A hypothetical intervention to reduce inequities in anxiety for Multiracial people: simulating an intervention on childhood adversity.

Multiracial people report higher mean Adverse Childhood Experiences (ACEs) scores and prevalence of anxiety than other racial groups. Studies using statistical interactions to estimate racial differences in ACEs-anxiety associations do not show stronger associations for Multiracial people. Using data from Waves 1 (1995-97) through 4 (2008-09) of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we simulated a stochastic intervention over 1,000 resampled datasets to estimate the race-specific cases averted per 1,000 of anxiety if all racial groups had the same exposure distribution of ACEs as Whites. Simulated cases averted were greatest for the Multiracial group, (median = -4.17 cases per 1,000, 95% CI: -7.42, -1.86). The model also predicted smaller risk reductions for Black participants (-0.76, 95% CI: -1.53, -0.19). CIs around estimates for other racial groups included the null. An intervention to reduce racial disparities in exposure to ACEs could help reduce the inequitable burden of anxiety on the Multiracial population. Stochastic methods support consequentialist approaches to racial health equity, and can encourage greater dialogue between public health researchers, policymakers, and practitioners.

Neighborhood-level Fatal Police Violence and Severe Maternal Morbidity in California.

Police violence is a pervasive issue that may have adverse implications for severe maternal morbidity (SMM). We assessed how the occurrence of fatal police violence (FPV) in one's neighborhood before/during pregnancy may influence SMM risk. Hospital discharge records from California between 2002-2018 were linked with the Fatal Encounters database (N=2,608,682). We identified 2,184 neighborhoods (census-tracts) with at least one FPV incident during the study period and used neighborhood fixed-effects models adjusting for individual sociodemographic characteristics to estimate odds of SMM associated with experiencing FPV in one's neighborhood anytime within the 24-months before childbirth. We did not find conclusive evidence on the link between FPV occurrence before delivery and SMM. However, estimates show that birthing people residing in neighborhoods where one or more FPV events had occurred within the preceding 24-months of giving birth may have a mildly elevated odds of SMM than those residing in the same neighborhoods with no FPV occurrence during the 24-months preceding childbirth (Odds Ratio (OR)=1.02; 95% Confidence Interval (CI): 0.99-1.05), particularly among those living in neighborhoods with fewer (1-2) FPV incidents throughout the study period (OR=1.03; 95% CI:1.00-1.06). Our findings provide evidence for the need to continue to examine the health consequences of police violence.

Body composition and cancer survival: a narrative review.

Interest in understanding the relationship between body composition and cancer survival has remained strong for decades, with a number of recent systematic reviews on the topic. However, the current state of evidence is based on heterogeneous exposure definitions based on anthropometry, yielding inconsistent findings with regard to this association. Recently the field has taken an exciting direction with the application of radiological assessments to measure specific aspects of body composition, yet reconciliation of findings from these modern assessment tools with those from the historic use of anthropometric data proves challenging. In this paper, I briefly review the biological basis for a link between body composition and cancer survival and summarize the epidemiological evidence with consideration to specific exposure measures. As enthusiasm is building around novel assessments, I conclude with a discussion of issues that researchers should be aware of when interpreting results from these new modalities.

The association between the Mediterranean Diet Score and death from cancer of the head and neck.

PURPOSE: The association between diet quality, captured by the Mediterranean Diet Score (MDS), and mortality was studied among 1184 individuals diagnosed with head and neck cancer (HNC) who reflected on the year preceding diagnosis about their usual diet using National Cancer Institute's Diet History Questionnaire (DHQ). METHODS: Intakes of nine dietary components were scored and summed to construct the MDS (sample: median = 4; range (0-9); lower MDS reflected poorer diet quality; 5-year survival probability = 0.62). Cox regression estimated 5-year hazard ratios (HR) and 95% confidence intervals (95CI) for all-cause mortality and for HNC-specific death for contrasts of MDS quintiles. Effect measure modification (EMM) by tumor features [human papillomavirus (HPV) positivity; anatomic site] and sociodemographic behavioral factors [race, body mass index (BMI), smoking, alcohol consumption] was explored. RESULTS: The 5-year [HR (95CI); P-trend] for all-cause mortality and HNC-specific mortality for highest versus lowest MDS quintile contrasts were [0.51 (0.33, 0.80); 0.014] and [0.43 (0.22, 0.85); 0.004], respectively. A unit increase in MDS adherence resulted in a 15% reduction of the 5-year HR for HNC-specific death for tumors located at the oral cavity [HR (95CI): 0.85 (0.75, 0.96)]. Poor diet quality (MDS ≤ 4) interacted with lower BMI (kg/m2 < 25) and separately with ever-using alcohol to produce 5-year HRs for all-cause and HNC-specific mortality that were statistically significantly larger than the sum of the individual HRs representing each combination (Poor diet quality + lower BMI; Poor diet quality + ever-using alcohol). CONCLUSION: Greater adherence to a Mediterranean diet pattern prior to HNC diagnosis may reduce post-diagnosis mortality.

Accounting for Misclassification and Selection Bias in Estimating Effectiveness of Self-managed Medication Abortion.

BACKGROUND: Studies on the effectiveness of self-managed medication abortion may suffer from misclassification and selection bias due to self-reported outcomes and loss of follow-up. Monte Carlo sensitivity analysis can estimate self-managed abortion effectiveness accounting for these potential biases. METHODS: We conducted a Monte Carlo sensitivity analysis based on data from the Studying Accompaniment model Feasibility and Effectiveness Study (the SAFE Study), to generate bias-adjusted estimates of the effectiveness of self-managed abortion with accompaniment group support. Between July 2019 and April 2020, we enrolled a total of 1051 callers who contacted accompaniment groups in Argentina and Nigeria for self-managed abortion information; 961 took abortion medications and completed at least one follow-up. Using these data, we calculated measures of effectiveness adjusted for ineligibility, misclassification, and selection bias across 50,000 simulations with bias parameters drawn from pre-specified Beta distributions in R. RESULTS: After accounting for the potential influence of various sources of bias, bias-adjusted estimates of effectiveness were similar to observed estimates, conditional on chosen bias parameters: 92.68% (95% simulation interval: 87.80%, 95.74%) for mifepristone in combination with misoprostol (versus 93.7% in the observed data) and 98.47% (95% simulation interval: 96.79%, 99.39%) for misoprostol alone (versus 99.3% in the observed data). CONCLUSIONS: After adjustment for multiple potential sources of bias, estimates of self-managed medication abortion effectiveness remain high. Monte Carlo sensitivity analysis may be useful in studies measuring an epidemiologic proportion (i.e., effectiveness, prevalence, cumulative incidence) while accounting for possible selection or misclassification bias.

Development and validation of prediction models for gestational diabetes treatment modality using supervised machine learning: a population-based cohort study.

BACKGROUND: Gestational diabetes (GDM) is prevalent and benefits from timely and effective treatment, given the short window to impact glycemic control. Clinicians face major barriers to choosing effectively among treatment modalities [medical nutrition therapy (MNT) with or without pharmacologic treatment (antidiabetic oral agents and/or insulin)]. We investigated whether clinical data at varied stages of pregnancy can predict GDM treatment modality. METHODS: Among a population-based cohort of 30,474 pregnancies with GDM delivered at Kaiser Permanente Northern California in 2007-2017, we selected those in 2007-2016 as the discovery set and 2017 as the temporal/future validation set. Potential predictors were extracted from electronic health records at different timepoints (levels 1-4): (1) 1-year preconception to the last menstrual period, (2) the last menstrual period to GDM diagnosis, (3) at GDM diagnosis, and (4) 1 week after GDM diagnosis. We compared transparent and ensemble machine learning prediction methods, including least absolute shrinkage and selection operator (LASSO) regression and super learner, containing classification and regression tree, LASSO regression, random forest, and extreme gradient boosting algorithms, to predict risks for pharmacologic treatment beyond MNT. RESULTS: The super learner using levels 1-4 predictors had higher predictability [tenfold cross-validated C-statistic in discovery/validation set: 0.934 (95% CI: 0.931-0.936)/0.815 (0.800-0.829)], compared to levels 1, 1-2, and 1-3 (discovery/validation set C-statistic: 0.683-0.869/0.634-0.754). A simpler, more interpretable model, including timing of GDM diagnosis, diagnostic fasting glucose value, and the status and frequency of glycemic control at fasting during one-week post diagnosis, was developed using tenfold cross-validated logistic regression based on super learner-selected predictors. This model compared to the super learner had only a modest reduction in predictability [discovery/validation set C-statistic: 0.825 (0.820-0.830)/0.798 (95% CI: 0.783-0.813)]. CONCLUSIONS: Clinical data demonstrated reasonably high predictability for GDM treatment modality at the time of GDM diagnosis and high predictability at 1-week post GDM diagnosis. These population-based, clinically oriented models may support algorithm-based risk-stratification for treatment modality, inform timely treatment, and catalyze more effective management of GDM.

Interactions of agricultural pesticide use near home during pregnancy and adverse childhood experiences on adolescent neurobehavioral development in the CHAMACOS study.

BACKGROUND: Studies have documented independent adverse associations between prenatal and early-life exposure to environmental chemicals and social adversity with child neurodevelopment; however, few have considered these exposures jointly. The objective of this analysis is to examine whether associations of pesticide mixtures and adolescent neurobehavioral development are modified by early-life adversity in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort. METHODS: We used linear mixed effects Bayesian Hierarchical Models (BHM) to examine the joint effect of applications of 11 agricultural pesticides within 1 km of maternal homes during pregnancy and youth-reported Adverse Childhood Experiences (ACEs) with maternal and youth-reported internalizing behaviors, hyperactivity, and attention problems assessed via the Behavior Assessment for Children (BASC) (mean = 50, standard deviation = 10) at ages 16 and 18 years (n = 458). RESULTS: The median (25th-75th percentiles) of ACEs was 1 (0-3); 72.3% of participants had low ACEs (0-2 events) and 27.7% had ACEs (3+ events). Overall, there was little evidence of modification of exposure-outcome associations by ACEs. A two-fold increase in malathion use was associated with increased internalizing behaviors among those with high ACEs from both maternal- (ß = 1.9; 95% Credible Interval (CrI): 0.2, 3.7 for high ACEs vs. ß = -0.1; 95% CrI: 1.2, 0.9 for low ACEs) and youth-report (ß = 2.1; 95% CrI: 0.4, 3.8 for high ACEs vs. ß = 0.2; 95% CrI: 0.8, 1.2 for low ACEs). Applications of malathion and dimethoate were also associated with higher youth-reported hyperactivity and/or inattention among those with high ACEs. CONCLUSION: We observed little evidence of effect modification of agricultural pesticide use near the home during pregnancy and adolescent behavioral problems by child ACEs. Future studies should examine critical windows of susceptibility of exposure to chemical and non-chemical stressors and should consider biomarker-based exposure assessment methods.

Residential proximity to agricultural pesticide use and risk-taking behaviors in young adults from the CHAMACOS study.

BACKGROUND: Prenatal pesticide exposure has been associated with poorer neurodevelopment during childhood, which could lead to greater risk-taking behaviors and delinquency in adolescence. This association may be augmented by adversity exposure. OBJECTIVES: Evaluate the relationship between prenatal pesticide exposure and risk-taking behavior in young adults at 18-years of age. Assess whether adversity exposure modifies these associations. METHODS: Participants included mother-child dyads (n = 467) enrolled in the Center for the Health Assessment of Mothers and Children Of Salinas (CHAMACOS) study, a longitudinal birth cohort set in the agricultural Salinas Valley of California. We estimated agricultural pesticide use within one km of maternal residences during pregnancy using a geographic information system, residential addresses, and California's Pesticide Use Reporting data. We used Bayesian hierarchical regression to evaluate associations of prenatal exposure to a mixture of 11 neurotoxic pesticides with self-reported police encounters, risk-taking behaviors, and unique types and frequency of delinquent acts. We also evaluated effect modification of these relationships by adversity exposure. RESULTS: We observed generally null associations of neurotoxic pesticide use with risk-taking behaviors. Prenatal residential proximity to chlorpyrifos use was associated with higher risk of a police encounter, a delinquent act, and higher incidence of both unique types of acts committed and total frequency of delinquent acts. Prenatal residential proximity to dimethoate use was associated with a higher incidence of police encounters and methomyl with a higher risk of committing a delinquent act. There were no consistent differences when stratified by the number of adverse childhood experiences. CONCLUSIONS: We observed mostly null associations between prenatal residential proximity to agricultural pesticide use and risk-taking behaviors at age 18, with little evidence of effect modification by childhood adversity. There were suggestive associations for chlorpyrifos use with having any police encounter and with all measures of delinquent acts that warrant confirmation in other studies.

Predicting Non-Alcoholic Fatty Liver Disease for Adults Using Practical Clinical Measures: Evidence from the Multi-ethnic Study of Atherosclerosis.

BACKGROUND: Many adults have risk factors for non-alcoholic fatty liver disease (NAFLD). Screening all adults with risk factors for NAFLD using imaging is not feasible. OBJECTIVE: To develop a practical scoring tool for predicting NAFLD using participant demographics, medical history, anthropometrics, and lab values. DESIGN: Cross-sectional. PARTICIPANTS: Data came from 6194 white, African American, Hispanic, and Chinese American participants from the Multi-Ethnic Study of Atherosclerosis cohort, ages 45-85 years. MAIN MEASURES: NAFLD was identified by liver computed tomography (≤ 40 Hounsfield units indicating > 30% hepatic steatosis) and data on 14 predictors was assessed for predicting NAFLD. Random forest variable importance was used to identify the minimum subset of variables required to achieve the highest predictive power. This subset was used to derive (n = 4132) and validate (n = 2063) a logistic regression-based score (NAFLD-MESA Index). A second NAFLD-Clinical Index excluding laboratory predictors was also developed. KEY RESULTS: NAFLD prevalence was 6.2%. The model included eight predictors: age, sex, race/ethnicity, type 2 diabetes, smoking history, body mass index, gamma-glutamyltransferase (GGT), and triglycerides (TG). The NAFLD-Clinical Index model excluded GGT and TG. In the NAFLD-MESA model, the derivation set achieved an AUCNAFLD-MESA = 0.83 (95% CI, 0.81 to 0.86), and the validation set an AUCNAFLD-MESA = 0.80 (0.77 to 0.84). The NAFLD-Clinical Index model was AUCClinical = 0.78 [0.75 to 0.81] in the derivation set and AUCClinical = 0.76 [0.72 to 0.80] in the validation set (pBonferroni-adjusted < 0.01). CONCLUSIONS: The two models are simple but highly predictive tools that can aid clinicians to identify individuals at high NAFLD risk who could benefit from imaging.

Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.

Abdominal and gluteofemoral size and risk of liver cancer: The liver cancer pooling project.

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to <25 kg/m2 ; HR = 1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR = 1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR = 0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements.

The association between diet quality and cancer incidence of the head and neck.

The association between diet quality and head and neck cancer (HNC) was explored using a population-based case-control study of 1170 HNC cases and 1303 age-, race-, and sex-matched controls from the United States. Diet quality was assessed with three diet quality scores (DQS): (a) Healthy Eating Index 2005 (HEI-2005), (b) Mediterranean Diet Score (MDS), and (c) HNC-specific Mediterranean Diet Score (MDS-HNC), a modified MDS that we developed to be more applicable to HNC. Logistic regression models estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) representing diet quality-incident HNC associations. We examined effect measure modification (EMM) by body mass index (BMI), race, cigarette smoking, and alcohol consumption and associational heterogeneity by HPV-positivity and tumor site. A one standard deviation summary DQS decrement suggested a consistent inverse association (ORs (CIs)) for the HEI-2005, MDS, and MDS-HNC: 1.35 (1.21, 1.50), 1.13 (1.02, 1.25), and 1.17 (1.06, 1.31), respectively. This association did not vary by tumor site or tumor HPV status, though additive EMM by alcohol use and by BMI was observed. Our findings suggest the Mediterranean diet can be used to study HNC in American populations, and that poor diet quality elevates HNC incidence, particularly among alcohol users.

Diabetes and cardiovascular disease mortality among a population-based cohort of women with and without breast cancer.

PURPOSE: We investigated whether the relationship between diabetes and all-cause and CVD-related mortality differed between women with and without breast cancer among a cohort drawn from the same source population. METHODS: We interviewed 1,363 women newly diagnosed with breast cancer in 1996-1997, and 1,358 age-matched women without breast cancer, to assess history of physician-diagnosed diabetes. All-cause (n = 631) and CVD-specific mortality (n = 234) was determined by the National Death Index through 2009. We estimated multivariable-adjusted hazard ratios (HRs) for the rates of all-cause and CVD-specific mortality and, to account for competing causes of death, and subdistribution HRs (sHRs) for risk of CVD-related death. RESULTS: Among women with and without breast cancer, respectively, diabetes was associated with: all-cause mortality [HR (95% CI) 1.52 (1.13, 2.05) and 2.17 (1.46, 3.22)]; CVD-specific deaths [1.74 (1.06, 2.84) and 2.06 (1.11, 3.84)]; and risk of CVD-related death [sHR 1.36 (0.81, 2.27) and 1.79 (0.94, 3.40)]. Differences in effect estimates between women with and without breast cancer did not reach statistical significance (p-interaction > 0.10). CONCLUSION: We found that the positive association between a history of physician-diagnosed diabetes and risk of all-cause and CVD-related mortality is of similar magnitude among a population-based cohort of women with or without breast cancer.

Relationship between inorganic ion distribution, resting membrane potential, and the ΔG' of ATP hydrolysis: a new paradigm.

Cell membrane potential and inorganic ion distributions are currently viewed from a kinetic electric paradigm, which ignores thermodynamics. The resting membrane potential is viewed as a diffusion potential. The 9 major inorganic ions found in blood plasma (Ca2+, Na+, Mg2+, K+, H+, Cl-, HCO3-, H2PO4-, and HPO42-) are distributed unequally across the plasma membrane. This unequal distribution requires the energy of ATP hydrolysis through the action of the Na+-K+ ATPase. The cell resting membrane potential in each of 3 different tissues with widely different resting membrane potentials has been shown to be equal to the Nernst equilibrium potential of the most permeant inorganic ion. The energy of the measured distribution of the 9 major inorganic ions between extra- and intracellular phases was essentially equal to the independently measured energy of ATP hydrolysis, showing that the distribution of these 9 major ions was in near-equilibrium with the ΔG' of ATP. Therefore, thermodynamics does appear to play an essential role in the determination of the cell resting membrane potential and the inorganic ion distribution across the plasma membrane.-Veech, R. L., King, M. T., Pawlosky, R., Bradshaw, P. C., Curtis, W. Relationship between inorganic ion distribution, resting membrane potential, and the ΔG' of ATP hydrolysis: a new paradigm.

A Bayesian Sensitivity Analysis to Partition Body Mass Index Into Components of Body Composition: An Application to Head and Neck Cancer Survival.

Previous studies have suggested a "J-shaped" relationship between body mass index (BMI, calculated as weight (kg)/height (m)2) and survival among head and neck cancer (HNC) patients. However, BMI is a vague measure of body composition. To provide greater resolution, we used Bayesian sensitivity analysis, informed by external data, to model the relationship between predicted fat mass index (FMI, adipose tissue (kg)/height (m)2), lean mass index (LMI, lean tissue (kg)/height (m)2), and survival. We estimated posterior median hazard ratios and 95% credible intervals for the BMI-mortality relationship in a Bayesian framework using data from 1,180 adults in North Carolina with HNC diagnosed between 2002 and 2006. Risk factors were assessed by interview shortly after diagnosis and vital status through 2013 via the National Death Index. The relationship between BMI and all-cause mortality was convex, with a nadir at 28.6, with greater risk observed throughout the normal weight range. The sensitivity analysis indicated that this was consistent with opposing increases in risk with FMI (per unit increase, hazard ratio = 1.04 (1.00, 1.08)) and decreases with LMI (per unit increase, hazard ratio = 0.90 (0.85, 0.95)). Patterns were similar for HNC-specific mortality but associations were stronger. Measures of body composition, rather than BMI, should be considered in relation to mortality risk.

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

BACKGROUND: The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS: Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions. RESULTS: All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null. CONCLUSIONS: The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.

The "great" controlling nucleotide coenzymes.

Nucleotide coenzymes dot the map of metabolic pathways providing energy to drive the reactions of the pathway and play an important role in regulating and controlling energy metabolism through their shared potential energy, which is widely unobserved due to the paradox that the energy in the coenzyme pools cannot be determined from the concentration of the coenzyme couples. The potential energy of the nucleotide couples in the mitochondria or the cytoplasm is expressed in the enzyme reactions in which they take part. The energy in these couples, [NAD+]/[NADH], [NADP+]/[NADPH], [acetyl CoA]/[CoA], and [ATP]/[ADP]x[Pi], regulates energy metabolism. The energy contained in the couples can be altered by suppling energy equivalents in the form of ketones, such as, D-ß-hydroxybutyrate to overcome insulin resistance, to restore antioxidants capacity, to form potential treatments for Alzheimer's and Parkinson's diseases, to enhance life span, and to increase physiological performance. © 2019 IUBMB Life, 71(5):565-579, 2019.

Effects of a high protein diet and liver disease in an in silico model of human ammonia metabolism.

BACKGROUND: After proteolysis, the majority of released amino acids from dietary protein are transported to the liver for gluconeogenesis or to peripheral tissues where they are used for protein synthesis and eventually catabolized, producing ammonia as a byproduct. High ammonia levels in the brain are a major contributor to the decreased neural function that occurs in several pathological conditions such as hepatic encephalopathy when liver urea cycle function is compromised. Therefore, it is important to gain a deeper understanding of human ammonia metabolism. The objective of this study was to predict changes in blood ammonia levels resulting from alterations in dietary protein intake, from liver disease, or from partial loss of urea cycle function. METHODS: A simple mathematical model was created using MATLAB SimBiology and data from published studies. Simulations were performed and results analyzed to determine steady state changes in ammonia levels resulting from varying dietary protein intake and varying liver enzyme activity levels to simulate liver disease. As a toxicity reference, viability was measured in SH-SY5Y neuroblastoma cells following differentiation and ammonium chloride treatment. RESULTS: Results from control simulations yielded steady state blood ammonia levels within normal physiological limits. Increasing dietary protein intake by 72% resulted in a 59% increase in blood ammonia levels. Simulations of liver cirrhosis increased blood ammonia levels by 41 to 130% depending upon the level of dietary protein intake. Simulations of heterozygous individuals carrying a loss of function allele of the urea cycle carbamoyl phosphate synthetase I (CPS1) gene resulted in more than a tripling of blood ammonia levels (from roughly 18 to 60 µM depending on dietary protein intake). The viability of differentiated SH-SY5Y cells was decreased by 14% by the addition of a slightly higher amount of ammonium chloride (90 µM). CONCLUSIONS: Data from the model suggest decreasing protein consumption may be one simple strategy to decrease blood ammonia levels and minimize the risk of developing hepatic encephalopathy for many liver disease patients. In addition, the model suggests subjects who are known carriers of disease-causing CPS1 alleles may benefit from monitoring blood ammonia levels and limiting the level of protein intake if ammonia levels are high.

Breast Cancer Incidence and Exposure to Metalworking Fluid in a Cohort of Female Autoworkers.

Breast cancer is the leading cancer diagnosed among women, and environmental studies have produced few leads on modifiable risk factors for breast cancer. Following an Institute of Medicine recommendation for occupational studies of women highly exposed to potential breast cancer risk factors, we took advantage of an existing cohort of 4,503 female autoworkers in Michigan exposed to metalworking fluid (MWF), complex mixtures of oils and chemicals widely used in metal manufacturing worldwide. Cox proportional hazards models were fit to estimate hazard ratios for incident breast cancer (follow-up, 1985-2013) and cumulative exposure (20-year lag) to straight mineral oils (a known human carcinogen) and water-based soluble and synthetic MWF. Because the state cancer registry began decades after the cohort was defined, we restricted our analyses to subcohorts of women hired closer to the start of follow-up. Among those hired after 1969, the hazard ratio associated with a 1 interquartile-range increase in straight MWF exposure was 1.13 (95% confidence interval: 1.03, 1.23). In separate analyses of premenopausal breast cancer, defined by age at diagnosis, the hazard ratio was elevated for exposure to synthetic MWF (chemical lubricants with no oil content), possibly suggesting a different mechanism in the younger women with breast cancer. This study adds to the limited literature regarding quantitative chemical exposures and breast cancer risk.

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients.

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post-mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease.