DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2–5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Purpose To examine the association between parity and long term all-cause mortality and mortality due to specific causes in women. Methods This prospective population-based study included 40,454 mothers who gave birth in Western Jerusalem, Israel, to 125,842 children and were followed for an average of 37 years following the birth of their first child. Cox Proportional Hazards Models were used to evaluate long-term total and specific cause mortality of women by their parity. Results We found a U-shaped relationship between the number of offspring and risk of all-cause mortality in mothers. After adjustment for sociodemographic characteristics and maternal health and obstetric conditions, higher mortality rates were observed for mothers of 1 child (HR=1.18; 95% CI 1.04–1.4), mothers of 5–9 children (HR=1.21;95%CI 1.09–1.33), and mothers of ≥10 children (HR=1.49;95%CI 1.12–1.99) as compared to mothers of 2–4 children. Mortality risk from specific causes including coronary disease, circulatory disease, and cancer were increased for multiparous women. Conclusions In this long-term follow-up study, there was an association between number of children mortality risk of mothers. These findings suggest that maternal pregnancies and post-natal characteristics as reflected by number of children may have consequences for long-term maternal health.

Research Question We aimed to investigate the effect of the BNT162b2 COVID-19 vaccine on sperm parameters of patients with a normal and abnormal semen analysis. Design We collected data of male patients undergoing in vitro fertilization (IVF) treatment after vaccination completion between February and June 2021 (POST vaccine). For comparison, we reviewed records of the same patients before the vaccination (PRE vaccine) up to January 2017. Azoospermia patients were excluded. Sperm parameters were compared between PRE and POST vaccine groups. Each patient served as self-control. Results Seventy-two patients were included in the study (mean age 38.1±6.7 years), of whom 57 had a normal semen analysis. The mean time between the first vaccine and the POST vaccine sperm analysis was 66.3±44.0 days. The median [IQR] of the sperm parameters before and after the vaccination were: sperm volume before 3.0 [2.0-4.0] and after 3.0 [1.6-3.9] ml, p=0.02; sperm concentration: before 26.5 [14.0-64.7] and after 31.0 [14.2-80.0] 10 6 /ml, p=0.35; and total motile count: before 33.7 [9.0-66.0] and after 29 [6.0-97.5] 10 6 , p=0.96. Sub-group analyses were performed for patients with male infertility and patients with a normal semen analysis. Neither of the sub-groups showed significant changes post-vaccination. Conclusion Sperm parameters showed no significant changes following vaccination among men with a normal and abnormal semen analysis. Therefore, the BNT162b2 vaccine appears not to affect sperm parameters. The preliminary results are reassuring for the entire global population, currently undergoing intense vaccination campaigns against COVID-19.

Background Current recommendations for treating acute calculus cholecystitis include the use of intravenous antibiotics, although these recommendations were never tested scientifically. The aim of this study was to evaluate the role of intravenous antibiotic therapy in patients with mild acute calculus cholecystitis. Methods In this prospective, randomized controlled trial, 84 patients with a diagnosis of mild acute calculus cholecystitis were randomly assigned to supportive treatment only or supportive treatment with intravenous antibiotic treatment (42 patients in each arm). Patients were followed through their index admission and until delayed laparoscopic cholecystectomy was performed. Results The two study groups did not differ in their demographic data or in the clinical presentation and disease severity. Analysis was conducted on the intent‐to‐treat basis. Patients in the intravenous antibiotics arm resumed a liquid diet earlier (1.7 vs. 2.2 days, p = 0.02) but did not significantly differ in resumption of regular diet (2.8 vs. 3.2 days, p = 0.16) or hospital length of stay (LOS) (3.9 vs. 3.8 days, p = 0.89). Patients in the intravenous antibiotics arm had rates of percutaneous cholecystostomy tube placement (12 vs. 5 %, p = 0.43), readmissions (19 vs. 13 %, p = 0.73), and perioperative course similar to those not receiving antibiotics. The overall hospital LOS, including initial hospitalization and subsequent cholecystectomy, was similar for both groups (5.6 vs. 5.1 days, p = 0.29). Eight (19 %) patients in the supportive arm were crossed over to the intravenous antibiotic arm during the index admission. Conclusions Intravenous antibiotic treatment does not improve the hospital course or early outcome in most of the patients with mild acute calculus cholecystitis.

Chronic hypertension and obesity are independent risk factors for Bell's palsy. Bell's palsy during pregnancy is significantly associated with severe preeclampsia. Nevertheless, no significant association exists between Bell's palsy and adverse perinatal outcomes.

Introduction: There is a well-established inverse relationship between body mass index and frequency of endometriosis. However, these population-based studies have relied mostly on self-reported cases of endometriosis, rather than surgically confirmed endometriosis where disease severity has been objectively assessed. The aim of the current retrospective study was to establish whether the established relationship between endometriosis and low body mass index was independent of disease severity. Methods: Women with menstrual and/or pelvic pain undergoing laparoscopy for suspected endometriosis were recruited for this retrospective study (n = 509). Women were grouped by body mass index (kg/m 2) according to World Health Organization criteria: underweight (<18.5), normal (18.5-24.99), pre-obese (25-29.99) or obese (≥30). Endometriosis was scored according to the revised American Fertility Society system. Data were analysed based on body mass index and endometriosis status to identify any relationship between body mass index and disease. Results: The average body mass index of women with endometriosis was 25.0 kg/m 2. The body mass index distribution of women with endometriosis differed relative to women in the general population. As expected, fewer obese women had endometriosis than in the lower body mass index categories. However, the obese women who did have endometriosis had significantly higher revised American Fertility Society scores compared to women with normal and pre-obese body mass indices. Discussion: Our results are consistent with the established finding of an inverse relationship between body mass index and endometriosis. The novel finding from this study is that obesity is associated with increased disease severity and reduced frequency of stage I endometriosis. It remains unclear what role body mass index has in the cause or effect of endometriosis; we speculate that body mass index may be useful for sub-classifying the disease.

Objective To examine the association of maternal and/or paternal smoking during pregnancy with offspring cardio-metabolic risk (CMR) factors at adolescence and early adulthood, taking into account socio-demographic, medical and lifestyle characteristics of parents and offspring, as well as offspring common genetic variation. Methods We used a population-based cohort of all 17 003 births in Jerusalem during 1974–76, with available archival data on parental and birth characteristics. Measurements at age 17 were assessed at military induction examinations for 11 530 offspring. 1440 offspring from the original 1974–1976 birth cohort were sampled using a stratified sampling approach, and were interviewed and examined at age 32. Parental smoking during pregnancy (i.e. maternal, paternal and any parent) was primarily defined dichotomously (any number of cigarettes smoked daily by mother or father during pregnancy vs. non-smokers). Additionally, smoking was assessed by quantity of cigarettes smoked daily. Linear regression models were used to evaluate the associations of parental smoking during pregnancy with various offspring CMR factors, after controlling for potential confounders and for genetic variation in candidate genes. Results Prevalence of exposure to parental smoking in-utero (i.e. smoking of any parent) was 53.2% and 48.4% among the 17 years old and 32 years old samples, respectively. At age 17, smoking of at least one parent during pregnancy was significantly associated with weight (B=1.39), height (B=0.59), BMI (B=0.32) and pulse rate (B=−0.78) (p-values<0.001). At age 32, parental smoking, adjusted for covariates, was associated with 2.22 kg higher mean offspring weight, 0.95 cm higher mean offspring height, 0.57 kg/m2 higher BMI, and 1.46 cm higher waist-circumference (p-values≤0.02). Similar results, reflecting a dose response, were observed when maternal and paternal smoking were assessed by number of cigarettes smoked daily. Conclusions This prospective study demonstrates a potential long-term adverse effect of parental smoking during pregnancy on offspring health and calls for increasing efforts to promote smoking cessation of both parents before pregnancy.

Background: Intrapartum fever is a well-known risk factor for adverse perinatal outcomes. Maternal intrapartum fever ≥39.0°C at term is a rare event during labor, and there is scarce evidence regarding its implications. Objectives: To investigate the association between very high intrapartum maternal fever and perinatal outcomes in term pregnancies. Methods: A retrospective cohort analysis including 43,560 term, singleton live births in two medical centers between the years 2003 and 2011 was performed. We compared parturients who experienced a maximal intrapartum fever of <38.0°C with two subgroups of parturients who experienced respective maximal fevers of 38.0-38.9°C and ≥39°C. Adjusted risks for adverse perinatal outcomes were calculated by using multiple logistic regression models to control for confounders. Results: Compared with normal intrapartum temperature, intrapartum fever ≥39.0°C was associated with an extremely elevated risk for neonatal sepsis 16.08 (95% CI: 2.15, 120.3) as well as with low Apgar scores and neonatal intensive care unit admissions (p < 0.001). Additionally, very high intrapartum fever was related to significantly higher risk for operative delivery (p < 0.001). Conclusions: Extremely elevated intrapartum fever is an important indicator of severe neonatal morbidity and operative delivery.