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Background Given the global burden of disease of psychotic disorders and the promise of benefit from early intervention, there is an imperative to understand the developmental trajectories from onset of psychotic experiences to clinical disorder and to improve identification of individuals at greatest risk. The aims of this study therefore were: 1) to describe, for the first time, the change in incidence of psychotic experiences in the general population from childhood through early adulthood; 2) to describe the prevalence and burden of unmet clinical need of at-risk mental states and psychotic disorder among young adults in the general population; 3) to examine the predictive ability of both self-reported and interviewer-rated measures of psychotic experiences during childhood and adolescence in identifying psychotic disorder by early adulthood; and 4) to describe longitudinal profiles of psychotic experiences from childhood through early adulthood and investigate a comprehensive range of childhood determinants of symptom persistence. Methods We used data from the ALSPAC birth cohort study. Psychotic experiences and disorder were assessed using semi-structured interviews at ages 12, 18, and 24 (N=7,900 with any data). Incidence rates were estimated using flexible parametric modeling, and positive predictive values (PPVs), sensitivity, specificity, and area under the curve were estimated for prediction. Longitudinal profiles were constructed based on interviewer ratings and frequency of experiences, with profiles describing no experiences (62.5%), episodic experiences (26.5%), persistent/recurrent low frequency (9.1%), and persistent/recurrent high frequency (1.9%) groups. Multinomial regression was used to examine risk factors for persistence, covering socio-demographic, genetic, behavioural, cognitive, and psychological characteristics during childhood. Results The incidence rate of psychotic experiences increased between ages 12 and 24, peaking during la

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy for HCV has high efficacy and limited toxicity. We hypothesised that the efficacy of glecaprevir-pibrentasvir for chronic HCV with a simplified treatment monitoring schedule would be non-inferior to a standard treatment monitoring schedule. METHODS: In this open-label multicentre phase IIIb trial, treatment-naïve adults with chronic HCV without cirrhosis were randomly assigned (2:1) to receive glecaprevir-pibrentasvir 300 mg-120 mg daily for 8 weeks administered with a simplified or standard monitoring strategy. Clinic visits occurred at baseline and post-treatment week 12 in the simplified arm, and at baseline, week 4, week 8, and post-treatment week 12 in the standard arm. Study nurse phone contact occurred at week 4 and week 8 in both arms. Participants requiring adherence support were not eligible, including those reporting recent injecting drug use. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12), with a non-inferiority margin of 6%. RESULTS: Overall, 380 participants (60% male, 47% genotype 1, 32% genotype 3) with chronic HCV were randomised and treated with glecaprevir-pibrentasvir in the simplified (n = 253) and standard (n = 127) arms. In the intention-to-treat population, SVR12 was 92% (95% CI 89%-95%) in the simplified and 95% (95% CI 92%-99%) in the standard arm (difference between arms -3.2%; 95% CI -8.2% to 1.8%) and did not reach non-inferiority. In the per-protocol population, SVR12 was 97% (95% CI 96%-99%) in the simplified and 98% (95% CI 96%-100%) in the standard arm. No treatment-related serious adverse events were reported. CONCLUSIONS: In patients with chronic HCV infection without cirrhosis, treatment with glecaprevir-pibrentasvir was safe and effective. In comparison to standard monitoring, a simplified monitoring schedule did not achieve non-inferiority. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03117569. LAY SUMMARY: Direct-acting

OBJECTIVE: The authors investigated the incidence, course, and outcome of psychotic experiences from childhood through early adulthood in the general population and examined prediction of psychotic disorder. METHODS: This was a population-based cohort study using the semistructured Psychosis-Like Symptoms Interview at ages 12, 18, and 24 (N=7,900 with any data). Incidence rates were estimated using flexible parametric modeling, and positive predictive values (PPVs), sensitivity, specificity, and area under the curve were estimated for prediction. RESULTS: The incidence rate of psychotic experiences increased between ages 13 and 24, peaking during late adolescence. Of 3,866 participants interviewed at age 24, 313 (8.1%, 95% CI=7.2, 9.0) had a definite psychotic experience since age 12. A total of 109 individuals (2.8%) met criteria for a psychotic disorder up to age 24, of whom 70% had sought professional help. Prediction of current psychotic disorder at age 24 (N=47, 1.2%), by both self-report and interviewer-rated measures of psychotic experiences at age 18 (PPVs, 2.9% and 10.0%, respectively), was improved by incorporating information on frequency and distress (PPVs, 13.3% and 20.0%, respectively), although sensitivities were low. The PPV of an at-risk mental state at age 18 predicting incident disorder at ages 18-24 was 21.1% (95% CI=6.1, 45.6) (sensitivity, 14.3%, 95% CI=4.0, 32.7). CONCLUSIONS: The study results show a peak in incidence of psychotic experiences during late adolescence as well as an unmet need for care in young people with psychotic disorders. Because of the low sensitivity, targeting individuals in non-help-seeking samples based only on more severe symptom cutoff thresholds will likely have little impact on population levels of first-episode psychosis.

Background Individuals at clinical high risk (CHR) of psychosis have an approximately 20% probability of developing psychosis within 2 years, as well as an associated risk of non-psychotic disorders and functional impairment. People with subclinical psychotic experiences (PEs) are also at risk of future psychotic and non-psychotic disorders and decreased functioning. It is difficult to accurately predict outcomes in individuals at risk of psychosis on the basis of symptoms alone. Biomarkers for accurate prediction of outcomes could inform the clinical management of this group. Methods We conducted two nested case-control studies. We employed discovery-based proteomic methods to analyse protein expression in baseline plasma samples in EU-GEI and age 12 plasma samples in ALSPAC using liquid chromatography mass spectrometry. Differential expression of quantified proteomic markers was determined by analyses of covariance (with false discovery rate of 5%) comparing expression levels for each marker between those who did not and did not develop psychosis in Study 1 (adjusting for age, gender, body mass index and years in education), and between those who did and did not develop PEs in Study 2 (adjusting for gender, body mass index and maternal social class). Support vector machine algorithms were used to develop models for prediction of transition vs. non-transition (as determined by the Comprehensive Assessment of At Risk Mental States) and poor vs. good functional outcome at 2 years in Study 1 (General Assessment of Functioning: Disability subscale score 60). Similar algorithms were used to develop a model for prediction of PEs vs. no PEs at age 18 in Study 2 (as determined by the Psychosis Like Symptoms Interview). Results In Study 1, 35 of 166 quantified proteins were significantly differentially expressed between CHR participants who did and did not develop psychosis. Functional enrichment analysis provided evidence for particular im

AIM: Over the past two decades, the youth mental health field has expanded and advanced considerably. Yet, mental disorders continue to disproportionately affect adolescents and young adults. Their prevalence and associated morbidity and mortality in young people have not substantially reduced, with high levels of unmet need and poor access to evidence-based treatments even in high-income countries. Despite the potential return on investment, youth mental disorders receive insufficient funding. Motivated by these continual disparities, we propose a strategic agenda for youth mental health research. METHOD: Youth mental health experts and funders convened to develop youth mental health research priorities, via thematic roundtable discussions, that address critical evidence-based gaps. RESULTS: Twenty-one global youth mental health research priorities were developed, including population health, neuroscience, clinical staging, novel interventions, technology, socio-cultural factors, service delivery, translation and implementation. CONCLUSIONS: These priorities will focus attention on, and provide a basis for, a systematic and collaborative strategy to globally improve youth mental health outcomes.