Pharmacokinetics, Safety, and Tolerability of Cariprazine in Pediatric Patients with Bipolar I Disorder or Schizophrenia.

Objective: Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This sequential-cohort, dose-escalation study was the first to evaluate the pharmacokinetic, safety, and tolerability profile of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), in pediatric patients with schizophrenia or bipolar I disorder. Methods: This phase I open-label study enrolled patients with schizophrenia (13-17 years of age) or bipolar I disorder (10-17 years of age). Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia or bipolar I disorder and had Positive and Negative Syndrome Scale (PANSS) total scores ≥70 or Young Mania Rating Scale (YMRS) total scores ≥20. Patients were assigned to one of four treatment groups to receive 6 weeks of cariprazine treatment through slow titration to 1.5, 3, or 4.5 mg/d or fast titration to 4.5 mg/d. Pharmacokinetics, adverse events (AEs), and various safety parameters were analyzed. Efficacy was evaluated as an exploratory outcome. Results: A total of 50 participants were enrolled. Based on mean trough levels, steady state appeared to be reached within 1-2 weeks for cariprazine and DCAR and within 4-5 weeks for DDCAR. Systemic exposure of cariprazine, DCAR, and DDCAR generally increased approximately in proportion to the increases in dose from 1.5 to 4.5 mg/d. The most frequent treatment-related, treatment-emergent AEs included sedation, parkinsonism, tremor, dystonia, and blurred vision. Improvements from baseline on the PANSS and YMRS were observed throughout treatment. Conclusion: In this first investigation of cariprazine in a pediatric population with schizophrenia or bipolar disorder, pharmacokinetic parameters were consistent with those observed in adults. Cariprazine appeared to be safe and tolerable in children and adolescents.

Assessment of the QuantiFERON-TB Gold In-Tube test for the detection of Mycobacterium tuberculosis infection in United States Navy recruits.

BACKGROUND: Immunologic tests such as the tuberculin skin test (TST) and QuantiFERON®-TB Gold In-Tube test (QFT-GIT) are designed to detect Mycobacterium tuberculosis infection, both latent M. tuberculosis infection (LTBI) and infection manifesting as active tuberculosis disease (TB). These tests need high specificity to minimize unnecessary treatment and high sensitivity to allow maximum detection and prevention of TB. METHODS: Estimate QFT-GIT specificity, compare QFT-GIT and TST results, and assess factor associations with test discordance among U.S. Navy recruits. RESULTS: Among 792 subjects with completed TST and QFT-GIT, 42(5.3%) had TST indurations ≥10mm, 23(2.9%) had indurations ≥15mm, 14(1.8%) had positive QFT-GIT results, and 5(0.6%) had indeterminate QFT-GITs. Of 787 subjects with completed TST and determinate QFT-GIT, 510(64.8%) were at low-risk for infection, 277(35.2%) were at increased risk, and none had TB. Among 510 subjects at low-risk (presumed not infected), estimated TST specificity using a 15mm cutoff, 99.0% (95%CI: 98.2-99.9%), and QFT-GIT specificity, 98.8% (95%CI: 97.9-99.8%), were not significantly different (p>0.99). Most discordance was among recruits at increased risk of infection, and most was TST-positive but QFT-GIT-negative discordance. Of 18 recruits with TST ≥15mm but QFT-GIT negative discordance, 14(78%) were at increased risk. TB prevalence in country of birth was the strongest predictor of positive TST results, positive QFT-GIT results, and TST-positive but QFT-GIT-negative discordance. Reactivity to M. avium purified protein derivative (PPD) was associated with positive TST results and with TST-positive but QFT-GIT-negative discordance using a 10 mm cutoff, but not using a 15 mm cutoff or with QFT-GIT results. CONCLUSIONS: M. tuberculosis infection prevalence was low, with the vast majority of infection occurring in recruits with recognizable risks. QFT-GIT and TST specificities were high and not significantly different. Negative QFT-GIT results among subjects with TST induration ≥15 mm who were born in countries with high TB prevalence, raise concerns.

Accelerometer-measured sedentary time among Hispanic adults: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Excessive sedentary behavior is associated with negative health outcomes independent of physical activity. Objective estimates of time spent in sedentary behaviors are lacking among adults from diverse Hispanic/Latino backgrounds. The objective of this study was to describe accelerometer-assessed sedentary time in a large, representative sample of Hispanic/Latino adults living in the United States, and compare sedentary estimates by Hispanic/Latino background, sociodemographic characteristics and weight categories. This study utilized baseline data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) that included adults aged 18-74 years from four metropolitan areas (N = 16,415). Measured with the Actical accelerometer over 6 days, 76.9% (n = 12,631) of participants had > 10 h/day and > 3 days of data. Participants spent 11.9 h/day (SD 3.0), or 74% of their monitored time in sedentary behaviors. Adjusting for differences in wear time, adults of Mexican background were the least (11.6 h/day), whereas adults of Dominican background were the most (12.3 h/day), sedentary. Women were more sedentary than men, and older adults were more sedentary than younger adults. Household income was positively associated, whereas employment was negatively associated, with sedentary time. There were no differences in sedentary time by weight categories, marital status, or proxies of acculturation. To reduce sedentariness among these populations, future research should examine how the accumulation of various sedentary behaviors differs by background and region, and which sedentary behaviors are amenable to intervention.

Body mass index, sex, and cardiovascular disease risk factors among Hispanic/Latino adults: Hispanic community health study/study of Latinos.

BACKGROUND: All major Hispanic/Latino groups in the United States have a high prevalence of obesity, which is often severe. Little is known about cardiovascular disease (CVD) risk factors among those at very high levels of body mass index (BMI). METHODS AND RESULTS: Among US Hispanic men (N=6547) and women (N=9797), we described gradients across the range of BMI and age in CVD risk factors including hypertension, serum lipids, diabetes, and C-reactive protein. Sex differences in CVD risk factor prevalences were determined at each level of BMI, after adjustment for age and other demographic and socioeconomic variables. Among those with class II or III obesity (BMI ≥35 kg/m(2), 18% women and 12% men), prevalences of hypertension, diabetes, low high-density lipoprotein cholesterol level, and high C-reactive protein level approached or exceeded 40% during the fourth decade of life. While women had a higher prevalence of class III obesity (BMI ≥40 kg/m(2)) than did men (7% and 4%, respectively), within this highest BMI category there was a >50% greater relative prevalence of diabetes, hypertension, and hyperlipidemia in men versus women, while sex differences in prevalence of these CVD risk factors were ≈20% or less at other BMI levels. CONCLUSIONS: Elevated BMI is common in Hispanic/Latino adults and is associated with a considerable excess of CVD risk factors. At the highest BMI levels, CVD risk factors often emerge in the earliest decades of adulthood and they affect men more often than women.

Social relationships and longitudinal changes in body mass index and waist circumference: the coronary artery risk development in young adults study.

Few studies have examined longitudinal associations between close social relationships and weight change. Using data from 3,074 participants in the Coronary Artery Risk Development in Young Adults Study who were examined in 2000, 2005, and 2010 (at ages 33-45 years in 2000), we estimated separate logistic regression random-effects models to assess whether patterns of exposure to supportive and negative relationships were associated with 10% or greater increases in body mass index (BMI) (weight (kg)/height (m)(2)) and waist circumference. Linear regression random-effects modeling was used to examine associations of social relationships with mean changes in BMI and waist circumference. Participants with persistently high supportive relationships were significantly less likely to increase their BMI values and waist circumference by 10% or greater compared with those with persistently low supportive relationships after adjustment for sociodemographic characteristics, baseline BMI/waist circumference, depressive symptoms, and health behaviors. Persistently high negative relationships were associated with higher likelihood of 10% or greater increases in waist circumference (odds ratio = 1.62, 95% confidence interval: 1.15, 2.29) and marginally higher BMI increases (odds ratio = 1.50, 95% confidence interval: 1.00, 2.24) compared with participants with persistently low negative relationships. Increasingly negative relationships were associated with increases in waist circumference only. These findings suggest that supportive relationships may minimize weight gain, and that adverse relationships may contribute to weight gain, particularly via central fat accumulation.

Diet composition and activity level of at risk and metabolically healthy obese American adults.

OBJECTIVE: Obesity often clusters with other major cardiovascular disease risk factors, yet a subset of the obese appears to be protected from these risks. Two obesity phenotypes are described, (i) "metabolically healthy" obese, broadly defined as body mass index (BMI) ≥ 30 kg/m(2) and favorable levels of blood pressure, lipids, and glucose; and (ii) "at risk" obese, BMI ≥ 30 with unfavorable levels of these risk factors. More than 30% of obese American adults are metabolically healthy. Diet and activity determinants of obesity phenotypes are unclear. We hypothesized that metabolically healthy obese have more favorable behavioral factors, including less adverse diet composition and higher activity levels than at risk obese in the multi-ethnic group of 775 obese American adults ages 40-59 years from the International Population Study on Macro/Micronutrients and Blood Pressure (INTERMAP) cohort. DESIGN AND METHODS: In gender-stratified analyses, mean values for diet composition and activity behavior variables, adjusted for age, race, and education, were compared between metabolically healthy and at risk obese. RESULTS: Nearly one in five (149/775 or 19%) of obese American INTERMAP participants were classified as metabolically healthy obese. Diet composition and most activity behaviors were similar between obesity phenotypes, although metabolically healthy obese women reported higher sleep duration than at risk obese women. CONCLUSIONS: These results do not support hypotheses that diet composition and/or physical activity account for the absence of cardiometabolic abnormalities in metabolically healthy obese.

Association of metabolic risk with longitudinal physical activity and fitness: coronary artery risk development in young adults (CARDIA).

BACKGROUND: Despite established relationships between physical activity (PA) or physical fitness (fitness) and metabolic risk, the prospective association is not well understood. The purpose of this study was to determine whether metabolic risk in young adults is associated with 20-year PA or fitness trajectories. METHODS: Young adults were from the Coronary Artery Risk Development in Young Adults (CARDIA) study, baseline ages 18-30 years (n=4161). PA was determined from a self-reported questionnaire administered at baseline and at follow-up exams at years 2, 5, 7, 10, 15, and 20. Fitness (seconds) was estimated from a graded exercise treadmill test at baseline and years 7 and 20. Baseline metabolic risk was calculated using age-adjusted principal components analysis (elevated=top 10% of first factor), for each sex-race group, from mean arterial pressure, glucose, waist circumference, triglycerides, and high-density lipoprotein cholesterol. Repeated measures general linear modeling estimated PA and fitness trajectories over 20 years, separately in sex-race groups, adjusting for age and smoking status. RESULTS: PA was significantly lower among those with elevated metabolic risk compared with normal risk at baseline and each subsequent time point (black and white men, white women; all P<0.0001; black women P=0.27). Significant and consistent results were also found with fitness trajectories for all sex-race groups (P<0.0001). Despite these lower PA and fitness levels at baseline in young adults with elevated metabolic compared with normal risk, 20-year trajectories declined at similar rates. CONCLUSION: Elevated metabolic risk is associated with lower levels of PA and fitness in early adulthood, and these differences persist over 20 years.

Duration of abdominal obesity beginning in young adulthood and incident diabetes through middle age: the CARDIA study.

OBJECTIVE: To examine whether the duration of abdominal obesity determined prospectively using measured waist circumference (WC) is associated with the development of new-onset diabetes independent of the degree of abdominal adiposity. RESEARCH DESIGN AND METHODS: The Coronary Artery Risk Development in Young Adults Study is a multicenter, community-based, longitudinal cohort study of 5,115 white and black adults aged 18-30 years in 1985 to 1986. Years spent abdominally obese were calculated for participants without abdominal obesity (WC >102 cm in men and >88 cm in women) or diabetes at baseline (n = 4,092) and was based upon repeat measurements conducted 2, 5, 7, 10, 15, 20, and 25 years later. RESULTS: Over 25 years, 392 participants developed incident diabetes. Overall, following adjustment for demographics, family history of diabetes, study center, and time varying WC, energy intake, physical activity, smoking, and alcohol, each additional year of abdominal obesity was associated with a 4% higher risk of developing diabetes [hazard ratio (HR) 1.04 (95% CI 1.02-1.07)]. However, a quadratic model best represented the data. HRs for 0, 1-5, 6-10, 11-15, 16-20, and >20 years of abdominal obesity were 1.00 (referent), 2.06 (1.43-2.98), 3.45 (2.28-5.22), 3.43 (2.28-5.22), 2.80 (1.73-4.54), and 2.91 (1.60-5.29), respectively; P-quadratic < 0.001. CONCLUSIONS: Longer duration of abdominal obesity was associated with substantially higher risk for diabetes independent of the degree of abdominal adiposity. Preventing or at least delaying the onset of abdominal obesity in young adulthood may lower the risk of developing diabetes through middle age.

Lower extremity fat mass is associated with insulin resistance in overweight and obese individuals: the CARDIA study.

Lower extremity fat mass (LEFM) has been shown to be favorably associated with glucose metabolism. However, it is not clear whether this relationship is similar across varying levels of obesity. We hypothesized that lower amounts of LEFM is associated with higher insulin resistance (IR) and this association may vary according to weight status. Participants with available measures were examined from the Coronary Artery Risk Development in Young Adults study (CARDIA), a multi-center longitudinal study of the etiology of atherosclerosis in black and white men and women aged 38-50 years old in 2005-2006 (n = 1,579). The homeostasis model assessment of IR (HOMA(IR)) was calculated to estimate IR, regional adiposity was measured using dual energy X-ray absorptiometry (DXA), and weight status was defined according to BMI categories. Obese and overweight participants exhibited higher IR, total fat mass (FM), trunk FM (TFM), and LEFM compared to normal weight participants. After controlling for age, height, race, study center, education, smoking, and cardiorespiratory fitness (CRF), greater LEFM was significantly associated with higher IR only in normal weight men and women. Further adjustment for TFM revealed that lower LEFM was significantly associated with higher IR in overweight and obese men and women and the positive association in normal weight individuals was attenuated. These results suggest that excess adiposity in the lower extremities may attenuate the metabolic risk observed at a given level of abdominal adiposity in overweight and obese individuals. Weight status presents additional complexity since the metabolic influence of adipose tissue may not be homogenous across anatomic regions or level of obesity.

Maintaining a high physical activity level over 20 years and weight gain.

CONTEXT: Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs. OBJECTIVE: To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years. DESIGN, SETTING, AND PARTICIPANTS: The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-1986 to 2005-2006. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multicenter cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline. MAIN OUTCOME MEASURES: Average annual changes in BMI and waist circumference. RESULTS: Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Men maintaining high activity gained 2.6 fewer kilograms (0.15 BMI units per year; 95% confidence interval [CI], 0.11-0.18 vs 0.20 in the lower activity group; 95% CI, 0.17-0.23), and women maintaining higher activity gained 6.1 fewer kilograms (0.17 BMI units per year; 95% CI, 0.12-0.21 vs 0.30 in the lower activity group; 95% CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference (0.52 cm per year; 95% CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95% CI,0.60-0.75 cm) and women maintaining higher activity gained 3.8 fewer centimeters(0.49 cm per year; 95% CI, 0.39-0.58 cm vs 0.67 cm in the lower activity group; 95% CI, 0.60-0.75 cm) [corrected]. CONCLUSION: Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.

Relation of heart rate with cardiovascular disease in normal-weight individuals: the Chicago Heart Association Detection Project in Industry.

The authors investigated the association of resting heart rate (RHR) with cardiovascular disease (CVD) risk factors and mortality among normal-weight individuals. Using data from our cohort (baseline examination in 1967-1973), individuals with a body mass index of 18.5 to 24.9 kg/m(2) (men [n=3724] and women [n=4929] aged 18-39; men [n=1959] and women [n=3735] aged 40-59), were grouped by RHR: <75, 75-84, and > or =85 beats per minute (bpm). A lower RHR was associated with lower mean blood pressure (BP) and cigarette use in each subgroup and total cholesterol (TC) and diabetes in men (P<.05). After a 32-year follow-up, hazard ratios (95% confidence intervals) for CVD mortality for an RHR <75 compared with > or =85 bpm adjusted for age, race, education level, BP, cigarette use, diabetes, and TC were 0.58 (0.34-0.84), 0.73(0.56-0.95), and 0.77 (0.61-0.98) for men aged 18 to 39 and men and women aged 40 to 59, respectively. In women aged 18 to 39, the relationship was not significant. In general, normal-weight individuals with lower RHRs have lower levels of CVD risk factors and mortality.

Detection of Mycobacterium tuberculosis infection in United States Navy recruits using the tuberculin skin test or whole-blood interferon-gamma release assays.

BACKGROUND: Military personnel are at risk for acquiring Mycobacterium tuberculosis infection because of activities in close quarters and in regions with a high prevalence of tuberculosis (TB). Accurate tests are needed to avoid unnecessary treatment because of false-positive results and to avoid TB because of false-negative results and failure to diagnose and treat M. tuberculosis infection. We sought to estimate the specificity of the tuberculin skin test (TST) and 2 whole-blood interferon-gamma release assays (QuantiFERON-TB assay [QFT] and QuantiFERON-TB Gold assay [QFT-G]) and to identify factors associated with test discordance. METHODS: A cross-sectional comparison study was performed in which 856 US Navy recruits were tested for M. tuberculosis infection using the TST, QFT, and QFT-G. RESULTS: Among the study subjects, 5.1% of TSTs resulted in an induration > or = 10 mm, and 2.9% of TSTs resulted in an induration > or = 15 mm. Eleven percent of QFT results and 0.6% of QFT-G results were positive. Assuming recruits at low risk for M. tuberculosis exposure were not infected, estimates of TST specificity were 99.1% (95% confidence interval [CI], 98.3%-99.9%) when a 15-mm cutoff value was used and 98.4% (95% CI, 97.3%-99.4%) when a 10-mm cutoff value was used. The estimated QFT specificity was 92.3% (95% CI, 90.0%-94.5%), and the estimated QFT-G specificity was 99.8% (95% CI, 99.5%-100%). Recruits who were born in countries with a high prevalence of TB were 26-40 times more likely to have discordant results involving a positive TST result and a negative QFT-G result than were recruits born in countries with a low prevalence of TB. Nineteen (50%) of 38 recruits with this type of discordant results had a TST induration > or = 15 mm. CONCLUSIONS: The QFT-G and TST are more specific than the QFT. No statistically significant difference in specificity between the QFT-G and TST was found using a 15-mm induration cutoff value. The discordant results observed among recruits with increased risk of M. tuberculosis infection may have been because of lower TST specificity or lower QFT-G sensitivity. Negative QFT-G results for recruits born in countries where TB is highly prevalent and whose TST induration was > or = 15 mm suggest that the QFT-G may be less sensitive than the TST. Additional studies are needed to determine the risk of TB when TST and QFT-G results are discordant.