Showing papers by "Hospital for Sick Children published in 2021"

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Abstract: Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

Abstract: From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.

Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group.

Abstract: Background Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival. Methods In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus. Results The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia. Conclusions This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.

Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932.

Abstract: Purpose:AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (...

Interaction hot spots for phase separation revealed by NMR studies of a CAPRIN1 condensed phase.

Abstract: The role of biomolecular condensates in regulating biological function and the importance of dynamic interactions involving intrinsically disordered protein regions (IDRs) in their assembly are increasingly appreciated. While computational and theoretical approaches have provided significant insights into IDR phase behavior, establishing the critical interactions that govern condensation with atomic resolution through experiment is more difficult, given the lack of applicability of standard structural biological tools to study these highly dynamic large-scale associated states. NMR can be a valuable method, but the dynamic and viscous nature of condensed IDRs presents challenges. Using the C-terminal IDR (607 to 709) of CAPRIN1, an RNA-binding protein found in stress granules, P bodies, and messenger RNA transport granules, we have developed and applied a variety of NMR methods for studies of condensed IDR states to provide insights into interactions driving and modulating phase separation. We identify ATP interactions with CAPRIN1 that can enhance or reduce phase separation. We also quantify specific side-chain and backbone interactions within condensed CAPRIN1 that define critical sequences for phase separation and that are reduced by O-GlcNAcylation known to occur during cell cycle and stress. This expanded NMR toolkit that has been developed for characterizing IDR condensates has generated detailed interaction information relevant for understanding CAPRIN1 biology and informing general models of phase separation, with significant potential future applications to illuminate dynamic structure-function relationships in other biological condensates.

Impacts of the COVID-19 pandemic on youth mental health among youth with physical health challenges.

Abstract: Aim To examine mental health in conjunction with physical health during the COVID-19 pandemic among youth with physical health conditions compared to those without. Methods A cross-sectional survey of 622 youth aged 14 to 28 was conducted. Analyses were conducted to understand the changes in mental and physical health among youth in four groups: (a) participants with a friend or family member diagnosed with COVID-19, (b) participants with symptoms associated with COVID-19, (c) participants with atopic conditions (asthma and allergies), and (d) participants with other preexisting physical health conditions. Results Many participants with physical health concerns met screening criteria for an internalizing disorder, which was significantly higher than the rate found among participants without physical health conditions. Significantly greater declines in self-reported mental health were observed during the COVID-19 period compared to 3 months earlier among youth reporting physical health concerns compared to those without physical health concerns. Substance use does not appear to have been affected. Conclusions Mental health concerns are highly prevalent among youth with physical health concerns, and also appear to be exacerbated by the COVID-19 pandemic. Physical health concerns appear to constitute risk factors for heightened mental health responses to the pandemic situation. System planners striving to adapt mental health services to meet social/physical distancing recommendations are urged to consider youth with physical health conditions and ensure that adequate integrated mental health and physical health supports are available to them.

Food Reintroduction after Passing an Oral Food Challenge: A Cross-Sectional Structured Interview-Based Assessment of Barriers, Challenges, and Impact on Quality of Life

Abstract: 001 Penicillin Allergy Evaluation in Pregnancy Impacts Antibiotic Utilization and Neonatal Clinical Outcomes Jamie Waldron, MD, Nerlyne Desravines, MD, Kim Boggess, MD, Mildred Kwan, MD PhD FAAAAI, University of North Carolina Chapel Hill, University of North Carolina at Chapel Hill, UNC, University of North Carolina 002 Nebulized MIDD0301 is Efficacious in Allergic and Microbial Lung Inflammation Models Leggy Arnold, Brandon Mikulsky, BS, M. S. Rashid Roni, MS, RA, Daniel Knutson, Md Yeunus Mian, Gene Yocum, Charles Emala, MD, Nicolas Zahn, Daniel Webb, James Cook, Douglas Stafford, UW Milwaukee, Pantherics Inc., Columbia University, UW-Milwaukee 003 Significant Hypogammaglobulinemia in Patients Receiving CAR T-cell therapy Sara Barmettler, MD, Nancy Yang, Jocelyn Farmer, MD PhD, Aidan Long, MD FAAAAI, Marcela Maus, MD/PhD, Carlos Camargo, MD DrPH, Massachusetts General Hospital, Mass General Hospital 004 SARS-CoV-2 entry factors are expressed in nasal, ocular, and oral tissues: implications for COVID-19 prophylaxes/therapeutics Ivan Lee, Tsuguhisa Nakayama, Sizun Jiang, Yury Goltsev, Christian Sch€urch, Bokai Zhu, David McIlwain, Pauline Chu, Han Chen, Alexandar Tzankov, Matthias Matter, Jayakar Nayak, Garry Nolan, Stanford University School of Medicine, Institute of Medical Genetics and Pathology, University of Basel, Switzerland 005 Picornavirus Infection of Esophageal Epithelial Cells Vinay Goswamy, Paul Fichtinger, BS, Elizabeth McKernan, BS, Sameer Mathur, MD PhD FAAAAI, University of Wisconsin Madison, University of Wisconsin, University of Wisconsin School of Medici 006 Food Reintroduction after Passing an Oral Food Challenge: A Cross-Sectional Structured Interview-Based Assessment of Barriers, Challenges, and Impact on Quality of Life Christina Ditlof, Roxanne Hummel, Samantha Wong, MSc, RD, Mara Alexanian-Farr, MSc, RD, Slavka Zahrebelny, Jennifer Hoang, Lisa Hung, Julia Upton, MD, ADELLE ATKINSON, MD, FRCP, Maria Asper, MD, David Hummel, MD, Thomas Eiwegger, MD, Hospital for Sick Children 007 Identification of severe eosinophilic chronic rhinosinusitis based on eosinophil, mast cell and basophil microparticles in nasal lavage fluids Toru Takahashi, MD, PhD, Atsushi Kato, PhD, Lydia Suh, BS, Roderick Carter, BS, Whitney Stevens, MD, PhD, Caroline Price, CCRC, James Norton, MS, Anju Peters, MD MSCI FAAAAI, Leslie Grammer, MD FAAAAI, Kevin Welch, MD, Stephanie Shintani Smith, MD, David Conley, MD, Sergejs Berdnikovs, PhD, Bruce Tan, MD MS, Robert Kern, MD, Robert Schleimer, PhD FAAAAI, Northwestern University, Feinberg School of Medicine, Northwestern University Feinberg School of Medicine 008 Food-allergic children have decreased peripheral regulatory B cells and altered B cell responses to IL-10 Adora Lin, MD PhD, Hemant Sharma, MD, MHS, Pamela Guerrerio, MD PhD, Catherine Bollard, MD, Children’s National Hospital, National Institute of Allergy and Infectious Diseases 009 Androgen Receptor Signaling Augments Regulatory T Cell Functions to Attenuate Allergic Airway Inflammation Vivek Gandhi, PhD, Jacqueline Cephus, MS, Nowrin Chowdhury, Allison Norlander, PhD, Stokes Peebles, MD FAAAAI, Dawn Newcomb, PhD, Vanderbilt University Medical Center, Vanderbilt Univ School of Medicine 010 Dupilumab Treatment Leads to Clinical Asthma Remission in Patients With Uncontrolled Moderate-to-Severe Asthma With Type 2 Inflammation Ian Pavord, MD, William Busse, MD FAAAAI, Elliot Israel, MD FAAAAI, Stanley Szefler, MD FAAAAI, Zhen Chen, PhD, Nadia Daizadeh, David Lederer, Leda Mannent, MD, Nikhil Amin, MD, Elizabeth Laws, Marcella Ruddy, MD, Paul Rowe, MD, Yamo Deniz, Asif Khan, Yi Zhang, NIHR Oxford Biomedical Research Centre, University of Oxford, University of Wisconsin School of Medicine and Public Health, Harvard Medical School and Brigham & Women’s Hospital, University of Colorado School of Medicine, Regeneron Pharmaceuticals, Inc., Sanofi 011 Implementation of Virtual Training Visits During the Coronavirus Pandemic: a Nursing Perspective Linda Trotto, RN, BSN, CRNI, Christopher Vanname, RN, Timothy Kingas, RN, Specialty Pharmacy Nursing Network, Inc.

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Abstract: Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80–160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication. In a randomized phase 2 clinical trial, the angiotensin receptor blocker valsartan improved cardiac structure and function in patients with early-stage hypertrophic cardiomyopathy, a condition for which there are no effective therapies for modifying disease progression.

Biological and therapeutic implications of a unique subtype of NPM1 mutated AML.

Abstract: In acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit. Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.

Knowledge, attitude and perception of Pakistanis towards COVID-19; a large cross-sectional survey.

Abstract: The Novel Coronavirus Disease (COVID-19) has created havoc globally as countries worldwide struggle to combat this pandemic. Since prevention and social isolation are known to be the only ways to prevent the spread of COVID-19, this has created challenges among the lower-middle income countries (LMIC) including Pakistan, as it battles between an under-resourced healthcare, an economic shutdown, and widespread myths and misconceptions. Therefore, a study was conducted to evaluate the knowledge, attitude and perceptions regarding COVID-19 as public understanding is vital to help facilitate the control of this outbreak. A pre-validated online questionnaire was distributed among the general population of Pakistan from 1st to 12th June 2020. Descriptive statistics were analyzed using SPSS v25. Adequate knowledge was assigned as a score of > 4 (range: 0–8) and good perception as a score of > 3 (range: 0–5). Chi-square test was used to determine the significance of difference in knowledge and perception of COVID-19 with socio-demographic characteristics. Logistic regression analysis was run to identify factors associated with adequate knowledge and perception. P < 0.05 was considered as significant. A total of 1200 respondents participated in this study with a wide range of age groups and education. Majority of the respondents had adequate knowledge (93.3%) with a mean score of 6.59 ± 1.35, and good perception (85.6%) with a mean score of 4.29 ± 0.82. Significant differences in knowledge and perception were observed among genders, age groups, education and between students and employees in the healthcare and non-healthcare department. A multivariate analysis revealed a higher educational status and female gender to be significant predictors of adequate knowledge and perception. Albeit the surge of COVID-19 cases in Pakistan, the participants demonstrated an overall adequate knowledge and good perception towards COVID-19. There is a need to follow the preventive protocols and dissemination of correct information through conducting educational interventions that target safe health practices and provide appropriate information on this infection.

Transcriptome-Wide Off-Target Effects of Steric-Blocking Oligonucleotides.

Abstract: Steric-blocking oligonucleotides (SBOs) are short, single-stranded nucleic acids designed to modulate gene expression by binding to RNA transcripts and blocking access from cellular machinery such as splicing factors. SBOs have the potential to bind to near-complementary sites in the transcriptome, causing off-target effects. In this study, we used RNA-seq to evaluate the off-target differential splicing events of 81 SBOs and differential expression events of 46 SBOs. Our results suggest that differential splicing events are predominantly hybridization driven, whereas differential expression events are more common and driven by other mechanisms (including spurious experimental variation). We further evaluated the performance of in silico screens for off-target splicing events, and found an edit distance cutoff of three to result in a sensitivity of 14% and false discovery rate (FDR) of 99%. A machine learning model incorporating splicing predictions substantially improved the ability to prioritize low edit distance hits, increasing sensitivity from 4% to 26% at a fixed FDR of 90%. Despite these large improvements in performance, this approach does not detect the majority of events at an FDR <99%. Our results suggest that in silico methods are currently of limited use for predicting the off-target effects of SBOs, and experimental screening by RNA-seq should be the preferred approach.

The clinical utility of exome and genome sequencing across clinical indications: a systematic review

Abstract: Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37–70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4–100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time. Prospero registration CRD42019094101.

Minimum important difference of the EQ-5D-5L and EQ-VAS in fibrotic interstitial lung disease.

Abstract: Rationale The European Quality of Life 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) is a multidimensional patient-reported questionnaire that supports calculation of quality-adjusted life-years. Our objectives were to demonstrate feasibility of use and to calculate the minimum important difference (MID) of the EQ-5D-5L and its associated visual analogue scale (EQ-VAS) in patients with fibrotic interstitial lung disease (ILD). Methods Patients who completed the EQ-5D-5L were identified from the prospective multicentre CAnadian REgistry for Pulmonary Fibrosis. Validity, internal consistency and responsiveness of the EQ-5D-5L were assessed, followed by calculation of the MID for the EQ-5D-5L and EQ-VAS. Anchor-based methods used an unadjusted linear regression against pulmonary function tests (PFTs) and dyspnoea and other quality of life questionnaires. Distribution-based method used one-half SD and SE measurement (SEM) calculations. Results 1816 patients were analysed, including 472 (26%) with idiopathic pulmonary fibrosis. EQ-5D-5L scores were strongly correlated with the dyspnoea and other quality of life questionnaires and weakly associated with PFTs. The estimated MID for EQ-5D-5L ranged from 0.0050 to 0.054 and from 0.078 to 0.095 for the anchor-based and distribution-based methods, respectively. The MID for EQ-VAS ranged from 0.5 to 5.0 and from 8.0 to 9.7 for the anchor-based and distribution-based methods. Findings were similar across ILD subtypes, sex and age. Conclusion We used a large and diverse cohort of patients with a variety of fibrotic ILD subtypes to suggest validity and MID of both the EQ-5D-5L and EQ-VAS. These findings will assist in designing future clinical trials and supporting cost-effectiveness analyses of potential treatments for patients with fibrotic ILD.

Cryo-EM structure and kinetics reveal electron transfer by 2D diffusion of cytochrome c in the yeast III-IV respiratory supercomplex

Abstract: Energy conversion in aerobic organisms involves an electron current from low-potential donors, such as NADH and succinate, to dioxygen through the membrane-bound respiratory chain. Electron transfer is coupled to transmembrane proton transport, which maintains the electrochemical proton gradient used to produce ATP and drive other cellular processes. Electrons are transferred from respiratory complexes III to IV (CIII and CIV) by water-soluble cytochrome (cyt.) c. In Saccharomyces cerevisiae and some other organisms, these complexes assemble into larger CIII2CIV1/2 supercomplexes, the functional significance of which has remained enigmatic. In this work, we measured the kinetics of the S. cerevisiae supercomplex cyt. c-mediated QH2:O2 oxidoreductase activity under various conditions. The data indicate that the electronic link between CIII and CIV is confined to the surface of the supercomplex. Single-particle electron cryomicroscopy (cryo-EM) structures of the supercomplex with cyt. c show the positively charged cyt. c bound to either CIII or CIV or along a continuum of intermediate positions. Collectively, the structural and kinetic data indicate that cyt. c travels along a negatively charged patch on the supercomplex surface. Thus, rather than enhancing electron transfer rates by decreasing the distance that cyt. c must diffuse in three dimensions, formation of the CIII2CIV1/2 supercomplex facilitates electron transfer by two-dimensional (2D) diffusion of cyt. c. This mechanism enables the CIII2CIV1/2 supercomplex to increase QH2:O2 oxidoreductase activity and suggests a possible regulatory role for supercomplex formation in the respiratory chain.

Measures of organizational culture, organizational climate, and implementation climate in behavioral health: A systematic review:

Abstract: Background:Organizational culture, organizational climate, and implementation climate are key organizational constructs that influence the implementation of evidence-based practices. However, there...

Brain charts for the human lifespan

Abstract: Over the past 25 years, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over the lifespan, in contrast to growth charts for anthropometric traits such as height and weight. Here, we built an interactive resource (www.brainchart.io) to benchmark individual differences in brain morphology, measured from any current or future magnetic resonance imaging (MRI) study, against normative age-related trends. With the goal of basing these reference charts on the largest and most inclusive dataset available, we aggregated 123,984 MRI scans from 101,457 participants in over 100 studies - from 115 days post-conception through 100 postnatal years. Cerebrum tissue volumes and other global or regional MRI metrics were quantified by centile scores, relative to non-linear trajectories, demonstrating concurrent validity with non-MRI brain growth milestones, high stability over longitudinal assessments, and robustness to differences between studies. Brain charts identified previously unreported neurodevelopmental milestones, and centile scores had increased heritability compared to non-centiled MRI phenotypes. Crucially, for clinical purposes, centile scores provided a standardised and interpretable measure of deviation that revealed new patterns of neuroanatomical differences across neurological and psychiatric disorders. In sum, brain charts for the human lifespan are an essential first step towards robust, standardised quantification of deviation from age-related trends in multiple commonly-used neuroimaging phenotypes. Our global collaborative study provides such an anchorpoint for neuroimaging research and will facilitate implementation of quantitative standards in clinical studies.

Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study.

Abstract: Background The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results The study population included 269 children (105 [39%] Crohn's disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn's disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn's disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.

Novel, Flexible, and Ultrathin Pressure Feedback Sensor for Miniaturized Intraventricular Neurosurgery Robotic Tools

Abstract: Remote-controlled minimally invasive neuroendoscopic robotic surgical tools can be miniaturized to a size of less than 2 mm while maintaining their dexterity and force required to perform operations in brain without an open-skull surgery. However, these platforms lack haptic information to be received by the surgeons, leading to loss of control over tissue and causing unexpected slippage and trauma. This study presents the design of a small and highly sensitive material-based sensor being integrated to the tool shaft, known as the concentric tube manipulators, to achieve static and quasi-static force sensing and feedback. Through a nine-element design and contact mechanics modeling, the sensor system can generate real-time polar visual pressure profile displays. Optimizations are performed on the subcomponents of the sensor design including microstructures and electrodes to improve detection threshold with reduced hysteresis. The finalized design can sense a force from as low as 14.8 ± 1.22 mN to 1 N with excellent proportionality between the acquired signal and force applied while retaining its flexibility and sterilizability. The sensor will also enhance more intuitive force feedback for surgeons to use the dexterous neurosurgical tool, ensuring safety and quality of operations for minimally invasive surgeries for brain tumor and epilepsy practice.

Trait impulsivity in juvenile myoclonic epilepsy

Abstract: Objective Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta‐analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs). Methods 322 participants with JME and 126 age and gender‐matched controls completed the Barratt’s Impulsiveness Scale (BIS‐brief) alongside information on seizure history and AED use. We compared group BIS‐brief scores and assessed associations of JME BIS‐brief scores with seizure characteristics and AED adverse effects. Results The mean BIS‐brief score in JME was 18.1 ± 4.4 compared with 16.2 ± 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse effects. Interpretation Trait impulsivity is elevated in JME and comparable to scores in personality and neurotic disorders. Increased seizure frequency and absence of circadian seizure pattern moderate BIS score, suggesting disruption of both cortico‐striatal and thalamocortical networks as a shared mechanism between seizures and impulsivity in JME. These findings warrant consideration of impulsivity as a distinct target of intervention, and as a stratifying factor for AED treatment in JME, and perhaps other types of epilepsy. The role of impulsivity in treatment adherence and psychosocial outcome requires further investigation.

Composition and Associations of the Infant Gut Fungal Microbiota with Environmental Factors and Childhood Allergic Outcomes.

Abstract: Although often neglected in gut microbiota studies, recent evidence suggests that imbalanced, or dysbiotic, gut mycobiota (fungal microbiota) communities in infancy coassociate with states of bacterial dysbiosis linked to inflammatory diseases such as asthma. In the present study, we (i) characterized the infant gut mycobiota at 3 months and 1 year of age in 343 infants from the CHILD Cohort Study, (ii) defined associations among gut mycobiota community composition and environmental factors for the development of inhalant allergic sensitization (atopy) at age 5 years, and (iii) built a predictive model for inhalant atopy status at age 5 years using these data. We show that in Canadian infants, fungal communities shift dramatically in composition over the first year of life. Early-life environmental factors known to affect gut bacterial communities were also associated with differences in gut fungal community alpha diversity, beta diversity, and/or the relative abundance of specific fungal taxa. Moreover, these metrics differed among healthy infants and those who developed inhalant allergic sensitization (atopy) by age 5 years. Using a rationally selected set of early-life environmental factors in combination with fungal community composition at 1 year of age, we developed a machine learning logistic regression model that predicted inhalant atopy status at 5 years of age with 81% accuracy. Together, these data suggest an important role for the infant gut mycobiota in early-life immune development and indicate that early-life behavioral or therapeutic interventions have the potential to modify infant gut fungal communities, with implications for an infant's long-term health. IMPORTANCE Recent evidence suggests an immunomodulatory role for commensal fungi (mycobiota) in the gut, yet little is known about the composition and dynamics of early-life gut fungal communities. In this work, we show for the first time that the composition of the gut mycobiota of Canadian infants changes dramatically over the course of the first year of life, is associated with environmental factors such as geographical location, diet, and season of birth, and can be used in conjunction with knowledge of a small number of key early-life factors to predict inhalant atopy status at age 5 years. Our study highlights the importance of considering fungal communities as indicators or inciters of immune dysfunction preceding the onset of allergic disease and can serve as a benchmark for future studies aiming to examine infant gut fungal communities across birth cohorts.

Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory region of ABCC transporters.

Abstract: ATP binding cassette (ABC) proteins typically function in active transport of solutes across membranes. The ABC core structure is composed of two transmembrane domains (TMD1 and TMD2) and two cytosolic nucleotide binding domains (NBD1 and NBD2). Some members of the C-subfamily of ABC (ABCC) proteins, including human multidrug resistance proteins (MRPs), also possess an N-terminal transmembrane domain (TMD0) that contains five transmembrane α-helices and is connected to the ABC core by the L0 linker. While TMD0 was resolved in SUR1, the atypical ABCC protein that is part of the hetero-octameric ATP-sensitive K+ channel, little is known about the structure of TMD0 in monomeric ABC transporters. Here, we present the structure of yeast cadmium factor 1 protein (Ycf1p), a homolog of human MRP1, determined by electron cryo-microscopy (cryo-EM). A comparison of Ycf1p, SUR1, and a structure of MRP1 that showed TMD0 at low resolution demonstrates that TMD0 can adopt different orientations relative to the ABC core, including a ∼145° rotation between Ycf1p and SUR1. The cryo-EM map also reveals that segments of the regulatory (R) region, which links NBD1 to TMD2 and was poorly resolved in earlier ABCC structures, interacts with the L0 linker, NBD1, and TMD2. These interactions, combined with fluorescence quenching experiments of isolated NBD1 with and without the R region, suggest how posttranslational modifications of the R region modulate ABC protein activity. Mapping known mutations from MRP2 and MRP6 onto the Ycf1p structure explains how mutations involving TMD0 and the R region of these proteins lead to disease.

Prenatal Opioid Analgesics and the Risk of Adverse Birth Outcomes.

Abstract: Background It is unclear whether confounding accounts for the increased risk of preterm birth and small for gestational age (SGA) birth in opioid analgesic exposed pregnancies. Methods Using universal coverage health data for Ontario, we assembled a cohort of mother-infant pairs without opioid use disorder (627,172 pregnancies and 509,522 women). We estimated risk ratios (RRs) between opioid analgesics and preterm birth, SGA birth, and stillbirth; neonatal abstinence syndrome was a secondary outcome. We used high-dimensional propensity scores and sensitivity analyses for confounding adjustment. Results 4% of pairs were exposed, mainly to codeine (2%), morphine (1%), and oxycodone (1%). Compared with unexposed, the adjusted risk of preterm birth was higher with any (1.3, 95% confidence interval [CI] = 1.2, 1.3), first- (RR: 1.2, 95% CI = 1.2, 1.3), and second-trimester (RR: 1.3, 95% CI = 1.2, 1.4) opioid analgesic exposure. Preterm birth risk was higher for first- and second-trimester codeine, morphine, and oxycodone exposure, and for third-trimester morphine. There was a small increase in SGA with first-trimester exposure to any opioid analgesic or to codeine. Exposed pregnancies had an elevated stillbirth risk with any (RR: 1.6, 95% CI = 1.4, 1.8), first- and second-trimester exposure. Few infants had neonatal abstinence syndrome (N = 143); the risk was higher in exposed (RR: 3.6, 95% CI = 2.1, 6.0). In sensitivity analyses of unmeasured confounding, an elevated risk in exposed pregnancies persisted for preterm birth but not SGA. Conclusions Opioid analgesic-exposed pregnancies had a small increased risk of preterm birth and possibly stillbirth after accounting for confounding by indication and sociodemographic factors.

COVID-19 Economic Response and Recovery: A Rapid Scoping Review.

Abstract: This rapid scoping review of existing evidence and research gaps addressed the following question: what research evidence exists and what are the research gaps at global, regional, and national levels on interventions to protect jobs, small- and medium-sized enterprises, and formal/informal sector workers in socioeconomic response to the coronavirus disease 2019 (COVID-19) pandemic? The results are based on 79 publications deemed eligible for inclusion after the screening and prioritizing of 1,658 records. The findings are organized according to the 3 main categories of socioeconomic interventions-protecting jobs, enterprises, and workers-although the 3 are intertwined. Most results were derived from global-level gray literature with recommendations for interventions and implicit links to the sustainable development goals. Based on research gaps uncovered in the review, future implementation science research needs to focus on designing, implementing, evaluating, and scaling: effective evidence-based socioeconomic interventions; equity-focused, redistributive, and transformative interventions; comprehensive packages of complementary interventions; interventions to upend root causes of systemic social inequities; collaborative and participatory approaches; interventions that integrate environmental sustainability; and city-level interventions. Failing to consider the environmental dimensions of economic recovery is shortsighted and will ultimately exacerbate social inequities and poverty and undermine economic stability in the long term.

Career aspirations and workplace expectations among youth with physical disabilities.

Abstract: Purpose Youths with disabilities have lower employment rates than youths without disabilities, which are often a result of inaccessible environments, employer's lack of knowledge about people with disabilities and discriminatory attitudes. Exploring youths' career aspirations is important because it can prompt or hinder career planning, and contribute to youths' preparation for adult life. The purpose of our study was to explore the career aspirations and workplace expectations of youths with physical disabilities. Method We drew on qualitative discussion forum data from a larger study focusing on employment preparation e-mentoring intervention for youths with physical disabilities. Our sample comprised 44 youths aged 15-25 years (mean age 18.9, 47% female) with physical disabilities. We analyzed the data using a qualitative, content analysis approach. Results Youths described several areas that helped to develop their occupational capacity including self-advocacy, pursuing post-secondary education, volunteering/co-op, family support, and social networks. Areas where youths anticipated encountering occupational constraints involved: transportation, attitudes and discrimination, physicality of work and self-care, communication skills, and finding work or volunteer positions. Youths' expectations for the workplace included: disability disclosure and requesting accommodations, and a respectful environment. Conclusions Our findings highlighted that youths with physical disabilities had diverse career aspirations that are shaped by various occupational capacities and constraints.Implications for rehabilitationYouth with physical disabilities may need further support with accessing and navigating public transportation independently to gain employment, and also developing their communication skills, specifically how to disclose their condition to employers and coping with potential discrimination.Clinicians and educators should help youth with disabilities to gain exposure to a variety of career options (including STEM) while supporting them to find accessible positions that are compatible with their abilities.Clinicians and educators could consider helping to foster self-advocacy skills among youth with disabilities which are needed to disclose their condition and request accommodations.