Assessing the Impact of Morphine on Adverse Outcomes in ACS Patients Treated with P2Y12 Inhibitors: Insights from Multiple Real-World Evidence.

Purpose: Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Patients and Methods: Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Results: Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. Conclusion: The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

Long-term PM2.5 exposure and early-onset diabetes: Does BMI link this risk?

OBJECTIVE: Limited studies investigated the association between high-level fine particulate matter (PM2.5) pollution and early-onset diabetes, leaving the possible metabolic mechanisms unclear. We assessed the association of cumulative PM2.5 exposure with diabetes, including early-onset, in high-pollution areas of China and explored whether metabolic factors mediated this association. METHODS: 124,204 participants (≥18 years) from 121 counties in Hunan province, China, were enrolled between 2005 and 2020, with follow-up until 2021. The ground-level air pollution concentrations at each participant's residence were calculated using a high-quality dataset in China. The independent association of PM2.5 with incident diabetes and early-onset diabetes was assessed by Cox proportional hazards models. Restricted cubic splines were utilized to establish the exposure-response relationships. The role of metabolism-related mediators was estimated by mediation analysis. RESULTS: During a median follow-up of 8.47 (IQR, 6.65-9.82) years, there were 3650 patients with new-onset diabetes. Each 1 µg/m3 increase in the level of cumulative PM2.5 exposure was positively related to an increased incidence of diabetes (HR 1.177, 95 % CI 1.172-1.181) among individuals in the PM2.5 > 50 µg/m3 group after adjusting for multiple variables. The relationship of the PM2.5 dose-response curve for diabetes was non-linear. Significant associations between PM2.5 exposure and early-onset diabetes risk were observed, with this risk showing an increase with the earlier age of early diabetes onset. Males, young individuals (≤45 years), and those with a lower body mass index (BMI <24 kg/m2) appeared to be more susceptible to diabetes. Moreover, change in BMI significantly mediated 31.06 % of the PM2.5-diabetes relationship. CONCLUSIONS: Long-term cumulative PM2.5 exposure increased the risk of early-onset diabetes, which is partially mediated by BMI. Sustained air pollution control measures, priority protection of vulnerable individuals, and effective management of BMI should be taken to reduce the burden of diabetes.

Non-high-density lipoprotein cholesterol levels as a risk factor for short-term mortality in elderly Chinese: a large-scale, population-based cohort study.

OBJECTIVES: To explore the association between non-high-density lipoprotein (non-HDL) and mortality risk, both short-term and long-term, in Chinese people. DESIGN: A prospective cohort study. SETTING: The National Basic Public Health Service (BPHS) in China. PARTICIPANTS: Including 621 164 elderly individuals around Hunan Province who underwent healthcare management receiving check-ups in China BPHS from 2010 to 2020. EXCLUSION CRITERIA: (1) missing information on gender; (2) missing records of lipid screening; (3) missing information on key covariates; and (4) missing records of comorbidities (cardiovascular disease, hypertension, diabetes, cancer.) PRIMARY AND SECONDARY OUTCOME MEASURES: The study's primary endpoint was all-cause and cause-specific mortality, sourced from Hunan's CDC(Center for Disease Control and Prevention)-operated National Mortality Surveillance System, tracking participants until 24 February 2021. RESULTS: 26 758 (4.3%) deaths were recorded, with a median follow-up of 0.83 years. Association between non-HDL and mortality was non-linear after multivariable adjustment, with the optimum concentration (OC) being 3.29 and 4.85 mmol/L. Compared with OC, the risk increased by 1.12-fold for non-HDL <3.29 mmol/L (HR: 1.12 (1.09 to 1.15)) and 1.08-fold for non-HDL ≥4.85 mmol/L (HR: 1.08 (1.02 to 1.13)) for all-cause mortality. Furthermore, there is also an increased risk of cardiovascular mortality (HR for non-HDL <3.29: 1.10 (1.06 to 1.32) and HR for non-HDL ≥4.85: 1.07 (1.01 to 1.14)). However, cancer mortality risk was significantly increased only for non-HDL <3.29 mmol/L (HR: 1.11 (1.04 to 1.18)). Non-optimum concentration of non-HDL had significant effects on both the long-term and the short-term risk of mortality, especially for risks of mortality for all-cause (log HR:0 .086 (0.038 to 0.134)), cardiovascular (log HR:0 .082 (0.021 to 0.144)), and cancer (log HR:0 .187 (0.058 to 0.315)) within 3 months. A two-sided value of p <0.05 was considered to be statistically significant. CONCLUSIONS: Non-HDL was non-linearly associated with the risk of mortality, and non-optimal concentrations of non-HDL significantly increased short-term mortality in elderly Chinese, which needs more attention for cardiovascular disease prevention.

Global burden of type 2 diabetes attributable to non-high body mass index from 1990 to 2019.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) currently was increased in some countries of the world like China. However, the epidemiological trends of T2DM attributable to non-high body mass index (BMI) remain unclear. Thus, we aimed to describe the burden of T2DM attributable to non-high BMI. METHODS: To estimate the burden of T2DM attributable to non-high BMI, data from the Global Burden of Disease Study 2019 were used to calculate the deaths and disability-adjusted life years (DALYs) by age, sex, year, and location. The estimated annual percentage change (EAPC) was applied in the analysis of temporal trends in T2DM from 1990 to 2019. RESULTS: Globally in 2019, the number of death cases and DALYs of T2DM attributable to non-high BMI accounted for 57.9% and 48.1% of T2DM-death from all risks, respectively. Asia accounted for 59.5% and 63.6% of the global non-high-BMI-related death cases and DALYs of T2DM in 2019, respectively. From 1990 to 2019, regions in the low-income experienced a rise in DALYs attributable to non-high BMI. As compared to other age groups, older participants had higher deaths and DALYs of T2DM attributable to non-high BMI. The death and DALY rates of T2DM due to non-high BMI were higher in males and people in regions with low socio-demographic index (SDI) countries. CONCLUSIONS: The burden of T2DM attributable to non-high BMI is higher in the elderly and in people in regions with low- and middle-SDI, resulting in a substantial burden on human health and the social cost of healthcare.

Association of joint exposure to various ambient air pollutants during adolescence with blood pressure in young adulthood.

The association of various air pollutants exposure during adolescence with blood pressure (BP) in young adulthood is uncertain. We intended to evaluate the long-term association of individual and joint air pollutants exposure during adolescence with BP in young adulthood. This cross-sectional study of incoming students was conducted in five geographically disperse universities in China during September and October 2018. Mean concentrations of particulate matter with diameters ≤2.5 µm (PM2.5 ), ≤10 µm (PM10 ), nitrogen dioxides (NO2 ), carbon monoxide (CO), sulfur dioxide (SO2 ), and ozone (O3 ) at participants' residential addresses during 2013-2018 were collected from the Chinese Air Quality Reanalysis dataset. Generalized linear mixed models (GLM) and quantile g-computation (QgC) models were utilized to estimate the association between individual and joint air pollutants exposure and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). A total of 16,242 participants were included in the analysis. The GLM analyses showed that PM2.5 , PM10 , NO2 , CO, and SO2 were significantly positively associated with SBP and PP, while O3 was positively associated with DBP. The QgC analyses indicated that long-term exposure to a mixture of the six air pollutants had a significant positive joint association with SBP and PP. In conclusion, air pollutant co-exposure during adolescence may influence BP in young adulthood. The findings of this study emphasized the impacts of multiple air pollutants interactions on potential health and the need of minimizing pollution exposures in the environment.

Association of long-term ambient fine particulate matter (PM2.5) and incident non-alcoholic fatty liver disease in Chinese adults.

Air pollution is increasingly recognized as an important environmental risk factor for non-alcoholic fatty liver disease (NAFLD). However, epidemiologic evidence on long-term exposure to high air pollution concentrations with incident NAFLD is still very limited. Here, we constructed a population-based dynamic cohort involving 17,106 subjects who were enrolled between 2005 and 2013 and subsequently followed until 2017, combined with a high-resolution ambient fine particulate matter ≤2.5 µm (PM2.5) dataset, to investigate the association of long-term PM2.5 exposure (cumulative annual average levels ranged from 36.67 to 111.16 µg/m3) with NAFLD incidence (N = 4,640). We estimated the adjusted hazard ratio (HR) for incident NAFLD among those exposed to the highest quartile of PM2.5 was 2.04 [95% confidence interval (CI), 1.80-2.30] compared with individuals exposed to the lowest quartile of PM2.5. The dose-response relationships for PM2.5 are non-linear for NAFLD across the exposure distribution. Further stratified analyses revealed that lean (<23 kg/m2), younger (<40-year-old), and women individuals appeared more vulnerable to the harmful effects of PM2.5 exposure. Our study suggests a greater long-term high ambient PM2.5 exposure is associated with an increased risk of NAFLD in Chinese adults, particularly in specific groups, including lean, women, and younger people.

Gut microbiome and risk of ischaemic stroke: a comprehensive Mendelian randomization study.

AIMS: Increasing evidence implicates the microbiome as a susceptibility factor for ischaemic stroke (IS). Interpretation of this evidence is difficult, for the composition of the microbiome is influenced by various factors and might affect differently in IS subtypes. We aim to determine if the specific gut microbiome is causally associated with IS subtypes and suggest potential approaches for stroke prevention. METHODS AND RESULTS: We conducted a two-sample Mendelian randomization (MR) analysis to test the causal relationship between gut microbiome and IS subtypes. For exposure data, we extracted genetic variants associated with 194 bacterial traits from MiBioGen consortium (n = 18 340). For outcomes, we selected three IS subtypes including cardioembolic stroke (CES, n = 410 484), small vessel stroke (SVS, n = 198 048), and large artery stroke (LAS, n = 198 048). Additionally, we performed a sequence of sensitivity analyses to validate preliminary MR results. There were four, three, and four bacteria showing an increased risk for LAS, SVS, and CES, respectively, and there were five, six, and five bacteria leading a decreasing risk for LAS, SVS, and CES, respectively. Amongst these, the genus_Intestinimonas showed negative associations with LAS [odds ratio (OR) = 0.77, 95% confidence interval (CI) (0.61-0.98)] and SVS (0.85, 0.73-0.98). The genus_LachnospiraceaeNK4A136group was genetically associated with decreased risk of both SVS (0.81, 0.66-0.99) and CES (0.75, 0.60-0.94). CONCLUSION: The study revealed the causal effect of the abundance of specific bacterial features on the risk of IS subtypes. Notably, genus_Intestinimonas and genus_LachnospiraceaeNK4A136group displayed significant protection against more than one IS subtype, further suggesting potential applications of targeted probiotics in IS prevention.

This Mendelian randomization study supports the causal effects of the gut microbiome on ischaemic stroke. Several types of intestinal bacterial traits were detected to potentially increase or decrease the risk of incident ischaemic stroke. These may have prospects for the prevention of different ischaemic stroke subtypes. In addition, the clinical benefits of the gut microbiome should be further evaluated in future large-scale people research.

Association between trauma exposure and respiratory disease-A Mendelian randomization study.

Background: Trauma is a well-known risk factor for many disease, but the effect of trauma on respiratory disease is unclarified. In the present study, we aimed to evaluate the association between trauma and respiratory disease. Method: Using both United Kingdom biobank and Finnish biobank genome-wide association study data (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between trauma and respiratory disease. We used four methods including inverse-variance weighted (IVW), weighted median, Maximum likelihood, and MR-Egger in this MR analysis. The IVW MR was selected as the main method. We also performed multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of trauma exposure on respiratory disease. Results: In the main two-sample MR analysis, trauma exposure was significantly associated with increased risk of respiratory disease (OR 1.15, 95%CI: 1.05-1.25). Besides, there was no heterogeneity and horizontal pleiotropy observed in the sensitivity analysis. After adjusting for pack years of smoking and body mass index (BMI), trauma exposure retained its association with respiratory disease (OR, 1.13, 95%CI, 1.04-1.23 adjusted by pack years of smoking; and OR, 1.11, 95%CI, 1.04-1.18 adjusted by BMI). Conclusion: Our study discovered the association between trauma exposure and the increased risk of respiratory disease, suggesting the prevention and treatment with trauma to reduce the risk of respiratory disease.

Association of Long-term Ambient Fine Particulate Matter (PM2.5) and Incident CKD: A Prospective Cohort Study in China.

RATIONALE & OBJECTIVE: Increasing evidence has linked ambient fine particulate matter (ie, particulate matter no larger than 2.5 µm [PM2.5]) to chronic kidney disease (CKD), but their association has not been fully elucidated, especially in regions with high levels of PM2.5 pollution. This study aimed to investigate the long-term association of high PM2.5 exposure with incident CKD in mainland China. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 72,425 participants (age ≥18 years) without CKD were recruited from 121 counties in Hunan Province, China. EXPOSURE: Annual mean PM2.5 concentration at the residence of each participant derived from a long-term, full-coverage, high-resolution (1 × 1 km2), high-quality dataset of ground-level air pollutants in China. OUTCOMES: Incident CKD during the interval between the baseline examination of each participant (2005-2017) and the end of follow-up through 2018. ANALYTICAL APPROACH: Cox proportional hazards models were used to estimate the independent association of PM2.5 with incident CKD and the joint association of PM2.5 with temperature or humidity on the development of PM2.5-related CKD. Restricted cubic splines were used to model exposure-response relationships. RESULTS: Over a median follow-up of 3.79 (IQR, 2.03-5.48) years, a total of 2,188 participants with incident CKD were identified. PM2.5 exposure was associated with incident CKD with an adjusted hazard ratio of 1.71 (95% CI, 1.58-1.85) per 10-µg/m3 greater long-term exposure. Multiplicative interactions between PM2.5 and humidity or temperature on incident CKD were detected (all P < 0.001 for interaction), whereas an additive interaction was detected only for humidity (relative risk due to interaction, 3.59 [95% CI, 0.97-6.21]). LIMITATIONS: Lack of information on participants' activity patterns such as time spent outdoors. CONCLUSIONS: Greater long-term ambient PM2.5 pollution is associated with incident CKD in environments with high PM2.5 exposure. Ambient humidity has a potentially synergetic effect on the association of PM2.5 with the development of CKD. PLAIN-LANGUAGE SUMMARY: Exposure to a form of air pollution known as fine particulate matter (ie, particulate matter ≤2.5 µm [PM2.5]) has been linked to an increased risk of chronic kidney disease (CKD), but little is known about how PM2.5 affects CKD in regions with extremely high levels of PM2.5 pollution. This longitudinal cohort study in China investigates the effect of PM2.5 on the incidence of CKD and whether temperature or humidity interact with PM2.5. Our findings suggest that long-term exposure to high levels of ambient PM2.5 significantly increased the risk of CKD in mainland China, especially in terms of cumulative average PM2.5. The associations of PM2.5 and incident CKD were greater in high-humidity environments. These findings support the recommendation that reducing PM2.5 pollution should be a priority to decrease the burden of associated health risks, including CKD.

Diet-Derived Circulating Antioxidants and Risk of Stroke: A Mendelian Randomization Study.

BACKGROUND: Oxidative stress is crucial in stroke pathogenesis. Many cohort-based studies suggested that the intake of exogenous antioxidants originated from food may prevent stroke. However, the corresponding randomized controlled trials did not show diet-derived antioxidants have a protective effect on stroke. OBJECTIVES: To examine the association of genetically proxied diet-derived antioxidants with stroke risk using Mendelian randomization. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of diet-derived antioxidants on stroke risk. For exposure data, we extracted genetic variants as instrumental variables (IVs) that are strongly associated with frequently used diet-derived antioxidants, including vitamin C, vitamin E (α-tocopherol, γ-tocopherol), carotene, retinol, zinc, and selenium, from a large-scale genome-wide association study (GWAS). We obtained IVs' corresponding effect estimates on the risk of total stroke and ischemic stroke from a GWAS meta-analysis with 40,585 cases and 406,111 controls. Finally, we applied five types of Mendelian randomization analysis to obtain preliminary MR results and performed four three kinds of sensitivity analysis to verify them. RESULTS: According to the primary MR estimations and further sensitivity analyses, we established two robust associations after Bonferroni correction: genetically proxied circulating γ-tocopherol was causally associated with total stroke [odds ratio (OR) = 0.68, 95% confidence interval (CI) (0.52-0.88), p = 3.78E - 03] and ischemic stroke [OR = 0.66, 95% CI (0.51-0.86), p = 2.34E - 03]. There was no evidence to support the causal effect of other diet-derived antioxidants on the risk of total stroke and ischemic stroke. CONCLUSION: Our study revealed a protective impact of genetic susceptibility to high circulating γ-tocopherol levels on stroke risk, providing new information on the potential therapeutic targets for primary stroke prevention.

Inflammatory Cytokines and Risk of Ischemic Stroke: A Mendelian Randomization Study.

Background: Observational studies have revealed the association between some inflammatory cytokines and the occurrence of ischemic stroke, but the causal relationships remain unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of thirty inflammatory cytokines and the risk of ischemic stroke. For exposure data, we collected genetic variants associated with inflammatory cytokines as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis from Finland (sample size up to 8,293). For the outcome data, we collected summary data of ischemic stroke from a large-scale GWAS meta-analysis involved 17 studies (34,217 cases and 406,111 controls). We further performed a series of sensitivity analyses as validation of primary MR results. Results: According to the primary MR estimations and further sensitivity analyses, we established one robust association after Bonferroni correction: the odds ratio (95% CI) per unit change in genetically increased IL-4 was 0.84 (0.89-0.95) for ischemic stroke. The chemokine MCP3 showed a nominally significant association with ischemic stroke risk (OR: 0.93, 95% CI: 0.88-0.99, unadjusted p < 0.05). There was no evidence of a causal effect of other inflammatory cytokines and the risk of ischemic stroke. Conclusions: Our study suggested that genetically increased IL-4 levels showed a protective effect on the risk of ischemic stroke, which provides important new insights into the potential therapeutic target for preventing ischemic stroke.