First-line Osimertinib for Lung Cancer With Uncommon EGFR Exon 19 Mutations and EGFR Compound Mutations.

Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases. Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS). Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression. Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient.

Photonic next-generation reservoir computer based on distributed feedback in optical fiber.

Reservoir computing (RC) is a machine learning paradigm that excels at dynamical systems analysis. Photonic RCs, which perform implicit computation through optical interactions, have attracted increasing attention due to their potential for low latency predictions. However, most existing photonic RCs rely on a nonlinear physical cavity to implement system memory, limiting control over the memory structure and requiring long warm-up times to eliminate transients. In this work, we resolve these issues by demonstrating a photonic next-generation reservoir computer (NG-RC) using a fiber optic platform. Our photonic NG-RC eliminates the need for a cavity by generating feature vectors directly from nonlinear combinations of the input data with varying delays. Our approach uses Rayleigh backscattering to produce output feature vectors by an unconventional nonlinearity resulting from coherent, interferometric mixing followed by a quadratic readout. Performing linear optimization on these feature vectors, our photonic NG-RC demonstrates state-of-the-art performance for the observer (cross-prediction) task applied to the Rössler, Lorenz, and Kuramoto-Sivashinsky systems. In contrast to digital NG-RC implementations, we show that it is possible to scale to high-dimensional systems while maintaining low latency and low power consumption.

Effects of Two Early Parenting Programmes on Child Aggression and Risk for Violence in Brazil: a Randomised Controlled Trial.

Violence is a major public health problem globally, with the highest rates in low- and middle-income countries (LMICs) in the Americas and southern Africa. Parenting programmes in high-income countries can diminish risk for violence, by reducing risk factors such as child aggression and harsh parenting, and increasing protective factors such as child cognitive development and school readiness. However, there is critical need to identify low-cost programmes with replicable benefits that work in real-world LMICs contexts. A three-arm, randomised, single-blind trial evaluated effects of two low-cost, group-based parenting programmes recommended for LMICs (ACT: Raising Safe Kids; DBS: dialogic book-sharing) on child aggression (primary outcome), child development, parenting, maltreatment, and stress. Participants were 369 children with medium-high levels of aggression (mean age 3.1 years at baseline) in poor households. Interventions were implemented in city health and education services in southern Brazil. Maternal reports, filmed observations, child tasks, and hair cortisol were assessed at baseline, 1-month post-intervention, and 8-month follow-up. Intention-to-treat analyses compared each of ACT and DBS with a control group. Three hundred sixty-eight (99.7%) participants completed follow-up assessments 8 months after the interventions. There was no effect of ACT (standardised mean difference, SMD 0.11, 95% CI - 0.05, 0.27) or DBS (SMD 0.05, 95% CI - 0.11, 0.21) on the primary outcome of child aggression. ACT reduced harsh parenting behaviour post-intervention (SMD - 0.23; 95% CI - 0.46, - 0.01), but not at follow-up. DBS improved book-sharing practices at both time points (e.g., maternal sensitivity at follow-up SMD 0.33; 95% CI 0.08, 0.57). There were no benefits of either programme for other parenting, child development, or stress outcomes. Two parenting programmes in Brazil had small effects on parenting practices but did not reduce child aggression or several other important risk/protective factors for violence. Effective early interventions that reduce violence in real-world LMIC settings are highly desirable but may be challenging to achieve.

Gender Division of Housework and Intimate Partner Violence Among Mothers of Toddlers During the COVID-19 Pandemic: Findings from the 2019 Rio Grande (Brazil) Birth Cohort.

During the COVID-19 pandemic, we evaluated the association between gender division of housework and intimate partner violence (IPV) victimization in a population-based cohort of mothers. We collected data on psychological, physical, and sexual IPV using an adapted version of the World Health Organization Violence Against Women instrument and division of housework using a validated questionnaire. We used logistic regression to calculate adjusted odds ratios. We found that in mothers who reported an unequal gender division of housework (higher load), the odds of suffering psychological, physical, or sexual IPV were higher during the first and second years of the pandemic.

Gene - maltreatment interplay in adult ADHD symptoms: main role of a gene-environment correlation effect in a Brazilian population longitudinal study.

Childhood maltreatment correlates with attention-deficit/hyperactivity disorder (ADHD) in previous research. The interaction between ADHD genetic predisposition and maltreatment's impact on ADHD symptom risk remains unclear. We aimed to elucidate this relationship by examining the interplay between a polygenic score for ADHD (ADHD-PGS) and childhood maltreatment in predicting ADHD symptoms during young adulthood. Using data from the 2004 Pelotas (Brazil) birth cohort comprising 4231 participants, we analyzed gene-environment interaction (GxE) and correlation (rGE). We further explored rGE mechanisms through mediation models. ADHD symptoms were assessed at age 18 via self-report (Adult Self Report Scale - ASRS) and mother-reports (Strength and Difficulties Questionnaire - SDQ). The ADHD-PGS was derived from published ADHD GWAS meta-analysis. Physical and psychological child maltreatment was gauged using the Parent-Child Conflict Tactics Scale (CTSPC) at ages 6 and 11, with a mean score utilized as a variable. The ADHD-PGS exhibited associations with ADHD symptoms on both ASRS (ß = 0.53; 95% CI: 0.03; 1.03, p = 0.036), and SDQ (ß = 0.20; 95% CI: 0.08; 0.32, p = 0.001) scales. The total mean maltreatment score was associated with ADHD symptoms using both scales [(ßASRS = 0.51; 95% CI: 0.26;0.77) and (ßSDQ = 0.24; 95% CI: 0.18;0.29)]. The ADHD-PGS was associated with total mean maltreatment scores (ß = 0.09; 95% CI: 0.01; 0.17; p = 0.030). Approximately 47% of the total effect of ADHD-PGS on maltreatment was mediated by ADHD symptoms at age 6. No evidence supported gene-environment interaction in predicting ADHD symptoms. Our findings underscore the significant roles of genetics and childhood maltreatment as predictors for ADHD symptoms in adulthood, while also indicating a potential evocative mechanism through gene-environment correlation.

The Economic Iceberg of Celiac Disease: More Than the Cost of Gluten-Free Food.

Celiac disease (CeD) is a chronic autoimmune disorder of global relevance, with the potential for acute and long-term complications. However, the economic burden of CeD is rarely considered and largely thought of as limited to the cost of gluten-free food. Fortunately, recent research has shed light on the various societal costs of CeD across the health care continuum. This article summarizes the current evidence on the economic impacts of CeD, which suggest that the societal economic burden of CeD stretches beyond the cost of gluten-free food. This review provides ample evidence of larger but hidden costs related to excess health care use for complications and comorbidities, as well as reduced productivity. Although significant advances are expected in the management of CeD, their effect on the economic burden of CeD remain uncertain. The aim of this review was to inform stakeholders across society and contribute to improved policies to support patients with CeD.

The effects of a large-scale home visiting programme for child development on use of health services in Brazil.

Partnership between early childhood development interventions and primary health care services can help catalyse health care uptake by socially vulnerable families. This study aimed to assess the real-life effects of a large-scale home visiting programme [Primeira Infância Melhor (PIM)] in Brazil on the use of preventive (prenatal visits, well child visits, dentist visits and vaccination) and recovery (emergency room visits and hospitalization) health services. A quasi-experiment nested in a population-based birth cohort study was conducted. The intervention group was firstly defined as all children enrolled in PIM up to age 6 months, and afterwards stratified between those enrolled during pregnancy or after birth up to 6 months. Children receiving PIM were matched with controls on propensity scores based on 27 confounders to estimate effects on health service use from prenatal to age 2 years. Double adjustment was applied in outcome Quasi-Poisson regressions. No evidence was found for effects of PIM starting anytime up to 6 months (262 pairs), or for the children enrolled only after birth (133 pairs), on outcomes occurring after age 6 months. When the programme started during pregnancy (129 pairs), there was a 13% higher prevalence of adequate prenatal visits (prevalence ratio = 1.13; 95% confidence interval 1.01-1.27), but no effect on use of any other health service. Sensitivity analyses suggested longer participation in the programme with reduced visitor turnover might improve its impact on prenatal visits. Integration between PIM and primary health care was not adequate to affect overall patterns of contacts with health services. Nevertheless, prenatal home visits showed potential to increase health service contact during a sensitive period of development, indicating the need to start such programmes before birth, when there is more time for maternal care, and family engagement in a network of services is facilitated.

Unique and shared risk factors for early childhood victimisation and polyvictimisation in a Brazilian population-based birth cohort.

Background: Identifying modifiable risk factors for child victimisation and polyvictimisation (exposure to multiple types of victimisation) is critical for informing prevention efforts, yet little evidence is available in low- and middle-income countries. The authors aimed to estimate the prevalence of child victimisation and polyvictimisation, and examine unique and shared risk factors in a population-based cohort in Southern Brazil. Methods: Lifetime child victimisation was based on maternal report when children were aged 4 years old (N∼3900) and included five types of victimisation (conventional crime, child maltreatment, peer/sibling victimisation, sexual victimisation, and witnessing/indirect victimisation) and polyvictimisation. Based on a socioecological model, possible risk factors were examined in four levels: community, maternal and family, parent, and child. Findings: Conventional crime and peer/sibling victimisation were the most common types of victimisation (46.0 and 46.5%, respectively), followed by witnessing/indirect victimisation (27.0%), and child maltreatment (11.3%). Sexual victimisation had the lowest prevalence (1.4%). One in 10 (10.1%) children experienced polyvictimisation. In general, boys had higher victimisation rates than girls. There were few risk factors related only to specific types of victimisation (e.g., child disability was uniquely associated with child maltreatment and peer/sibling victimisation). Instead, most risk factors were shared across nearly all victimisation types and also associated with polyvictimisation. These shared risk factors were: violent neighbourhood and low social cohesion, maternal adverse childhood experiences, younger maternal age, parental antisocial behaviour, intimate partner violence against mothers, and maternal depression. Interpretation: These findings reveal a general pattern of accumulative risk effects for different types of victimisation and polyvictimisation, rather than unique risk profiles in children aged four year Prevention efforts should target risk factors at multiple levels (e.g.,: community, maternal and family and parent) during early childhood. Funding: Wellcome Trust grant 10735_Z_18_Z.

Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Adverse childhood experiences and crime outcomes in early adulthood: A multi-method approach in a Brazilian birth cohort.

This study aimed to investigate alternative approaches to a cumulative risk score in the relationship between adverse childhood experiences (ACEs) and crime. Using data from the 1993 Pelotas (Brazil) Birth Cohort (n = 3236), we measured 12 ACEs up to 15 years, and past-year violent and non-violent crime at 22 years. We used four analytical approaches: single adversities, cumulative risk, latent class analysis, and network analysis. When examined individually, physical abuse, emotional abuse, and domestic violence were associated with both crime outcomes, whereas maternal mental illness and discrimination were associated with violent crime only, and parental divorce and poverty with non-violent crime only. There was a cumulative effect of ACEs on crime. The class with child maltreatment and household challenges was associated with both crime outcomes; exposure to household challenges and social risks was associated with violent crime only. In network models, crime showed conditional associations with physical abuse, maternal mental illness, and parental divorce. Although cumulative ACEs did associate with crime, some individual and combinations of ACEs showed particularly strong and robust effects, which were not captured by the cumulative score. Many ACEs are closely connected and/or cluster together, and the usefulness of the ACE score needs to be further evaluated.

Towards a better understanding of real-world home-visiting programs: a large-scale effectiveness study of parenting mechanisms in Brazil.

BACKGROUND: The scale-up of parenting programmes to support early childhood development (ECD) is poorly understood. Little is known about how and when early interventions are most effective. Sustainability of ECD programming requires a better understanding of the mechanisms of real-world interventions. We examined the effects on caregiving practices of Primeira Infância Melhor (PIM), a state-wide home-visiting programme in Brazil. METHODS: This propensity score matched, longitudinal, quasiexperimental study uses data from the 2015 Pelotas Birth Cohort. We matched children who received PIM at any age with other cohort children on 25 key covariates. Sensitivity, guidance and responsiveness were assessed using video-recorded play tasks. Coerciveness and the parent-child relationship were assessed using the Parenting and Family Adjustment Scales. All parenting outcomes were examined at age 4 years. Separate moderation analyses were conducted for each effect modifier: family income, child age and duration of participation. RESULTS: Out of 4275 children in the cohort, 797 were enrolled in PIM up to age 4 years. 3018 children (70.6%) were included in the analytic sample, of whom 587 received PIM and 2431 were potential controls. We found a positive effect of PIM on responsiveness (ß=0.08, 95% CIs 0.002 to 0.16) and sensitivity (ß=0.10, 95% CIs 0.02 to 0.19). No effect was found for any secondary outcomes. Moderation analyses revealed a stronger positive effect on sensitivity for low-income parents (ß=0.18, 95% CIs 0.03 to 0.34). CONCLUSION: A state-wide, home-visiting programme in Brazil improved aspects of responsive caregiving. Effects were more pronounced for low-income families, suggesting benefits of purposeful targeting.

Adolescent Mental Health Before and During COVID-19: Longitudinal Evidence From the 2004 Pelotas Birth Cohort in Brazil.

PURPOSE: There is great interest in examining the consequences of the COVID-19 pandemic on adolescent mental health, but most studies were conducted in high-income countries. The identification of overall effects and protective factors is essential to understand the determinants of mental wellbeing in contexts of stress. We aimed to study changes in adolescent mental health during the pandemic and the risk and protective factors associated with these changes in a Brazilian birth cohort. METHODS: One thousand nine hundred forty nine adolescents from the 2004 Pelotas Birth Cohort were assessed prepandemic (T1, November 2019 to March 2020, mean age 15.69 years) and mid-pandemic (T2, August to December 2021, mean age 17.41 years). Mental health was assessed using the Strengths and Difficulties Questionnaire. Prepandemic and pandemic-related predictors were examined as predictors of change in multivariate latent change scores models. RESULTS: There was a mean increase in adolescent total mental health difficulties (M = 1.071, p < .001), hyperactivity/inattention (M = 0.208, p < .001), emotion symptoms (M = 0.409, p < .001), and peer problems (M = 0.434, p < .001) during the pandemic. This increase was associated with several negative family context variables, including harsh parenting and maternal depressive symptoms at T2. Higher emotion regulation levels protected against increases in adolescent mental health difficulties related to the COVID-19 pandemic. DISCUSSION: Family-context variables emerged as important risk factors for the deterioration of adolescent mental health during the COVID-19 pandemic. Interventions promoting emotion regulation strategies are a promising approach to protecting adolescent wellbeing in periods of stress.

Prevalence and Predictors of Concomitant Meniscal and Ligamentous Injuries Associated With ACL Surgery: An Analysis of 20 Years of ACL Reconstruction at a Tertiary Care Children's Hospital.

BACKGROUND: There is an increasing rate of procedures being performed for concomitant injuries during anterior cruciate ligament (ACL) surgery. Few studies have examined risk factors for these associated injuries in young patients. HYPOTHESIS: There are patient-related factors predictive of concomitant knee pathology that differ between age-based cohorts. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Natural language processing was used to extract clinical variables from available notes of patients undergoing ACL surgery between 2000 and 2020 at a single institution (5174 ACL surgeries; mean age, 17 ± 4 years; 53.1% female; accuracy, >98%). Patients were stratified to pediatric (5-13 years), adolescent (14-19 years), and young adult (20-35 years) cohorts. Logistic regression was used to determine predictors of concomitant injury to the menisci, medial collateral ligament (MCL), posterolateral corner (PLC), and posterior cruciate ligament (PCL). RESULTS: Between 2000 and 2020, 54% of pediatric, 71% of adolescent, and 70% of adult patients had ≥1 concomitant soft tissue injury. In children and adolescents, increased age was consistently predictive of sustaining a concomitant injury (P < .02). Female children had increased odds of concomitant medial meniscal injury, while female adults had decreased odds (P≤ .046). Adolescent and adult female patients had decreased odds of concomitant lateral meniscal injury (P≤ .027). Female children had increased odds of injury to the MCL (P = .015), whereas female children and adolescents had decreased odds of PCL injury (P≤ .044). Adolescents undergoing revision ACL surgery had increased odds of meniscal injury (P≤ .001) and decreased odds of concomitant MCL injury (P = .028). Increased body mass index (BMI) was associated with increased odds of concomitant medial meniscal injury in all cohorts (P≤ .041), lateral meniscal injury in adults (P = .045), and PLC injury in children (P = .016). Contact injuries were associated with increased odds of MCL injury in adolescents (P = .017) and PLC injury in adolescents and adults (P < .014). CONCLUSION: These findings support the hypothesis, as there were multiple factors that significantly affected the risk of concomitant injuries that differed between cohorts. Increased age, BMI, and contact injury history were generally associated with increased odds of sustaining a concomitant injury, whereas female sex and revision ACL surgery had mixed effects. Further studies are essential to investigate the sex-based differences in risk for concomitant injuries and to develop tailored treatment plans that minimize the risk of secondary ACL injury.

Cross-sectional and prospective associations between screen time and childhood neurodevelopment in two Brazilian cohorts born 11 years apart.

BACKGROUND: The aim of this study was to investigate the associations between screen time from ages 2 to 4 years and child neurodevelopment at age 4. METHODS: The participants were from the 2004 (N = 3787) and 2015 (N = 3604) Pelotas (Brazil) birth cohort studies. Childhood neurodevelopment was assessed at age 4 using the Battelle Development Inventory. The time children spent on screen devices was reported by their guardians at ages 2 and 4 years. Linear regression models were used to investigate the association of: (i) time spent on television at ages 2 and 4 years; (ii) time spent on other screens at age 4; and (iii) total screen time at age 4 (television + other screens) with childhood neurodevelopment at age 4. RESULTS: Average daily screen time among children born in 2004 and those born in 2005 aged 4 years were 3.4 (SD: 2.4) and 4.4 h (SD: 2.9), respectively. Overall, few associations of very small magnitude between screen time and child neurodevelopment were observed. Television time at 2 years of age was statistically associated with lower neurodevelopment at 4 years of age in the 2015 cohort (ß = -0.30, 95%CI = -0.55; -0.05). Conversely, television time (ß = 0.17, 95%CI = 0.07, 0.26) and total screen time (ß = 0.22, 95%CI = 0.13, 0.31) at age 4 were associated with higher neurodevelopment at age 4 in the 2004 cohort. CONCLUSIONS: The findings of this study suggest that the amount of time spent on screen devices might not be associated with neurodevelopment of children under 5 years of age. The small magnitude and inconsistencies in the direction of associations did not find evidence to support the current guidelines for screen time at this age. Therefore, more studies, especially those with longitudinal data, are important to comprehend the true effect of screen time on neurodevelopment and other health outcomes.

The Effect of Renin-Angiotensin-Aldosterone System Blocking Agents on the Long-term Disease Course of Patients With Crohn's Disease.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) has been associated with gastrointestinal inflammation and fibrosis, suggesting that RAAS blockade may be beneficial in patients with inflammatory bowel disease. Using retrospective analysis, we aimed to compare the disease course of patients with Crohn's disease (CD) taking two commonly prescribed classes of RAAS-blocking agents. STUDY: Patients with CD initiated on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) between 2000 and 2016 were enrolled. Data on clinical, radiologic, and procedural surrogate markers of inflammatory bowel disease were collected in the subsequent 3, 5, and 10 years and compared with matched controls using univariate and multivariate analyses. RESULTS: Compared with controls, patients taking ARBs had fewer instances of corticosteroid use (1.06 vs 2.88, P < 0.01) at 10 years. Patients taking ACEIs had an overall worse disease course, with more imaging studies (3.00 vs 1.75, P = 0.03) and endoscopic procedures (2.70 vs 1.78, P = 0.01) at 5 years, and more imaging studies (6.19 vs 3.50, P < 0.01), endoscopic procedures (5.91 vs 3.78, P < 0.01), and gastrointestinal operations (0.59 vs 0.18, P < 0.02) at 10 years. Results remained significant on multivariate analysis, adjusting for CD characteristics and the use of other antihypertensive medications. CONCLUSIONS: Our study provides insight into the long-term use of RAAS-blocking agents in patients with CD, suggesting that differences exist among commonly prescribed medication classes. While ACEIs were associated with an overall worse disease course at 5 and 10 years, patients taking ARBs were noted to have fewer instances of corticosteroid use at 10 years. Future large-scale studies are needed to further explore this association.

Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Early risk factors for conduct problem trajectories from childhood to adolescence: the 2004 Pelotas (BRAZIL) Birth Cohort.

Conduct problems are associated with an increased risk of a wide range of physical, mental, and social problems. However, there is still uncertainty about how early risk factors differentiate different developmental patterns of conduct problems and whether findings replicate across diverse social contexts. We aimed to identify developmental trajectories of conduct problems, and test early risk factors, in the 2004 Pelotas Birth Cohort in Brazil. Conduct problems were measured at ages 4, 6, 11, and 15 years from caregiver reports on the Child Behaviour Checklist (CBCL) and Strengths and Difficulties Questionnaire (SDQ). Conduct problem trajectories were estimated using group-based semi-parametric modeling (n = 3938). Multinomial logistic regression was used to examine associations between early risk factors and conduct problem trajectories. We identified four trajectories: three with elevated conduct problems, including early-onset persistent (n = 150; 3.8%), adolescence-onset (n = 286; 17.3%), and childhood-limited (n = 697; 17.7%), and one with low conduct problems (n = 2805; 71.2%). The three elevated conduct problem trajectories were associated with a wide range of sociodemographic risk factors, prenatal smoking, maternal mental health, harsh parenting, childhood trauma, and child neurodevelopmental risk factors. Early-onset persistent conduct problems were particularly associated with trauma, living without a father figure, and attention difficulties. The four trajectories of conduct problems from ages 4 to 15 years in this Brazilian cohort have similar longitudinal patterns to those identified in high-income countries. The results confirm previous longitudinal research and developmental taxonomic theories on the etiology of conduct problems in a Brazilian sample.