Monash Children’s Hospital

BACKGROUND/AIMS: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. METHODS: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. RESULTS AND CONCLUSION: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls.

Stroke is the second leading cause of death and the third leading cause of disability worldwide and its burden is increasing rapidly in low-income and middle-income countries, many of which are unable to face the challenges it imposes. In this Health Policy paper on primary stroke prevention, we provide an overview of the current situation regarding primary prevention services, estimate the cost of stroke and stroke prevention, and identify deficiencies in existing guidelines and gaps in primary prevention. We also offer a set of pragmatic solutions for implementation of primary stroke prevention, with an emphasis on the role of governments and population-wide strategies, including task-shifting and sharing and health system re-engineering. Implementation of primary stroke prevention involves patients, health professionals, funders, policy makers, implementation partners, and the entire population along the life course.

Preterm birth is commonly defined as any birth before 37 weeks completed weeks of gestation. An estimated 15 million infants are born preterm globally, disproportionately affecting low and middle income countries (LMIC). It contributes directly to estimated one million neonatal deaths annually and is a significant contributor to childhood morbidity. However, in many clinical settings, the information available to calculate completed weeks of gestation varies widely. Accurate dating of the last menstrual period (LMP), as well as access to clinical and ultrasonographic evaluation are important components of gestational age assessment antenatally. This case definition assign levels of confidence to categorisation of births as preterm, utilising assessment modalities which may be available across different settings. These are designed to enable systematic safety evaluation of vaccine clinical trials and post-implementation programmes of immunisations in pregnancy.

Being born small lays the foundation for short-term and long-term implications for life. Intrauterine or fetal growth restriction describes the pregnancy complication of pathological reduced fetal growth, leading to significant perinatal mortality and morbidity, and subsequent long-term deficits. Placental insufficiency is the principal cause of FGR, which in turn underlies a chronic undersupply of oxygen and nutrients to the fetus. The neonatal morbidities associated with FGR depend on the timing of onset of placental dysfunction and growth restriction, its severity, and the gestation at birth of the infant. In this review, we explore the pathophysiological mechanisms involved in the development of major neonatal morbidities in FGR, and their impact on the health of the infant. Fetal cardiovascular adaptation and altered organ development during gestation are principal contributors to postnatal consequences of FGR. Clinical presentation, diagnostic tools and management strategies of neonatal morbidities are presented. We also present information on the current status of targeted therapies. A better understanding of neonatal morbidities associated with FGR will enable early neonatal detection, monitoring and management of potential adverse outcomes in the newborn period and beyond.

INTRODUCTION AND HYPOTHESIS: A terminology and standardized classification has yet to be developed for those complications arising directly from the insertion of synthetic (prostheses) and biological (grafts) materials in female pelvic floor surgery. METHODS: This report on the above terminology and classification combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS) and a Joint IUGA/ICS Working Group on Complications Terminology, assisted at intervals by many expert external referees. An extensive process of 11 rounds of internal and external review took place with exhaustive examination of each aspect of the terminology and classification. Decision-making was by collective opinion (consensus). RESULTS: A terminology and classification of complications related directly to the insertion of prostheses and grafts in female pelvic floor surgery has been developed, with the classification based on category (C), time (T) and site (S) classes and divisions, that should encompass all conceivable scenarios for describing insertion complications and healing abnormalities. The CTS code for each complication, involving three (or four) letters and three numerals, is likely to be very suitable for any surgical audit or registry, particularly one that is procedure-specific. Users of the classification have been assisted by case examples, colour charts and online aids (www.icsoffice.org/complication). CONCLUSION: A consensus-based terminology and classification report for prosthesis and grafts complications in female pelvic floor surgery has been produced, aimed at being a significant aid to clinical practice and research.

BACKGROUND: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. RESULTS: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. CONCLUSIONS: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.

Kawasaki disease (KD) is a childhood vasculitis and the most frequent cause of paediatric acquired heart disease in North America, Europe and Japan. It is increasingly recognised in rapidly industrialising countries such as China and India where it may replace rheumatic heart disease as the most common cause of acquired heart disease in children. We review the current global epidemiology of KD and discuss some public health implications.

BACKGROUND: Children's exposure to other people's cigarette smoke (environmental tobacco smoke, or ETS) is associated with a range of adverse health outcomes for children. Parental smoking is a common source of children's exposure to ETS. Older children are also at risk of exposure to ETS in child care or educational settings. Preventing exposure to cigarette smoke in infancy and childhood has significant potential to improve children's health worldwide. OBJECTIVES: To determine the effectiveness of interventions aiming to reduce exposure of children to ETS. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register and conducted additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, EMBASE, CINAHL, ERIC, and The Social Science Citation Index & Science Citation Index (Web of Knowledge). Date of the most recent search: September 2013. SELECTION CRITERIA: Controlled trials with or without random allocation. Interventions must have addressed participants (parents and other family members, child care workers and teachers) involved with the care and education of infants and young children (aged 0 to 12 years). All mechanisms for reduction of children's ETS exposure, and smoking prevention, cessation, and control programmes were included. These include health promotion, social-behavioural therapies, technology, education, and clinical interventions. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies and extracted data. Due to heterogeneity of methodologies and outcome measures, no summary measures were possible and results were synthesised narratively. MAIN RESULTS: Fifty-seven studies met the inclusion criteria. Seven studies were judged to be at low risk of bias, 27 studies were judged to have unclear overall risk of bias and 23 studies were judged to have high risk of bias. Seven interventions were targeted at populations or community settings, 23 studies were conducted in the 'well child' healthcare setting and 24 in the 'ill child' healthcare setting. Two further studies conducted in paediatric clinics did not make clear whether the visits were to well or ill children, and another included both well and ill child visits. Thirty-six studies were from North America, 14 were in other high income countries and seven studies were from low- or middle-income countries. In only 14 of the 57 studies was there a statistically significant intervention effect for child ETS exposure reduction. Of these 14 studies, six used objective measures of children's ETS exposure. Eight of the studies had a high risk of bias, four had unclear risk of bias and two had a low risk of bias. The studies showing a significant effect used a range of interventions: seven used intensive counselling or motivational interviewing; a further study used telephone counselling; one used a school-based strategy; one used picture books; two used educational home visits; one used brief intervention and one study did not describe the intervention. Of the 42 studies that did not show a significant reduction in child ETS exposure, 14 used more intensive counselling or motivational interviewing, nine used brief advice or counselling, six used feedback of a biological measure of children's ETS exposure, one used feedback of maternal cotinine, two used telephone smoking cessation advice or support, eight used educational home visits, one used group sessions, one used an information kit and letter, one used a booklet and no smoking sign, and one used a school-based policy and health promotion. In 32 of the 57 studies, there was reduction of ETS exposure for children in the study irrespective of assignment to intervention and comparison groups. One study did not aim to reduce children's tobacco smoke exposure, but rather aimed to reduce symptoms of asthma, and found a significant reduction in symptoms in the group exposed to motivational interviewing. We found little evidence of difference in effectiveness of interventions between the well infant, child respiratory illness, and other child illness settings as contexts for parental smoking cessation interventions. AUTHORS' CONCLUSIONS: While brief counselling interventions have been identified as successful for adults when delivered by physicians, this cannot be extrapolated to adults as parents in child health settings. Although several interventions, including parental education and counselling programmes, have been used to try to reduce children's tobacco smoke exposure, their effectiveness has not been clearly demonstrated. The review was unable to determine if any one intervention reduced parental smoking and child exposure more effectively than others, although seven studies were identified that reported motivational interviewing or intensive counselling provided in clinical settings was effective.

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.

BACKGROUND: About 47% of preschool children worldwide are anaemic. Daily oral iron supplementation is a commonly recommended intervention for treatment and prevention of anaemia, but the efficacy and safety of iron supplementation programmes is debated. Thus, we systematically reviewed the evidence for benefit and safety of daily iron supplementation in children aged 4-23 months. METHODS: We searched Scopus and Medline, from inception to Feb 5, 2013, WHO databases, theses repositories, grey literature, and references. Randomised controlled trials that assigned children 4-23 months of age to daily oral iron supplementation versus control were eligible. We calculated mean difference (MD) or standard MD (SMD) for continuous variables, risk ratios for dichotomous data, and rate ratios for rates. We quantified heterogeneity with the I(2) test and synthesised all data with a random-effects model. This review is registered with the International Prospective Register of Systematic Reviews, number CRD42011001208. FINDINGS: Of 9533 citations identified by the search strategy, 49 articles from 35 studies were eligible; these trials included 42,306 children. Only nine studies were judged to be at low risk of bias. In children receiving iron supplements, the risk ratio for anaemia was 0·61 (95% CI 0·50-0·74; 17 studies, n=4825), for iron deficiency was 0·30 (0·15-0·60; nine studies, n=2464), and for iron deficiency anaemia was 0·14 (0·10-0·22; six studies, n=2145). We identified no evidence of difference in mental (MD 1·65, 95% CI -0·63 to 3·94; six studies, n=1093) or psychomotor development (1·05, -1·36 to 3·46; six studies, n=1086). We noted no significant differences in final length or length-for-age, or final weight or weight-for-age. Children randomised to iron had slightly lesser length (SMD -0·83, -1·53 to -0·12; eight studies, n=868) and weight gain (-1·12, -1·19 to -0·33) over the course of the studies. Vomiting (risk ratio 1·38, 95% CI 1·10-1·73) and fever (1·16, 1·02-1·31) were more prevalent in children receiving iron. INTERPRETATION: In children aged 4-23 months, daily iron supplementation effectively reduces anaemia. However, the adverse effect profile of iron supplements and effects on development and growth are uncertain. Adequately powered trials are needed to establish the non-haematological benefits and risks from iron supplementation in this group. FUNDING: Victoria Fellowship (Government of Victoria, Australia); CRB Blackburn Scholarship (Royal Australasian College of Physicans); Overseas Research Experience Scholarship, University of Melbourne.

Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9. Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.

INTRODUCTION: : Rotavirus vaccines were introduced into the funded Australian National Immunization Program (NIP) in July 2007. Due to purchasing arrangements, individual states and territories chose either a 2-dose RV1 (Rotarix, GSK) regimen or 3-dose RV5 (Rotateq, Merck/CSL) regimen. This allowed comparison of both vaccines in similar populations with high infant vaccination coverage. METHODS: : Admission and rotavirus identification data from the major pediatric hospitals in 3 states (2 using RV5, 1 RV1), together with state-based hospitalization and vaccination data from Queensland (RV5) were analyzed for the years before, and up to 30 months following rotavirus vaccine introduction. Emergency encounters and short-stay unit admissions for gastroenteritis are also described. RESULTS: : Rotavirus vaccine coverage in Australia is high, with 87% of infants receiving at least 1 dose. Hospital admissions for both rotavirus gastroenteritis and nonrotavirus-coded gastroenteritis were reduced following vaccine introduction in all states, not only for the age group eligible for NIP rotavirus vaccination, but also for children born prior. RV5 vaccine efficacy in Queensland has been estimated at 89.3%. Marked reductions in acute gastroenteritis emergency presentations and short-stay unit admissions have also been observed. CONCLUSIONS: : Early evidence from the NIP in Australia has demonstrated high rotavirus coverage with both RV1 and RV5. The introduction of both vaccines has been associated with a marked reduction in gastroenteritis admissions, supportive of both direct vaccine protection, as well as with indirect herd protection.

BACKGROUND: Treatment with nasal high-flow therapy has efficacy similar to that of nasal continuous positive airway pressure (CPAP) when used as postextubation support in neonates. The efficacy of high-flow therapy as the primary means of respiratory support for preterm infants with respiratory distress has not been proved. METHODS: In this international, multicenter, randomized, noninferiority trial, we assigned 564 preterm infants (gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. The primary outcome was treatment failure within 72 hours after randomization. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the chosen margin of noninferiority was 10 percentage points. Infants in whom high-flow therapy failed could receive rescue CPAP; infants in whom CPAP failed were intubated and mechanically ventilated. RESULTS: Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants (13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval [CI], 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events. CONCLUSIONS: When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP. (Funded by the National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12613000303741 .).

BACKGROUND: Estimates of the risk of intussusception (IS) associated with currently licensed rotavirus vaccines (RV1 [Rotarix; GSK] and RV5 [RotaTeq; Merck]) diverge. Contemporaneous introduction of both vaccines in Australia enabled a population-based assessment of risk. METHODS: Confirmed cases of IS in infants aged 1 to <12 months were identified from national hospitalization databases, supplemented by active hospital-based surveillance, from July 2007 through June 2010. Vaccination histories were verified by the Australian Childhood Immunisation Register, which was also used to identify age-matched controls. Self-controlled case series and case-control methods were used to assess the risk of IS associated with both vaccines in prespecified periods after vaccination. The estimated burden of vaccine-attributable IS was compared with estimated reductions in gastroenteritis hospitalizations. RESULTS: Based on 306 confirmed cases of IS, the relative incidence of IS in the 1-7-day period after the first vaccine dose, was 6.8 (95% confidence interval, 2.4-19.0; P < .001) for RV1, and 9.9 (95% confidence interval, 3.7-26.4; P < .001) for RV5. There was a smaller increased risk 1-7 days after the second dose of each vaccine. The case-control analysis gave similar results. We estimate an excess of 14 IS cases and >6500 fewer gastroenteritis hospitalizations in young children annually in Australia after vaccine introduction. CONCLUSIONS: We found a similarly increased risk of IS after both vaccines, but the balance of benefits and risks at population level was highly favorable, a finding likely to extend to other settings despite varying incidence of IS and potentially higher morbidity and mortality from both gastroenteritis and IS.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a complex condition with high heritability. However, both biochemical investigations and association and linkage studies have failed to define fully the underlying genetic factors associated with ADHD. We have identified a family co-segregating an early onset behavioural/developmental condition, with features of ADHD and intellectual disability, with a pericentric inversion of chromosome 3, 46N inv(3)(p14:q21). METHODS: We hypothesised that the inversion breakpoints affect a gene or genes that cause the observed phenotype. Large genomic clones (P1 derived/yeast/bacterial artificial chromosomes) were assembled into contigs across the two inversion breakpoints using molecular and bioinformatic technologies. Restriction fragments crossing the junctions were identified by Southern analysis and these fragments were amplified using inverse PCR. RESULTS: The amplification products were subsequently sequenced to reveal that the breakpoints lay within an intron of the dedicator of cytokinesis 3 (DOCK3) gene at the p arm breakpoint, and an intron of a novel member of the solute carrier family 9 (sodium/hydrogen exchanger) isoform 9 (SLC9A9) at the q arm. Both genes are expressed in the brain, but neither of the genes has previously been implicated in developmental or behavioural disorders. CONCLUSION: These two disrupted genes are candidates for involvement in the pathway leading to the neuropsychological condition in this family.

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

BACKGROUND: Unilateral cerebral palsy (CP) is a condition that affects muscle control and function on one side of the body. Children with unilateral CP experience difficulties using their hands together secondary to disturbances that occur in the developing fetal or infant brain. Often, the more affected limb is disregarded. Constraint-induced movement therapy (CIMT) aims to increase use of the more affected upper limb and improve bimanual performance. CIMT is based on two principles: restraining the use of the less affected limb (for example, using a splint, mitt or sling) and intensive therapeutic practice of the more affected limb. OBJECTIVES: To evaluate the effect of constraint-induced movement therapy (CIMT) in the treatment of the more affected upper limb in children with unilateral CP. SEARCH METHODS: In March 2018 we searched CENTRAL, MEDLINE, Embase, CINAHL, PEDro, OTseeker, five other databases and three trials registers. We also ran citation searches, checked reference lists, contacted experts, handsearched key journals and searched using Google Scholar. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster-RCTs or clinically controlled trials implemented with children with unilateral CP, aged between 0 and 19 years, where CIMT was compared with a different form of CIMT, or a low dose, high-dose or dose-matched alternative form of upper-limb intervention such as bimanual intervention. Primarily, outcomes were bimanual performance, unimanual capacity and manual ability. Secondary outcomes included measures of self-care, body function, participation and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts to eliminate ineligible studies. Five review authors were paired to extract data and assess risk of bias in each included study. GRADE assessments were undertaken by two review authors. MAIN RESULTS: We included 36 trials (1264 participants), published between 2004 and 2018. Sample sizes ranged from 11 to 105 (mean 35). Mean age was 5.96 years (standard deviation (SD) 1.82), range three months to 19.8 years; 53% male and 47% participants had left hemiplegia. Fifty-seven outcome measures were used across studies. Average length of CIMT programs was four weeks (range one to 10 weeks). Frequency of sessions ranged from twice weekly to seven days per week. Duration of intervention sessions ranged from 0.5 to eight hours per day. The mean total number of hours of CIMT provided was 137 hours (range 20 to 504 hours). The most common constraint devices were a mitt/glove or a sling (11 studies each).We judged the risk of bias as moderate to high across the studies. KEY RESULTS: Primary outcomes at primary endpoint (immediately after intervention)CIMT versus low-dose comparison (e.g. occupational therapy)We found low-quality evidence that CIMT was more effective than a low-dose comparison for improving bimanual performance (mean difference (MD) 5.44 Assisting Hand Assessment (AHA) units, 95% confidence interval (CI) 2.37 to 8.51).CIMT was more effective than a low-dose comparison for improving unimanual capacity (Quality of upper extremity skills test (QUEST) - Dissociated movement MD 5.95, 95% CI 2.02 to 9.87; Grasps; MD 7.57, 95% CI 2.10 to 13.05; Weight bearing MD 5.92, 95% CI 2.21 to 9.6; Protective extension MD 12.54, 95% CI 8.60 to 16.47). Three studies reported adverse events, including frustration, constraint refusal and reversible skin irritations from casting.CIMT versus high-dose comparison (e.g. individualised occupational therapy, bimanual therapy)When compared with a high-dose comparison, CIMT was not more effective for improving bimanual performance (MD -0.39 AHA Units, 95% CI -3.14 to 2.36). There was no evidence that CIMT was more effective than a high-dose comparison for improving unimanual capacity in a single study using QUEST (Dissociated movement MD 0.49, 95% CI -10.71 to 11.69; Grasp MD -0.20, 95% CI -11.84 to 11.44). Two studies reported that some children experienced frustration participating in CIMT.CIMT versus dose-matched comparison (e.g. Hand Arm Bimanual Intensive Therapy, bimanual therapy, occupational therapy)There was no evidence of differences in bimanual performance between groups receiving CIMT or a dose-matched comparison (MD 0.80 AHA units, 95% CI -0.78 to 2.38).There was no evidence that CIMT was more effective than a dose-matched comparison for improving unimanual capacity (Box and Blocks Test MD 1.11, 95% CI -0.06 to 2.28; Melbourne Assessment MD 1.48, 95% CI -0.49 to 3.44; QUEST Dissociated movement MD 6.51, 95% CI -0.74 to 13.76; Grasp, MD 6.63, 95% CI -2.38 to 15.65; Weightbearing MD -2.31, 95% CI -8.02 to 3.40) except for the Protective extension domain (MD 6.86, 95% CI 0.14 to 13.58).There was no evidence of differences in manual ability between groups receiving CIMT or a dose-matched comparison (ABILHAND-Kids MD 0.74, 95% CI 0.31 to 1.18). From 15 studies, two children did not tolerate CIMT and three experienced difficulty. AUTHORS' CONCLUSIONS: The quality of evidence for all conclusions was low to very low. For children with unilateral CP, there was some evidence that CIMT resulted in improved bimanual performance and unimanual capacity when compared to a low-dose comparison, but not when compared to a high-dose or dose-matched comparison. Based on the evidence available, CIMT appears to be safe for children with CP.

• The recommended level for serum 25-hydroxyvitamin D (25(OH)D) in infants, children, adolescents and during pregnancy and lactation is ≥ 50 nmol/L. This level may need to be 10-20 nmol/L higher at the end of summer to maintain levels ≥ 50 nmol/L over winter and spring. • Sunlight is the most important source of vitamin D. The US recommended dietary allowance for vitamin D is 600 IU daily in children aged over 12 months and during pregnancy and lactation, assuming minimal sun exposure. • Risk factors for low vitamin D are: lack of skin exposure to sunlight, dark skin, southerly latitude, conditions affecting vitamin D metabolism and storage (including obesity) and, for infants, being born to a mother with low vitamin D and exclusive breastfeeding combined with at least one other risk factor. • Targeted measurement of 25(OH)D levels is recommended for infants, children and adolescents with at least one risk factor for low vitamin D and for pregnant women with at least one risk factor for low vitamin D at the first antenatal visit. • Vitamin D deficiency can be treated with daily low-dose vitamin D supplements, although barriers to adherence have been identified. High-dose intermittent vitamin D can be used in children and adolescents. Treatment should be paired with health education and advice about sensible sun exposure. Infants at risk of low vitamin D should be supplemented with 400 IU vitamin D₃ daily for at least the first year of life. • There is increasing evidence of an association between low vitamin D and a range of non-bone health outcomes, however there is a lack of data from robust randomised controlled trials of vitamin D supplementation.

BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.