Epigenetic gestational age acceleration:A prospective cohort study investigating associations with familial, sociodemographic and birth characteristics

Abstract Background Gestational age at delivery is associated with health and social outcomes. Recently, cord blood DNA methylation data has been used to predict gestational age. The discrepancy between gestational age predicted from DNA methylation and determined by ultrasound or last menstrual period is known as gestational age acceleration. This study investigated associations of sex, socioeconomic status, parental behaviours and characteristics and birth outcomes with gestational age acceleration. Results Using data from the Avon Longitudinal Study of Parents and Children (n = 863), we found that pre-pregnancy maternal overweight and obesity were associated with greater gestational age acceleration (mean difference = 1.6 days, 95% CI 0.7 to 2.6, and 2.9 days, 95% CI 1.3 to 4.4, respectively, compared with a body mass index < 25 kg/m2, p < .001). There was evidence of an association between male sex and greater gestational age acceleration. Greater gestational age acceleration was associated with higher birthweight, birth length and head circumference of the child (mean differences per week higher gestational age acceleration: birthweight 0.1 kg, 95% CI 0.1 to 0.2, p < .001; birth length 0.4 cm, 95% CI 0.2 to 0.7, p < .001; head circumference 0.2 cm, 95% CI 0.1 to − 0.4, p < .001). There was evidence of an association between gestational age acceleration and mode of delivery (assisted versus unassisted delivery, odds ratio = 0.9 per week higher gestational age acceleration, 95% CI 0.7, 1.3 (p = .05); caesarean section versus unassisted delivery, odds ratio = 0.6, 95% CI 0.4 to 0.9 per week higher gestational age acceleration (p = .05)). There was no evidence of association for other parental and perinatal characteristics. Conclusions The associations of higher maternal body mass index and larger birth size with greater gestational age acceleration may imply that maternal overweight and obesity is associated with more rapid development of the fetus in utero. The implications of gestational age acceleration for postnatal health warrant further investigation

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas and pancreatic neuroendocrine tumors.

BACKGROUND Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown. METHODS We performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas. RESULTS Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. CONCLUSIONS Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification

Investigating the DNA methylation profile of e-cigarette use

BACKGROUND: Little evidence exists on the health effects of e-cigarette use. DNA methylation may serve as a biomarker for exposure and could be predictive of future health risk. We aimed to investigate the DNA methylation profile of e-cigarette use. RESULTS: Among 117 smokers, 117 non-smokers and 116 non-smoking vapers, we evaluated associations between e-cigarette use and epigenome-wide methylation from saliva. DNA methylation at 7 cytosine-phosphate-guanine sites (CpGs) was associated with e-cigarette use at p < 1 × 10(–5) and none at p < 5.91 × 10(–8). 13 CpGs were associated with smoking at p < 1 × 10(–5) and one at p < 5.91 × 10(–8). CpGs associated with e-cigarette use were largely distinct from those associated with smoking. There was strong enrichment of known smoking-related CpGs in the smokers but not the vapers. We also tested associations between e-cigarette use and methylation scores known to predict smoking and biological ageing. Methylation scores for smoking and biological ageing were similar between vapers and non-smokers. Higher levels of all smoking scores and a biological ageing score (GrimAge) were observed in smokers. A methylation score for e-cigarette use showed poor prediction internally (AUC 0.55, 0.41–0.69) and externally (AUC 0.57, 0.36–0.74) compared with a smoking score (AUCs 0.80) and was less able to discriminate lung squamous cell carcinoma from adjacent normal tissue (AUC 0.64, 0.52–0.76 versus AUC 0.73, 0.61–0.85). CONCLUSIONS: The DNA methylation profile for e-cigarette use is largely distinct from that of cigarette smoking, did not replicate in independent samples, and was unable to discriminate lung cancer from normal tissue. The extent to which methylation related to long-term e-cigarette use translates into chronic effects requires further investigation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-021-01174-7

Seasonal variation in chemical composition, ruminal fermentation, and biological characteristics of Paulownia shan tong: in vitro potential use by sheep and goats

15 páginas, 2 figuras, 4 tablas.This study was conducted to determine the seasonal variation (two seasonal harvests during winter and spring) in some chemical and biochemical characteristics of Paulownia shan tong leaves. To achieve this, we analyzed the chemical composition in terms of dry matter (DM), organic matter (OM), crude protein (CP), cell-wall content (neutral detergent fiber (NDF)), acid detergent fiber (ADF), acid detergent lignin (ADL), and lipids. The phenolic compounds (PC) and antioxidant activity (AA) of the leaves were also determined. In vitro gas production (GP) and nutrient degradability were evaluated using two ruminal-content donors (sheep and goats). Higher (p < 0.05) antioxidant activities were observed in the winter harvest of P. shan tong, while higher concentrations of OM (90.5%), lipids (3.02%), NDF (69.7%), ADF (54.8%), ADL (35.4%), total flavonoids (0.45 mg catechin equivalents/mg DM), and total phenolics (2.52 mg gallic acid equivalents/mg DM) were observed in the spring harvest. Higher asymptotic GP and rate of GP (p < 0.05) were observed when the leaves were incubated with rumen liquor of goats compared to sheep; however, higher (p < 0.05) lag time of GP and half-time of GP were observed with rumen liquor from sheep. Moreover, higher asymptotic GP, rate of GP, and half-time of GP were observed with the winter harvest of P. shan tong. Higher (p < 0.001) metabolizable energy, OM degradability, and microbial protein supplies were obtained when the leaves were incubated with rumen fluids from goats and from the winter harvest of P. shan tong compared to the spring harvest. In conclusion, based on the chemical composition and the kinetics of in vitro gas production, P. shan tong leaves seem to be characterized by a good nutritive value and could be considered as an alternative feed resource for ruminants.Peer reviewe

Genetic drivers in the natural history of chronic lymphocytic leukemia development as early as 16 years before diagnosis

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a potential CLL precursor state which can be detected in up to 17% in aged individuals. Recently, we described significant B-cell receptor immunoglobulin heavy chain (BCR IGH) gene repertoire skewing and clonotypic evolution up to 22 years before CLL diagnosis. However, pathobiological drivers during the earliest stages of MBL development remain incompletely characterized. In this study, we utilized the EuroClonality-NDC panel to sequence recurrently mutated genes in CLL in 39 peripheral blood samples from 16 CLL patients sampled up to 16 years prior to diagnosis. CLL diagnosis ranged from 5 months to 16 years after first blood sampling. Of 16 CLL patients, 8 (50%) presented with variants of interest in genes recurrently mutated in CLL such as NOTCH1, ATM, and SF3B1 . ATM variants and the IGLV3-21R110 mutation were present from the early stages of (pre)MBL development, while NOTCH1, SF3B1, and XPO1 variants arose closer to diagnosis. We additionally detected variants in FAT1 and PLCG2 as early as 10 years prior to CLL diagnosis. Overall, our data shows specific genetic drivers of CLL are associated with early and late stages of CLL development

A coordination mechanism for supply chains with capacity expansions and order-dependent lead times

This paper considers a supply chain consisting of a retailer for short life cycle products facing stochastic customer demand and a manufacturer that initiates production upon receipt of retail orders. Departing from the common view of the newsvendor problem, we assume that the delivery lead time is not fixed, but that both the retailer and the manufacturer have the option to shorten it. Shorter lead times enable the retailer to place orders closer to the start of the selling season where additional information on customer preferences has become available, reducing demand uncertainty. In the work at hand, lead time is assumed to depend on the order quantity, on the supplier's production capacity, and a fixed transportation delay. This paper proposes a model for determining the optimal order quantity and production capacity in centralized and decentralized settings. For the uncoordinated case, we show that if the retailer's ability to gather and analyze additional demand information is revealed to the manufacturer, the arising information asymmetry between the two parties can aggravate the double marginalization effect and, in turn, erode supply chain efficiency. In a coordinated supply chain, however, both parties have an incentive to align both order quantity and investments in lead time reduction. To coordinate the decentralized supply chain, we propose a buy-back contract that helps to leverage supply chain profitability. We conclude with an outlook on future research opportunities

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely