MicroRNAs targeting TGF-ß signaling exacerbate central nervous system autoimmunity by disrupting regulatory T cell development and function.

Transforming growth factor beta (TGF-ß) signaling is essential for a balanced immune response by mediating the development and function of regulatory T cells (Tregs) and suppressing autoreactive T cells. Disruption of this balance can result in autoimmune diseases, including multiple sclerosis (MS). MicroRNAs (miRNAs) targeting TGF-ß signaling have been shown to be upregulated in naïve CD4 T cells in MS patients, resulting in a limited in vitro generation of human Tregs. Utilizing the murine model experimental autoimmune encephalomyelitis, we show that perinatal administration of miRNAs, which target the TGF-ß signaling pathway, enhanced susceptibility to central nervous system (CNS) autoimmunity. Neonatal mice administered with these miRNAs further exhibited reduced Treg frequencies with a loss in T cell receptor repertoire diversity following the induction of experimental autoimmune encephalomyelitis in adulthood. Exacerbated CNS autoimmunity as a result of miRNA overexpression in CD4 T cells was accompanied by enhanced Th1 and Th17 cell frequencies. These findings demonstrate that increased levels of TGF-ß-associated miRNAs impede the development of a diverse Treg population, leading to enhanced effector cell activity, and contributing to an increased susceptibility to CNS autoimmunity. Thus, TGF-ß-targeting miRNAs could be a risk factor for MS, and recovering optimal TGF-ß signaling may restore immune homeostasis in MS patients.

Paternal Preconceptional Alcohol Use Disorder With the Offspring's Mortality Risk.

INTRODUCTION: Paternal preconceptional alcohol use may contribute to early pregnancy loss. However, the link between paternal preconceptional alcohol use disorder and long-term offspring's mortality risk remains unclear. This study examined the association of paternal preconceptional alcohol use disorder and recency of diagnosis with offspring's mortality and further stratified the mortality after the first year of birth by age. METHODS: This is a nationwide cohort study with 1,973,174 Danish births (1980-2012), with follow-up from birth until death; emigration; or December 31, 2016. Paternal conceptional alcohol use disorder was identified from Danish National Patient Register and Prescription Registry, categorizing recency of diagnosis into <1 year, 1 to <4 years, 4 to <8 years, and ≥8 years. Logistic regression estimated the ORs and 95% CIs for offspring mortality risk. All data were analyzed in 2023. RESULTS: Paternal preconceptional alcohol use disorder was associated with a 28% increased mortality after 1 year of birth (95% CI=1.09, 1.51), 23% increased infant mortality (95% CI=1.07, 1.42), and 23% increased odds of stillbirth (95% CI=1.06, 1.43). Paternal alcohol use disorder diagnosed <1 year before conception was associated with an 85%-111% increased risk of mortality in offspring aged 15-40 years. More recent alcohol use disorder diagnosis (i.e., 1 year before conception) had a higher risks of death from infectious and circulatory diseases in offsprings. CONCLUSIONS: Offspring of fathers with alcohol use disorder before conception had higher mortality risk from birth to early adulthood, especially when alcohol use disorder diagnosis is close to conception. Current awareness regarding paternal preconceptional alcohol dependence use is insufficient. Promoting alcohol dependence avoidance, including educating men on the impact of alcohol on child health during prepregnancy examination, may help reduce or prevent long-term offspring mortality.

The Impact of 90 Parkinson's Disease-Risk Single Nucleotide Polymorphisms on Urinary Bis(monoacylglycerol)phosphate Levels in the Prodromal and PD Cohorts.

Parkinson's disease (PD) is a common neurodegenerative disorder with a prolonged prodromal phase. Higher urinary bis(monoacylglycerol)phosphate (BMP) levels associate with LRRK2 (leucine-rich repeat kinase 2) and GBA1 (glucocerebrosidase) mutations, and are considered as potential noninvasive biomarkers for predicting those mutations and PD progression. However, their reliability has been questioned, with inadequately investigated genetics, cohorts, and population. In this study, multiple statistical hypothesis tests were employed on urinary BMP levels and sequences of 90 PD-risk single nucleotide polymorphisms (SNPs) from Parkinson's Progression Markers Institution (PPMI) participants. Those SNPs were categorized into four groups based on their impact on BMP levels in various cohorts. Variants rs34637584 G/A and rs34637584 A/A (LRRK2 G2019S) were identified as the most relevant on increasing urinary BMP levels in the PD cohort. Meanwhile, rs76763715 T/T (GBA1) was the primary factor elevating BMP levels in the prodromal cohort compared to its T/C and C/C variants (N370S) and the PD cohort. Proteomics analysis indicated the changed transport pathways may be the reasons for elevated BMP levels in prodromal patients. Our findings demonstrated that higher urinary BMP levels alone were not reliable biomarkers for PD progression or gene mutations but might serve as supplementary indicators for early diagnosis and treatment.

CHIP suppresses the proliferation and migration of A549 cells by mediating the ubiquitination of eIF2α and upregulation of tumor suppressor RBM5.

The protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2 subunit α (eIF2α) pathway plays an essential role in endoplasmic reticulum (ER) stress. When the PERK-eIF2α pathway is activated, PERK phosphorylates eIF2α (p-eIF2α) at Ser51 and quenches global protein synthesis. In this study, we verified eIF2α as a bona fide substrate of the E3 ubiquitin ligase carboxyl terminus of the HSC70-interaction protein (CHIP) both in vitro and in cells. CHIP mediated the ubiquitination and degradation of nonphosphorylated eIF2α in a chaperone-independent manner and promoted the upregulation of the cyclic AMP-dependent transcription factor under endoplasmic reticulum stress conditions. Cyclic AMP-dependent transcription factor induced the transcriptional enhancement of the tumor suppressor genes PTEN and RBM5. Although transcription was enhanced, the PTEN protein was subsequently degraded by CHIP, but the expression of the RBM5 protein was upregulated, thereby suppressing the proliferation and migration of A549 cells. Overall, our study established a new mechanism that deepened the understanding of the PERK-eIF2α pathway through the ubiquitination and degradation of eIF2α. The crosstalk between the phosphorylation and ubiquitination of eIF2α shed light on a new perspective for tumor progression.

Sibling Death in Childhood and Early Adulthood and Risk of Early-Onset Cardiovascular Disease.

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.

Association of Maternal Body Mass Index During Early Pregnancy With Offspring Lower Respiratory Infections: A Nationwide Cohort Study.

OBJECTIVE: To assess whether or to what extent maternal obesity during early pregnancy could increase the risk of offspring lower respiratory infections (LRI). STUDY DESIGN: This population-based cohort included 688,457 live singleton births born in Denmark between 2004 and 2016. The exposure was maternal body mass index (BMI) during early pregnancy, and the outcome was LRI in offspring. Cox regression models were used to estimate hazard ratios with their 95% confidence intervals (CI) for the association. We also performed subanalysis stratified by the LRI onset age, number of infection episodes before the age of 3, infection pathogens, infection sites, duration of hospital stay due to LRI and allergic constitution of children. RESULTS: A total of 64,725 LRIs in offspring were identified during follow-up. Maternal overweight (BMI 25.0-29.9 kg/m 2 ), moderate or severe obesity (BMI 30.0-39.9 kg/m 2 ) and very severe obesity (BMI ≥40 kg/m 2 ) were associated with a 7% (95% CI: 5%-9%), 16% (95% CI: 14%-19%) and 21% (95% CI: 13%-28%) increased risk of LRI in offspring, respectively. Higher maternal BMI was positively associated with earlier onset age, more episodes before the age of 3, and longer hospital stay of LRI in offspring. In addition, allergic constitution of offspring significantly enhanced the effect of maternal BMI on offspring LRI (44% increased risk, 95% CI: 5%-97% for very severe obesity). CONCLUSIONS: Maternal BMI during early pregnancy might be a risk factor for offspring LRI, especially in children with allergic constitution.

Association between matched chronotype and poor mental health among shift workers: a systematic review and meta-analysis.

BACKGROUND: Nearly 0.7 billion workers are involved in the shift work system, leading to concerns about its potential impacts on the large-scale population mental health. This study aimed to synthesise evidence of the associations between matched chronotype and the risk of poor mental health among shift workers. METHODS: Six computerised databases were searched from inception to September 2022. Observational studies were selected if they reported any association between common mental health parameters and chronotype scores/types of shift workers. The Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist was followed. We extracted adjusted risk estimates to calculate pooled effect sizes and explore sources of heterogeneity. The study was registered in PROSPERO: CRD42022357437. RESULTS: Fourteen studies including 49 909 workers were identified. Ever shift workers had a higher risk of poor mental health than the day workers (pooled OR 1.15, 95% CI 1.03 to 1.28; I2=14%, p=0.29), with the evening chronotype ever shift workers having a 1.47 times higher risk than those who worked during the day (pooled OR 1.47, 95% CI 1.13 to 1.91; I2=42%, p=0.16). Sensitivity analysis excluding studies with the highest risk of bias of each group demonstrated consistent findings. CONCLUSIONS: Evening chronotype ever shift workers have poorer mental health than shift workers with other chronotypes. Chronotype remains unrecognised in the contemporary rostering system, making it a hidden contributor to occupational mental health. Work-related physical and mental stresses may be prevented/mitigated with further investigation on optimising shift work schedule combined with individual chronotype preference.

Evaluation of Hypertensive Disorder of Pregnancy and High Refractive Error in Offspring During Childhood and Adolescence.

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.

Sex differences in the associations of sleep-wake characteristics and rest-activity circadian rhythm with specific obesity types among Hong Kong community-dwelling older adults.

BACKGROUND: Sex differences exist in sleep characteristics, circadian rhythm and body composition but the evidence on their associations with obesity risk remains unclear. We aimed to examine sex differences in the associations of sleep-wake cycle and rest-activity circadian rhythm with specific obesity types among aged Chinese population. METHODS: This report pooled data from 2 population-based surveys conducted during 4/2018-9/2018 and 7/2019-9/2020. All participants wore actigraphy on wrists for 7 days to measure their objective sleep patterns and rest-activity circadian rhythm. We measured participants' anthropometric data, and obtained their body weight, body fat percentage(fat%), visceral fat rating, muscle mass by calibrated bioelectrical impedance analysis device. Hand-grip strength was assessed by Jamar Hydraulic hand dynamometer. Multinomial logistic regression was performed to assess the odds ratio(OR) and 95% confidence intervals(95%CI). RESULTS: We recruited 206 male and 134 female older adults with complete actigraphy data, with obesity prevalence of 36.9% and 31.3%, respectively. Male participants who had delayed sleep-wake cycle(i.e.,sleep-onset-time and wake-up time) was associated with higher risk of obesity(late sleep-onset-time:OR=5.28, 95%CI=2.00-13.94), and the results remained consistent for different types of obesity. Males with late M10(i.e., most active 10-hours) onset had higher adipose outcomes with an adjusted OR of 2.92(fat%:95%CI=1.10-7.71; visceral fat:95%CI=1.12-7.61). Among female participants, those with lower relative amplitude were associated with higher BMI and lower hand-grip strength. CONCLUSIONS: This study revealed that circadian rhythm fragmentation was associated with obesity and muscle loss. Promoting good sleep quality and maintaining robust circadian rhythm and physical activity can prevent poor muscle strength among older adults.

DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer.

BACKGROUND: Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong. METHODS: We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath's pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson's correlation (r), Kruskal-Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors. RESULTS: DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e-16) than in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e-06) and PGR (Pearson r = 0.36, P = 2.4e-05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA. CONCLUSIONS: Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.

Maternal hypertensive disorders during pregnancy and the risk of offspring diabetes mellitus in childhood, adolescence, and early adulthood: a nationwide population-based cohort study.

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.

Association of intellectual disability with overall and type-specific cardiovascular diseases: a population-based cohort study in Denmark.

BACKGROUND: Individuals with mental health problems have been shown to have an increased risk of cardiovascular disorder (CVD), but little is known about the risk of early-onset CVD among those with intellectual disability. We aimed to investigate the association between intellectual disability and subsequent CVD, taking into consideration the severity of intellectual disability and neurodevelopmental and neurologic comorbidity. METHODS: This population-based cohort study used individual-level linked data from Danish national health registries. Participants were all live-born singletons born in Denmark during 1978-2016 (n = 2,288,393). Follow-up began from birth and continued until the onset of CVD, death, emigration, or December 31, 2018, whichever came first. Clinical diagnosis of any CVD or type-specific CVDs was identified in the Danish National Patient Register. Time-varying Cox regression analyses were used to estimate the hazard ratio (HR) of intellectual disability associated with overall and type-specific CVDs. RESULTS: A total of 11,954 individuals received a diagnosis of intellectual disability (7434 males and 4520 females). During a median follow-up time of 18.5 years (interquartile range, 18.1 years), 652 individuals with intellectual disability (5.5%) received a diagnosis of CVD (incidence rate, 2.4 per 1000 person-years), compared with 78,088 (3.4%) CVD cases in individuals without intellectual disability (incidence rate, 1.9 per 1000 person-years), corresponding to a HR of 1.24 (95% CI, 1.15-1.34). Increased risks of CVD were similar in both childhood (HR, 1.24; 95% CI, 1.08-1.43) and early adulthood (HR, 1.25; 95% CI, 1.14-1.38). For type-specific CVDs, intellectual disability was significantly associated with cerebrovascular disease (HR, 2.50; 95% CI, 2.02-3.10), stroke (HR, 2.20; 95% CI, 1.69-2.86), heart failure (HR, 3.56; 95% CI, 2.37-5.35), hypertensive disease (HR, 1.30; 95% CI, 1.22-1.39), and deep vein thrombosis (HR, 2.10; 95% CI, 1.60-2.75). Stratified HRs of overall CVD were 1.14 (95% CI, 1.01-1.30) for borderline/mild intellectual disability, 1.25 (95% CI, 1.01-1.54) for moderate intellectual disability, and 1.91 (95% CI, 1.47-2.48) for severe/profound intellectual disability. After the exclusion of individuals with neurodevelopmental and neurologic comorbidity, intellectual disability remained significantly associated with increased risks of CVD. CONCLUSIONS: Individuals with intellectual disability had increased risks of early-onset CVD, in particular, for cerebrovascular disease, stroke, heart failure, and deep vein thrombosis, and the risks also increased with the severity of intellectual disability. Our findings highlight the awareness of increased risks of CVD in intellectual disability patients.

Familial clustering of intrahepatic cholestasis of pregnancy: A nationwide population-based study in Denmark.

BACKGROUND AND AIMS: Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP. APPROACH AND RESULTS: This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first-degree (n=2279), second-degree (n=1373), and third-degree (n=1758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. The first-degree relatives of women who had recurrent ICP or first-trimester ICP seemed to be at higher risks [RRR, 4.30 (2.85-6.48), 3.04 (1.93-4.77), respectively]. A minor increased risk was observed in nonbiological relatives [RRR, 1.35 (1.05-1.73); n=4274, including women's full-brothers' partner and women's husbands' full sisters]. CONCLUSIONS: Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second-degree and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family clustering. Further investigation is needed to investigate the increased risk of ICP in nonbiological relatives.

Association of circadian rhythm with mild cognitive impairment among male pneumoconiosis workers in Hong Kong: a cross-sectional study.

Weakened circadian activity rhythms (CARs) were associated with mild cognitive impairment (MCI) in the general population. However, it remains unclear among pneumoconiosis patients. We aimed to address this knowledge gap. This cross-sectional study comprised 186 male pneumoconiosis patients (71.3 ± 7.8 years) and 208 healthy community men. Actigraphy was used to determine CARs parameters (percent rhythm, amplitude, MESOR, and acrophase). Values below the corresponding medians of the CARs parameters represented weakened CARs. The Cantonese version of Mini-Mental State Examination (CMMSE) was used to assess cognitive function, MCI, and the composite outcome of MCI plus cognitive impairment. Compared with the community referents, pneumoconiosis patients had worse cognition and dampened CARs. Compared with the community referents or pneumoconiosis patients with robust circadian rhythm, pneumoconiosis patients with weakened circadian rhythm were consistently associated with increased risk of MCI and the composite outcome. However, significant association was only observed between MESOR and the composite outcome (adjusted OR = 1.99, 95%: 1.04-3.81). A delayed phase of CARs was insignificantly associated with MCI and the composite outcome. Our findings showed that weakened CARs were associated with worse cognitive function among male pneumoconiosis workers. Intervention in improving CARs may mitigate cognitive deterioration in male pneumoconiosis workers.

Prenatal Carbamazepine Exposure and Academic Performance in Adolescents: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: To investigate whether children born to mothers who used carbamazepine during pregnancy had worse academic performance in adolescence. METHODS: This population-based cohort study included all live-born singletons in Denmark between 1996 and 2002 who participated in the national ninth-grade exit examination (n = 370,859). Those born to mothers with prescription of antiseizure medications other than carbamazepine during pregnancy were excluded. We examined the association of in utero exposure to maternal carbamazepine redeemed during pregnancy (n = 290) with academic performance of offspring, defined by the scores in Danish and mathematics in ninth-grade exit examination. We estimated mean z-score difference with linear regression adjusted for socioeconomic factors and potential indications, including epilepsy and medication for other psychiatric disorders. Additional analyses addressing confounding by indication included comparison between in utero exposed vs past exposed and between past exposed and never exposed. In utero exposure to valproate monotherapy was used as a positive control and in utero exposure to lamotrigine as a negative control. RESULTS: At the age of 16.1 (SD 0.4) years, adolescents in utero exposed to maternal carbamazepine monotherapy had lower scores both in Danish and mathematics in ninth-grade exit examination (adjusted z-score difference, -0.14 [95% CI -0.24 to -0.05] and -0.17 [95% CI -0.28 to -0.07], respectively). In utero exposure to carbamazepine monotherapy was associated with lower scores than past exposure only (adjusted z-score difference, -0.24 [95% CI -0.41 to -0.06] for Danish and -0.25 [95% CI -0.44 to -0.06] for mathematics), while past exposure to carbamazepine was associated with minor decrease in offspring's academic performance (adjusted z-score difference, -0.02 [95% CI -0.09 to 0.06] for Danish and -0.07 [95% CI -0.16 to 0.01] for mathematics). The association was also observed for in utero exposure to valproate monotherapy, but not for in utero exposure to lamotrigine. DISCUSSION: In utero exposure to carbamazepine was associated with poorer academic performance in adolescence, as represented by lower scores in ninth-grade exit examination in Danish and mathematics. Additional studies are needed to confirm these findings because of limitations in this study and variable findings in prior studies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that academic performance, as reflected in ninth-grade exit examinations in Danish and mathematics, was worse among those exposed to carbamazepine monotherapy in utero, compared with those without in utero exposure to antiseizure medications.

Childhood diabetes mellitus and early-onset kidney diseases later in life: a nationwide population-based matched cohort study.

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

Maternal hypertensive disorder of pregnancy and mortality in offspring from birth to young adulthood: national population based cohort study.

OBJECTIVE: To examine the association of maternal hypertensive disorder of pregnancy (HDP) with overall and cause specific mortality in offspring from birth to young adulthood. DESIGN: Nationwide population based cohort study. SETTING: Danish national health registers. PARTICIPANTS: All 2 437 718 individuals live born in Denmark, 1978-2018, with follow-up from date of birth until date of death, emigration, or 31 December 2018, whichever came first. MAIN OUTCOME MEASURES: The primary outcome was all cause mortality. Secondary outcomes were 13 specific causes of death in offspring from birth to young adulthood (age 41 years). Cox regression was used to assess the association, taking into consideration several potential confounders. The role of timing of onset and severity of pre-eclampsia, maternal history of diabetes, and maternal education were also studied. RESULTS: 102 095 mothers had HDP: 67 683 with pre-eclampsia, 679 with eclampsia, and 33 733 with hypertension. During follow-up to 41 years (median 19.4 (interquartile range 9.7-28.7) years), deaths occurred in 781 (58.94 per 100 000 person years) offspring born to mothers with pre-eclampsia, 17 (133.73 per 100 000 person years) born to mothers with eclampsia, 223 (44.38 per 100 000 person years) born to mothers with hypertension, and 19 119 (41.99 per 100 000 person years) born to mothers with no HDP. The difference in cumulative incidence in overall mortality between cohorts exposed and unexposed to maternal HDP was 0.37% (95% confidence interval 0.11% to 0.64%), and the population attributable fraction for maternal HDP was estimated as 1.09% (95% confidence interval 0.77% to 1.41%). Maternal HDP was associated with a 26% (hazard ratio 1.26, 95% confidence interval 1.18 to 1.34) higher risk of all cause mortality in offspring. The corresponding estimates for maternal pre-eclampsia, eclampsia, and hypertension were 1.29 (1.20 to 1.38), 2.88 (1.79 to 4.63), and 1.12 (0.98 to 1.28). Increased risks were also observed for several cause specific mortalities, such as deaths from conditions originating in the perinatal period (2.04, 1.81 to 2.30), cardiovascular diseases (1.52, 1.08 to 2.13), digestive system diseases (2.09, 1.27 to 3.43), and endocrine, nutritional, and metabolic diseases (1.56, 1.08 to 2.27). The increased risks were more pronounced among offspring of mothers with early onset and severe pre-eclampsia (6.06, 5.35 to 6.86) or with both HDP and diabetes history (1.57, 1.16 to 2.14) or HDP and low education level (1.49, 1.34 to 1.66). CONCLUSION: Maternal HDP, particularly eclampsia and severe pre-eclampsia, is associated with increased risks of overall mortality and various cause specific mortalities in offspring from birth to young adulthood.

Determinants of workplace safety towards SARS-Cov-2 and combating COVID-19 among non-healthcare workers in Hong Kong, Nanjing and Wuhan, China.

There has been no validated tool to assess workplace infection control towards SARS-Cov-2 in non-healthcare industries. In this first year survey during 07/2020-04/2021, 6684 workers were recruited from varied non-healthcare settings of Hong Kong, Nanjing and Wuhan of China and responded standard questionnaires containing information of prevention measures and policies implemented by companies and personal preventive behaviour towards infection control. All participants were randomly stratified into two sub-samples as training and validation sample. Workplace safety index towards SARS-Cov-2 (WSI-SC2) was developed and validated using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). We identified 14 manifest variables in WSI-SC2, with three sub-indices named "Workplace infection control measures and prevention", "Company occupational safety and health management and commitment" and "Worker's personal preventive behavior and awareness towards infectious control". WSI-SC2 obtained a good internal consistency reliability (Cronbach's alpha coefficients ranged: 0.76-0.91), good composite reliability (composite reliability ranged: 0.70-0.95) and satisfactory fit of the model (GFI = 0.95; SRMR = 0.05; RMSEA = 0.07). We further performed stratified analysis according to cities, and the index remained stable. Workers with higher scores of WSI-SC2 were more likely to uptake COVID-19 test. This multi-city large study developed a novel and validated tool that could horizontally measure the workplace safety towards SARS-Cov-2 in non-healthcare workers.