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Simple Summary: The PELICan hypothesis speaks to the role of perinatal and early life stressors (including malnutrition) in the causation of young-onset cancers. To date, there is no evidence correlating perinatal malnutrition and the risk of young-onset cancer. The Great Famine of China was a significant event in human history. The present study compared the incidence of young-onset cancers in individuals born during and just after the famine to those born prior to the famine. 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. 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. [ABSTRACT FROM AUTHOR]

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

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

Background The prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited. Methods and findings We conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare. Conclusions Offspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring., Author(s): Chen Huang 1, Jiong Li 2,3, Guoyou Qin 1, Zeyan Liew 4,5, Jing Hu 1, Krisztina D. László 6, Fangbiao Tao 7,8, Carsten Obel 9, Jørn Olsen 3, Yongfu [...]

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 (<7 h per night), optimal (7–9 h), and long nighttime sleep duration (>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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Background Socioeconomic disparities in infant mortality have persisted for decades in high-income countries and may have become stronger in some populations. Therefore, new understandings of the mechanisms that underlie socioeconomic differences in infant deaths are essential for creating and implementing health initiatives to reduce these deaths. We aimed to explore whether and the extent to which preterm birth (PTB) and small for gestational age (SGA) at birth mediate the association between maternal education and infant mortality. Methods and findings We developed a population-based cohort study to include all 1,994,618 live singletons born in Denmark in 1981-2015. Infants were followed from birth until death, emigration, or the day before the first birthday, whichever came first. Maternal education at childbirth was categorized as low, medium, or high. An inverse probability weighting of marginal structural models was used to estimate the controlled direct effect (CDE) of maternal education on offspring infant mortality, further split into neonatal (0-27 days) and postneonatal (28-364 days) deaths, and portion eliminated (PE) by eliminating mediation by PTB and SGA. The proportion eliminated by eliminating mediation by PTB and SGA was reported if the mortality rate ratios (MRRs) of CDE and PE were in the same direction. The MRRs between maternal education and infant mortality were 1.63 (95% CI 1.48-1.80, P < 0.001) and 1.19 (95% CI 1.08-1.31, P < 0.001) for low and medium versus high education, respectively. The estimated proportions of these total associations eliminated by reducing PTB and SGA together were 55% (MRR.sub.PE = 1.27, 95% CI 1.15-1.40, P < 0.001) for low and 60% (MRR.sub.PE = 1.11, 95% CI 1.01-1.22, P = 0.037) for medium versus high education. The proportions eliminated by eliminating PTB and SGA separately were, respectively, 46% and 11% for low education (versus high education) and 48% and 13% for medium education (versus high education). PTB and SGA together contributed more to the association of maternal educational disparities with neonatal mortality (proportion eliminated: 75%-81%) than with postneonatal mortality (proportion eliminated: 21%-23%). Limitations of the study include the untestable assumption of no unmeasured confounders for the causal mediation analysis, and the limited generalizability of the findings to other countries with varying disparities in access and quality of perinatal healthcare. Conclusions PTB and SGA may play substantial roles in the relationship between low maternal education and infant mortality, especially for neonatal mortality. The mediating role of PTB appeared to be much stronger than that of SGA. Public health strategies aimed at reducing neonatal mortality in high-income countries may need to address socially related prenatal risk factors of PTB and impaired fetal growth. The substantial association of maternal education with postneonatal mortality not accounted for by PTB or SGA could reflect unaddressed educational disparities in infant care or other factors., Author(s): Yongfu Yu 1,2,3,4, Zeyan Liew 5,6, Aolin Wang 7,8, Onyebuchi A. Arah 2,9, Jialiang Li 10,11, Jørn Olsen 1,2, Sven Cnattingius 12, Guoyou Qin 13, Carsten Obel 14, Bo [...]

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 (r2=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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 log10 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. [ABSTRACT FROM AUTHOR]