Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures.

BACKGROUND: The Total Exposure Study was a stratified, multi-center, cross-sectional study designed to estimate levels of biomarkers of tobacco-specific and non-specific exposure and of potential harm in U.S. adult current cigarette smokers (≥one manufactured cigarette per day over the last year) and tobacco product non-users (no smoking or use of any nicotine containing products over the last 5 years). The study was designed and sponsored by a tobacco company and implemented by contract research organizations in 2002-2003. Multiple analyses of smoking behavior, demographics, and biomarkers were performed. Study data and banked biospecimens were transferred from the sponsor to the Virginia Tobacco and Health Research Repository in 2010, and then to SRI International in 2012, for independent analysis and dissemination. METHODS: We analyzed biomarker distributions overall, and by biospecimen availability, for comparison with existing studies, and to evaluate generalizability to the entire sample. We calculated genome-wide statistical power for a priori hypotheses. We performed clinical chemistries, nucleic acid extractions and genotyping, and report correlation and quality control metrics. RESULTS: Vital signs, clinical chemistries, and laboratory measures of tobacco specific and non-specific toxicants are available from 3585 current cigarette smokers, and 1077 non-users. Peripheral blood mononuclear cells, red blood cells, plasma and 24-h urine biospecimens are available from 3073 participants (2355 smokers and 719 non-users). In multivariate analysis, participants with banked biospecimens were significantly more likely to self-identify as White, to be older, to have increased total nicotine equivalents per cigarette, decreased serum cotinine, and increased forced vital capacity, compared to participants without. Effect sizes were small (Cohen's d-values ≤ 0.11). Power for a priori hypotheses was 57 % in non-Hispanic Black (N = 340), and 96 % in non-Hispanic White (N = 1840), smokers. All DNA samples had genotype completion rates ≥97.5 %; 68 % of RNA samples yielded RIN scores ≥6.0. CONCLUSIONS: Total Exposure Study clinical and laboratory assessments and biospecimens comprise a unique resource for cigarette smoke health effects research. The Total Exposure Study Analysis Consortium seeks to perform molecular studies in multiple domains and will share data and analytic results in public repositories and the peer-reviewed literature. Data and banked biospecimens are available for independent or collaborative research.

Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans' Health Administration Patients.

OBJECTIVE: Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids. SUBJECTS, DESIGN, AND METHODS: A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. RESULTS: Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P > 0.05). CONCLUSION: RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated.

Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients.

OBJECTIVE: Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids. DESIGN: Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data. SUBJECTS: Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987). METHODS: Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome. RESULTS: The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated. CONCLUSIONS: Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids.

Abuse and diversion of buprenorphine sublingual tablets and film.

Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned.

Root causes, clinical effects, and outcomes of unintentional exposures to buprenorphine by young children.

OBJECTIVE: To characterize the rates, root causes, and clinical effects of unintentional exposures to buprenorphine sublingual formulations among young children and to determine whether exposure characteristics differ between formulations. STUDY DESIGN: Unintentional exposures to buprenorphine-containing products among children 28 days to less than 6 years old were collected from the Researched Abuse, Diversion, and Addiction-Related Surveillance System Poison Center Program and Reckitt Benckiser Pharmaceuticals' pharmacovigilance system from October 2009-March 2012. After adjustment for drug availability, negative binomial regression was used to estimate average exposure rates. Root cause assessment was conducted, and an expert clinician panel adjudicated causality and severity of moderate to severe adverse events (AEs). RESULTS: A total of 2380 cases were reviewed, including 4 deaths. Exposures to buprenorphine-naloxone combination film were significantly less frequent than exposures to buprenorphine tablets (rate ratio 3.5 [95% CI, 2.7-4.5]) and buprenorphine-naloxone combination tablets (rate ratio 8.8 [7.2-10.6]). The most commonly identified root causes were medication stored in sight, accessed from a bag or purse, and not stored in the original packaging. Among 536 panel review cases, the most common AEs reported for all formulations were lethargy, respiratory depression, miosis, and vomiting. The highest level AE severity did not differ significantly by formulation. CONCLUSIONS: Unintentional exposure to buprenorphine can cause central nervous system depression, respiratory depression, and death in young children. Exposure rates to film formulations are significantly less than to tablet formulations. Package and storage deficiencies contribute to unintentional exposures in young children.

A pharmacoepidemiologic analysis of the impact of calendar packaging on adherence to self-administered medications for long-term use.

BACKGROUND: Calendar blister packaging (CBP) that incorporates a day or date feature is a simple medication packaging technology that is designed to improve medication adherence and persistence. OBJECTIVE: This study was conducted to assess the effect of a new calendar packaging technology on prescription refill adherence and persistence for daily, self-administered, long-term medication use. METHODS: Anonymized pharmacy dispensing data from a large US mass merchandiser were analyzed. This retrospective cohort study included people aged 18 to 75 years who filled prescriptions for oral lisinopril or enalapril (control group) at a study pharmacy during 1 year before and after the switch of lisinopril packaging from vials to CBP. Cohorts were stratified into new and prevalent medication users. We used linear and logistic regression modeling and propensity score matching to assess the impact of CBP on refill adherence, using medication possession ratio (MPR) and proportion of days covered (PDC), and persistence using length of therapy (LOT). RESULTS: Our sample comprised 76,321 new users and 249,040 prevalent users. Across all user, medication, and packaging groups, the mean unadjusted LOT decreased in the follow-up year, possibly due to economic recession. The LOT decline was attenuated in the CBP cohort. After adjustment for covariates, CBP use in new and prevalent medication users was associated with significantly higher LOT and PDC but not MPR. The odds of achieving PDC ≥80% were higher by 15% in new users (odds ratio [OR] = 1.15; 95% CI, 1.09-1.21) and 12% in prevalent users (OR = 1.12; 95% CI, 1.09-1.15) who switched to CBP, compared with continued vial use. CONCLUSIONS: CBP of medication prescribed for daily, self-administered, long-term use was associated with modest improvement in prescription refill adherence and persistence. An adherence strategy of even small effect size that is broadly implemented on a population level could significantly leverage therapeutic effect and provide substantial cumulative public health benefit. Clinical benefit, or harm, associated with use of CBP should be investigated. Usability assessments of CBP in patient subgroups may provide insight about differential impact on adherence and persistence.

Does packaging with a calendar feature improve adherence to self-administered medication for long-term use? A systematic review.

BACKGROUND: The therapeutic benefit of self-administered medications for long-term use is limited by an average 50% nonadherence rate. Patient forgetfulness is a common factor in unintentional nonadherence. Unit-of-use packaging that incorporates a simple day-and-date feature (calendar packaging) is designed to improve adherence by prompting patients to maintain the prescribed dosing schedule. OBJECTIVE: To review systematically, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, randomized controlled trial evidence of the adherence benefits and harms of calendar blister packaging (CBP) and calendar pill organizers (CPO) for self-administered, long-term medication use. METHODS: Data sources included the MEDLINE and Web of Science and Cochrane Library databases from their inception to September 2010 and communication with researchers in the field. Key search terms included blister-calendar pack, blister pack, drug packaging, medication adherence, medication compliance, medication compliance devices, medication containers, medication organizers, multicompartment compliance aid, persistence, pill-box organizers, prescription refill, randomized controlled trials, and refill compliance. Selected studies had an English-language title; a randomized controlled design; medication packaged in CBP or CPO; a requirement of solid, oral medication self-administered daily for longer than 1 month in community-dwelling adults; and at least 1 quantitative outcome measure of adherence. Two reviewers extracted data independently on study design, sample size, type of intervention and control, and outcomes. RESULTS: Ten trials with a total of 1045 subjects met the inclusion criteria, and 9 also examined clinical outcomes (seizures, blood pressure, psychiatric symptoms) or health care resource utilization. Substantial heterogeneity among trials precluded meta-analysis. In 3 studies, calendar packaging was part of a multicomponent adherence intervention. Six of 10 trials reported higher adherence, but it was associated with clinically significant improvement in only 1 study: 50% decreased seizure frequency with a CPO-based, multicomponent intervention. No study reported sufficient information to examine conclusively potential harms related to calendar packaging. LIMITATIONS: All trials had significant methodological limitations, such as inadequate randomization or blinding, or reported insufficient information regarding enrolled subjects and attrition, which resulted in a moderate-to-high risk of bias and, in 2 studies, unevaluable outcome data. Trials were generally short and sample sizes small, with heterogeneous adherence outcome measures. CONCLUSIONS: Calendar packaging, especially in combination with education and reminder strategies, may improve medication adherence. Methodological limitations preclude definitive conclusions about the effect size of adherence and clinical benefits or harms associated with CBP and CPO. High-quality trials of adequate size and duration are needed to assess the clinical effectiveness of such interventions.

Further considerations on the evaluation of potential reduced-risk tobacco products. Part II: Re-assessment of a heuristic using the CPS-II database.

In a previous analysis (see Part I) we proposed a heuristic for assessing the efficacy of potential reduced-risk tobacco products (PRRPs) on lung cancer (LC) rates, using smoking cessation data published in a report from the Iowa Women's Health Study (IWHS) as a basis for sample size estimates. In this study, an additional analysis was performed using cessation data from the much larger Cancer Prevention Study II (CPS-II), which also provides data on different durations of cessation. Statistical methods were used to assess whether smokers switching to a PRRP would reduce their risk of LC. Furthermore, non-inferiority tests compared the LC risk in switchers to that in smokers who had quit smoking. The present work shows that similar sample size estimates were obtained whether the analysis was based on the IWHS or the CPS-II data sets, suggesting that the heuristic may be generally applicable to prospective real-life studies to evaluate PRRPs. Non-inferiority testing of switchers compared with quitters required approximately 10-fold more subjects than did superiority testing of switchers compared with smokers. Altogether, these estimates indicate that it is feasible, in terms of study duration and sample size, to clinically assess the LC risk-reducing potential of a PRRP.

Hypotheses and fundamental study design characteristics for evaluating potential reduced-risk tobacco products. Part I: Heuristic.

The risk-reducing effect of a potential reduced-risk tobacco product (PRRP) can be investigated conceptually in a long-term, prospective study of disease risks among cigarette smokers who switch to a PRRP and in appropriate comparison groups. Our objective was to provide guidance for establishing the fundamental design characteristics of a study intended to (1) determine if switching to a PRRP reduces the risk of lung cancer (LC) compared with continued cigarette smoking, and (2) compare, using a non-inferiority approach, the reduction in LC risk among smokers who switched to a PRRP to the reduction in risk among smokers who quit smoking entirely. Using standard statistical methods applied to published data on LC incidence after smoking cessation, we show that the sample size and duration required for a study designed to evaluate the potential for LC risk reduction for an already marketed PRRP, compared with continued smoking, varies depending on the LC risk-reducing effectiveness of the PRRP, from a 5-year study with 8000-30,000 subjects to a 15-year study with <5000 to 10,000 subjects. To assess non-inferiority to quitting, the required sample size tends to be about 10 times greater, again depending on the effectiveness of the PRRP.

Risk and protective factors for adolescent substance use: findings from a study in selected Central American countries.

PURPOSE: To identify the prevalence of substance use and problems with use, and risk and protective factors at different levels of the adolescent's ecology associated with substance use among adolescents in selected Central American countries. METHODS: Results of a survey of 17,215 students from Panama, Costa Rica, and Guatemala conducted in 2000-2001 served as the basis for the analyses. Lifetime use of alcohol, tobacco, marijuana, and five other drugs (inhalants, tranquilizers, cocaine, crack, and ecstasy), and problems with drugs and alcohol were the outcome variables. Risk factors included dysregulation, family problems with drugs/alcohol, negative family interactions, school disengagement, peer deviance, and exposure to community violence. Protective factors included a personal belief in God, positive family interactions, parent religiosity, and positive student-teacher interaction. Both hierarchical linear regression and logistic regression analyses were used to model main and interaction effects of risk and protective factors. RESULTS: There was a linear association between number of risk and protective factors and substance use, however, risk factors were more strongly associated with substance use than were protective factors. There were significant risk-by-protective-factor interactions for alcohol and marijuana use, and for problems with drugs and alcohol. Risk interacted most consistently with a personal belief in God, but also with parent religiosity and with student-teacher communication. CONCLUSIONS: It is important to consider risk and protective factors at different levels of an adolescent's ecology. Prevention and intervention efforts should focus on interactions adolescents have in different microsystems (e.g., with parents, teachers, and peers).

Genetics and diagnostic refinement.

For many psychiatric conditions it is speculated that, rather than being single disease entities, they are a set of several disorders sharing clinical features but having (partly) different underlying causes. The possibility of measuring genetic variation on a large scale has given researchers new hope of identifying these disease subtypes that may differ with respect to prognosis, course, and response to treatment. However, although a considerable number of articles have been published suggesting that we may even be on the verge of making genotype-based diagnoses, the reality is that we do not have a good answer to even the most basic question of how measured genes could best be used to refine diagnostic categories. In this article, we show that for common psychiatric disorders, it may not be possible to simply look for similar genetic profiles in groups of patients. Instead, we propose a model assuming that genotypes affect phenotypes through more or less coherent etiological systems or pathogenic processes and argue that these etiological systems may provide a more fruitful basis for defining disease subtypes. Several examples from the literature that support the face validity of different aspects of our model are given. Finally, we argue that, given our limited knowledge of disease etiology, the use of discovery-oriented techniques requiring extensive data collection and (artificial) intelligent computer searches may be imperative, and discuss the prospect of model-based diagnosis to classify etiologically different disease subtypes.

Factor structure and external validity of the PANSS revisited.

Considerable controversy exists concerning the positive and negative syndrome scale (PANSS), one of the most widely used instruments in schizophrenia research. In this article we revisited the factor structure and external validity of the PANSS in a sample of 500 participants with DSM IV diagnoses of schizophrenia. We found that a model with six latent factors provided a relatively good fit, considered adequate by two rules of thumb. Five factors corresponded closely to those typically derived in other studies: Negative, Positive, Excited/Activation, Anxious-Depressed/Dysphoric, and Disorganized/Autistic preoccupation. The sixth factor seemed to have face validity and was labeled Withdrawn. With the exception of Anxious-Depressed/Dysphoric, Cronbach's Alpha ranged from 0.70 to 0.85 suggesting an acceptable internal consistency. External validity was studied through correlations with socio-demographic variables, DSM IV (subtype) diagnoses, clinical characteristics, and drug use. The many significant correlations suggested that the six PANSS scales measure meaningful aspects of schizophrenia. Furthermore, the pattern of correlations varied, providing evidence that the scales assessed partly different aspects of the disease. Our analyses also suggested that some of the controversy about the PANSS can possibly be attributed to methodological factors where the substantial cross-loadings of some PANSS items may play an important role.

The comorbidity of substance abuse and depressive symptoms in Costa Rican adolescents.

Patterns of comorbidity between depressive symptoms and substance use were examined simultaneously in community and clinical-based samples of 5268 Costa Rican adolescents, ages 12-20, through a series of descriptive, ANCOVA and logistic regression analyses. Groups surveyed included high school students, street youth, and youth in treatment for substance abuse problems. Results revealed significant group differences in substance use and significant correlations between depressive symptoms and problems with alcohol and drugs. The association between depressive symptoms and overall substance use involvement was significant for all youth, but strongest for female street youth. Logistic regression analyses revealed that depressive symptoms were associated with increased odds of specific substance use for all three groups, though in the case of street youth and youth in treatment, these associations only were observed in males. Analyses of covariance indicated that problems with drugs and alcohol differed across group and sex. Youth in treatment had more problems with drugs and alcohol than other groups. Among street youth, males had more problems with drugs than females. This study provides a unique cross-cultural perspective on the comorbidity of depression and substance use among youth, and allows for comparative analyses between community and clinical-based participants.

Spanish translation and reliability testing of the Child Depression Inventory.

The goal of this study was to test the internal reliability of a Spanish translation of the CDI, (i.e., CDI-LA), a potentially useful screening instrument for Hispanic youngsters in their native language at a primary-care level. Self-reported symptoms of depression were assessed with the CDI-LA in a school sample of 205 Hispanic students. Girls and boys ranging from 8 to 15 years (mean age 11.5 +/- 1.9 years) were tested on a designated day. The CDI-LA mean score was 9.7 +/- 7.2. Eleven percent of the subjects scored higher than the instruments' cutoff score (CDI > or = 19), and were considered at risk of clinical depression. Females scored higher than males, and children 8-12 years of age (mean CDI-LA = 8.8, SD = 6.6) had significantly (t = -2.07, 203 df, p < 0.05) lower mean CDI-LA total scores compared to those ages 13 or older (mean CDI-LA = 11.0, SD = 7.9). The internal consistency reliability of the CDI-LA was similar to that found in English speaking populations. These results suggest that the general psychometric properties of our Spanish translation of the 10 and 27 item versions of the CDI appear to be adequate according to a Cronbach's coefficient alpha estimate of internal reliability and Spearman correlation coefficient split-half reliability.

The Mid-Atlantic Twin Registry.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of twin pairs ascertained from birth records and school system records of Virginia, North Carolina, and South Carolina. The MATR was formed in 1997 with the merging of the Virginia and North Carolina Twin Registries, and it expanded to include South Carolina when access to twin birth records in that state was granted in 1998. Registered twins ("participants") number more than 51,000, with approximately 46,000 of these individuals representing complete pairs. Roughly two-thirds of MATR participants are over age 18, with a mean age of approximately 35 years. These participants have primarily been drawn from the more than 170,000 identical and fraternal twin pairs born in the three states between 1913 and 2000. Twins and their family members have participated in numerous research projects, ranging from general health surveys to studies on specific health topics such as cardiovascular disease; depression and anxiety; seizures; behavioral development; pregnancy complications; conduct disorder; drug use, abuse, and dependence; cleft lip/palate; obesity; and chronic fatigue syndrome. The MATR has established a privacy policy and strict standard operating procedures to protect the confidentiality of participant data. The MATR considers a limited number of qualified requests per year from investigators interested in recruiting MATR participants into their research studies.

Pittsburgh Registry of Infant Multiplets (PRIM).

This paper describes the Pittsburgh Registry of Infant Multiplets (PRIM; Pittsburgh, Pennsylvania), the results of pilot research conducted in this registry, and the plans for future studies. The main focus of the registry is on psychological development and the risk for behavioral disorders. Particularly, characteristics associated with antisociality and the risk for substance use disorders (e.g., aggressivity, hyperactivity/impulsivity), as well as language development and other traits (e.g., dental health) are among the research targets.

Exposure to violence against a family member and internalizing symptoms in Colombian adolescents: the protective effects of family support.

Associations between exposure to serious violence against a family member and internalizing symptoms, and the protective effects of support from family versus friends, were examined in 5,775 adolescents (50% female; mean age = 15.2 years, SD = 2.0) with data from a national, random household survey of residents in Colombia, South America. After accounting for the effects of age, gender, and family life events other than violence, support from family buffered the relations between exposure to violence and adjustment; this relation was strongest for girls and younger adolescents. Disclosure to friends appeared to be protective for younger adolescents but harmful for older adolescents, and this relation was only observed for hopelessness. Results are discussed in terms of cognitive processing models of adjustment to violence.

Validación del inventario de depresión para niños (IDN) en Costa Rica / Validation of the inventary of depression for children (IDN) in Costa Rica

Dada la creciente importancia de los problemas depresivos y suicidios en niños y adolescentes, asi como su relación con otros problemas conductuales y académicos, se hace necesario explorar más este fenómeno. El objetivo del presente estudio es validar para Costa Rica el inventario de depresión para niños y adolescentes. El instrumento se aplicó a 727 estudiantes de 8 a 19 años y a 97 adolescentes previamente diagnosticados como depresivos. Los resultados evidenciaron altos índices de confiabilidad interna y temporal. Lo que demuestra la homogeneidad del cuestionario y su consistencia en el tiempo. También se encontró que aproximadamente cada uno de diez estudiantes presentaba sufucientes síntomas depresivos para ameritar un mayor estudio y posiblemente un tratamiento específico. Se recomienda realizar una exploración más profunda al respecto, así como despertar mayor interés sobre el tema y ofrecer capacitación a padres y educadores