Showing papers by "Hospital for Sick Children published in 2022"

Saturation variant interpretation using CRISPR prime editing

Abstract: High-throughput functional characterization of genetic variants in their endogenous locus has so far been possible only with methods that rely on homology-directed repair, which are limited by low editing efficiencies. Here, we adapted CRISPR prime editing for high-throughput variant classification and combined it with a strategy that allows for haploidization of any locus, which simplifies variant interpretation. We demonstrate the utility of saturation prime editing (SPE) by applying it to the NPC intracellular cholesterol transporter 1 gene (NPC1), mutations in which cause the lysosomal storage disorder Niemann-Pick disease type C. Our data suggest that NPC1 is very sensitive to genetic perturbation, with 410 of 706 assayed missense mutations being classified as deleterious, and that the derived function score of variants is reflective of diverse molecular defects. We further applied our approach to the BRCA2 gene, demonstrating that SPE is translatable to other genes with an appropriate cellular assay. In sum, we show that SPE allows for efficient, accurate functional characterization of genetic variants.

Evaluation of domain generalization and adaptation on improving model robustness to temporal dataset shift in clinical medicine

Abstract: Temporal dataset shift associated with changes in healthcare over time is a barrier to deploying machine learning-based clinical decision support systems. Algorithms that learn robust models by estimating invariant properties across time periods for domain generalization (DG) and unsupervised domain adaptation (UDA) might be suitable to proactively mitigate dataset shift. The objective was to characterize the impact of temporal dataset shift on clinical prediction models and benchmark DG and UDA algorithms on improving model robustness. In this cohort study, intensive care unit patients from the MIMIC-IV database were categorized by year groups (2008-2010, 2011-2013, 2014-2016 and 2017-2019). Tasks were predicting mortality, long length of stay, sepsis and invasive ventilation. Feedforward neural networks were used as prediction models. The baseline experiment trained models using empirical risk minimization (ERM) on 2008-2010 (ERM[08-10]) and evaluated them on subsequent year groups. DG experiment trained models using algorithms that estimated invariant properties using 2008-2016 and evaluated them on 2017-2019. UDA experiment leveraged unlabelled samples from 2017 to 2019 for unsupervised distribution matching. DG and UDA models were compared to ERM[08-16] models trained using 2008-2016. Main performance measures were area-under-the-receiver-operating-characteristic curve (AUROC), area-under-the-precision-recall curve and absolute calibration error. Threshold-based metrics including false-positives and false-negatives were used to assess the clinical impact of temporal dataset shift and its mitigation strategies. In the baseline experiments, dataset shift was most evident for sepsis prediction (maximum AUROC drop, 0.090; 95% confidence interval (CI), 0.080-0.101). Considering a scenario of 100 consecutively admitted patients showed that ERM[08-10] applied to 2017-2019 was associated with one additional false-negative among 11 patients with sepsis, when compared to the model applied to 2008-2010. When compared with ERM[08-16], DG and UDA experiments failed to produce more robust models (range of AUROC difference, - 0.003 to 0.050). In conclusion, DG and UDA failed to produce more robust models compared to ERM in the setting of temporal dataset shift. Alternate approaches are required to preserve model performance over time in clinical medicine.

Donor–Acceptor Pyridinium Salts for Photo-Induced Electron-Transfer-Driven Modification of Tryptophan in Peptides, Proteins, and Proteomes Using Visible Light

Abstract: Tryptophan (Trp) plays a variety of critical functional roles in protein biochemistry; however, owing to its low natural frequency and poor nucleophilicity, the design of effective methods for both single protein bioconjugation at Trp as well as for in situ chemoproteomic profiling remains a challenge. Here, we report a method for covalent Trp modification that is suitable for both scenarios by invoking photo-induced electron transfer (PET) as a means of driving efficient reactivity. We have engineered biaryl N-carbamoyl pyridinium salts that possess a donor–acceptor relationship that enables optical triggering with visible light whilst simultaneously attenuating the probe’s photo-oxidation potential in order to prevent photodegradation. This probe was assayed against a small bank of eight peptides and proteins, where it was found that micromolar concentrations of the probe and short irradiation times (10–60 min) with violet light enabled efficient reactivity toward surface exposed Trp residues. The carbamate transferring group can be used to transfer useful functional groups to proteins including affinity tags and click handles. DFT calculations and other mechanistic analyses reveal correlations between excited state lifetimes, relative fluorescence quantum yields, and chemical reactivity. Biotinylated and azide-functionalized pyridinium salts were used for Trp profiling in HEK293T lysates and in situ in HEK293T cells using 440 nm LED irradiation. Peptide-level enrichment from live cell labeling experiments identified 290 Trp modifications, with 82% selectivity for Trp modification over other π-amino acids, demonstrating the ability of this method to identify and quantify reactive Trp residues from live cells.

Novel treatments in autism spectrum disorder

Abstract: There are currently no approved medications for the core symptoms of autism spectrum disorder (ASD), and only limited data on the management of co-occurring mental health and behavioural symptoms. The purpose of this review is to synthesize recent trials on novel treatments in ASD, with a focus on research trends in the past 2 years.No new pharmacologic agents received regulatory approval for use in ASD. Several large randomized controlled trials (RCTs) had negative or ambiguous results (e.g. fluoxetine, oxytocin). A cross-over RCT of an oral cannabinoid suggested possible benefits for disruptive behaviours. Two large-scale multicentre trials of bumetanide were terminated early for lack of efficacy. Multicenter trials using repetitive transcranial magnetic stimulation are underway. Recent meta-analyses indicate that specific behavioural and psychological interventions can support social communication and treat anxiety. Numerous novel treatment targets informed by biological mechanisms are under investigation.Recent data support the use of behavioural and psychological interventions for social communication and anxiety in ASD; data are more limited regarding pharmacotherapy for core and associated symptoms. Next steps include replication of early findings, trials of new molecular targets, and the identification of novel biomarkers, including genetic predictors, of treatment response.

Coordinated conformational changes in the V1 complex during V-ATPase reversible dissociation

Abstract: Vacuolar-type ATPases (V-ATPases) are rotary enzymes that acidify intracellular compartments in eukaryotic cells. These multi-subunit complexes consist of a cytoplasmic V1 region that hydrolyzes ATP and a membrane-embedded VO region that transports protons. V-ATPase activity is regulated by reversible dissociation of the two regions, with the isolated V1 and VO complexes becoming autoinhibited on disassembly and subunit C subsequently detaching from V1. In yeast, assembly of the V1 and VO regions is mediated by the regulator of the ATPase of vacuoles and endosomes (RAVE) complex through an unknown mechanism. We used cryogenic-electron microscopy of yeast V-ATPase to determine structures of the intact enzyme, the dissociated but complete V1 complex and the V1 complex lacking subunit C. On separation, V1 undergoes a dramatic conformational rearrangement, with its rotational state becoming incompatible for reassembly with VO. Loss of subunit C allows V1 to match the rotational state of VO, suggesting how RAVE could reassemble V1 and VO by recruiting subunit C. V-ATPases acidify the intracellular compartments of eukaryotic cells and their activity is regulated by reversible dissociation of the complex. Cryo-EM structures show the conformational changes associated with assembly and autoinhibition of V-ATPase.

Characterizing pain in long-term survivors of childhood cancer.

Abstract: Many long-term survivors of childhood cancer (LTSCC), individuals at least 5 years post-diagnosis or 2 years post-treatment, experience late- and long-term effects from their treatments, including pain. Yet, pain is poorly understood among LTSCC. The current study aimed to (1a) describe rates and multiple dimensions of pain; (1b) identify patterns of chronic pain; and (2) test correlates of chronic pain in LTSCC. Survivors (n = 140; 48.6% male, Mage = 17.3 years (range = 8–25)) were recruited from across Canada. Between 2017 and 2019, participants completed the Pain Questionnaire, Pain Catastrophizing Scale, Pediatric Quality of Life Inventory, Patient-Reported Outcome Measurement Information System (PROMIS)–Pain Interference, Anxiety, and Depression scales, Child Posttraumatic Stress Scale, the Posttraumatic Stress Disorder Checklist for the DSM-V, and the Cancer Worry Scale. Twenty-six percent of LTSCC reported experiencing chronic pain. Exploratory cluster analysis showed 20% of survivors had moderate to severe chronic pain based on measures of pain intensity and interference. The combination of higher posttraumatic stress symptoms, older current age, more pain catastrophizing, and sex (being female) significantly predicted the presence of chronic pain in logistic regression, χ2 (4, N = 107) = 28.10, p < .001. Higher pain catastrophizing (OR = 1.09; 95% CI = 1.02–1.16), older current age (OR = 1.20; 95% CI = 1.07–1.34), and higher posttraumatic stress (OR = 1.92; 95% CI = 1.01–3.63) were significant predictors of chronic pain. LTSCC should be screened for the presence and magnitude of chronic pain during long-term follow-up visits so appropriate interventions can be offered and implemented. Future research should investigate pain interventions tailored for this population. Findings support regular screening for the presence and magnitude of chronic pain in survivors of childhood cancer in long-term follow-up care.

Characteristics and birth outcomes of pregnant adolescents compared to older women: An analysis of individual level data from 140,000 mothers from 20 RCTs

Abstract: Adolescence is a critical period of maturation when nutrient needs are high, especially among adolescents entering pregnancy. Using individual-level data from 140,000 participants, we examined socioeconomic, nutrition, and pregnancy and birth outcomes for adolescent mothers (10-19 years) compared to older mothers in low and middle-income countries.This study was conducted between March 16, 2018 and May 25, 2021. Data were obtained from 20 randomised controlled trials of micronutrient supplementation in pregnancy. Stratified analyses were conducted by age (10-14 years, 15-17 years, 18-19 years, 20-29 years, 30-39 years, 40+ years) and geographical region (Africa, Asia). Crude and confounder-adjusted means, prevalence and relative risks of pregnancy, nutrition and birth outcomes were estimated using multivariable linear and log-binomial regression models with 95% confidence intervals.Adolescent mothers comprised 31.6% of our data. Preterm birth, small-for-gestational age (SGA), low birthweight (LBW) and newborn mortality followed a U-shaped trend in which prevalence was highest among the youngest mothers (10-14 years) and then reduced gradually, but increased again for older mothers (40+ years). When compared to mothers aged 20-29 years, there was a 23% increased risk of preterm birth, a 60% increased risk of perinatal mortality, a 63% increased risk of neonatal mortality, a 28% increased risk of LBW, and a 22% increased risk of SGA among mothers 10-14 years. Mothers 40+ years experienced a 22% increased risk of preterm birth and a 103% increased risk of stillbirth when compared to the 20-29 year group.The youngest and oldest mothers suffer most from adverse pregnancy and birth outcomes. Policy and programming agendas should consider both biological and socioeconomic/environmental factors when targeting these populations.Bill and Melinda Gates Foundation (Grant No: OP1137750).

GATA4/5/6 family transcription factors are conserved determinants of cardiac versus pharyngeal mesoderm fate

Abstract: GATA4/5/6 transcription factors play essential, conserved roles in heart development. To understand how GATA4/5/6 modulates the mesoderm-to-cardiac fate transition, we labeled, isolated, and performed single-cell gene expression analysis on cells that express gata5 at precardiac time points spanning zebrafish gastrulation to somitogenesis. We found that most mesendoderm-derived lineages had dynamic gata5/6 expression. In the absence of Gata5/6, the population structure of mesendoderm-derived cells was substantially altered. In addition to the expected absence of cardiac mesoderm, we confirmed a concomitant expansion of cranial-pharyngeal mesoderm. Moreover, Gata5/6 loss led to extensive changes in chromatin accessibility near cardiac and pharyngeal genes. Functional analyses in zebrafish and the tunicate Ciona, which has a single GATA4/5/6 homolog, revealed that GATA4/5/6 acts upstream of tbx1 to exert essential and cell-autonomous roles in promoting cardiac and inhibiting pharyngeal mesoderm identity. Overall, cardiac and pharyngeal mesoderm fate choices are achieved through an evolutionarily conserved GATA4/5/6 regulatory network.

Digital Interventions for Universal Health Promotion in Children and Adolescents: A Systematic Review

Abstract: Digital media has been used mostly to deliver clinical treatments and therapies; however limited evidence evaluates digital interventions for health promotion. The objective of this review is to identify digital interventions for universal health promotion in school-aged children and adolescents globally.Eligible articles were searched in PubMed, Embase, Medline, Ovid SP, The Cochrane Library, Cochrane Central Register of Controlled Trials, WHO regional databases, Google Scholar, and reference lists from 2000 to March 2021. Randomized controlled trials and quasi-experimental studies evaluating interventions that promote health in school-aged children and adolescents (5-19.9 years) were included. Methods were conducted in duplicate. Where possible, data were pooled with a random-effects model.Seventy-four studies were included (46 998 participants), of which 37 were meta-analyzed (19 312 participants). Interventions increased fruit and vegetable consumption (servings per day) (mean difference [MD] 0.63, 95% confidence interval [CI] 0.21 to 1.04; studies = 6; P = .003; high quality of evidence), and probably reduced sedentary behavior (MD -19.62, 95% CI -36.60 to -2.65; studies = 6; P = .02; moderate quality of evidence), and body fat percentage (MD -0.35%, 95% CI -0.63 to -0.06; studies = 5; P = .02; low quality of evidence). The majority of studies were conducted in high-income countries and significant heterogeneity in design and methodology limit generalizability of results.There is great potential in digital platforms for universal health promotion; however, more robust methods and study designs are necessitated. Continued research should assess factors that limit research and program implementation in low- to middle-income countries.

Nutritional Status and Dietary Intake of School-Age Children and Early Adolescents: Systematic Review in a Developing Country and Lessons for the Global Perspective

Abstract: Background The prevalence of double burden of malnutrition (DBM) is high in low- and middle-income countries (LMICs). Data on malnutrition trends is present for children &lt;5 years of age, however the data for school-going children and adolescents aged 5–15 years is scarce. Objective This systematic review presents the pooled prevalence of nutritional status and dietary intake among school-going children and adolescents (5–15 years of age) in an LMIC of Pakistan and the perspective for broader global nutrition in this age group. Methods An electronic search of databases was run on Pubmed and Medline (via Ovid) along with gray literature and archives of local scientific journals till 2nd January 2021. Studies meeting the eligibility criteria were included and relevant data were extracted, and a pooled proportional analysis was performed. Results A total of 51 studies including 62,148 children of 5–15 years met the inclusion criteria, of which 30 studies reported on anthropometric indices alone, eight on dietary intake patterns while 13 reported both. All of the included studies had a cross-sectional study design. There were 20 studies from the province of Punjab, 15 from Sindh, eight from Khyber Pakhtoonkhwa, two from Balochistan, and three from multiple cities across Pakistan. The pooled proportional analysis showed that the proportion of underweight children and adolescents was 25.1% (95% CI 17.3–33.7%); stunting 23% (95% CI 11.8–36.7%); wasting 24% (95% CI 15.2–34%); thinness 12.5% (95% CI 9.4–16.1%); overweight 11.4% (95% CI 7.2–16.3%); and obesity 6.9% (95% CI 3–12%). A relatively high intake of carbohydrates, soft drinks, and sweets/chocolates; and a low intake of protein-rich foods, fruits, and vegetables, compared to the recommended daily allowance (RDA), was reported. Conclusion The limited data suggests the presence of DBM amongst children aged 5–15 years and also identified that dietary intake patterns are not meeting the recommended allowance. This review highlights the gaps and the need for larger, well-designed studies for this age group with the representation of different contexts and the need for similar studies in various LMICs, so that appropriate actions be deliberated and appropriate programs should be designed focusing on this vital population.

Accuracy and Interrater Reliability of Point-of-Care Ultrasonography Image Interpretation for Intussusception

Abstract: The aim of this study was to determine the accuracy and interrater reliability of (1) point-of-care ultrasound (POCUS) image interpretation for identification of intussusception and (2) reliability of secondary signs associated with intussusception among experts compared with novice POCUS reviewers.We conducted a planned secondary analysis of a prospective, convenience sample of children aged 3 months to 6 years who were evaluated with POCUS for intussusception across 17 international pediatric emergency departments between October 2018 and December 2020. A random sample of 100 POCUS examinations was reviewed by novice and expert POCUS reviewers. The primary outcome was identification of the presence or absence of intussusception. Secondary outcomes included intussusception size and the presence of trapped free fluid or echogenic foci. Accuracy was summarized using sensitivity and specificity, which were estimated via generalized mixed effects logistic regression. Interrater reliability was summarized via Light's κ statistics with bootstrapped standard errors (SEs). Accuracy and reliability of expert and novice POCUS reviewers were compared.Eighteen expert and 16 novice POCUS reviewers completed the reviews. The average expert sensitivity was 94.5% (95% confidence interval [CI], 88.6-97.5), and the specificity was 94.3% (95% CI, 90.3-96.7), significantly higher than the average novice sensitivity of 84.7% (95% CI, 74.3-91.4) and specificity of 80.4% (95% CI, 72.4, 86.7). κ was significantly greater for expert (0.679, SE 0.039) compared with novice POCUS reviewers (0.424, SE 0.044; difference 0.256, SE 0.033). For our secondary outcome measure of intussusception size, κ was significantly greater for experts (0.661, SE 0.038) compared with novices (0.397, SE 0.041; difference 0.264, SE 0.029). Interrater reliability was weak for expert and minimal for novice reviewers regarding the detection of trapped free fluid and echogenic foci.Expert POCUS reviewers demonstrate high accuracy and moderate interrater reliability when identifying intussusception via image interpretation and perform better than novice reviewers.

A Practical Approach to Identifying Pediatric Disease-Associated Undernutrition: A Position Statement from the ESPGHAN Special Interest Group on Clinical Malnutrition

Abstract: Disease-associated undernutrition (DAU) is still common in hospitalized children and is generally accepted to be associated with adverse effects on disease outcomes; hence making proper identification and assessment essential in the management of the sick child. There are however several barriers to routine screening, assessment, and treatment of sick children with poor nutritional status or DAU, including limited resources, lack of nutritional awareness, and lack of agreed nutrition policies. We recommend all pediatric facilities to 1) implement procedures for identification of children with (risk of) DAU, including nutritional screening, criteria for further assessment to establish diagnosis of DAU, and follow-up, 2) assess weight and height in all children asa minimum, and 3) have the opportunity for children at risk to be assessed by a hospital dietitian. An updated descriptive definition of pediatric DAU is proposed as "Undernutrition is a condition resulting from imbalanced nutrition or abnormal utilization of nutrients which causes clinically meaningful adverse effects on tissue function and/or body size/composition with subsequent impact on health outcomes." To facilitate comparison of undernutrition data, it is advised that in addition to commonly used criteria for undernutrition such as z score < -2 for weight-for-age, weight-for-length, or body mass index <-2, an unintentional decline of >1inthese z scores over time should be considered as an indicator requiring further assessment to establish DAU diagnosis. Since the etiology of DAU is multifactorial, clinical evaluation and anthropometry should ideally be complemented by measurements of body composition, assessment of nutritional intake, requirements, and losses, and considering disease specific factors.

The Pain Coping Questionnaire short-form: preliminary reliability and validity

Abstract: The Pain Coping Questionnaire (PCQ) has support for its validity and reliability as a tool to understand how a child copes with pain of an extended duration. However, measure length may limit feasibility in clinical settings.The primary goal of this study was to develop a short-form (PCQ-SF) that could be used for screening how children cope with chronic or recurrent pain and examine its reliability and validity.The PCQ-SF was developed in a stepwise manner. First, a confirmatory factor analysis was computed using an amalgamated data set from the validation studies of the PCQ (N = 1225). Next, ratings from researchers and clinicians were obtained on PCQ item content and clarity (n = 12). Finally, the resulting 16-item short-form was tested in a pediatric sample living with chronic and recurrent pain (65 parent-child dyads; n = 128).The PCQ-SF has acceptable preliminary reliability and validity. Both statistical and expert analyses support the collective use of the 16 items as an alternative to the full measure.The compact format of the PCQ-SF will allow practitioners in high-volume clinical environments to quickly determine a child's areas of strengths and weaknesses when coping with pain. Future research using larger more diverse samples to confirm clinical validity is warranted.

Identifying and Treating Severe Bone Marrow Necrosis and Fat Embolism Syndrome in Pediatric Patients With Sickle Cell Disease: A Case Report

Abstract: Fat embolism syndrome after bone marrow necrosis is an extremely rare complication in sickle cell disease associated with significant morbidity and mortality. A high index of suspicion is required for diagnosis. This case report will assist pediatric clinicians and hematologists to recognize this severe complication in patients with sickle cell disease and to promptly initiate treatment. Red flags include severe bone pain, respiratory distress, neurological impairment, decreasing platelet count, peripheral leukocyte left shift, elevated nucleated red blood cells, and significant elevation in plasma ferritin and lactate dehydrogenase. We report a pediatric patient who was diagnosed early, received urgent red cell exchange transfusion and plasma exchange, and ultimately survived this devastating complication.

A Randomized, Controlled Comparison of NCX 470 (0.021%, 0.042%, and 0.065%) and Latanoprost 0.005% in Patients With Open-angle Glaucoma or Ocular Hypertension: The Dolomites Study

Abstract: NCX 470 0.042% and 0.065% were statistically superior in intraocular pressure (IOP) lowering to latanoprost 0.005%, and NCX 470 0.021% was noninferior. All NCX 470 concentrations were safe and well tolerated.The purpose of this study was to compare varying concentrations of NCX 470 (a nitric oxide-donating bimatoprost) to latanoprost in a dose-response safety and efficacy trial.Adult patients with bilateral open-angle glaucoma or ocular hypertension were randomized to NCX 470 0.021% (n=111), 0.042% (n=108), 0.065% (n=107), or latanoprost 0.005% (n=107) once daily in the evening. IOP was measured at 8:00 am, 10:00 am, and 4:00 pm at weeks 1, 2, and 4. The primary efficacy endpoint was the reduction from baseline in mean diurnal IOP at week 4. Secondary efficacy endpoints included reductions from baseline in mean diurnal IOP at weeks 1 and 2, and reductions from baseline in time-matched IOP at 8:00 am, 10:00 am, and 4:00 pm at weeks 1, 2, and 4. Adverse events were evaluated.All concentrations of NCX 470 resulted in significant reductions of mean diurnal IOP. The 0.042% and 0.065% concentrations were statistically superior to latanoprost 0.005%, and 0.021% was noninferior to latanoprost for change from baseline in mean diurnal IOP at week 4. The 0.065% concentration was also superior to latanoprost by up to 1.4 mm Hg for reduction from baseline at 8:00 am, 10:00 am, and 4:00 pm at week 4. NCX 470 was safe and well tolerated; conjunctival hyperemia was the most frequently reported adverse event.NCX 470 demonstrated dose-dependent reductions in IOP. The 0.042% and 0.065% concentrations demonstrated significantly greater reductions from baseline in mean diurnal IOP than latanoprost 0.005% at week 4, suggesting that higher concentrations may show even greater efficacy.

Rationale and Approach to Evaluating Interventions to Promote Child Health in LMICs

Abstract: The age at which children enter school represents a transitional period between early childhood and adolescence that involves increasing autonomy, interaction with peers, and exposure to environments outside the home. Although mortality is generally much lower in the 5 to 9 age group compared with infancy and early childhood, there are many preventable causes of mortality, morbidity, and disability that emerge in this age group, including injuries, noncommunicable diseases, and vaccine-preventable and highly treatable infections.1 Partly because of relatively low mortality rates and less frequent contacts with the health system, school-age children and younger adolescents ages 5 to 14 have been referred to as the “missing middle,” in that there is a dearth of robust data on key health indicators, morbidity burden, and cause-specific mortality in this group.2 Many health issues that have a high burden in early childhood can persist in older children, especially in low- and middle-income countries (LMIC), resource-constrained settings, and marginalized communities worldwide. Undernutrition and infections occurring in the context of poverty remain leading causes of morbidity and mortality in school-age children living in LMIC,3 whereas those children in higher-income settings are more likely to die due to injuries or noncommunicable disease (NCD). In addition, the prevalence of overweight and obesity in children and adolescents has increased steadily over the last few decades,4 though the rate of these increases varies widely among countries.5New risk factors relating to diet, lifestyle, mental health, injuries, and NCDs also become more prominent as children approach and enter adolescence, many of which can contribute to the development of chronic NCDs over the life course. Within this period, school-age children begin to establish healthy lifestyle habits (eg, diet, physical activity, avoidance of substance use), and are learning about sexual and reproductive health and rights, as well as the measures they can take to protect themselves and others. This represents a window of opportunity for educational interventions to support good health, optimal development, and well-being. A growing body of evidence suggests that school-based and digital platforms and delivery strategies are promising tools that aid in the delivery of health interventions to older children.The methodology and reviews described herein contributed to the portion of the upcoming 2022 Lancet Optimizing Child and Adolescent Health and Development Series6 related to school-age child and adolescent health interventions. This Lancet Series is the product of an ongoing academic collaboration involving global child health researchers worldwide, including many who are authors on articles within this supplement. The aim of the specific Lancet Series article citing this supplement is to provide a comprehensive overview of systematic reviews describing the most recent evidence for effective interventions to support maternal, newborn, child, and adolescent health and development from preconception through to 20 years of age.Figure 1 provides an overview of the key child health domains, and a breakdown of the intervention review topics addressing key risk factors covered by the articles included in this journal supplement. On the basis of work done in previous comprehensive overviews of interventions for child and adolescent health (eg, Disease Control Priorities, 3rd edition7; Lancet Adolescent Health Commission8), we identified a comprehensive set of key child health domains that represented priority areas for interventions to address modifiable risks for the major causes of child mortality and morbidity. The factors that informed which domains were covered in this supplement included: conditions with a high global burden of disease, conditions with disproportionate impacts on vulnerable and marginalized populations, potential to support improved human capital development across the life course, and pragmatic considerations including whether the topic had recently been covered elsewhere. In cases where the child health domain was deemed too broad in scope for a single review (eg, infectious diseases), the subtopics for individual reviews were also chosen on the basis of these factors. The age group of specific interest for these reviews was older school-age children (ages 5–9.9), though the period of early adolescence (ages 10–14.9) was also recognized as an important area of overlap and transition. The general outcomes of interest aligned with those chosen through consensus by the Lancet Series working group. These included, but were not limited to, mortality, severe morbidity, disability, growth and development, knowledge and behavior, and indicators of improved human capital development such as academic achievement.The methodological approaches taken, and child health domains covered in this supplement of reviews, was informed by a broad initial literature-scoping and evidence-mapping process to identify key health interventions and associated evidence for their effectiveness in the form of systematic reviews. This was done across all domains, from preconception and pregnancy to ages 0 to 20 to inform the 2022 Lancet Optimizing Child and Adolescent Health and Development Series.6 This involved leveraging existing large-scale intervention overviews (eg, Disease Control Priorities 3rd edition, Lancet Series) that had already highlighted existing effective interventions and the most recent systematic reviews detailing the evidence for their effectiveness. Additional targeted searches for newer interventions and systematic reviews in each domain were also conducted. Through this evidence-mapping process, we explored coverage and extent of LMIC-specific evidence across all child health domains to identify areas where school-age evidence was lacking and determined that there were significant gaps in existing evidence for intervention effectiveness in school-age children.We funneled the reviews identified during this initial scoping process that contained studies covering school-age children and adolescents into the individual reviews for each domain of child health covered in this supplement. We elected to conduct targeted overviews of systematic reviews if there was deemed to be a large body of existing evidence syntheses. In cases where there was a lack of evidence syntheses of intervention effectiveness for a given domain of school-age child health, conventional systematic reviews of primary literature (ie, experimental studies) were conducted. The general methodology for these 2 approaches are described below. See Table 1 and Fig 1 for a summary of the review methods used for each child health domain, and Fig 2 for a breakdown of the main methodology followed in each type of review.For those child health domains that encompassed a variety of intervention types addressing a wide range of risk factors and health conditions, and for which the initial scoping process identified a variety of existing systematic reviews of intervention effectiveness, an overview of systematic reviews was undertaken. This approach was taken to ensure comprehensiveness, reduce duplication of review efforts, and make the review process feasible.In addition to incorporating those relevant reviews previously identified in the initial literature-scoping and evidence-mapping exercise, tailored searches were executed in several databases (eg, Medline, Cochrane Database of Systematic Reviews, Campbell Library) to identify literature published up until the end of 2020. Evidence derived from Cochrane reviews and other high-quality systematic reviews that synthesized evidence from randomized controlled trials and quasi-experimental studies examining the effectiveness of interventions was prioritized for inclusion. A first pass of title and abstract screening for relevance was conducted, followed by a full text screening that was done by at least 2 reviewers against inclusion criteria. Two reviewers independently filled a standardized data abstraction form to capture review characteristics, the characteristics of included studies and interventions (eg, age coverage, country representation, delivery platform), and pooled-effect estimates (eg, risk ratios, odds ratios, mean differences, 95% confidence intervals) derived from meta-analyses where they were reported. The main outcomes of interest across the reviews included measures of child morbidity, mortality, development, academic achievement, and mental and physical well-being. The extracted data were then matched among reviewers to check for errors and ensure consistency, and then consolidated into a single table for inclusion in the article. The AMSTAR 2 tool12 was used for review quality assessment, and was also conducted in duplicate, with any disagreements in ratings resolved by consensus or the involvement of a third reviewer.If for a given domain the initial evidence-mapping exercise revealed that the existing evidence-synthesis literature was lacking for the school-age group, we proceeded with a conventional systematic review of primary literature. All systematic reviews were reported in accordance with the reporting guidance provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria.13Search strategies were developed using the population, intervention, control, and outcomes methodology, relevant medical subject headings terms, and keywords derived from the scoping search. The search terms were adapted for use in other bibliographic databases in combination with database-specific filters for controlled trials, where these were available. Searches for the individual, domain-specific reviews were conducted in a variety of databases, including but not limited to: PubMed, Embase, Medline, PsycINFO, Ovid SP, The Cochrane Library, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, and the World Health Organization regional databases. Evidence derived from LMIC was prioritized for synthesis, though evidence from high-income countries (HIC) settings was leveraged to highlight whether effective interventions exist in cases where LMIC evidence was sparse. Gray literature searches and additional hand searching were conducted in Google Scholar and reference lists of relevant articles, book chapters, and reviews.After removal of duplicate studies, a multistage screening process was performed to select studies that met the eligibility criteria. Each title and abstract was assessed by at least 1 reviewer, who excluded those that were deemed irrelevant. At the full-text review stage, at least 2 reviewers assessed all full texts. Any disagreements in inclusion decisions were resolved by discussion and, where necessary, by consulting a third reviewer. At this stage, reasons for exclusion were documented. The methods section of each individual review in this supplement describes their selection and eligibility criteria, which differed depending on the child health domain being assessed. Data from included studies were independently extracted and coded by 2 review authors using standardized, previously piloted data extraction forms, which sought general study characteristics, details of the population, intervention, comparison groups, and quantitative outcome data. Data extraction forms were matched and checked, and if necessary, a third review author was consulted in the event of any disagreements to establish consensus.Assessment of risk of bias for included studies was conducted according to criteria and tools outlined in the Cochrane Effective Practice and Organization of Care guidelines14 for randomized trials, nonrandomized trials, controlled before–after, interrupted time series, and the Cochrane Handbook for Systematic Reviews of Interventions.15 Assessments were conducted independently by 2 review authors; scores were compared, and a final risk of bias judgement was reported for the included studies of each systematic review. Randomized trials were assessed using the Cochrane Risk of Bias tool15 across the following domains: randomization process, deviations from the intended interventions (blinding of personnel, participants, and outcome assessment), missing outcome data, outcome measurement, the selection of the reported result, disclosure of funding, and conflicts of interest. Studies were assigned an overall risk of bias judgement accordingly (low risk, high risk, or some concerns/medium risk). Quasi-experimental study designs were assessed using the Risk of Bias Tool for Nonrandomized Studies of Interventions (ROBINS-I) tool.15,16 Studies were assessed according to the following domains: bias because of confounding, bias in selection of study participants, bias in classification of interventions, bias because of deviations from intended interventions, bias because of missing data, bias in measurement of outcomes, and bias in selection of the reported result. Each study was assigned an overall risk of bias judgement (low, moderate, serious, and critical risk).Meta-analyses were conducted where possible using Review Manager 5.4 software.17 Randomized controlled trials and cluster-randomized controlled trials were analyzed separately from quasi-experimental study designs. To mitigate heterogeneity within included studies, a random-effects meta-analysis was used for pooled outcomes. For those situations where meta-analysis was not possible, data on the effect of interventions from individual studies was tabulated and reported, and a narrative synthesis was conducted for each key intervention domain.Where there were a sufficient quantity of comparable studies (in both interventions and outcome), a summary of the intervention effect and a measure of quality for key outcomes were produced using the Grading of Recommendations Assessment, Development and Evaluation approach.18 The Grading of Recommendations Assessment, Development and Evaluation approach considers 5 domains (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence for each outcome. The evidence was downgraded from “high quality” by 1 level for serious (or by 2 levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias.The aim of the authors of this supplement of reviews is to comprehensively assess the available evidence for the effectiveness of interventions to improve health and well-being in school-age children and adolescents. The initial literature-scoping and evidence-mapping process, followed by the different review approaches taken, has helped to maximize the scope covered across this set of reviews, and has allowed us to provide the most comprehensive assessment of the state of the published literature covering interventions for school-age children and adolescents. The individual reviews in this supplement have also highlighted child health domain-specific gaps in the evidence for both primary literature in the school-age group, and gaps in existing evidence syntheses.It is important to note that, for the reviews within this supplement, the descriptions of intervention effects are meant to provide an overview of what is currently known in terms of evidence for effectiveness, and do not imply that other interventions were ineffective simply because there was an evidence gap. Given the limited space and large scope, it was only possible to provide the highlights of specific comparisons and outcomes in each of the results sections. Comprehensive tables of study characteristics, outcomes, and effect estimates are provided in both the main articles and appendices.Although we were specifically interested in focusing on LMIC research, this was only feasible for a few review topics (eg, sexual and reproductive health and rights, neglected tropical diseases) because of a dearth of literature. Instead of being used to attempt to generalize their effectiveness to LMIC settings, evidence from intervention effectiveness in HIC settings are included and described to establish that effective interventions do indeed exist and may differ in their impact between settings. This approach has previously been used in the context of adolescent health interventions.19 This evidence from HIC could act as a starting point for future research and implementation in various LMIC settings, with program components tailored to local contexts.In the case of those reviews taking the overview of systematic reviews approach, we were limited to including only those primary studies already included in systematic reviews and could not cover each subdomain in depth. Thus, we were unable to identify and include those primary studies that may not have been included in systematic reviews because of studies not being identified in review authors’ database searches, not meeting their inclusion criteria, or falling out of the time frame of the review. Furthermore, some systematic reviews of primary literature were unable to perform meta-analyses because of high heterogeneity or a lack of high-quality evidence from randomized trials, which makes synthesizing the existing evidence more difficult.

Delivery Strategies Supporting School-Age Child Health: A Systematic Review

Abstract: School-aged children (SAC; 5-9 years) remain understudied in global efforts to examine intervention effectiveness and scale up evidence-based interventions.This review summarizes the available evidence describing the effectiveness of key strategies to deliver school-age interventions.We searched Medline, PsycINFO, Campbell Collaboration, and The Cochrane Library during November 2020.Systematic reviews and meta-analyses that: target SAC, examine effective delivery of well-established interventions, focus on low- and middle-income countries (LMICs), were published after 2010, and focus on generalizable, rather than special, populations.Two reviewers conducted title and abstract screening, full-text screening, data extraction, and quality assessments.Sixty reviews met the selection criteria, with 35 containing evidence from LMICs. The outcomes assessed and the reported effectiveness of interventions varied within and across delivery strategies. Overall, community, school, and financial strategies improved several child health outcomes. The greatest evidence was found for the use of community-based interventions to improve infectious disease outcomes, such as malaria control and prevention. School-based interventions improved child development and infectious disease-related outcomes. Financial strategies improved school enrollment, food security, and dietary diversity.Relatively few LMIC studies examined facility, digital, and self-management strategies. Additionally, we found considerable heterogeneity within and across delivery strategies and review authors reported methodological limitations within the studies.Despite limited research, available information suggests community-based strategies can be effective for the introduction of a range of interventions to support healthy growth and development in SAC. These also have the potential to reduce disparities and reach at-risk and marginalized populations.

GWAS of Hematuria

Abstract: Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy.We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hematuria were enriched by excluding participants with genitourinary conditions. A strongly associated locus on chromosome 2 (COL4A4-COL4A3) was identified. The region was reimputed using the Trans-Omics for Precision Medicine Program followed by sequential rounds of regional conditional analysis, conditioning on previous genetic signals. Similarly, we applied conditional analysis to identify independent variants in the MHC region on chromosome 6 using imputed HLA haplotypes.In total, 16,866 hematuria cases and 391,420 controls were included. Cases had higher urinary albumin-creatinine compared with controls (women: 13.01 mg/g [8.05-21.33] versus 12.12 mg/g [7.61-19.29]; P<0.001; men: 8.85 mg/g [5.66-16.19] versus 7.52 mg/g [5.04-12.39]; P<0.001) and lower eGFR (women: 88±14 versus 90±13 ml/min per 1.72 m2; P<0.001; men: 87±15 versus 90±13 ml/min per 1.72 m2; P<0.001), supporting enrichment of glomerular hematuria. Variants at six loci (PDPN, COL4A4-COL4A3, HLA-B, SORL1, PLLP, and TGFB1) met genome-wide significance (P<5E-8). At chromosome 2, COL4A4 p.Ser969X (rs35138315; minor allele frequency=0.00035; P<7.95E-35; odds ratio, 87.3; 95% confidence interval, 47.9 to 159.0) had the most significant association, and two variants in the locus remained associated with hematuria after conditioning for this variant: COL4A3 p.Gly695Arg (rs200287952; minor allele frequency=0.00021; P<2.16E-7; odds ratio, 45.5; 95% confidence interval, 11.8 to 168.0) and a common COL4A4 intron 25 variant (not previously reported; rs58261427; minor allele frequency=0.214; P<2.00E-9; odds ratio, 1.09; 95% confidence interval, 1.06 to 1.12). Of the HLA haplotypes, HLA-B (*0801; minor allele frequency=0.14; P<4.41E-24; odds ratio, 0.84; 95% confidence interval, 0.82 to 0.88) displayed the most statistically significant association. For remaining loci, we identified three novel associations, which were replicated in the deCODE dataset for dipstick hematuria (nearest genes: PDPN, SORL1, and PLLP).Our study identifies six loci associated with hematuria, including independent variants in COL4A4-COL4A3 and HLA-B. Additionally, three novel loci are reported, including an association with an intronic variant in PDPN expressed in the podocyte.This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN13711021.mp3.

Photochemical protein modification in complex biological environments: recent advances and considerations for future chemical methods development

Abstract: The development of organic reactions that covalently modify biological matter in complex biological mixtures has become an invaluable asset in drug discovery. Out of the techniques developed to date, optically controlled chemistries are of particular utility owing to both the spatiotemporal control afforded by optical control as well as the impressive array of transformations that are driven by the highly reactive intermediates generated upon excitation. This minireview discusses recent advances in the development of photochemical reactions for use in complex mixtures and highlights key considerations for future photochemical reaction designs.

The Transitions to Long-term In Home Ventilator Engagement Study (Transitions to LIVE): study protocol for a pragmatic randomized controlled trial

Abstract: We co-developed a multi-component virtual care solution (TtLIVE) for the home mechanical ventilation (HMV) population using the aTouchAway™ platform (Aetonix). The TtLIVE intervention includes (1) virtual home visits; (2) customizable care plans; (3) clinical workflows that incorporate reminders, completion of symptom profiles, and tele-monitoring; and (4) digitally secure communication via messaging, audio, and video calls; (5) Resource library including print and audiovisual material.Our primary objective is to evaluate the TtLIVE intervention compared to a usual care control group using an eight-center, pragmatic, parallel-group single-blind (outcome assessors) randomized controlled trial. Eligible patients are children and adults newly transitioning to HMV in Ontario, Canada. Our target sample size is 440 participants (220 each arm). Our co-primary outcomes are a number of emergency department (ED) visits in the 12 months after randomization and change in family caregiver (FC) reported Pearlin Mastery Scale score from baseline to 12 months. Secondary outcomes also measured in the 12 months post randomization include healthcare utilization measured using a hybrid Ambulatory Home Care Record (AHCR-hybrid), FC burden using the Zarit Burden Interview, and health-related quality of life using the EQ-5D. In addition, we will conduct a cost-utility analysis over a 1-year time horizon and measure process outcomes including healthcare provider time using the Care Coordination Measurement Tool. We will use qualitative interviews in a subset of study participants to understand acceptability, barriers, and facilitators to the TtLIVE intervention. We will administer the Family Experiences with Care Coordination (FECC) to interview participants. We will use Poisson regression for a number of ED visits at 12 months. We will use linear regression for the Pearlin Mastery scale score at 12 months. We will adjust for the baseline score to estimate the effect of the intervention on the primary outcomes. Analysis of secondary outcomes will employ regression, causal, and linear mixed modeling. Primary analysis will follow intention-to-treat principles. We have Research Ethics Board approval from SickKids, Children's Hospital Eastern Ontario, McMaster Children's Hospital, Children's Hospital-London Health Sciences, Sunnybrook Hospital, London Health Sciences, West Park Healthcare Centre, and Ottawa Hospital.This pragmatic randomized controlled single-blind trial will determine the effectiveness and cost-effectiveness of the TtLIVE virtual care solution compared to usual care while providing important data on patient and family experience, as well as process measures such as healthcare provider time to deliver the intervention.ClinicalTrials.gov NCT04180722 . Registered on November 27, 2019.

The Diverse Phenotype of Intestinal Dysmotility Secondary to ACTG2-related Disorders

Abstract: The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease.Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored.One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3-29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (P = 0.009), PN dependency (P = 0.003), and death/transplant (P = 0.029) compared with boys, and early disease onset (<2 years of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores.Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.