Search

Background: Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular events. This study evaluated the relationship between Lp(a) and high-risk attributes by coronary computed tomography angiography as well as their prognostic value. Methods: Lp(a) and coronary computed tomography angiography from 377 consecutive patients at Zhongshan Hospital (Shanghai, China) were evaluated. High-risk attributes were defined as high-risk morphological attributes (low attenuation plaque, positive remodeling, napkin-ring sign, spotty calcification, minimum lumen area <4 mm2, or plaque burden [ratio between cross-sectional plaque area at the site of maximum stenosis and cross-sectional vessel area] ≥70%); inflammatory attribute represented by fat attenuation index; high-risk physiological attributes [lesion-specific ischemia defined by fractional flow reserve by coronary computed tomography angiography ≤0.8, physiologic diffuseness defined by fractional flow reserve by coronary computed tomography angiography pullback pressure gradient]. Total plaque volume in mm3 was also quantified. Quintiles or binary classification of Lp(a) levels were used to evaluate its relationships with plaque features and clinical outcomes with ANOVA, Cox models, and log-rank tests, as appropriate. The major adverse cardiovascular event included cardiovascular death, nonfatal myocardial infarction, and target vessel revascularization. Results: Lp(a) was significantly associated with total plaque volume (P =0.004), fat attenuation index (P =0.031), and fractional flow reserve by coronary computed tomography angiography pullback pressure gradient (P =0.038). Patients with a high Lp(a) level had a higher total plaque volume (393.3 mm3 versus 293.9 mm3, P <0.001), lower pullback pressure gradient (0.62 versus 0.69, P =0.023), higher fat attenuation index (−70.5HU versus −73.9HU, P =0.004), and higher incidence of major adverse cardiovascular event (14.5% versus 6.3%, adjusted hazard ratio: 2.52, 95% CI: 1.12–5.63, P =0.025). In a 4-group classification according to Lp(a) and high-risk attributes, patients with high Lp(a) and ≥3 high-risk attributes had the highest risk of major adverse cardiovascular event (25.9%; overall P <0.001). Causal mediation analysis revealed that around 40% of the prognostic effect of Lp(a) was mediated by high-risk attributes. Conclusions: Lp(a) level is associated with coronary computed tomography angiography high-risk characteristics, including morphologic, physiologic, and inflammatory attributes as well as major adverse cardiovascular event. This effect is partly mediated by inflammation and vulnerable plaque. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05323227 [ABSTRACT FROM AUTHOR]

Purpose: PIK3CA gene encoding a catalytic subunit of the phosphatidylinositol-3-kinase (PI3K) is mutated and/or amplified in various neoplasia, including lung cancer. Here we investigated PIK3CA gene alterations, the expression of core components of PI3K pathway, and evaluated their clinical importance in non-small cell lung cancer (NSCLC). Materials and methods: Oncogenic mutations/rearrangements in PIK3CA, EGFR, KRAS, HER2, BRAF, AKT1 and ALK genes were detected in tumors from 1117 patients with NSCLC. PIK3CA gene copy number was examined by fluorescent in situ hybridization and the expression of PI3K p110 subunit alpha (PI3K p110α), p-Akt, mTOR, PTEN was determined by immunohistochemistry in PIK3CA mutant cases and 108 patients without PIK3CA mutation. Results: PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma. Among 34 PIK3CA mutant cases, 17 tumors harbored concurrent EGFR mutations and 4 had KRAS mutations. PIK3CA mutation was significantly associated with high expression of PI3K p110α (p<0.0001), p-Akt (p = 0.024) and mTOR (p = 0.001), but not correlated with PIK3CA amplification (p = 0.463). Patients with single PIK3CA mutation had shorter overall survival than those with PIK3CA-EGFR/KRAS co-mutation or wildtype PIK3CA (p = 0.004). A significantly worse survival was also found in patients with PIK3CA mutations than those without PIK3CA mutations in the EGFR/KRAS wildtype subgroup (p = 0.043) Conclusions: PIK3CA mutations frequently coexist with EGFR/KRAS mutations. The poor prognosis of patients with single PIK3CA mutation in NSCLC and the prognostic value of PIK3CA mutation in EGFR/KRAS wildtype subgroup suggest the distinct mutation status of PIK3CA gene should be determined for individual therapeutic strategies in NSCLC. [ABSTRACT FROM AUTHOR]

Gao L, Zheng Z, Cao L, Shen S, Yang Y, Zhao Z, Zhi D, Cheng R, Pei Z, Yongfu Y, Luo F. The growth hormone receptor (GHR) exon 3 polymorphism and its correlation with metabolic profiles in obese Chinese children. Objective: We investigated the correlation between the growth hormone receptor (GHR) exon 3 polymorphism and the metabolic profiles of Chinese children with obesity. Subjects and methods: A total of 409 obese/overweight children and 206 normal weight children were recruited. Anthropological and biochemical indexes including insulin and lipid profiles were measured. Genomic DNA was extracted from the peripheral blood leukocytes, and the GHR exon 3 polymorphism was genotyped by polymerase chain reaction. Homeostasis model of assessment for insulin resistance index (HOMA-IR) and insulin sensitivity index (ISI) were calculated using the homeostasis model. Results: The frequency of the exon 3-deleted GHR (d3-GHR) polymorphism within the obese group was significantly higher than that of the control group (p < 0.05). Body mass index (BMI), fasting insulin (FIns), HOMA-IR, total cholesterol, and triglycerides were significantly lower in the d3-GHR (d3/d3 and d3/fl) group than in the full-length GHR (fl/fl, fl-GHR) group (p < 0.05). After adjustment for BMI, cholesterol level was still significantly lower and HOMA-IR was marginally lower (p = 0.079) in the d3-GHR obese group. There was no statistically significant difference in BMI, FIns, HOMA-IR, ISI, total cholesterol, or triglyceride levels between the two genotypes in the control group. Conclusion: We report that the d3-GHR polymorphism has a significant effect on BMI and the metabolic parameters of Chinese children with obesity. The d3 allele may have a protective effect on the development of metabolic syndrome by increasing insulin sensitivity. [ABSTRACT FROM AUTHOR]

To determine the incidence of acute cardiac injury (ACI), the factors associated with ACI and the in-hospital mortality in patients with COVID-19, especially in severe patients. All consecutive in-patients with laboratory-confirmed COVID-19 from Tongji Hospital in Wuhan during February 1 and March 29, 2020 were included. The demographic, clinical characteristics, laboratory, radiological and treatment data were collected. Univariate and Firth logistic regression analyses were used to identify factors associated with ACI and in-hospital mortality, and Kaplan–Meier method was used to estimate cumulative in-hospital mortality. Among 1031 patients included, 215 (20.7%) had ACI and 501 (48.6%) were severe cases. Overall, 165 patients died; all were from the severe group, and 131 (79.39%) had ACI. ACI (OR = 2.34, P = 0.009), male gender (OR = 2.58, P = 0.001), oximeter oxygen saturation (OR = 0.90, P < 0.001), lactate dehydrogenase (OR = 3.26, P < 0.001), interleukin-6 (IL-6) (OR = 8.59, P < 0.001), high sensitivity C-reactive protein (hs-CRP) (OR = 3.29, P = 0.016), N-terminal pro brain natriuretic peptide (NT-proBNP) (OR = 2.94, P = 0.001) were independent risk factors for the in-hospital mortality in severe patients. The mortality was significantly increased among severe patients with elevated hs-CRP, IL-6, hs-cTnI, and/or NT-proBNP. Moreover, the mortality was significantly higher in patients with elevation of both hs-cTnI and NT proBNP than in those with elevation of either of them. ACI develops in a substantial proportion of patients with COVID-19, and is associated with the disease severity and in-hospital mortality. A combination of hs-cTnI and NT-proBNP is valuable in predicting the mortality. [ABSTRACT FROM AUTHOR]

Few studies focus on the associations of green space composition and configuration with children's allergic rhinitis (AR). A multi-center population-based cross-sectional study was performed in 7 cities in mainland of China between 2019 and 2020, recruiting 36,867 preschool children. Information on the current AR symptoms and demographics were collected by questionnaire. Exposure to residential greenness was estimated by Normalized Difference Vegetation Index (NDVI, 1000 m buffer) around the residences. Greenness composition was estimated in 3 main categories: forest, grassland, shrubland. Configuration of each category and total greenness (a spatial resolution of 10 m × 10 m) was estimated by 6 landscape pattern metrics to quantify their area, shape complexity, aggregation, connectivity, and patch density. Exposure to daily ambient particulate matter (PM 1 , PM 2.5 and PM 10 , a spatial resolution of 1 km × 1 km) was estimated. Multilevel logistic regression models were applied to analyze the associations of greenness and its composition and configuration with AR, and mediation effects by PMs were examined by mediation analysis models. The prevalence of self-reported current AR in preschool children was 33.1%. Two indicators of forest, Aggregation Index of forest patches (AIforest) (odds ratio (OR):0.92, 95% Confidential Interval (CI): 0.88–0.97), and Patch Cohesion of forest (COHESIONforest) (OR: 0.93, 95% CI:0.89–0.98) showed significantly negative associations with AR symptoms. Mediation analyses found the associations were partially mediated by PMs. Age, exclusive breastfeed duration and season were the potential effect modifiers. The associations varied across seven cities. Our findings suggest the inverse associations of the aggregation and connectivity of forest patches surrounding residence addresses with AR symptoms. Since the cross-sectional study only provides associations rather than causation, further studies are needed to confirm our results as well as the underlying mechanisms. • Forest aggregation and connectivity were negatively associated with AR symptoms. • Particulate matters mediated the inverse association of forest configuration with AR. • Age, exclusive breastfeed duration and season were the effect modifiers. [ABSTRACT FROM AUTHOR]

Background: Whether labour epidural analgesia impacts risk of neurodevelopmental disorders in offspring is unsettled, raising public and scientific concerns. We explored the association between maternal labour epidural analgesia and autism spectrum disorder, and specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy in offspring.Methods: This nationwide population-based cohort study included 624 952 live-born singletons delivered by women who intended to deliver vaginally (i.e. vaginal and intrapartum Caesarean deliveries) in Denmark from 2005 to 2016. A total of 80 862 siblings discordant for exposure to labour epidural analgesia were analysed in a sibling-matched analysis. Both full-cohort and sibling-matched analyses were performed to estimate hazard ratios (HRs) of offspring risk of autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, and epilepsy, according to exposure to labour epidural analgesia, adjusted for maternal socio-economic, pregnancy, and perinatal covariates.Results: In the full cohort, maternal labour epidural analgesia was associated with autism spectrum disorder in offspring (HR 1.11; 95% confidence interval [CI]: 1.04-1.18); however, in the sibling-matched analysis, no association with autism spectrum disorder was found (HR 1.03; 95% CI: 0.84-1.27). The association between labour epidural analgesia and specific developmental disorder (HR 1.12; 95% CI: 1.03-1.22) in the full cohort also disappeared in the sibling-matched analysis (HR 1.01; 95% CI: 0.78-1.31). No association between maternal labour epidural analgesia and the remaining neurodevelopmental disorders was found overall (attention-deficit hyperactivity disorder, HR 0.98; 95% CI: 0.92-1.03; intellectual disability, HR 0.98; 95% CI: 0.85-1.14; epilepsy, HR 0.89; 95% CI: 0.79-1.00) or in the sibling-matched analyses.Conclusions: Our findings did not support an association between maternal attention-deficit hyperactivity disorder and autism spectrum disorder, specific developmental disorder, attention-deficit hyperactivity disorder, intellectual disability, or epilepsy. [ABSTRACT FROM AUTHOR]

Background: The urban ambient air quality has been largely improved in the past decade. It is unknown whether childhood asthma prevalence is still increasing in ever top‐ranking city of Shanghai, whether the improved air quality is beneficial for children's asthma and what time window of exposure plays critical roles. Methods: Using a repeat cross‐sectional design, we analyzed the association between early life exposure to particles and wheezing/asthma in each individual and combined surveys in 2011 and 2019, respectively, in 11,825 preschool children in Shanghai. Results: A significantly lower prevalence of doctor‐diagnosed asthma (DDA) (6.6% vs. 10.5%, p < 0.001) and wheezing (10.5% vs. 23.2%, p < 0.001) was observed in 2019 compared to 2011. Exposure to fine particulate matter (PM2.5), coarse particles (PM2.5–10) and inhalable particles (PM10) was decreased in 2019 by 6.3%, 35.4%, and 44.7% in uterus and 24.3%, 20.2%, and 31.8% in infancy, respectively. Multilevel log‐binomial regression analysis showed exposure in infancy had independent association with wheezing/DDA adjusting for exposure in uterus. For each interquartile range (IQR) increase of infancy PM2.5, PM2.5–10 and PM10 exposure, the odds ratios were 1.39 (95% confidence interval (CI): 1.24–1.56), 1.51 (95% CI:1.15–1.98) and 1.53 (95% CI:1.27–1.85) for DDA, respectively. The distributed lag non‐linear model showed the sensitive exposure window (SEW) was 5.5–11 months after birth. Stratified analysis showed the SEWs were at or shortly after weaning, but only in those with <6 months of exclusive breastfeeding. Conclusions: Improved ambient PM benefits in decreasing childhood asthma prevalence. We firstly reported the finding of SEW to PM at or closely after weaning on childhood asthma. [ABSTRACT FROM AUTHOR]

Recently, there has been a growing interest in variable selection for causal inference within the context of high-dimensional data. However, when the outcome exhibits a skewed distribution, ensuring the accuracy of variable selection and causal effect estimation might be challenging. Here, we introduce the generalized median adaptive lasso (GMAL) for covariate selection to achieve an accurate estimation of causal effect even when the outcome follows skewed distributions. A distinctive feature of our proposed method is that we utilize a linear median regression model for constructing penalty weights, thereby maintaining the accuracy of variable selection and causal effect estimation even when the outcome presents extremely skewed distributions. Simulation results showed that our proposed method performs comparably to existing methods in variable selection when the outcome follows a symmetric distribution. Besides, the proposed method exhibited obvious superiority over the existing methods when the outcome follows a skewed distribution. Meanwhile, our proposed method consistently outperformed the existing methods in causal estimation, as indicated by smaller root-mean-square error. We also utilized the GMAL method on a deoxyribonucleic acid methylation dataset from the Alzheimer's disease (AD) neuroimaging initiative database to investigate the association between cerebrospinal fluid tau protein levels and the severity of AD. [ABSTRACT FROM AUTHOR]

Sleep duration has been associated with depression. However, mean regression, such as linear regression or logistic regression, may not capture relationships that occur mainly in the tails of outcome distribution. This study aimed to evaluate the associations between sleep duration and depression along the entire distribution of depression using quantile regression approach. This study included 55,954 adults aged 18 to 80 years from the National Health and Nutrition Examination Survey (N = 34,156) and the Korea National Health and Nutrition Examination Survey (N = 21,798). The coefficients corresponding to cross-group differences in PHQ-9 scores were estimated when comparing short or long sleep duration with normal sleep duration on deciles of PHQ-9 score distribution. At lower quantiles, either short or long sleep duration was not associated with depression. At higher quantiles, the association of both short and long sleep duration with depression became much more pronounced. Compared with normal sleep duration, short and long sleep duration were associated with increases of 1.34 (95 % CI: 1.16, 1.51) and 0.28 (95 % CI: 0.04, 0.52) in PHQ-9 scores at the 50th quantile, while the corresponding increases were 3.27 (95 % CI: 2.83, 3.72) and 1.65 (95 % CI: 0.86, 2.45) at the 90th quantile, respectively. We also found that the magnitude of association between short sleep duration and depression was stronger among females and individuals with chronic diseases. The beneficial effect of sufficient sleep in decreasing depression severity may be more evident among individuals with severe depression. Further studies could explore whether these heterogeneous associations can be generalized to populations with different characteristics. • The association of either short or long sleep duration with depression was not significant at lower quantiles. • The associations of both short and long sleep duration with depression became much more pronounced at higher quantiles. • The magnitude of association between short sleep duration and depression was stronger than that of long sleep duration. • Females and individuals with chronic disease under short sleep duration had a greater increase in depression severity. [ABSTRACT FROM AUTHOR]

Background: When estimating the causal effect on survival outcomes in observational studies, it is necessary to adjust confounding factors due to unbalanced covariates between treatment and control groups. There is no study on multiple robust method for estimating the difference in survival functions. In this study, we propose a multiply robust (MR) estimator, allowing multiple propensity score models and outcome regression models, to provide multiple protection. Method: Based on the previous MR estimator (Han 2014) and pseudo-observation approach, we proposed a new MR estimator for estimating the difference in survival functions. The proposed MR estimator based on the pseudo-observation approach has several advantages. First, the proposed estimator has a small bias when any PS and OR models were correctly specified. Second, the proposed estimator considers the advantage pf the pseudo-observation approach, which avoids proportional hazards assumption. A Monte Carlo simulation study was performed to evaluate the performance of the proposed estimator. And the proposed estimator was used to estimate the effect of chemotherapy on triple-negative breast cancer (TNBC) in real data. Results: The simulation studies showed that the bias of the proposed estimator was small, and the coverage rate was close to 95% when any model for propensity score or outcome regression is correctly specified regardless of whether the proportional hazard assumption holds, finite sample size and censoring rate. And the simulation results also showed that even though the propensity score models are misspecified, the bias of the proposed estimator was still small when there is a correct model in candidate outcome regression models. And we applied the proposed estimator in real data, finding that chemotherapy could improve the prognosis of TNBC. Conclusions: The proposed estimator, allowing multiple propensity score and outcome regression models, provides multiple protection for estimating the difference in survival functions. The proposed estimator provided a new choice when researchers have a "difficult time" choosing only one model for their studies. [ABSTRACT FROM AUTHOR]

Background: When data is distributed across multiple sites, sharing information at the individual level among sites may be difficult. In these multi-site studies, propensity score model can be fitted with data within each site or data from all sites when using inverse probability-weighted Cox regression to estimate overall hazard ratio. However, when there is unknown heterogeneity of covariates in different sites, either approach may lead to potential bias or reduced efficiency. In this study, we proposed a method to estimate propensity score based on covariate balance-related criterion and estimate the overall hazard ratio while overcoming data sharing constraints across sites. Methods: The proposed propensity score was generated by choosing between global and local propensity score based on covariate balance-related criterion, combining the global propensity score fitted in the entire population and the local propensity score fitted within each site. We used this proposed propensity score to estimate overall hazard ratio of distributed survival data with multiple sites, while requiring only the summary-level information across sites. We conducted simulation studies to evaluate the performance of the proposed method. Besides, we applied the proposed method to real-world data to examine the effect of radiation therapy on time to death among breast cancer patients. Results: The simulation studies showed that the proposed method improved the performance in estimating overall hazard ratio comparing with global and local propensity score method, regardless of the number of sites and sample size in each site. Similar results were observed under both homogeneous and heterogeneous settings. Besides, the proposed method yielded identical results to the pooled individual-level data analysis. The real-world data analysis indicated that the proposed method was more likely to find a significant effect of radiation therapy on mortality compared to the global propensity score method and local propensity score method. Conclusions: The proposed covariate balance-related propensity score in multi-site distributed survival data outperformed the global propensity score estimated using data from the entire population or the local propensity score estimated within each site in estimating the overall hazard ratio. The proposed approach can be performed without individual-level data transfer between sites and would yield the same results as the corresponding pooled individual-level data analysis. [ABSTRACT FROM AUTHOR]

Background: In observational studies, double robust or multiply robust (MR) approaches provide more protection from model misspecification than the inverse probability weighting and g-computation for estimating the average treatment effect (ATE). However, the approaches are based on parametric models, leading to biased estimates when all models are incorrectly specified. Nonparametric methods, such as machine learning or nonparametric double robust approaches, are robust to model misspecification, but the efficiency of nonparametric methods is low. Method: In the study, we proposed an improved MR method combining parametric and nonparametric models based on the previous MR method (Han, JASA 109(507):1159-73, 2014) to improve the robustness to model misspecification and the efficiency. We performed comprehensive simulations to evaluate the performance of the proposed method. Results: Our simulation study showed that the MR estimators with only outcome regression (OR) models, where one of the models was a nonparametric model, were the most recommended because of the robustness to model misspecification and the lowest root mean square error (RMSE) when including a correct parametric OR model. And the performance of the recommended estimators was comparative, even if all parametric models were misspecified. As an application, the proposed method was used to estimate the effect of social activity on depression levels in the China Health and Retirement Longitudinal Study dataset. Conclusions: The proposed estimator with nonparametric and parametric models is more robust to model misspecification. [ABSTRACT FROM AUTHOR]

To investigate the association of baseline nocturnal sleep duration and sleep changes with functional disability in middle-aged and elderly Chinese. Data for this study were collected from the China Health and Retirement Longitudinal Study (CHARLS) from baseline (2011) to the Wave 3 follow-up (2018). 8361 participants free of IADL disability in 2011 and aged ≥ 45 years old were recruited and prospectively followed till 2018 to analyze the association between baseline nocturnal sleep duration and IADL disability. Of these 8361 participants, a total of 6948 participants had no IADL disability at the first three follow-up visits and completed the 2018 follow-up to analyze the association between nocturnal sleep changes and IADL disability. Nocturnal sleep duration (hours) was self-reported at baseline. The coefficient of variation (CV) of nocturnal sleep duration at baseline and three follow-up visits was used to calculate sleep changes and classified into mild, moderate, and severe degrees by the quantiles. Cox proportional hazards regression model was used to analyze the association of baseline nocturnal sleep duration with IADL disability, and the binary logistic regression model was used to analyze the association of nocturnal sleep changes with IADL disability. Among the 8361 participants of 50237.5 person-years follow-up with a median follow-up of 7 years, 2158 (25.81%) participants developed IADL disabilities. Higher risks of IADL disability were observed among participants with sleep duration <7 h [HR(95%): 1.23(1.09–1.38)], 8∼<9 h [HR(95%): 1.05(1.00–1.32)] and ≥9 h [HR(95%): 1.21(1.01–1.45)] compared to those with 7∼<8 h. Among the 6948 participants, a total of 745 (10.72%) participants finally developed IADL disabilities. Compared with mild nocturnal sleep changes, moderate [OR(95%): 1.48(1.19–1.84)] and severe [OR(95%): 2.43(1.98–3.00)] sleep changes increased the probability of IADL disability. The restricted cubic spline model showed that a higher degree of nocturnal sleep changes was associated with a greater probability of IADL disability. Both insufficient and excessive nocturnal sleep duration were associated with higher risk of IADL disability in middle-aged and elderly adults, independent of the participants' gender, age, and napping habits. Higher nocturnal sleep changes were associated with a higher probability of disability in IADL. These findings highlight the importance of appropriate and stable nocturnal sleep, and the need to pay attention to population differences in the impact of nocturnal sleep duration on health. • Inadequate and excess nocturnal sleep duration increase IADL disability risk. • Moderate and severe sleep changes lead to higher IADL disability probability. • Appropriate and stable nocturnal sleep is vital for middle-aged and elderly health. [ABSTRACT FROM AUTHOR]

Association between calcium intake and premature mortality in the general population has been well studied, but little is known about the association among specific populations. The authors aim to evaluate the association among people with hypertension and to provide a proper reference range of dietary calcium intake. This prospective cohort study included 8534 US adults with hypertension from National Health and Nutrition Examination Survey cycles 2003–2014. Dietary calcium intakes were self‐reported and mortality status was ascertained by National Death Index records. During a median follow‐up of 5.9 years, 1357 death occurred. Compared with participants of dietary calcium intake in quintile 1, participants in quintiles 2 and 4 had a 27% (HR: 0.73, 95% CI: 0.60–0.89) and a 29% lower risk (HR: 0.71, 95% CI: 0.57–0.88) of all‐cause mortality respectively. The authors also observed a 34% lower risk (HR: 0.66, 95% CI: 0.45–0.97) of CVD death among participants in quintile 3 and a 37% lower risk (HR: 0.63, 95% CI: 0.40–0.99) of cancer‐related death in participants in quintile 4 respectively. Restricted cubic spline (RCS) regression revealed a consistent protective effect of dietary calcium in participants with a daily intake of over 1000 mg, but a daily intake over 1200 mg fails to show further protective effect. Our findings suggest that elevated dietary calcium was associated with lower mortality risk from all‐causes, cardiovascular disease (CVD) and cancer, and supplying sufficient dietary calcium intake, between 1000 and 1200 mg per day, in people with hypertension may be considered cost‐effective to decrease risk of premature death. [ABSTRACT FROM AUTHOR]

Purpose: Esophageal squamous cell carcinoma (ESCC) metastasizes in an unpredictable fashion to adjacent lymph nodes, including those along the recurrent laryngeal nerves (RLNs). This study is to apply machine learning (ML) for prediction of RLN node metastasis in ESCC. Methods: The dataset contained 3352 surgically treated ESCC patients whose RLN lymph nodes were removed and pathologically evaluated. Using their baseline and pathological features, ML models were established to predict RLN node metastasis on each side with or without the node status of the contralateral side. Models were trained to achieve at least 90% negative predictive value (NPV) in fivefold cross-validation. The importance of each feature was measured by the permutation score. Results: Tumor metastases were found in 17.0% RLN lymph nodes on the right and 10.8% on the left. In both tasks, the performance of each model was comparable, with a mean area under the curve ranging from 0.731 to 0.739 (without contralateral RLN node status) and from 0.744 to 0.748 (with contralateral status). All models showed approximately 90% NPV scores, suggesting proper generalizability. The pathology status of chest paraesophgeal nodes and tumor depth had the highest impacts on the risk of RLN node metastasis in both models. Conclusion: This study demonstrated the feasibility of ML in predicting RLN node metastasis in ESCC. These models may potentially be used intraoperatively to spare RLN node dissection in low-risk patients, thereby minimizing adverse events associated with RLN injuries. [ABSTRACT FROM AUTHOR]

Background: Maternal hypertensive disorders during pregnancy (HDP) have been suggested to contribute to the development of offspring cardiovascular disease later in life, but empirical evidence remains inconsistent. This study was aimed to assess the association of maternal overall and type-specific HDPs with diabetes in offspring from childhood to early adulthood. Methods: Using Danish national health registers, a total of 2,448,753 individuals born in Denmark from 1978 to 2018 were included in this study. Maternal HDP included chronic hypertension, gestational hypertension, and preeclampsia. The outcome of interest was diabetes in offspring (including type 1, type 2, and gestational diabetes). The follow-up of offspring started at birth and ended at the first diagnosis of diabetes, emigration from Denmark, death, or time end on 31 December 2018, whichever came first. Cox proportional hazards regression was used to evaluate the hazard ratios (HRs) with 95% confidence intervals (CIs) of the association between maternal HDP and diabetes (including type 1, type 2, and gestational diabetes) in offspring from birth to young adulthood (up to 41 years), with the offspring’s age as the time scale. Results: During a follow-up of up to 41 (median: 19.3) years, 1247 offspring born to mothers with HDP and 23,645 offspring born to mothers without HDP were diagnosed with diabetes. Compared with offspring born to mothers without HDP, those born to mothers with HDP had an increased risk for overall diabetes (HR=1.27, 95% CI=1.20–1.34), as well as for type 2 diabetes (HR=1.57, 95% CI=1.38–1.78) and gestational diabetes (HR=1.37, 95% CI=1.25–1.49). We did not observe obvious increased risk for type 1 diabetes (HR=1.08, 95% CI=0.98–1.18). Offspring of mothers with gestational hypertension (HR=1.37, 95% CI=1.00–1.88) or preeclampsia (HR=1.62, 95% CI=1.41–1.87) had higher risks of type 2 diabetes. The strongest association was observed for severe preeclampsia, with a 2-fold risk of type 2 diabetes (HR=2.00, 95% CI=1.42–2.82). The association between maternal HDP and type 1 diabetes did not reach statistical significance, except for maternal gestational hypertension (HR=1.41, 95%CI=1.17–1.71). In addition, we found that offspring born to mothers with any subtypes of maternal HDP had higher risk of gestational diabetes, and the corresponding HRs (95%CIs) for chronic hypertension, gestational hypertension, and preeclampsia were 1.60 (1.06–2.41), 1.29 (1.04–1.59), and 1.38 (1.24–1.53), respectively. We also observed stronger associations among offspring of mothers with HDP and comorbid diabetes (HR=4.64, 95%CI=3.85–5.60) than offspring of mothers with HDP or diabetes alone. Conclusions: Offspring of mothers with HDP, especially mothers with comorbid diabetes, had an increased risk of diabetes later in their life. Our findings suggest that timely and effective prevention of HDP in women of childbearing age should be taken into consideration as diabetes prevention and control strategies for their generations. [ABSTRACT FROM AUTHOR]

Background: Estimating the average effect of a treatment, exposure, or intervention on health outcomes is a primary aim of many medical studies. However, unbalanced covariates between groups can lead to confounding bias when using observational data to estimate the average treatment effect (ATE). In this study, we proposed an estimator to correct confounding bias and provide multiple protection for estimation consistency. Methods: With reference to the kernel function-based double-index propensity score (Ker.DiPS) estimator, we proposed the artificial neural network-based multi-index propensity score (ANN.MiPS) estimator. The ANN.MiPS estimator employed the artificial neural network to estimate the MiPS that combines the information from multiple candidate models for propensity score and outcome regression. A Monte Carlo simulation study was designed to evaluate the performance of the proposed ANN.MiPS estimator. Furthermore, we applied our estimator to real data to discuss its practicability. Results: The simulation study showed the bias of the ANN.MiPS estimators is very small and the standard error is similar if any one of the candidate models is correctly specified under all evaluated sample sizes, treatment rates, and covariate types. Compared to the kernel function-based estimator, the ANN.MiPS estimator usually yields smaller standard error when the correct model is incorporated in the estimator. The empirical study indicated the point estimation for ATE and its bootstrap standard error of the ANN.MiPS estimator is stable under different model specifications. Conclusions: The proposed estimator extended the combination of information from two models to multiple models and achieved multiply robust estimation for ATE. Extra efficiency was gained by our estimator compared to the kernel-based estimator. The proposed estimator provided a novel approach for estimating the causal effects in observational studies. [ABSTRACT FROM AUTHOR]

Background: The empirical evidence remains inconclusive for an association between diabetes mellitus (DM) in children and early-onset kidney disease later in life, and little is known about the effects of DM types (i.e., type 1 diabetes [T1DM] and type 2 diabetes [T2DM]) in childhood on type-specific kidney diseases. We aimed to evaluate the association of childhood DM with overall and type-specific early-onset kidney diseases later in life.Methods: The population-based matched cohort study included 9356 individuals with DM (T1DM: 8470, T2DM: 886) diagnosed in childhood (< 18 years) who were born between 1977 and 2016, and 93,560 individuals without DM matched on sex and year of birth in Denmark. The main outcomes were overall and type-specific early-onset kidney diseases. The follow-up period of all included participants was from the date of DM diagnosis in the exposure group until the first diagnosis of kidney disease, emigration, or 31 December 2018, whichever came first.Results: During a median follow-up of 13 years, children with DM had a 154% increased risk of early-onset kidney diseases than children without DM (adjusted hazard ratios 2.54, 95% confidence intervals 2.38-2.72), and T1DM (2.48, 2.31-2.67) and T2DM (2.75, 2.28-3.31) showed similar results. Children with DM also had a higher risk of multiple specific kidney diseases including glomerular diseases, renal tubulo-interstitial diseases, renal failure, and urolithiasis. The risks of type-specific kidney diseases including glomerular diseases and renal failure tended to be higher for children with T2DM (glomerular diseases: 5.84, 3.69-9.24; renal failure: 14.77, 8.53-25.59) than those with T1DM (glomerular diseases: 3.14, 2.57-3.83; renal failure: 8.24, 6.66-10.20).Conclusions: Children with DM had a higher increased risk of early-onset overall and specific kidney diseases later in life. Early prevention and treatment of both T1DM and T2DM in childhood may significantly reduce the risk of kidney diseases later in life. [ABSTRACT FROM AUTHOR]

Background: The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited.Methods and Findings: We conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare.Conclusions: Offspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring. [ABSTRACT FROM AUTHOR]

[Display omitted] • Venous thromboembolism risk associated with 30-day mortality in COVID-19 patients. • Venous thromboembolism (VTE) risk assessment models (RAMs) used. • Higher score of Padua, IMPROVE or Caprini VTE RAMs means higher mortality risk. • Increased VTE risk associated with higher sequential organ failure assessment score. • VTE RAMs indicate higher accuracy to predict 30-day mortality in these patients. To investigate the association of risk of venous thromboembolism with 30-day mortality in COVID-19 patients. A total of 1030 COVID-19 patients were retrospectively collected, with baseline data on demographics, sequential organ failure assessment (SOFA) score, and VTE risk assessment models (RAMs), including Padua prediction score (PPS), International Medical Prevention Registry (IMPROVE), and Caprini. Thirty-day mortality increased progressively from 2% in patients at low VTE risk to 63% in those at high risk defined by PPS. Similar findings were observed in IMPROVE and Caprini scores. Progressive increases in VTE risk were also associated with higher SOFA score. High risk of VTE was independently associated with mortality regardless of adjusted gender, smoking status and some comorbidities, with hazard ratios of 29.19, 37.37 and 20.60 for PPS, IMPROVE and Caprini RAM, respectively (P < 0.001 for all comparisons). The predictive accuracy of PPS (area under curve (AUC) 0.900), IMPROVE (AUC 0.917), or Caprini (AUC 0.861) RAM for risk of hospitalized mortality was unexpectedly strong. We established that the presence of a high risk of VTE identifies a group of COVID-19 patients at higher risk for mortality. Furthermore, there is a high accuracy of VTE RAMs to predict mortality in these patients. [ABSTRACT FROM AUTHOR]

Background: Previous published prognostic models for COVID-19 patients have been suggested to be prone to bias due to unrepresentativeness of patient population, lack of external validation, inappropriate statistical analyses, or poor reporting. A high-quality and easy-to-use prognostic model to predict in-hospital mortality for COVID-19 patients could support physicians to make better clinical decisions.Methods: Fine-Gray models were used to derive a prognostic model to predict in-hospital mortality (treating discharged alive from hospital as the competing event) in COVID-19 patients using two retrospective cohorts (n = 1008) in Wuhan, China from January 1 to February 10, 2020. The proposed model was internally evaluated by bootstrap approach and externally evaluated in an external cohort (n = 1031).Results: The derivation cohort was a case-mix of mild-to-severe hospitalized COVID-19 patients (43.6% females, median age 55). The final model (PLANS), including five predictor variables of platelet count, lymphocyte count, age, neutrophil count, and sex, had an excellent predictive performance (optimism-adjusted C-index: 0.85, 95% CI: 0.83 to 0.87; averaged calibration slope: 0.95, 95% CI: 0.82 to 1.08). Internal validation showed little overfitting. External validation using an independent cohort (47.8% female, median age 63) demonstrated excellent predictive performance (C-index: 0.87, 95% CI: 0.85 to 0.89; calibration slope: 1.02, 95% CI: 0.92 to 1.12). The averaged predicted cumulative incidence curves were close to the observed cumulative incidence curves in patients with different risk profiles.Conclusions: The PLANS model based on five routinely collected predictors would assist clinicians in better triaging patients and allocating healthcare resources to reduce COVID-19 fatality. [ABSTRACT FROM AUTHOR]

Introduction: Mutated tumor suppressor genes (TSG) such as TP53, STK11, and MGA are widely-reported. We hypothesized the presence of single mutation or co-occurring mutations in these specific genes may represent a significant therapeutic target for lung adenocarcinoma.Methods: We sequenced lung adenocarcinoma samples from 677 East-Asian patients, combined them with those from cBioPortal public database (including TCGA) and performed a comparative analysis between Asian and Caucasian populations.Results: East-Asian lung adenocarcinomas presented distinct driver-mutational distribution compared to that of Caucasians (79% vs 56%, p < 0.001). Similar results were observed in TSG mutations of TP53 (35% vs 46%, p = 0.150), STK11 (4% vs 17%, p = 0.006) and MGA (10% vs 4%, p = 0.166). Compared with none-mutational cases, the patients harboring TSG mutations are more likely to be male (p = 0.009), smokers (p < 0.001), and more advanced disease (p = 0.004). In addition, the TSG-mutated tumors had poorer differentiation (p < 0.001), and more likely to be solid or micropapillary-predominant adenocarcinomas (p < 0.001). Survival analysis showed that both overall survival (OS, p < 0.001) and post-recurrence survival (PRS, p < 0.001) became worse with the accumulation of TSG mutations. However, the prognostic variety was not found in Caucasian patients. Moreover, multivariate analysis proved the accumulation of TSG mutations independently predicts both unfavorable OS (HR = 0.435, 95% CI 0.245-0.774, p = 0.005) and PRS (HR = 0.491, 95% CI 0.269-0.894, p = 0.020) in East-Asian patients, adjusting all other survival-associated factors.Conclusions: Co-occurring mutations of specific TSGs define unfavorable subgroups of lung adenocarcinoma, implying that the tumor promotion mechanisms contribute to the heterogeneity in tumor evolution. However, the Caucasian population did not show the same results, providing insights into the molecular basis underlying the striking racial disparities of this disease and evidence for different gene-panel designs for different population in the purpose of targeted therapy. [ABSTRACT FROM AUTHOR]

The link between sodium and obesity has been accumulated over years. However, there has been few data reported on such sodium-obesity association from the general US population. This study is designed to assess the hypothesis that dietary sodium intake is independently and positively associated with obesity, central obesity, and measures of body composition among generally healthy US adults. We analyzed data on 9162 healthy participants aged 24 to 48 years (4813 men and 4349 women) with at least one valid diet recall from the 8-year National Health and Nutrition Examination Survey (1999-2006). Measures of body composition, including fat mass, lean mass, and total fat percent, were determined by dual-energy x-ray absorptiometry. We assessed the association between dietary sodium and obesity and measures of body composition by using multivariable logistic regression models. After adjustment for total energy intake and other prespecified confounders, high sodium intake (>2300 mg/d) was significantly associated with elevated risk of obesity and central obesity as compared with moderate sodium intake (1500-2300 mg/d). On average, each 1-g/d increment in dietary sodium intake resulted in a 15% (odds ratio, 1.15; 95% confidence interval, 1.00-1.33) increase in the risk of obesity and 24% (odds ratio, 1.24; 95% confidence interval, 1.11-1.39) increase in the risk of central obesity. After stratification by sex and ethnicity, significant associations between sodium and obesity/abdominal obesity were apparent only among women and non-Hispanic whites. In addition, all measures of body composition were positively associated with sodium consumption levels. We found that high sodium intake is independently associated with elevated risk of obesity and central obesity in the general US adult population. [ABSTRACT FROM AUTHOR]

• Depression was associated with all-cause mortality among persons at high baseline risk of CVD. • Depression was not statistically significantly associated with all-cause mortality in people at low baseline risk of CVD, which may be due to small number of events. • Depression was statistically significantly associated with all-cause and CVD mortality in adults with different baseline risks of CVD. The intervention of depression was considered a prevention and treatment option for cardiovascular disease (CVD). However, evidence regarding whether association of depression with mortality differed among people at high or low risk of CVD yielded conflicting results. We aimed to investigate associations between depression and all-cause and CVD mortality among 3854 and 3044 US adults at high and low baseline risk of CVD, respectively. Among participants at high risk of CVD, depression and per 5-point increase in PHQ-9 score were associated with 81% (HR=1.81, 95%CI: 1.15–2.86) and 33% (HR=1.33, 95%CI: 1.14–1.55) increased all-cause mortality, respectively. We did not find statistically significant associations between depression (HR=1.40, 95%CI: 0.67–2.95) and PHQ-9 score (HR=1.28, 95%CI: 1.00–1.63) with CVD mortality due to a small number of mortality events. Among people with low risk of CVD, each 5-point increment in PHQ-9 score was associated with all-cause mortality (HR=1.26, 95%CI: 1.02–1.56), while there was no statistically significant association of depression with all-cause mortality (HR=1.69, 95%CI: 0.75–3.81) and CVD mortality (HR=1.99, 95%CI: 0.83–4.81). This study found that depression was associated with all-cause mortality among individuals at a high baseline risk of CVD, but no significant association was observed in people at a low baseline risk of CVD. [ABSTRACT FROM AUTHOR]

Background/Objectives: Perinatal exposure to malnutrition has been hypothesised to influence the development of young-onset cancer (≤50 years of age). This study aimed to determine if perinatal malnutrition in individuals exposed to the Great Famine of China increased their risk of developing young-onset cancer compared to other individuals born prior to the famine. Subjects/Methods: This cross-sectional study involved 7272 participants from the China Health and Nutrition Survey who were classified into four groups based on birth year: participants born between 1953 and 1955 (before the famine) were designated as the pre-famine group (unexposed); the remainder formed perinatal exposure groups comprised of those exposed during the famine (1959-1961), those exposed in the early post-famine period (1962-1964), and those exposed in the late post-famine period (1965-1967). Multivariable adjusted log-binomial regression models were used to calculate the RR and 95% CI of young-onset cancer (including genitourinary cancer) across four groups. Results: Perinatal exposure to early post-famine (RR 2.08; 95%CI 1.04, 4.34; p = 0.043) and the female sex (RR 15.6, 95%CI 4.54, 60.3; p < 0.001) were noted to have a significantly increased risk of young-onset cancer. In addition, the early (RR 13.8; 95%CI 2.68, 253; p = 0.012) and late post-famine (RR 12.3; 95%CI 2.16, 231; p = 0.020) cohorts demonstrated a significantly increased risk of young-onset genitourinary cancer. The latter was accompanied by an increased risk of hypertension (RR 3.30; 95%CI 1.28, 7.87; p = 0.009). Conclusions: Perinatal exposure to famine, especially in females, was associated with a higher risk of young-onset cancer. This was particularly evident for young-onset genitourinary cancers. These findings highlight the potential long-term impact of perinatal malnutrition on young-onset carcinogenesis.

Purpose: To investigate fundus tessellation density (TD) and its association with axial length (AL) elongation and spherical equivalent (SE) progression in children., Methods: The school-based prospective cohort study enrolled 1,997 individuals aged 7 to 9 years in 11 elementary schools in Mojiang, China. Cycloplegic refraction and biometry were performed at baseline and 4-year visits. The baseline fundus photographs were taken, and TD, defined as the percentage of exposed choroidal vessel area in the photographs, was quantified using an artificial intelligence-assisted semiautomatic labeling approach. After the exclusion of 330 ineligible participants because of loss to follow-up or ineligible fundus photographs, logistic models were used to assess the association of TD with rapid AL elongation (>0.36 mm/year) and SE progression (>1.00 D/year)., Results: The prevalence of tessellation was 477 of 1,667 (28.6%) and mean TD was 0.008 ± 0.019. The mean AL elongation and SE progression in 4 years were 0.90 ± 0.58 mm and -1.09 ± 1.25 D. Higher TD was associated with longer baseline AL (β, 0.030; 95% confidence interval: 0.015-0.046; P < 0.001) and more myopic baseline SE (β, -0.017; 95% confidence interval: -0.032 to -0.002; P = 0.029). Higher TD was associated with rapid AL elongation (odds ratio, 1.128; 95% confidence interval: 1.055-1.207; P < 0.001) and SE progression (odds ratio, 1.123; 95% confidence interval: 1.020-1.237; P = 0.018)., Conclusion: Tessellation density is a potential indicator of rapid AL elongation and refractive progression in children. TD measurement could be a routine to monitor AL elongation.

Background: Sex-specific differences in coronary phenotypes in response to stress have not been elucidated. This study investigated the sex-specific differences in the coronary computed tomography angiography-assessed coronary response to mental stress., Methods: This retrospective study included patients with coronary artery disease and without cancer who underwent resting 18 F-fluorodexoyglucose positron emission tomography/computed tomography and coronary computed tomography angiography within 3 months. 18 F-flourodeoxyglucose resting amygdalar uptake, an imaging biomarker of stress-related neural activity, coronary inflammation (fat attenuation index), and high-risk plaque characteristics were assessed by coronary computed tomography angiography. Their correlation and prognostic values were assessed according to sex., Results: A total of 364 participants (27.7% women and 72.3% men) were enrolled. Among those with heightened stress-related neural activity, women were more likely to have a higher fat attenuation index (43.0% versus 24.0%; P =0.004), while men had a higher frequency of high-risk plaques (53.7% versus 39.3%; P =0.036). High amygdalar 18 F-flourodeoxyglucose uptake (B-coefficient [SE], 3.62 [0.21]; P <0.001) was selected as the strongest predictor of fat attenuation index in a fully adjusted linear regression model in women, and the first-order interaction term consisting of sex and stress-related neural activity was significant ( P <0.001). Those with enhanced imaging biomarkers of stress-related neural activity showed increased risk of major adverse cardiovascular event both in women (24.5% versus 5.1%; adjusted hazard ratio, 3.62 [95% CI, 1.14-17.14]; P =0.039) and men (17.2% versus 6.9%; adjusted hazard ratio, 2.72 [95% CI, 1.10-6.69]; P =0.030)., Conclusions: Imaging-assessed stress-related neural activity carried prognostic values irrespective of sex; however, a sex-specific mechanism linking psychological stress to coronary plaque phenotypes existed in the current hypothesis-generating study., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05545618., Competing Interests: Disclosures None.

Importance: Sibling death is a highly traumatic event, but empirical evidence on the association of sibling death in childhood and early adulthood with subsequent risk of incident cardiovascular disease (CVD) remains limited., Objective: To evaluate the association between sibling death in the early decades of life and subsequent risk of incident early-onset CVD., Design, Setting, and Participants: This population-based cohort study included 2 098 659 individuals born in Denmark from 1978 to 2018. Follow-up started at age 1 year or the date of the first sibling's birth, whichever occurred later, and it ended at the first diagnosis of CVD, the date of death, emigration, or December 31, 2018, whichever came first. Data analyses were conducted from November 1, 2021, through January 10, 2022., Exposures: The death of a sibling., Main Outcomes and Measures: The outcome was early-onset CVD. Cox models were used to estimate hazard ratios (HRs) with 95% CIs., Results: This study included 2 098 659 individuals (1 076 669 [51.30%] male; median [IQR] age at death of sibling, 11.48 [4.68-21.32] years). During the median (IQR) follow-up of 17.52 (8.85-26.05) years, 1286 and 76 862 individuals in the bereaved and nonbereaved groups, respectively, were diagnosed with CVD. Sibling death in childhood and early adulthood was associated with a 17% increased risk of overall CVD (HR, 1.17; 95% CI, 1.10-1.23; cumulative incidence in bereaved individuals, 1.96% [1.61%-2.34%]; cumulative incidence in nonbereaved individuals at age 41 years, 1.35% [1.34%-1.37%]; cumulative incidence difference: 0.61% [95% CI, 0.24%-0.98%]). Increased risks were also observed for most type-specific CVDs, in particular for myocardial infarction (HR, 1.66; 95% CI, 1.12-2.46), ischemic heart disease (HR, 1.52; 95% CI, 1.22-1.90), and heart failure (HR, 1.50; 95% CI, 1.00-2.26). The association was observed whether the sibling died due to CVD (HR, 2.54; 95% CI, 2.04-3.17) or non-CVD (HR, 1.13; 95% CI, 1.06-1.19) causes. The increased risk of CVD was more pronounced for individuals who lost a twin or younger sibling (HR, 1.25; 95% CI, 1.15-1.36) than an elder sibling (HR, 1.11; 95% CI, 1.03-1.20)., Conclusions and Relevance: In this cohort study of the Danish population, sibling death in childhood and early adulthood was associated with increased risks of overall and most type-specific early-onset CVDs, with the strength of associations varying by cause of death and age difference between sibling pairs. The findings highlight the need for extra attention and support to the bereaved siblings to reduce CVD risk later in life.

Background: China has long been with high Hepatitis B Virus(HBV) prevalence in the world. The HBV prevalence of people aged 1-59 decreased to less than 8% in 2006, and by 2020, HBsAg positive rate of children aged <5 decreased to less than <1% which was due to the free three-dose hepatitis B(HepB) immunization for newborns nationwide since 2002. Huangpu district was selected as one of the pilot areas for free Hep B vaccination in newborns since 1986, which formed an early protection in the population from mother-to-child transmission. However, the existed HBV infected people were still needed to be discovered, evaluated whether to receive antiviral therapies and intervened with health education in order to reduce the incidence of viral hepatitis related hepatocellular carcinoma (HCC) and also reach the goal to eliminate public health hazards of viral hepatitis by 2030., Objective: To know HepB immunization status among people aged 1 to 69 in Huangpu district of Shanghai, and find out risk factors changes of HBV infection., Methods: Cross-sectional study was applied to analyze the HepB immunization status and related risk factors by carrying out survey among 706 participants aged 1 to 69 years old. Blood samples were collected for detection of serological HBV markers including hepatitis B surface antigen(HBsAg), hepatitis B surface antibody(HBsAb) and hepatitis B core antibody(HBcAb). Participants with HBsAg positive were required to complete additional examinations such as alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bilirubin, albumin, globulin, liver fibroscan and liver ultrasound., Results: For participants aged 1 to 14, the positive rate of HBsAg, HBsAb and HBcAb was 0.00, 50.00 and 30.46%, respectively. The HBsAb positive rate reached a peak of 90.91% at 2 years old, and then showed a significant downward trend (χ 2  = 55.612, p  < 0.001). All the participants have completed three-dose Hep B vaccination, however for the second dose, those who vaccinated 30 days later than the appointed time(aged one month) got higher HBcAb prevalence than those who vaccinated on time(χ 2  = 5.87, p  = 0.015). Two mothers were found HBsAg positive, but there was no significant difference in children's HBcAb positive rates regardless of the mothers' HBsAg results. For participants aged 15 to 69, the positive rate of HBsAg, HBsAb and HBcAb was 4.21, 44.25 and 49.23%, respectively. Multivariate analysis for HBcAb positive among people aged 15 to 69 showed that age(50-69) and HBsAb positive were the risk factors for HBcAb positive( p  < 0.05). Higher education was the protective factor for HBcAb positive(p < 0.05). After the screening for HBsAg, 22 participants were tested HBsAg positive and required additional examinations, and a total of 12 completed all the examinations. One participant was recognized as active HBV infection without antivirus treatment. Among the 12 participants, 2 have received antiviral treatment before and 4 had a history of HBV infection in family members., Conclusion: In this study, HBsAg positive rate of those who aged 1 to 14 was 0.00%, which indicated that the HepB immunization has achieved a lot in protecting children from being infected. However, failing to get timely Hep B vaccination could be an influencing factor for HBcAb positive in children. As a result, additional tests for HBV DNA could be done to specify an HBV infection and more attention should be paid to the timeliness of Hep B vaccination in the next step. The HBcAb positive rate of people aged 1 to 69 was relatively higher than that of other provinces. Despite of the limited participants with full examinations, we should still put emphasis on HBV treatment and the possibility of transmission within families., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Shu, Chen, Shen, Ren and Yu.)

Background: Stress-related neural activity (SNA) assessed by amygdalar activity can predict cardiovascular events. However, its mechanistic linkage with plaque vulnerability is not fully elucidated., Objectives: The authors aimed to investigate the association of SNA with coronary plaque morphologic and inflammatory features as well as their ability in predicting major adverse cardiovascular events (MACE)., Methods: A total of 299 patients with coronary artery disease (CAD) and without cancer underwent 18 F-fluorodexoyglucose positron emission tomography/computed tomography (PET/CT) and available coronary computed tomographic angiography (CCTA) between January 1, 2013, and December 31, 2020. SNA and bone-marrow activity (BMA) were assessed with validated methods. Coronary inflammation (fat attenuation index [FAI]) and high-risk plaque (HRP) characteristics were assessed by CCTA. Relations between these features were analyzed. Relations between SNA and MACE were assessed with Cox models, log-rank tests, and mediation (path) analyses., Results: SNA was significant correlated with BMA (r = 0.39; P < 0.001) and FAI (r = 0.49; P < 0.001). Patients with heightened SNA are more likely to have HRP (40.7% vs 23.5%; P = 0.002) and increase risk of MACE (17.2% vs 5.1%, adjusted HR 3.22; 95% CI: 1.31-7.93; P = 0.011). Mediation analysis suggested that higher SNA associates with MACE via a serial mechanism involving BMA, FAI, and HRP., Conclusions: SNA is significantly correlated with FAI and HRP in patients with CAD. Furthermore, such neural activity was associated with MACE, which was mediated in part by leukopoietic activity in the bone marrow, coronary inflammation, and plaque vulnerability., Competing Interests: Funding Support and Author Disclosures This work was supported by National Key Research and Development Program of China (2021YFC2500500 and 2020YFC1316700), Shanghai Clinical Research Center for Interventional Medicine (19MC1910300), and China Cardiovascular Health Alliance-Access Research Fund (2020-CCA-ACCESS-124). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension affects 31.1% of adults worldwide, with higher prevalence of great than 60% in elderly. Advanced hypertension stage was associated with the higher risk of mortality. However, little is known about the age-specific association of stage of hypertension at diagnosis on cardiovascular mortality or all-cause mortality. Therefore, we aim to explore this age-specific association among the hypertensive elderly through stratified and interaction analyses., Methods: This cohort study included 125,978 elderly hypertensive patients aged 60+ years from Shanghai of China. Cox regression was used to estimate the independent and joint effect of hypertension stage and age at diagnosis on cardiovascular and all-cause mortality. Interactions were evaluated both additively and multiplicatively. Multiplicative interaction was examined by the Wald test of the interaction term. Additive interaction was assessed by relative excess risk due to interaction (RERI). All analyses were performed stratified by sex., Results: 28,250 patients died during the follow-up up to 8.85 years, and 13,164 died of cardiovascular events. Older age and advanced hypertension stage were risk factors of cardiovascular mortality and all-cause mortality. Besides, smoking, rarely exercise, BMI < 18.5 and diabetes were also the risk factors. When we compared stage 3 hypertension with stage 1 hypertension, hazard ratios (95% confidence interval) of cardiovascular mortality and all-cause mortality were 1.56(1.41-1.72) and 1.29(1.21-1.37) for males aged 60-69 years, 1.25(1.14-1.36) and 1.13(1.06-1.20) for males aged 70-85 years, 1.48(1.32-1.67) and 1.29(1.19-1.40) for females aged 60-69 years, and 1.19(1.10-1.29) and 1.08(1.01-1.15) for females aged 70-85 years, respectively. Negative multiplicative interaction and positive additive interaction between age at diagnosis and stage of hypertension at diagnosis on cardiovascular mortality were observed in males (HR: 0.81, 95% CI: 0.71-0.93 RERI: 0.59, 95% CI: 0.09-1.07) and females (HR: 0.81, 95% CI: 0.70-0.93 RERI: 0.66, 95% CI: 0.10-1.23)., Conclusions: Diagnosed with stage 3 hypertension was associated with higher risks of cardiovascular mortality and all-cause mortality, which were stronger among patients with age at diagnosis of 60-69 years compared with those with age at diagnosis of 70-85 years. Therefore, for the younger part of the elderly, the Department of Health should pay more attention to treating patients with stage 3 hypertension., (© 2023. The Author(s).)

Background: Hearing loss has occurred as a critical concern for aging and health. However, it remains unknown whether nocturnal sleep and midday napping duration are associated with hearing loss in middle-aged and older adults., Methods: The study comprised 9,573 adults from China Health and Retirement Longitudinal Study, who have completed the survey for sleep characteristics and subjective functional hearing. We collected self-reported nocturnal sleep duration (<5, 5 to <6, 6 to <7, 7 to <9, ≥9 h/night) and midday napping duration (≤5, 5 to ≤30, and >30 min). The sleep information was classified into different sleep patterns. The primary outcome was self-reported hearing loss events. Multivariate Cox regression models and restricted cubic splines were used to investigate the longitudinal association of sleep characteristics with hearing loss. We applied Cox generalized additive models and bivariate exposure-response surface diagrams to visualize the effects of different sleep patterns on hearing loss., Results: We confirmed 1,073 cases of hearing loss (55.1% female) during the follow-up. After adjusting for demographic characteristics, lifestyle factors and health condition, nocturnal sleep with < 5 h was positively associated with hearing loss [hazard ratio (HR): 1.45, 95% confidence interval [CI]: 1.20, 1.75]. Individuals with napping for 5 to ≤30 min had a 20% (HR: 0.80, 95%CI: 0.63, 1.00) lower risk of hearing loss compared with those with napping ≤ 5 min. Restrictive cubic splines showed the reverse J-shaped association between nocturnal sleep and hearing loss. Moreover, we found significant joint effects of sleeping < 7 h/night and midday napping ≤ 5 min (HR: 1.27, 95% CI: 1.06, 1.52) on hearing loss. Bivariate exposure-response surface diagrams also reflected the finding that short sleep without napping existed the highest risk of hearing loss. Compared with persistently sleeping moderately (7-9 h/night), those who persistently slept < 7 h/night or shifted from < 7 h/night to moderate or > 9 h/night had higher risks of hearing loss., Conclusion: Inadequate nocturnal sleep was associated with an elevated risk of poor subjective hearing in middle-aged and older adults, while moderate napping decreased the risk of hearing loss. Keeping sleep stable within recommendation duration may be a useful strategy for preventing poor hearing loss., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cui, Lu, Guo, Dai, Huang, Liu, Lin, Yu, Qin and Chen.)