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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.

Background: Few studies focus on the associations of green space composition and configuration with children's allergic rhinitis (AR)., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Zhuohui zhao reports financial support was provided by the Shanghai 3-year Public Health Action Plan [grant numbers GWVI-11.2-XD11]. Zhuohui zhao reports financial support was provided by Shanghai International Science and Technology Partnership Project (No. 21230780200). Zhuohui zhao reports financial support was provided by Shanghai B&R Joint Laboratory Project [grant numbers No.22230750300]., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 (PM 2.5 ), coarse particles (PM 2.5-10 ) and inhalable particles (PM 10 ) 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 PM 2.5 , PM 2.5-10 and PM 10 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., (© 2023 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

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.

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., (© The Author(s) 2024. Published by Oxford University Press.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2023. Published by Elsevier B.V.)

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: 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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: To investigate the association of baseline nocturnal sleep duration and sleep changes with functional disability in middle-aged and elderly Chinese., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To compare mydriatic and eye-steering ultrawide field imaging (UWFI) with standard non-mydriatic UWFI examination in detecting peripheral retinal lesions in myopic patients., Methods: Cross-sectional, observational study. 220 eyes of 110 myopic patients with known peripheral retinal lesions in at least one eye under Goldmann three mirror contact lens examination were recruited. Non-mydriatic standard and eye-steering UWFI images were taken centrally and with eye-steering technique in upper, lower, nasal and temporal gazes under Optomap UWFI (Daytona, Optos, UK). Mydriatic standard and eye-steering UWFI was captured in central gaze and four different peripheral gazes. Sensitivity of detecting peripheral retinal lesions under different UWFI settings was compared., Results: 141 (64.09%) eyes were with peripheral retinal lesions. The sensitivity for detecting peripheral lesions from low to high was 41.84% (95% CI 33.62% to 50.54%) under non-mydriatic standard UWFI setting, 52.48% (95% CI 44.08% to 60.75%) under mydriatic standard setting, 75.18% (95% CI 67.21% to 82.06%) under non-mydriatic eye-steering setting and 86.52% (95% CI 79.76% to 91.69%) under mydriatic eye-steering setting. Both mydriasis and eye-steering technique increased sensitivity of detecting peripheral lesions with statistical significance (p<0.001). By applying eye-steering technique, sensitivity of detecting lesions located in superior and inferior quadrants witnessed a greater increase compared with other two quadrants (p<0.05). Neither spherical equivalence (p>0.05) nor axial length (p>0.05) was an independent influence factor for detecting peripheral lesions., Conclusions: Eye-steering technique and mydriasis could both efficiently improve the sensitivity of detecting peripheral retinal lesions in myopic patients. Lesions of superior and inferior quadrants benefited more from eye-steering technique., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The association between intrauterine growth restriction and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a binational register-based cohort study to assess associations of birth weight for gestational age (GA), a proxy for intrauterine growth restriction, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live nonmalformed singleton births from Sweden (1973-1996) and Denmark (1978-1998). During a median follow-up period of 10 years from age 18 years onwards, 29,742 individuals developed incident CVD (hypertension, ischemic heart disease, or cerebrovascular disease). Compared with individuals born with appropriate birth weight for GA (AGA; 10th-90th percentiles) or full term (39-40 gestational weeks), individuals born severely small for GA (SGA; ≤3rd percentile) or preterm (22-36 weeks) were at increased risk of CVD (hazard ratio (HR) = 1.38 (95% confidence interval (CI): 1.32, 1.45) and HR = 1.31 (95% CI: 1.25, 1.38), respectively). The association was attenuated when comparing individuals born SGA with their AGA siblings (HR = 1.11, 95% CI: 0.99, 1.25) but remained robust when comparing individuals born preterm with their term siblings (HR = 1.21, 95% CI: 1.07, 1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA birth., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

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).)

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., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

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.)

Importance: Growing evidence indicates that adverse prenatal or intrauterine environments might contribute to the development of high refractive error (RE) later in life. However, the association of maternal hypertensive disorder of pregnancy (HDP) with high RE in offspring during childhood and adolescence remains unknown., Objective: To investigate the association between maternal HDP and overall and type-specific high REs in offspring in childhood and adolescence., Design, Setting, and Participants: This nationwide population-based cohort study included live-born individuals born in Denmark from 1978 to 2018 in the Danish national health registers. Follow-up started at the date of birth and ended at the date of RE diagnosis, 18th birthday, death, emigration, or December 31, 2018, whichever came first. Data analyses were conducted from November 12, 2021, through June 30, 2022., Exposures: Maternal HDP (n = 104 952), including preeclampsia or eclampsia (n = 70 465) and hypertension (n = 34 487)., Main Outcomes and Measures: The main outcomes were the first occurrence of high RE (hyperopia, myopia, and astigmatism) in offspring. A Cox proportional hazards regression model was used to examine the association between maternal HDP and risk of high RE in offspring from birth until age 18 years, adjusting for multiple potential confounders., Results: This study included 2 537 421 live-born individuals, 51.30% of whom were male. During the follow-up of up to 18 years, 946 offspring of 104 952 mothers with HDP (0.90%) and 15 559 offspring of 2 432 469 mothers without HDP (0.64%) were diagnosed with high RE. The cumulative incidence of high RE was higher in the exposed cohort (1.12%; 95% CI, 1.05%-1.19%) than in the unexposed cohort (0.80%; 95% CI, 0.78%-0.81%) at 18 years of age (difference: 0.32%; 95% CI, 0.25%-0.40%). Offspring born to mothers with HDP had a 39% increased risk of overall high RE (hazard ratio [HR], 1.39; 95% CI, 1.31-1.49). Sibling-matched analysis revealed an increased risk of overall high RE in half siblings (HR, 1.21; 95% CI, 1.05-1.39) and full siblings (HR, 1.15; 95% CI, 0.99-1.34), but the difference was not significant for the latter. The elevated risks were observed for hypermetropia (HR, 1.41; 95% CI, 1.30-1.52), myopia (HR, 1.30; 95% CI, 1.10-1.53), and astigmatism (HR, 1.45; 95% CI, 1.22-1.71). The increased risk of high RE persisted among offspring aged 0 to 6 years (HR, 1.51, 95% CI, 1.38-1.65), 7 to 12 years (HR, 1.28; 95% CI, 1.11-1.47), and 13 to 18 years (HR, 1.16; 95% CI, 0.95-1.41), but the difference was not significant for the oldest group. When considering both timing of diagnosis and severity of maternal preeclampsia, the highest risk was observed in offspring prenatally exposed to early-onset and severe preeclampsia (HR, 2.59; 95% CI, 2.17-3.08)., Conclusions and Relevance: In this cohort study of the Danish population, maternal HDP, especially early-onset and severe preeclampsia, was associated with an increased risk of high RE in offspring during childhood and adolescence. These findings suggest that early and regular RE screening should be recommended for children of mothers with HDP.

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., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

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., (© 2023. The Author(s).)

Introduction: Maternal inflammatory bowel disease (IBD) during pregnancy may be associated with increased susceptibility to infection in offspring. We aimed to assess this association, taking into consideration the mediating role of anti-tumor necrosis factor α (anti-TNFα) agents and adverse birth outcomes., Methods: This population-based cohort study included all live-born singletons born in Denmark during 1995-2016 (n = 1,343,960). The exposure was maternal IBD. Main outcome of interest was offspring infection younger than 5 years, defined by either infection-related hospitalization or systemic antibiotic prescription, whose corresponding risk estimates were hazard ratios (HRs) and incidence rate ratios (IRRs), respectively. We applied an inverse probability-weighted marginal structural model for mediation analysis., Results: Offspring born to mothers with Crohn's disease (CD) had an 18% increased risk of infection-related hospitalization (HR 1.18, 95% confidence interval 1.10-1.26) and a 16% increased frequency of prescribed antibiotics (IRR 1.16, 95% confidence interval 1.11-1.21). Anti-TNFα agents could explain 10% and 3% of the 2 estimated total associations, respectively, while a composite of preterm birth, low birth weight, and small for gestational age could explain 4% and 0%, respectively. The association between prenatal anti-TNFα and frequency of antibiotics attenuated after additional adjustment for maternal CD (IRR from 1.23 [0.98-1.55] to 1.10 [0.87-1.40]). Maternal ulcerative colitis, however, was not associated with offspring infection., Discussion: Maternal CD, but not ulcerative colitis, was associated with an increased risk of infection in offspring younger than 5 years, of which adverse birth outcomes and anti-TNFα had a minor role. The association between anti-TNFα agents and pediatric infection could be partially explained by maternal CD., (Copyright © 2023 by The American College of Gastroenterology.)

Background: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy., Methods: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence., Findings: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects., Interpretation: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects., Funding: None., Competing Interests: Declaration of interests DG is employed part-time by Novo Nordisk. The other authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s).)

Importance: Maternal infection is common during pregnancy and is an important potential cause of fetal genetic and immunological abnormalities. Maternal infection has been reported to be associated with childhood leukemia in previous case-control or small cohort studies., Objective: To evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study., Design, Setting, and Participants: This population-based cohort study used data from 7 Danish national registries (including the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Cancer Registry, and others) for all live births in Denmark between 1978 and 2015. Swedish registry data for all live births between 1988 and 2014 were used to validate the findings for the Danish cohort. Data were analyzed from December 2019 to December 2021., Exposures: Maternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry., Main Outcomes and Measures: The primary outcome was any leukemia; secondary outcomes were acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Offspring childhood leukemia was identified in the Danish National Cancer Registry. Associations were first assessed in the whole cohort using Cox proportional hazards regression models, adjusted for potential confounders. A sibling analysis was performed to account for unmeasured familial confounding., Results: This study included 2 222 797 children, 51.3% of whom were boys. During the approximately 27 million person-years of follow-up (mean [SD], 12.0 [4.6] years per person), 1307 children were diagnosed with leukemia (ALL, 1050; AML, 165; or other, 92). Children born to mothers with infection during pregnancy had a 35% increased risk of leukemia (adjusted hazard ratio [HR], 1.35 [95% CI, 1.04-1.77]) compared with offspring of mothers without infection. Maternal genital and urinary tract infections were associated with a 142% and 65% increased risk of childhood leukemia, with HRs of 2.42 (95% CI, 1.50-3.92) and 1.65 (95% CI, 1.15-2.36), respectively. No association was observed for respiratory tract, digestive, or other infections. The sibling analysis showed comparable estimates to the whole-cohort analysis. The association patterns for ALL and AML were similar to that for any leukemia. No association was observed for maternal infection and brain tumors, lymphoma, or other childhood cancers., Conclusions and Relevance: In this cohort study of approximately 2.2 million children, maternal genitourinary tract infection during pregnancy was associated with childhood leukemia among offspring. If confirmed in future studies, our findings may have implications for understanding the etiology and developing preventive measures for childhood leukemia.

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., Competing Interests: Declaration of Competing Interest All authors declare not to have any conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: The cohort study aimed to assess the association of nighttime sleep duration and the change in nighttime sleep duration with chronic kidney disease (CKD) and whether the association between nighttime sleep duration and CKD differed by daytime napping., Methods: This study included 11,677 individuals from the China Health and Retirement Longitudinal Study (CHARLS) and used data from the 2011 baseline survey and four follow-up waves. Nighttime sleep duration was divided into three groups: short (&lt;7 h per night), optimal (7-9 h), and long nighttime sleep duration (&gt;9 h). Daytime napping was divided into two groups: no nap and with a nap. We used Cox proportional hazards model to examine the effect of nighttime sleep duration at baseline and change in nighttime sleep duration on incident CKD and a joint effect of nighttime sleep duration and nap time on onset CKD., Results: With a follow-up of 7 years, the incidence of CKD among those with short, optimal, and long nighttime sleep duration was 9.89, 6.75, and 9.05 per 1,000 person-years, respectively. Compared to individuals with optimal nighttime sleep duration, short nighttime sleepers had a 44% higher risk of onset CKD (hazard ratio [HR]: 1.44, 95% confidence interval [CI]: 1.21-1.72). Compared to participants with persistent optimal nighttime sleep duration, those with persistent short or long nighttime sleep duration had an increased risk of incident CKD (HR: 1.44, 95% CI: 1.15-1.80). We found a lower incidence of CKD in participants with short nighttime sleep duration and a nap (HR: 0.74, 95% CI: 0.60-0.93), compared to those with short nighttime sleep duration and no nap., Conclusion: Short nighttime sleep duration and persistent long or short nighttime sleep duration were associated with a higher risk of onset CKD. Keeping persistent optimal nighttime sleep duration may help reduce CKD risk later in life. Daytime napping may be protective against CKD incidence., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2022. The Author(s).)

Purpose: Infants with macrosomia are more likely to be born to mothers with gestational diabetes mellitus (GDM). This study aimed to investigate the associations between maternal blood glucose levels and fetal weight, placental weight, and risk of macrosomia in mothers with GDM., Patients and Methods: This retrospective study included 3211 singletons of mothers with GDM at the Shanghai First Maternity and Infant Hospital between January 2017 and December 2019. All women underwent an oral glucose tolerance test (OGTT) during the 24-28 weeks gestation period. Data on fetal and placental parameters were collected at delivery. Multiple linear regression models were used to evaluate the associations of maternal blood glucose levels with fetal weight and placental weight, while multiple logistic regression model was used to estimate the association between maternal blood glucose levels and the risk of macrosomia., Results: The prevalence of GDM in our study was 7%. Fasting plasma glucose (FPG) was positively correlated with fetal weight (r 2 =0.0329, P<0.001), and macrosomia risk (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.93-3.04; P<0.001). After adjusting for gestational age, the result remained significant (OR, 2.67; 95% CI, 2.11-3.38; P<0.001). In contrast, there was no significant relationship between 1-h plasma glucose (1hPG) or 2-h plasma glucose (2hPG) and fetal weight (P=0.18, P=0.46). Additionally, 1hPG or 2hPG was not strongly associated with macrosomia risk (OR, 0.95; 95% CI, 0.85-1.05; P=0.32 vs OR, 0.94; 95% CI, 0.85-1.05; P=0.28). Maternal blood glucose levels did not affect placental weight. The associations were similar in women carrying male and female fetuses., Conclusion: Maternal fasting plasma glucose levels were strongly associated with increased birth weight and macrosomia risk. Our findings suggest that fasting plasma glucose may predict birth weight., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Wei et al.)

Aims: To assess the independent and combined impacts of visit-to-visit fasting blood glucose variability (VVV-FBG) and mean fasting blood glucose level (M-FBG) on all-cause mortality., Materials and Methods: This prospective cohort study included 48 843 Chinese patients with type 2 diabetes. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate the association of VVV-FBG and M-FBG with all-cause mortality. The potential nonlinear associations were examined using restricted cubic splines, and additive interaction was evaluated using relative excess risk due to interaction (RERI). Cox generalized additive models (CGAMs) and bivariate response surface models were further used to assess the combined effects of VVV-FBG and M-FBG., Results: A total of 4087 deaths were observed during a median follow-up of 6.99 years. Compared with patients with values at the 5th percentile of average real variability (ARV) and M-FBG, we observed a 23% and 38% increased risk of premature deaths among those with values at the 95th percentile of ARV (HR 1.23, 95% CI 1.10, 1.37) and M-FBG (HR 1.38, 95% CI 1.26, 1.51), respectively. The interaction between glycaemic variability (ARV) and M-FBG was significant on both the additive scale (RERI 0.80 [0.29, 1.32]) and the multiplicative scale (HR 1.90 [1.10, 3.28]). High VVV-FBG and high M-FBG conferred the highest risk of all-cause mortality (HR 1.89, 95% CI 1.64, 2.17), compared to low VVV-FBG and low M-FBG. The CGAMs showed significant synergistic effects between glycaemic variability and M-FBG (P < 0.05). Moreover, a bivariate surface plot showed that risk of death increased more rapidly in type 2 diabetes patients with lower M-FBG combined with lower VVV-FBG., Conclusions: The coexistence of high glycaemic variability and high glucose level might exacerbate the independent risk of premature mortality in type 2 diabetes patients, highlighting the importance of achieving normal and stable glucose levels simultaneously in the management of glucose., (© 2022 John Wiley & Sons Ltd.)

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 mm 2 , 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 mm 3 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 mm 3 versus 293.9 mm 3 , 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.

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 (&lt; 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., (© 2022. The Author(s).)

Importance: An association between maternal preeclampsia and an increased risk of cardiovascular disease in the offspring is plausible, but evidence in this area is limited., Objective: To investigate (1) the association between maternal preeclampsia and risks of ischemic heart disease (IHD) and stroke in the offspring, (2) whether the association varies by severity or timing of onset of preeclampsia, and (3) the role of preterm birth and small for gestational age (SGA) birth, both of which are related to preeclampsia and cardiovascular diseases, in this association., Design, Setting, and Participants: This multinational population-based cohort study obtained data from Danish, Finnish, and Swedish national registries. Live singleton births from Denmark (1973-2016), Finland (1987-2014), and Sweden (1973-2014) were followed up until December 31, 2016, in Denmark and December 31, 2014, in Finland and Sweden. Data analyses were performed between September 2020 and September 2022., Exposures: Preeclampsia and its subtypes, including early onset (<34 gestational weeks) and late onset (≥34 gestational weeks), severe and mild or moderate, and with and without SGA birth., Main Outcomes and Measures: Diagnoses of IHD and stroke were extracted from patient and cause-of-death registers. Cox proportional hazards regression models and flexible parametric survival models were used to analyze the associations. Sibling analyses were conducted to control for unmeasured familial factors., Results: The cohort included of 8 475 819 births (2 668 697 [31.5%] from Denmark, 1 636 116 [19.3%] from Finland, and 4 171 006 [49.2%] from Sweden, comprising 4 350 546 boys [51.3%]). Of these offspring, 188 670 (2.2%) were exposed to maternal preeclampsia, 7446 (0.1%) were diagnosed with IHD, and 10 918 (0.1%) were diagnosed with stroke during the median (IQR) follow-up of 19.3 (9.0-28.1) years. Offspring of individuals with preeclampsia had increased risks of IHD (adjusted hazard ratio [HR], 1.33; 95% CI, 1.12-1.58) and stroke (adjusted HR, 1.34; 95% CI, 1.17-1.52). These associations were largely independent of preterm or SGA birth. Severe forms of preeclampsia were associated with a higher stroke risk than less severe forms (severe vs mild or moderate: adjusted HR, 1.81 [95% CI, 1.41-2.32] vs 1.22 [95% CI, 1.05-1.42]; early vs late onset: adjusted HR, 2.55 [95% CI, 1.97-3.28] vs 1.18 [95% CI, 1.01-1.39]; with vs without SGA birth: adjusted HR, 1.84 [95% CI, 1.44-2.34] vs 1.25 [95% CI, 1.07-1.48]). Sibling analyses suggested that the associations were partially explained by unmeasured familial factors., Conclusions and Relevance: Results of this study suggest that offspring born to individuals with preeclampsia had increased IHD and stroke risk that were not fully explained by preterm or SGA birth, and that the associated risks for stroke were higher for severe forms of preeclampsia.

Purpose: To evaluate the incidence, causes, and outcomes of implantable collamer lens (ICL) realignment or exchange after implantation of the EVO-ICL., Setting: Eye and ENT Hospital of Fudan University, China., Design: Retrospective study., Methods: The study included 10 258 consecutive eyes after ICL implantation. Preoperative refractive and biometric measurements were compared between eyes with and without realignment or exchange. For eyes with ICL realignment or exchange, visual and biometric outcomes were also compared before and after ICL realignment or exchange., Results: The overall incidence of ICL realignment or exchange was 0.21% 22 eyes. 12 eyes (0.12%) underwent ICL realignment by axis rotation (10 eyes) or ICL exchange (2 eyes) due to toric ICL (TICL) misalignment. After realignment, uncorrected distance visual acuity improved, and residual cylinder decreased from -1.75 ± 0.48 diopters (D) to -0.87 ± 0.59 D ( P = .01). 10 eyes (0.10%) underwent vertical rotation of ICL (3 eyes) or ICL exchange (7 eyes) due to excessive vault. After either vertical rotation or ICL exchange, vault decreased significantly ( P < .05)., Conclusions: The incidence of ICL realignment or exchange after ICL implantation is low. TICL misalignment and excessive vault are 2 main causes. Implant exchange may be performed for excessive vault or misalignment with an insufficient vault. In addition, vertical rotation of an ICL may be a less invasive method to treat excessive vault in certain cases., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of ASCRS and ESCRS.)

Background: Although 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., Methods: We 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)., Results: Among 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)]., Conclusion: Our 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., 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 © 2022 Yang, Xu, Liu, Li, Liew, Liu, Huang, Zhu, Zhang, Chen, Hao, Qin and Yu.)

Purpose: Previous 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., Methods: The 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)., Results: During 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., Conclusions: Our 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., 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 © 2022 Wang, Lu, Cronin-Fenton, Huang, Liew, Wei, Qin, Yu and Li.)

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 < 0.001) occurred in the control group, while 0 occurred in the TDF prophylaxis group. The HBV level at delivery was the lowest (1.6 log 10 IU/ml) for those who received TDF during the pregestation period with a good safety profile. More adverse maternal outcomes were observed in the control group (odds ratio: 0.19, 95% CI: 0.05-0.77, p = 0.021), including one death from fulminant hepatitis and two cases of vertical transmission. No HBVr was recorded in HBcAb-positive participants. Among immunocompromised pregnant women, prophylactic TDF during pregestation was necessary for HBsAg-positive women, whereas regular monitoring was recommended for HBcAb-positive women., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Immune 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., Method: We 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)., Results: We 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]., Conclusion: Neoadjuvant 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., Competing Interests: Author MT was employed by Mayo Clinic. The remaining 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 © 2022 Ma, Zhao, Li, Yu, Ma, Thomas, Zhang, Xiang and Zhang.)

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.

Purpose: This 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., Methods: Data 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., Results: A 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 (<12), and radiotherapy were significantly associated with an elevated SPM risk. The DCA revealed that the net benefit obtained by our proposed model was higher than the all-screening or no-screening scenarios within a wide range of risk thresholds (1% to 23%)., Conclusion: The competing risk nomogram can be potentially helpful for assisting physicians in identifying patients with different risks of SPMs and scheduling risk-adapted clinical management. More comprehensive data on treatment regimens and patient characteristics may help improve the predictability of the risk model for SPMs., 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 © 2022 Xu, Huang, Wu, Xu, Li, Chen, Wang, Zhu, Qin, Zheng and Yu.)

Importance: Maternal immune activation during pregnancy is associated with increased risks of several mental disorders in offspring during childhood, but little is known about how maternal autoimmune diseases during pregnancy are associated with mental health in offspring during and after childhood., Objective: To investigate the association between maternal autoimmune diseases before childbirth and risk of mental disorders among offspring up to early adulthood., Design, Setting, and Participants: This population-based nationwide cohort study used data from Danish national registers on singletons born in Denmark from 1978 to 2015 with up to 38 years of follow-up. Data analyses were conducted from March 1, 2020, through September 30, 2021., Exposures: Maternal autoimmune disease diagnosed before or during pregnancy according to the Danish National Patient Register., Main Outcomes and Measures: The main outcome was mental disorders, defined by hospital diagnoses, in offspring. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mental disorders., Results: Of the 2 254 234 singleton infants included in the study (median age, 16.7 years [IQR, 10.5-21.7 years]; 51.28% male), 2.26% were born to mothers with autoimmune diseases before childbirth. Exposed participants had an increased risk of overall mental disorders compared with their unexposed counterparts (HR, 1.16; 95% CI, 1.13-1.19; incidence, 9.38 vs 7.91 per 1000 person-years). Increased risks of overall mental disorders in offspring were seen in different age groups for type 1 diabetes (1-5 years: HR, 1.35 [95% CI, 1.17-1.57]; 6-18 years: HR, 1.24 [95% CI, 1.15-1.33]; >18 years: HR, 1.19 [95% CI, 1.09-1.30]) and rheumatoid arthritis (1-5 years: HR, 1.42 [95% CI, 1.16-1.74]; 6-18 years: HR, 1.19 [95% CI, 1.05-1.36]; >18 years: HR, 1.28 [95% CI, 1.02-1.60]). Regarding specific mental disorders, increased risk after exposure to any maternal autoimmune disorder was observed for organic disorders (HR, 1.54; 95% CI, 1.21-1.94), schizophrenia (HR, 1.35; 95% CI, 1.21-1.51), obsessive-compulsive disorder (HR, 1.42; 95% CI, 1.24-1.63), mood disorders (HR, 1.12; 95% CI, 1.04-1.21), and a series of neurodevelopmental disorders (eg, childhood autism [HR, 1.21; 95% CI, 1.08-1.36] and attention-deficit/hyperactivity disorder [HR, 1.19; 95% CI, 1.12-1.26])., Conclusions and Relevance: In this cohort study in Denmark, prenatal exposure to maternal autoimmune diseases was associated with increased risks of overall and type-specific mental disorders in offspring. Maternal type 1 diabetes and rheumatoid arthritis during pregnancy were associated with offspring's mental health up to early adulthood. Individuals prenatally exposed to autoimmune disease may benefit from long-term surveillance for mental disorders.

Aim: We aimed to develop a new signature based on immune-related genes to predict prognosis and response to immune checkpoint inhibitors in patients with triple-negative breast cancer (TNBC). Materials & methods: Single-sample gene set enrichment was used to develop an immune-based prognostic signature (IPRS) for TNBC patients. We conducted multivariate Cox analysis to evaluate the prognosis value of the IPRS. Result: An IPRS based on 66 prognostic genes was developed. Multivariate Cox analysis indicated that the IPRS was an independent factor for prognosis. PD-1 , PD-L1 , PD-L2 and CTLA4 gene expression was higher in the low-risk group, suggesting IPRS could predict the response to immune checkpoint inhibitors. Conclusion: The IPRS might be a reliable signature to predict TNBC patients' prognosis and response to immune checkpoint inhibitors, but needs prospective validation.

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., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Relationship between BMI and all-cause mortality in patients with hypertension remains controversial. This study aimed to evaluate the time-varying association between BMI in patients with hypertension and all-cause mortality., Methods: This population-based cohort study included 212,394 Chinese adults with hypertension from 2007 to 2015 and was followed up until death, loss-to-follow-up, or December 31, 2018. According to the World Health Organization criteria for Asians, BMI was categorized into five groups: underweight (BMI < 18.5 kg/m 2 ), normal weight (18.5-22.9 kg/m 2 ), overweight (23-24.9 kg/m 2 ), class I obesity (25-29.9 kg/m 2 ) and class II obesity (BMI ≥ 30 kg/m 2 ). Cox model was used to estimate the time-varying association of BMI on the risk of mortality by including the interaction term between BMI and time using restricted cubic spline., Results: Compared with normal weight, underweight and class II obesity were associated with higher mortality (Hazard ratio [HRs] at 1 and 10 years of follow-up: 1.51 [95% CI: 1.39-1.65], and 1.27 (1.15-1.41) for underweight, respectively; 1.08 (0.96-1.21), and 1.16 (1.03-1.30) for class II obesity, respectively). However, overweight and class I obesity were associated with lower mortality, although the protective effects gradually attenuated over time (HRs at 1 and 10 years of follow-up: 0.85 (0.81-0.90), and 0.96 (0.91-1.02) for overweight, respectively; 0.80 (0.76-0.84), and 1.04 (0.99-1.10) for class I obesity, respectively)., Conclusions: We found increased mortality among hypertensive patients with underweight and class II obesity while decreased mortality with overweight and class I obesity was observed during the first 5 years of follow-up. Management efforts for hypertension may target controlling body weight in a reasonable range for patients, and probably more attention should be given to underweight patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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., 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 © 2022 He, Yu, Wang, Obel, Li and Li.)

Objective: To evaluate associations between gestational diabetes mellitus (GDM) and various incident cardiovascular disease (CVD) end points, considering the effects of the mediating role of type 2 diabetes and shared environmental/familial factors., Research Design and Methods: This population-based cohort study included 10,02,486 parous women in Denmark during 1978-2016. We used Cox regression to 1) examine the associations of GDM with overall and type-specific CVDs using full-cohort and sibling-matched analysis, 2) quantify the impact of type 2 diabetes after GDM using mediation analysis, and 3) assess whether these associations were modified by prepregnancy obesity or maternal history of CVD., Results: Women with a history of GDM had a 40% increased overall CVD risk (hazard ratio [HR] 1.40, 95% CI 1.35-1.45). Sibling-matched analyses yielded similar results (HR 1.44, 95% CI 1.28-1.62). The proportion of association between GDM and overall CVD explained by subsequent type 2 diabetes was 23.3% (15.4-32.8%). We observed increased risks of specific CVDs, including 65% increased stroke risk and more than twofold risks for myocardial infarction, heart failure, and peripheral artery disease. The elevated overall risks were more pronounced among women with GDM and prepregnancy obesity or maternal history of CVD., Conclusions: A history of GDM was associated with increased risks of overall and specific CVDs. Increased risks were partly explained by subsequent type 2 diabetes, and the need to identify other pathways remains important. Continuous monitoring of women with a history of GDM, especially those with prepregnancy obesity or maternal history of CVD, may provide better opportunities to reduce their cardiovascular risk., (© 2021 by the American Diabetes Association.)