Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results.

Rationale: Pretomanid is a new nitroimidazole with proven treatment-shortening efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide combinations are potent in mice but have not been tested clinically. Rifampicin, but not rifabutin, reduces pretomanid exposures. Objectives: To evaluate the safety and efficacy of regimens containing pretomanid-rifamycin-pyrazinamide among participants with drug-sensitive pulmonary tuberculosis. Methods: A phase 2, 12-week, open-label randomized trial was conducted of isoniazid and pyrazinamide plus 1) pretomanid and rifampicin (arm 1), 2) pretomanid and rifabutin (arm 2), or 3) rifampicin and ethambutol (standard of care; arm 3). Laboratory values of safety and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. Time to culture conversion on liquid medium was the primary outcome. Measurements and Main Results: Among 157 participants, 125 (80%) had cavitary disease. Median time to liquid culture negativity in the modified intention-to-treat population (n = 150) was 42 (arm 1), 28 (arm 2), and 56 (arm 3) days (P = 0.01) (adjusted hazard ratio for arm 1 vs. arm 3, 1.41 [95% confidence interval (CI), 0.93-2.12; P = 0.10]; adjusted hazard ratio for arm 2 vs. arm 3, 1.89 [95% CI, 1.24-2.87; P = 0.003]). Eight-week liquid culture conversion was 79%, 89%, and 69%, respectively. Grade ≥3 adverse events occurred in 3 of 56 (5%), 5 of 53 (9%), and 2 of 56 (4%) participants. Six participants were withdrawn because of elevated transaminase concentrations (five in arm 2, one in arm 1). There were three serious adverse events (arm 2) and no deaths. Conclusions: Pretomanid enhanced the microbiologic activity of regimens containing a rifamycin and pyrazinamide. Efficacy and hepatic adverse events appeared highest with the pretomanid and rifabutin-containing regimen. Whether this is due to higher pretomanid concentrations merits exploration. Clinical trial registered with www.clinicaltrials.gov (NCT02256696).

Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial.

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBACFU0-14) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty participants enrolled. Median EBACFU0-14 counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log10 h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).

Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis.

Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid. Pretomanid may also have benefit as a treatment-shortening agent for drug-sensitive tuberculosis. It is unclear how and whether it can be used together with rifamycins, which are key sterilizing first-line drugs. In this analysis, data were pooled from two studies: the Assessing Pretomanid for Tuberculosis (APT) trial, in which patients with drug-sensitive pulmonary TB received pretomanid, isoniazid, and pyrazinamide plus either rifampin or rifabutin versus standard of care under fed conditions, and the AIDS Clinical Trials Group 5306 (A5306) trial, a phase I study in healthy volunteers receiving pretomanid alone or in combination with rifampin under fasting conditions. In our population pharmacokinetic (PK) model, participants taking rifampin had 44.4 and 59.3% reductions in pretomanid AUC (area under the concentration-time curve) compared to those taking rifabutin or pretomanid alone (due to 80 or 146% faster clearance) in the APT and A5306 trials, respectively. Median maximum concentrations (Cmax) in the rifampin and rifabutin arms were 2.14 and 3.35 mg/liter, while median AUC0-24 values were 30.1 and 59.5 mg·h/liter, respectively. Though pretomanid exposure in APT was significantly reduced with rifampin, AUC0-24 values were similar to those associated with effective treatment in registrational trials, likely because APT participants were fed with dosing, enhancing pretomanid relative bioavailability and exposures. Pretomanid concentrations with rifabutin were high but in range with prior observations. While pretomanid exposures with rifampin are unlikely to impair efficacy, our data suggest that pretomanid should be taken with food if prescribed with rifampin. (This study has been registered at ClinicalTrials.gov under identifier NCT02256696.).

Post-trial perceptions of a symptom-based TB screening intervention in South Africa: implementation insights and future directions for TB preventive healthcare services.

BACKGROUND: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts. METHODS: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted. RESULTS: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers. CONCLUSIONS: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care. TRIAL REGISTRATION: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

Improving Tuberculosis Preventive Therapy Uptake: A Cluster-randomized Trial of Symptom-based Versus Tuberculin Skin Test-based Screening of Household Tuberculosis Contacts Less Than 5 Years of Age.

BACKGROUND: Tuberculosis preventive therapy (TPT) is highly effective at preventing tuberculosis disease in household child contacts (<5 years), but is poorly implemented worldwide. In 2006, the World Health Organization recommended symptom-based screening as a replacement for tuberculin skin testing (TST) to simplify contact evaluation and improve implementation. We aimed to determine the effectiveness of this recommendation. METHODS: We conducted a pragmatic, cluster-randomized trial to determine whether contact evaluation using symptom screening improved the proportion of identified child contacts who initiated TPT, compared to TST-based screening, in Matlosana, South Africa. We randomized 16 clinics to either symptom-based or TST-based contact evaluations. Outcome data were abstracted from customized child contact management files. RESULTS: Contact tracing identified 550 and 467 child contacts in the symptom and TST arms, respectively (0.39 vs 0.32 per case, respectively; P = .27). There was no significant difference by arm in the adjusted proportion of identified child contacts who were screened (52% in symptom arm vs 60% in TST arm; P = .39). The adjusted proportion of identified child contacts who initiated TPT or tuberculosis treatment was 51.5% in the symptom clinics and 57.1% in the TST clinics (difference -5.6%, 95% confidence interval -23.7 to 12.6; P = .52). Based on the district's historic average of 0.7 child contacts per index case, 14% and 15% of child contacts completed 6 months of TPT in the symptom and TST arms, respectively (P = .89). CONCLUSIONS: Symptom-based screening did not improve the proportion of identified child contacts evaluated or initiated on TPT, compared to TST-based screening. Further research is needed to identify bottlenecks and evaluate interventions to ensure all child contacts receive TPT. CLINICAL TRIALS REGISTRATION: NCT03074799.

Screening for Tuberculosis With Xpert MTB/RIF Assay Versus Fluorescent Microscopy Among Adults Newly Diagnosed With Human Immunodeficiency Virus in Rural Malawi: A Cluster Randomized Trial (Chepetsa).

BACKGROUND: Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV)-infected individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality. METHODS: We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi. Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF assay (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED-FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis. RESULTS: Prevalent TB was diagnosed in 24 of 1001 (2.4%) individuals enrolled in clinics randomized to Xpert, compared with 10 of 841 (1.2%) in clinics randomized to LED-FM. All-cause mortality was 22% lower in the Xpert arm than in the LED-FM arm (6.7 vs 8.6 per 100 person-years; RR, 0.78 [95% confidence interval {CI}, .58-1.06]). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage 3 or 4) disease had lower mortality in clinics randomized to Xpert than to LED-FM (RR, 0.43 [95% CI, .22-.87]). CONCLUSIONS: In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV. CLINICAL TRIALS REGISTRATION: NCT01450085.

Gambling involvement among Native Americans, Blacks, and Whites in the United States.

BACKGROUND AND OBJECTIVES: This paper examines risk factors of gambling and problem gambling among racial subgroups in the U.S. population, namely Native Americans and blacks, for whom research data are lacking. METHODS: Findings are based on a large representative general population survey (n = 3,474) of gambling in the U.S. with an oversample of Native Americans (n = 549). Multiple domains were assessed including sociodemographic factors; ecological factors (census-defined neighborhood disadvantage, geocoded density of casinos within 30 miles of respondents' homes, and perceived gambling convenience); impulsivity; and alcohol abuse. RESULTS: After controlling for all variables in the study, neighborhood disadvantage has a significantly greater effect on overall gambling, frequent gambling, and problem gambling for Native Americans than for the rest of the U.S. POPULATION: In addition, the relationship between frequent gambling and heavier drinking is much stronger for blacks than for the rest of the U.S. DISCUSSION AND CONCLUSIONS: There is a lack of research on gambling involvement among minority groups in the U.S. Blacks and Native Americans are at a higher risk for problem gambling as compared with the rest of the population. Furthermore, social factors and alcohol abuse may show a stronger co-occurrence with gambling involvement among minority groups than among whites. SCIENTIFIC SIGNIFICANCE: This study is a large representative U.S. sample with sizeable numbers of Native Americans and blacks. Thus, prevalence rates and risk factors can be assessed for these important population subgroups. This will allow for targeted intervention programs for Native Americans and blacks with problem gambling and alcohol abuse. (Am J Addict 2017;26:713-721).

Predictors of Problem Gambling in the U.S.

In this article we examine data from a national U.S. adult survey of gambling to determine correlates of problem gambling and discuss them in light of theories of the etiology of problem gambling. These include theories that focus on personality traits, irrational beliefs, anti-social tendencies, neighborhood influences and availability of gambling. Results show that males, persons in the 31-40 age range, blacks, and the least educated had the highest average problem gambling symptoms. Adults who lived in disadvantaged neighborhoods also had the most problem gambling symptoms. Those who attended religious services most often had the fewest problem gambling symptoms, regardless of religious denomination. Respondents who reported that it was most convenient for them to gamble had the highest average problem gambling symptoms, compared to those for whom gambling was less convenient. Likewise, adults with the personality traits of impulsiveness and depression had more problem gambling symptoms than those less impulsive or depressed. Respondents who had friends who approve of gambling had more problem gambling symptoms than those whose friends did not approve of gambling. The results for the demographic variables as well as for impulsiveness and religious attendance are consistent with an anti-social/impulsivist pathway to problem gambling. The results for depression are consistent with an emotionally vulnerable pathway to problem gambling.

The Relationship Between Distance from Gambling Venues and Gambling Participation and Problem Gambling Among U.S. Adults.

In this article we examine the relationship between extent of gambling for U.S. adults and the distance from their residence to the nearest casino or track. We employ data from a telephone survey of U.S. adults conducted in 2011-2013. The chances that the respondents gambled in the past year, were frequent gamblers, or were problem gamblers were greater if they lived close to a casino. The chances that the respondents gambled in the past year or were frequent gamblers were greater if they lived close to a horse or dog track. The effects of closeness to a casino on the likelihood of past-year gambling, frequent gambling, and problem gambling, as well as the effect of closeness to a track on past-year gambling, extended to about 30 miles from the respondent's home. In addition, the concentration of casinos within 30 miles of the respondent's home was positively related to the respondents' chance of being a frequent or problem gambler. If a respondent had no casinos within 30 miles, he or she had a 2.7 % chance of being a problem gambler; if one casino, a 3.9 % chance; if six or more, a 6.2 % chance. The authors estimate that at least part of this effect is causal.

The Relationship Between the Number of Types of Legal Gambling and the Rates of Gambling Behaviors and Problems Across U.S. States.

In this article, we examine the relationship between the total number of types of gambling that are legal in a state and the gambling involvement of state residents. Of particular interest is whether more types of legal gambling are associated with higher rates of problem gambling. Telephone surveys of U.S. adults were conducted in 1999-2000 and 2011-2013. The same questions were used and the data sets were combined for most of the analyses. Gambling exposure was defined as the sum of the number of years that all types were legal. Results tabulated by state showed progressively higher rates of problem gambling, frequent gambling and any past year gambling as the number of legal types of gambling increased. Holding constant the number of legal types, problem gambling rates increased as exposure increased. States with longer exposure to legal lotteries or casinos tended to have higher rates of problem gambling. An analysis was also conducted in which the data sets from 1999 to 2000 and from 2011 to 2013 were compared. Among the states, there was a striking positive relationship between changes in the number of legal types of gambling between the two studies and changes in rates of frequent gambling between the two studies. For states that had fewer types of legal gambling in 2011 than in 1999, the rates of frequent gambling went down. For states that increased their types of legal gambling, rates of frequent gambling typically, but not always, went up. Possible explanations for these results were discussed.

Gambling and Problem Gambling in the United States: Changes Between 1999 and 2013.

Telephone surveys of US adults were conducted in 1999-2000 and again in 2011-2013. The same questions and methods were used so as to make the surveys comparable. There was a reduction in percentage of past-year gambling and in frequency of gambling. Rates of problem gambling remained stable. Lottery was included among the specific types of gambling for which past year participation and frequency of play declined. Internet gambling was the only form of gambling for which the past-year participation rate increased. The average win/loss increased for several forms of gambling, providing a modest indication that gamblers were betting more, albeit less frequently. Between the two surveys, the rates of past-year participation in gambling declined markedly for young adults. In both surveys, rates of problem gambling were higher for males than females, and this difference increased markedly between surveys as problem gambling rates increased for males and decreased for females. For the combined surveys, rates of problem gambling were highest for blacks and Hispanics and lowest for whites and Asians. In both surveys, the rates of problem gambling declined as socio-economic status became higher. Possible explanations for these trends are discussed.

Sociocultural Influences on Gambling and Alcohol Use Among Native Americans in the United States.

Gambling opportunities on and near Native American lands have increased in recent decades; yet there is a lack of research examining the patterns of problem gambling and alcohol abuse among Native Americans in the US. Traditional Native American cultural identity may be a protective factor for problem gambling and alcohol abuse among Native Americans. Telephone interviews were conducted with 415 Native American adults aged 18 years and older across the US. The past-year prevalence of gambling among Native Americans is similar to the rate for non-Native Americans in the US (80 vs. 77%). However, Native Americans have over twice the rate of problem gambling as the US sample (18 vs. 8%). Although Native Americans have a lower rate of past-year alcohol use than the US population (47 vs. 68%), they have a somewhat higher rate of alcohol abuse than their US counterparts (5.5 vs. 4.3%). Logistic regression analysis, with problem gambling as the dependent variable, revealed that lower socioeconomic status is significantly associated with an increased odds of problem gambling for Native Americans. Counter to the hypothesis, the higher the score on the Native American orientation, the higher the odds of being a problem gambler. Further, living by the "White way of life" was associated with a decreased odds of being a problem gambler; and perceived gambling convenience was associated with an increased odds of being a problem gambler. None of the Native American factors was significant in predicting alcohol abuse. These findings highlight the need for further investigation into the influence of cultural factors on Native American gambling.

New regimens to prevent tuberculosis in adults with HIV infection.

BACKGROUND: Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment. METHODS: We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival. RESULTS: The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine-isoniazid group, 2.9 per 100 person-years in the rifampin-isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance. CONCLUSIONS: On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.).

Meningococcal factor H-binding protein: implications for disease susceptibility, virulence, and vaccines.

Neisseria meningitidis is a human-adapted pathogen that causes meningitis and sepsis worldwide. N. meningitidis factor H-binding protein (fHbp) provides a mechanism for immune evasion by binding human complement factor H (CFH) to protect it from complement-mediated killing. Here, we discuss features of fHbp which enable it to engage human CFH (hCFH), and the regulation of fHbp expression. Studies of host susceptibility and bacterial genome-wide association studies (GWAS) highlight the importance of the interaction between fHbp and CFH and other complement factors, such as CFHR3, on the development of invasive meningococcal disease (IMD). Understanding the basis of fHbp:CFH interactions has also informed the design of next-generation vaccines as fHbp is a protective antigen. Structure-informed refinement of fHbp vaccines will help to combat the threat posed by the meningococcus, and accelerate the elimination of IMD.

Pregnancy in Women With HIV in a Tuberculosis Preventive Therapy Trial.

BACKGROUND: Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented. METHODS: We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes. RESULTS: 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown. CONCLUSIONS: Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid-based regimens.

The co-occurrence of gambling with substance use and conduct disorder among youth in the United States.

The co-occurrence of gambling with substance use and conduct disorder was examined in a representative U.S. household sample of 2,274 youth 14-21 years old. The findings show that problem gambling occurs within a problem-behavior syndrome with other substance-use behaviors and conduct disorder. Male gender, being black, and being Hispanic were found to be significant in predicting problem gambling over and above the effects of all four substance use and conduct disorder variables. Clinical interventions for one specific problem behavior in youth should consider assessing the other problem behaviors as well.

Tobacco use, heavy use, and dependence among adolescents and young adults in the United States.

Tobacco involvement among US youth was investigated in a national survey conducted in 2005-2007 of 2,274 respondents aged 14-21, including those not in school. Logistic regressions predicted tobacco involvement. Males had higher rates of tobacco use than females, but males and females had equal rates of heavy use and dependence. Tobacco involvement increased with age. Whites were more tobacco involved than minorities. Tobacco involvement declined with increasing socioeconomic status. Reduced tobacco use was associated with being married and with being a student. Smokeless tobacco use was associated with being male, older, white, and lower socioeconomic status. The implications of these results are discussed.

Gambling and problem gambling across the lifespan.

Two national U.S. telephone surveys of gambling were conducted, an adult survey (age 18 and over, N = 2,631) in 1999-2000 and a youth (age 14-21, N = 2,274) survey in 2005-2007. The data from these surveys were combined to examine the prevalence of any gambling, frequent gambling and problem gambling across the lifespan. These types of gambling involvement increased in frequency during the teens, reached a high level in the respondents' 20s and 30s, and then fell off in as the respondents aged. The notion that gambling involvement generally, and especially problem gambling, is most prevalent during the teens was not supported. A comparison of the age patterns of gambling involvement and alcohol involvement showed that alcohol involvement peaks at a younger age than gambling involvement; and thus, the theory that deviant behaviors peak at an early age applies more to alcohol than to gambling.

Gambling on the lottery: sociodemographic correlates across the lifespan.

Two representative U.S. telephone surveys of gambling were conducted-an adult survey of adults aged 18 years and older (n = 2,631) and a youth survey of young people aged 14-21 years old (n = 2,274). Because the questions and methods were the same or similar in both surveys, the data from these two surveys were combined into a single dataset to examine the prevalence and sociodemographic correlates of gambling and problem gambling across the lifespan. The present work focused specifically on gambling on the lottery which is the most prevalent form of gambling in the U.S. The frequency of gambling on the lottery increased sharply from mid adolescence to age 18 which is the legal age to purchase lottery tickets in most states; lottery play continued to increase into the thirties when it leveled off and remained high through the sixties and then decreased among those 70 years and older. Considering multiple sociodemographic factors together in a negative binomial regression, the average number of days of lottery gambling was significantly predicted by male gender, age, neighborhood disadvantage and whether or not lottery was legal in the state where the respondent lived. These findings can be used to inform policies regarding lotteries in the U.S.

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis.

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.