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Background Machine learning methods for suicidal behavior so far have failed to be implemented as a prediction tool. In order to use the capabilities of machine learning to model complex phenomenon, we assessed the predictors of suicide risk using state-of-the-art model explanation methods. Methods Prospective cohort study including a community sample of 1,560 young adults aged between 18 and 24. The first wave took place between 2007 and 2009, and the second wave took place between 2012 and 2014. Sociodemographic and clinical characteristics were assessed at baseline. Incidence of suicide risk at five-years of follow-up was the main outcome. The outcome was assessed using the Mini Neuropsychiatric Interview (MINI) at both waves. Results The risk factors for the incidence of suicide risk at follow-up were: female sex, lower socioeconomic status, older age, not studying, presence of common mental disorder symptoms, and poor quality of life. The interaction between overall health and socioeconomic status in relation to suicide risk was also captured and shows a shift from protection to risk by socioeconomic status as overall health increases. Limitations Proximal factors associated with the incidence of suicide risk were not assessed. Conclusions Our findings indicate that factors related to poor quality of life, not studying, and common mental disorder symptoms of young adults are already in place prior to suicide risk. Most factors present critical non-linear patterns that were identified. These findings are clinically relevant because they can help clinicians to early detect suicide risk.

Introduction Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. Methods We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. Results PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. Conclusion As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

We conducted a randomized trial of portable HEPA air cleaners in the homes of children age 6-12 years with asthma in the Yakima Valley, Washington. All families received asthma education while intervention families also received two HEPA cleaners (child's bedroom, living room). We collected 14-day integrated samples of endotoxin in settled dust and PM10 and PM10-2.5 in the air of the children's bedrooms at baseline and one-year follow-up, and used linear regression to compare follow-up levels, adjusting for baseline. Seventy-one families (36 HEPA, 35 control) completed the study. Baseline geometric mean (GSD) endotoxin loadings were 1565 (6.3) EU/m2 and 2110 (4.9) EU/m2 , respectively, in HEPA vs. control homes while PM10 and PM10-2.5 were 22.5 (1.9) μg/m3 and 9.5 (2.9) μg/m3 , respectively, in HEPA homes, and 19.8 (1.8) μg/m3 and 7.7 (2.0) μg/m3 , respectively, in control homes. At follow-up, HEPA families had 46% lower (95% CI, 31%-57%) PM10 on average than control families, consistent with prior studies. In the best-fit heterogeneous slopes model, HEPA families had 49% (95% CI, 6%-110%) and 89% lower (95% CI, 28%-177%) PM10-2.5 at follow-up, respectively, at 50th and 75th percentile baseline concentrations. Endotoxin loadings did not differ significantly at follow-up (4% lower, HEPA homes; 95% CI, -87% to 50%).

This study aimed to assess the association between tobacco smoking and body composition in patients with HIV/AIDS in combination antiretroviral therapy (cART). This is a cross-sectional study with people of HIV followed in specialized care service for HIV patients located in the South of Brazil. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) was used to assess smoking and other psychoactive substance use. Body mass index (BMI) was calculated as the ratio of body weight (in kilograms) to squared height (in meters). Patients also had their body composition evaluated with a multi-frequency bioelectrical impedance (Bodystat® Quadscan 4000, RU) to estimate skeletal muscle index (SMI). In total, 320 subjects were included in the study. The prevalence of smoking was 54.7%. Tobacco smoking was associated with malnutrition, lower body mass index scores, and lower skeletal muscle mass index. It is concluded that there is a high prevalence of smoking among patients with HIV/AIDS and that this behavior is associated with worse body composition. Thus, it is suggested to implement strategies to support smoking cessation among people with HIV/AIDS. Resumo O objetivo deste estudo foi avaliar a relação entre tabagismo e composição corporal em pacientes com HIV/AIDS em terapia antirretroviral combinada (TARVc). Trata-se de um estudo transversal com portadores de HIV acompanhados em um serviço de atendimento especializado localizado no Sul do Brasil. O instrumento Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) foi utilizado para avaliar o uso de tabaco e outras substâncias psicoativas. O índice de massa corporal (IMC) foi calculado como a razão do peso corporal (em quilogramas) pela altura ao quadrado (em metros). Os pacientes também tiveram sua composição corporal avaliada com uma impedância bioelétrica de múltiplas frequências (Bodystat® Quadscan 4000, RU) a fim de estimar o índice de massa muscular esquelética. No total, 320 sujeitos foram incluídos no estudo. A prevalência de tabagismo foi de 54,7%. O tabagismo foi associado à desnutrição, menores escores do índice de massa corporal e menor índice de massa muscular esquelética. Conclui-se que há uma alta prevalência de tabagismo entre pacientes com HIV/AIDS e que esse comportamento está associado a pior composição corporal. Assim, sugere-se a implementação de estratégias de apoio à cessação do tabagismo entre pessoas com HIV/AIDS.

We conducted a randomized trial of portable HEPA air cleaners with pre-filters designed to also reduce NH3 in non-smoking homes of children age 6-12 with asthma in Yakima Valley (Washington, USA). Participants were recruited through the Yakima Valley Farm Workers Clinic asthma education program. All participants received education on home triggers while intervention families additionally received two HEPA cleaners (child's sleeping area, main living area). Fourteen-day integrated samples of PM2.5 and NH3 were measured at baseline and one-year follow-up. We fit ANCOVA models to compare follow-up concentrations in HEPA versus control homes, adjusting for baseline concentrations. Seventy-one households (36 HEPA, 35 control) completed the study. Most were single-family homes, with electric heat and stove, A/C, dogs/cats, and mean (SD) 5.3 (1.8) occupants. In the sleeping area, baseline geometric mean (GSD) PM2.5 was 10.7 (2.3) µg/m3 (HEPA) versus 11.2 (1.9) µg/m3 (control); in the living area, it was 12.5 (2.3) µg/m3 (HEPA) vs. 13.6 (1.9) µg/m3 (control). Baseline sleeping area NH3 was 62.4 (1.6) µg/m3 (HEPA) vs. 65.2 (1.8) µg/m3 (control). At follow-up, HEPA families had 60% (95% CI, 41%-72%; p < 0.0001) and 42% (19%-58%; p = 0.002) lower sleeping and living area PM2.5 , respectively, consistent with prior studies. NH3 reductions were not observed.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Background Studies on the field of mood disorders has mainly focusing on the risk factors associated to develop the illness or the clinical factors associated with the clinical progression. Less attention was given to factors such as resilience that may be associated with better outcomes in the course of mood disorders. In this study, we assessed the mediation effect of resilience on the relationship between childhood trauma and mood disorders, as well as the severity of depressive symptoms in a population-based sample. Methods This is a cross-sectional study with a community sample of young adults with bipolar disorder (BD), major depressive disorder (MDD), and community controls without any mood disorder. The trauma experiences during childhood were assessed by Childhood Trauma Questionnaire (CTQ). The severity of depressive symptoms was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and to assess the resilience was used the Resilience Scale (RS-25). Results All subtypes of trauma were associated with both MDD and BD, however, only physical and emotional abuse differentiated BD from MDD subjects. Bootstrapping-enhanced mediation analyses indicated that resilience partly mediated the association of childhood trauma to both mood disorder and severity of depression. Limitation The employed mediation analyses are cross-sectional in nature, which limits any firm conclusions regarding causality. Conclusions The findings support the clinical assumption that resilient subjects may be partly protected against the detrimental long-term effects of childhood trauma. This study provides important information regarding the relationships among childhood trauma, resilience, and mood disorder.

Introduction Childhood trauma has been suggested to be involved in susceptibility to bipolar disorder (BP). However, it remains unclear whether the occurrence of childhood trauma is differently distributed in subthreshold bipolar disorder (SBP). Objective To assess childhood trauma in young adults with SBP, as compared to young adults with BP and population controls (PC). Method This was a cross-sectional, population-based study. The Mini International Neuropsychiatric Interview (MINI) was used to define the groups with BP (subjects with a lifetime or current manic episode or lifetime or current hypomania with a history of a depressive episode), SBP (subjects with a history of hypomanic episode without lifetime or current depressive episode), and subjects without mood disorders (PC). Childhood trauma was assessed using de Childhood Trauma Questionnaire (CTQ). We investigated differences regarding childhood trauma across the three groups (BP, SBP and PC). Result Except for sexual abuse, all subtypes of childhood trauma remained associated with the BP group as compared to PC. Additionally, when we compared SBP and BP, significant differences were found only for emotional abuse. No significant differences were found in relation to childhood trauma between the SBP and PC groups after adjusting for confounding factors. Conclusion These findings suggest that investigating childhood trauma, with a particular focus on emotional abuse, could be considered a preventive measure and potentially improve the prognosis.

Background While little is known about the occupational hazards associated with Cannabis cultivation, both historical research in the hemp industry and preliminary data from modern grow houses, suggest that Cannabis workers may be at increased risk of respiratory and allergic diseases. Objectives We sought to investigate the association between workplace exposures and health symptoms in an indoor Cannabis grow facility in Washington State, USA. Methods We performed a cross-sectional study with all consenting employees in an indoor Cannabis grow facility in Seattle, WA using a questionnaire. The questionnaire gathered data on respiratory, ocular, nasal, and dermal symptoms. A subset of employees with work-related symptoms underwent repeated cross-shift and cross-week measurement of spirometry, fractional exhaled nitrogen oxide (FeNO), and skin prick testing for Cannabis sensitization. Exposure to Cannabis dust was classified based on self-described tasks, expert opinion, and exposure monitoring of particulate matter. Multivariable logistic regression was undertaken to examine associations between exposure to Cannabis dust (classified as low, medium, and high) and health symptoms. Linear mixed effects models examined the relationship between cross-shift and cross-week changes in spirometry and FeNO. Results Ninety-seven percent (97%) of the employees (n = 31) surveyed were recreational cannabis users, with 81% (n = 25) smoking cannabis multiple times per day. Twenty-two (71%) employees reported one or more work-related symptoms: 65% respiratory, 39% ocular, 32% nasal, and 26% dermal symptoms. There was a trend toward increased likelihood of work-related symptoms with increasing exposure to Cannabis dust, although none of these results were statistically significant. Of the 10 employees with work-aggravated symptoms, 5 had borderline-high or high FeNO, 7 had abnormal spirometry, and 5 had evidence of Cannabis sensitization on skin prick testing. FeNO increased by 3.78 ppb (95% confidence interval 0.68–6.88 ppb) across the work-week and there was a trend toward cross-week and cross-shift reduced airflow. Conclusions We found a high prevalence of work-related allergic- and particularly respiratory symptoms in the employees of one indoor Cannabis grow facility in Washington State. A high proportion of employees with work-aggravated symptoms had findings consistent with probable work-related asthma based on high FeNO, airflow obstruction on spirometry, and Cannabis sensitization on skin prick testing. However, due to the high incidence of recreational cannabis use among these workers, the relative influence of occupational versus recreational exposure to Cannabis dust on the respiratory health and sensitization status of these workers could not be resolved in this study.

Suicide is the second leading cause of death among young adults worldwide, and few studies have assessed the factors associated with suicidality in this specific population. Thus, the aim of this study was to assess the association between mixed episodes and suicidality in a community sample of young adults. For this aim, we compared young adults in a mixed episode with individuals in a depressive or (hypo)manic episode, and community controls.This is a cross-sectional population-based study including young adults aged 18-24 years old. Information about participants' age, sex, self-reported skin color and study status were obtained using a sociodemographic questionnaire. Mixed, (hypo)manic and depressive episodes, as well as suicide risk were assessed using the Mini International Neuropsychiatric Interview.The sample included 1560 individuals. Young adults in a mixed episode showed a 13.50 times higher probability to have suicide risk, as compared to community controls (p 0.001), 5.67 higher probability to have suicide risk as compared to individuals in a (hypo)manic episode (p 0.001), and 2.18 times higher probability to have suicide risk as compared to young adults in a depressive episode (p 0.001).The assessment of suicide risk includes both suicide attempts and ideation.Young adults in a mixed episode showed a higher rate of suicide risk than individuals with depression or mania/hypomania. Considering the already increasing prevalence of suicide among young adults, there is an urgent need for the early diagnosis and treatment of mixed episodes in this specific population.

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f −/− mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.

Background Data on pediatric asthma morbidity and effective environmental interventions in U.S. agricultural settings are few. We evaluated the effectiveness of HEPA air cleaners on asthma morbidity among a cohort of rural Latino children. Methods Seventy-five children with poorly controlled asthma and living in non-smoking homes were randomly assigned to asthma education alone or along with HEPA air cleaners placed in their sleeping area and home living room. The Asthma Control Test (ACT) score, asthma symptoms in prior 2 weeks, unplanned clinical utilization, creatinine-adjusted urinary leukotriene E4 (uLTE4 [ng/mg]), and additional secondary outcomes were evaluated at baseline, six, and 12 months. Group differences were assessed using multivariable-adjusted generalized estimating equations. Incident rate ratios of ever experiencing the metrics of poorer asthma health during follow-up (suboptimal asthma management) were estimated using Poisson regression models in secondary analysis. Results Mean child age was 9.2 and 8.6 years in intervention and control groups, respectively, and two-thirds of participants were male. Primary analysis of repeated measures of ACT score did not differ between groups (HEPA group mean change compared to controls 10% [95% CI: − 12-39%]). A suggestion of greater decrease in uLTE4 (ng/mg creatinine) was observed (− 10% [95% CI: − 20 -1%]). Secondary analysis showed children with HEPAs were less likely to have an ACT score meeting a clinically defined cutoff for poorly controlled asthma using repeated measures (IRR: 0.45 [95% CI: 0.21–0.97]). In Poisson models, intervention participants had reduced risk of ever meeting this cutoff (IRR: 0.43 [95% CI: 0.21–0.89]), ever having symptoms in the past 2 weeks (IRR: 0.71 [95% CI: 0.52–0.98]), and lower risk of any unplanned clinical utilization (IRR: 0.35 [95% CI: 0.13–0.94]) compared to control participants. Discussion The HAPI study showed generally improved outcomes among children in the HEPA air cleaner group. However, primary analyses did not meet statistical significance and many outcomes were subjective (self-report) in this unblinded study, so findings must be interpreted cautiously. HEPA air cleaners may provide additional benefit for child asthma health where traditional asthmagens (traffic, tobacco smoke) are not prominent factors, but larger studies with more statistical power and blinded designs are needed. Trial registration ClinicalTrials.gov Identifier: NCT04919915. Date of retrospective registration: May 19, 2021.

Background Bipolar disorder (BD) has a high heritability rate. Current studies have been dedicated to identifying prodromes of BD in the offspring of parents with BD (BO), and the sleep patterns of these individuals have been considered important factors. Objective To describe the changes in sleep parameters among offspring of parents with BD when compared to offspring of controls and to identify if changes in parameters and quality of sleep predict the onset of BD among these individuals. Methods PubMed, PsycINFO, and Embasewere systematically searched with no year or language restrictions, up to August 18, 2020. We searched for a combination of the following search items ("sleep*") AND ("bipolar disorder*" OR "mania" OR "hypomania" OR "bipolar depression") AND ("ultra-high risk" OR "high risk" OR "offspring" OR "first degree relatives"). Results A total of 10 studies were included in the systematic review and 4 studies were included in the meta-analysis. Our meta-analysis showed that the BO showed greater daytime sleepiness as compared to the offspring of control parents. The systematic review indicates that shorter sleep duration, sleep disorders and other related features can differentiate the two groups. Finally, some sleep patterns such as: decreased sleep, difficulty falling asleep, and overall sleep problems might be predictors for the development of BD. Conclusion To describe the changes in sleep parameters among offspring of parents with BD when compared to offspring of controls and to identify if changes in parameters and quality of sleep predict the onset of BD among these individuals.

The aim of this paper is to analyse the factors associated with the dropout from brief psychotherapy for adults with major depressive disorder (MDD) treated at a mental health outpatient clinic. This is a randomized clinical trial with two models of psychotherapy: cognitive behavioural therapy (CBT) and supportive expressive dynamic psychotherapy (SEDP). MDD and anxiety disorders were evaluated through the Mini International Neuropsychiatric Interview-Plus. The personality disorders were evaluated by the Millon Clinical Multiaxial Inventory-III. The severity of depressive symptoms was measured using the Beck Depression Inventory-II and resilience through Resilience Scale. Of the 215 participants, 41.9% abandoned psychotherapy (n = 90), and, of these, 54.4% (n = 49) abandoned after the fourth session. The proportion of psychotherapy dropout was higher among those with nonwhite skin colour, belonging to economic classes C and D, who had children and whose depressive symptoms were moderate. Presence of obsessive-compulsive personality trait was protective against dropout. The damage caused by this abrupt interruption is evident for all those involved in the psychotherapeutic process, so the clinician should pay attention to the predictors found in this study in order to develop strategies that promote therapeutic adherence.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes., Brain damage marker in COVID-19 SARS-CoV-2 infection, the cause of coronavirus disease 2019 (COVID-19), causes neurological manifestations in a substantial proportion of patients. Determining the extent of neuronal injury is essential to better understand disease pathophysiology and to evaluate potential therapies. Prudencio et al. analyzed serum from 142 patients hospitalized with COVID-19 and showed that the expression of the neurofilament light protein (NFL), a marker of neuroaxonal injury, was elevated compared to healthy controls. In addition, serum NFL expression correlated with disease severity and tended to be reduced in subjects treated with remdesivir. The results suggest that serum NFL analysis should be incorporated when evaluating therapeutic trials for COVID-19., Brain imaging studies of patients with COVID-19 show evidence of macro- and microhemorrhagic lesions, multifocal white matter hyperintensities, and lesions consistent with posterior reversible leukoencephalopathy. Imaging studies, however, are subject to selection bias, and prospective studies are challenging to scale. Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without overt neurological manifestations. Higher NFL serum concentrations were associated with worse clinical outcomes. In 100 hospitalized patients with COVID-19 treated with remdesivir, a trend toward lower NFL serum concentrations was observed. These data suggest that patients with COVID-19 may experience neuroaxonal injury and may be at risk for long-term neurological sequelae. Neuroaxonal injury should be considered as an outcome in acute pharmacotherapeutic trials for COVID-19.

Introduction The Brazilian psychiatric reform has revolutionized the way that mental health care is provided all over the country, introducing the Psychosocial Care Centers (CAPS) and encouraging care at liberty. The CAPS have been assigned many objectives, such as prevention of hospitalizations and intervention in crises or suicide. This paper aims to describe the correlation between the implementation of CAPS and the rates of psychiatric hospitalizations and suicides from 2008 to 2018. Methods This study has an ecological time series design and included residents of the city of Porto Alegre, RS, Brazil, who were hospitalized through the Sistema Único de Saúde (SUS). The data were obtained from official databases (DATASUS, CNES, and IBGE) and indicators were calculated (CAPS coverage, hospitalization rate, and suicide rate). Associations between the indicators were tested using Pearson’s correlation coefficients. Results We found a negative correlation between provision of CAPS and psychiatric hospitalizations (r = -0.607 p = 0.048). Conclusion These results support the hypothesis that there is a negative correlation between implementation of the CAPS and psychiatric hospitalizations. This reinforces the importance of implementing policies related to improving psychiatric reform.

Leptin is an anorexigenic hormone well recognized by its role in mediating energy homeostasis. Recently, leptin has been associated with psychiatric disorders and interestingly, leptin treatment has shown antidepressant and anxiolytic effects. We examined the association of leptin levels and leptin (LEP) gene rs3828942 polymorphism with anxiety disorders considering sex differences. A cross-sectional population-based study, including 1067 young adults, of whom 291 presented anxiety disorders diagnosed by the Mini International Neuropsychiatric Interview (MINI 5.0). The rs3828942 polymorphism was genotyped by real-time PCR and ELISA measured leptin levels. Leptin levels were not associated with anxiety disorders after adjusting for sex and body mass index (BMI) [ß = - 0.009 (- 0.090-0.072); p = 0.832]. The distribution of rs3828942 genotypes was not associated with anxiety disorders. However, in a sex-stratified sample, the A-allele of rs3828942 polymorphism was associated with risk for GAD in women even when adjusting for confounding variables [OR = 1.87 (1.17-2.98); p = 0.008]. In a subsample of 202 individuals with GAD and control matched by sex and BMI, results suggest an interaction between genotypes and GAD diagnosis based on leptin levels only in the male group [F (1, 54) = 6.464; p = 0.0139]. Leptin is suggested to be related with the neurobiology of anxiety disorders in a sex-dependent manner since women carrying the A-allele of LEP rs3828942 present a higher risk for GAD, while leptin levels seem to be lower in men with GAD carrying A-allele. Studies on the relationship between leptin polymorphisms and levels are scarce and, therefore, further research is necessary.

This study aims to assess the effect of childhood trauma on the outcomes of brief cognitive therapies for major depressive disorder. This is a follow-up clinical study nested in a randomized clinical trial of cognitive therapies. Sixty-one patients were assessed at baseline, post-intervention and six-month follow-up. The study showed that brief cognitive therapies improved depressive and anxious symptoms at post-intervention and six-month follow-up. Higher childhood trauma scores at baseline were significantly associated with higher severity of depressive and anxious symptoms at six-month follow-up. Longer courses of psychotherapy may be needed to improve the long-lasting effects of traumatic experiences.

Biological rhythm is the daily metabolic cycle of mammals that involves the sleep-wake cycles, hormone release, eating habits and digestion, body temperature, and other important bodily functions that are repeated daily. Thus, greater difficulty in maintaining the circadian rhythms may be involved in the increased risk of obesity. This study assessed the association between biological rhythm disruption and childhood obesity among school children.This is a cross-sectional study with 7-8-year-old school children enrolled in a public school in the city of Pelotas-RS. The sample was drawn through multistage sampling. The Biological Rhythms Interview of Assessment in Neuropsychiatry-Kids (BRIAN-Kids) was used to assess the degree of difficulty maintaining the biological rhythm. BMI was calculated as weight/heightA total of 596 children and their caregivers participated in this study. The prevalence of obesity was 24% among school children, 28.9% for girls, and 19.4 for boys (p = 0.009). Obese children had greater difficulties in maintaining the biological rhythm compared to nonobese children (p = 0.007). Some of these difficulties included sleep (p = 0.008), overall activities (p = 0.027), social rhythm (p = 0.033), and eating (p = 0.032) pattern.Approximately one-quarter of children were obese. This finding was associated with the caregiver characteristics and some difficulties in maintaining the biological rhythm.

Objective: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. Methods: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. Results: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. Conclusion: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.

Tauopathies are neurodegenerative disorders characterized by aggregation of microtubule associated tau protein in neurons and glia. They are clinically and pathologically heterogeneous depending on the isoform of tau protein that accumulates (three or four 31-to-32-amino-acid repeats [3R or 4R] in the microtubule binding domain), as well as the cellular and neuroanatomical distribution of tau pathology. Growing evidence suggests that distinct tau conformers may contribute to the characteristic features of various tauopathies. Globular glial tauopathy (GGT) is a rare 4R tauopathy with globular cytoplasmic inclusions within neurons and glial cells. Given the unique cellular distribution and morphology of tau pathology in GGT, we sought to determine if tau species in GGT had distinctive biological properties. To address this question, we performed seeding analyses with postmortem brain tissues using a commercial tau biosensor cell line. We found that brain lysates from GGT cases had significantly higher seeding competency than other tauopathies, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD). The robust seeding activity of GGT brain lysates was independent of phosphorylated tau burden and diminished upon removal of tau from samples, suggesting that seeding properties were indeed mediated by tau in the lysates. In addition, cellular inclusions in the tau biosensor cell line induced by GGT had a distinct, globular morphology that was markedly different from inclusions induced by other tauopathies, further highlighting the unique nature of tau species in GGT. Characterization of different tau species in GGT showed that detergent-insoluble, fibril-like tau contained the highest seeding activity, as reflected in its ability to increase tau aggregation in primary glial cultures. Taken together, our data suggest that unique seeding properties differentiate GGT-tau from other tauopathies, which provides new insight into pathogenic heterogeneity of primary neurodegenerative tauopathies. Electronic supplementary material The online version of this article (10.1186/s40478-019-0691-9) contains supplementary material, which is available to authorized users.

Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, TauA152T-AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. To investigate the possibility that the A152T variant might alter the phosphorylation state of tau on T152 or the neighboring T153 residue, we generated a novel antibody that revealed significant accumulation of soluble tau species that were hyperphosphorylated on T153 (pT153) in TauA152T-AAV mice, which were absent the soluble fraction of TauP301L-AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the TauA152T-AAV model, we demonstrate that the presence of soluble pT153-positive tau species in human postmortem brain tissue differentiates A152T carriers from noncarriers, independent of disease classification. These results implicate both phosphorylation of T153 and an altered solubility profile in the mechanism by which A152T modulates disease risk. Electronic supplementary material The online version of this article (10.1186/s40478-019-0661-2) contains supplementary material, which is available to authorized users.

Subjects with bipolar disorder suffering of a depressive episode are frequently misdiagnosed as unipolar depression, being important studies assessing the differential diagnosis between bipolar and unipolar depression.To assess the sociodemographic and clinical features of drug-free young adults in a depressive episode of bipolar or unipolar disorder in order to identify factors that may differentiate these psychiatric conditions.This is a cross-sectional study with 241 young adults aged between 18 and 29 years who were evaluated using the Structured Clinical Interview for DSM-IV (SCID). The sample comprised patients with BD (n = 89) and major depressive disorder (n = 152), experiencing a depressive episode and not using psychoactive drugs or illicit psychoactive substances.The characteristics associated with bipolar depression were being male (p 0.001), with a family history of BD (p = 0.013), a higher frequency of childhood traumatic experiences (p = 0.001), younger age of onset of mood disorder (p = 0.004), many previous depressive episodes (p = 0.027), greater severity of depressive symptoms (p 0.001) and day/night reversal (p = 0.013). Those with unipolar depression showed a higher frequency of biological rhythm disturbances (p 0.001), and diurnal preference (p = 0.028).The sample has not included subjects with severe suicide risk, a possible important marker in differentiate unipolar from bipolar depression.Some clinical aspects may contribute to an early differential diagnosis of both bipolar and unipolar depression even in the initial stages of the disease.

The aim of this study was to assess the association between anhedonia and metabolic syndrome (MetS) in a well-characterized community sample of individuals with a current depressive episode. This is a cross-sectional study with young adults aged 24-30 years old. Depressive episode and the presence of anhedonia was assessed using the Mini International Neuropsychiatric Interview - Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III). The sample included 931 subjects, being 22 had depression without anhedonia, whereas 55 had depression with anhedonia. MetS was more prevalent among subjects with depression and anhedonia (43.6%) when compared to individuals without anhedonia and population control group. Moreover, subjects with depression and anhedonia have a significant increase of levels of glucose, triglycerides, total-cholesterol and LDL-cholesterol, as well as significant decreased in the HDL-cholesterol level. The present study showed that individuals with depression and anhedonia present higher prevalence of MetS. Our study suggests that the use of the concept of anhedonia may contribute to a better understanding of the complex relationship between depression and metabolic syndrome.

A hallmark pathological feature of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing. Single nucleotide polymorphisms (SNPs) in UNC13A are among the strongest genome-wide association study (GWAS) hits associated with FTD/ALS in humans, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines, and iPSC-derived motor neurons resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. Remarkably, the top variants associated with FTD/ALS risk in humans are located in the cryptic exon harboring intron itself and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD/ALS (UNC13A genetic variants) and loss of TDP-43 function.

This study is aimed at assessing changes in functioning among young people from the general population with bipolar disorder and major depressive disorder over a period of five years. Specifically, we hypothesized that significant illness progression would take place during euthymia over time in bipolar disorder. We conducted a longitudinal study with 231 people, assessed at baseline and again at a five-year follow-up. A structured clinical interview was used to diagnose participants with mood disorders. A control group without mood disorders was also included. Functioning was assessed with the Functioning Assessment Short Test, and linear mixed models were used to analyze the effect of psychopathology on change in functioning. Mood disorders were associated with significant functional impairment, but functioning significantly improved in both groups over the 5-year follow-up period. Depressive episodes, however, were associated with worse functioning at follow-up, independently of depression severity. In contrast to our initial hypothesis, we found a worsening of functioning in a five-year period associated only with depressive episodes. This suggests that interventions focused on the prevention of mood episodes early in the course of illness may be particularly promising to reduce adverse functioning outcomes.

Objectives : To assess the differences in sleep impairments in major depressive disorder (MDD) and individuals recently diagnosed with bipolar disorder (BD) across different mood stages. Methods This is a cross-sectional study corresponding to the second wave of a prospective clinical cohort of a sample of outpatients. The first wave included subjects diagnosed with MDD aged 18 to 60 years. Averaging 3 years after the first phase (second wave), conversion from MDD to BD diagnosis was assessed using the Mini International Neuropsychiatric Interview. The total sample was divided into four groups: euthymic MDD, MDD in a current episode, euthymic BD, and BD in a current mood episode. The sleep alterations were assessed using the Pittsburgh Sleep Quality Index. Results The sample included 468 subjects (261 euthymic MDD, 149 MDD currently depressed, 16 euthymic BD, and 42 BDs currently in a (hypo)manic or depressive episode). Euthymic BD differed from euthymic MDD only in the domains of sleep efficiency and sleep disturbances, showing lower sleep efficiency (PR 4.91 [95%CI 1.94 – 12.42]) and higher sleep disturbances (PR 3.38 [95%CI 1.32 – 8.67]) in subjects recently diagnosed with BD during euthymia. These differences remained significant after adjusting for the potential confounding factors. Conclusions The findings point out the relevance of regular sleep assessments in individuals recently diagnosed with BD, since the differences in sleep quality observed could provide insights regarding prognosis, treatment, and the extent to which these individuals display significant subsyndromal symptomatology, even in the absence of a mood episode.

Given the substantial heterogeneity of stroke brain injury, there is a clear need for a biomarker that determines the degree of neuroaxonal injury across diverse stroke types. We evaluated whether blood neurofilament light (NFL), a major component of neuronal axons, would fulfill this purpose for patients with acute cerebral infarction (ACI, N=227), aneurysmal subarachnoid hemorrhage (aSAH, N=58) or non-traumatic intracerebral hemorrhage (ICH, N=29). We additionally validated our findings in two independent cohorts of patients with ICH (N=96 and N=54) given the scarcity of blood biomarker studies for this deadliest stroke type. Compared to healthy individuals (N=79 and 48 for the discovery and validation cohorts, respectively), NFL was higher for all stroke types. NFL associated with radiographic markers of brain tissue damage. It correlated with the extent of early ischemic injury in patients with ACI, hemorrhage severity in patients with aSAH, and intracranial hemorrhage volume in patients with ICH. In all patients, NFL independently correlated with scores from the NIH Stroke Scale, the modified Rankin Scale, and the Mini-Mental State Examination at blood draw, which respectively assess neurological, functional, and cognitive status. Furthermore, higher NFL concentrations independently associated with 3- or 6-month functional disability and higher all-cause mortality. These data support NFL as a uniform method to estimate neuroaxonal injury and forecast mortality regardless of stroke mechanism. As a prognostic biomarker, blood NFL has the potential to assist with planning supportive and rehabilitation services, and improving the efficiency of acute therapeutic drug and device trials, and of recovery trials.

The aim of this study was to assess the risk factors for new-onset Bipolar Disorder (BD) in a community sample of young adults. This is a prospective cohort study including a population-based sample of young adults aged between 18-24 years. The baseline took place from 2007 to 2009, and 1560 subjects were included. Five years after, 1244 individuals were re-evaluated (79.7% retention). Substance abuse/dependence was assessed using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), and mental disorders were assessed using the Mini International Neuropsychiatric Interview 5.0 (MINI) at both waves. The cumulative incidence of BD in five years was 4.6%. There was no significant association between sociodemographic factors and BD incidence. Tobacco, cannabis, cocaine/crack, other substances abuse/dependence increased the relative risk for BD. Depressive, anxiety, post-traumatic stress disorders, and the suicide risk increased the relative risk to BD. Depressive episode was the strongest risk factor for BD, followed by other mental disorders and substance abuse/dependence in a probabilistic community sample of young adults. Preventive actions in mental health directed at the non-clinical population are needed for early detection and better management of BD.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Background Self-assembly of the amyloid-β (Aβ) peptide into aggregates, from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However, it is clear that not all forms of Aβ are equally harmful and that linking a specific aggregate to toxicity also depends on the assays and model systems used (Haass et al., J Biol. Chem 269:17741–17748, 1994; Borchelt et al., Neuron 17:1005–1013, 1996). Though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration. Methods In this study, we examined familial mutations of Aβ that increase aggregation and oligomerization, E22G and ΔE22, and induce cerebral amyloid angiopathy, E22Q and D23N. We also investigated synthetic mutations that stabilize dimerization, S26C, and a phospho-mimetic, S8E, and non-phospho-mimetic, S8A. To that end, we utilized BRI2-Aβ fusion technology and rAAV2/1-based somatic brain transgenesis in mice to selectively express individual mutant Aβ species in vivo. In parallel, we generated PhiC31-based transgenic Drosophila melanogaster expressing wild-type (WT) and Aβ40 and Aβ42 mutants, fused to the Argos signal peptide to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different Aβ40 and Aβ42 species. Results When expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of Drosophila. In contrast, flies expressing a copy of Aβ40 (WT or mutants), in addition to Aβ42WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40. Conclusions These studies suggest that while some Aβ40 mutants form unique amyloid aggregates in mouse brains, they do not exacerbate Aβ42 toxicity in Drosophila, which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

Schizophrenia and common mental disorders are noteworthy social and economic concern worldwide. Epidemiologic studies on the impact of specific mental disorders in emerging countries are scarce. Objectives: We aimed to characterize the demographic, social, and economic burden of schizophrenia and common mental disorders patients in the health system in Brazil. Methods: Data on these conditions in Brazil between 2008 and 2019 were collected through the website of the Departamento de Informática do Sistema Único de Saúde (Information Technology Department of the Unified Health System - DATASUS) maintained by the Brazilian Ministry of Health. Mean annual hospital admissions were 154,009.67, and cumulative incidence of 77.44 admissions per 100,000 inhabitants. Results: Average annual hospital expenses were US$ 67,216,056.04, with an average admission cost of US$ 432.58. The most affected age groups were older adults albeit younger individuals showed a trend towards increase of occurrences in recent years. There were a higher number of admissions in men compared to women. Conclusions: We consider the results obtained important to assist in evaluating and guiding public policies regarding the prevention and treatment in health systems. RESUMO. A esquizofrenia e os transtornos mentais comuns são uma preocupação social e econômica notável em todo o mundo. Estudos epidemiológicos sobre o impacto de transtornos mentais específicos em países emergentes são escassos. Objetivos: Nosso objetivo foi caracterizar a carga demográfica, social e econômica de pacientes com esquizofrenia e transtornos mentais comuns no sistema de saúde no Brasil. Métodos: Os dados sobre essas condições no Brasil entre 2008 e 2019 foram coletados por meio do site do Departamento de Informática do Sistema Único de Saúde (DATASUS), mantido pelo Ministério da Saúde do Brasil. As internações hospitalares anuais médias foram de 154.009,67, e a incidência acumulada de 77,44 internações por 100.000 habitantes. Resultados: As despesas hospitalares médias anuais foram de US$ 67.216.056,04, com um custo médio de internação de US$ 432,58. As faixas etárias mais afetadas foram os adultos mais velhos, embora os mais jovens tenham demonstrado tendência a aumento de ocorrências nos últimos anos. Houve um número maior de admissões entre os homens em comparação às mulheres. Conclusões: Consideramos importantes os resultados obtidos para auxiliar na avaliação e orientação de políticas públicas de prevenção e tratamento nos sistemas de saúde.

TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G(4)C(2) repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G(4)C(2) repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR)(200) mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G(4)C(2) repeat–expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G(4)C(2)-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

Aim To assess the differences in subjective cognitive dysfunction between major depressive disorder (MDD) and recently diagnosed Bipolar Disorder (BD) across euthymia and mood episodes. Methods This is a cross-sectional study corresponding to the second wave of a longitudinal study. The first wave consisted of subjects aged between 18 and 60 diagnosed with MDD. In the follow up after three years (second wave), conversion from MDD to BD diagnosis was assessed by qualified psychologists using the Mini International Neuropsychiatric Interview (MINI-Plus). Subjects were categorized in four diagnostic groups: euthymic MDD, MDD in a current mood episode, euthymic BD, and BD in a current mood episode. All subjects completed the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA), an instrument specifically designed for detecting subjective cognitive deficits in BD. Results The total sample (n = 468) included 410 subjects with MDD and 58 individuals recently diagnosed with BD. We subdivided the 2 groups based on their current mood state, and found a significant difference in COBRA total scores between euthymic BD individuals (median 17.00 [IQR: 8.75 - 20.75]) and euthymic MDD subjects (median 8.00 [IRQ: 5.00 - 14.00], p = 0.002), showing higher subjective cognitive dysfunction in individuals recently diagnosed with BD. The differences remained significant after adjusting for the presence of lifetime psychotic symptoms. We found no differences between MDD and BD during an acute mood episode. Limitation The small sample size of individuals with BD. Conclusion The findings suggest a higher presence of subjective cognitive complaints among individuals recently diagnosed with BD in comparison to individuals with MDD during euthymia.

Objectives The purpose of this study is to assess the independent effects of depression and excess body weight (EBW) on cognition and functioning in a community sample of young adults. Methods This was a cross-sectional of 943 young adults. The diagnosis of a current depressive episode was performed using the Mini International Neuropsychiatric Interview (MINI). Cognition and functioning were assessed using the Montreal Cognitive Assessment (MoCA) and the Functional Assessment Short Test (FAST), respectively. The EBW was defined as BMI ≥ 25.0 kg/m2. The independent main effects of depression and EBW, as well as the analysis interaction were performed using two-way analysis of covariance (ANCOVA). Results The total sample comprised 943 adults, with 75 (8.0%) individuals diagnosed with a current depressive episode and 493 (52,6%) with EBW. Of the 75 subjects with depression, 40 were identified with EBW comorbidity. Subjects with depression and EBW comorbidity reported greater cognitive and functional impairment, as compared to individuals with depression without EBW. There was a significant interaction between depression and EBW on MoCA total (p Conclusions The adverse effects of depression and EBW are independent and cumulative with respect to cognition and functioning of individuals. The understanding of the complex interactions between cognition, functioning, EBW and depression are important for development of preventive and therapeutic strategies.

Background Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer’s disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective. Results We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu+/−) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu+/− mice compared to wild-type (APP/PS1; Clu+/+) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis. Conclusions Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology.

Objective To evaluate the prevalence of Internet addiction (IA) and its associated factors among students at an Educational Institution in Southern Brazil. Method This is a cross-sectional study, targeting a sample of students aged from 14 to 20 years. They were selected by random sampling to be representative of the 4038 students enrolled at the institute at the time. IA was assessed using the Internet Addiction Test (IAT). Screening for anxiety and/or depressive disorders was performed using the Well-Being Index (WHO-5). Results The prevalence of IA was 50.8% and the rate was higher among individuals who had screened positive for depressive or anxiety disorders than among those who had not (p = 0.003). There was an association between IA and access to certain types of content, such as gaming (p = 0.010), work and study related content (p = 0.030), and using the internet to access sexual content (p < 0.001). Conclusion Further studies are needed to confirm the high prevalence of IA and explore factors associated with it in samples with similar characteristics to ours. The associations between this dependency and positive screening for anxiety and/or depressive disorders and the types of content accessed are an alert to the existence of these important relationships and illustrate the importance of studying them further. Knowledge about these associations provides an opportunity to implement measures for prevention, such as psychoeducation, and to offer adequate treatment.

Background Frontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD. Methods We studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X−/− KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X. Results The R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X−/− KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X−/− KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X−/− KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice. Conclusions Taken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

BACKGROUND –: Data addressing air quality effects on children with asthma in rural U.S. communities are rare. Our community engaged research partnership previously demonstrated associations between neighborhood NH(3) and ambient PM(2.5) and asthma in the agricultural lower Yakima Valley of Washington. As a next step, the partnership desired an intervention approach to address concerns about pediatric asthma in this largely Latino immigrant, farm worker community. OBJECTIVE –: The Home Air in Agriculture Pediatric Intervention (HAPI) sought to examine the effectiveness of enrichment of an existing asthma education program with portable high-efficiency particulate air (HEPA) cleaners designed to reduce PM(2.5) and NH(3.) We investigated the effect of this enriched approach on these exposures and asthma health measures. DESIGN –: We randomized children with poorly controlled asthma to a control arm (current asthma education program) or an intervention arm (current asthma education program + placement of two indoor air cleaners in the family’s home). Outcomes included (1) 14-day integrated samples of indoor air contaminants (PM(2.5) and NH(3)) at baseline and one-year follow-up and (2) child asthma health metrics at baseline, midpoint (4–6 months) and one-year follow-up. These included the Asthma Control Test, symptoms days, clinical utilization, oral corticosteroid use, pulmonary function, fractional exhaled nitric oxide, and urinary leukotriene E(4) concentration. DISCUSSION –: To our knowledge, this is the first randomized HEPA cleaner intervention designed to assess NH(3) as well as PM(2.5) and to evaluate health outcomes of children with asthma in an agricultural region.