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.

Discordant High Remnant Cholesterol With LDL-C Increases the Risk of Stroke: A Chinese Prospective Cohort Study.

BACKGROUND: Previous studies focusing on assessing the effects of remnant cholesterol (RC) and low-density lipoprotein cholesterol (LDL-C) on stroke may not consider their mutual influence. We aimed to explore the associations of RC and discordant high RC with LDL-C with stroke, ischemic stroke (IS), and hemorrhagic stroke. METHODS: This prospective cohort study was conducted based on 3 cohorts of the China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China) project. RC was calculated as non-high-density lipoprotein cholesterol minus LDL-C estimated by Martin/Hopkins equations. Concordant/discordant categories for RC versus LDL-C were determined based on cut-points of 130 mg/dL for LDL-C and equivalent percentile (32.50 mg/dL) for RC. Cox models were used to estimate adjusted hazard ratios and 95% CIs for incident stroke. RESULTS: Among 113 448 participants recruited at baseline, a total of 98 967 participants were eligible for the final analysis (mean age of 51.44 years; 40.45% were men). During 728 776.87 person-years of follow-up, 2859 stroke cases, 1811 IS cases, and 849 hemorrhagic stroke cases were observed. RC was positively associated with stroke and IS, but not hemorrhagic stroke, with adjusted hazard ratios (95% CIs) of 1.06 (1.02-1.10), 1.09 (1.04-1.13), and 0.95 (0.88-1.03) for per SD increase in RC. Compared with low LDL-C/low RC group, low LDL-C/high RC group had higher risks of stroke (adjusted hazard ratio, 1.15 [95% CI, 1.02-1.30]) and IS (1.19, 1.03-1.38), while high LDL-C/low RC group had no increased risk of stroke (1.07 [0.95-1.20]) and IS (1.09 [0.94-1.25]). CONCLUSIONS: Higher RC was associated with increased risks of stroke and IS but not hemorrhagic stroke. Discordantly high RC, not discordantly high LDL-C, conferred higher risks of stroke and IS. Our findings support further lowering RC by interventions to reduce residual IS risk.

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.

Nine months of bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine chemotherapy for rifampicin/multidrug-resistant tuberculosis: a multicenter, randomized, open-label non-inferiority trial in China.

BACKGROUND: We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. METHODS: This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. RESULTS: Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI - 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). CONCLUSIONS: The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

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.

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.

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.