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Abstract 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 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 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.

BackgroundChina 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

Abstract 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 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

Abstract 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 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 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 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 (

Abstract The appropriate prophylaxis for hepatitis B virus reactivation (HBVr) during gestation for immunocompromised pregnant women has yet to be determined. The prophylactic efficacy and safety of tenofovir disoproxil fumarate (TDF) in hepatitis B surface antigen (HBsAg)–positive patients and the HBVr risk in hepatitis B core antibody (HBcAb)–positive patients during gestation were investigated. Eligible pregnant women were diagnosed with rheumatic diseases and were administered prednisone (≤10 mg daily) with permitted immunosuppressants at screening. HBsAg‐positive participants were instructed to take TDF; those unwilling to take TDF were followed up as the control group. Propensity score matching was applied to control for differences in confounding factors between the HBcAb‐positive and uninfected groups. Hepatopathy, maternal, pregnancy, and safety outcomes were documented as endpoints. A cohort of 1292 women was recruited from 2017 to 2020, including 58 HBsAg‐positive patients (29 in each group). A total of 120 pairs in the HBcAb‐positive and noninfection groups were analyzed. Among HBsAg‐positive patients, 6 (20.7%) cases of hepatitis flare (hazard ratio [HR]: 7.44; 95% confidence interval [CI]: 1.50–36.89; p = 0.014) and 12 (41.4%) cases of HBVr (HR: 8.71; 95% CI: 2.80–27.17; p

BackgroundHearing 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.MethodsThe 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 (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.ResultsWe 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 9 h/night had higher risks of hearing loss.ConclusionInadequate 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.

Abstract Though gut microbiome disturbance may be involved in the etiology of gestational diabetes mellitus (GDM), data on the gut microbiome's dynamic change during pregnancy and associations with gestational glucose metabolism are still inadequate. In this prospective study comprising 120 pairs of GDM patients and matched pregnant controls, a decrease in the diversity of gut microbial species and changes in the microbial community composition with advancing gestation are found in controls, while no such trends are observed in GDM patients. Multivariable analysis identifies 10 GDM‐related species (e.g., Alistipes putredinis), and the integrated associations of these species with glycemic traits are modified by habitual intake of fiber‐rich plant foods. In addition, the microbial metabolic potentials related to fiber fermentation (e.g., mannan degradation pathways) and their key enzymes consistently emerge as associated with both GDM status and glycemic traits. Microbial features especially those involved in fiber fermentation, provide an incremental predictive value in a prediction model with established risk factors of GDM. These data suggest that the gut microbiome remodeling with advancing gestation is different in GDM patients compared with controls, and dietary fiber fermentation contributes to the influence of gut microbiome on gestational glycemic regulation.

BackgroundAlthough associations of physical activity and smoking with mortality have been well-established, the joint impact of physical activity and smoking on premature mortality among elderly hypertensive population was still unclear. This study aimed to assess association of physical activity, smoking, and their interaction with all-cause and cardiovascular disease (CVD) mortality risk in elderly hypertensive patients.MethodsWe included 125,978 Chinese hypertensive patients aged 60–85 years [mean (SD) age, 70.5 (6.9) years] who had records in electronic health information system of Minhang District of Shanghai, China in 2007–2015. Cox regression was used to estimate individual and joint association of smoking and physical activity on all-cause and CVD mortality. Interactions were measured both additively and multiplicatively. Additive interaction was evaluated by relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S).ResultsAmong 125,978 elderly hypertensive patients (median age 70.1), 28,250 deaths from all causes and 13,164 deaths from CVD were observed during the follow-up up to 11 years. There was an additive interaction between smoking and physical inactivity [RERI: all-cause 0.19 (95% CI: 0.04–0.34), CVD 0.28 (0.06–0.50); AP: all-cause 0.09 (0.02–0.16), CVD 0.14 (0.04–0.23); S: all-cause 1.21 (1.04–1.42), CVD 1.36 (1.06–1.75)], while the concurrence of both risk factors was associated with more than 2-fold risk of death [hazard ratio (HR): all-cause 2.10 (1.99–2.21), CVD 2.19 (2.02–2.38)].ConclusionOur study suggested that smoking and physical inactivity together may have amplified association on premature death compared to the sum of their individual associations, highlighting the importance of improving behavioral factors in combination and promoting a comprehensive healthy lifestyle in hypertensive elderly.

PurposePrevious studies have suggested a link between cardiovascular disease (CVD) and the subsequent development of lung cancer. However, empirical evidence on the association of CVDs, particularly type-specific CVDs, with lung cancer incidence and survival remains limited.MethodsThe cohort study included 306,285 patients with CVD and 1,222,140 individuals without CVD. We performed stratified Cox regression to estimate the hazard ratio (HR).ResultsDuring up to 42 years of follow-up, 243 (0.08%) and 537 (0.04%) participants were diagnosed with lung cancer among CVD patients and matched individuals, respectively. Patients with CVD had a 67% increased risk of lung cancer (HR: 1.67, 95% confidence interval [CI]: 1.42–1.96). The increased risks were observed in patients with heart disease (1.93, 1.30–2.85), vascular disease (1.88, 1.35–2.61), and hypertensive disease (1.46, 1.15–1.85), respectively. Patients with CVD had a 95% increased risk of lung cancer mortality (1.95, 1.50–2.55), particularly vascular disease (3.24, 1.74–6.02) and heart disease (2.29, 1.23–4.26). Patients with CVD diagnosed in middle adulthood (>40 years old) tended to have a higher incidence risk (3.44, 2.28–5.19) and mortality (3.67, 1.80–7.46) than those diagnosed at younger ages.ConclusionsOur findings on the association of CVD diagnosis, especially heart and vascular disease, with increased risk of lung cancer incidence and mortality suggest that CVD contributes to the development and worsening of lung cancer survival. In particular, people with CVD diagnosed in middle adulthood (>40 years old) would benefit from early preventive evaluation and screening for lung cancer.

Objectives: To investigate the association of risk of venous thromboembolism with 30-day mortality in COVID-19 patients. Methods: 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. Results: 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. Conclusions: 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.

BackgroundImmune checkpoint inhibitors (ICI) improve survival in patients with late-stage esophageal squamous cell carcinoma (ESCC) but have not been fully evaluated in locally advanced ESCC.MethodWe retrospectively assessed outcomes of consecutive, treatment-naïve locally advanced ESCC (stage III or IVA) adults treated with neoadjuvant ICI plus chemotherapy followed by surgery, who refused or lacked access to radiotherapy, with regards to surgery feasibility, pathological response, and relapse-free survival (RFS).ResultsWe uneventfully treated 34 patients with the combined regimen in 2020. None reported grade III or higher toxic effects. All underwent surgery as planned: 32 received complete (R0) resections and 2 had microscopically positive margins (R1). Tumor downstaging occurred in 33 (97.1%) patients and 11 (32.4%) had pathologically complete response of the primary lesion. Median postoperative length of stay was 12 days (interquartile range: 11 to 17). All patients resumed a semi-liquid diet on discharge. The 90-day postoperative morbidity rate was 20.6% (7/34) with no mortalities. The 1-year RFS was 77.8% [95% CI, 64.2-94.2].ConclusionNeoadjuvant ICI plus chemotherapy was safe and resulted in significant downstaging, rendering inoperable tumors operable, relieving symptoms of dysphagia and prolonging survival for locally advanced ESCC patients who refused or lacked access to radiotherapy.

Background Coronary diffuse disease associates with poor outcomes, but little is known about its role after percutaneous coronary intervention (PCI). We aimed to investigate the prognostic implication of pre‐PCI focal or diffuse disease patterns combined with post‐PCI quantitative flow ratio (QFR). Methods and Results Pre‐PCI QFR derived pullback pressure gradient (PPG) (QFR‐PPG) was measured to assess physiological disease patterns for 1685 included vessels; the vessels were classified according to dichotomous pre‐PCI QFR‐PPG and post‐PCI QFR. Vessel‐oriented composite outcome, a composite of vessel‐related ischemia‐driven revascularization, vessel‐related myocardial infarction, or cardiac death at 2 years was compared among these groups. Vessels with low pre‐PCI PPG (3.9% versus 2.0%, hazard ratio [HR], 1.93; 95% CI, 1.08–3.44; P=0.02) or low post‐PCI QFR (9.8% versus 2.7%, HR, 3.78; 95% CI, 1.61–8.87; P=0.001) demonstrated higher vessel‐oriented composite outcome risk after stent implantation. Of note, despite high post‐PCI QFR achieved, vessels with low pre‐PCI QFR‐PPG presented higher risk of vessel‐oriented composite outcome than those with high pre‐PCI QFR‐PPG (3.7% versus 1.8%, HR, 2.03; 95% CI, 1.09–3.76; P=0.03) and pre‐PCI QFR‐PPG demonstrated direct prognostic effect not mediated by post‐PCI QFR. Integration of groups classified by pre‐PCI QFR‐PPG and post‐PCI QFR showed significantly higher discriminant and reclassification abilities than clinical factors (C‐index 0.77 versus 0.72, P=0.03; integrated discrimination improvement 0.93%, P=0.04; net reclassification index 0.33, P=0.02). Conclusions Prognostic value of pre‐PCI focal or diffuse disease patterns assessed by QFR‐PPG index was retained even after successful PCI, which is mostly explained by its direct effect that was not mediated by post‐PCI QFR. Integration of both pre‐PCI and post‐PCI physiological information can provide better risk stratification in vessels with stent implantation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05104580.

Abstract 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.

PurposeThis study aimed to characterize the clinical features of early-stage ovarian cancer (OC) survivors with second primary malignancies (SPMs) and provided a prediction tool for individualized risk of developing SPMs.MethodsData were obtained from the Surveillance, Epidemiology and End Results (SEER) database during 1998–2013. Considering non-SPM death as a competing event, the Fine and Gray model and the corresponding nomogram were used to identify the risk factors for SPMs and predict the SPM probabilities after the initial OC diagnosis. The decision curve analysis (DCA) was performed to evaluate the clinical utility of our proposed model.ResultsA total of 14,314 qualified patients were enrolled. The diagnosis rate and the cumulative incidence of SPMs were 7.9% and 13.6% [95% confidence interval (CI) = 13.5% to 13.6%], respectively, during the median follow-up of 8.6 years. The multivariable competing risk analysis suggested that older age at initial cancer diagnosis, white race, epithelial histologic subtypes of OC (serous, endometrioid, mucinous, and Brenner tumor), number of lymph nodes examined (

Abstract 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

Objectives:The associations of long-term risks of the full spectrum of mental disorders with clinically reassuring but suboptimal score range 7–9 remain unclear. This study investigated these associations during up to 38 years of follow-up.Methods:In a nationwide cohort study of 2,213,822 singletons born in Denmark during 1978–2015, we used cox regression to estimate the hazard ratio (HR) of mental disorders with a 95% CI.Results:A total of 3,00,679 (13.6%) individuals were diagnosed with mental disorders. The associations between suboptimal Apgar score 7–9 and mental disorders differed by attained age. In childhood (≤ 18 years), declining Apgar scores were associated with increased risks of overall mental disorders with HRs (95% CI) of 1.13(1.11-1.15), 1.34 (1.27–1.41), and 1.48 (1.31–1.67) for Apgar scores of 7–9, 4–6, and 1–3, respectively, compared with a score of 10. A dose-response association was seen even within the score range from 9 to 7 (HR 1.11 [95% CI: 1.08–1.13], 1.14 [1.10–1.18], and 1.20 [1.14–1.27], respectively). Of note, individuals with scores of 7–9 had increased risks of organic disorders (HR: 1.27, 95% CI: 1.05–1.53), neurotic disorders (HR: 1.07, 95% CI: 1.03–1.11), and a wide range of neurodevelopmental disorders, such as intellectual disability (1.87, 1.76–1.98), childhood autism (1.13, 1.05–1.22) and attention deficit hyperactivity disorder (1.10, 1.06–1.15). In early adulthood (19–39 years), suboptimal Apgar scores 7–9 were not associated with the risks of overall and specific mental disorders.Conclusion:Infants born with clinically reassuring but suboptimal 5-min scores 7–9 are at increased risks of a wide spectrum of mental disorders in childhood.

Abstract Background Atopic diseases are characterized by dysregulated inflammatory response, which may incur the onset of peripartum mental disorders, but the impact remains unknown. This study examined whether and to what extent the history of atopic diseases is associated with newly onset peripartum mental disorders. Methods Using population‐based registries, we identified all primiparous women who gave birth to live singletons in Denmark during 1978–2016 (n = 937,422). The exposure was hospital contact due to the three major types of atopic diseases—asthma, atopic dermatitis, and allergic rhinitis—before conception. The primary outcome was any hospital contact for mental disorder during pregnancy and 1‐year postpartum, which was further classified into affective disorders, neurotic, stress‐related and somatoform disorders, and substance abuse. The follow‐up started from the date of conception and ended at the date of the first diagnosis of mental disorders, 1‐year postpartum, death, emigration, or December 31, 2016, whichever came first. Cox regression was used, adjusted for calendar year, age at childbirth, education, residence, and Charlson comorbidity index. Results A total of 24,016 (2.6%) women received diagnosis of at least one of the three atopic diseases before conception (asthma, 1.7%; atopic dermatitis, 0.6%; and allergic rhinitis, 0.8%). Exposure to asthma, atopic dermatitis, or allergic rhinitis was associated with a 37% increased overall risk of peripartum mental disorders (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.27–1.49). Higher risks were observed among women with more frequent hospital contacts for atopic disease (HR, 1.80; 95% CI, 1.37–2.35; ≥5 times), and with recent hospital contacts for atopic disease (HR, 1.74; 95% CI, 1.48–2.06; within 2 years before conception). Specific associations were observed between asthma and neurotic, stress‐related and somatoform disorders (HR, 1.40; 95% CI, 1.21–1.62), and between atopic dermatitis and substance abuse (HR, 1.62; 95% CI, 1.12–2.34). Conclusions History of asthma, atopic dermatitis, and allergic rhinitis before conception was associated with increased risks of peripartum mental disorders. Women who have atopic diseases before pregnancy may benefit from systematic mental health monitoring.

BackgroundThe 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 findingsWe 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.ConclusionsOffspring 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.

BackgroundNo previous study has examined the effect of maternal hypothyroidism on a broad spectrum of cardiovascular disease (CVD) endpoints in the offspring.MethodsA nationwide population-based cohort study based on the linkage of several Danish nationwide registries was conducted to explore whether maternal hypothyroidism is associated with offspring’s CVD. Altogether 1,041,448 singletons born between the 1st of January 1978 and the 31st of December 1998 were investigated from the age of 8 years to the 31st of December 2016. Exposure was maternal diagnosis of hypothyroidism across lifespan and the outcome of interest was a CVD diagnosis in the offspring. Cox regression models were performed to estimate the hazard ratios (HRs) of CVD.ResultsOffspring born to mothers with hypothyroidism had an increased risk of CVD (hazard ratios (HR)=1.23, 95% confidence interval (CI): 1.12-1.35), and of several subcategories of CVD including hypertension, arrhythmia, and acute myocardial infarction in offspring. The magnitude of association was the most pronounced in an exposure occur during pregnancy (HR=1.71, 95% CI: 1.10-2.67), which is consistent across all the subgroup analysis, including sibling analysis.ConclusionsMaternal hypothyroidism is associated with an increased risk of CVD in offspring. Thyroid hormone insufficiency during pregnancy may predominantly contribute to the observed associations; however, the effects of a shared genetic background and a time-stable familial environment/lifestyle factors cannot be excluded.

Abstract Purpose Results from studies of internal mammary lymph node sentinel biopsy are inconsistent. Methods A comprehensive literature search was conducted in MEDLINE, EMBASE, Scopus, Cochrane database, and Clinical Trials. Studies reporting the rate of internal mammary lymph node sentinel biopsy (IMN-SLNB) positivity were identified. We performed pooled proportion meta-analysis using random-effects meta-analyses. The correlation of IMN and axillary lymph node (AXN) metastasis was also investigated. Results After application of inclusion and exclusion criteria, a total of 18 articles (total number of patients = 2427) were included. The pooled estimate for IMN-SLNB positivity rate was 15% (95% confidence interval (CI) 12–17%). Significant between-study heterogeneity was observed. Our results indicate that axillary lymph node metastasis is a strong predictor of IMN involvement (OR 6.01, 95% CI, 3.49, 10.34). Conclusion Internal mammary lymph nodes metastasis might be underestimated. Patients with positive axillary lymph nodes have a higher risk of internal lymph nodes metastasis. As a result, IMN-SLNB might be considered in these patients. Future work needs to be done to assess whether pathological confirmed IMN metastasis can affect patients’ survival.

BackgroundMost of the women who smoke before pregnancy continue smoking during pregnancy, and some start to quit smoking after being pregnant, although existing guidelines for pregnancy recommend that women who smoke should quit smoking before pregnancy. Findings about the timing and intensity of maternal smoking, especially low-intensity smoking (1-9 cigarettes per day), and preterm birth are still inconsistent and ambiguous. This study aimed to examine the association of the timing of smoking and doses of smoking before pregnancy and during the first or second trimester of pregnancy with preterm birth in a large-scale population-based retrospective cohort study.Methods and findingsWe used nationwide birth certificate data from singleton mother-infant pairs in the United States National Vital Statistics System, 2011-2018. All adult women with live singleton births, without preexisting hypertension or diabetes, and with complete data on smoking and gestational age at delivery were included. Participants reported their smoking status (yes or no) and daily number of cigarettes consumed before and during each trimester of pregnancy. The outcome of interest was preterm birth, defined as a birth before 37 weeks of gestation. Logistic regression models were used to estimate the odds ratio (OR) with 95% confidence intervals (CIs) of preterm birth associated with smoking status and the number of cigarettes consumed, adjusting for maternal age, race/ethnicity, parity, education levels, prepregnancy BMI, previous history of preterm birth, marital status, infant sex, and initiation of prenatal care. This study included 25,623,479 women, with a mean age of 29 years (range 20-50 years); 13,742,486 (53.6%) participants were of non-Hispanic white ancestry, 5,971,598 (23.3%) of Hispanic ancestry, and 3,417,456 (13.34%) of non-Hispanic black ancestry. The prevalence of preterm birth was 9.3% (n = 2,378,398). We found that maternal smoking during pregnancy, even at a very low level of intensity, was associated with an increased risk of preterm delivery. The adjusted ORs (95% CI) of preterm birth for mothers who smoked 1-2, 3-5, 6-9, 10-19, and ≥20 cigarettes per day during the first trimester compared with mothers who did not smoke were 1.31 (1.29-1.33), 1.31 (1.30-1.32), 1.33 (1.31-1.35), 1.44 (1.43-1.45), and 1.53 (1.52-1.55), respectively (all P values < 0.001), whereas for those who smoked during the second trimester, the corresponding ORs were 1.37 (1.35-1.39), 1.36 (1.35-1.38), 1.36 (1.34-1.38), 1.48 (1.47-1.49), and 1.59 (1.58-1.61), respectively (all P values < 0.001). Furthermore, smokers who quit before pregnancy, regardless of smoking intensity, had a comparable risk of preterm birth with nonsmokers, although this was not the case when cessation occurred in the first or second trimester of pregnancy. The major limitation of this study is the self-reported information about smoking, which may be subject to information bias. In addition, we cannot rule out the possibility of residual confounding caused by unmeasured factors in an observational research design.ConclusionsIn this study, we observed that low-intensity cigarette consumption during either the first or second trimester of pregnancy, even as low as 1-2 cigarettes per day, was associated with an increased risk of preterm birth. These findings suggest that there is no safe level or safe trimester for maternal smoking during pregnancy. Women of reproductive age who smoke should be strongly encouraged and supported to quit smoking before pregnancy.

A prospective community-based cohort study was conducted to investigate the effects of obesity on hyperhomocysteinemia (HHcy) in community residents from Shanghai, China, with a median follow-up period of 2.98 years. The exposures were high body mass index (BMI) (BMI ≥ 28.0 kg/m2) and high waist circumference (WC) (WC ≥ 85.0 cm for female and WC ≥ 90.0 for male) at baseline investigation, and the outcome was the incident of HHcy after the follow-up. A restricted cubic spline (RCS) was performed to assess the possible nonlinear relationship of BMI and WC with HHcy. A Cox proportional hazard regression model was used to evaluate the association between BMI and WC measured obesity and the risk of HHcy (Hcy level > 15 µmol/L). No significant non-linearity was found between BMI and WC with HHcy. Cox regression model showed that underweight measured by BMI was negatively associated with the risk of HHcy after controlling for confounder variables (adjusted HR = 0.64, 95% CI = 0.42 to 0.99). While abdominal obesity was positively associated with the risk of HHcy for those without CVD-related comorbidities (adjusted HR = 1.26, 95% CI = 1.05 to 1.51). Our results suggested that individuals could maintain a relatively low BMI and normal WC to lower the risk of HHcy.

BackgroundSocioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality.Methods and findingsWe developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981-2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0-27 days) and postneonatal (28-364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48-1.80, P < 0.001) and 1.19 (95% CI 1.08-1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRRPE = 1.27, 95% CI 1.15-1.40, P < 0.001) for low and 60% (MRRPE = 1.11, 95% CI 1.01-1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%-81%) than with postneonatal mortality (proportion eliminated: 21%-23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare.ConclusionsPTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors.

Intrauterine malnutrition has a long-term effect on human health. This study aimed to evaluate the associations between exposure to famine in early life and obesity in adulthood in Chinese adults. A total of 5033 participants (22,132 observations) of the China Health and Nutrition Survey (CHNS) in 1991–2015 were classified into three famine exposure groups according to their birth year: unexposed (1963–1966), fetal-exposed (1959–1962) and childhood-exposed (1955–1958). Compared with the unexposed group, the fetal-exposed group had higher levels of body-mass-index (BMI) and waist-circumference (WC), and higher prevalence of overweight and central obesity, whereas the childhood-exposed group had lower levels of the measurements. However, the positive associations of fetal exposure with BMI, WC and prevalence of overweight and central obesity were attenuated by additionally adjusting for age at survey. Stratified analysis showed that the adverse effect of fetal exposure to famine was only observed in subjects at several specific age-groups, and in men living in rural areas and in women living in more severe famine exposed areas (p for interaction < 0.05). Our results provide evidence for the weak effect of fetal exposure to famine on body measurements in adulthood, and suggest the importance of severity of famine exposure and timing of exposure.

BACKGROUND:Cerebral palsy (CP) is the most common physical developmental disability in childhood with a prevalence of 2 to 3 per 1000 live births. β2-adrenoreceptor agonist (β2AA) are widely used for the treatment of asthma. Maternal use of β2AAs may increase the risk of adverse neuro-psychiatric health outcomes in the offspring. No study, however, has evaluated the effect of prenatal exposure to β2AAs on the risk of CP. OBJECTIVE:To examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy. METHODS:This population-based cohort study included all live singleton births in Denmark from January 1, 1997 to December 31, 2003. The information on outpatient prescriptions of β2AAs was extracted from Danish National Prescription Registry. Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. To differentiate the effect of β2AAs from the underlying indications, the exposure window was further extended to 2 years before pregnancy and the exposed groups were re-defined to represent different periods of exposure to maternal use of β2AAs (use only before pregnancy, use only during pregnancy, and use both before and during pregnancy). Cases of CP were identified from the Danish Cerebral Palsy Register. Logistic regression was used to estimate incidence odds ratio (OR) of CP. RESULTS:Among all the 442,278 singletons, 19,616 (4.44%) were exposed to β2AAs in utero (from 30 days before pregnancy until delivery). The risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an adjusted OR (aOR) 1.12 (95% confidence interval (CI): 0.82, 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 95%CI: 0.92, 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 95%CI: 1.02, 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 95%CI: 0.99, 3.33). CONCLUSIONS:We observed an association between maternal β2AAs use during pregnancy and an increased risk of CP in female offspring, but we could not rule out confounding by the underlying indications for β2AAs.

ABSTRACT Objectives Higher rates of infant mortality in the UK than in the Nordic countries are partly explained by wider socio-economic disparities in the UK. We examined the extent to which low birth weight mediates the association between socioeconomic status (SES) and infant mortality using causal mediation analysis. We used cohorts of live births identified in administrative hospital data for the whole of Scotland and Denmark to explore the contribution of prenatal factors, represented by low birth weight, to differences in infant mortality between the two countries. Approach We included live-born children born in Denmark (n=1,432,205) and Scotland (n=1,427,163) from 1981-2004. Follow up was to 12 months of age. Information on deaths in first year of life was obtained through linkage with cause of death registers. We determined the effect of socioeconomic status on all cause infant mortality by comparing the highest and lowest quintiles of area-based deprivation (based on Carstairs score in Scotland) or level of maternal education in Denmark. Causal mediation analysis was used for survival outcomes with adjustment for maternal age at birth, sex, birth year of the child, and records indicating congenital malformation. Results During the follow-up, there were 8,158(0.57%) deaths in Denmark and 8,271(0.58%) deaths in Scotland. Comparing with the very high SES group, the overall hazard ratios of death for each SES quintile (starting with the lowest) compared with the highest SES quintile were 1.58(95% Confidence interval: 1.47-1.71), 1.40(1.32-1.49),1.25(1.20-1.30), 1.11(1.09-1.14) in Denmark, and 1.50(1.36-1.65),1.35(1.25-1.45),1.22(1.16-1.28),1.10(1.08-1.13) in Scotland. The proportions of excess infant deaths mediated through low birth weight (starting with the lowest) compared with the highest SES quintile were 54.7%, 52.1%, 49.5%, 46.9% in Denmark, and 26.0%, 23.9%, 22.0%, 20.1% in Scotland. Conclusion Our result suggests that SES has similar effects on infant mortality in Denmark and Scotland but more of the effect of SES on infant mortality is mediated through low birth weight in Denmark. Public health preventive strategies for infant mortality in both countries need to address prenatal risk factors for low birth weight. The substantial direct effects of SES on infant mortality seen in Scotland, which were not mediated through low birth weight, may be explained by other birth characteristics or could reflect persisting SES disparities in the care of infants after birth.

BACKGROUND:Mortality in children under five years has been widely studied, whereas mortality at 5-9 years has received little attention. Using unique data from national registers in three Nordic countries, we aimed to characterize mortality directionality in children aged 0 to 9 years. METHODS AND FINDINGS:The cohort study included all children born in Denmark from 1973 to 2008 (n = 2,433,758), Sweden from 1973 to 2006 (n = 3,400,212), and a random sample of 89.3% of children born in Finland from 1987 to 2007 (n = 1,272,083). Children were followed from 0 to 9 years, and cumulative mortality and mortality rates were compared by age, gender, cause of death, and calendar periods. Among the 7,105,962 children, there were 48,299 deaths during study period. From 1981-1985 to 2001-2005, all-cause mortality rates were reduced by between 34% and 62% at different ages. Overall mortality rate ratio between boys and girls decreased from 1.25 to 1.21 with the most prominent reduction in children aged 5-9 years (from 1.59 to 1.19). Neoplasms, diseases of the nervous system and transport accidents were the most frequent cause of death after the first year of life. These three leading causes of death declined by 42% (from 6.2 to 3.6 per 100,000 person years), 43% (from 3.7 to 2.1) and 62% (from 3.9 to 1.5) in boys, and 25% (from 4.1 to 3.1 per 100000 person years), 42% (from 3.4 to 1.9) and 63% (from 3.0 to 1.1) in girls, respectively. Mortality from neoplasms was the highest in each age except infants when comparing cause-specific mortality, and half of deaths from diseases of the nervous system occurred in infancy. Mortality rate due to transport accidents increased with age and was highest in boys aged 5-9 years. CONCLUSIONS:Mortality rate in children aged 0-9 years has been decreasing with diminished difference between genders over the past decades. Our results suggest the importance of further research on mortality by causes of neoplasms, and causes of transport accidents-especially in children aged 5-9 years.

PurposePIK3CA 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 methodsOncogenic 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.ResultsPIK3CA 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 (pConclusionsPIK3CA 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.

PURPOSE: To investigate the changes in dry eye symptoms and clinical signs and corneal sensitivity after small incision lenticule extraction (SMILE) and femtosecond LASIK (femto-LASIK). DESIGN: Prospective, non-randomized comparative study. METHODS: The study included a total of 71 eyes of 71 patients; the SMILE group comprised 38 eyes of 38 patients, and the femto-LASIK group comprised 33 eyes of 33 patients. Ocular Surface Disease Index (OSDI), Tear film breakup time (TBUT), the Schirmer test without anesthesia (S1T), corneal fluorescein staining, and central corneal sensation were evaluated before surgery and at 1 week, 1 month, 3 months, and 6 months after surgery. RESULTS: OSDI scores in both groups were increased immediately and returned to preoperative level at 1 month after surgeries. The TBUT values in both groups were reduced after surgeries relative to their preoperative scores. Patients in SMILE group were less likely to have corneal staining compared with those in the femto-LASIK group ([odds ratio] OR = 0.50, 95% [confidence interval] CI 0.28 to 0.93, P = 0.03). Central corneal sensitivity was decreased at all postoperative time points in both groups. However, the central corneal sensation scores in the SMILE group were greater than that in the femto-LASIK group at all of the postoperative time points (all P

In this paper, a surfactant, atlox4862 (formaldehyde condensate of methyl naphthalene sulfonic sodium salt) (MF), was introduced as a depressant for reverse flotation separation of sericite from graphite. Natural flake graphite has a strong hydrophobic property. After interacting with MF, the graphite became moderately hydrophilic. The flotation results showed that MF had a depressing ability for both sericite and graphite and that the flotation separation of sericite from graphite was attributed to the different declining levels of recovery between graphite and sericite with increased MF concentration. For a pulp pH of 8 and a MF concentration of 250 mg/L, the recovery rates of sericite and graphite were 89.7% and 11.3%, respectively. The results of the FTIR spectra and zeta potential measurements demonstrated that the interaction of MF with graphite and sericite is mainly through electrostatic attraction. MF was preferred to adsorb on the surface of graphite, decreasing its zeta potential and improving its hydrophilicity more than that of sericite.