Benchmark dose modeling for epidemiological dose-response assessment using prospective cohort studies.

Benchmark dose (BMD) methodology has been employed as a default dose-response modeling approach to determine the toxicity value of chemicals to support regulatory chemical risk assessment. Especially, a relatively standardized BMD analysis framework has been established for modeling toxicological data regarding the formats of input data, dose-response models, definitions of benchmark response, and model uncertainty consideration. However, the BMD approach has not been well developed for epidemiological data mainly because of the diverse designs of epidemiological studies and various formats of data reported in the literature. Although most of the epidemiological BMD analyses were developed to solve a particular question, the methods proposed in two recent studies are able to handle cohort and case-control studies using summary data with consideration of adjustments for confounders. Therefore, the purpose of the present study is to investigate and compare the "effective count"-based BMD modeling approach and adjusted relative risk (RR)-based BMD analysis approach to identify an appropriate BMD modeling framework that can be generalized for analyzing published data of prospective cohort studies for BMD analysis. The two methods were applied to the same set of studies that investigated the association between bladder and lung cancer and inorganic arsenic exposure for BMD estimation. The results suggest that estimated BMDs and BMDLs are relatively consistent; however, with the consideration of established common practice in BMD analysis, modeling adjusted RR values as continuous data for BMD estimation is a more generalizable approach harmonized with the BMD approach using toxicological data.

Birth weight moderates the association between obesity and mortality rate.

PURPOSE: The strength of the association between obesity and mortality rate (MR) varies by body mass index (BMI) and sociodemographic groups. We test the hypothesis that the association between obesity and MR varies, in part, due to the moderating effect of parental BMI and birth weight. METHODS: Data come from the 1958 National Child Development Study, an ongoing longitudinal dataset initiated in 1958 with baseline measures of birth weight from 18,059 infants born in Great Britain over 1 week. We tested whether the association between BMI and MR was moderated by parental BMI and birth weight using generalized additive proportional hazards models. RESULTS: The association between adult BMI and MR was moderated by birth weight and maternal BMI, such that the association between BMI and MR was weaker among individuals with a higher birth weight (P = .0148) and stronger among individuals born to mothers with a higher BMI (P = .032). At any given level of BMI approximately greater than 25, individuals with low birth weight or born to mothers with a higher BMI, had a higher MR. Paternal BMI did not significantly modify the relationship between BMI and MR (P = .5168). CONCLUSIONS: Results suggest that the relationship between obesity and MR is modified by birth weight and maternal BMI.

Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families.

PURPOSE: Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. METHODS: The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. RESULTS: Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. CONCLUSION: Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.

The associations between relative and absolute body mass index with mortality rate based on predictions from stigma theory.

Background: The social consequences of obesity may influence health and mortality rate (MR), given obesity's status as a highly stigmatized condition. Hence, a high absolute body mass index (BMI) in conjunction with the stigmatization of a high BMI may each independently increase the rate of MR. Objectives: We tested whether relative BMI, defined as ordinal rank within a social reference group jointly defined by age, sex, and race/ethnicity, is associated with MR independent of absolute BMI. Methods: Data were from three nationally representative datasets: the Health and Retirement Study (n = 31,115), the National Health Interview Survey (NHIS, n = 529,362), and the National Health and Nutrition Examination Survey (n = 31,115). Relative BMI kg/m2 deciles were calculated within twenty-four subgroups jointly defined by age (6 levels), sex (2 levels), and race/ethnicity (4 levels). The association between ordinal rank BMI and MR was assessed using Cox survival generalized additive models in each dataset with adjustments for age, race, sex, smoking, educational attainment, and absolute BMI. Results: Absolute BMI had a significant non-monotonic association with MR, such that BMI was positively associated with mortality at BMI levels above approximately 25 kg/m2. Contrary to expectations, results from NHIS indicated that individuals in the first decile of relative BMI had the highest MR whereas relative BMI was not associated with MR in the NHANES and HRS. Conclusion: We hypothesized that the stigmatization of obesity might lead to an increased MR after controlling for absolute BMI. Contrary to expectations, a higher relative BMI was not associated with an increased MR independent of absolute BMI.

Metformin and thyroid carcinoma incidence and prognosis: A systematic review and meta-analysis.

Metformin has been suggested to reduce thyroid cancer incidence and to improve thyroid cancer prognosis. We aimed to evaluate the associations between metformin and thyroid cancer incidence and prognosis (metastasis/recurrence/progression-free survival). Cochrane Library, PubMed, ClinicalTrials.gov, and U.S. National Library of Medicine Clinical Trials were searched through the end of December 2021. Data were collected from original observational studies or clinical trials on the incidence or prognosis of thyroid carcinoma outcomes in type 2 diabetes mellitus (T2DM) patients with and without metformin use. Risk of bias in non-randomized studies of interventions (ROBINS-I) tool and Grading of Recommendations, and Assessment, Development and Evaluations (GRADE) approach were used to evaluate the risk of bias and quality of the body of evidence, respectively. In general, 4 studies were related to the thyroid cancer incidence, including 1,705,123 participants metformin users and non-users and yielding a total of 3,238 thyroid cancer events; 3 studies reported the prognosis of thyroid carcinoma based on a total of 4,972 individuals with primary thyroid carcinoma and comorbid type 2 diabetes, and the number of thyroid cancer prognosis cases ranged from 3 to 79. The overall risk of bias of the included studies ranged from moderate to serious. In the random-effects model, the summary relative risk (SRR) for thyroid cancer incidence was 0.743 (95% CI: 0.453-1.220; I2 = 88.7%, low certainty) comparing metformin users to non-users; and SRR for the prognosis of thyroid cancer was 0.504 (95% CI: 0.178-1.430; I2 = 57.5%, low certainty). Non-statistically significant negative associations between metformin use and incidence and prognosis of thyroid cancer were found in the current analysis, although the quantity and quality of the evidence were limited. Futher investigation is needed to evaluate the clinical benefits of metformin on thyroid cancer prevention and treatments.

Do B Vitamins Enhance the Effect of Omega-3 Polyunsaturated Fatty Acids on Cardiovascular Diseases? A Systematic Review of Clinical Trials.

Studies have suggested that B vitamins or omega-3 polyunsaturated fatty acids (PUFAs) may deter the development of cardiovascular disease (CVD). This systematic review aims to examine whether the combined supplementation of both B vitamins and omega-3 PUFAs could provide additional beneficial effects to prevent CVD beyond the effect of each supplement based on clinical trials published up to December 2021. The overall findings are inconsistent and inconclusive, yet the combined supplementation of these two nutrients may be more effective at reducing plasma homocysteine, triglyceride, and low-density lipoprotein-cholesterol than the individual components. The underlying mechanisms mainly include alleviating endothelial dysfunction, inhibiting atherosclerosis and lesion initiation, reducing oxidative stress, suppressing activation of pro-inflammatory cytokines, regulating endothelial nitric oxide synthase, and interfering with methylation of genes that promote atherogenesis. Although biologically plausible, the existing literature is insufficient to draw any firm conclusion regarding whether B vitamins can further enhance the potential beneficial effects of omega-3 PUFA intake on either primary or secondary prevention of CVD. The inconsistent findings may be largely explained by the methodological challenges. Therefore, well-designed high-quality trials that will use the combined supplementation of B vitamins and omega-3 PUFAs or dietary patterns rich in these two types of nutrients are warranted.

Association between dietary intake of polyunsaturated fatty acid and prevalence of hypertension in U.S. adults: A cross-sectional study using data from NHANES 2009-2016.

This study aimed to evaluate the association between dietary polyunsaturated fatty acid (PUFA) intake and the prevalence of hypertension in U.S. adults. Data from the National Health and Nutrition Examination Survey (NHANES) 2009-2016 were used. Total PUFAs and subtypes of PUFAs, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), linoleic acid (LA), and arachidonic acid (AA), were obtained through two 24 h recalls and adjusted by body weight. Hypertension was defined as the average of three measurements of blood pressure above 130/80 mmHg or taking antihypertensive medication. Weighted odds ratios (ORs) of hypertension and adjusted rate differences (ARDs) in prevalence, as well as their 95% confidence intervals (CIs), were estimated by using the logistic regression model of survey design. A total of 17,108 participants were included in this study. Dietary intake of PUFAs was significantly associated with a lower prevalence of hypertension for the highest versus lowest quartiles. The weighted ORs with 95% CIs of hypertension for total PUFA, omega-3 fatty acid, fish oil, ALA, omega-6 fatty acid, LA and AA were 0.47(0.40-0.55), 0.61(0.51-0.72), 0.85(0.74-0.97), 0.65(0.55-0.76), 0.49(0.42-0.58), 0.49(0.42-0.57) and 0.75(0.64-0.89), and the ARDs with 95% CIs were -18.06%(-22.54%, -13.58%), -12.06%(-16.68%, -7.44%), -4.13%(-8.25%, -0.01%), -10.54%(-15.31%, -5.78%), -17.03%(-21.49%, -12.58%), -17.23%(-21.76%, -12.69%) and -6.91%(-11.37%, -2.46%), respectively. Our study proposed that the intake of total PUFAs, omega-3 fatty acids, fish oil, ALA, omega-6 fatty acids, LA, and AA was associated with a lower prevalence of hypertension in the U.S. adults.

Efficacy and safety of a specific commercial high-protein meal-replacement product line in weight management: meta-analysis of randomized controlled trials.

BACKGROUND: Protein is suggested to be the nutrient providing the most satiety and is frequently used in meal-replacement products to achieve weight loss. Commercial products such as Herbalife high-protein (HP) products have been studied in various clinical trials, but controversy remains regarding their efficacy and safety. METHODS: We searched the PubMed, Center for Clinical and Translational Research (CCTR), and Google Scholar databases for randomized controlled trials of Herbalife HP products used as meal replacement (MR) published through July 2019 in peer-reviewed journals. We reviewed changes in efficacy and safety-related outcomes in treatment and control groups, and we estimated the pooled standardized mean difference (SMD) and corresponding 95% confidence intervals (CIs) with a DerSimonian and Laird random-effects method. RESULTS: By pooling data from nine identified studies (934 participants: 463 in treatment groups and 471 in control groups), we found that participants who consumed HP products experienced significantly larger decreases in body weight (SMD = -0.24; 95% CI: -0.37 to -0.10), body mass index (SMD = -0.31; 95% CI: -0.50 to -0.11), and fat mass (SMD = -0.37; 95% CI: -0.65 to -0.09) than did individuals consuming control diets. Concerning safety outcomes, the participants in the treatment group had a significantly larger decrease in aspartate aminotransferase (SMD = -0.23; 95% CI: -0.42 to -0.03). There were no significant between-group differences in alanine aminotransferase or creatinine. However, blood urea nitrogen levels increased in both groups, with a significantly larger increase in the treatment group (SMD = 0.53; 95% CI: 0.15 to 0.92). CONCLUSIONS: Herbalife HP MR products appear effective and do not evidence significant risk in reducing body weight.

Associations of dietary PUFA with dyslipidaemia among the US adults: the findings from National Health and Nutrition Examination Survey (NHANES) 2009-2016.

Dyslipidaemia, a significant risk factor of CVD, is threatening human health worldwide. PUFA are crucial long-chain fatty acids for TAG synthesis and removal, potentially decreasing dyslipidaemia risk. We examined dyslipidaemia prevalence among 15 244 adults aged ≥ 20 years from National Health and Nutrition Examination Survey 2009-2016. Dyslipidaemia was defined as total cholesterol ≥ 240 mg/dl, or HDL-cholesterol < 40 mg/dl/50 mg/dl for males/females, respectively, or LDL-cholesterol ≥ 160 mg/dl, or TAG ≥ 200 mg/dl, or taking lipid-modifying medications. We measured the daily PUFA intake using a 24-h dietary recall. Demographics, social economics, and lifestyle factors were collected using questionnaires/interviews. Additionally, we measured Se and Hg levels in the whole blood. Logistic regression models were used to examine the association between PUFA and dyslipidaemia. The unweighted and weighted dyslipidaemia prevalences were 72·4% and 71·0 %, respectively. When grouped into tertiles, PUFA intake above 19·524 g/d was associated with an independent 19 % decrease in dyslipidaemia risk (OR = 0·81 (95 % CI 0·71, 0·94)) compared with the lowest tertile (PUFA intake ≤ 12·349 g/d). A threshold inverse association was further determined by the restricted cubic spline analysis. When PUFA intake was increased to its turning point, that is, 19 g/d, the lower nadir risk for dyslipidaemia was obtained (OR = 0·72 (95 % CI 0·56, 0·89)). When the exposure was the sum of α-linolenic acid and octadecatetraenoic acid, the inverse linear association remained. Dietary PUFA intake is a beneficial factor for dyslipidaemia among American adults, independent of many potential confounders, including Hg and Se.

Randomization, design and analysis for interdependency in aging research: no person or mouse is an island.

Investigators traditionally use randomized designs and corresponding analysis procedures to make causal inferences about the effects of interventions, assuming independence between an individual's outcome and treatment assignment and the outcomes of other individuals in the study. Often, such independence may not hold. We provide examples of interdependency in model organism studies and human trials and group effects in aging research and then discuss methodologic issues and solutions. We group methodologic issues as they pertain to (1) single-stage individually randomized trials; (2) cluster-randomized controlled trials; (3) pseudo-cluster-randomized trials; (4) individually randomized group treatment; and (5) two-stage randomized designs. Although we present possible strategies for design and analysis to improve the rigor, accuracy and reproducibility of the science, we also acknowledge real-world constraints. Consequences of nonadherence, differential attrition or missing data, unintended exposure to multiple treatments and other practical realities can be reduced with careful planning, proper study designs and best practices.

Contribution of Total Screen/Online-Course Time to Asthenopia in Children During COVID-19 Pandemic via Influencing Psychological Stress.

Objectives: During the coronavirus disease 2019 (COVID-19) self-quarantine period, the transition to online-course has profoundly changed the learning modes of millions of school-aged children and put them at an increased risk of asthenopia. Therefore, we aimed to determine associations of the total screen/online-course time with asthenopia prevalence among that children during the COVID-19 pandemic, and whether the associations were mediated by psychological stress. Methods: Asthenopia was defined according to a validated computer vision syndrome questionnaire (CVS-Q). We used CVS-Q to collect the frequency and intensity of 16 asthenopia-related eye symptoms of 25,781 children. Demographic features, eye care habits, visual disorders, lifestyle, psychological and environmental factors, were also collected. Results: The overall asthenopia prevalence was 12.1%, varying from 5.4 to 18.2% across grade/gender-classified subgroups. A 100-h increment of total screen/online-course time were associated with an increased risk of asthenopia by 9% [odds ratio (OR) = 1.09] and 11% (OR = 1.11), respectively. Mediation analysis showed that the proportions of total effects mediated by psychological stress were 23.5 and 38.1%, respectively. Age, female gender, having myopia or astigmatism, bad habits when watching screens were also risk factors. Conversely, keeping 34-65 cm between eyes and screen, increased rest time between classes, and increased eye exercise were all associated with a decreased risk. Conclusion: Our study indicated that the influence of long total screen or online-course time on psychological stress increases asthenopia risk. The findings of this study have provided a new avenue for intervening screen-related asthenopia in addition to incorporating a reasonable schedule of online courses into educational policy.

Dietary Inflammatory Index and Cardiometabolic Risk in Ecuadorian Women.

Low-grade systemic inflammation is implicated in metabolic syndrome (MetS) and cardiometabolic diseases. Diet is hypothesized to be an important low-grade inflammation modifier. However, few studies have examined the association of dietary inflammation with MetS and cardiometabolic risk in Latin American populations and their findings are inconsistent. Our cross-sectional study examined the association of dietary inflammatory potential with MetS and cardiometabolic risk components in 276 urban Ecuadorian women. Dietary inflammation was evaluated using an energy-adjusted Dietary Inflammatory Index (E-DII), divided into quartiles (Q). E-DII scores ranged from -4.89 (most anti-inflammatory) to 4.45 (most pro-inflammatory). Participants in the most pro-inflammatory (Q4) compared to the least inflammatory E-DII quartile (Q1) had a 4.4 increased adjusted odds for MetS (95% C.I. = 2.0, 9.63; p < 0.001). Every one-unit increase in E-DII was associated with a 1.4 increase in MetS (95% CI = 1.22, 1.52; p < 0.001). In other adjusted models, the most pro-inflammatory E-DII quartile (Q4) was positively associated with total blood cholesterol and triglycerides (p < 0.001), LDL-c (p = 0.007), diastolic blood pressure (p< 0.002), mean arterial pressure (p < 0.006), waist circumference (p < 0.008), and Framingham risk score (p < 0.001). However, the previously identified associations with pulse wave velocity and BMI were no longer evident in the models. These findings suggest that more pro-inflammatory diets may contribute to poorer cardiometabolic health. Promoting healthier diets with a lower inflammatory potential may help to prevent or slow development of cardiometabolic disorders.

Senolytics reduce coronavirus-related mortality in old mice.

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse ß-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2.

The daily Self-Weighing for Obesity Management in Primary Care Study: Rationale, design and methodology.

Background Daily self-weighing (DSW) may be an effective harm-reduction intervention to disrupt continued weight gain. Self-Weighing for Obesity Management in Primary Care (SWOP) is a 24-month randomized controlled trial in 400 adults with obesity (BMI: kg/m2 ≥ 30) receiving primary care through a clinical network affiliated with an academic medical center. Objective To test DSW as a potentially scalable way to deter age-related weight gain among primary care patients with obesity. Methods Randomized-controlled trial with two conditions: DSW (instruction to weigh daily and provision of a web-enabled digital scale with graphical weight feedback) or Standard Care (receive a monetary gift card equivalent to value of the scale). Both groups receive standardized weight management educational material. SWOP will test the causal effect of assignment to DSW (Aim 1) and adherence to DSW (Aim 2) on weight (primary outcome) and adoption of weight management practices (secondary outcomes), as well as evaluate the cost-effectiveness of DSW compared to standard care (Aim 3). Findings may inform clinical guidelines for weight management by providing evidence that DSW attenuates continued age-related weight gain among adults with obesity. This trial is registered with ClinicalTrials.gov (NCT04044794).

Magnesium intake was inversely associated with hostility among American young adults.

Hostility is a complex personality trait associated with many cardiovascular risk factor phenotypes. Although magnesium intake has been related to mood and cardio-metabolic disease, its relation with hostility remains unclear. We hypothesize that high total magnesium intake is associated with lower levels of hostility because of its putative antidepressant mechanisms. To test the hypothesis, we prospectively analyzed data in 4,716 young adults aged 18-30 years at baseline (1985-1986) from four U.S. cities over five years of follow-up using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Magnesium intake was estimated from a dietary history questionnaire plus supplements at baseline. Levels of hostility were assessed using the Cook-Medley scale at baseline and year 5 (1990-1991). Generalized estimating equations were applied to estimate the association of magnesium intake with hostility as repeated measures at the two time-points (baseline and year 5). General linear model was used to determine the association between magnesium intake and change in hostility over 5 years. After adjustment for socio-demographic and major lifestyle factors, a significant inverse association was observed between magnesium intake and hostility level over 5 years of follow-up. Beta coefficients (95% CI) across higher quintiles of magnesium intake were 0 (reference), -1.28 (-1.92, -0.65), -1.45 (-2.09, -0.81), -1.41 (-2.08, -0.75) and -2.16 (-2.85, -1.47), respectively (Plinear-trend<.01). The inverse association was independent of socio-demographic and major lifestyle factors, supplement use, and depression status at year 5. This prospective study provides evidence that in young adults, high magnesium intake was inversely associated with hostility level independent of socio-demographic and major lifestyle factors.

Association of Self-Paced Physical and Cognitive Activities Across the First Week Postconcussion With Symptom Resolution in Youth.

OBJECTIVE: To examine the association of objectively measured, self-paced physical and cognitive activities across the first week postconcussion with symptom resolution in youth. SETTING: Emergency department or concussion clinics. PARTICIPANTS: Youth aged 11 to 17 years with physician-confirmed concussion. DESIGN: Prospective cohort with repeated measures. MAIN MEASURES: Days from injury to symptom resolution, based on daily ratings by youth on the Post-Concussive Symptom Scale. Physical and cognitive activities were assessed using an ActiGraph and a Narrative Clip, respectively. RESULTS: A total of 83 youth participants were included (n = 54 [65%] males; mean age = 14.2 years, SD = 1.9). While self-paced daily physical and cognitive activities increased across the first week postinjury, daily postconcussion symptoms decreased. Increased daily step count was associated with an increased likelihood of early symptom resolution (hazard ratio [HR] = 1.17; 95% confidence interval [CI], 1.02-1.34). However, this association was not statistically significant after adjusting for acute postconcussion symptoms and other covariates. Greater school attendance time was associated with earlier symptom resolution (adjusted HR = 1.14; 95% CI, 1.02-1.27). CONCLUSION: Self-paced physical and cognitive activities across the first week postinjury alone neither hastened nor prolonged concussion recovery. Youth with concussion may have some latitude to determine their activity levels.

Bayesian benchmark dose analysis for inorganic arsenic in drinking water associated with bladder and lung cancer using epidemiological data.

Abundant epidemiological evidence has shown that there is a strong causal relationship between long-term exposure to inorganic arsenic (iAs) through drinking water and a few types of cancer (e.g., lung and bladder cancer). Traditionally, a linear low-dose extrapolation assumption was applied in risk assessment for iAs which resulted in a relatively conservative cancer risk estimate. Growing biological evidence suggests that the mode of action of iAs-induced cancer follows a threshold process (e.g., sufficient concentration of trivalent arsenic is required to disrupt normal cellular function). In this study, we applied the benchmark dose (BMD) methodology to model the relationship between the relative risk of bladder and lung cancer and the iAs concentration in drinking water using the high-quality epidemiological data reported in recently published papers, with a special focus on the low exposure range (i.e., <150 µg/L). Because of its biological plausibility and statistical flexibility, the Hill model has been chosen to model the data under a Bayesian framework. A Bayesian hierarchal model together with a bootstrap method for exposure estimation were applied to quantify uncertainty from various sources, including the within-study, between-study, and exposure uncertainties. Dose-response assessment results obtained from a number of alternative model structures and methods consistently demonstrate a threshold type dose-response curve with a threshold in the range between 40-60 µg/L of iAs concentration in drinking water. The BMD for iAs in drinking water associated with 0.1 % increase in relative risk of bladder cancer is 42.2 µg/L (BMDL 39.2 µg/L); for 0.05 % increase, the BMD is 41.6 µg/L (BMDL 38.6 µg/L). For lung cancer, the two counterpart BMD estimates are 57.0 µg/L (BMDL 43.6 µg/L) and 55.7 µg/L (BMDL 42.5 µg/L) for 0.1 % and 0.05 % increase, respectively. These analyses provide additional statistical support for a non-linear dose response for cancer risk from inorganic arsenic which may have important policy implications.

Skeletal muscle mitochondrial DNA copy number and mitochondrial DNA deletion mutation frequency as predictors of physical performance in older men and women.

Mitochondrial DNA (mtDNA) quality and quantity relate to two hallmarks of aging-genomic instability and mitochondrial dysfunction. Physical performance relies on mitochondrial integrity and declines with age, yet the interactions between mtDNA quantity, quality, and physical performance are unclear. Using a validated digital PCR assay specific for mtDNA deletions, we tested the hypothesis that skeletal muscle mtDNA deletion mutation frequency (i.e., a measure of mtDNA quality) or mtDNA copy number predicts physical performance in older adults. Total DNA was isolated from vastus lateralis muscle biopsies and used to quantitate mtDNA copy number and mtDNA deletion frequency by digital PCR. The biopsies were obtained from a cross-sectional cohort of 53 adults aged 50 to 86 years. Before the biopsy procedure, physical performance measurements were collected, including VO2max, modified physical performance test score, 6-min walk distance, gait speed, grip strength, and total lean and leg mass. Linear regression models were used to evaluate the relationships between age, sex, and the outcomes. We found that mtDNA deletion mutation frequency increased exponentially with advancing age. On average from ages 50 to 86, deletion frequency increased from 0.008 to 0.15%, an 18-fold increase. Females may have lower deletion frequencies than males at older ages. We also measured declines in VO2max and mtDNA copy number with age in both sexes. The mtDNA deletion frequency measured from single skeletal muscle biopsies predicted 13.3% of the variation in VO2max. Copy number explained 22.6% of the variation in mtDNA deletion frequency and 10.4% of the lean mass variation. We found predictive relationships between age, mtDNA deletion mutation frequency, mtDNA copy number, and physical performance. These data are consistent with a role for mitochondrial function and genome integrity in maintaining physical performance with age. Analyses of mtDNA quality and quantity in larger cohorts and longitudinal studies could extend our understanding of the importance of mitochondrial DNA in human aging and longevity.