No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

Dynamic relationships between depressive symptoms and insulin resistance over 20 years of adulthood.

BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.

Does #Tamojunto alter the dynamic between drug use and school violence among youth? Secondary analysis from a large cluster-randomized trial.

The present study investigated how intervention might alter the relationship between perpetrating violence and later drug use. A cluster-randomized controlled trial design involving 72 schools (38 intervention, 34 control) and 6390 students attending grades 7 and 8 was employed in Brazil. Drug use and violence were assessed at three points. A random-intercept cross-lagged panel model examined the reciprocal association between drug use and school violence domains across the three data collection waves. For both groups, we found that the cross-lagged effect of perpetration on further drug use in adolescents was stronger than the reverse, but the interrelationship was not statistically significant between #Tamojunto and control schools. The carry-over effects of drug use and violence were also not significantly different between groups. There is a lack of evidence showing that #Tamojunto can modify the dynamics between drug use and school violence across the 21-month period. The direction of the causal effect (i.e., the more perpetration behavior, the more subsequent drug use behavior) is present, but weak in both groups. The trial registration protocol at the national Brazilian Register of Clinical Trials (REBEC) is #RBR-4mnv5g.

Adolescent depression beyond DSM definition: a network analysis.

Calls for refining the understanding of depression beyond diagnostic criteria have been growing in recent years. We examined the prevalence and relevance of DSM and non-DSM depressive symptoms in two Brazilian school-based adolescent samples with two commonly used scales, the Patient Health Questionnaire (PHQ-A) and the Mood and Feelings Questionnaire (MFQ). We analyzed cross-sectional data from two similarly recruited samples of adolescents aged 14-16 years, as part of the Identifying Depression Early in Adolescence (IDEA) study in Brazil. We assessed dimensional depressive symptomatology using the PHQ-A in the first sample (n = 7720) and the MFQ in the second sample (n = 1070). We conducted network analyses to study symptom structure and centrality estimates of the two scales. Additionally, we compared centrality of items included (e.g., low mood, anhedonia) and not included in the DSM (e.g., low self-esteem, loneliness) in the MFQ. Sad mood and worthlessness items were the most central items in the network structure of the PHQ-A. In the MFQ sample, self-hatred and loneliness, two non-DSM features, were the most central items and DSM and non-DSM items in this scale formed a highly interconnected network of symptoms. Furthermore, analysis of the MFQ sample revealed DSM items not to be more frequent, severe or interconnected than non-DSM items, but rather part of a larger network of symptoms. A focus on symptoms might advance research on adolescent depression by enhancing our understanding of the disorder.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Bullying as a Risk Factor for Eating Disorder Behaviors Among Students: Secondary Analysis for a Cluster Randomized Controlled Trial.

This study aimed to examine whether being a victim of bullying predicted body dissatisfaction and eating disorder behavior (EDB). In this study, we performed secondary analysis from a cluster randomized controlled trial among 5208 eight grade students from 73 public schools in three Brazilian cities. Data were collected in 2019 through an anonymous self-report questionnaire on bullying, body dissatisfaction, and EDB. We used factor analysis, multivariate linear regression, and multinomial logistic regression to verify whether being a victim of bullying during the baseline results in body dissatisfaction and EDB at the nine months follow-up for the control and intervention groups. Our results showed that being female (OR 1.41, 95% CI 1.22-1.63) is a risk factor for dissatisfaction by overweight. Bullying was not a predictor of body dissatisfaction; however, being a victim of bullying (ß 0.40, 95% CI 0.35-0.46) is a predictor of having more EDB, independent of the exposure to the program. Therefore, bullying deserves attention in the school environment.

Disentangling change across the time and true stability of employees' resilience using latent state model.

There is debate within the literature about whether resilience should be considered a stable character trait or a dynamic, changeable process (state). Two widely used measures to assess resilience are the Connor-Davidson Resilience Scale (CD-RISC) and the Resilience Scale for Adults (RSA). The aim of this study was to evaluate the true stability (invariance) and change across time in resilience captured by these two measures. Using the perspective of Latent State-Trait theory, the aim was to decipher if the CD-RISC and the RSA are more trait-like or more state-like and to address whether true differences in resilience between participants increased (or decreased) across time. In this longitudinal study, UK-based employees (N = 378) completed the CD-RISC (10-item version) and the RSA (33-item version, aggregated and analyzed under six parcels) at three occasions over six months. A latent-state model and latent-state model with indicator specific residual factors were utilized. The analysis suggested that both questionnaires capture trait and state components of resilience. These results contribute to the discussion about how resilience scales are measuring change and stability, and how we define resilience as a more trait-like or state-like phenomena. The findings also highlight the issue of what resilience scales are measuring and whether resilience is a quantifiable construct.

Investigating the Measurement Invariance and Method-Trait Effects of Parent and Teacher SNAP-IV Ratings of Preschool Children.

The Swanson, Nolan, and Pelham scale version IV (SNAP-IV) is widely used to assess symptoms of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) in children and adolescents. Nevertheless, there is insufficient data to support its use in preschool children. The study had three goals: First, to test the factorial validity of the three correlated-factors model of ADHD and ODD items of the SNAP-IV. Second, to investigate the measurement invariance of the items over time (6-month longitudinal interval) and by sex. Third, to investigate the convergent validity and method-specific influences on ADHD/ODD assessments with respect to multiple raters (parents/teachers) of children's symptoms. Participants were 618 preschool children (3.5-6 years) at baseline and 6-month follow-up. For model testing, we used confirmatory factor analysis for categorical observed variables. Method and trait effects were examined using the CT-C(M-1) model. The analyses showed partial measurement invariance over time and according to sex. Moreover, strong rater-specific effects were detected. The implication of the results for construct validation of the instrument and clinical assessment of ADHD and ODD traits are discussed.

Reciprocal Predictive Relationships between Amyloid and Tau Biomarkers in Alzheimer's Disease Progression: An Empirical Model.

There is an urgent need to understand the relationships between amyloid-ß (Aß) and tau in the progression of Alzheimer's disease to identify treatment targets. Here we examine reciprocal predictions of brain Aß burden quantified by positron emission tomography and CSF concentrations of Aß42 and phosphorylated tau (p-tau). Each biomarker was examined over 48 months in two separate cross-lagged models; one in asymptomatic healthy elderly people (men and women), and one in patients with Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI). The models examine predictions of each biomarker on the progression of the others, considering each previous and concurrent measure. In healthy elderly, lower CSF Aß42 predicted Aß deposition and reciprocally, Aß burden predicted a decrease in CSF Aß42. Lower CSF Aß42 predicted an increase in CSF p-tau, and CSF p-tau predicted Aß deposition. In AD/MCI, lower CSF Aß42 predicted Aß deposition and Aß burden reciprocally predicted CSF Aß42 changes; however, in contrast to healthy elderly, CSF p-tau concentrations did not predict Aß biomarkers, or vice versa. In post hoc models examining cognitive status, CSF Aß42 predicted Mini Mental State Examination (MMSE) scores in healthy elderly, whereas Aß burden and CSF p-tau predicted MMSE scores in AD/MCI. The findings describe reciprocal predictions between Aß and tau biomarkers in healthy elderly and they implicate mechanisms underlying low CSF Aß42 in Alzheimer's disease pathogenesis and progression. In symptomatic Alzheimer's disease, CSF Aß42 and Aß deposition predicted each other; however, Aß and CSF p-tau progressed independently and they independently predicted cognitive decline.SIGNIFICANCE STATEMENT This study offers empirical evidence concerning the hypothesized "amyloid cascade", as it progressed over 4 years in healthy elderly people and in Alzheimer's disease patients. In healthy elderly, CSF amyloid changes predicted amyloid deposition, CSF phosphorylated tau concentrations, and a decline in cognitive status. Phosphorylated tau concentrations specifically predicted amyloid deposition. In Alzheimer's disease patients, although amyloid deposition and CSF amyloid changes continued to "cascade", there was no evidence to suggest that amyloid and tau biomarkers predicted each other, although both amyloid deposition and CSF tau progression predicted cognitive decline independently. Taking advantage of repeated amyloid PET and CSF measures, this dynamic view offers new insight into the progression of Alzheimer's disease biomarkers and their relationships with cognitive decline.

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer's disease.

BACKGROUND: Studies suggest a role of the innate immune system, including the activity of neutrophils, in neurodegeneration related to Alzheimer's disease (AD), but prospective cognitive data remain lacking in humans. We aimed to investigate the predictive relationship between neutrophil-associated inflammatory proteins in peripheral blood and changes in memory and executive function over 1 year in patients with AD. METHODS: Participants with AD were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neutrophil gelatinase-associated lipocalin (NGAL), myeloperoxidase (MPO), interleukin-8 (IL-8), macrophage inflammatory protein-1 beta (MIP-1ß), and tumor necrosis factor (TNF) were assayed by luminex immunofluorescence multiplex assay at baseline. Confirmatory factor analysis was used to test an underlying neutrophil associated plasma inflammatory factor. Composite z-scores for memory and executive function were generated from multiple tests at baseline and at 1 year. A multiple linear regression model was used to investigate the association of the baseline inflammatory factor with changes in memory and executive function over 1 year. RESULTS: Among AD patients (n = 109, age = 74.8 ± 8.1, 42% women, Mini Mental State Examination [MMSE] = 23.6 ± 1.9), the neutrophil-related inflammatory proteins NGAL (λ = 0.595, p < .001), MPO (λ = 0.575, p < .001), IL-8 (λ = 0.525, p < .001), MIP-1ß (λ = 0.411, p = .008), and TNF (λ = 0.475, p < .001) were found to inform an underlying factor. Over 1 year, this inflammatory factor predicted a decline in executive function (ß = - 0.152, p = 0.015) but not memory (ß = 0.030, p = 0.577) in models controlling for demographics, brain atrophy, white matter hyperintensities, the ApoE ε4 allele, concomitant medications, and baseline cognitive performance. CONCLUSIONS: An inflammatory factor constructed from five neutrophil-related markers in peripheral blood predicted a decline in executive function over 1 year in people with mild AD.

Are serum brain-derived neurotrophic factor concentrations related to brain structure and psychopathology in late childhood and early adolescence?

OBJECTIVE: Mental disorders can have a major impact on brain development. Peripheral blood concentrations of brain-derived neurotrophic factor (BDNF) are lower in adult psychiatric disorders. Serum BDNF concentrations and BDNF genotype have been associated with cortical maturation in children and adolescents. In 2 large independent samples, this study tests associations between serum BDNF concentrations, brain structure, and psychopathology, and the effects of BDNF genotype on BDNF serum concentrations in late childhood and early adolescence. METHODS: Children and adolescents (7-14 years old) from 2 cities (n = 267 in Porto Alegre; n = 273 in São Paulo) were evaluated as part of the Brazilian high-risk cohort (HRC) study. Serum BDNF concentrations were quantified by sandwich ELISA. Genotyping was conducted from blood or saliva samples using the SNParray Infinium HumanCore Array BeadChip. Subcortical volumes and cortical thickness were quantified using FreeSurfer. The Development and Well-Being Behavior Assessment was used to identify the presence of a psychiatric disorder. RESULTS: Serum BDNF concentrations were not associated with subcortical volumes or with cortical thickness. Serum BDNF concentration did not differ between participants with and without mental disorders, or between Val homozygotes and Met carriers. CONCLUSIONS: No evidence was found to support serum BDNF concentrations as a useful marker of developmental differences in brain and behavior in early life. Negative findings were replicated in 2 of the largest independent samples investigated to date.

Evaluating the effects of parenting styles dimensions on adolescent drug use: secondary analysis of #Tamojunto randomized controlled trial.

The present study examined parenting style dimensions (demandingness and responsiveness) as predictors of adolescent drug use and also evaluated whether parenting styles dimensions moderate the effects of the implemented prevention program. 6.391 students in the 7th and 8th grades at 72 Brazilian public schools participated in a three-wave randomized controlled trial to evaluate a school drug-use prevention program. We used structural equation modeling to test if baseline parenting style dimensions (demandingness and responsiveness) would predict the use of drugs (alcohol, binge drinking, cannabis, inhalants, and tobacco) after 21 months. Additionally, we evaluated an interaction version of the above-described model to test if the effect of the prevention program would be moderated by either or both parenting style dimensions. Higher levels of parent demandingness predicted lower chances of adolescent drug use (e.g., Cigarette use OR 0.76, 95% CI 0.64-0.89); responsiveness on the five outcomes showed p value superior to 0.01. The effect of the #Tamojunto intervention is unlikely to be conditioned to either parenting style dimensions on the assessed outcomes.Clinical trial registration Brazilian Register of Clinical Trials (REBEC): #RBR-4mnv5g ( https://www.ensaiosclinicos.gov.br/rg/?q=tamojunto ).

Dimensional analysis of depressive, anxious and somatic symptoms presented by primary care patients and their relationship with ICD-11 PHC proposed diagnoses.

BACKGROUND: A study conducted as part of the development of the Eleventh International Classification of Mental Disorders for Primary Health Care (ICD-11 PHC) provided an opportunity to test the relationships among depressive, anxious and somatic symptoms in PHC. METHOD: Primary care physicians participating in the ICD-11 PHC field studies in five countries selected patients who presented with somatic symptoms not explained by known physical pathology by applying a 29-item screening on somatic complaints that were under study for bodily stress disorder. Patients were interviewed using the Clinical Interview Schedule-Revised and assessed using two five-item scales that measure depressive and anxious symptoms. Structural models of anxious-depressive symptoms and somatic complaints were tested using a bi-factor approach. RESULTS: A total of 797 patients completed the study procedures. Two bi-factor models fit the data well: Model 1 had all symptoms loaded on a general factor, along with one of three specific depression, anxiety and somatic factors [x2 (627) = 741.016, p < 0.0011, RMSEA = 0.015, CFI = 0.911, TLI = 0.9]. Model 2 had a general factor and two specific anxious depression and somatic factors [x2 (627) = 663.065, p = 0.1543, RMSEA = 0.008, CFI = 0.954, TLI = 0.948]. CONCLUSIONS: These data along with those of previous studies suggest that depressive, anxious and somatic symptoms are largely different presentations of a common latent phenomenon. This study provides support for the ICD-11 PHC conceptualization of mood disturbance, especially anxious depression, as central among patients who present multiple somatic symptoms.

Birth weight, verbal cognition in early adolescence, and lexical and reading skills in late adolescence: a formal mediation analysis using a potential outcomes approach.

BACKGROUND: Oral and written language in late adolescence are influenced by many pre- and postnatal factors, including cognitive performance at earlier ages. We investigated whether the association between birth weight and lexical knowledge and reading comprehension in late adolescence (14-16 years) is mediated by verbal cognition during early adolescence (10-11 years). METHODS: We conducted a mediation analysis via a potential outcomes approach to data from three United Kingdom (UK) prospective birth cohorts - The National Child Development Study (NCDS; year of birth (Y.B.) = 1,958; analytic sample size (A.N.) = 9,399; original sample size (O.N.) = 18,558), British Cohort Study (BCS70; Y.B. = 1,970; A.N. = 6,591; O.N. = 17,196), and Millennium Cohort Study (MCS; Y.B. = 2,000-2,001; A.N. = 3,950; O.N. = 18,552) - to evaluate the indirect effects of birth weight on lexical knowledge (BCS and MCS) and reading comprehension measures (NCDS) in adolescence. RESULTS: We found an indirect effect but no statistically significant direct effects for the BCS and MCS cohorts. The proportion of the effect of birth weight on oral and written language in late adolescence mediated by early adolescence verbal cognition was 59.19% (BCS) and 8.41% (MCS) for lexical knowledge and 61.00% when the outcome was reading comprehension (NCDS). Sensitivity analyses, used to assess whether unmeasured variables could have affected our mediation estimates, showed that for reading comprehension, in NCDS, the indirect effect is robust; only unmeasured confounders highly correlated with the mediator and outcome (ρ = .68) would explain away the indirect effect. For lexical knowledge, smaller correlations with hypothetical confounders (ρ = .33 for BCS) would suffice to render the indirect effect non-significant; the indirect effect for MCS non statistical significant. CONCLUSIONS: Birth weight affects oral and written language skills (lexical knowledge and reading comprehension) in late adolescence via verbal cognition in early adolescence in two cohorts born in 1958 and 1970, but not in a cohort born at the turn of the millennium. These indirect effects were stronger than the direct effects and are unlikely to be explained by unmeasured confounders when the outcome involves complex skills such as reading comprehension.

Effectiveness evaluation of the school-based drug prevention program #Tamojunto2.0: protocol of a cluster randomized controlled trial.

BACKGROUND: The European school-based drug addiction prevention program Unplugged was adapted to the Brazilian context by the Ministry of Health and renamed #Tamojunto. Its first implementations, in the form of a public policy in Brazil, showed contradictory and different effects from those observed in Europe. Adaptations were made to #Tamojunto in 2018 to reintroduce the essential content of the original program. METHODS: A parallel, two-arm, randomized controlled trial (RCT) will be conducted to evaluate the effectiveness of the new version of the school-based government program #Tamojunto2.0 for the prevention of drug use among 8th grade middle school students from 70 public schools in three Brazilian cities, totaling approximately 6.300 participating students distributed in 210 classes. For intervention, the experimental group will receive the 12 lessons of the #Tamojunto2.0 program under the supervision of a Brazilian Ministry of Health team. The control group will not receive any intervention. Information will be collected from the students at three time points: preintervention and 9 and 18 months postintervention. Multilevel analyses will be performed using the Gllamm Stata program to assess simultaneous differences in prevalence, in time and among groups for the outcomes of interest. Structural equation modeling will be used to evaluate the effectiveness of the intervention in changing the behavioral patterns of the adolescents through latent transition analysis. The effect of the mediators involved in the program effectiveness outcomes will also be analyzed. The program doses applied in all classes of the intervention group will be collected using a form completed by the teacher at the end of each lesson, indicating the activities taught and not taught in each lesson. DISCUSSION: This study will show whether the #Tamojunto2.0 program can be expanded as a public policy for all schools with the aim of preventing drug use among Brazilian students. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (RBR-8cnkwq) under the name "Avaliação do Efeito do Programa de Prevenção Escolar ao Uso de Drogas #Tamojunto2.0, Versão 2018", on August 30th, 2018 ( http://www.ensaiosclinicos.gov.br/rg/RBR-8cnkwq/ ).

Predicting latent classes of drug use among adolescents through parental alcohol use and parental style: a longitudinal study.

PURPOSE: The present study examined the roles of parental alcohol use and parental style as predictors of adolescent patterns of drug use. METHODS: 6391 students in the 7th and 8th grades at 72 Brazilian public schools participated in a three-wave randomized controlled trial to evaluate a school drug-use prevention program. Patterns of drug use were identified through two latent class analyses using measures of the adolescents' past-year drug use. Multinomial logistic regression analyses examined whether parental alcohol use and parenting style at baseline predicted patterns of drug use in waves 2 and 3 of the study after controlling for sociodemographic covariates. RESULTS: In each of the two waves, three latent classes of drug use were identified among the students, defining three different groups of individuals: (1) abstainers/low users, (2) alcohol users/binge drinkers, and (3) polydrug users. First, parenting style (especially monitoring) was the strongest predictor for the prevention of polydrug use among adolescents. Second, occasional alcohol use by parents can act as a central predictor for adolescent alcohol use and binge drinking. Above all, maternal episodes of drunkenness were involved in the predictive models for both drug use classes in both waves. CONCLUSION: Parental alcohol use and parenting style seem to be important predictors of adolescent's likelihood of belonging to different latent classes of drug use. This conclusion may point to the importance of considering the inclusion of parenting skills and parental alcohol use within the scope of adolescents' preventive interventions.

Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: A report from the Latin American Group of Osteosarcoma Treatment.

BACKGROUND: Metronomic chemotherapy (MC) consists of the administration of a low dose of chemotherapy on a daily or weekly basis without a long break to achieve an antitumoral effect through an antiangiogenic effect or stimulation of the immune system. The potential effect of MC with continuous oral cyclophosphamide and methotrexate in patients with high-grade operable osteosarcomas (OSTs) of the extremities was investigated. METHODS: Patients with high-grade OSTs who were 30 years old or younger were eligible for registration at diagnosis. Eligibility for randomization included 1) nonmetastatic disease and 2) complete resection of the primary tumor. The study design included a backbone of 10 weeks of preoperative therapy with methotrexate, adriamycin, and platinum (MAP). After surgery, patients were randomized between 2 arms to complete 31 weeks of MAP or receive 73 weeks of MC after MAP. The primary endpoint was event-free survival (EFS) from randomization. RESULTS: There were 422 nonmetastatic patients registered (May 2006 to July 2013) from 27 sites in 3 countries (Brazil, Argentina and Uruguay), and 296 were randomized to MAP plus MC (n = 139) or MAP alone (n = 157). At 5 years, the EFS cumulative proportions surviving in the MAP-MC group and the MAP-alone group were 61% (standard error [SE], 0.5%) and 64% (SE, 0.5%), respectively, and they were not statistically different (Wilcoxon [Gehan] statistic = 0.724; P =.395). The multivariate analysis showed that necrosis grades 1 and 2, tumor size, and amputation were associated with shorter EFS. CONCLUSIONS: According to the current follow-up, EFS with MAP plus MC is not statistically superior to EFS with MAP alone in patients with high-grade, resectable OSTs of the extremities. Cancer 2017;123:1003-10. © 2016 American Cancer Society.

New evidence in support of staging approaches in schizophrenia: Differences in clinical profiles between first episode, early stage, and late stage.

Few studies have examined the progression of symptom dimensions in schizophrenia patients over the course of the illness. The objective of this study was to investigate whether clinical and psychopathological differences exist between first-episode schizophrenia (FES) and multiple-episode patients in an inpatient setting. Patients (N=203) were evaluated using the Positive and Negative Syndrome Scale (PANSS) over time. Five different generalized estimating equations were built for the PANSS factors using the following as covariates: sex, patient's age, assessment time point (i.e., moment of patient's evaluation, with a minimum of two and a maximum of four assessments throughout the study timeframe). The FES group was used as the reference to which the groups with up to five years of illness and more than five years of illness were compared. Remission rates and treatment resistance (TRS) rates were also compared. Generalized estimating equations were used to allow for different numbers of assessments over the study period. Patients with FES showed significantly milder severity in positive, disorganized, and hostility factors. Also, FES patients were more likely to achieve remission (P=0.002) and had lower rates of TRS (P=0.001). First-episode schizophrenia seems to be the critical period to improve outcome, as multiple-episode patients were similar in clinical characteristics regardless of illness duration.

Psychopathology and friendship in children and adolescents: disentangling the role of co-occurring symptom domains with serial mediation models.

The consolidation of social friendship groups is a vital part of human development. The objective of this study is to understand the direct and indirect influences of three major symptomatic domains-emotional, hyperkinetic, and conduct-on friendship. Specifically, we aim to study if the associations of one domain with friendship may be mediated by co-occurring symptoms from another domain. A total of 2512 subjects aged 6-14 years participated in this study. Friendship was evaluated by the Development and Well-Being Assessment's friendship section. We evaluated two main constructs as outcomes: (1) social isolation and (2) friendship latent construct. Emotional, hyperkinetic, and conduct symptomatic domains were evaluated with the Strengths and Difficulties Questionnaire (SDQ). All SDQ domains were positively associated with social isolation and negatively associated with friendship latent construct in univariate analysis. However, serial mediation models showed that the association between conduct domains with social isolation was mediated by emotion and hyperkinetic domains. Moreover, the associations between emotional and hyperkinetic domains with friendship latent construct in non-isolated children were mediated by the conduct domain. Emotion and hyperkinetic domains were directly and indirectly associated with social isolation, whereas conduct was directly and indirectly associated with overall friendship in non-isolated children. Results suggest that interventions aimed to improve social life in childhood and adolescence may have stronger effects if directed towards the treatment of emotion and hyperkinetic symptoms in socially isolated children and directed towards the treatment of conduct symptoms in children with fragile social connections.