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An estimated 200 million people live with coronary heart disease, which remains one of the leading causes of mortality and morbidity worldwide. Those living with coronary heart disease are at an increased risk of cardiovascular events, such as stroke, myocardial infarction and cardiovascular death. The pathophysiology of coronary heart disease revolves around inflammation, which leads to plaque build up. Antibiotics are known to hold anti-inflammatory and anti-oxidative properties. It has been theorised that reductions in inflammation could prevent cardiovascular events, which may reduce symptoms, risk of death and hospital admission rates in patients with coronary heart disease. This article critically appraises a systematic review that assessed the risks associated with using antibiotics as secondary prevention for coronary heart disease.

36 Importance: We previously demonstrated that some cancer therapies are strong risk factors for 37 epigenetic age acceleration (EAA) among childhood cancer survivors, and EAA is associated with chronic 38 health conditions (CHCs). However, these data included few survivors that were Objective: We aimed to evaluate the annual mean change rate of epigenetic age and EAA in children 41 and adolescent survivors and compare to survivors with older chronological age, and further associated 42 EAA with early-onset obesity, severity/burden of all CHCs and late-mortality. 43 Design, Setting and Participants: A total of 2,846 survivors of European ancestry from the St. Jude 44 Lifetime Cohort (SJLIFE) was included in the analysis. Annual change in EA and EAA were compared in 5 45 different chronological age groups, i.e., 0-9 (children), 10-19 (adolescent), 20-34 (young adults), 35-49 46 (middle aged adults), and >50 (old adults) years. Logistic regression evaluated the association between 47 EAA and early-onset obesity ( Main Outcomes and Measures: Early-onset obesity, severity/burden of all CHCs and late-mortality 50 based on current SJLIFE data freeze were the outcomes. Expanded DNAm profiling increased the 51 number of survivors aged Results: The annual mean change in EA_Horvath or EA_Levine was higher in children (2.18; 1.63, years) 54 and adolescents (0.80; 1.14, years), and the mean EAA_Horvath or EAA_Levine was lower in children (-55 3.57; -0.22, years) and older adults (-2.34; -1.70, years). EAA_Levine or EAA_GrimAge was significantly 56 associated with risk in developing early-onset obesity (odds ratio [OR], 1.05; 95%CI, 1.01-1.08; OR, 1.12; 57 95%CI, 1.03-1.21), severity/burden of CHCs (OR, 1.02; 95%CI, 1.00-1.04; OR, 1.03; 95% CI, 1.00-1.04) and 58 late-mortality (hazard ratio [HR], 1.10; 95%CI, 1.05-1.15, HR, 1.17; 95% CI, 1.10-1.26). 59 4 Conclusion and Relevance: EAA measured in children and adolescent survivors was associated with 60 early-onset obesity, severity/burden of all CHCs and late-mortality. Evaluating EAA may help identify 61 survivors at increased risk for early-onset obesity, morbidity in general as well as mortality., Plonski N, Chen C, Dong Q, et al. Epigenetic Age in Peripheral Blood Among Children, Adolescent, and Adult Survivors of Childhood Cancer. JAMA Netw Open. 2023;6(4):e2310325. doi:10.1001/jamanetworkopen.2023.10325

We examined whether there were gains in lifespan among patients who died from hematological cancers in Japan between 1990 and 2015 using the novel average lifespan shortened (ALSS) measure. We obtained mortality data from the World Health Organization mortality database. Years of life lost (YLL) was calculated using Japanese life tables. ALSS measure was calculated as a ratio of YLL to the expected lifespan. The ALSS results showed that the lifespan of patients who died from hematological cancers has improved over time. For instance, women who died of leukemia in 1990 lost about 34% of their lifespan; conversely, those who died in 2015 lost about 20%. Likewise, men dying from non-Hodgkin lymphoma lost about 22% of their lifespan in 1990, whereas men lost about 14% in 2015. In summary, the new ALSS measure shows prolonged lifespans among patients who died from hematological cancers in Japan over the study period.

Type 2 diabetes (T2D) is associated with compromised identity of insulin-producing pancreatic islet beta (β) cells, characterized by inappropriate production of other islet cell-enriched hormones. Here we examined how hormone misexpression was influenced by the MAFA and MAFB transcription factors, closely related proteins that maintain islet cell function. Mice specifically lacking MafA in β cells demonstrated broad, population-wide changes in hormone gene expression with an overall gene signature closely resembling islet gastrin (Gast)-positive cells generated under conditions of chronic hyperglycemia and obesity. A human β cell line deficient in MAFB, but not one lacking MAFA, also produced a gastrin (GAST)-positive gene expression pattern. In addition, GAST was detected in human T2D β cells with low levels of MAFB. Moreover, evidence is provided that human MAFB can directly repressGASTgene transcription. These results support a novel, species-specific role for MafA and MAFB in maintaining adult mouse and human β cell identity, respectively, by repressing expression of Gast/GAST and other non-β cell hormones.

1.Data_for_Table1_ADI: The derived variables in Table 1 for ADI (area deprivation index). 2.Data_for_Table1_EDU: The derived variables in Table 1 for EDU(educational attainment). 3.Data_for_Table1_PINC: The derived variables in Table 1 for PINC (personal income). How to cite our paper: Song N, Dong Q, Chen C, Li Q, Mulder H, Plyler E, Easton J, Walker E, Olson S, Neale G, Krull KR, Srivastava DK, Ness KK, Zhang J, Hudson MM, Robison LL, Huang IC, Wang Z. Social-epigenetic mediators for racial disparities in pulmonary impairment among childhood cancer survivors. Cancer Commun (Lond). 2023 Feb;43(2):290-293. doi: 10.1002/cac2.12371. Epub 2022 Oct 18. PMID: 36256508; PMCID: PMC9926953.

Comprendre où et quand une espèce est présente est central en écologie. Pour aller au-delà des approches corrélatives et expliciter les processus écologiques sous-jacents aux distributions observées nous montrons ici comment expliciter les mécanismes dans les modèles de distribution d’espèces. Nous verrons comment définir mathématiquement ces modèles et mener leur inférence dans une approche mécanistico-statistique. Ce chapitre ce terminera sur trois exemples.

Our assessment of epigenetic age acceleration (EAA), calculated with DNA methylation (DNAm) data generated from bulk DNA derived from peripheral blood mononuclear cells (PBMC), supports accelerated aging in childhood cancer survivors (CCS). It is challenging to disentangle variation of DNAm at cell-type specific levels from the effects of age-dependent cell type composition, and bulk measurements may obfuscate the links between EAA and age-related outcomes (e.g., cardiomyopathy). Methylation profiling was generated using Infinium EPIC BeadChips on PBMC-derived DNA from CCS in the St. Jude Lifetime Cohort. Tensor composition analysis was employed to deconvolute bulk DNAm and infer DNAm at each leukocyte subtype level, i.e., a single n (individuals) by m (DNAm sites) matrix of observed DNAm data was deconvoluted into multiple n by m matrices of DNAm data. Epigenetic age (EA, using Levine’s clock) and EAA (residuals from the fit of a simple linear regression of EA on chronological age at blood draw) were calculated for bulk PBMCs and each cell subtype (CD4T, CD8T, B, natural killer, and monocyte). Cardiomyopathy (CMP) was assessed by echocardiography, and severity graded (2 = moderate, 3 = severe/disabling, 4 = life-threatening and 5 = fatal) using a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events. Cumulative doses of anthracyclines and mean heart radiation doses (heart-RT) calculated through radiation dosimetry were abstracted from medical records. Associations between EAA and CMP were evaluated by multivariable Cox regression. Cell-type specific EA was highly correlated with bulk EA with Pearson r2 between 0.63 (CD8T) and 0.79 (CD4T), but the linear regression lines of cell-type specific EA against bulk EA differed in both intercept and slope, suggesting heterogeneity across leukocyte subtypes. Cell-type specific EAA was moderately correlated with bulk EAA with Pearson r2 between 0.23 (monocyte) and 0.29 (CD8T). Among 2,044 CCS (median age = 33.7 years), 104 (5.1%) developed CMP (≥grade 3). Among bulk EAA and five cell-type specific EAAs, monocyte EAA was the only one significantly associated with CMP (hazard ratio per standard deviation increase in EAA = 1.25, 95% CI = 1.04-1.50, P = 0.018). Cell sorting of PBMC followed by DNAm is currently underway for further validation. We showed an in-depth view of the variability of EAA across leukocyte subtypes, and more importantly, demonstrated that monocyte EAA was associated with CMP risk. Our novel finding is plausible and consistent with the literature implicating monocyte-derived cardiac macrophages in cardiac remodeling, which can be induced by cardiotoxic cancer treatment exposures in CCS. Therapeutic strategies that prevent deleterious effects of monocytes contributing to adverse cardiac remodeling, while sparing their essential immune functions, may prevent or ameliorate CMP among CCS. Citation Format: Cheng Chen, Qian Dong, Qin Na, Nan Song, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Emily R. Finch, Qian Li, Yutaka Yasui, Daniel A. Mulrooney, Melissa M. Hudson, Kirsten K. Ness, Jinghui Zhang, Xiang Chen, Hui Wang, Leslie L. Robison, Zhaoming Wang. Monocyte-specific epigenetic age acceleration and cardiomyopathy risk among survivors of childhood cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4363.

We previously showed that cancer treatment associated DNA methylation (DNAm) signatures were present decades following the cancer diagnosis in childhood cancer survivors (CCS) of European ancestry (EA) and that treatment associated DNAm sites mediated the causal pathway from specific treatment exposures to increased risk of chronic health conditions (CHCs). This new analysis further evaluated and compared the treatment and DNAm associations in CCS of African ancestry (AA) from the St. Jude Lifetime Cohort Study. Cancer treatments were abstracted from medical records. DNAm was measured using MethylationEPIC BeadChip with blood-derived DNA. Among 370 AA CCS (53.2% female, median age at blood draw=31.2 [range=18.4-65.1] years), treatments included alkylating agents (54.6%), anthracyclines (48.6%), epipodophyllotoxins (29.2%), corticosteroids (33.0%), and vincristine (61.6%), and radiation therapy (RT) to brain (26.5%), chest (27.6%), abdomen (22.7%), and pelvis (21.6%). Epigenome-wide association study (EWAS) for each treatment, using multivariable linear regression adjusting for sex, age at blood draw, leukocyte cell subtype proportions, genotype principal components and DNAm principal components, showed little inflation with genomic control (GC) factor between 1.1 (brain-RT) and 1.2 (chest-RT). A total of 93 5′-cytosine-phosphate-guanine-3′ (CpG) was associated with one or more cancer treatments (GC-adjusted P Citation Format: Qian Dong, Sarmistha Das, Cheng Chen, John Easton, Heather L. Mulder, Emily Walker, Geoffrey Neale, Deo Kumar Srivastava, I-Chan Huang, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness, Nan Song, Zhaoming Wang. Variations of blood DNA methylation associated with cancer treatment exposures among childhood cancer survivors of African ancestry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4514.

Our published studies demonstrated that epigenetic age acceleration (EAA) is significantly higher in childhood cancer survivors than non-cancer controls. Additionally, EAA is associated with germline genetics, cancer treatments, unfavorable health behaviors, and chronic health conditions. However, our previous studies were limited to non-Hispanic whites (NHW). We aimed to investigate and compare the EAA between non-Hispanic blacks (NHB) and NHW, and evaluate the contribution of social determinants of health (SDOH) to potential racial disparity in EAA. Methylation profiling was generated using Infinium EPIC BeadChips on blood derived DNA from 460 NHB and 2,052 NHW from the St. Jude Lifetime Cohort. EAA was estimated as the residual from the fit of a simple linear regression of epigenetic age (EA, using Levine’s clock) on chronological age (CA, i.e., age at DNA sampling). Cumulative doses of chemotherapy and region-specific radiation exposures were abstracted from medical records. Educational attainment was categorized into 3 levels (< high school, high school, ≥ college). Personal income was categorized into 3 levels (none, < $40,000 and ≥ $40,000). For socioeconomic area deprivation index (ADI), we considered >75th percentile, 40th to 75th percentile, and Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Nan Song, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Jinghui Zhang, Kevin Krull, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, I-Chan Huang, Zhaoming Wang. Racial disparity and roles of social determinants of health in epigenetic age acceleration among survivors of childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3503.

Background In patients receiving mechanical ventilation, spontaneous awakening trials reduce morbidity and mortality when paired with spontaneous breathing trials. However, spontaneous awakening trials are not performed every day they are indicated and little is known about spontaneous awakening trial protocol use in cardiac intensive care units. Local Problem Spontaneous awakening trial completion rate at the study institution was low and no trial protocol was regularly used. Methods A preintervention-postintervention retrospective cohort study was performed in adult patients with at least 24 hours of invasive mechanical ventilation in Michigan Medicine’s cardiac intensive care unit. Patients with SARS-CoV-2 infection were excluded. Data included demographics, sedation, mechanical ventilation duration, and in-hospital mortality. A nurse-driven spontaneous awakening trial protocol modified for the cardiac intensive care unit was implemented in October 2020. Results Compared with the preintervention cohort (n = 29, May through July 2020), the postintervention cohort (n = 27, October 2020 through February 2021) had a higher ratio of number of trials performed to number of days eligible for trial (0.91 vs 0.52; P < .01). Median continuous sedative infusion duration was shorter after intervention (2.3 vs 3.6 days; P = .02). Median mechanical ventilation duration (3.8 vs 4.7 days; P = .18) and mortality (41% vs 41%; P = .95) were similar between groups. Conclusions Spontaneous awakening trial protocol implementation led to a higher trial completion rate and a shorter duration of continuous sedative infusion. Larger studies are needed to assess the impact of protocolized spontaneous awakening trials on cardiac intensive care unit patient outcomes.

Background Mounting evidence supports the occurrence of accelerating aging among long-term survivors of childhood cancer. We aimed to investigate epigenetic age acceleration (EAA) in survivors and evaluate associations between EAA, treatment exposures, health behaviors, and chronic health conditions (CHCs). Methods Genome-wide methylation data were generated with Infinium EPIC BeadChip on blood-derived DNA from 2139 survivors and 282 frequency matched controls from the St Jude Lifetime Cohort Study. EAAs were estimated as residuals from a linear regression of epigenetic age (Levine’s clock) against chronological age. Adjusted least square mean (ALSM) of EAA was calculated and compared between survivors and controls, across treatment exposures and health behaviors. Associations of EAA with 20 clinically assessed CHCs were evaluated with multivariable piecewise-exponential models. All statistical tests for P values below were 2-sided. Results EAA was statistically significantly higher in survivors than controls (ALSM = 0.63, 95% confidence interval [CI] = 0.26 to 1.01 vs −3.61, 95% CI = −4.43 to 2.80). In a multivariable model among survivors, statistically significantly higher EAA (P Conclusions EAA is statistically significantly higher in survivors of childhood cancer than in noncancer controls and is associated with specific treatment exposures, unfavorable health behaviors, and presence of specific CHCs.

Background. Methylmercury contamination of the environment represents a substantial environmental health concern. Human exposure to methylmercury occurs primarily through consumption of fish and marine mammals. Heavily exposed subgroups include sport or subsistence fishers residing in Arctic communities. We aimed to estimate the association of fish/whale consumption patterns of Canadian Arctic subsistence fishers with the internal dose of methylmercury as measured in hair. Methods. This research was conducted within ongoing community projects led by the CANHelp Working Group in Aklavik and Fort McPherson, Northwest Territories and Old Crow, Yukon. We interviewed each participant using a fish-focused food-frequency questionnaire during September-November 2016 and collected hair samples concurrently. Methylmercury was measured in the full-length of each hair sample using gas chromatography inductively-coupled plasma-mass spectrometry. Multivariable linear regression estimated beta-coefficients and 95% confidence intervals (CIs) for the effect of fish/whale consumption on hair-methylmercury concentrations. Results. Among 101 participants who provided hair samples and diet data, the mean number of fish/whale species eaten was 3.5 (SD:1.9). The mean hair-methylmercury concentration was 0.60μg/g (SD:0.47). Fish/whale consumption was positively associated with hair-methylmercury concentration, after adjusting for sex, hair length and use of permanent hair treatments. Hair-methylmercury concentrations among participants who consumed the most fish/whale in each season ranged from 0.30- 0.50μg/g higher than those who consumed Conclusions. In this population of Canadian Arctic subsistence fishers, hair-methylmercury concentration increased with fish/whale consumption, but the maximum concentrations were below Health Canada’s 6.0μg/g threshold for safe exposure.

Background: We have previously reported that epigenetic age acceleration (EAA) was associated with prior cancer treatment exposures and certain chronic health conditions (CHCs) among adult survivors of childhood cancer, but the early epigenetic aging pattern among children and adolescent survivors and its implication in CHCs, especially early-onset CHCs, remain to be explored. Methods: Expanded DNAm profiling with EPIC array for survivors in the St. Jude Lifetime Cohort covered the age Citation Format: Noel-Marie Plonski, Cheng Chen, Qian Dong, Na Qin, Kyla C. Shelton, Emily Finch, John Easton, Heather Mulder, Jinghui Zhang, Geoffrey Neale, Emily Walker, Hui Wang, Kevin Krull, Kirsten K. Ness, Melissa M Hudson, Leslie L. Robinson, Qian Li, AnnaLynn Williams, Zhaoming Wang. Epigenetic age in peripheral blood among children, adolescent, and adult survivors of childhood cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B017.

The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s disease, and Huntington’s disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here, we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesized, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies.

The Ataxin-2 (Atx2) protein contributes to the progression of neurodegenerative phenotypes in animal models of amyotrophic lateral sclerosis (ALS), type 2 spinocerebellar ataxia (SCA-2), Parkinson’s Disease (PD) and Huntington’s Disease (HD). However, because the Atx2 protein contains multiple separable activities, deeper understanding requires experiments to address the exact mechanisms by which Atx2 modulates neurodegeneration (ND) progression. Recent work on two ALS models, C9ORF72 and FUS, in Drosophila has shown that a C-terminal intrinsically disordered region (cIDR) of Atx2 protein, required for assembly of ribonucleoprotein (RNP) granules, is essential for the progression of neurodegenerative phenotypes as well as for accumulation of protein inclusions associated with these ALS models. Here we show that the Atx2-cIDR also similarly contributes to the progression of degenerative phenotypes and accumulation of Huntingtin protein aggregates in Drosophila models of HD. Because Huntingtin is not an established component of RNP granules, these observations support a recently hypothesised, unexpected protein-handling function for RNP granules, which could contribute to the progression of Huntington’s disease and, potentially, other proteinopathies.

Aim Our aim was to assess FY1/FY2 doctors’ experiences and confidence in performing urethral catheterisation in a teaching hospital. Methods This was a single centre, survey based study. An anonymous online questionnaire was circulated to all foundation doctors at the trust. The survey contained 18 questions. The domains included the number of catheterisations performed, confidence levels and whether they had been signed off as competent. This was followed by a series of knowledge questions. Results The survey was sent to 71 email addresses and the response rate was 53%. The results showed that respondents’ lacked experience and confidence in urethral catheterisation. We also found that 32% trainees had not inserted a female catheter during foundation training, and 55% had failed to insert a catheter in the last year. The vast majority (71%) of respondents did not feel confident in female catheterisation. Conclusions This study shows that knowledge and competency in urethral catheterisation (which is an essential GMC requirement) amongst junior doctors is still inadequate.

Established in 2016, the Brain Tumour Registry of Canada Surveillance Research Collaboration aims to address the lack of detailed information on CNS tumours in Canada. Using Canadian Cancer Registry (CCR) data with linked vital status, we present survival estimates for all primary CNS tumours (excluding Quebec) among pediatric patients (age 0-14). Pediatric patients diagnosed with primary CNS tumours during 2010-2017 were included. Vital status was obtained by Statistics Canada through linkage to the Canadian Vital Statistics Database and the income tax returns file, with a cut-off date of December 31, 2017. We used the Pohar-Perme method to estimate the net survival rate (NSR) through the period approach. International Classification of Diseases for Oncology (3rd edition) site/histology codes were grouped into 25 histological categories, irrespective of tumour behaviour, according to the schema developed by the Central Brain Tumor Registry of the United States. Of 1725 pediatric CNS tumours, the 1-, 2- and 5-year NSR are 0.89 (95%CI 0.87-0.90), 0.84 (95%CI 0.81-0.86) and 0.80 (95%CI 0.78-0.82), respectively. All non-malignant CNS tumours have a median survival over 8 years. The 5-year NSR range from 0.90 (95%CI 0.47-0.99) for unique astrocytoma variants, 0.95 for tumour of sellar region (95%CI 0.85-0.98) and germ cell tumours, cysts and heterotopias (95%CI 0.67-0.99), to 1.0 for choroid plexus tumours, tumours of cranial and spinal nerves, and meningioma. For malignant CNS tumours, NSR vary greatly depending on histology grouping. 5-year NSR from lowest to highest are glioblastoma (0.10, 95%CI 0.03-0.23), anaplastic astrocytoma (0.19, 95%CI 0.05-0.40), glioma not otherwise specified (0.54, 95%CI 0.46-0.62), embryonal tumours (0.72, 95%CI 0.65-0.79), diffuse astrocytoma (0.74, 95%CI 0.59-0.85), ependymal tumours (0.78, 95%CI 0.67-0.87), germ cell tumours, cysts and heterotopias (0.85, 95%CI 0.70-0.93) and pilocytic astrocytoma (1.0). We report the most comprehensive and up-to-date data on the pediatric primary CNS tumour survival experience in Canada.

BackgroundIncreased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.MethodsGenome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.ResultsFor EAA-Horvath, a genome-wide significant association was mapped to theSELPgene with the strongest SNP rs732314 (meta-GWAS:β=0.57,P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS:β=0.97 vs. 0.51,I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31,I2=66.3%). For EAA-Hannum, an association was mapped to theHLAlocus with the strongest SNP rs28366133 (meta-GWAS:β=0.78,P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09,P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21,P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.ConclusionsWe identified novel genetic variants in theSELPgene andHLAregion associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

Indigenous Arctic Canadians have a higher prevalence of gastric neoplasms relative to North Americans of European ancestry. We investigated the hypothesis that low-dose methylmercury exposure from eating fish/whale increases the risk of gastric cancer in Arctic communities. We used intermediate endpoints from an established model of gastric carcinogenesis: intestinal metaplasia, atrophy, and severe chronic gastritis. During 2008–2012, we obtained gastric biopsies from participants of community-driven projects in 3 communities. In 2016, we collected hair samples to measure methylmercury levels and interviewed them about diet. In cross-sectional analysis, logistic regression estimated odds ratios for the estimated effect of hair-methylmercury concentration on the prevalence of each pathology outcome stratified by selenium intake. Among 80 participants, prevalence of intestinal metaplasia, atrophy and severe chronic gastritis was 17, 29 and 38%, respectively. Adjusted Odds of severe chronic gastritis and atrophy were highest at hair-methylmercury concentrations ≥1μg/g when estimated selenium intake was 0, and approached 0 for all methylmercury levels as estimated selenium intake increased. Gastric pathology increased with methylmercury exposure when selenium intake was low. Though limited by small numbers, these findings suggest selenium ingested by eating fish/whale may counter harmful effects of methylmercury exposure in Arctic populations.

In symbiotic interactions, spatiotemporal variation in the distribution or population dynamics of one species represents spatial and temporal heterogeneity of the landscape for the other. Such interdependent demographic dynamics result in situations where the relative importance of biotic and abiotic factors in determining ecological processes is complicated to decipher. Using a detailed survey of three metapopulations of the succulent plant