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The Health and Retirement Study was designed to evaluate changes in health and labor force participation during and after the transition from working to retirement. Every 2 years, participants provided information about their self-rated health (SRH), body mass index (BMI), smoking status, and other characteristics. Our goal was to assess the effects of smoking and gender on trajectories of change in BMI and SRH over time. Joint longitudinal analysis of outcome measures is preferable to separate analyses because it allows to account for the correlation between the measures, to test the effects of predictors while controlling type I error, and potentially to improve efficiency. However, because SRH is an ordinal measure while BMI is continuous, formulating a joint model and parameter estimation is challenging. A joint correlated probit model allowed us to seamlessly account for the correlations between the measures over time. Established estimating procedures for such models are based on quasi-likelihood or numerical approximations that may be biased or fail to converge. Therefore, we proposed a novel expectation-maximization algorithm for parameter estimation and a Monte Carlo bootstrap approach for standard errors approximation. Expectation-maximization algorithms have been previously considered for combinations of binary and/or continuous repeated measures; however, modifications were needed to handle combinations of ordinal and continuous responses. A simulation study demonstrated that the algorithm converged and provided approximately unbiased estimates with sufficiently large sample sizes. In the Health and Retirement Study, male gender and smoking were independently associated with steeper deterioration in self-rated health and with lower average BMI. Copyright © 2016 John Wiley & Sons, Ltd.
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Algoritmos , Estado de Salud , Jubilación , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Método de Montecarlo , Probabilidad , FumarRESUMEN
N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.
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Corteza Cerebral/fisiopatología , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Esquizofrenia/fisiopatología , Adulto , Mapeo Encefálico , Corteza Cerebral/efectos de los fármacos , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Voluntarios Sanos/psicología , Humanos , Ketamina/sangre , Masculino , Persona de Mediana Edad , Esquizofrenia/inducido químicamente , Esquizofrenia/diagnósticoRESUMEN
BACKGROUND: Undue influence of body shape or weight on self-evaluation - referred to as overvaluation - is considered a core feature across eating disorders, but is not a diagnostic requirement for binge eating disorder (BED). This study examined the concurrent and predictive significance of overvaluation of shape/weight in obese patients with BED participating in a randomized clinical trial testing cognitive behavioral therapy (CBT) and behavioral weight loss (BWL). Method A total of 90 participants were randomly assigned to 6-month group treatments of CBT or BWL. Assessments were performed at baseline, throughout- and post-treatment, and at 6- and 12-month follow-ups after completing treatments with reliably administered semi-structured interviews and established measures. RESULTS: Participants categorized with overvaluation (n = 52, 58%) versus without overvaluation (n = 38, 42%) did not differ significantly in demographic features (age, gender and ethnicity), psychiatric co-morbidity, body mass index or binge eating frequency. The overvaluation group had significantly greater levels of eating disorder psychopathology and poorer psychological functioning (higher depression and lower self-esteem) than the non-overvaluation group. Overvaluation of shape/weight significantly predicted non-remission from binge eating and higher frequency of binge eating at the 12-month follow-up, even after adjusting for group differences in depression and self-esteem levels. CONCLUSIONS: Our findings suggest that overvaluation does not simply reflect concern commensurate with being obese or more frequent binge eating, but also is strongly associated with heightened eating-related psychopathology and psychological distress, and has negative prognostic significance for longer-term treatment outcomes. Overvaluation of shape/weight warrants consideration as a diagnostic specifier for BED as it provides important information about severity and treatment outcome.
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Trastorno por Atracón/psicología , Imagen Corporal/psicología , Obesidad/psicología , Autoevaluación (Psicología) , Adulto , Trastorno por Atracón/terapia , Terapia Cognitivo-Conductual , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Autoimagen , Resultado del Tratamiento , Programas de Reducción de PesoRESUMEN
UNLABELLED: Prior work by our group has shown the feasibility, safety, and validity of a multi-day, multi-dose paradigm of self-regulated cocaine administration in humans. The current work sought to consolidate these methods in a single-day design focused on reducing logistical complexity, decreasing research burden to human subjects, and increasing suitability for medication development designs. METHODS: Eleven experienced cocaine users participated in a 6-hour, single-day design, consisting of one safety/eligibility and three experimental cocaine periods (during which subjects were allowed to self-administer 8, 16, and 32 mg/70 kg cocaine doses under a fixed-ratio 1:5 minute timeout schedule). Changes in cocaine-induced cardiovascular response, self-administration behavior, and subjective effects were assessed. RESULTS: Procedures were well tolerated by participants, and no significant adverse events were noted. Significant (p < 0.05), changes in measures of cocaine self-administration (e.g., responses, infusions, interinfusion intervals, consumption, and plasma levels), cardiovascular response (HR), and subjective effects ("high") were observed. In contrast, cocaine-induced increases in other vital signs (e.g., SBP, DBP) and subjective effect measures (e.g., paranoia) did not differ between doses. CONCLUSIONS: These data support the safety, tolerability and validity of our single-day design. Depending on the application, such methods may afford advantages for assessing the self-regulation of cocaine administration behavior in humans (e.g., including medication development designs).
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Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/psicología , Cocaína/administración & dosificación , Adulto , Presión Sanguínea/efectos de los fármacos , Protocolos Clínicos , Cocaína/sangre , Trastornos Relacionados con Cocaína/sangre , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Bombas de Infusión , Masculino , Persona de Mediana Edad , Autoadministración , Factores de TiempoRESUMEN
BACKGROUND: We examined rapid response in obese patients with binge-eating disorder (BED) in a clinical trial testing cognitive behavioral therapy (CBT) and behavioral weight loss (BWL). METHOD: Altogether, 90 participants were randomly assigned to CBT or BWL. Assessments were performed at baseline, throughout and post-treatment and at 6- and 12-month follow-ups. Rapid response, defined as 70% reduction in binge eating by week four, was determined by receiver operating characteristic curves and used to predict outcomes. RESULTS: Rapid response characterized 57% of participants (67% of CBT, 47% of BWL) and was unrelated to most baseline variables. Rapid response predicted greater improvements across outcomes but had different prognostic significance and distinct time courses for CBT versus BWL. Patients receiving CBT did comparably well regardless of rapid response in terms of reduced binge eating and eating disorder psychopathology but did not achieve weight loss. Among patients receiving BWL, those without rapid response failed to improve further. However, those with rapid response were significantly more likely to achieve binge-eating remission (62% v. 13%) and greater reductions in binge-eating frequency, eating disorder psychopathology and weight loss. CONCLUSIONS: Rapid response to treatment in BED has prognostic significance through 12-month follow-up, provides evidence for treatment specificity and has clinical implications for stepped-care treatment models for BED. Rapid responders who receive BWL benefit in terms of both binge eating and short-term weight loss. Collectively, these findings suggest that BWL might be a candidate for initial intervention in stepped-care models with an evaluation of progress after 1 month to identify non-rapid responders who could be advised to consider a switch to a specialized treatment.
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Trastorno por Atracón/terapia , Terapia Cognitivo-Conductual/métodos , Obesidad/terapia , Adolescente , Adulto , Trastorno por Atracón/psicología , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Humanos , Entrevista Psicológica , Masculino , Persona de Mediana Edad , Obesidad/psicología , Pronóstico , Curva ROC , Inducción de Remisión , Factores de Tiempo , Resultado del Tratamiento , Pérdida de Peso/fisiología , Adulto JovenRESUMEN
RATIONALE: We recently conducted a pilot study supporting the feasibility, safety, and validity of a human laboratory model of ad libitum cocaine administration in which subjects self-selected the timing of infusions. The current study extends this work to include a randomized design with a test-retest component in a larger sample. OBJECTIVES: To investigate the regulation of cocaine intake by humans and its effects on subjective and cardiovascular responses. MATERIALS AND METHODS: Subjects were 14 non-treatment seeking volunteers (10 M, 4 F) with cocaine abuse/dependence. Subjects self-administered cocaine infusions (0, 8, 16, and 32 mg/70 kg) over a 2-h period under a fixed ratio 1, 5-min time-out schedule on 4 consecutive days. A fifth session was conducted at 16-mg dose to assess the paradigm's test-retest reliability. RESULTS: Subjects regulated their cocaine intake in a dose-dependent fashion. Self-reports of cocaine-related subjective effects (e.g., "high" and "stimulated") also varied in a dose-dependent way. Test-retest data and the randomized design support the conclusion that such effects are not due to tolerance or other experimental artifacts. CONCLUSION: The current study replicates prior work demonstrating the feasibility, safety, and validity of our human laboratory paradigm of cocaine administration in a larger sample using a randomized design. The current study also shows the test-retest reliability of these methods, establishing its utility for comparisons of experimental interventions (e.g., pharmacological treatments). Finally, the current study suggests that factors other than drug-induced euphoria (i.e., "high") contribute to the regulation of cocaine-taking behaviors in humans.
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Conducta Adictiva/fisiopatología , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/administración & dosificación , Adulto , Presión Sanguínea/efectos de los fármacos , Cocaína/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , AutoadministraciónRESUMEN
In biomedical studies often multiple measures of disease severity are recorded over time. Although correlated, such measures are frequently analysed separately of one another. Joint analysis of the outcomes variables has several potential advantages over separate analyses. However, models for response variables of different types (discrete and continuous) are challenging to define and to fit. Herein we propose correlated probit models for joint analysis of repeated measurements on ordinal and continuous variables measuring the same underlying disease severity over time. We demonstrate how to rewrite the models so that maximum-likelihood estimation and inference can be performed with standard software. Simulation studies are performed to assess efficiency gains in fitting the responses together rather than separately and to guide response variable selection for future studies. Data from a depression clinical trial are used for illustration.
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Biometría/métodos , Interpretación Estadística de Datos , Funciones de Verosimilitud , Análisis de Regresión , Índice de Severidad de la Enfermedad , Ensayos Clínicos como Asunto , Simulación por Computador , Depresión/tratamiento farmacológico , Fluoxetina/administración & dosificación , Humanos , Estudios Longitudinales , Escalas de Valoración Psiquiátrica , Programas Informáticos , Yohimbina/administración & dosificaciónRESUMEN
OBJECTIVE: Pharmacological treatment of postpartum depression is frequently complicated by the mother's desire to breast-feed. Although breast milk levels of several selective serotonin reuptake inhibitors (SSRIs) have been reported to be relatively low, a critical question is whether SSRI exposure during nursing results in clinically significant blockade of serotonin (5-HT) reuptake in infants. This study determined the degree of transporter blockade in infants exposed to sertraline through maternal breast milk. METHOD: The extent of maternal and infant transporter blockade was assessed by measurement of platelet levels of 5-HT in 14 breast-feeding mother-infant pairs before and after 6-16 weeks of maternal treatment with sertraline for major depression with postpartum onset. Plasma sertraline and desmethylsertraline levels were obtained in 13 of these mothers and 11 of their infants. RESULTS: Marked declines in platelet 5-HT levels of 70%-96% were observed in mothers after sertraline treatment, 25-200 mg/day. In contrast, infants showed little or no change in platelet 5-HT levels after exposure through breast-feeding. Mean levels of maternal plasma sertraline and its major metabolite, desmethylsertraline, were 30.7 ng/ml and 45.3 ng/ml, respectively. Drug and drug metabolite concentrations in the infants were at or below the lower limit of quantitation. CONCLUSIONS: The data indicate that while mothers receiving clinical doses of sertraline experience substantial blockade of the platelet 5-HT transporter, platelet 5-HT uptake in nursing infants of treated mothers is unaltered. The observations suggest that mothers taking sertraline can breast-feed without appreciably affecting peripheral or central 5-HT transport in their infants.
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Lactancia Materna , Depresión Posparto/tratamiento farmacológico , Recién Nacido/sangre , Proteínas de Transporte de Membrana , Leche Humana/metabolismo , Proteínas del Tejido Nervioso , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Serotonina/metabolismo , Sertralina/uso terapéutico , Plaquetas/química , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/metabolismo , Depresión Posparto/sangre , Depresión Posparto/metabolismo , Femenino , Humanos , Glicoproteínas de Membrana/efectos de los fármacos , Glicoproteínas de Membrana/metabolismo , Leche Humana/química , Leche Humana/efectos de los fármacos , Serotonina/sangre , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Inhibidores Selectivos de la Recaptación de Serotonina/análisis , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sertralina/análogos & derivados , Sertralina/análisis , Sertralina/sangre , Sertralina/farmacocinéticaRESUMEN
Teenage pregnancies have become a public health issue because of their observed negative effects on perinatal outcomes and long-term morbidity. The association of young maternal age and long-term morbidity is usually confounded, however, by the high prevalence of poverty, low level of education, and single marital status among teenage mothers. The authors assess the independent effect of teenage pregnancy on educational disabilities and educational problems in a total population of children who entered kindergarten in Florida in 1992--1994 and investigate how controlling for potentially confounding factors affects the relation between teenage pregnancies and poor outcome. When no other factors are taken into account, children of teenage mothers have significantly higher odds of placement in certain special education classes and significantly higher occurrence of milder education problems, but when maternal education, marital status, poverty level, and race are controlled, the detrimental effects disappear and even some protective effects are observed. Hence, the increased risk for educational problems and disabilities among children of teenage mothers is attributed not to the effect of young age but to the confounding influences of associated sociodemographic factors. In contrast to teen age, older maternal age has an adverse effect on a child's educational outcome regardless of whether other factors are controlled for or not.
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Discapacidades para el Aprendizaje/epidemiología , Edad Materna , Embarazo en Adolescencia/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Factores de Confusión Epidemiológicos , Escolaridad , Femenino , Florida/epidemiología , Humanos , Modelos Logísticos , Modelos Estadísticos , Oportunidad Relativa , Embarazo , Embarazo de Alto Riesgo , Factores de Riesgo , Tamaño de la Muestra , Factores SocioeconómicosRESUMEN
OBJECTIVE: To assess the relative effects and the impact of perinatal and sociodemographic risk factors on long-term morbidity within a total birth population in Florida. METHODS: School records for 339 171 children entering kindergarten in Florida public schools in the 1992-1993, 1993-1994, or 1994-1995 academic years were matched with Florida birth records from 1985 to 1990. Effects on long-term morbidity were assessed through a multivariate analysis of an educational outcome variable, defined as placement into 9 mutually exclusive categories in kindergarten. Of those categories, 7 were special education (SE) classifications determined by statewide standardized eligibility criteria, 1 was academic problems, and the reference category was regular classroom. Generalized logistic regression was used to simultaneously estimate the odds of placement in SE and academic problems. The impact of all risk factors was assessed via estimated attributable excess/deficit numbers, based on the multivariate analysis. RESULTS: Educational outcome was significantly influenced by both perinatal and sociodemographic factors. Perinatal factors had greater adverse effects on the most severe SE types, with birth weight <1000 g having the greatest effect. Sociodemographic predictors had greater effects on the mild educational disabilities. Because of their greater prevalence, the impact attributable to each of the factors (poverty, male gender, low maternal education, or non-white race) was between 5 and 10 times greater than that of low birth weight and >10 times greater than that of very low birth weight, presence of a congenital anomaly, or prenatal care. CONCLUSIONS: Results are consistent with the hypothesis that adverse perinatal conditions result in severe educational disabilities, whereas less severe outcomes are influenced by sociodemographic factors. Overall, sociodemographic factors have a greater total impact on adverse educational outcomes than perinatal factors.
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Discapacidades del Desarrollo/etiología , Educación Especial/estadística & datos numéricos , Escolaridad , Recién Nacido de Bajo Peso , Peso al Nacer , Preescolar , Discapacidades del Desarrollo/epidemiología , Niños con Discapacidad/educación , Niños con Discapacidad/estadística & datos numéricos , Educación Especial/economía , Femenino , Florida/epidemiología , Humanos , Recién Nacido , Modelos Logísticos , Masculino , Análisis Multivariante , Factores de Riesgo , Factores Sexuales , Factores SocioeconómicosRESUMEN
Current knowledge of genes that regulate pattern formation and differentiation processes during mammalian embryonic development is limited. In an effort to isolate developmentally relevant genes, 20 novel, end-sequenced cDNAs selected from a Day 10.5 postcoitum mouse embryo library were genetically mapped in intersubspecific backcross mice. Eleven of 20 cDNA clones mapped to three mouse autosomes (Chr 5, 11, and 14), a result that was unlikely (P < 0.03) if the distribution of genes expressed in embryos is random within the mouse genome. Several clones were candidates for mouse developmental mutations by virtue of genetic colocalization and concordance of embryonic expression patterns with the distribution of defects in mutant mice: Estm11 was a candidate for the mouse mutation wabbler-lethal (wl), since Estm11 mapped in the vicinity of wl on mouse Chr 14 and was expressed in those regions of embryonic brain that exhibit axonal degeneration in wl. End-sequence analysis, genetic mapping, and in situ hybridization appeared to be an effective combination of methods for identification and characterization of genes with potential regulatory functions during mammalian embryogenesis.