Maternal Exposure to PM2.5 and the Risk of Congenital Heart Defects in 1.4 Million Births: A Nationwide Surveillance-Based Study.

BACKGROUND: Evidence remains limited about the association of maternal exposure to ambient fine particulate matter (airborne particles with an aerodynamic diameter ≤2.5 µm [PM2.5]) with fetal congenital heart defects (CHDs) in highly polluted regions, and few studies have focused on preconception exposure. METHODS: Using a nationwide surveillance-based case-control design in China, we examined the association between maternal exposure to PM2.5 during periconception (defined as 3 months before conception until 3 months into pregnancy) and risk of CHD in offspring. The study included 1 434 998 births involving 7335 CHDs from 2014 through 2017 on the basis of the National Population-Based Birth Defects Surveillance System, covering 30 provinces, municipalities, or municipal districts in China. We assigned maternal PM2.5 exposure during the periconception period to each participant using satellite-based PM2.5 concentrations at 1-km spatial resolution. Multilevel logistic regression models were used to calculate the multivariable-adjusted odds ratio and 95% CI for CHDs in offspring associated with maternal PM2.5 exposure, and the exposure-response association was investigated using restricted cubic spline analysis. Subgroup or sensitivity analyses were conducted to identify factors that may modify the association. RESULTS: The average maternal exposure to PM2.5 levels across all participants was 56.51 µg/m3 (range, 10.95 to 182.13 µg/m3). For each 10 µg/m³ increase in maternal PM2.5 exposure, the risk of CHDs in offspring was increased by 2% (odds ratio, 1.02 [95% CI, 1.00 to 1.05]), and septal defect was the most influenced subtype (odds ratio, 1.04 [95% CI, 1.01 to 1.08]). The effect of PM2.5 on CHD risk was more pronounced during the preconception period. Mothers <35 years of age, those living in northern China, and those living in low-income areas were more susceptible to PM2.5 exposure than their counterparts (all P<0.05). PM2.5 exposure showed a linear association with total CHDs or specific CHD types. CONCLUSIONS: High maternal PM2.5 exposure, especially during the preconception period, increases risk of certain types of CHD in offspring. These findings are useful for CHD prevention and highlight the public health benefits of improving air quality in China and other highly polluted regions.

Fine Particulate Matter Exposure, Genetic Susceptibility, and the Risk of Incident Stroke: A Prospective Cohort Study.

BACKGROUND: Both genetic factors and environmental air pollution contribute to the risk of stroke. However, it is unknown whether the association between air pollution and stroke risk is influenced by the genetic susceptibilities of stroke and its risk factors. METHODS: This prospective cohort study included 40 827 Chinese adults without stroke history. Satellite-based monthly fine particulate matter (PM2.5) estimation at 1-km resolution was used for exposure assessment. Based on 534 identified genetic variants from genome-wide association studies in East Asians, we constructed 6 polygenic risk scores for stroke and its risk factors, including atrial fibrillation, blood pressure, type 2 diabetes, body mass index, and triglyceride. The Cox proportional hazards model was applied to evaluate the hazard ratios and 95% CIs for the associations of PM2.5 and polygenic risk score with incident stroke and the potential effect modifications. RESULTS: Over a median follow-up of 12.06 years, 3147 incident stroke cases were documented. Compared with the lowest quartile of PM2.5 exposure, the hazard ratio (95% CI) for stroke in the highest quartile group was 2.72 (2.42-3.06). Among individuals at high genetic risk, the relative risk of stroke was 57% (1.57; 1.40-1.76) higher than those at low genetic risk. Although no statistically significant interaction was found, participants with both the highest PM2.5 and high genetic risk showed the highest risk of stroke, with ≈4× that of the lowest PM2.5 and low genetic risk group (hazard ratio, 3.55 [95% CI, 2.84-4.44]). Similar upward gradients were observed in the risk of stroke when assessing the joint effects of PM2.5 and genetic risks of blood pressure, type 2 diabetes, body mass index, atrial fibrillation, and triglyceride. CONCLUSIONS: Long-term exposure to PM2.5 was associated with a higher risk of incident stroke across different genetic susceptibilities. Our findings highlighted the great importance of comprehensive assessment of air pollution and genetic risk in the prevention of stroke.

Utilizing a novel model of PANoptosis-related genes for enhanced prognosis and immune status prediction in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is the most common histopathologic type of renal cell carcinoma. PANoptosis, a cell death pathway that involves an interplay between pyroptosis, apoptosis and necroptosis, is associated with cancer immunity and development. However, the prognostic significance of PANoptosis in KIRC remains unclear. RNA-sequencing expression and mutational profiles from 532 KIRC samples and 72 normal samples with sufficient clinical data were retrieved from the Cancer Genome Atlas (TCGA) database. A prognostic model was constructed using differentially expressed genes (DEGs) related to PANoptosis in the TCGA cohort and was validated in a Gene Expression Omnibus (GEO) cohorts. Incorporating various clinical features, the risk model remained an independent prognostic factor in multivariate analysis, and it demonstrated superior performance compared to unsupervised clustering of the 21 PANoptosis-related genes alone. Further mutational analysis showed fewer VHL and more BAP1 alterations in the high-risk group, with alterations in both genes also associated with patient prognosis. The high-risk group was characterized by an unfavorable immune microenvironment, marked by reduced levels of CD4 + T cells and natural killer cells, but increased M2 macrophages and regulatory T cells. Finally, the risk model was predictive of response to immune checkpoint blockade, as well as sensitivity to sunitinib and paclitaxel. The PANoptosis-related risk model developed in this study enables accurate prognostic prediction in KIRC patients. Its associations with the tumor immune microenvironment and drug efficacy may offer potential therapeutic targets and inform clinical decisions.

Association of genetic variants related to combined lipid-lowering and antihypertensive therapies with risk of cardiovascular disease: 2 × 2 factorial Mendelian randomization analyses.

BACKGROUND: Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes. METHODS: We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of ß-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization. RESULTS: Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94-0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94-0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92-0.97; P = 0.87 for interaction). CONCLUSIONS: Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.

Left Versus Right Destroyed Lung Pneumonectomy: Long Term Prognosis and Key Factors Associated With Poor Treatment Outcomes.

INTRODUCTION: To compare and analyze postoperative short-term and long-term prognosis of destroyed lung (DL) disease patients undergoing left versus right pneumonectomy and to identify potential key factors associated with poor treatment outcomes. METHODS: Retrospective analysis was conducted on clinical data of 128 DL patients who underwent pneumonectomy in the thoracic surgery department of the Beijing Chest Hospital from November 2001 to May 2022. Cases were assigned to two groups according to lesion site: a left pneumonectomy group (104 cases) and right pneumonectomy group (24 cases). Postoperative short-term and long-term DL disease clinical features and prognostic factors were analyzed and compared between groups. RESULTS: As compared with the left pneumonectomy group, the right pneumonectomy group experienced greater rates of preoperative diabetes, chronic pulmonary aspergillosis, intraoperative blood loss, postoperative respiratory failure, rehospitalization, tuberculosis (TB) recurrence, bronchopleural fistula (BPF) and empyema. Binary logistic regression analysis revealed a potential correlation between chronic pulmonary aspergillosis and increased odds of developing secondary respiratory failure (adjusted odds ratio: 5.234, 95% confidence interval [CI]: 1.768-15.498). Results of Cox Proportional Hazards Model regression analysis suggested that right pneumonectomy was correlated with increased odds of TB recurrence (adjusted hazard ratio: 4.017, 95% CI: 1.282-12.933) and BPF/empyema (adjusted hazard ratio: 5.655, 95% CI: 1.254-25.505). CONCLUSIONS: Compared to the group undergoing left pneumonectomy, patients with DL who undergo right-sided pneumonectomy may be at a heightened risk of experiencing secondary postoperative TB recurrence and BPF or edema. It is advised to exercise utmost caution and deliberate consideration of these potential risks when contemplating pneumonectomy, with the intention of proactively preventing adverse events.

The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening.

NLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1ß and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole series of high affinity, reversible inhibitors of NLRP3 activation through screening of DNA-encoded libraries and the potent lead compound 3 (BAL-0028, IC50 = 25 nM) that was identified directly from the screen. SPR studies showed that compound 3 binds tightly (KD range 104-123 nM) to the NACHT domain of NLRP3. A CADD analysis of the interaction of compound 3 with the NLRP3 NACHT domain proposes a binding site that is distinct from those of ADP and MCC950 and includes specific site interactions. We anticipate that compound 3 (BAL-0028) and other members of this novel indazole class of neutral inhibitors will demonstrate significantly different physical, biochemical, and biological properties compared to NLRP3 inhibitors previously identified.

Value of preoperative evaluation of FEV1 in patients with destroyed lung undergoing pneumonectomy - a 20-year real-world study.

BACKGROUND: Clinical guidelines recommend a preoperative forced expiratory volume in one second (FEV1) of > 2 L as an indication for left or right pneumonectomy. This study compares the safety and long-term prognosis of pneumonectomy for destroyed lung (DL) patients with FEV1 ≤ 2 L or > 2 L. METHODS: A total of 123 DL patients who underwent pneumonectomy between November 2002 and February 2023 at the Department of Thoracic Surgery, Beijing Chest Hospital were included. Patients were sorted into two groups: the FEV1 > 2 L group (n = 30) or the FEV1 ≤ 2 L group (n = 96). Clinical characteristics and rates of mortality, complications within 30 days after surgery, long-term mortality, occurrence of residual lung infection/tuberculosis (TB), bronchopleural fistula/empyema, readmission by last follow-up visit, and modified Medical Research Council (mMRC) dyspnea scores were compared between groups. RESULTS: A total of 96.7% (119/123) of patients were successfully discharged, with 75.6% (93/123) in the FEV1 ≤ 2 L group. As compared to the FEV1 > 2 L group, the FEV1 ≤ 2 L group exhibited significantly lower proportions of males, patients with smoking histories, patients with lung cavities as revealed by chest imaging findings, and patients with lower forced vital capacity as a percentage of predicted values (FVC%pred) (P values of 0.001, 0.027, and 0.023, 0.003, respectively). No significant intergroup differences were observed in rates of mortality within 30 days after surgery, incidence of postoperative complications, long-term mortality, occurrence of residual lung infection/TB, bronchopleural fistula/empyema, mMRC ≥ 1 at the last follow-up visit, and postoperative readmission (P > 0.05). CONCLUSIONS: As most DL patients planning to undergo left/right pneumonectomy have a preoperative FEV1 ≤ 2 L, the procedure is generally safe with favourable short- and long-term prognoses for these patients. Consequently, the results of this study suggest that DL patient preoperative FEV1 > 2 L should not be utilised as an exclusion criterion for pneumonectomy.

Analysis of clinical characteristics of different types of lung function impaiement in TDL patients.

AIM: The clinical characteristics associated with pulmonary function decline in patients with Tuberculosis-destroyed lung (TDL) remain uncertain. We categorize them based on the pattern of pulmonary function impairment, distinguishing between restrictive spirometric pattern (RSP) and obstructive spirometric pattern (OSP). We aim to compare the severity of these patterns with the clinical characteristics of TDL patients and analyze their correlation. METHOD: We conducted a retrospective analysis on the clinical data of TDL patients who underwent consecutive pulmonary function tests (PFT) from November 2002 to February 2023. We used the lower limit formula for normal values based on the 2012 Global Lung Function Initiative. We compared the clinical characteristics of RSP patients with those of OSP patients. The characteristics of RSP patients were analyzed using the tertiles of forced vital capacity percentage predicted (FVC% pred) decline based on PFT measurements, and the characteristics of OSP patients were analyzed using the tertiles of forced expiratory volume in 1 s percentage predicted (FEV1% pred) decline. RESULT: Among the RSP patients, those in the Tertile1 group (with lower FVC% pred) were more likely to have a higher of body mass index (BMI), spinal deformities, and C-reactive protein (CRP) compared to the other two groups (P for trend < 0.001, 0.027, and 0.013, respectively). Among OSP patients, those in the Tertile1 group (with lower FEV1% pred) showed an increasing trend in cough symptoms and contralateral lung infection compared to the Tertile 2-3 group (P for trend 0.036 and 0.009, respectively). CONCLUSION: For TDL patients, we observed that Patients with high BMI, a higher proportion of spinal scoliosis, and abnormal elevation of CRP levels were more likely to have reduced FVC. Patients with decreased FEV1% pred have more frequent cough symptoms and a higher proportion of lung infections on the affected side.

Association of Long-Term Exposure to Ambient Fine Particulate Matter with Atherosclerotic Cardiovascular Disease Incidence Varies across Populations with Different Predicted Risks: The China-PAR Project.

Previous studies have established a significant link between ambient fine particulate matter (PM2.5) exposure and atherosclerotic cardiovascular disease (ASCVD) incidence, but whether this association varies across populations with different predicted ASCVD risks was uncertain previously. We included 109,374 Chinese adults without ASCVD at baseline from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project. We obtained PM2.5 data of participants' residential address from 2000 to 2015 using a satellite-based spatiotemporal model. Participants were classified into low-to-medium and high-risk groups according to the ASCVD 10-year and lifetime risk prediction scores. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PM2.5 exposure-related incident ASCVD, as well as the multiplication and additive interaction, were calculated using stratified Cox proportional hazard models. The additive interaction between risk stratification and PM2.5 exposure was estimated by the synergy index (SI), the attributable proportion due to the interaction (API), and the relative excess risk due to interaction (RERI). Over the follow-up of 833,067 person-years, a total of 4230 incident ASCVD cases were identified. Each 10 µg/m3 increment of PM2.5 concentration was associated with 18% (HR: 1.18; 95% CI: 1.14-1.23) increased risk of ASCVD in the total population, and the association was more pronounced among individuals having a high predicted ASCVD risk than those having a low-to-medium risk, with the HR (95% CI) of 1.24 (1.19-1.30) and 1.11 (1.02-1.20) per 10 µg/m3 increment in PM2.5 concentration, respectively. The RERI, API, and SI were 1.22 (95% CI: 0.62-1.81), 0.22 (95% CI: 0.12-0.32), and 1.37 (95% CI: 1.16-1.63), respectively. Our findings demonstrate a significant synergistic effect on ASCVD between ASCVD risk stratification and PM2.5 exposure and highlight the potential health benefits of reducing PM2.5 exposure in Chinese, especially among those with high ASCVD risk.

His-Purkinje system pacing versus biventricular pacing in clinical efficacy: a systematic review and meta-analysis.

BACKGROUND: His-Purkinje system pacing (HPSP), including his-bundle pacing (HBP) and left bundle branch area pacing (LBBaP), imitates the natural conduction of the heart as an alternative to biventricular pacing (BVP) in cardiac resynchronization therapy (CRT). However, the feasibility and efficacy of HPSP were currently only evidenced by studies with a limited sample size, so this study aimed to provide a comprehensive assessment through a systematic review and meta-analysis. METHODS: In order to compare the clinical outcomes associated with HPSP and BVP in patients for CRT, PubMed, EMBASE, Cochrane Library and Web of Science database were searched from inception to April 10, 2023. Clinical outcomes of interest including QRS duration (QRSd), left ventricular (LV) function and New York Heart Association (NYHA) functional classification, pacing threshold, echocardiographic and clinical response, hospitalization rate of HF and all-cause mortality were also extracted and summarized for meta-analysis. RESULTS: A total of 13 studies (ten observational studies and three randomized studies) involving 1,121 patients were finally included. The patients were followed up for 6-27 months. Compared with BVP, CRT patients treated by HPSP presented shorter QRSd [mean difference (MD): -26.23 ms, 95% confidence interval (CI): -34.54 to -17.92, P < 0.001, I2 = 91%], greater LV functional improvement with increased left ventricular ejection fraction (LVEF) (MD: 6.01, 95% CI: 4.81 to 7.22, P < 0.001, I2 = 0%), decreased left ventricular end-diastolic dimension (LVEDD) (MD: -2.91, 95% CI: -4.86 to -0.95, P = 0.004, I2 = 35%), and more improved NYHA functional classification (MD: -0.45, 95% CI: -0.67 to -0.23, P < 0.001, I2 = 70%). In addition, HPSP was more likely to have higher echocardiographic [odds ratio (OR): 2.76, 95% CI: 1.74 to 4.39, P < 0.001, I2 = 0%], clinical (OR: 2.10, 95% CI: 1.16 to 3.80, P = 0.01, I2 = 0%) and super clinical (OR: 3.17, 95% CI: 2.09 to 4.79, P < 0.001, I2 = 0%) responses than BVP, and a lower hospitalization rate of HF (OR: 0.34, 95% CI: 0.22 to 0.51, P < 0.001, I2 = 0%), while presented no difference (OR: 0.68, 95% CI: 0.44 to 1.06, P = 0.09, I2 = 0%) in all-cause mortality compared with BVP. With threshold change taking into account, BVP was less stable than LBBaP (MD: -0.12 V, 95% CI: -0.22 to -0.03, P = 0.01, I2 = 57%), but had no difference with HBP (MD: 0.11 V, 95% CI: -0.09 to 0.31, P = 0.28, I2 = 0%). CONCLUSION: The present findings suggested that HPSP was associated with greater improvement of cardiac function in patients with indication for CRT and was a potential alternative to BVP to achieve physiological pacing through native his-purkinje system.

Clinical characteristics and predictive model of pulmonary tuberculosis patients with pulmonary fungal coinfection.

BACKGROUND: In clinical settings, pulmonary tuberculosis (PTB) patients were often found to have pulmonary fungal coinfection. This study aimed to assess the clinical characteristics of patients suffering from coinfection with TB and pulmonary fungal and construct a predictive model for evaluating the probability of pulmonary fungal coinfection in patients with pulmonary tuberculosis. METHODS: The present case-control study retrospectively collected information from 286 patients affected by PTB who received treatment from December 6,2016- December 6,2021 at Beijing Chest Hospital, Capital Medical University. As control subjects, patients with sex and address corresponding to those of the case subjects were included in the study in a ratio of 1:1. These 286 patients were randomly divided into the training and internal validation sets in a ratio of 3:1. Chi-square test and logistic regression analysis were performed for the training set, and a predictive model was developed using the selected predictors. Bootstrapping was performed for internal validation. RESULTS: Seven variables [illness course, pulmonary cavitation, broad-spectrum antibiotics use for at least 1 week, chemotherapy or immunosuppressants, surgery, bacterial pneumonia, and hypoproteinemia] were validated and used to develop a predictive model which showed good discrimination capability for both training set [area under the curve (AUC) = 0.860, 95% confidence interval (CI) = 0.811-0.909] and internal validation set (AUC = 0.884, 95% CI = 0.799-0.970). The calibration curves also showed that the probabilities predicted using the predictive model had satisfactory consistency with the actual probability for both training and internal validation sets. CONCLUSIONS: We developed a predictive model that can predict the probability of pulmonary fungal coinfection in pulmonary tuberculosis patients. It showed potential clinical utility.

The 17-y spatiotemporal trend of PM2.5 and its mortality burden in China.

Investigations on the chronic health effects of fine particulate matter (PM2.5) exposure in China are limited due to the lack of long-term exposure data. Using satellite-driven models to generate spatiotemporally resolved PM2.5 levels, we aimed to estimate high-resolution, long-term PM2.5 and associated mortality burden in China. The multiangle implementation of atmospheric correction (MAIAC) aerosol optical depth (AOD) at 1-km resolution was employed as a primary predictor to estimate PM2.5 concentrations. Imputation techniques were adopted to fill in the missing AOD retrievals and provide accurate long-term AOD aggregations. Monthly PM2.5 concentrations in China from 2000 to 2016 were estimated using machine-learning approaches and used to analyze spatiotemporal trends of adult mortality attributable to PM2.5 exposure. Mean coverage of AOD increased from 56 to 100% over the 17-y period, with the accuracy of long-term averages enhanced after gap filling. Machine-learning models performed well with a random cross-validation R2 of 0.93 at the monthly level. For the time period outside the model training window, prediction R2 values were estimated to be 0.67 and 0.80 at the monthly and annual levels. Across the adult population in China, long-term PM2.5 exposures accounted for a total number of 30.8 (95% confidence interval [CI]: 28.6, 33.2) million premature deaths over the 17-y period, with an annual burden ranging from 1.5 (95% CI: 1.3, 1.6) to 2.2 (95% CI: 2.1, 2.4) million. Our satellite-based techniques provide reliable long-term PM2.5 estimates at a high spatial resolution, enhancing the assessment of adverse health effects and disease burden in China.

A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study.

AIMS: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. METHODS AND RESULTS: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS. CONCLUSION: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.

Using genetics to assess the association of commonly used antihypertensive drugs with diabetes, glycaemic traits and lipids: a trans-ancestry Mendelian randomisation study.

AIMS/HYPOTHESIS: Diabetes and hyperlipidaemia are common comorbidities in people with hypertension. Despite similar protective effects on CVD, different classes of antihypertensive drugs have different effects on CVD risk factors, including diabetes, glucose metabolism and lipids. However, these pleiotropic effects have not been assessed in long-term, large randomised controlled trials, especially for East Asians. METHODS: We used Mendelian randomisation to obtain unconfounded associations of ACE inhibitors, ß-blockers (BBs) and calcium channel blockers (CCBs). Specifically, we used genetic variants in drug target genes and related to systolic BP in Europeans and East Asians, and applied them to the largest available genome-wide association studies of diabetes (74,124 cases and 824,006 controls in Europeans, 77,418 cases and 356,122 controls in East Asians), blood glucose levels, HbA1c, and lipids (LDL-cholesterol, HDL-cholesterol and triacylglycerols) (approximately 0.5 million Europeans and 0.1 million East Asians). We used coronary artery disease (CAD) as a control outcome and used different genetic instruments and analysis methods as sensitivity analyses. RESULTS: As expected, genetically proxied ACE inhibition, BBs and CCBs were related to lower risk of CAD in both ancestries. Genetically proxied ACE inhibition was associated with a lower risk of diabetes (OR 0.85, 95% CI 0.78-0.93), and genetic proxies for BBs were associated with a higher risk of diabetes (OR 1.05, 95% CI 1.02-1.09). The estimates were similar in East Asians, and were corroborated by systematic review and meta-analyses of randomised controlled trials. In both ancestries, genetic proxies for BBs were associated with lower HDL-cholesterol and higher triacylglycerols, and genetic proxies for CCBs were associated with higher LDL-cholesterol. The estimates were robust to the use of different genetic instruments and analytical methods. CONCLUSIONS/INTERPRETATION: Our findings suggest protective association of genetically proxied ACE inhibition with diabetes, while genetic proxies for BBs and CCBs possibly relate to an unfavourable metabolic profile. Developing a deeper understanding of the pathways underlying these diverse associations would be worthwhile, with implications for drug repositioning as well as optimal CVD prevention and treatment strategies in people with hypertension, diabetes and/or hyperlipidaemia.

Development and Validation of a Nomogram for Prediction of QT Interval Prolongation in Patients Administered Bedaquiline-Containing Regimens in China: a Modeling Study.

Corrected QT duration (QTc) interval prolongation is the most frequent adverse event associated with bedaquiline (BDQ) use. It may affect the safety of antituberculosis therapy, which leads to the consequent demands of needing to monitor during therapy. Our objective was to establish and validate a prediction model for estimating the risk of QTc prolongation after initiation of BDQ-containing regimens to multidrug-resistant tuberculosis (MDR-TB) patients. We constructed an individualized nomogram model based on baseline demographic and clinical characteristics of each patient within a Chinese cohort during BDQ treatment. The generalizability of this model was further validated through use of externally acquired data obtained from Beijing Chest Hospital from 2019 to 2020. Overall, 1,215 and 165 patients were included in training and external validation cohorts, respectively, whereby during anti-TB drug treatment, QTc prolongation was observed in 273 (22.5%) and 29 (17.6%) patients within these respective cohorts, for whom QTc values were >500 ms in 86 (31.5%) and 10 (34.7%) patients, respectively. Next, a total of four Cox proportional hazards models were created and assessed; then, nomograms derived from the models were plotted based on independent predictors of clofazimine, baseline QTc interval, creatinine, extensive drug-resistance (XDR), moxifloxacin, levofloxacin, and sex. Nomogram analysis revealed concordance index values of 0.723 (95% confidence interval [CI], 0.695 to 0.750) for the training cohort and 0.710 (95% CI, 0.627 to 0.821) for the external validation cohort, thus indicating relatively fair agreement between predicted and observed probabilities of QTc prolongation occurrence based on data obtained during 8-week, 16-week, and 24-week anti-TB treatment of both cohorts. Taken together, results obtained using these models demonstrated that coadministration of clofazimine and abnormal baseline QTc interval significantly contributed to QTc prolongation development during MDR-TB patient treatment with a BDQ-containing anti-TB treatment regimen.

Key Factors Associated With Administration of Ventilator Support After Thymoma Resection.

INTRODUCTION: In clinical practice, some patients undergoing surgery for thymoma require post-surgical ventilator support, although, factors associated with administration of ventilator support are unclear. This study aimed to explore factors associated with incidence of post-surgical severe respiratory failure requiring ventilator support after thymoma resection. METHODS: Clinical data of patients who underwent thymoma re-section in our thoracic surgery department between January 2001 and February 2020 was retrospectively analyzed. Multiple logistic regression analysis was used to identify factors associated with patient need for post-surgical ventilator support after thymoma resection. RESULTS: Among 157 patients who underwent thymoma resection, 17.8% (28/157) required post-surgical ventilator support. Results of univariate analysis revealed that gender, myasthenia gravis (MG) grade, anti-MG medication use (neostigmine or prednisone), Masaoka thymoma stage, pulmonary function test index values, surgical approach, and intraoperative blood loss were associated with increased incidence of severe respiratory failure requiring post-operative ventilator support (P < 0.05). Results of multivariable logistic regression analysis revealed that median sternotomy, MG grade three status, and patient use of anti-MG drug treatments before thymoma resection surgery were associated with greater need for post-surgical ventilator support. CONCLUSIONS: Our data suggest that median sternotomy, MG grade three status, and preoperative use of anti-MG drugs are associated with greater incidence of severe respiratory failure requiring respiratory support after thymoma surgery. Therefore, patients with these risk factors should be closely monitored to reduce the incidence of severe postoperative respiratory failure.

Epidemiology of recurrent pulmonary tuberculosis by bacteriological features of 100 million residents in China.

BACKGROUND: Recurrence continues to place significant burden on patients and tuberculosis programmes worldwide, and previous studies have rarely provided analysis in negative recurrence cases. We characterized the epidemiological features of recurrent pulmonary tuberculosis (PTB) patients, estimated its probability associated with different bacteriology results and risk factors. METHODS: Using 2005-2018 provincial surveillance data from Henan, China, where the permanent population approximately were 100 million, we described the epidemiological and bacteriological features of recurrent PTB. The Kaplan-Meier method and Cox proportional hazard models, respectively, were used to estimate probability of recurrent PTB and risk factors. RESULTS: A total of 7143 (1.5%) PTB patients had recurrence, and of 21.1% were bacteriological positive on both laboratory tests (positive-positive), and of 34.9% were negative-negative. Compared with bacteriological negative recurrent PTB at first episodes, the bacteriological positive cases were more male (81.70% vs 72.79%; P < 0.001), higher mortality risk (1.78% vs 0.92%; P = 0.003), lower proportion of cured or completed treatment (82.81% vs 84.97%; P = 0.022), and longer time from onset to end-of-treatment. The probability of recurrence was higher in bacteriological positive cases than those in bacteriological negative cases (0.5% vs 0.4% at 20 months; P < 0.05). CONCLUSIONS: Based on patient's epidemiological characteristics and bacteriological type, it was necessary to actively enact measures to control their recurrent.

Long-term follow-up of tuberculosis-destroyed lung patients after surgical treatment.

BACKGROUND: To monitor dypsnea and mortality at 5 and 10 years, respectively, after surgical treatment of tuberculosis-destroyed lung (TDL) patients. METHODS: TDL patients treated surgically at Beijing Chest Hospital from November 2007 to June 2019 were monitored in this observational study. Follow-up assessments of respiratory function indicators and survival conducted 5 and 10 years post-surgery led to patient grouping based on mMRC score into a dyspnea group (mMRC ≥ 1) and a non-dyspnea group (mMRC = 0). Cox regression analysis detected effects of patient demographics, clinical characteristics, surgical factors and respiratory function on 5 year post-surgical survival. RESULTS: By study completion (June 30, 2020), 32 of 104 patients were lost and 72 completed follow-up for a study total of 258.9 person-years. 45 patients (62.5%, 45/72) had mMRC scores of 0, while 12 (16.7%, 12/72), 21 (36.2%, 21/58) and 27 (60.0%, 27/45) patients exhibited dyspnea by 1, 3 and 5 years post-surgery, respectively. Low lung carbon monoxide diffusion score (DLCO% pred) and scoliosis contributed to dyspnea occurrence. CONCLUSIONS: Most TDL patients lacked subjective dyspnea signs post-surgery, while dyspnea rates increased with time. Preoperative low lung diffusion function and Scoliosis were associated with factors for postoperative dyspnea. Surgical treatment increased TDL patient survival overall.

Paternal smoking and preterm birth: a population-based retrospective cohort study among non-smoking women aged 20-49 years in rural China.

BACKGROUND: To comprehensively evaluate the association of paternal smoking and preterm birth (PTB). METHODS: We performed a population-based retrospective cohort study in rural areas of China among 5,298,043 reproductive-aged couples who participated in the National Free Pre-Pregnancy Checkups Project (NFPCP), regarding outcome events that occurred in 2010-2016. Multivariate Cox proportional regression was used to estimate hazard ratio (HR) and 95% confident intervals (95%CI), and restricted cubic spline (RCS) were used to estimate the dose-response relationship. RESULTS: Compared to neither-smoker couples, the fully adjusted HR for PTB was 1.04 (95% CI, 1.03-1.04), 1.08 (0.96-1.22), and 1.11 (1.03-1.19) in the couples where only the female smoked, only the male smoked and both, respectively. HR of PTB for paternal smoking was 1.07 (1.06-1.07), compared with women without paternal smoking. Consistent with paternal smoking, preconception paternal smoking showed 1.07-fold higher risk of PTB (95%CI, 1.06-1.09). The multivariable-adjusted HRs of PTB were 1.05 (1.03-1.06), 1.04 (1.03-1.05), 1.05 (1.04-1.07), 1.07 (1.05-1.10) and 1.13 (1.12-1.14) for participants whose husband smoked 1-4, 5-9, 10-14, 15-19, and ≥ 20 cigarettes/day respectively, compared with participants without paternal smoking. The HRs of PTB also increased with the increment of paternal smoking and preconception paternal smoking categories (Plinear < 0.05). CONCLUSIONS: Paternal smoking and preconception paternal smoking was independently positively associated with PTB risk. The importance of tobacco control, should be emphasized during preconception and pregnancy counselling should be towards not only women but also their husband.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality, as well as other system immaturity problem. But as one of important environmental tobacco smoking sources of maternal secondhand smoking in the family, paternal smoking is worthy for deep exploring of its potential impacts on PTB. Moreover, evidence on the independent role of preconception paternal smoking is still lacking. Thus, we conducted a population-based retrospective cohort study to evaluate the association between paternal smoking and risk of PTB among among 5,298,043 reproductive-aged couples who participated in the National Free Pre-Pregnancy Checkups Project (NFPCP), regarding outcome events that occurred in 2010­2016.We found a significant association between paternal smoking and PTB. Smoking reduction should not only be advised to pregnant women but also to their partners to reduce PTB in their fetal. In addition, supporting patients to continue smoking reduction will be crucial when considering the adverse health outcome of smoking. Intervention of tobacco use before and during pregnancy, are critical for prevention of PTB. Avoiding both maternal and paternal smoking during pregnancy will benefit the developing fetus.

Association of decreases in PM2.5 levels due to the implementation of environmental protection policies with the incidence of obesity in adolescents: A prospective cohort study.

AIMS: To explore the association between decreased levels of particulate matter (≤2.5 µm; PM2.5) due to the implementation of environmental protection policies and the incidence of obesity in adolescents in Chongqing, China through a prospective cohort study. METHODS: A total of 2105 children (52.02% male; aged 7.33 ± 0.60 years at baseline) were enrolled from the Chongqing Children's Health Cohort. A mixed linear regression model was used to analyse the relationships of PM2.5 levels with obesity indicators after adjusting for covariates. Additionally, a Poisson regression model was used to determine the relationship between PM2.5 exposure and the incidence of overweight/obesity. RESULTS: The average PM2.5 exposure levels from participant conception to 2014, from 2015 to 2017, and from 2018 to 2019 were 66.64 ± 5.33 µg/m3, 55.49 ± 3.78 µg/m3, and 42.50 ± 1.87 µg/m3, respectively; these levels significantly decreased over time (P < 0.001). Throughout the entire follow-up period, the incidence of overweight/obesity after a ≥ 25 µg/m3 decrease in the PM2.5 level was 4.57% among females; this incidence was the lowest among females who experienced remarkable decreases in PM2.5 exposure. A 1-µg/m3 decrease in the PM2.5 level significantly decreased the body mass index (BMI), BMI z score (BMIz), and weight of adolescents (all P < 0.001). Compared with a < 20-µg/m3 decrease in the PM2.5 level, a ≥ 25-µg/m3 decrease protected against increased BMI (net difference= -0.93; 95% confidence interval [CI]: (-1.23,-0.63) kg/m2), BMIz (-0.28 (-0.39, -0.17)), weight (-1.59 (-2.44, -0.74) kg), and incidence of overweight/obesity (0.48 (0.37, 0.62), P < 0.001). Moreover, compared with a < 20-µg/m3 decrease in the PM2.5 level, a ≥ 25-µg/m3 decrease resulted in significant absolute differences in BMI (-1.26 (-1.56, -0.96) kg/m2), BMIz (-0.53 (-0.65, -0.40)) and weight (-3.01 (-3.8, -2.19) kg) (all P < 0.001). CONCLUSIONS: This study showed the etiological relevance of declining PM2.5 concentrations for the incidence of obesity in children and adolescents, suggesting that controlling ambient air pollutants may prevent the development of obesity in this age group. Continuous implementation of environmental protection policies in China has led to substantial health benefits.