An Analysis of Clinical Outcomes of Exploratory Pediatric Metformin Ingestions Reported to the Texas Poison Center Network From 2011 to 2021.

Background: Poison centers develop triage threshold guidelines for pediatric metformin ingestions. Our network uses 1700 mg, or 85 mg/kg. Objective: To describe the dose, clinical course, and outcomes for inadvertent metformin ingestions in children 5 years old and younger reported to our statewide poison center network. Methods: We searched the poison center database 2011 to 2021 for metformin ingestions in patients 5 years and younger. Variables included age, sex, weight, dose, symptoms, outcome, and more. We used descriptive statistics with medians and interquartile ranges (IQR) for continuous variables. Results: Of 669 cases, exposures by age were 208 (31.1%) 1 to 2 years, and 275 (41.1%) 2 years. Weight was recorded in 342 (51.1%) (median 13.5 kg; IQR: 3.7 kg), and dose in 149 (22.3%) (median 500 mg; IQR: 500 mg). Milligram/kilogram values were available for 103 (15.4%) with median 42.4 mg/kg, IQR: 39 mg/kg. Most (647, 98.5%) exposures were unintentional. Most (445/669, 66.5%) were managed at a non-healthcare facility, while 204 (30.7%) were already at or referred to a healthcare facility. Of these 204 patients, 169 (82.8%) were evaluated and treated at the emergency department and discharged. Four (2%) were admitted to critical care, and 7 (3.4%) to the ward. Medical outcomes by effect were 5 (0.7%) minor, 2 (0.3%) moderate, 253 (37.8%) none, 292 (43.6%) not followed (minimal effects possible), and no major effects or deaths. Of 20 clinical occurrences reported, vomiting was most common (8, 1.2%). Conclusion: Despite little recorded dosage information, pediatric metformin ingestions under 85 mg/kg had predominantly uneventful medical outcomes.

Fatal Viscerocutaneous Brown Recluse Envenomation With Orbital Compartment Syndrome.

Loxosceles is an arachnid genus comprising several species in the United States, popularly known as brown recluse spiders. The venom is cytotoxic, complex, and has a mixture of many proteins, some of which function as proteases. Envenomation can cause necrotic skin lesions that may become extensive and take many months to heal. Even more rarely, venom may cause systemic effects, leading to widespread hemolysis, coagulopathy, and death. These symptoms typically occur rapidly within 24-48 hours following the bite. We describe a rare case of a 44-year-old male with fatal systemic loxoscelism with orbital compartment syndrome requiring emergent lateral canthotomy and cantholysis.

Fasciotomy following North American pit viper envenomation in Texas 2004-2021.

INTRODUCTION: North American pit viper envenomation occurs over 4,000 times annually in the United States, with polyvalent Fab antivenom being the primary treatment. Fasciotomy is occasionally performed due to concerns about compartment syndrome. We utilized our direct access to Texas Poison Center Network data to create a new snakebite abstraction form and database on relevant available information between 2004 and 2021 and to identify, describe, and estimate the incidence of fasciotomy following pit viper envenomation in Texas. METHODS: We searched the Texas Poison Center Network database for cases during 2004-2021 using keywords such as fasciotomy, surgery, compartment pressure, and compartment syndrome. Descriptive statistics summarized the data. RESULTS: Of 16,911 reported envenomations, 0.69 percent involved fasciotomies (n = 117). Most common bite sites were digits/hands and lower extremities. Patients who underwent fasciotomy were typically male, aged 20-59, and 10 years younger than the total snakebite population. Only 6 percent of reported compartment syndrome cases had a compartment pressure measurement. Antivenom was administered in 101 (86.3 percent) cases, 92 (91.1 percent) of which received only Fab antivenom product. Patients with bites from rattlesnakes (47.9 percent) were associated with most fasciotomies. DISCUSSION: Our findings suggest a potential increase in snakebite exposures, accompanied by a decrease in fasciotomies. Overall, copperheads constituted the majority of snakebites, but most fasciotomies were from rattlesnake envenomations (47.9 percent). In this cohort, compartment syndrome diagnosis and decisions regarding fasciotomy were primarily based on clinical evaluation/surgeon expertise without compartment pressure measurements. Despite the efficacy of antivenom, only 86.3 percent of patients in our study received antivenom. CONCLUSIONS: Fasciotomy after North American pit viper envenomation in Texas is uncommon (0.69 percent) and has decreased over time, possibly due to increased antivenom use or surgeon comfort with nonsurgical management.

Ancestry, ethnicity, and race: explaining inequalities in cardiometabolic disease.

Population differences in cardiometabolic disease remain unexplained. Misleading assumptions over genetic explanations are partly due to terminology used to distinguish populations, specifically ancestry, race, and ethnicity. These terms differentially implicate environmental and biological causal pathways, which should inform their use. Genetic variation alone accounts for a limited fraction of population differences in cardiometabolic disease. Research effort should focus on societally driven, lifelong environmental determinants of population differences in disease. Rather than pursuing population stratifiers to personalize medicine, we advocate removing socioeconomic barriers to receipt of and adherence to healthcare interventions, which will have markedly greater impact on improving cardiometabolic outcomes. This requires multidisciplinary collaboration and public and policymaker engagement to address inequalities driven by society rather than biology per se.

An epigenome-wide analysis of DNA methylation, racialized and economic inequities, and air pollution.

Importance: DNA methylation (DNAm) provides a plausible mechanism by which adverse exposures become embodied and contribute to health inequities, due to its role in genome regulation and responsiveness to social and biophysical exposures tied to societal context. However, scant epigenome-wide association studies (EWAS) have included structural and lifecourse measures of exposure, especially in relation to structural discrimination. Objective: Our study tests the hypothesis that DNAm is a mechanism by which racial discrimination, economic adversity, and air pollution become biologically embodied. Design: A series of cross-sectional EWAS, conducted in My Body My Story (MBMS, biological specimens collected 2008-2010, DNAm assayed in 2021); and the Multi Ethnic Study of Atherosclerosis (MESA; biological specimens collected 2010-2012, DNAm assayed in 2012-2013); using new georeferenced social exposure data for both studies (generated in 2022). Setting: MBMS was recruited from four community health centers in Boston; MESA was recruited from four field sites in: Baltimore, MD; Forsyth County, NC; New York City, NY; and St. Paul, MN. Participants: Two population-based samples of US-born Black non-Hispanic (Black NH), white non-Hispanic (white NH), and Hispanic individuals (MBMS; n=224 Black NH and 69 white NH) and (MESA; n=229 Black NH, n=555 white NH and n=191 Hispanic). Exposures: Eight social exposures encompassing racial discrimination, economic adversity, and air pollution. Main outcome: Genome-wide changes in DNAm, as measured using the Illumina EPIC BeadChip (MBMS; using frozen blood spots) and Illumina 450k BeadChip (MESA; using purified monocytes). Our hypothesis was formulated after data collection. Results: We observed the strongest associations with traffic-related air pollution (measured via black carbon and nitrogen oxides exposure), with evidence from both studies suggesting that air pollution exposure may induce epigenetic changes related to inflammatory processes. We also found suggestive associations of DNAm variation with measures of structural racial discrimination (e.g., for Black NH participants, born in a Jim Crow state; adult exposure to racialized economic residential segregation) situated in genes with plausible links to effects on health. Conclusions and Relevance: Overall, this work suggests that DNAm is a biological mechanism through which structural racism and air pollution become embodied and may lead to health inequities.

A history of asthma may be associated with grandparents' exposures to stress and cigarette smoking.

Introduction: Within human epidemiological studies, associations have been demonstrated between grandparental exposures during childhood and grandchildren's outcomes. A few studies have assessed whether asthma has ancestral associations with exposure to cigarette smoking, but results have been mixed so far. Material and methods: In this study we used four generations: (F0 great-grandparents, F1 grandparents, F2 parents, F3 study children) of the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether there is evidence of associations between asthma in generations F2 or F3 and exposures to severe trauma in childhood and/or active cigarette smoking during the adolescence of grandmothers and grandfathers in generations F0 and F1 respectively, or of a history of a F0 or F1 grandmother smoking during pregnancy. Results: We have shown that: a) stress exemplified by the death of a F1 grandparent's parent during the grandparents' childhood was associated with increased risk of asthma in generation F3, especially if the grandparent involved was the paternal grandmother; b) if the grandparents of generations F0 or F1 smoked during adolescence (i.e. < 17 years), their grandchildren in generations F2 and F3 were more likely to have a history of asthma; c) paternal F1 grandmother's smoking in pregnancy was associated with her F3 grandchild's asthma at age 7; d) There were differences between the results for the grandsons and granddaughters of the paternal grandmother with exposure to smoking in adolescence and with smoking in pregnancy. e) The addition of all of the individual exposure variables to the different analyses often provided a considerable increase in goodness of fit compared with only adding demographic factors associated with asthma at P < 0.10 such as social class; this was particularly true when all four exposure variables were combined in one model, suggesting possible synergistic effects between them. Discussion: We have shown associations between all four types of exposure to the grandparents to be associated with asthma in the grandchildren, such that the results both depended on whether the male or female line was involved, and the sex of the grandchildren. It was notable that the paternal grandmother was particularly involved in many of the associations. We emphasize that these are exploratory analyses, that asthma diagnostic criteria likely changed over time and may not be consistent between generations, and that the results should be tested in other cohorts.

Fathers' preconception smoking and offspring DNA methylation.

BACKGROUND: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father's preconception smoking. METHODS: We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7-50 years) on father's any preconception smoking (n = 875 offspring) and father's pubertal onset smoking < 15 years (n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father's smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure. RESULTS: Father's smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) < 0.05) in PRR5 and CENPP. Father's pubertal onset smoking was associated with 19 CpGs (FDR < 0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (p < 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father's smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR < 0.05), and all sites remained significant (p < 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure. CONCLUSION: Father's preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.

Epigenetic clocks and research implications of the lack of data on whom they have been developed: a review of reported and missing sociodemographic characteristics.

Epigenetic clocks are increasingly being used as a tool to assess the impact of a wide variety of phenotypes and exposures on healthy ageing, with a recent focus on social determinants of health. However, little attention has been paid to the sociodemographic characteristics of participants on whom these clocks have been based. Participant characteristics are important because sociodemographic and socioeconomic factors are known to be associated with both DNA methylation variation and healthy ageing. It is also well known that machine learning algorithms have the potential to exacerbate health inequities through the use of unrepresentative samples - prediction models may underperform in social groups that were poorly represented in the training data used to construct the model. To address this gap in the literature, we conducted a review of the sociodemographic characteristics of the participants whose data were used to construct 13 commonly used epigenetic clocks. We found that although some of the epigenetic clocks were created utilizing data provided by individuals from different ages, sexes/genders, and racialized groups, sociodemographic characteristics are generally poorly reported. Reported information is limited by inadequate conceptualization of the social dimensions and exposure implications of gender and racialized inequality, and socioeconomic data are infrequently reported. It is important for future work to ensure clear reporting of tangible data on the sociodemographic and socioeconomic characteristics of all the participants in the study to ensure that other researchers can make informed judgements about the appropriateness of the model for their study population.

Veterinarians show resilience during COVID-19: challenges faced and successful coping strategies.

OBJECTIVE: To identify challenges veterinarians faced during the COVID-19 pandemic, explore how they coped, identify coping strategies associated with greater resilience, and determine incentives and barriers to performing healthy coping behaviors. SAMPLES: 266 surveys completed by veterinarians in the Potomac region. PROCEDURES: A cross-sectional survey was distributed electronically through veterinary medical boards and professional associations between June and September 2021. RESULTS: Most survey responses came from veterinarians working in Maryland (128/266 [48%]) and Virginia (63/266 [24%]) who were predominantly white (186/266 [70%]), female (162/266 [61%]), and working in small-animal clinical practice (185/266 [70%]). The greatest workplace challenges experienced were increased workloads (195/266 [73%]) and reevaluating existing workflows (189/266 [71%]). Separation from loved ones (161/266 [61%]) was the greatest personal challenge. Of the veterinarians who completed the 10-point Connor-Davidson Resilience Scale (n = 219), which measures resilience on a scale from 0 (no resilience) to 40 (greatest resilience), the mean score was 29.6 (SD, 6.9), with a median of 30 (IQR = 10). Intrinsic factors most strongly associated with greater resilience were increasing age (P = .01) and later career stage (P = .002). Job satisfaction, autonomy, good work-life balance, and approach-focused coping strategies were positively associated with resilience. Overwhelmingly, the primary reported barrier to performing healthy coping behaviors was limited time to devote to self-care (177/266 [67%]). CLINICAL RELEVANCE: A combination of individual approach-focused coping strategies and organizational interventions are crucial to support a resilient veterinary workforce.

Use of Correct and Incorrect Methods of Accounting for Age in Studies of Epigenetic Accelerated Aging: Implications and Recommendations for Best Practices.

Motivated by our conduct of a literature review on social exposures and accelerated aging as measured by a growing number of epigenetic "clocks" (which estimate age via DNA methylation (DNAm) patterns), we report on 3 different approaches in the epidemiologic literature-1 incorrect and 2 correct-on the treatment of age in these and other studies using other common exposures (i.e., body mass index and alcohol consumption). Among the 50 empirical articles reviewed, the majority (n = 29; 58%) used the incorrect method of analyzing accelerated aging detrended for age as the outcome and did not control for age as a covariate. By contrast, only 42% used correct methods, which are either to analyze accelerated aging detrended for age as the outcome and control for age as a covariate (n = 16; 32%) or to analyze raw DNAm age as the outcome and control for age as a covariate (n = 5; 10%). In accord with prior demonstrations of bias introduced by use of the incorrect approach, we provide simulation analyses and additional empirical analyses to illustrate how the incorrect method can lead to bias towards the null, and we discuss implications for extant research and recommendations for best practices.

Epigenetic aging & embodying injustice: US My Body My Story and Multi-Ethnic Atherosclerosis Study.

Importance: Epigenetic accelerated aging is associated with exposure to social and economic adversity and may increase risk of premature morbidity and mortality. However, no studies have included measures of structural racism and few have compared estimates within or across the 1st and 2nd generation of epigenetic clocks (the latter additionally trained on phenotypic data). Objective: To determine if accelerated epigenetic aging is associated with exposures to diverse measures of racialized, economic, and environmental injustice measured at different levels and time periods. Design: Cross-sectional My Body My Story Study (MBMS; US, 2008-2010) and Exam 5 Multi-Ethnic Atherosclerosis Study (MESA; US, 2010-2012). MBMS DNA extraction: 2021; linkage of structural measures to MBMS and MESA: 2022. Setting: MBMS recruited a random sample of US-born Black non-Hispanic (BNH) and white non-Hispanic (WNH) participants from 4 community health centers in Boston, MA. The MESA Exam 5 epigenetic component included 975 randomly selected US-born BNH, WNH, and Hispanic participants from four field sites: Baltimore, MD; Forsyth County, NC; New York City, NY; St. Paul, MN. Participants: US-born persons (MBMS: 224 BNH, 69 WNH; MESA: 229 BNH, 555 WNH, 191 Hispanic). Main outcome and measures: 10 epigenetic clocks (six 1st generation; four 2nd generation), computed using DNA methylation data (DNAm) from blood spots (MBMS; N = 293) and purified monocytes (MESA; N = 975). Results: Among Black non-Hispanic MBMS participants, epigenetic age acceleration was associated with being born in a Jim Crow state by 0.14 standard deviations (95% confidence interval [CI] 0.00, 0.27) and with birth state conservatism (0.06, 95% CI 0.00, 0.05), pooling across all clocks, as was low parental education for both Black non-Hispanic and white non-Hispanic MBMS participants (respectively: 0.24, 95% CI 0.08, 0.39, and 0.27, 95% CI 0.03, 0.51. Adult impoverishment was positively associated with the pooled 2nd generation clocks among the MESA participants (Black non-Hispanic: 0.06, 95% CI 0.01, 0.12; white non-Hispanic: 0.05, 95% CI 0.01, 0.08; Hispanic: 0.07, 95% CI 0.01, 0.14). Conclusions and Relevance: Epigenetic accelerated aging may be one of the biological mechanisms linking exposure to racialized and economic injustice to well-documented inequities in premature morbidity and mortality.

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip.

DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.

The EWAS Catalog: a database of epigenome-wide association studies.

Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10 -4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From January 7, 2022, The EWAS Catalog contained 1,737,746 associations from 2,686 EWAS. This includes 1,345,398 associations from 342 peer-reviewed publications. In addition, it also contains summary statistics for 392,348 associations from 427 EWAS, performed on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Omnibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to query EWAS associations quickly and easily, and gain insight into the molecular underpinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog data extraction team continue to update the database monthly and we encourage any EWAS authors to upload their summary statistics to our website. Details of how to upload data can be found here: http://www.ewascatalog.org/upload. The EWAS Catalog is available at http://www.ewascatalog.org.

Individual-, family- and school-based interventions to prevent multiple risk behaviours relating to alcohol, tobacco and drug use in young people aged 8-25 years: a systematic review and meta-analysis.

BACKGROUND: Engagement in multiple substance use risk behaviours such as tobacco smoking, alcohol and drug use during adolescence can result in adverse health and social outcomes. The impact of interventions that address multiple substance use risk behaviours, and the differential impact of universal versus targeted approaches, is unclear given findings from systematic reviews have been mixed. Our objective was to assess effects of interventions targeting multiple substance use behaviours in adolescents. METHODS: Eight databases were searched to October 2019. Individual and cluster randomised controlled trials were included if they addressed two or more substance use behaviours in individuals aged 8-25 years. Data were pooled in random-effects meta-analyses, reported by intervention and setting. Quality of evidence was assessed using GRADE. Heterogeneity was assessed using between-study variance, τ2 and Ι2, and the p-value of between-study heterogeneity statistic Q. Sensitivity analyses were undertaken using the highest and lowest intra-cluster correlation coefficient (ICC). RESULTS: Of 66 included studies, most were universal (n=52) and school-based (n=41). We found moderate quality evidence that universal school-based interventions are likely to have little or no short-term benefit (up to 12 months) in relation to alcohol use (OR 0.94, 95% CI: 0.84, 1.04), tobacco use (OR 0.98, 95% CI: 0.83, 1.15), cannabis use (OR 1.06, 95% CI: 0.86, 1.31) and other illicit drug use (OR 1.09, 95% CI: 0.85, 1.39). For targeted school-level interventions, there was low quality evidence of no or a small short-term benefit: alcohol use (OR 0.90, 95% CI: 0.74-1.09), tobacco use (OR 0.86, 95% CI: 0.66, 1.11), cannabis use (OR 0.84, 95% CI: 0.66-1.07) and other illicit drug use (OR 0.79, 95% CI 0.62-1.02). There were too few family-level (n=4), individual-level (n=2) and combination level (n=5) studies to draw confident conclusions. Sensitivity analyses of ICC did not change results. CONCLUSIONS: There is low to moderate quality evidence that universal and targeted school-level interventions have no or a small beneficial effect for preventing substance use multiple risk behaviours in adolescents. Higher quality trials and study reporting would allow better evidence syntheses, which is needed given small benefit of universal interventions can have high public health benefit. TRIAL REGISTRATION: Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD011374. DOI: 10.1002/14651858.CD011374.

Grandmaternal smoking during pregnancy is associated with differential DNA methylation in peripheral blood of their grandchildren.

The idea that information can be transmitted to subsequent generation(s) by epigenetic means has been studied for decades but remains controversial in humans. Epidemiological studies have established that grandparental exposures are associated with health outcomes in their grandchildren, often with sex-specific effects; however, the mechanism of transmission is still unclear. We conducted Epigenome Wide Association Studies (EWAS) to test whether grandmaternal smoking during pregnancy is associated with altered DNA methylation (DNAm) in peripheral blood from their adolescent grandchildren. We used data from a birth cohort, with discovery and replication datasets of up to 1225 and 708 individuals (respectively, for the maternal line), aged 15-17 years, and tested replication in the same individuals at birth and 7 years. We show for the first time that DNAm at a small number of loci in cord blood is associated with grandmaternal smoking in humans. In adolescents we see suggestive associations in regions of the genome which we hypothesised a priori could be involved in transgenerational transmission - we observe sex-specific associations at two sites on the X chromosome and one in an imprinting control region. All are within transcription factor binding sites (TFBSs), and we observe enrichment for TFBS among the CpG sites with the strongest associations; however, there is limited evidence that the associations we see replicate between timepoints. The implication of this work is that effects of smoking during pregnancy may induce DNAm changes in later generations and that these changes are often sex-specific, in line with epidemiological associations.

Human transgenerational observations of regular smoking before puberty on fat mass in grandchildren and great-grandchildren.

Previously, using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we showed that sons of fathers who had started smoking regularly before puberty (< 13 years) had increased fat mass during childhood, adolescence, and early adulthood. We now show that if the paternal grandfather had started smoking pre-puberty, compared with later in childhood (13-16 years), his granddaughters, but not grandsons, had evidence of excess fat mass at two ages: mean difference + 3.54 kg; (P with 1-tailed test) = 0.043 at 17 years, and + 5.49 kg; (P1 = 0.016) at age 24. When fathers of maternal grandfathers had started smoking pre-puberty, their great-granddaughters, but not great-grandsons, had excess body fat: + 5.35 kg (P1 = 0.050) at 17, and + 6.10 kg (P1 = 0.053) at 24 years. Similar associations were not found with lean mass, in a sensitivity analysis. To determine whether these results were due to the later generations starting to smoke pre-puberty, further analyses omitted those in subsequent generations who had smoked regularly from < 13 years. The results were similar. If these associations are confirmed in another dataset or using biomarkers, this will be one of the first human demonstrations of transgenerational effects of an environmental exposure across four generations.

Regular smoking of male ancestors in adolescence and fat mass in young adult grandchildren and great-grandchildren.

Background: Previous studies using the Avon Longitudinal Study of Parents and Children (ALSPAC) have shown that if men commenced smoking prior to the onset of puberty their sons, their granddaughters and great-granddaughters were more likely to have excess fat (but not lean) mass during childhood, adolescence and early adulthood. In this study we assess associations between ancestral smoking during adolescence (ages 11-16 years) with fat and lean mass of subsequent generations at two ages. Methods: We analysed data on exposures of grandparents and great-grandparents collected by ALSPAC. The outcomes were the fat masses of their grandchildren and great-grandchildren measured at ages 17 and 24. Measures of lean mass were used as controls. Adjustment was made for 8-10 demographic factors using multiple regression. Results: We found associations between adolescent smoking of the paternal grandfathers and the adjusted fat mass of their grandchildren, but no associations with the grandchildren's lean mass. Grandchildren at age 17 had an average excess fat mass of +1.65 [95% CI +0.04, +3.26] Kg, and at age 24 an average excess of +1.55 [95% CI -0.27, +3.38] Kg. Adolescent smoking by the maternal grandfather showed similar, but weaker, associations: at 17 an average excess fat mass of +1.02 Kg [95% CI -0.20, +2.25] Kg, and at 24 an average excess of +1.28 [95% CI -0.11, +2.66] Kg. There were no pronounced differences between the sexes of the children. For the great-grandparents there were few convincing results, although numbers were small. Conclusions: We have shown associations between grandfathers' smoking in adolescence and increased fat (but not lean) mass in their children. Confirmation of these associations is required, either in a further data set or by demonstrating the presence of supportive biomarkers.

Ancestral smoking and developmental outcomes: a review of publications from a population birth cohort†.

The adverse effects on the child of maternal smoking in pregnancy is well-recognized, but little research has been carried out on the possible non-genetic effects of ancestral smoking prior to the pregnancy including parental initiation of cigarette smoking in their own childhoods or a grandmother smoking during pregnancy. Here, we summarize the studies that have been published mainly using data from the Avon Longitudinal Study of Parents and Children. We demonstrate evidence that ancestral smoking prior to or during pregnancy can often be beneficial for offspring health and both ancestor- and sex-specific. More specifically, we report evidence of (i) adverse effects of the father starting to smoke pre-puberty on his son's development; (ii) beneficial effects on the grandson if his maternal grandmother had smoked in pregnancy; and (iii) mainly adverse effects on the granddaughter when the paternal grandmother had smoked in pregnancy. The ancestor- and sex-specificity of these results are consistent with earlier studies reporting associations of health and mortality with ancestral food supply in their parents' and grandparents' pre-pubertal childhoods.

An exploration of the genetic epidemiology of non-suicidal self-harm and suicide attempt.

BACKGROUND: Empirical evidence supporting the distinction between suicide attempt (SA) and non-suicidal self-harm (NSSH) is lacking. Although NSSH is a risk factor for SA, we do not currently know whether these behaviours lie on a continuum of severity, or whether they are discrete outcomes with different aetiologies. We conducted this exploratory genetic epidemiology study to investigate this issue further. METHODS: We explored the extent of genetic overlap between NSSH and SA in a large, richly-phenotyped cohort (the Avon Longitudinal Study of Parents and Children; N = 4959), utilising individual-level genetic and phenotypic data to conduct analyses of genome-wide complex traits and polygenic risk scores (PRS). RESULTS: The single nucleotide polymorphism heritability of NSSH was estimated to be 13% (SE 0.07) and that of SA to be 0% (SE 0.07). Of the traits investigated, NSSH was most strongly correlated with higher IQ (rG = 0.31, SE = 0.22), there was little evidence of high genetic correlation between NSSH and SA (rG = - 0.1, SE = 0.54), likely due to the low heritability estimate for SA. The PRS for depression differentiated between those with NSSH and SA in multinomial regression. The optimal PRS prediction model for SA (Nagelkerke R2 0.022, p < 0.001) included ADHD, depression, income, anorexia and neuroticism and explained more variance than the optimal prediction model for NSSH (Nagelkerke R2 0.010, p < 0.001) which included ADHD, alcohol consumption, autism spectrum conditions, depression, IQ, neuroticism and suicide attempt. CONCLUSIONS: Our findings suggest that SA does not have a large genetic component, and that although NSSH and SA are not discrete outcomes there appears to be little genetic overlap between the two. The relatively small sample size and resulting low heritability estimate for SA was a limitation of the study. Combined with low heritability estimates, this implies that family or population structures in SA GWASs may contribute to signals detected.