Life course socioeconomic position and DNA methylation age acceleration in mid-life

BACKGROUND: Ageing biomarkers can help us better understand how well-established socioeconomic position (SEP) disparities in ageing occur. A promising new set of DNAm methylation (DNAm)-based ageing biomarkers indicate through their age acceleration (AA) measures if biological ageing is slower or faster than chronological ageing. Few studies have investigated the association between SEP and DNAm AA. METHODS: We used linear regression to examine the sex-adjusted relationships between childhood social class, adult social class, intergenerational social class change, education and adult household earnings with first (Horvath AA and Hannum AA) and second generation (PhenoAge AA and GrimAge AA) DNAm AA markers using data from the MRC National Survey of Health and Development. RESULTS: In the first-generation biomarkers, there was little evidence of any associations with Horvath AA but associations of childhood social class and income with Hannum AA were observed. Strong associations were seen between greater disadvantage in childhood and adult SEP and greater AA in the second generation biomarkers. For example, those with fathers in an unskilled occupational social class in childhood had 3.6 years greater PhenoAge AA (95% CI 1.8 to 5.4) than those with fathers from a professional social class. Individuals without qualifications had higher AA compared with those with higher education (4.1 years greater GrimAge AA (95% CI 3.1 to 5.0)). CONCLUSION: Our findings highlight the importance of exposure to social disadvantage in childhood to the biological ageing process. The second generation clocks appear to be more sensitive to the accumulation of social disadvantage across the life course

Childhood growth and development and DNA methylation age in mid-life

Background: In the first study of its kind, we examine the association between growth and development in early life and DNAm age biomarkers in mid-life. / Methods: Participants were from the Medical Research Council National Survey of Health and Development (n = 1376). Four DNAm age acceleration (AgeAccel) biomarkers were measured when participants were aged 53 years: AgeAccelHannum; AgeAccelHorvath; AgeAccelLevine; and AgeAccelGrim. Exposure variables included: relative weight gain (standardised residuals from models of current weight z-score on current height, and previous weight and height z-scores); and linear growth (standardised residuals from models of current height z-score on previous height and weight z-scores) during infancy (0–2 years, weight gain only), early childhood (2–4 years), middle childhood (4–7 years) and late childhood to adolescence (7–15 years); age at menarche; and pubertal stage for men at 14–15 years. The relationship between relative weight gain and linear growth and AgeAccel was investigated using conditional growth models. We replicated analyses from the late childhood to adolescence period and pubertal timing among 240 participants from The National Child and Development Study (NCDS). / Results: A 1SD increase in relative weight gain in late childhood to adolescence was associated with 0.50 years (95% CI 0.20, 0.79) higher AgeAccelGrim. Although the CI includes the null, the estimate was similar in NCDS [0.57 years (95% CI − 0.01, 1.16)] There was no strong evidence that relative weight gain and linear growth in childhood was associated with any other AgeAccel biomarker. There was no relationship between pubertal timing in men and AgeAccel biomarkers. Women who reached menarche ≥ 12 years had 1.20 years (95% CI 0.15, 2.24) higher AgeAccelGrim on average than women who reached menarche < 12 years; however, this was not replicated in NCDS and was not statistically significant after Bonferroni correction. / Conclusions: Our findings generally do not support an association between growth and AgeAccel biomarkers in mid-life. However, we found rapid weight gain during pubertal development, previously related to higher cardiovascular disease risk, to be associated with older AgeAccelGrim. Given this is an exploratory study, this finding requires replication

Iberian cured-ham consumption improves endothelial function in healthy subjects

Objectives: Previous studies have shown that dietary components such as oleic acid or polyphenols exert beneficial effects on endothelium. We aimed to assess the impact of regular consumption of Iberian cured-ham (ICH) on endothelial function. Design: An open-label, randomized controlled parallel study. Setting: Volunteers recruited through advertisements at a hospital in Madrid, Spain. Participants: 102 Caucasian adults (76.8% females) aged 25-55 years, and free from cardiometabolic disease. Intervention: Participants were randomized to an ICH-enriched ad libitum diet or an ad libitum diet without ICH for 6 weeks. Subjects in ICH group were randomly provided with either acorn- or mixed-fed ICH, and followed up for an additional 6-week period under their usual diet. Measurements: Clinical parameters, biomarkers of endothelial function and oxidative stress, microvascular vasodilatory response to hyperemia and arterial stiffness were measured before and after the intervention. Results: After 6 weeks, a larger decrease in PAI-1 was observed in subjects consuming ICH compared to the Control group (-6.2±17.7 vs. 0.3±1.4 ng/ml; p=0.020). Similarly, microvascular vasodilatory response to hyperemia showed a significant increase (112.4±391.7 vs. -56.0±327.9%; p=0.007). However, neither oxidative stress, hemodynamic nor clinical parameters differed significantly over the study. Additionally, after stopping ICH consumption, improvements in PAI-1 remained for 6 additional weeks with respect to baseline (p=0.006). Conclusion: The present study demonstrates, for the first time, that regular consumption of ICH improves endothelial function in healthy adults. Strategies aimed to preserve or improve the endothelial function may have implications in vascular aging beyond the prevention of the atherothrombotic disease

Determining ‘Age at Death’ for Forensic Purposes using Human Bone by a Laboratory-based Analytical Method

Determination of age-at-death (AAD) is an important and frequent requirement in contemporary forensic science and in the reconstruction of past populations and societies from their remains. Its estimation is relatively straightforward and accurate (±3 years) for immature skeletons by using morphological features and reference tables within the context of forensic anthropology. However, after skeletal maturity (>35 yrs) estimates become inaccurate, particularly in the legal context. In line with the general migration of all the forensic sciences from reliance upon empirical criteria to those which are more evidence-based, AAD determination should rely more-and-more upon more quantitative methods. We explore here whether well-known changes in the biomechanical properties of bone and the properties of bone matrix, which have been seen to change with age even after skeletal maturity in a traceable manner, can be used to provide a reliable estimate of AAD. This method charts a combination of physical characteristics some of which are measured at a macroscopic level (wet & dry apparent density, porosity, organic/mineral/water fractions, collagen thermal degradation properties, ash content) and others at the microscopic level (Ca/P ratios, osteonal and matrix microhardness, image analysis of sections). This method produced successful age estimates on a cohort of 12 donors of age 53–85 yr (7 male, 5 female), where the age of the individual could be approximated within less than ±1 yr. This represents a vastly improved level of accuracy than currently extant age estimation techniques. It also presents: (1) a greater level of reliability and objectivity as the results are not dependent on the experience and expertise of the observer, as is so often the case in forensic skeletal age estimation methods; (2) it is purely laboratory-based analytical technique which can be carried out by someone with technical skills and not the specialised forensic anthropology experience; (3) it can be applied worldwide following stringent laboratory protocols. As such, this technique contributes significantly to improving age estimation and therefore identification methods for forensic and other purposes

DNA methylation age and physical and cognitive ageing

Background: DNA methylation (DNAm) age acceleration (AgeAccel) has been shown to be predictive of all-cause mortality but it is unclear what functional aspect/s of ageing it captures. We examine associations between four measures of AgeAccel in adults aged 45-87 years and physical and cognitive performance and their age-related decline. / Methods: AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno and AgeAccelGrim were calculated in the Medical Research Council National Survey of Health and Development (NSHD), National Child Development Study (NCDS) and TwinsUK. Three measures of physical (grip strength, chair rise speed and forced expiratory volume in one second[FEV1]) and two measures of cognitive (episodic memory and mental speed) performance were assessed. / Results: AgeAccelPheno and AgeAccelGrim, but not AgeAccelHannum and AgeAccelHorvath were related to performance in random effects meta-analyses (n=1388-1685). For example, a one year increase in AgeAccelPheno/AgeAccelGrim was associated with a 0.01ml[95%CI:0.01,0.02]/0.03ml[95%CI:0.01,0.05] lower mean FEV1. In NSHD, AgeAccelPheno and AgeAccelGrim at 53 years were associated with age-related decline in performance between 53 and 69 years as tested by linear mixed models (p<0.05). In a subset of NSHD participants(n=482), there was little evidence that change in any AgeAccel measure was associated with change in performance conditional on baseline performance. / Conclusions: We found little evidence to support associations between the first generation of DNAm-based biomarkers of ageing and age-related physical or cognitive performance in mid-life to early old age. However, there was evidence that the second generation biomarkers, AgeAccelPheno and AgeAccelGrim, could act as makers of an individual’s health-span as proposed

Host genetic and environmental factors shape the human gut resistome

BACKGROUND: Understanding and controlling the spread of antimicrobial resistance is one of the greatest challenges of modern medicine. To this end many efforts focus on characterising the human resistome or the set of antibiotic resistance determinants within the microbiome of an individual. Aside from antibiotic use, other host environmental and genetic factors that may shape the resistome remain relatively underexplored. METHODS: Using gut metagenome data from 250 TwinsUK female twins, we quantified known antibiotic resistance genes to estimate gut microbiome antibiotic resistance potential for 41 types of antibiotics and resistance mechanisms. Using heritability modelling, we assessed the influence of host genetic and environmental factors on the gut resistome. We then explored links between gut resistome, host health and specific environmental exposures using linear mixed effect models adjusted for age, BMI, alpha diversity and family structure. RESULTS: We considered gut microbiome antibiotic resistance to 21 classes of antibiotics, for which resistance genes were detected in over 90% of our population sample. Using twin modelling, we estimated that on average about 25% of resistome variability could be attributed to host genetic influences. Greatest heritability estimates were observed for resistance potential to acriflavine (70%), dalfopristin (51%), clindamycin (48%), aminocoumarin (48%) and the total score summing across all antibiotic resistance genes (38%). As expected, the majority of resistome variability was attributed to host environmental factors specific to an individual. We compared antibiotic resistance profiles to multiple environmental exposures, lifestyle and health factors. The strongest associations were observed with alcohol and vegetable consumption, followed by high cholesterol medication and antibiotic usage. Overall, inter-individual variation in host environment showed modest associations with antibiotic resistance profiles, and host health status had relatively minor signals. CONCLUSION: Our results identify host genetic and environmental influences on the human gut resistome. The findings improve our knowledge of human factors that influence the spread of antibiotic resistance genes and may contribute towards helping to attenuate it

The value of KRAS mutation testing with CEA for the diagnosis of pancreatic mucinous cysts

BACKGROUND AND AIMS: Pancreatic cyst fluid (PCF) CEA has been shown to be the most accurate preoperative test for detection of cystic mucinous neoplasms (CMNs). This study aimed to assess the added value of PCF KRAS mutational analysis to CEA for diagnosis of CMNs. PATIENTS AND METHODS: This is a retrospective study of prospectively collected endoscopic ultrasonography (EUS) fine-needle aspiration (FNA) data. KRAS mutation was determined by direct sequencing or equivalent methods. Cysts were classified histologically (surgical cohort) or by clinical (EUS or FNA) findings (clinical cohort). Performance characteristics of KRAS, CEA and their combination for detection of a cystic mucinous neoplasm (CMN) and malignancy were calculated. RESULTS: The study cohort consisted of 943 patients: 147 in the surgical cohort and 796 in the clinical cohort. Overall, KRAS and CEA each had high specificity (100 % and 93.2 %), but low sensitivity (48.3 % and 56.3 %) for the diagnosis of a CMN. The positivity of KRAS or CEA increased the diagnostic accuracy (80.8 %) and AUC (0.84) significantly compared to KRAS (65.3 % and 0.74) or CEA (65.8 % and 0.74) alone, but only in the clinical cohort (P < 0.0001 for both). KRAS mutation was significantly more frequent in malignant CMNs compared to histologically confirmed non-malignant CMNs (73 % vs. 37 %, P = 0.001). The negative predictive value of KRAS mutation was 77.6 % in differentiating non-malignant cysts. CONCLUSIONS: The detection of a KRAS mutation in PCF is a highly specific test for mucinous cysts. It outperforms CEA for sensitivity in mucinous cyst diagnosis, but the data does not support its routine use

Serous cystic neoplasm of the pancreas: A multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58\u2005years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40\u2005mm (2-200)), 9% had resection beyond 1\u2005year of follow-up (3\u2005years (1-20), size at diagnosis: 25\u2005mm (4-140)) and 39% had no surgery (3.6\u2005years (1-23), 25.5\u2005mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1\u2005year (n=1271), size increased in 37% (growth rate: 4\u2005mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN

Advancing Key Gaps in the Knowledge of Plasmodium vivax Cryptic Infections Using Humanized Mouse Models and Organs-on-Chips

Plasmodium vivax is the most widely distributed human malaria parasite representing 36.3% of disease burden in the South-East Asia region and the most predominant species in the region of the Americas. Recent estimates indicate that 3.3 billion of people are under risk of infection with circa 7 million clinical cases reported each year. This burden is certainly underestimated as the vast majority of chronic infections are asymptomatic. For centuries, it has been widely accepted that the only source of cryptic parasites is the liver dormant stages known as hypnozoites. However, recent evidence indicates that niches outside the liver, in particular in the spleen and the bone marrow, can represent a major source of cryptic chronic erythrocytic infections. The origin of such chronic infections is highly controversial as many key knowledge gaps remain unanswered. Yet, as parasites in these niches seem to be sheltered from immune response and antimalarial drugs, research on this area should be reinforced if elimination of malaria is to be achieved. Due to ethical and technical considerations, working with the liver, bone marrow and spleen from natural infections is very difficult. Recent advances in the development of humanized mouse models and organs-on-a-chip models, offer novel technological frontiers to study human diseases, vaccine validation and drug discovery. Here, we review current data of these frontier technologies in malaria, highlighting major challenges ahead to study P. vivax cryptic niches, which perpetuate transmission and burden

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. Methods: Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. Results: The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. Conclusions: A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM