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OBJECTIVE: Investigate associations of early-life residence and school segregation with cognitive change in the Minority Aging Research Study. METHODS: Four hundred ninety-eight blacks (age ~ 73.5; 75% = women) without dementia at baseline self-reported State of birth, residence at age 12, and school segregation status. Census Bureau definitions of South and Northeast/Midwest were used to categorize early-life residence. We evaluated global cognition and five cognitive domains at baseline and annually for ~7.5 years. Linear mixed effects models examined the associations of region of birth and residence at age 12 with baseline level and longitudinal change in cognition. Additional models examined school segregation experience. RESULTS: ~65% of Southern-born participants still lived in the South at age 12. Southern birth was associated with lower baseline global cognition and all cognitive domains (p-values ≤ .02) compared to Northern birth, but not cognitive change. A similar profile was seen for Southern residence at age 12. Segregation experience significantly modified associations of residence at age 12 on levels of cognition. Participants residing in the South attending a legally desegregated school demonstrated lower baseline levels of cognition (global, semantic, and working memory) than their Northeast/Midwest counterparts attending a legally desegregated or segregated school as well as their Southern counterparts attending a legally segregated school. This profile for participants attending a desegregated school in the South held for processing speed and visuospatial ability in comparisons to Northeast/Midwest counterparts, particularly those attending a legally desegregated school. CONCLUSION: Baseline cognition was poorer in individuals born and residing in the South, particularly those attending desegregated schools at age 12.

BackgroundThe most efficient approach for establishing family histories (FHs) asks informants about disorders in their relatives (a Family History Method [FHM]). However, FHMs underestimate family diagnoses. We evaluated if accuracies of young adult offspring report of their father's alcohol use disorders (AUDs) related to the age, sex, education, and/or substance-related patterns/problems of either the young adult informants or their AUD fathers.MethodsData from the San Diego Prospective Study (SDPS), a multigenerational 35-year investigation, compared father/offspring pairs where the proband father's alcohol problems were correctly (Group 1) or incorrectly (Group 2) noted by offspring. In the key analysis, Group 1 versus 2 results were entered into bootstrapped backward logistic regression analyses predicting Group 1 membership.ResultsFive proband and one offspring characteristic were associated with correct identification of their father's alcohol problems. None of these related to age, education, or sex. Characteristics associated with correct FHM diagnoses included the father's FH of AUDs, self-report of drinking despite social/interpersonal or physical/psychological alcohol-related problems, spending much time related to alcohol, and his having a religious preference. The single offspring item predicting correct identification of the father's problems was the number of DSM alcohol problems of the offspring.ConclusionsIn the SDPS, FHM sensitivity was most closely related to the father's drinking characteristics, not the offspring characteristics. While unique aspects of SDPS families potentially limit generalizability of results, the data demonstrate how the FHM can offer important initial steps in the search for genetically related AUD risks in a subset of families.

BackgroundExposure to household air pollution is associated with an increased risk of pneumonia in children in low- and middle-income countries; however, exposure-response data are limited, and there are uncertainties around the extent to which biomass-fueled cookstoves can reduce these exposures.Research questionWhat is the association between exposure to household air pollution and pneumonia in children under the age of 5 years in rural Malawi and what are the effects of a biomass-fueled cookstove intervention on personal exposure to household air pollution?Study design and methodsWe measured personal exposure to carbon monoxide (CO; 48 hours of continuous measurement and transcutaneous carboxyhemoglobin) every 6 months in children who participated in a cluster-randomized controlled trial of a cleaner burning biomass-fueled cookstove intervention to prevent pneumonia in children under the age of 5 years in rural Malawi (the Cooking And Pneumonia Study). Exposure-response and multivariable analyses were done.ResultsWe recruited 1805 (928 intervention; 877 control) children (mean age, 25.6 months; 50.6% female). We found no evidence of an association between exposure to CO (incident rate ratio, 1.0; 95% CI, 0.967 to 1.014; P = .53) or carboxyhemoglobin (incident rate ratio, 1.00; 95% CI, 0.993 to 1.003; P = .41) in children who experienced pneumonia vs those who did not. Median exposure to CO in the intervention and control groups was was 0.34 (interquartile range, 0.15 to 0.81) and 0.37 parts per million (interquartile range, 0.15 toa 0.97), respectively. The group difference in means was 0.46 (95% CI, -0.95 to 0.012; P = .06).InterpretationExposure to CO in our population was low with no association seen between exposure to CO and pneumonia incidence and no effect of the Cooking And Pneumonia Study intervention on these exposures. These findings suggest that CO may not be an appropriate measure of household air pollution exposure in settings such as rural Malawi and that there is a need to develop ways to measure particulate matter exposures directly in young children instead.Clinical trial registrationISRCTN59448623.

BackgroundSquamous cell carcinoma of the anus (SCCA) incidence is rising in the United States. Study of incidence trends by stage at diagnosis, age-specific and birth cohort patterns, and trends in mortality could provide evidence for a true increase and etiological clues for the increase in incidence.MethodsUsing the US Cancer Statistics dataset, we examined trends in SCCA incidence (2001-2015) and mortality (2001-2016) rates. Join-point regression was used to compute annual and average annual percentage change (AAPC). Incidence patterns by 5-year age group and birth cohort were evaluated using incidence rate ratios (IRRs) and age-period-cohort modeling.ResultsSCCA incidence increased 2.7% per year (95% confidence interval [CI] = 2.1% to 3.3%), with pronounced increases in age groups 50 years and older. Distant-stage SCCA incidence tripled (AAPC = 8.6%, 95% CI = 5.4% to 12.0%, among men and AAPC = 7.5%, 95% CI = 4.8% to 10.2%, among women) and regional-stage SCCA incidence nearly doubled (AAPC = 4.7% for men and women) in both sexes; the AAPC for localized stage was 1.3% (95% CI = 0.6% to 2.0%) in men and 2.3% (95% CI = 1.8% to 2.8%) in women. Compared with adults born circa 1946, recently born black men (born circa 1986) had a nearly fivefold higher risk (IRR = 4.7, 95% CI = 2.1 to 10.2) of SCCA, and the risk doubled among white men (IRR = 2.0, 95% CI = 1.7 to 2.2) and white women (IRR = 2.1, 95% CI = 1.9 to 2.3) born after circa 1960. Anal cancer mortality rates increased 3.1% per year (95% CI = 2.6% to 3.5%) with statistically significant increases in age groups 50 years and older. SCCA incidence-based mortality increased 1.9% annually (95% CI = 0.5% to 3.4%), with a notable (4.9%, 95% CI = 2.4% to 7.3%, per year) rise in adults ages 60-69 years.ConclusionThe increase in SCCA incidence, particularly advanced-stage disease, and a similar increase in mortality suggest a true increase in the occurrence of SCCA. Future research and improved prevention are urgently needed to mitigate the increasing disease burden.

Background & aimsColorectal cancer (CRC) incidence and mortality are increasing among persons younger than 50 years old in the United States, but risk factors associated with early-onset CRC (EOCRC) have not been widely studied.MethodsWe conducted a case-control study of US veterans 18 to 49 years old who underwent colonoscopy examinations from 1999 through 2014. EOCRC cases were identified from a national cancer registry; veterans who were free of CRC at their baseline colonoscopy through 3 years of follow-up were identified as controls. We collected data on age, sex, race/ethnicity, body weight, body mass index (BMI), diabetes, smoking status, and aspirin use. Multivariate-adjusted EOCRC odds were estimated for each factor, with corresponding 95% confidence interval (CI) values.ResultsOur final analysis included 651 EOCRC cases and 67,416 controls. Median age was 45.3 years, and 82.3% were male. Higher proportions of cases were older, male, current smokers, nonaspirin users, and had lower BMIs, compared with controls (P < .05). In adjusted analyses, increasing age and male sex were significantly associated with increased risk of EOCRC, whereas aspirin use and being overweight or obese (relative to normal BMI) were significantly associated with decreased odds of EOCRC. In post hoc analyses, weight loss of 5 kg or more within the 5-year period preceding colonoscopy was associated with higher odds of EOCRC (odds ratio 2.23; 95% CI 1.76-2.83).ConclusionsIn a case-control study of veterans, we found increasing age and male sex to be significantly associated with increased risk of EOCRC, and aspirin use to be significantly associated with decreased risk; these factors also affect risk for CRC onset after age 50. Weight loss may be an early clinical sign of EOCRC. More intense efforts are required to identify the factors that cause EOCRC and signs that can be used to identify individuals at highest risk.

BackgroundRising prevalence of overweight/obesity (OWOB) alongside persistent micronutrient deficiencies suggests many women face concomitant OWOB and undernutrition.ObjectivesWe aimed to 1) describe the prevalence of the double burden of malnutrition (DBM) among nonpregnant women of reproductive age, defined as intraindividual OWOB and either ≥1 micronutrient deficiency [micronutrient deficiency index (MDI) > 0; DBM-MDI] or anemia (DBM-anemia); 2) test whether the components of the DBM were independent; and 3) identify factors associated with DBM-MDI and DBM-anemia.MethodsWith data from 17 national surveys spanning low- and middle-income countries (LMICs) and high-income countries from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia project (n = 419 to n = 9029), we tested independence of over- and undernutrition using the Rao-Scott chi-square test and examined predictors of the DBM and its components using logistic regression for each survey.ResultsMedian DBM-MDI was 21.9% (range: 1.6%-39.2%); median DBM-anemia was 8.6% (range: 1.0%-18.6%). OWOB and micronutrient deficiencies or anemia were independent in most surveys. Where associations existed, OWOB was negatively associated with micronutrient deficiencies and anemia in LMICs. In 1 high-income country, OWOB women were more likely to experience micronutrient deficiencies and anemia. Age was consistently positively associated with OWOB and the DBM, whereas the associations with other sociodemographic characteristics varied. Higher socioeconomic status tended to be positively associated with OWOB and the DBM in LMICs, whereas in higher-income countries the association was reversed.ConclusionsThe independence of OWOB and micronutrient deficiencies or anemia within individuals suggests that these forms of over- and undernutrition may have unique etiologies. Decision-makers should still consider the prevalence, consequences, and etiology of the individual components of the DBM as programs move towards double-duty interventions aimed at addressing OWOB and undernutrition simultaneously.

This paper describes a study to estimate absorbed doses to various organs from film-based chest radiographs and their uncertainties in the periods 1930 to 1948, 1949 to 1955, and 1956 to 1969. Estimated organ doses will be used in new analyses of risks of cancer and other diseases in tuberculosis patients in Canada who had chest fluoroscopic and radiographic examinations in those periods. In this paper, doses to lungs, female breast, active bone marrow, and heart from a single chest radiograph in adults and children of ages 1, 5, 10, and 15 y in the Canadian cohort and their uncertainties are estimated using (1) data on the tube voltage (kV), total filtration (mm Al), tube-current exposure-time product (mA s), and tube output (mR [mA s]) in each period; (2) assumptions about patient orientation, distance from the source to the skin of a patient, and film size; and (3) new calculations of sex- and age-specific organ dose conversion coefficients (organ doses per dose in air at skin entrance). Variations in estimated doses to each organ across the three periods are less than 20% in adults and up to about 30% at younger ages. Uncertainties in estimated organ doses are about a factor of 2 to 3 in adults and up to a factor of 4 at younger ages and are due mainly to uncertainties in the tube voltage and tube-current exposure-time product.

Chronic stress can accelerate biological aging, offering one mechanism through which stress may increase age-related disease risk. Chronic activation of the sympathoadrenal system increases cellular energy production, resulting in cell stress that can initiate cellular senescence, a permanent state of cell growth arrest. Our previous research linked psychosocial stress with increased expression of senescence marker p16INK4a; however, less is known about the role of protective psychosocial factors in biological aging. We examined relationship closeness (perceived interconnectedness with one's spouse) as a protective buffer of the effects of stress on expression of the p16INK4a-encoding gene (CDKN2A) and transcription control pathways activated under cell stress. Seventy parents (Mage=43.2) completed interview-based and questionnaire measures of psychosocial stress and relationship closeness. Blood samples assessed CDKN2A expression and inferred activity of a priori-selected transcription factors Nrf2 and heat shock factors (HSFs) via genome-wide transcriptome profiling. Random intercept models adjusting for age, sex, and ethnicity/race revealed that perceived stress was associated with elevated CDKN2A expression for parents with low but not high closeness. Secondary bioinformatics analyses linked the interaction of perceived stress and relationship closeness to Nrf2 and HSF-1 activity. Findings identify relationship closeness as a protective factor that may buffer the impact of stress on cellular stress and senescence pathways.

Sepsis is the primary cause of burn-related mortality and morbidity. Traditional indicators of sepsis exhibit poor performance when used in this unique population due to their underlying hypermetabolic and inflammatory response following burn injury. To address this challenge, we developed the Machine Intelligence Learning Optimizer (MILO), an automated machine learning (ML) platform, to automatically produce ML models for predicting burn sepsis. We conducted a retrospective analysis of 211 adult patients (age ≥ 18 years) with severe burn injury (≥ 20% total body surface area) to generate training and test datasets for ML applications. The MILO approach was compared against an exhaustive "non-automated" ML approach as well as standard statistical methods. For this study, traditional multivariate logistic regression (LR) identified seven predictors of burn sepsis when controlled for age and burn size (OR 2.8, 95% CI 1.99-4.04, P = 0.032). The area under the ROC (ROC-AUC) when using these seven predictors was 0.88. Next, the non-automated ML approach produced an optimal model based on LR using 16 out of the 23 features from the study dataset. Model accuracy was 86% with ROC-AUC of 0.96. In contrast, MILO identified a k-nearest neighbor-based model using only five features to be the best performer with an accuracy of 90% and a ROC-AUC of 0.96. Machine learning augments burn sepsis prediction. MILO identified models more quickly, with less required features, and found to be analytically superior to traditional ML approaches. Future studies are needed to clinically validate the performance of MILO-derived ML models for sepsis prediction.

We apply a new quantitative method for investigating how children's exploration changes across age in order to gain insight into how exploration unfolds over the course of a human life from a life-history perspective. In this study, different facets of exploratory play were quantified using a novel touchscreen environment across a large sample and wide age range of children in the USA (n = 105, ages = 1 year and 10 months to 12 years and 2 months). In contrast with previous theories that have suggested humans transition from more exploratory to less throughout maturation, we see children transition from less broadly exploratory as toddlers to more efficient and broad as adolescents. Our data cast doubt on the picture of human life history as involving a linear transition from more curious in early childhood to less curious with age. Instead, exploration appears to become more elaborate throughout human childhood. This article is part of the theme issue 'Life history and learning: how childhood, caregiving and old age shape cognition and culture in humans and other animals'.

Natural selection has evidently mediated many species characteristics relevant to the evolution of learning, including longevity, length of the juvenile period, social organization, timing of cognitive and motor development, and age-related shifts in behavioural propensities such as activity level, flexibility in problem-solving and motivation to seek new information. Longitudinal studies of wild populations can document such changes in behavioural propensities, providing critical information about the contexts in which learning strategies develop, in environments similar to those in which learning strategies evolved. The Lomas Barbudal Monkey Project provides developmental data for the white-faced capuchin, Cebus capucinus, a species that has converged with humans regarding many life-history and behavioural characteristics. In this dataset, focused primarily on learned aspects of foraging behaviour, younger capuchins are more active overall, more curious and opportunistic, and more prone to inventing new investigative and foraging-related behaviours. Younger individuals more often seek social information by watching other foragers (especially older foragers). Younger individuals are more creative, playful and inventive, and less neophobic, exhibiting a wider range of behaviours when engaged in extractive foraging. Whereas adults more often stick with old solutions, younger individuals often incorporate recently acquired experience (both social and asocial) when foraging. This article is part of the theme issue 'Life history and learning: how childhood, caregiving and old age shape cognition and culture in humans and other animals'.

Emotion regulation (ER) substantially develops during the childhood years. This growth includes an increasing awareness that certain ER strategies are more appropriate in some contexts than others, but few studies have explored how children tailor ER strategies across contexts (i.e. context sensitivity). Understanding this could help clarify why some children have difficulties effectively regulating their emotions even when they have a broad strategy repertoire. The current study explored differences in Hispanic children's ER strategy context sensitivity across three emotions and explored attentional control as a possible moderator of this sensitivity. Children (N = 78; M = 9.91; SD = 1.14; 50% girls; household income M = 31-40k) completed an attentional control task and were interviewed about their ER strategy preferences for sadness, fear, and anger. Context sensitivity was measured as the proportion of endorsed ER strategies that theoretically "fit" the given emotion. Children showed more sensitivity for anger and fear compared to sadness. Attentional control predicted context sensitivity for sadness only, but this was qualified by age. Older children showed more context sensitivity with increasing attentional control. Findings provide insight into emotional development in late childhood by highlighting children's awareness of the context-appropriate nature of ER strategies across emotions.

BackgroundInitiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC.MethodsThe authors conducted a population-based, case-control study of individuals aged 40 to 49 years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied.ResultsFamily history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49 years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis.ConclusionsOf CRC cases aged 40 to 49 years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

Two HIV virologic control advances are in various stages of development, including long-acting antiretroviral therapy (ART) formulations and strategies aimed at sustained ART-free HIV control. Perceptions of risks and benefits toward HIV virologic control strategies may be different based on an individual's age due to differing experiences of the impacts of the domestic HIV epidemic, altruistic attitudes toward research participation, and general levels of engagement in health care. We examined preferences of HIV virologic control strategies by age groups. In 2018, we conducted a nationwide, online cross-sectional survey to examine differences in HIV virologic control strategies among a sample of people living with HIV who were

BackgroundSubjective cognitive decline (SCD) may represent a low-burden indicator of dementia risk. The value of SCD as a proxy marker, however, depends on the consistency of associations between subjective and objective cognitive measures across sociodemographic and psychological factors.MethodsWe evaluated baseline data from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study (n=1615). SCD was measured using the 12-item Everyday Cognition (ECog) scale. Using linear regression models with interaction terms, we evaluated 6 potential modifiers (age, sex, race/ethnicity, educational attainment, family history of dementia, and depressive symptoms) of the association between cognitive performance (episodic memory, executive function) and SCD.ResultsLower episodic memory and executive function scores were associated with higher log(ECog scores) (more SCD). Older age and elevated depressive symptoms were associated with higher log(ECog scores). Age (interaction P=0.002) and education (interaction P=0.01) modified the association between executive function and log(ECog scores). Specifically, associations between executive function and log(ECog scores) were stronger among participants with more education and less pronounced among older participants.ConclusionsThe association between cognitive performance and log(ECog scores) differed little across sociodemographic and psychological factors. SCD as measured by the ECog may be a valuable proxy for cognitive performance in diverse older adults.

Interoceptive awareness (IA), or the awareness of internal body states, is known to be impaired in individuals with eating disorders (EDs); however, little is understood about how IA and ED symptoms are connected. Network analysis is a statistical approach useful for examining how symptoms interrelate and how comorbidities may be maintained. The present study used network analysis to (1) test central symptoms within an IA-ED network, (2) identify symptoms that may bridge the association between IA and ED symptoms, and (3) explore whether central and bridge symptoms predict ED remission at discharge from intensive treatment. A regularized partial correlation network was estimated in a sample of 428 adolescent (n = 187) and adult (n = 241) ED patients in a partial hospital program. IA was assessed using items from the Multidimensional Assessment of Interoceptive Awareness, and ED symptoms were assessed using items from the Eating Disorder Examination-Questionnaire. Central symptoms within the network were strong desire to lose weight, feeling guilty, and listening for information from the body about emotional state. The most central symptom bridging IA and ED symptoms was (not) feeling safe in one's body. Of the central symptoms, greater desire to lose weight predicted lower likelihood of remission at treatment discharge. Bridge symptoms did not significantly predict remission. Body mistrust may be a mechanism by which associations between IA and EDs are maintained. Findings suggest targeting central and bridge symptoms may be helpful to improve IA and ED symptoms. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

ObjectiveTargeted testing and treatment of persons with latent tuberculosis infection (LTBI) is a critical component of the US tuberculosis (TB) elimination strategy. In January 2016, the California Department of Public Health issued a tool and user guide for TB risk assessment (California tool) and guidance for LTBI testing, and in September 2016, the US Preventive Services Task Force (USPSTF) issued recommendations for LTBI testing in primary care settings. We estimated the epidemiologic effect of adherence to both recommendations in California.MethodsWe used an individual-based Markov micro-simulation model to estimate the number of cases of TB disease expected through 2026 with baseline LTBI strategies compared with implementation of the USPSTF or California tool guidance. We estimated the risk of LTBI by age and country of origin, the probability of being in a targeted population, and the probability of presenting for primary care based on available data. We assumed 100% adherence to testing guidance but imperfect adherence to treatment.ResultsImplementation of USPSTF and California tool guidance would result in nearly identical numbers of tests administered and cases of TB disease prevented. Perfect adherence to either recommendation would result in approximately 7000 cases of TB disease averted (40% reduction compared with baseline) by 2026. Almost all of this decline would be driven by a reduction in the number of cases among non-US-born persons.ConclusionsBy focusing on the non-US-born population, adherence to LTBI testing strategies recommended by the USPSTF and the California tool could substantially reduce the burden of TB disease in California in the next decade.

BackgroundWe examined cross-sectional associations between dietary patterns, macronutrient intake, and measures of muscle mass and lean mass in older men.MethodsParticipants in the Osteoporotic Fractures in Men (MrOS) cohort (n = 903; mean ± SD age 84.2 ± 4 years) completed brief Block food frequency questionnaires (May 2014-May 2016); factor analysis was used to derive dietary patterns. The D3-creatine (D3Cr) dilution method was used to measure muscle mass; dual-energy x-ray absorptiometry (DXA) was used to measure appendicular lean mass (ALM). Generalized linear models were used to report adjusted means of outcomes by dietary pattern. Multiple linear regression models were used to determine associations between macronutrients and D3Cr muscle mass and DXA ALM. Multivariable models were adjusted for age, race, clinic site, education, depression, total energy intake, height, and percent body fat.ResultsGreater adherence to a Western dietary pattern (high factor loadings for red meat, fried foods, and high-fat dairy) was associated with higher D3Cr muscle mass (p-trend = .026). Adherence to the Healthy dietary pattern (high factor loadings for fruit, vegetables, whole grains, and lean meats) was not associated with D3Cr muscle mass or DXA ALM. Total protein (β = 0.09, 95% CI = 0.03, 0.14) and nondairy animal protein (β = 0.16, 95% CI = 0.10, 0.21) were positively associated with D3Cr muscle mass. Nondairy animal protein (β = 0.06, 95% CI = 0.002, 0.11) was positively associated with DXA ALM. Associations with other macronutrients were inconsistent.ConclusionsNondairy animal protein intake (within a Western dietary pattern and alone) was positively associated with D3Cr muscle mass in older men.

Background There are conflicting data regarding the benefit of primary prevention implantable cardioverter-defibrillators (ICDs) in patients with diabetes mellitus and heart failure (HF) with reduced ejection fraction. We aimed to assess the comparative effectiveness of ICD placement in patients with diabetes mellitus and HF with reduced ejection fraction. Methods and Results Data were obtained from the Get With the Guidelines-Health Failure registry, linked with claims from the Centers for Medicare & Medicaid Services. We used a Cox proportional hazards model censored at 5 years with propensity score matching. Of the 17 186 patients with HF with reduced ejection fraction from the Centers for Medicare & Medicaid Services claims database (6540 with diabetes mellitus; 38%), 1677 (646 with diabetes mellitus; 39%) received an ICD during their index HF hospitalization or were prescribed an ICD at discharge. Patients with diabetes mellitus and an ICD (n=646), as compared with those without an ICD (n=1031), were more likely to be younger (74 versus 78 years of age) and have coronary artery disease (68% versus 60%). After propensity matching, ICD use among patients with diabetes mellitus, as compared with those without an ICD, was associated with a reduced risk of all-cause mortality at 5 years after HF discharge (54% versus 59%; multivariable hazard ratio, 0.73; 95% CI, 0.64-0.82; P

As social animals, many primates use acoustic communication to maintain relationships. Vocal individuality has been documented in a diverse range of primate species and call types, many of which have presumably different functions. Auditory recognition of ones neighbors may confer a selective advantage if identifying conspecifics decreases the need to participate in costly territorial behaviors. Alternatively, vocal individuality may be nonadaptive and the result of a unique combination of genetics and environment. Pair-bonded primates, in particular, often participate in coordinated vocal duets that can be heard over long distances by neighboring conspecifics. In contrast to adult calls, infant vocalizations are short-range and used for intragroup communication. Here, we provide two separate but complementary analyses of vocal individuality in distinct call types of coppery titi monkeys (Plecturocebus cupreus) to test whether individuality occurs in call types from animals of different age classes with presumably different functions. We analyzed 600 trill vocalizations from 30 infants and 169 pulse-chirp duet vocalizations from 30 adult titi monkeys. We predicted that duet contributions would exhibit a higher degree of individuality than infant trills, given their assumed function for long-distance, intergroup communication. We estimated 7 features from infant trills and 16 features from spectrograms of adult pulse-chirps, then used discriminant function analysis with leave-one-out cross-validation to classify individuals. We correctly classified infants with 48% accuracy and adults with 83% accuracy. To further investigate variance in call features, we used a multivariate variance components model to estimate variance partitioning in features across two levels: within- and between-individuals. Between-individual variance was the most important source of variance for all features in adults, and three of four features in infants. We show that pulse-chirps of adult titi monkey duets are individually distinct, and infant trills are less individually distinct, which may be due to the different functions of the vocalizations.

IntroductionComprehensive geriatric assessment prior to oncologic surgery can help predict surgical outcomes. We tested whether an abbreviated geriatric assessment tool, the Vulnerable Elderly Surgical Pathways and outcomes Assessment (VESPA), would predict post-operative complications among older adults undergoing oncologic surgery.MethodFrom 2008 to 2011, geriatric assessments were completed using the VESPA tool for patients age ≥ 70 seen in a pre-operative clinic. The VESPA assessed functional status, mood, cognition, and mobility, and can be completed in

Little is known about factors that predict blood pressure (BP) reduction in overweight American Latinos. The aim of this secondary analysis was to explore predictors of changes in mean systolic and diastolic BPs over an 8-week weight loss intervention period in a sample of 54 overweight American Latinos using data collected during the Adelgaza trial. Baseline BP, exercise energy use (in units of metabolic equivalent of task), weight change, average daily intake of calories from beverages, average daily intake of calories from fat, age, and gender were considered as potential predictors of reductions in BP, as measured at baseline, 3, and 8 weeks. Baseline characteristics were as follows: mean age 45.3 (SD = 10.8) years, 31.5% male, 61.1% born in the United States. Mean baseline systolic and diastolic BPs were 122.1 (SD = 14.4) mmHg and 76.6 (SD = 9.8) mmHg, respectively. Both baseline systolic and diastolic BPs predicted reductions in systolic BP after adjusting for other factors (p < .001). None of the nine variables predicted reductions in diastolic BP (p > .05). This finding suggests that overweight American Latinos with higher baseline systolic or diastolic BP should be identified and provided with early intervention education to achieve better hypertension management or prevention.

Studies have reported associations between environmental manganese (Mn) exposure and impaired cognition, attention, impulse control, and fine motor function in children. Our recent rodent studies established that elevated Mn exposure causes these impairments. Here, rats were exposed orally to 0, 25, or 50 mg Mn kg-1  day-1 during early postnatal life (PND 1-21) or lifelong to determine whether early life Mn exposure causes heightened behavioral reactivity in the open field, lasting changes in the catecholaminergic systems in the medial prefrontal cortex (mPFC), altered dendritic spine density, and whether lifelong exposure exacerbates these effects. We also assessed astrocyte reactivity (glial fibrillary acidic protein, GFAP), and astrocyte complement C3 and S100A10 protein levels as markers of A1 proinflammatory or A2 anti-inflammatory reactive astrocytes. Postnatal Mn exposure caused heightened behavioral reactivity during the first 5-10 min intervals of daily open field test sessions, consistent with impairments in arousal regulation. Mn exposure reduced the evoked release of norepinephrine (NE) and caused decreased protein levels of tyrosine hydroxylase (TH), dopamine (DA) and NE transporters, and DA D1 receptors, along with increased DA D2 receptors. Mn also caused a lasting increase in reactive astrocytes (GFAP) exhibiting increased A1 and A2 phenotypes, with a greater induction of the A1 proinflammatory phenotype. These results demonstrate that early life Mn exposure causes broad lasting hypofunctioning of the mPFC catecholaminergic systems, consistent with the impaired arousal regulation, attention, impulse control, and fine motor function reported in these animals, suggesting that mPFC catecholaminergic dysfunction may underlie similar impairments reported in Mn-exposed children.

The study of deaf users of signed languages, who often experience delays in primary language (L1) acquisition, permits a unique opportunity to examine the effects of aging on the processing of an L1 acquired under delayed or protracted development. A cohort of 107 congenitally deaf adult signers ages 45-85 years who were exposed to American Sign Language (ASL) either in infancy, early childhood, or late childhood were tested using an ASL sentence repetition test. Participants repeated 20 sentences that gradually increased in length and complexity. Logistic mixed-effects regression with the variables of chronological age (CA) and age of acquisition (AoA) was used to assess sentence repetition accuracy. Results showed that CA was a significant predictor, with increased age being associated with decreased likelihood to reproduce a sentence correctly (odds ratio [OR] = 0.56, p = .010). In addition, effects of AoA were observed. Relative to native deaf signers, those who acquired ASL in early childhood were less likely to successfully reproduce a sentence (OR = 0.42, p = .003), as were subjects who learned ASL in late childhood (OR = 0.27, p < .001). These data show that aging affects verbatim recall in deaf users of ASL and that the age of sign language acquisition has a significant and lasting effect on repetition ability, even after decades of sign language use. These data show evidence for life-span continuity of early life effects. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

ObjectivesThe acute respiratory distress syndrome is common in critically ill patients. Recognition is crucial because acute respiratory distress syndrome is associated with a high mortality rate, and low tidal volume ventilation improves mortality. However, acute respiratory distress syndrome often goes unrecognized. Risk factors for under-recognition and trends over time have not been fully described.DesignRetrospective chart review of patients with acute respiratory distress syndrome from a prospective cohort study of critically ill patients. For each patient's ICU stay, we searched the chart for terms that indicated that acute respiratory distress syndrome was diagnosed, in the differential diagnosis, or treated with low tidal volume ventilation.SettingICUs at a tertiary hospital at the University of California, San Francisco between 2008 and 2016.PatientsCritically ill patients with acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsAcute respiratory distress syndrome was recognized in 70% of patients, and recognition increased from 60% in 2008-2009 to 92% in 2016 (p = 0.004). Use of tidal volumes less than 6.5 mL/kg also increased (p < 0.001) from 20% to 92%. Increased acute respiratory distress syndrome severity (p = 0.01) and vasopressor use (p = 0.04) were associated with greater recognition. Clinician diagnosis of acute respiratory distress syndrome and inclusion of acute respiratory distress syndrome in the differential diagnosis were associated with tidal volumes less than 6.5 mL/kg (51% use of tidal volume ≤ 6.5 mL/kg if acute respiratory distress syndrome recognized vs 15% if not recognized; p = 0.002). Diagnosing acute respiratory distress syndrome was associated with lower tidal volume in multivariate analysis.ConclusionsAlthough acute respiratory distress syndrome recognition and low tidal volume ventilation use have increased over time, they remain less than universal. Clinician recognition of acute respiratory distress syndrome is associated with both systemic and respiratory severity of illness and is also associated with use of low tidal volume ventilation.

This broad literature review considers advances in the study of cranial vault modification with an emphasis on investigations of Andean skeletal remains over the last two decades. I delimit three broad categories of research, building on Verano's synthesis of the state of Andean paleopathology in 1997. These are associations with skeletal pathological conditions, classification and morphology, and social identity. Progress is noted in each of these areas with a particular emphasis on methodological advances in studying morphology as well as the growth of contextualized bioarchaeology and the incorporation of social theory in the consideration of cranial modification as a cultural practice. The article concludes with avenues for future research on head shaping in the Andes specifically and paleopathology more broadly.

BackgroundAn outbreak of COVID-19 in Iran has spread throughout the country. Identifying the epidemiological characteristics of this disease will help to make appropriate decisions and thus control the epidemic. The aim of this study was characterization of the epidemiological features of COVID-19 in Iran.MethodsIn this retrospective study, data related to the epidemiological characteristics of COVID-19 patients admitted to Baqiyatallah Hospital in Tehran, Iran, from 19 February 2020 to 15 April 2020 have been analyzed and reported. Patient characteristics including age, gender and underlying diseases were investigated. Data were collected through patient records. Sex ratio, Case Fatality Rate (CFR) and daily trend of cases were also determined. A multiple logistic regression analysis was also performed to assess affecting factors on mortality.ResultsFrom February 19, 2020 to April 15, 2020, 12870 patients referred to the hospital emergency department, of which 2968 were hospitalized with COVID-19 diagnosis. The majority of cases were in the age group of 50 to 60 years of old. The male-to-female ratio was 1.93:1. A total of 239 deaths occurred among all cases for an overall CFR of 1.85% based on the total number of patients (both outpatient and inpatient) and 8.06% among hospitalized patients. Out of all patients 10.89% had comorbidity. Diabetes, chronic respiratory diseases, hypertension, cardiovascular diseases, chronic Kidney diseases and cancer were the most common comorbidities with 3.81, 2.02 , 1.99 , 1.25, 0.60 and 0.57 %, respectively. Male gender (OR=1.45, 95% CI: 1.08-1.96), older age (OR=1.05, 95% CI: 1.04-1.06) and having underlying diseases (OR=1.53, 95% CI: 1.04-2.24) were significantly associated with mortality.ConclusionsThe results of this study showed that Male gender, older age and having comorbidities were significantly associated with the risk of death among COVID-19 patients. It is important to pay special attention to male elderly patients with underlying diseases.

IntroductionInsufficient physical activity (PA) and obesity-related health conditions have reached epidemic proportions worldwide. Mexican American women (MAW) report low leisure time physical activity. Few studies examine activities beyond leisure time. Qualitative research suggests that partner support influence provides a cultural approach relevant to PA among MAW.MethodThis cross-sectional study used an ecological model to investigate community (the physical environment), interpersonal (partner support, attitudinal familism), and intrapersonal (age, health conditions, acculturation, employment, and body mass index) factors associated with PA among 112 MAW. Community-based participatory research recommendations guided the preparatory phase of the study and the face-to-face interviews. Frequencies and descriptive statistics were computed. Multivariable linear regression analyses were used to examine associations between study variables.ResultsModerate to high PA levels were found based on combined activities performed during leisure time, transportation, household tasks, and occupational duties. Women with greater partner support reported higher PA levels. Although acculturation levels were low among women, those with higher acculturation were found to be more physically active.ConclusionsFuture studies should examine strategies to increase partner support and address acculturation within intervention programs to enhance overall PA among MAW.

BACKGROUND AND OBJECTIVES: Early diagnosis of cerebral palsy (CP) is critical in obtaining evidence-based interventions when plasticity is greatest. In 2017, international guidelines for early detection of CP were published on the basis of a systematic review of evidence. Our study aim was to reduce the age at CP diagnosis throughout a network of 5 diverse US high-risk infant follow-up programs through consistent implementation of these guidelines. METHODS: The study leveraged plan-do-study-act and Lean methodologies. The primary outcome was age at CP diagnosis. Data were acquired during the corresponding 9-month baseline and quarterly throughout study. Balancing measures were clinic no-show rates and parent perception of the diagnosis visit. Clinic teams conducted strengths, weaknesses, opportunities, and threats analyses, process flow evaluations, standardized assessments training, and parent questionnaires. Performance of a 3- to 4-month clinic visit was a critical process step because it included a Hammersmith Infant Neurologic Examination, a General Movements Assessment, and standardized assessments of motor function. RESULTS: The age at CP diagnosis decreased from a weighted average of 19.5 (95% confidence interval 16.2 to 22.8) to 9.5 months (95% confidence interval 4.5 to 14.6), with P = .008; 3- to 4-month visits per site increased from the median (interquartile range) 14 (5.2-73.7) to 54 (34.5-152.0), with P < .001; and no-show rates were not different. Parent questionnaires revealed positive provider perception with improvement opportunities for information content and understandability. CONCLUSIONS: Large-scale implementation of international guidelines for early detection of CP is feasible in diverse high-risk infant follow-up clinics. The initiative was received positively by families and without adversely affecting clinic operational flow. Additional parent support and education are necessary.

BackgroundUltraviolet (UV) exposure may not affect melanoma development equally in different sexes and ages. Whether and how these factors interact with each other in relation to melanoma risk is unknown.ObjectiveThis study attempts to estimate interactions among UV index (UVI), sex, and age in melanoma risk.MethodsMelanoma incidence data were collected from 42 cancer registries. Geographic UVI was collected from local satellite stations. Negative binomial regression models were used to estimate the impact of each risk factor and their interactions.ResultsSex, UVI, and age, as well as interactions between any 2 of these factors, were significantly associated with melanoma risk. In younger age groups, female sex is an independent risk factor for melanoma that is not affected by ambient UV exposure. In older age groups, however, female sex interacts with UV exposure as a risk factor, exhibiting a protective effect. The switching age category is 45 to 49, which correlates with dramatic hormonal changes.LimitationsThe interaction between sex and UVI is measured at an ecologic level.ConclusionsThe interaction between sex and UVI is age dependent. Female sex is an independent risk factor for early-onset melanoma, but female sex also protects against UV-associated melanoma in older age groups.

PurposeSickle cell disease (SCD) is associated with high acute healthcare utilization. The purpose of this study was to examine whether Medicaid expansion in California increased Medicaid enrollment, increased hydroxyurea prescriptions filled, and decreased acute healthcare utilization in SCD.MethodsIndividuals with SCD (≤65 years and enrolled in Medicaid for ≥6 total calendar months any year between 2011 and 2016) were identified in a multisource database maintained by the California Sickle Cell Data Collection Program. We describe trends and changes in Medicaid enrollment, hydroxyurea prescriptions filled, and emergency department (ED) visits and hospital admissions before (2011-2013) and after (2014-2016) Medicaid expansion in California.ResultsThe cohort included 3635 individuals. Enrollment was highest in 2014 and lowest in 2016 with a 2.8% annual decease postexpansion. Although

Purpose/backgroundRE-KINECT (NCT03062033) was designed to assess the presence and impact of possible tardive dyskinesia (TD) in antipsychotic-treated outpatients.Methods/proceduresThe study included adults with 3 or more months of lifetime antipsychotic exposure and 1 or more psychiatric disorder. Based on clinician observation and assessment, patients were assigned to cohort 1 (without involuntary movements or with non-TD involuntary movements) or cohort 2 (with involuntary movements confirmed by clinician as possible TD). Baseline assessments included the following: patient characteristics; location/severity of involuntary movements; and impact of possible TD on health-related quality of life, including the EuroQoL 5-Dimensions 5-Level questionnaire.Findings/resultsOf 739 eligible patients, 204 (27.6%) had clinician-confirmed possible TD (cohort 2). Compared with cohort 1, patients in cohort 2 were significantly older (P < 0.0001), more likely to have schizophrenia or schizoaffective disorder (P < 0.0001) and longer lifetime exposure to antipsychotics (P < 0.0001), and less likely to be working or studying, based on clinician perception (P = 0.0010). Clinician- and patient-rated severity of possible TD movements was significantly correlated in each of 4 body regions (head/face, neck/trunk, upper extremities, lower extremities), for maximum severity in any region, and for total number of affected regions (P < 0.001 for all correlations). For the patient-rated EuroQoL 5-Dimensions 5-Level, the health state visual analog scale score was significantly lower (worse) in cohort 2 versus cohort 1 (66.8 vs 69.7; P = 0.0002), as was the utility index score (0.71 vs 0.76; P < 0.0175).Implications/conclusionsResults from this real-world population indicate that TD occurs frequently and can significantly reduce quality of life in patients with a psychiatric disorder.

COordinated Oral health Promotion (CO-OP) Chicago is a two-arm cluster-randomized trial with a wait-list control. The primary aim is to evaluate the efficacy of an oral health community health worker (CHW) intervention to improve oral health behaviors in low-income, urban children under the age of three years. Exploratory aims will determine cost-effectiveness, and if any CHW intervention impact on child tooth brushing behaviors varies when CHWs are based out of a medical clinic compared to a community setting. This paper describes progress toward achieving these aims. Participating families were recruited from community social service centers and pediatric primary care medical clinics in Cook County, Illinois. Sites were cluster-randomized to CHW intervention or usual services (a wait-list control). The intervention is oral health support from CHWs delivered in four visits to individual families over one year. The trial sample consists of 420 child/caregiver dyads enrolled at the 20 participating sites over 11 months. Participant demographics varied across the sites, but primary outcomes values at baseline did not. Data on brushing frequency, plaque, and other oral health behaviors are collected at three timepoints: baseline, 6-, and 12-months. The primary analysis will assess differences in caregiver-reported child brushing frequency and observed plaque score between the two arms at 12-months. The trial is currently in the active intervention phase. The trial's cluster-randomized controlled design takes a real-world approach by integrating into existing health and social service agencies and collecting data in participant homes. Results will address an important child health disparity. ClinicalTrials.gov identifier: NCT03397589. CLINICAL TRIAL REGISTRATION: University of Illinois at Chicago Protocol Record 2017-1090. National Institutes of Dental & Craniofacial Research of the National Institutes of Health (NIDCR) Protocol Number: 17-074-E. NCT03397589.

ImportanceBetter understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience).ObjectiveTo examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time.Design, setting, an participantsIn this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019.ExposuresStandard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET.Main outcomes and measuresSeparate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable.ResultsA total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to

PurposeTo study cone structure and function in patients with retinitis pigmentosa (RP) owing to mutations in rhodopsin (RHO), expressed in rod outer segments, and mutations in the RP-GTPase regulator (RPGR) gene, expressed in the connecting cilium of rods and cones.MethodsFour eyes of 4 patients with RHO mutations, 5 eyes of 5 patients with RPGR mutations, and 4 eyes of 4 normal subjects were studied. Cone structure was studied with confocal and split-detector adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral-domain optical coherence tomography. Retinal function was measured using a 543-nm AOSLO-mediated adaptive optics microperimetry (AOMP) stimulus. The ratio of sensitivity to cone density was compared between groups using the Wilcoxon rank-sum test.ResultsAOMP sensitivity/cone density in patients with RPGR mutations was significantly lower than normal (P < 0.001) and lower than patients with RHO mutations (P < 0.015), whereas patients with RHO mutations were similar to normal (P > 0.9).ConclusionsRetinal sensitivity/cone density was lower in patients with RPGR mutations than normal and lower than patients with RHO mutations, perhaps because cones express RPGR and degenerate primarily, whereas cones in eyes with RHO mutations die secondary to rod degeneration. High-resolution microperimetry can reveal differences in cone degeneration in patients with different forms of RP.

Background Coronary artery calcium (CAC) is a predictor for the development of cardiovascular disease (CVD) and to a lesser extent cancer. The age- and sex-specific relationship of CAC with CVD and cancer mortality is unknown. Methods and Results Asymptomatic patients aged 40 to 75 years old without known CVD were included from the CAC Consortium. We calculated sex-specific mortality rates per 1000 person-years' follow-up. Using parametric survival regression modeling, we determined the age- and sex-specific CAC score at which the risk of death from CVD and cancer were equal. Among the 59 502 patients included in this analysis, the mean age was 54.9 (±8.5) years, 34% were women, and 89% were white. There were 671 deaths attributable to CVD and 954 deaths attributable to cancer over a mean follow-up of 12±3 years. Among patients with CAC=0, cancer was the leading cause of death, the total mortality rate was low (women, 1.8; men, 1.5), and the CVD mortality rate was exceedingly low for women (0.3) and men (0.3). The age-specific CAC score at which the risk of CVD and cancer mortality were equal had a U-shaped relationship for women, while the relationship was exponential for men. Conclusions The age- and sex-specific relationship of CAC with CVD and cancer mortality differed significantly for women and men. Our age- and sex-specific CAC score provides a more precise estimate and further facilitates the use of CAC as a synergistic tool in strategies for the prediction and prevention of CVD and cancer mortality.

Aging-related chronic inflammation is a risk factor for many human disorders through incompletely understood mechanisms. Aged mice deficient in microRNA (miRNA/miR)-146a succumb to life-shortening chronic inflammation. In this study, we report that miR-155 in T cells contributes to shortened lifespan of miR-146a-/- mice. Using single-cell RNA sequencing and flow cytometry, we found that miR-155 promotes the activation of effector T cell populations, including T follicular helper cells, and increases germinal center B cells and autoantibodies in mice aged over 15 months. Mechanistically, aerobic glycolysis genes are elevated in T cells during aging, and upon deletion of miR-146a, in a T cell miR-155-dependent manner. Finally, skewing T cell metabolism toward aerobic glycolysis by deleting mitochondrial pyruvate carrier recapitulates age-dependent T cell phenotypes observed in miR-146a-/- mice, revealing the sufficiency of metabolic reprogramming to influence immune cell functions during aging. Altogether, these data indicate that T cell-specific miRNAs play pivotal roles in regulating lifespan through their influences on inflammaging.

BackgroundGenome-wide association studies (GWASs) have enriched the fields of genomics and drug development. Adrenocortical carcinoma (ACC) is a rare cancer with a bimodal age distribution and inadequate treatment options. Paediatric ACC is frequently associated with TP53 mutations, with particularly high incidence in Southern Brazil due to the TP53 p.R337H (R337H) germline mutation. The heterogeneous risk among carriers suggests other genetic modifiers could exist.MethodsWe analysed clinical, genotype and gene expression data derived from paediatric ACC, R337H carriers, and adult ACC patients. We restricted our analyses to single nucleotide polymorphisms (SNPs) previously identified in GWASs to associate with disease or human traits.ResultsA SNP, rs971074, in the alcohol dehydrogenase 7 gene significantly and reproducibly associated with allelic differences in ACC age-of-onset in both cohorts. Patients homozygous for the minor allele were diagnosed up to 16 years earlier. This SNP resides in a gene involved in the retinoic acid (RA) pathway and patients with differing levels of RA pathway gene expression in their tumours associate with differential ACC progression.ConclusionsThese results identify a novel genetic component to ACC development that resides in the retinoic acid pathway, thereby informing strategies to develop management, preventive and therapeutic treatments for ACC.

Background: In this study, we sought to determine factors relating to initiating injection drug use before the age of 18 years in Iran.Methods: In this cross-sectional survey, people who inject drugs were recruited using facility-based sampling in 10 cities in Iran in 2014. Adults (≥18 year) who reported injecting drugs at least one time during the last year were included. A structured questionnaire collected behaviors related to injection, sexual risk, and HIV testing. Based on the reported age of first injection, we grouped participants into that initiating injection drug use by before 18-year old versus 18- and after 18-year old.Results: Of 2356 participants, 199 (8.5%, 95% CI 7.4-9.6) started injecting before the age of 18 years. Initiating injection drug use before the age of 18 years were more likely to be

ObjectiveThe present research aimed to better understand deficits in emotion differentiation that accompany depressive symptoms. Depressive symptoms have been associated with more undifferentiated negative emotion experiences-experiencing multiple negative emotions simultaneously. We extend previous research by asking: (a) Are depressive symptoms and negative and positive emotion differentiation related above and beyond emotion intensity? (b) Are deficits in negative emotion differentiation specific to distinct categories of negative emotions (sadness, guilt, anger, and anxiety)? and (c) Do age or gender predict emotion differentiation or its associations with depressive symptoms?MethodIn 220 community participants (59% female; 21-60 years), we assessed depressive symptoms using surveys and emotion differentiation using daily diary emotion ratings in response to daily stressful events.ResultsGreater depressive symptoms were associated with lower negative, but not positive, emotion differentiation, above and beyond emotion intensity. Depressive symptoms were specifically related to lower differentiation among sadness-related emotions, and this sadness-specific deficit accounted for the deficit in negative emotion differentiation. Age and gender did not predict or moderate associations with emotion differentiation.ConclusionDepressive symptoms are associated with undifferentiated negative emotions above and beyond emotion intensity, and this association appears to be driven by undifferentiated sadness-related emotions, across gender and age.

BackgroundReadmissions after exacerbations of chronic obstructive pulmonary disease (COPD) are penalized under the Hospital Readmissions Reduction Program (HRRP). Understanding attributable diagnoses at readmission would improve readmission reduction strategies.ObjectivesDetermine factors that portend 30-day readmissions attributable to COPD versus non-COPD diagnoses among patients discharged following COPD exacerbations.Design, setting, and participantsWe analyzed COPD discharges in the Nationwide Readmissions Database from 2010 to 2016 using inclusion and readmission definitions in HRRP.Main outcomes and measuresWe evaluated readmission odds for COPD versus non-COPD returns using a multilevel, multinomial logistic regression model. Patient-level covariates included age, sex, community characteristics, payer, discharge disposition, and Elixhauser Comorbidity Index. Hospital-level covariates included hospital ownership, teaching status, volume of annual discharges, and proportion of Medicaid patients.ResultsOf 1,622,983 (a weighted effective sample of 3,743,164) eligible COPD hospitalizations, 17.25% were readmitted within 30 days (7.69% for COPD and 9.56% for other diagnoses). Sepsis, heart failure, and respiratory infections were the most common non-COPD return diagnoses. Patients readmitted for COPD were younger with fewer comorbidities than patients readmitted for non-COPD. COPD returns were more prevalent the first two days after discharge than non-COPD returns. Comorbidity was a stronger driver for non-COPD (odds ratio [OR] 1.19) than COPD (OR 1.04) readmissions.ConclusionThirty-day readmissions following COPD exacerbations are common, and 55% of them are attributable to non-COPD diagnoses at the time of return. Higher burden of comorbidity is observed among non-COPD than COPD rehospitalizations. Readmission reduction efforts should focus intensively on factors beyond COPD disease management to reduce readmissions considerably by aggressively attempting to mitigate comorbid conditions.

BACKGROUND: Current guidelines recommend evaluation for underlying heart disease and reversible conditions for patients with new-onset heart failure (HF). There are limited data on contemporary testing for coronary artery disease (CAD) in patients with new-onset HF. METHODS: We performed an observational cohort study using the Get With The Guidelines-Heart Failure registry linked to Medicare claims. All patients were aged ≥65 and hospitalized for new-onset HF from 2009 to 2015. We collected left ventricular ejection fraction (LVEF), prior HF history, and in-hospital CAD testing from the registry, as well as testing for CAD using claims from 90 days before to 90 days after index HF hospitalization. RESULTS: Among 17 185 patients with new-onset HF, 6672 (39%) received testing for CAD, including 3997 (23%) during the index hospitalization. Testing for CAD differed by LVEF: 53% in HF with reduced EF (LVEF ≤40%), 42% in HF with borderline EF (LVEF, 41%-49%), and 31% in HF with preserved EF (LVEF ≥50%). After multivariable adjustment, patients who received testing for CAD, compared with those who did not, were younger and more likely to be male, have a smoking history, have hyperlipidemia, and have HF with reduced ejection fraction or HF with borderline ejection fraction (all P

Targeting mitochondrial ion homeostasis using Kaempferol, a mitochondrial Ca2+ uniporter channel activator, improves energy metabolism and behavior soon after a traumatic brain injury (TBI) in developing rats. Because of broad TBI pathophysiology and brain mitochondrial heterogeneity, Kaempferol-mediated early-stage behavioral and brain metabolic benefits may accrue from diverse sources within the brain. We hypothesized that Kaempferol influences TBI outcome by differentially impacting the neural, vascular, and synaptic/axonal compartments. After TBI at early development (P31), functional magnetic resonance imaging and diffusion tensor imaging (DTI) were applied to determine imaging outcomes at adolescence (2 months post-injury). Vehicle and Kaempferol treatments were made at 1, 24, and 48 h post-TBI, and their effects were assessed at adolescence. A significant increase in neural connectivity was observed after Kaempferol treatment as assessed by the spatial extent and strength of the somatosensory cortical and hippocampal resting-state functional connectivity (RSFC) networks. However, no significant RSFC changes were observed in the thalamus. DTI measures of fractional anisotropy (FA) and apparent diffusion coefficient, representing synaptic/axonal and microstructural integrity, showed significant improvements after Kaempferol treatment, with highest changes in the frontal and parietal cortices and hippocampus. Kaempferol treatment also increased corpus callosal FA, indicating measurable improvement in the interhemispheric structural connectivity. TBI prognosis was significantly altered at adolescence by early Kaempferol treatment, with improved neural connectivity, neurovascular coupling, and parenchymal microstructure in select brain regions. However, Kaempferol failed to improve vasomotive function across the whole brain, as measured by cerebrovascular reactivity. The differential effects of Kaempferol treatment on various brain functional compartments support diverse cellular-level mitochondrial functional outcomes in vivo.

PurposeThe rise of noncigarette, alternative tobacco product (ATP) use among adolescents may be due in part to an increase in retail availability of ATPs. We examined whether proximity and density of tobacco retailers near students' homes are associated with a higher likelihood of initiating ATP use over time.MethodsUsing data from 728 adolescents (aged 13-19 years at baseline) residing in 191 different neighborhoods and attending 10 different California high schools, longitudinal multilevel and cross-classified random effect models evaluated individual-level, neighborhood-level, and school-level risk factors for ATP initiation after 1 year. Covariates were obtained from the American Community Survey and the California Department of Education.ResultsThe sample was predominantly female (63.5%) and was racially and ethnically diverse. Approximately one third of participants (32.5%) reported ever ATP use at baseline, with 106 (14.5%) initiating ATP use within 1 year. The mean number of tobacco retailers per square mile within a tract was 5.66 (standard deviation = 6.3), and the average distance from each participant's residence to the nearest tobacco retailer was .61 miles (standard deviation = .4). Living in neighborhoods with greater tobacco retailer density at baseline was associated with higher odds of ATP initiation (odds ratio = 1.22, 95% confidence interval = 1.07-2.12), controlling for individual and school factors.ConclusionsTobacco retailers clustered in students' home neighborhood may be an environmental influence on adolescents' ATP use. Policy efforts to reduce adolescent ATP use should aim to reduce the density of tobacco retailers and limit the proximity of tobacco retailers near adolescents' homes and schools.

BackgroundLike other cancer epidemiologic cohorts, the California Teachers Study (CTS) has experienced declining participation to follow-up questionnaires; neither the reasons for these declines nor the steps that could be taken to mitigate these trends are fully understood.MethodsThe CTS offered their 6th study questionnaire (Q6) in the fall of 2017 using an integrated, online system. The team delivered a Web and mobile-adaptive questionnaire to 45,239 participants via e-mail using marketing automation technology. The study's integrated platform captured data on recruitment activities that may influence overall response, including the date and time invitations and reminders were e-mailed and the date and time questionnaires were started and submitted.ResultsThe overall response rate was 43%. Participants ages 65 to 69 were 25% more likely to participate than their younger counterparts (OR = 1.25; 95% CI, 1.18-1.32) and nonwhite participants were 28% less likely to participate than non-Hispanic white cohort members (OR = 0.72; 95% CI, 0.68-0.76). Previous questionnaire participation was strongly associated with response (OR = 6.07; 95% CI, 5.50-6.70). Invitations sent after 2 pm had the highest response (OR = 1.75; 95% CI, 1.65-1.84), as did invitations sent on Saturdays (OR = 1.48; 95% CI, 1.36-1.60).ConclusionsAn integrated system that captures paradata about questionnaire recruitment and response can enable studies to quantify the engagement patterns and communication desires of cohort members.ImpactAs cohorts continue to collect scientific data, it is imperative to collect and analyze information on how participants engage with the study.See all articles in this CEBP Focus section, "Modernizing Population Science."

Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated HIV genome persists indefinitely within CD4+ T cells and perhaps other cells. Here, we describe the mechanisms thought to contribute to its persistence during treatment and highlight findings from numerous recent studies describing the importance of cell proliferation in that process. Continued progress elucidating the biology will enhance our ability to develop effective curative interventions.

BackgroundBenzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.MethodsIn this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.FindingsBetween Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.InterpretationChildren, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.FundingNational Institute of Neurological Disorders and Stroke, National Institutes of Health.

BackgroundChildhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.MethodsWithin the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.ResultsCM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.ConclusionsSeverity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.