Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

Rationality in Human Movement.

It long has been appreciated that humans behave irrationally in economic decisions under risk: they fail to objectively consider uncertainty, costs, and rewards and instead exhibit risk-seeking or risk-averse behavior. We hypothesize that poor estimates of motor variability (influenced by motor task) and distorted probability weighting (influenced by relevant emotional processes) contribute to characteristic irrationality in human movement decisions.

Forecast of demand for antiretroviral drugs in low and middle-income countries: 2007-2008.

BACKGROUND: Middle and low-income countries have scaled up HIV treatment in the past 5 years. To maintain this effort, information regarding the amounts and types of drugs is needed. Shortages or overstock of active pharmaceutical ingredients make the scale-up efforts more difficult and costly. To inform global planning and implementation, we estimate the volume of current and future demand for active pharmaceutical ingredients for first and second-line antiretroviral drugs. METHODS: Using regression analysis and documented assumptions, we estimated the number of individuals receiving antiretroviral drugs to 2008. The volume of active pharmaceutical ingredients was calculated using two methods: a normative approach modelling implementation of country-specific guidelines, and an empirical model projecting current trends in drug use estimated by a survey of country HIV programmes. RESULTS: The number of patients treated was estimated to reach 3.38 million by the end of 2008, of which 94.6% would be on first-line and 5.4% on second-line treatment. The largest estimated absolute demand volumes for 2008 were for nevirapine, lamivudine, and zidovudine using either approach; the largest proportional increases in 2007-2008, were observed for emtricitabine, tenofovir, indinavir, and nelfinavir. The gap between normative and empirical estimates was greatest (most positive) for tenofovir, zidovudine, didanosine, and smallest (most negative) for saquinavir and nelfinavir. CONCLUSION: A comparison of the results from the normative and empirical demand quantities suggests that more tenofovir, zidovudine and didanosine would be required if national treatment guidelines were fully implemented, whereas the countries seem to be using more saquinavir and nelfinavir than would be required by their current guidelines.

Substance use among school-based youths in northern Mexico.

A small base of research suggests that adolescent substance use is a growing public health concern in Mexico. Employing confidential methods, the International Longitudinal Survey of Adolescent Health was administered to assess substance use among 1,238 students in northern Mexico. A large proportion of students indicated lifetime use of tobacco and alcohol. Gender differences in tobacco, alcohol, and marijuana were also evident. The current findings are congruent with the sparse extant data on youths' substance use in Mexico and highlight the need for early prevention interventions.

Substance use among school-based youths in Puerto Rico: differences between gender and grade levels.

The present study examined substance use rates among adolescents in Grades 7-12 in Puerto Rico. Nine hundred eighty-nine students completed the Spanish version of the International Survey of Adolescent Health. More than 50% of middle school youths and 75% of high-school youths reported lifetime alcohol use. Female gender was associated with tobacco use in middle school while male gender was associated with marijuana use in high school. High-school females reported lower rates of tobacco use and marijuana use than middle-school females. High-school males exhibited substantially higher drug-use rates than middle-school males for each substance. These findings may suggest that universal drug prevention interventions may be needed for females in Puerto Rico before they enter middle school, while targeted interventions aimed at high-risk females who continue to smoke tobacco or marijuana may be more effective during high school. In contrast, targeted drug prevention interventions for males probably need to begin in middle school and be maintained if not increased in intensity throughout the high-school years.

Peer and sibling substance use: predictors of substance use among adolescents in Mexico.

OBJECTIVE: To examine the extent to which peer drug use and sibling drug use predict alcohol abuse/dependence disorder status and the use of drugs other than alcohol among school-based youth in Mexico. METHODS: Data were collected on 1 203 middle and high school students in northern Mexico in May 1998. Participation was voluntary, and responses were confidential. Logistic regression analyses estimated the association that peer drug use and that sibling drug use had with alcohol abuse/dependence diagnosis and the lifetime use of drugs other than alcohol. RESULTS: Students who had siblings or peers who used alcohol and other drugs were more likely to meet the standard alcohol abuse/dependence criteria defined by the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), and were more likely to have used drugs other than alcohol. Controlling for potentially important confounders, we found that adolescents with the highest level of peer substance use were eight times as likely to meet alcohol abuse/dependence criteria and four times as likely to use other drugs. Youth who had siblings who used drugs were about twice as likely to meet alcohol abuse/dependence criteria and about 2.5 times as likely to use drugs other than alcohol when compared to youth with no sibling substance use. CONCLUSIONS: Consistent with extant findings among youth in the United States of America, peer and sibling substance use are major risk factors for substance use among school-based youth in Mexico. Students in Mexico may benefit from prevention strategies found to be effective among students in the United States.

Screening for "substance abuse" among school-based youth in Mexico using the Problem Oriented Screening Instrument (POSIT) for Teenagers.

Indices of classification accuracy of the Substance Use/Abuse scale of a Spanish-language version of the Problem Oriented Screening Instrument for Teenagers (POSIT) were evaluated among school-based youth in Mexico. Participants were 1203 youth attending one middle school (N = 619) and one high school (N = 584) in the third largest city of Coahuila, a northern border state in Mexico in May 1998. More than 94% of youth enrolled in the participating middle school and 89% of youth enrolled in the participating high school completed the International Longitudinal Survey of Adolescent Health. Indices of classification accuracy of the POSIT Substance Use/Abuse scale were evaluated against a "drug abuse" problem severity criterion that combined youth meeting DSM-IV criteria for alcohol abuse/dependence disorders with youth having used other illicit drugs five or more times in their lifetime. The present study findings suggest that using a cut score of one or two on the POSIT Substance Use/Abuse scale generally yields optimal classification accuracy indices that vary somewhat by gender and school subgroups. Further, classification accuracy indices of the POSIT Substance Use/Abuse scale are slightly better when used among high school males due, in part, to the higher base rate of serious involvement among this group compared to others.

Peer and sibling substance use: predictors of substance use among adolescents in Mexico / El uso de sustancias por pares y hermanos como factor pronóstico del uso de sustancias por adolescentes en México

OBJECTIVO: Examinar en qué medida el uso de drogas por los pares y hermanos es factor pronóstico del abuso o la dependencia del alcohol y del uso de drogas distintas del alcohol en escolares mexicanos. MÉTODOS: Se recolectaron datos acerca de 1 203 estudiantes de los últimos años de primaria y de secundaria en el norte de México en mayo de 1998. La participación en el estudio fue voluntaria, y las respuestas fueron confidenciales. Mediante análisis de regresión logística se estimó la asociación entre el uso de drogas por los pares y hermanos por un lado, y por el otro el diagnóstico de abuso o dependencia del alcohol y el uso de sustancias distintas del alcohol en algún momento de la vida. RESULTADOS: Los estudiantes cuyos hermanos o pares ingerían bebidas alcohólicas y consumían otras drogas mostraron mayores probabilidades de satisfacer los criterios estándares de abuso o dependencia del alcohol, según los define el Manual diagnóstico y estadístico de enfermedades mentales, cuarta edición (MDE-IV), y de haber consumido drogas distintas del alcohol. Después de controlado el efecto de posibles factores de confusión, los adolescentes con los niveles más altos de abuso de sustancias por parte de sus pares se mostraron ocho veces más propensos a satisfacer los criterios de abuso o dependencia del alcohol y cuatro veces más propensos a consumir otros tipos de sustancias. Los adolescentes cuyos hermanos consumían drogas tenían una probabilidad dos veces mayor de satisfacer los criterios de abuso o dependencia del alcohol y una probabilidad 2,5 veces mayor de consumir drogas en comparación con jóvenes cuyos hermanos no consumían ninguna sustancia. CONCLUSIONES: Tal como indican otros resultados obtenidos con adolescentes en Estados Unidos de América, el uso de sustancias por los pares y hermanos es un factor de riesgo de consumo de sustancias en escolares en México. Estos últimos podrían beneficiarse de estrategias preventivas cuya eficacia en jóvenes estadounidenses se haya demostrado.

Objective. To examine the extent to which peer drug use and sibling drug use predict alcohol abuse/dependence disorder status and the use of drugs other than alcohol among schoolbased youth in Mexico. Methods. Data were collected on 1 203 middle and high school students in northern Mexico in May 1998. Participation was voluntary, and responses were confidential. Logistic regression analyses estimated the association that peer drug use and that sibling drug use had with alcohol abuse/dependence diagnosis and the lifetime use of drugs other than alcohol. Results. Students who had siblings or peers who used alcohol and other drugs were more likely to meet the standard alcohol abuse/dependence criteria defined by the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), and were more likely to have used drugs other than alcohol. Controlling for potentially important confounders, we found that adolescents with the highest level of peer substance use were eight times as likely to meet alcohol abuse/dependence criteria and four times as likely to use other drugs. Youth who had siblings who used drugs were about twice as likely to meet alcohol abuse/dependence criteria and about 2.5 times as likely to use drugs other than alcohol when compared to youth with no sibling substance use. Conclusions. Consistent with extant findings among youth in the United States of America, peer and sibling substance use are major risk factors for substance use among school-based youth in Mexico. Students in Mexico may benefit from prevention strategies found to be effective among students in the United States