Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

BACKGROUND: Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown. METHODS: We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years. RESULTS: Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis). CONCLUSIONS: Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Intramuscular versus enteral penicillin prophylaxis to prevent progression of rheumatic heart disease: Study protocol for a noninferiority randomized trial (the GOALIE trial).

BACKGROUND: Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. METHODS/DESIGN: The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. DISCUSSION: The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05693545.

Application of the Estimand Framework to Anesthesia Trials.

SUMMARY: Events occurring after randomization, such as use of rescue medication, treatment discontinuation, or death, are common in randomized trials. These events can change either the existence or interpretation of the outcome of interest. However, appropriate handling of these intercurrent events is often unclear. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9(R1) addendum introduced the estimand framework, which aligns trial objectives with the design, conduct, statistical analysis, and interpretation of results. This article describes how the estimand framework can be used in anesthesia trials to precisely define the treatment effect to be estimated, key attributes of an estimand, common intercurrent events in anesthesia trials with strategies for handling them, and use of the estimand framework in a hypothetical anesthesia trial on postoperative delirium. When planning anesthesia trials, clearly defining the estimand is vital to ensure that what is being estimated is clearly understood, is clinically relevant, and helps answer the clinical questions of interest.

A novel anterior nasal swab to detect respiratory viruses: a prospective study of diagnostic accuracy.

Detection of respiratory viruses requires testing of the upper respiratory tract to obtain specimens for analysis. However, nasal and throat swabs can cause discomfort and procedural anxiety in children. Respiratory sampling methods which are accurate and less invasive are needed. We aim to determine the positive and negative percentage agreement of a novel anterior nasal swab (ANS) compared with the combined throat and anterior nasal swab (CTN), the reference standard, for detection of respiratory viruses. Children 5 - 18 years of age presenting to a tertiary paediatric hospital with respiratory symptoms were tested with both swabs in randomised order. Respiratory samples were tested on a multiplex RT-PCR panel. Viral detections, RT-PCR cycle-threshold values and child/parent/clinician experience of the swab were recorded. There were 157 viral detections from 249 participant CTN swabs. In comparison with the CTN, the overall positive and negative percentage agreement of ANS for detection of respiratory viruses was 96.2% (95% CI, 91.8-98.3%) and 99.8% (95% CI, 99.6-99.9%), respectively. The ANS was "extremely comfortable", or only a "little uncomfortable" for 90% of children compared with 48% for CTN. 202 children (84%) rated the ANS as the preferred swab, and 208 (87%) indicated they would prefer ANS for future testing. The ANS required additional laboratory handling processes compared to the CTN. The ANS has high positive percentage agreement and is comparable to the current standard of care. The high acceptability from the less invasive ANS provides a more comfortable method for respiratory virus testing in children.Trial registrationClinicalTrials.gov ID NCT05043623.

Stick with the nose Saliva rapid antigen testing is not a viable method for testing children under 5 years old.

AIM: Respiratory testing with rapid antigen tests (RATs) in children under 5 years of age may be uncomfortable and presents specific challenges to testing due to compliance and procedural distress. The aim of this study was to investigate sensitivity and feasibility of self-collected nasal and saliva RAT tests compared with a combined nose and throat (CTN) swab PCR in children under 5. METHODS: Children aged between 1 month and 5 years, with confirmed COVID-19 or who were a household contact within 7 days were included. A saliva RAT, nasal RAT and CTN swab were collected by the parent. SARS-CoV-2 cycle threshold (Ct) values for CTN tested by PCR were compared with saliva and nasal RAT results. Parent preference for method of sample was recorded. RESULTS: Forty-one children were recruited with median age of 1.5 (interquartile range 0.7-4.0) years. Only 22/41 (54%) of parents were able to successfully collect a saliva RAT from their child. Sensitivity of the nasal RAT and saliva RAT was 0.889 (95% confidence interval (CI) 0.739-0.969) and 0.158 (95% CI 0.034-0.396), respectively. Upper limit of nasal RAT detection by CTN Ct value was higher than saliva (36.05 vs. 27.29). While saliva RAT was rated most comfortable, nasal RAT was rated the preferred specimen by parents for future testing, due to saliva collection difficulties and time taken. CONCLUSIONS: Rapid antigen testing with nasal RAT is a more feasible and sensitive method for SARS-CoV-2 detection in young children compared with saliva RAT.

Does inflammation mediate the association between obesity and hearing status in mid-childhood and mid-life?

BACKGROUND: Obesity is characterized by heightened inflammation, and both phenotypes are associated with hearing loss. We aimed to determine if inflammation mediates the associations between obesity and hearing ability in mid-childhood and mid-life. METHODS: Participants: 1165 11- to 12-year-old children and 1316 parents in the population-based cross-sectional Child Health CheckPoint within the Longitudinal Study of Australian Children. Adiposity measures: Body mass index (BMI) classified as normal, overweight and obesity; waist-to-height ratio (WHtR) classified as <0.5 and ≥0.5; fat mass index. Inflammatory biomarkers: Serum glycoprotein A (GlycA); high-sensitivity C-reactive protein (hsCRP). Audiometry: Composite high Fletcher Index (mean threshold of 1, 2, 4 kHz) in the better ear. ANALYSIS: Causal mediation analysis decomposed a 'total effect' (obesity on hearing status) into 'indirect' effect via a mediator (eg GlycA, hsCRP) and 'direct' effect via other pathways, adjusting for age, sex and socioeconomic position. RESULTS: Compared to adults with BMI within the normal range, those with obesity had hearing thresholds 1.9 dB HL (95% CI 1.0-2.8) higher on the high Fletcher Index; 40% of the total effect was mediated via GlycA (indirect effect: 0.8 dB HL, 95% CI 0.1-1.4). Children with obesity had hearing thresholds 1.3 dB HL (95% CI 0.2-2.5) higher than those with normal BMI, of which 67% (indirect effect: 0.9 dB HL, 95% CI 0.4-1.4) was mediated via GlycA. Similar mediation effects were noted using other adiposity measures. Similar but less marked mediation effects were observed when hsCRP was used as the inflammatory biomarker (6-23% in adults and 23-33% in children). CONCLUSIONS: Inflammation may play an important mediating role in the modest hearing reductions associated with obesity, particularly in children. These findings offer insights into possible mechanisms and early prevention strategies for hearing loss.

Does an inflammatory diet affect mental well-being in late childhood and mid-life? A cross-sectional study.

Inflammatory diets are increasingly recognised as a modifiable determinant of mental illness. However, there is a dearth of studies in early life and across the full mental well-being spectrum (mental illness to positive well-being) at the population level. This is a critical gap given that inflammatory diet patterns and mental well-being trajectories typically establish by adolescence. We examined the associations of inflammatory diet scores with mental well-being in 11-12-year-olds and mid-life adults. Throughout Australia, 1759 11-12-year-olds (49 % girls) and 1812 parents (88 % mothers) contributed cross-sectional population-based data. Alternate inflammatory diet scores were calculated from a twenty-six-item FFQ, based on the prior literature and prediction of inflammatory markers. Participants reported negatively and positively framed mental well-being via psychosocial health, quality of life and life satisfaction surveys. We used causal inference modelling techniques via generalised linear regression models (mean differences and risk ratios (RR)) to examine how inflammatory diets might influence mental well-being. In children and adults, respectively, a 1 sd higher literature-derived inflammatory diet score conferred between a 44 % (RR 95 % CI 1·2, 1·8) to 57 % (RR 95 % CI 1·3, 2·0) and 54 % (95 % CI 1·2, 2·0) to 86 % (RR 95 % CI 1·4, 2·4) higher risk of being in the worst mental well-being category (i.e. <16th percentile) across outcome measures. Results for inflammation-derived scores were similar. BMI mediated effects (21-39 %) in adults. Inflammatory diet patterns were cross-sectionally associated with mental well-being at age 11-12 years, with similar effects observed in mid-adulthood. Reducing inflammatory dietary components in childhood could improve population-level mental well-being across the life course.

Working out dads (WOD): a study protocol for a randomised controlled trial of a group-based peer support intervention for men experiencing mental health difficulties in early fatherhood.

BACKGROUND: Approximately one in ten men experience mental health difficulties during the early years of fatherhood, and these can have negative impacts on children and families. However, few evidence-based interventions targeting fathers' mental health are available. The aim of the trial is to evaluate the effectiveness and cost-effectiveness of Working Out Dads (WOD) - a facilitated peer support group intervention for fathers of young children, in reducing psychological distress and other mental health symptoms. METHODS: This trial will employ a parallel-arm randomised controlled trial (RCT) to evaluate the effectiveness and cost effectiveness of WOD peer support group intervention compared to usual care (a 30-min mental health and service focused phone consultation with a health professional). A total of 280 fathers of young children (aged 0-4 years) who are experiencing mental health difficulties and/or are at risk of poor mental health will be recruited. Randomisation and analyses will be at the level of the individual participant. The primary outcome is psychological distress symptoms, measured by the Kessler Psychological Distress Scale (K10) from baseline to 24 weeks post randomisation. A range of secondary outcomes will be assessed including suicidal ideation; mental health disorders, specific symptoms of depression, anxiety, and stress; social support, quality of life, health service use, and health care costs. Data will be collected at baseline, 10- and 24 weeks post-randomisation. DISCUSSION: This trial will examine the effectiveness of a novel group-based peer support intervention in reducing the psychological distress and other mental health symptoms of fathers compared to usual care. The economic and process evaluation will guide policy decision making along with informing the future implementation of WOD on a larger scale if effectiveness is demonstrated. TRIAL REGISTRATION: The current trial has been registered with ClinicalTrials.gov (Registration ID - NCT04813042 ). Date of Registration: March 22nd, 2021.

Individual Efficacy and Community Impact of Ivermectin, Diethylcarbamazine, and Albendazole Mass Drug Administration for Lymphatic Filariasis Control in Fiji: A Cluster Randomized Trial.

BACKGROUND: Bancroftian filariasis remains endemic in Fiji despite >10 years of mass drug administration (MDA) using diethylcarbamazine and albendazole (DA). The addition of ivermectin to this combination (IDA) has improved efficacy of microfilarial clearance at 12 months in individually randomized trials in nocturnal transmission settings, but impact in a setting of diurnally subperiodic filarial transmission has not been evaluated. METHODS: This cluster randomized study compared the individual efficacy and community impact of IDA vs DA as MDA for lymphatic filariasis in 35 villages on 2 islands of Fiji. Participants were tested at enrollment for circulating filarial antigen and, if positive, for microfilariae. Weight-dosed treatment was offered according to village randomization. Communities were visited at 12 months and retested for lymphatic filariasis. Infected individuals from Rotuma were retested at 24 months. RESULTS: A total of 3816 participants were enrolled and 3616 were treated. At 12 months, microfilariae clearance was achieved in 72 of 111 participants detected with infection at baseline, with no difference in efficacy between treatment groups: DA, 69.2% (95% confidence interval [CI], 57.2%-79.1%) vs IDA, 62.5% (95% CI, 43.6%-78.2%); risk difference, 11.3 % (95% CI, -10% to 32.7%); P = .30. There was no difference between treatment groups in community prevalence of microfilariae at 12 months or individual clearance at 24 months. CONCLUSIONS: We found no difference between IDA and DA in individual clearance or community prevalence of lymphatic filariasis at 12 months, and no improved efficacy following a second annual round of IDA. Possible explanations for the apparent lack of benefit of IDA compared to DA include drug and parasite factors affecting clearance, and higher than expected reinfection rates. Clinical Trials Registration: NCT03177993 and Australian New Zealand Clinical Trial Registry: N12617000738325.

Community control strategies for scabies: A cluster randomised noninferiority trial.

BACKGROUND: Scabies is a neglected tropical disease hyperendemic to many low- and middle-income countries. Scabies can be successfully controlled using mass drug administration (MDA) using 2 doses of ivermectin-based treatment. If effective, a strategy of 1-dose ivermectin-based MDA would have substantial advantages for implementing MDA for scabies at large scale. METHODS AND FINDINGS: We did a cluster randomised, noninferiority, open-label, 3-group unblinded study comparing the effectiveness of control strategies on community prevalence of scabies at 12 months. All residents from 35 villages on 2 Fijian islands were eligible to participate. Villages were randomised 1:1:1 to 2-dose ivermectin-based MDA (IVM-2), 1-dose ivermectin-based MDA (IVM-1), or screen and treat with topical permethrin 5% for individuals with scabies and their household contacts (SAT). All groups also received diethylcarbamazine and albendazole for lymphatic filariasis control. For IVM-2 and IVM-1, oral ivermectin was dosed at 200 µg/kg and when contraindicated substituted with permethrin. We designated a noninferiority margin of 5%. We enrolled 3,812 participants at baseline (July to November 2017) from the 35 villages with median village size of 108 (range 18 to 298). Age and sex of participants were representative of the population with 51.6% male and median age of 25 years (interquartile range 10 to 47). We enrolled 3,898 at 12 months (July to November 2018). At baseline, scabies prevalence was similar in all groups: IVM-2: 11.7% (95% confidence interval (CI) 8.5 to 16.0); IVM-1: 15.2% (95% CI 9.4 to 23.8); SAT: 13.6% (95% CI 7.9 to 22.4). At 12 months, scabies decreased substantially in all groups: IVM-2: 1.3% (95% CI 0.6 to 2.5); IVM-1: 2.7% (95% CI 1.1 to 6.5); SAT: 1.1% (95% CI 0.6 to 2.0). The risk difference in scabies prevalence at 12 months between the IVM-1 and IVM-2 groups was 1.2% (95% CI -0.2 to 2.7, p = 0.10). Limitations of the study included the method of scabies diagnosis by nonexperts, a lower baseline prevalence than anticipated, and the addition of diethylcarbamazine and albendazole to scabies treatment. CONCLUSIONS: All 3 strategies substantially reduced prevalence. One-dose was noninferior to 2-dose ivermectin-based MDA, as was a screen and treat approach, for community control of scabies. Further trials comparing these approaches in varied settings are warranted to inform global scabies control strategies. TRIAL REGISTRATION: Clinitrials.gov NCT03177993 and ANZCTR N12617000738325.

Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis.

BACKGROUND: Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. METHODS: PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. RESULTS: Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0-3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7-3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9-3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08-2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23-2.30; P=0.001). CONCLUSIONS: Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.

Backyard benefits? A cross-sectional study of yard size and greenness and children's physical activity and outdoor play.

BACKGROUND: The home environment is the most important location in young children's lives, yet few studies have examined the relationship between the outdoor home environment and child physical activity levels, and even fewer have used objectively measured exposures and outcomes. This study examined relationships between objectively assessed home yard size and greenness, and child physical activity and outdoor play. METHODS: Data were drawn from the HealthNuts study, a longitudinal study of 5276 children in Melbourne, Australia. We used cross-sectional data from a sample at Wave 3 (2013-2016) when participants were aged 6 years (n = 1648). A sub-sample of 391 children had valid accelerometer data collected from Tri-axial GENEActive accelerometers worn on their non-dominant wrist for 8 consecutive days. Yard area and greenness were calculated using geographic information systems. Objective outcome measures were minutes/day in sedentary, light, and moderate-vigorous physical activity (weekday and weekend separately). Parent-reported outcome measures were minutes/day playing outdoors (weekend and weekday combined). Multi-level regression models (adjusted for child's sex, mother's age at the birth of child, neighbourhood socioeconomic index, maternal education, and maternal ethnicity) estimated effects of yard size and greenness on physical activity. RESULTS: Data were available on outdoor play for 1648 children and usable accelerometer data for 391. Associations between yard size/greenness and components of physical activity were minimal. For example, during weekdays, yard size was not associated with daily minutes in sedentary behaviour (ß: 2.4, 95% CI: - 6.2, 11.0), light physical activity (ß: 1.4, 95% CI: - 5.7, 8.5) or MVPA (ß: -2.4, 95% CI: - 6.5, 1.7), with similar patterns at weekends. There was no relationship between median annual yard greenness and physical activity or play. CONCLUSION: In our study of young children residing in higher socio-economic areas of Melbourne yard characteristics did not appear to have a major impact on children's physical activity. Larger studies with greater variation in yard characteristics and identification of activity location are needed to better understand the importance of home outdoor spaces and guide sustainable city planning.

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.

BACKGROUND: In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. METHODS: In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI -2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. INTERPRETATION: Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population. FUNDING: US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment-National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.

Associations of retinal microvascular caliber with large arterial function and structure: A population-based study of 11 to 12 year-olds and midlife adults.

OBJECTIVE: We examined associations between retinal microvascular and large arterial phenotypes to explore relationships between the micro- and macro-vasculature in childhood and midlife. METHODS: Participants were 1288 children (11-12 years, 50.9% female) and 1264 adults (mean age 44 years, 87.6% female) in a cross-sectional population-based study. Exposures were retinal arteriolar and venular caliber quantified from retinal images. Outcomes included arterial function (pulse wave velocity; carotid arterial elasticity) and structure (carotid intima-media thickness). Multivariable regression models were performed adjusting for age, sex, and family socioeconomic position. RESULTS: In children, one standard deviation wider arteriolar caliber was associated with slower pulse wave velocity (-0.15 SD, 95% CI -0.21, -0.09) and higher elasticity (0.13 SD, 95% CI 0.06, 0.20); per SD wider venular caliber was associated with faster pulse wave velocity (0.09 SD, 95% CI 0.03, 0.15) and lower elasticity (-0.07 SD, 95% CI -0.13, -0.01). The size of adult associations was approximately double. Wider arteriolar caliber was associated with smaller carotid intima-media thickness (-0.09 SD, 95% CI -0.16, -0.03) in adults but not children. Venular caliber and carotid intima-media thickness showed little evidence of association. CONCLUSIONS: Narrower retinal arterioles and wider venules are associated with large arterial function as early as mid-childhood. Associations strengthen by midlife and also extend to arterial structure, although effect sizes remain small.

Early clinical markers of overweight/obesity onset and resolution by adolescence.

OBJECTIVES: We examined how combinations of clinical indicators at various ages predict overweight/obesity development, as well as resolution, by 10-11 and 14-15 years of age. METHODS: Data were derived from Birth (N = 3469) and Kinder (N = 3276) cohorts of the Longitudinal Study of Australian Children, followed from ages 2-3 and 4-5 years, respectively. Every two years, 25 potential obesity-relevant clinical indicators were quantified. Overweight/obesity was defined using International Obesity Taskforce cutpoints at 10-11 years and 14-15 years. RESULTS: In both cohorts, three factors predicted both development and resolution of overweight/obesity in multivariable models. Among normal weight children, increased odds of developing overweight/obesity were associated with higher child (odd ratio (OR) 1.67-3.35 across different study waves) and maternal (OR 1.05-1.09) BMI, and inversely with higher maternal education (OR 0.60-0.62, when assessed at age 2-7 years). Lower odds of resolving existing overweight/obesity were related with higher child (OR 0.51-0.79) and maternal (OR 0.89-0.95) BMI, and inversely with higher maternal education (OR 1.62-1.92, when assessed at age 2-5 years). The prevalence of overweight/obesity at the age of 14-15 years was 13% among children with none of these risk factors at age 6-7 years, compared with 71% among those with all 3 risk factors (P < 0.001). CONCLUSIONS: From early childhood onwards, child and maternal BMI and maternal education predict overweight/obesity onset and resolution by adolescence. A simple risk score, easily available to child health clinicians, could help target treatment or prevention.

Multiple imputation in the presence of an incomplete binary variable created from an underlying continuous variable.

Multiple imputation (MI) is used to handle missing at random (MAR) data. Despite warnings from statisticians, continuous variables are often recoded into binary variables. With MI it is important that the imputation and analysis models are compatible; variables should be imputed in the same form they appear in the analysis model. With an encoded binary variable more accurate imputations may be obtained by imputing the underlying continuous variable. We conducted a simulation study to explore how best to impute a binary variable that was created from an underlying continuous variable. We generated a completely observed continuous outcome associated with an incomplete binary covariate that is a categorized version of an underlying continuous covariate, and an auxiliary variable associated with the underlying continuous covariate. We simulated data with several sample sizes, and set 25% and 50% of data in the covariate to MAR dependent on the outcome and the auxiliary variable. We compared the performance of five different imputation methods: (a) Imputation of the binary variable using logistic regression; (b) imputation of the continuous variable using linear regression, then categorizing into the binary variable; (c, d) imputation of both the continuous and binary variables using fully conditional specification (FCS) and multivariate normal imputation; (e) substantive-model compatible (SMC) FCS. Bias and standard errors were large when the continuous variable only was imputed. The other methods performed adequately. Imputation of both the binary and continuous variables using FCS often encountered mathematical difficulties. We recommend the SMC-FCS method as it performed best in our simulation studies.

Determining the impact of Benzathine penicillin G prophylaxis in children with latent rheumatic heart disease (GOAL trial): Study protocol for a randomized controlled trial.

Rheumatic heart disease (RHD) remains a high prevalence condition in low- and middle-income countries. Most individuals with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis. Echocardiographic screening can detect latent RHD, but the impact of secondary prophylaxis in screen-detected individuals is not known. METHODS/DESIGN: This trial aims to determine if secondary prophylaxis with every-4-week injectable Benzathine penicillin G (BPG) improves outcomes for children diagnosed with latent RHD. This is a randomized controlled trial in consenting children, aged 5 to 17 years in Northern Uganda, confirmed to have borderline RHD or mild definite RHD on echocardiography, according to the 2012 World Heart Federation criteria. Qualifying children will be randomized to every-4-week injectable intramuscular BPG or no medical intervention and followed for a period of 2 years. Ongoing intervention adherence and retention in the trial will be supported through the establishment of peer support groups for participants in the intervention and control arms. A blinded echocardiography adjudication panel consisting of four independent experts will determine the echocardiographic classification at enrollment and trajectory through consensus review. The primary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic progression of latent RHD compared to those in the control arm. The secondary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic regression of latent RHD compared to those in the control arm. A sample size of 916 participants will provide 90% power to detect a 50% relative risk reduction assuming a 15% progression in the control group. The planned study duration is from 2018-2021. DISCUSSION: Policy decisions on the role of echocardiographic screening for RHD have stalled because of the lack of evidence of the benefit of secondary prophylaxis. The results of our study will immediately inform the standard of care for children diagnosed with latent RHD and will shape, over 2-3 years, practical and scalable programs that could substantially decrease the burden of RHD in our lifetime. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03346525. Date Registered: November 17, 2017.

Impact of a behavioral intervention, delivered by pediatricians or psychologists, on sleep problems in children with ADHD: a cluster-randomized, translational trial.

BACKGROUND: We have demonstrated the efficacy of a brief behavioral intervention for sleep in children with ADHD in a previous randomized controlled trial and now aim to examine whether this intervention is effective and cost-effective when delivered by pediatricians or psychologists in community settings. METHODS: Translational, cluster-randomized trial of a behavioral intervention versus usual care from 19th January, 2015 to 30th June, 2017. Participants (n = 361) were children aged 5-13 years with ADHD and parent report of a moderate/severe sleep problem who met criteria for American Academy of Sleep Medicine criteria for chronic insomnia disorder, delayed sleep-wake phase disorder, or were experiencing sleep-related anxiety. Participants were randomized at the level of the pediatrician (n = 61) to intervention (n = 183) or usual care (n = 178). Families in the intervention group received two consultations with a pediatrician or a psychologist covering sleep hygiene and tailored behavioral strategies. RESULTS: In an intention-to-treat analysis, at 3 and 6 months respectively, the proportion of children with moderate to severe sleep problems was lower in the intervention (28.0%, 35.8%) compared with usual care group (55.4%, 60.1%; 3 month: risk ratio (RR): 0.51, 95% CI 0.37, 0.70, p < .001; 6 month: RR: 0.58; 95% CI 0.45, 0.76, p < .001). Intervention children had improvements across multiple Children's Sleep Habits Questionnaire subscales at 3 and 6 months. No benefits of the intervention were observed in other domains. Cost-effectiveness of the intervention was AUD 13 per percentage point reduction in child sleep problem at 3 months. CONCLUSIONS: A low-cost brief behavioral sleep intervention is effective in improving sleep problems when delivered by community clinicians. Greater sample comorbidity, lower intervention dose or insufficient clinician supervisions may have contributed to the lack benefits seen in our previous trial.

Associations Between Telomere Length and Hearing Status in Mid-Childhood and Midlife: Population-Based Cross-Sectional study.

OBJECTIVES: The purpose of this study is to determine if telomere length (a biomarker of aging) is associated with hearing acuity in mid-childhood and midlife. DESIGN: The study was based on the population-based cross-sectional study within the Longitudinal Study of Australian Children with telomere length and audiometry data. We calculated high Fletcher Index (hFI, mean threshold of 1, 2, and 4 kHz), defining hearing loss as threshold >15 dB HL (better ear). Linear and logistic regression analyses quantified associations of telomere length with continuous hearing threshold and binary hearing loss outcomes, respectively. RESULTS: One thousand one hundred ninety-five children (mean age 11.4 years, SD 0.5) and 1334 parents (mean age 43.9 years, SD 5.1) were included in analyses. Mean (SD) telomere length (T/S ratio) was 1.09 (0.55) for children and 0.81 (0.38) for adults; hFI (dB HL) was 8.0 (5.6) for children and 13.1 (7.0) for adults, with 8.4% and 25.9%, respectively, showing hearing loss.Telomere length was not associated with hearing threshold or hearing loss in children (hFI: OR, 0.99; 95% confidence interval, 0.55 to 1.78) or adults (hFI: OR, 1.35; 95% confidence interval, 0.81 to 2.25). CONCLUSIONS: Telomere length was not associated with hearing acuity in children or their midlife parents.