considered comprehensively. We conducted cross-sectional (N = 4036) and longitudinal analyses (N = 2787) on data from Health 2000 and 2011 Surveys for associations of posterior occlusal support loss, anterior versus posterior tooth loss, and chewing ability with baseline cognition and 11-year cognitive decline. Additionally, 15-year incident dementia risk was investigated (N = 4073). After considering relevant confounders and potential reverse causality bias, posterior occlusal support loss significantly increased dementia risk across all categories indicative of posterior occlusal support loss (hazard ratios [HRs] between 1.99 and 2.89). Bilateral inadequate posterior occlusal support was associated with 11-year decline in overall cognition (odds ratio [OR] = 1.48:1.00-2.19), and unilateral inadequate posterior occlusal support with total immediate (OR = 1.62:1.14-2.30) and delayed recall decline (OR = 1.45:1.03-2.05). Moreover, posterior tooth loss was associated with dementia (HR = 2.23:1.27-3.91) and chewing ability with total immediate decline (OR = 1.80:1.04-3.13). Posterior tooth and occlusal support loss significantly increases dementia risk. The impact of posterior occlusal support loss appears to be dose-dependent, and this effect is distinct from that of dentures. Dental healthcare services should be particularly attentive to the state of posterior dentition. Further studies exploring possible mechanisms are warranted.

Physical Activity and Cognitive Decline Among Older Adults

Physical activity is associated with the risk for cognitive decline, but much of the evidence in this domain comes from studies with short follow-ups, which is prone to reverse causation bias. To examine how length of follow-up, baseline age, physical activity amount, and study quality modify the longitudinal associations of physical activity with cognition. Observational studies of adults with a prospective follow-up of at least 1 year, a valid baseline cognitive measure or midlife cohort, and an estimate of the association of baseline physical activity and follow-up cognition were sought from PsycInfo, Scopus, CINAHL, Web of Science, SPORTDiscus, and PubMed, with the final search conducted on November 2, 2022. Two independent researchers screened titles with abstracts and full-text reports. Two reviewers independently assessed study quality and extracted data. Pooled estimates of association were calculated with random-effects meta-analyses. An extensive set of moderators, funnel plots, and scatter plots of physical activity amount were examined. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Pooled estimates of the associations between physical activity and global cognition, as well as specific cognitive domains, were examined. A total of 104 studies with 341 471 participants were assessed. Analysis of binary outcomes included 45 studies with 102 452 individuals, analysis of follow-up global cognition included 14 studies with 41 045 individuals, and analysis of change in global cognition included 25 studies with 67 463 individuals. Physical activity was associated with a decreased incidence of cognitive impairment or decline after correction for funnel plot asymmetry (pooled risk ratio, 0.97; 95% CI, 0.97-0.99), but there was no significant association in follow-ups longer than 10 years. Physical activity was associated with follow-up global cognition (standardized regression coefficient, 0.03; 95% CI, 0.02-0.03) and change in global cognition (standardized regression coefficient, 0.01; 95% CI, 0.01 to 0.02) from trim-and-fill analyses, with no clear dose-response or moderation by follow-up length, baseline age, study quality or adjustment for baseline cognition. The specific cognitive domains associated with physical activity were episodic memory (standardized regression coefficient, 0.03; 95% CI, 0.02-0.04) and verbal fluency (standardized regression coefficient, 0.05; 95% CI, 0.03-0.08). In this meta-analysis of the association of physical activity with cognitive decline, physical activity was associated with better late-life cognition, but the association was weak. However, even a weak association is important from a population health perspective.

Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes

Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Treatment with GLP-1RA was compared with basal insulin. Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. ClinicalTrials.gov Identifier: NCT02072902.

Low follistatin level is a causal risk factor for spontaneous abortion: a two-sample mendelian randomization study.

Recurrent pregnancy loss is a distressing event during pregnancy, and understanding its causal factors is crucial. Follistatin, a glycoprotein involved in folliculogenesis and embryogenesis, has been implicated as a potential contributor to the risk of spontaneous abortion. However, establishing a causal relationship requires rigorous investigation using robust methods. In this study, we utilized mendelian randomization (MR), a powerful genetic epidemiological approach, to examine the causal relationship between follistatin levels and spontaneous abortion. We obtained instrumental variables strongly associated with follistatin levels from large-scale genome-wide association from the IEU database. The inverse variance weighting (IVW) method was taken as gold standard. We also performed sensitivity test to evaluate the robustness of our result. MR analysis revealed a significant causal relationship between low follistatin levels and spontaneous abortion (p = 0.03). Sensitivity analyses, including pleiotropy test, heterogeneity test, and leave-one-out analysis, all supported the robustness of our findings. Our study provides compelling evidence supporting the causal relationship between low follistatin levels and increased risk of spontaneous abortion. These findings underscore the importance of follistatin in the etiology of spontaneous abortion and suggest potential preventive interventions. Modulating follistatin levels or relevant pathways could hold promise for reducing the incidence of spontaneous abortion and improving reproductive outcomes. The utilization of MRs strengthens the validity of our results by mitigating confounding and reverse causality biases. Further research is needed to elucidate the underlying molecular mechanisms and explore therapeutic strategies targeting follistatin levels.

Reverse causation bias: A simulation study comparing first- and second-line treatments with an overlap of symptoms between treatment indication and studied outcome.

Reverse causation is a challenge in many drug-cancer associations, where the cancer symptoms are potentially mistaken for drug indication symptoms. However, tools to assess the magnitude of this type of bias are currently lacking. We used a simulation-based approach to investigate the impact of reverse causation on the association between the use of topical tacrolimus and cutaneous T-cell lymphoma (CTCL) in a multinational, population-based study using topical corticosteroids (TCS) as comparator. We used a multistate model to simulate patients' use over time of a first- (TCS) and second-line treatment (topical tacrolimus), onset of atopic dermatitis (indication for drugs) and CTCL (the studied outcome). We simulated different scenarios to mimic real-life use of the two treatments. In all scenarios, it was assumed that there was no causal effect of the first- or second-line treatment on the occurrence of CTCL. Simulated data were analysed using Cox proportional hazards models. The simulated hazard ratios (HRs) of CTCL for patients treated with tacrolimus vs. TCS were consistently above 1 in all 9 settings in the main scenario. In our main analysis, we observed a median HR of 3.09 with 95% of the observed values between 2.11 and 4.69. We found substantial reverse causation bias in the simulated CTCL risk estimates for patients treated with tacrolimus vs. TCS. Reverse causation bias may result in a false positive association between the second-line treatment and the studied outcome, and this simulation-based framework can be adapted to quantify the potential reverse causation bias.

An assessment of bilateral debt swap financing indispensable for economic growth and environment sustainability: a policy implication for heavily indebted countries.

Bilateral debt swap is an innovative global financing mechanism designed to support heavily indebted countries (HICs). It is a debt-restructuring process involving donor countries forgiving debt owed by HICs in exchange for commitments to undertake projects on environment and socio-economic development. It is a unique approach designed to help heavily indebted countries get back on their feet. Effective debt swap financing can lead to both economic growth and environment sustainability, but they are challenging to implement. This study examines the impact of bilateral debt swap financing on economic growth and environment sustainability. For the purpose, we have used debt swap index developed with Kaiser-Meyer-Olkin (KMO) methodology. KMO widely used approach of Principle Component Analysis (PCA) to solve the problem of "over-identification" and make strong correlation among endogenous variables of interest. In order to validate the nexus empirically between bilateral debt swap financing with economic growth and environment sustainability, we have employed the Two-Step System Generalized Method of Moments (SYS-GMM) approach in 25 countries for the period of 2002 to 2021. This modern econometric method addresses endogeneity issues and controls for unobserved heterogeneity in panel data. At the same time, the technique addresses the simultaneity problem, reverse causality, and remove selection bias. Findings of the study shows that effective bilateral debt swap financing can boost economic growth and environment sustainability by investing domestic resources for targeted activities along with reduced debt burden. Empirical results reveal that 1% change in debt swap financing can lead to a maximum of 0.23% growth in the economy and 0.28% improvement in environment sustainability. However, it is important to note that in most empirical specifications, results are inconclusive. One possible reason for this is often ineffective debt swap practices coupled with inadequate monitoring and evaluation in HICs. Policymakers should focus on enhancing debt swap policies to promote economic growth and environment sustainability.