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IMPORTANCE: Obstructive sleep-disordered breathing (SDB) in children is characterized by snoring and difficulty breathing during sleep. SDB affects at least 12% of otherwise healthy children and is associated with significant morbidity. Evidence from small clinical trials suggests that intranasal corticosteroids improve SDB as measured by polysomnography; however, the effect on symptoms and quality of life is unclear. OBJECTIVE: To determine whether intranasal mometasone furoate is more effective than intranasal saline for improving symptoms and quality of life in children with SDB. DESIGN, SETTING, AND PARTICIPANTS: The MIST trial was a multicenter, randomized, double-blind, placebo-controlled trial, recruiting participants from June 8, 2018, to February 13, 2020. Children aged 3 to 12 years who were referred to a specialist for significant SDB symptoms were included; exclusions were previous adenotonsillectomy, body mass index greater than the 97th percentile, and severe SDB. Randomization was stratified by site, and data were analyzed on an intention-to-treat basis from October 28, 2020, to September 25, 2022. INTERVENTIONS: Participants were randomly assigned to receive mometasone furoate, 50 μg, or sodium chloride (saline), 0.9%, 1 spray per nostril daily, dispensed in identical bottles. MAIN OUTCOMES AND MEASURES: The primary outcome was resolution of significant SDB symptoms (ie, reduction to a level no longer requiring referral to a specialist as per the American Academy of Pediatrics guidelines) at 6 weeks, measured by parental report of symptoms using the SDB Score. RESULTS: A total of 276 participants (mean [SD] age, 6.1 [2.3] years; 146 male individuals [53%]) were recruited, 138 in each treatment arm. Resolution of significant SDB symptoms occurred in 56 of 127 participants (44%) in the mometasone group and 50 of 123 participants (41%) in the saline group (risk difference, 4%; 95% CI, −8% to 16%; P = .51) with 26 participants lost to follow-up and missing values managed by multiple imputation. The main adverse effects were epistaxis, affecting 12 of 124 participants (9.7%) in the mometasone group and 18 of 120 participants (15%) in the saline group, and nasal itch/irritation, affecting 12 of 124 participants (9.7%) in the mometasone group and 22 of 120 participants (18%) in the saline group. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial suggest that there was no difference in treatment effect between intranasal mometasone and saline for the management of SDB symptoms. The results suggest that almost one-half of children with SDB could be initially managed in the primary care setting and may not require referral to specialist services, as is currently recommended. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ANZCTRN12618000448246

Background:Peritoneal dialysis (PD) is a commonly used therapy after infant cardiac surgery. It is unclear whether early PD commenced soon after admission to an intensive care unit (ICU) after cardiac surgery results in better outcomes.

There are several methodological challenges when conducting randomised controlled trials in palliative care. These include worsening function and high mortality, leading to treatment discontinuation, some of which will be unrelated to the intervention being evaluated.Recently, a new framework for handling postrandomisation events, such as attrition, has been released. This framework aims to align trial objectives, design, conduct and analysis by clarifying what and how to estimate treatment effects in the presence of data affected by postrandomisation events.The purpose of this paper is to introduce palliative care researchers to this framework and how it can guide trial design, and efficacy and safety analysis in a palliative care context where individual withdrawal from the trial is common.In this paper, we describe the estimand framework and the background for it. We also consider postrandomisation events that are frequently encountered in palliative care trials and how these might affect objectives of interest. We then construct efficacy and safety estimands for a trial in palliative care. Better trial design and alignment of objectives with analysis can improve our understanding of what treatments do and do not work in palliative care.

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.

IMPORTANCE: Microvascular phenotypes, which can be assessed using retinal imaging, may be informative about the life course pathogenesis of hearing loss. OBJECTIVE: To investigate whether differences in retinal vessel caliber (specifically wider venules and narrower arterioles) are associated with hearing threshold and hearing loss in mid-childhood and midlife. DESIGN, SETTING, AND PARTICIPANTS: A population-based cross-sectional study (Child Health CheckPoint) was nested within the Longitudinal Study of Australian Children. A total of 1281 children and 1255 attending parents were assessed using retinal microvasculature and air conduction audiometry data at a main assessment center in 7 large cities in Australia. MAIN OUTCOMES AND MEASURES: Air conduction audiometry was used to calculate the high Fletcher index (mean threshold of 1, 2, and 4 kHz), and bilateral hearing loss was defined as a high Fletcher index greater than 15 dB hearing level in the better-hearing ear. Retinal arteriolar and venular caliber were measured from fundus photographs using validated computer-based software. Linear and logistic regression quantified the associations of retinal vessel caliber with hearing threshold and hearing loss, respectively. RESULTS: Of the 1281 included children (mean age, 11.4 years; 49.1% boys), the mean (SD) high Fletcher index was 7.9 (5.8) dB hearing level. Of the 1255 included adults (mean age, 43.8 years; 86.6% women), the mean (SD) high Fletcher index was 13.0 (6.8) dB hearing level; 109 of 1281 children (8.5%) and 328 of 1255 adults (26.1%) had hearing loss. In adults, each 1-SD (18.6-μm) wider retinal venular caliber (worse) was associated with higher (worse) hearing threshold at lower individual frequencies (eg, 2 kHz: β = 0.63; 95% CI, 0.10-1.17) and overall high Fletcher index (eg, 2 kHz: β = 0.52; 95% CI, 0.07-0.96), as well as a 1.20-fold (95% CI, 1.03-1.40) higher odds of hearing loss. In children, patterns of venular associations were similar but smaller and less certain. Narrower retinal arteriolar caliber (worse) was associated with a 1.16-fold (95% CI, 1.00-1.37) higher odds of hearing loss in adults (per 1-SD [14.0-μm] narrower arteriolar caliber) but not in children. CONCLUSIONS AND RELEVANCE: Adverse retinal microvascular characteristics are associated with hearing loss by midlife, with venular associations possibly emerging by age 11 to 12 years. Microvascular health may contribute to the pathogenesis of hearing loss across the life course, warranting replication and mechanistic studies to inform causal inference and prevention efforts.

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Iron deficiency is common in colorectal cancer. Despite perioperative guidelines advocating for the correction of non-anaemic iron deficiency prior to major surgery, the impact of this pathology on postoperative outcome is unclear.We conducted a single-centre, historical cohort study of 141 elective resections for colorectal cancer. We stratified non-anaemic patients into iron deficient and iron replete groups, and collected data on baseline characteristics, preoperative laboratory results, intraoperative events and postoperative outcomes. As this study was an exploratory work for future research, a P-value of 0.25 was considered relevant. Patients in the deficient group demonstrated lower baseline ferritin (median (interquartile range, IQR) 76 (41–141) µg/L versus 207 (140–334) µg/L, P< 0.001) and transferrin saturation (mean (standard deviation, SD) 18% (8%) versus 32% (12%), P< 0.001) than those in the replete group, and lower starting haemoglobin (mean (SD) 138 (10) g/L versus 144 (12) g/L, P= 0.01). The deficient group had increased re-admission (25% (24%) versus 4% (11%), P= 0.15) and all-cause infection (25% (24%) versus 5% (14%), P= 0.24). A decrease of two days in days alive and out of hospital at postoperative day 90 was seen in the deficient group on univariate analysis (median (IQR) 81 (75–84) versus 83 (78–84), P= 0.25). This reduced to 1.24 days in multivariate adjusted quantile regression analysis (P= 0.22). Days alive and out of hospital at day 90, postoperative re-admission and postoperative infection may be meaningful outcome measures for future prospective observational work examining non-anaemic iron deficiency in patients undergoing major surgery for colorectal cancer.

ObjectiveTo investigate the associations of hearing thresholds and slight to mild hearing loss with academic, behavioural and quality of life outcomes in children at a population level.MethodsDesign and participants:children aged 11–12 years in the population-based cross-sectional Child Health CheckPoint study within the Longitudinal Study of Australian Children. Audiometry:mean hearing threshold across 1, 2 and 4 kHz (better and worse ear); slight/mild hearing loss (threshold of 16–40 decibels hearing loss (dB HL)). Outcomes:National Assessment Program – Literacy and Numeracy, language, teacher-reported learning, parent and teacher reported behaviour and self-reported quality of life. Analysis:linear regression quantified associations of hearing threshold/loss with outcomes.ResultsOf 1483 children (mean age 11.5 years), 9.2% and 13.1% had slight/mild bilateral and unilateral hearing loss, respectively. Per SD increment in better ear threshold (5.7 dB HL), scores were worse on several academic outcomes (eg, reading 0.11 SD, 95% CI 0.05 to 0.16), parent-reported behaviour (0.06 SD, 95% CI 0.01 to 0.11) and physical (0.09 SD, 95% CI 0.04 to 0.14) and psychosocial (0.06 SD, 95% CI 0.01 to 0.11) Pediatric Quality of Life Inventory (PedsQL). Compared with normally hearing children, children with bilateral slight/mild losses scored 0.2–0.3 SDs lower in sentence repetition, teacher-reported learning and physical PedsQL but not other outcomes. Similar but attenuated patterns were seen in unilateral slight/mild losses.ConclusionsHearing thresholds and slight/mild hearing loss showed small but important associations with some child outcomes at 11–12 years. Justifying hearing screening or intervention at this age would require better understanding of its longitudinal and indirect effects, alongside effective management and appropriate early identification programmes.

In high HIV burden settings, maximising the coverage of prevention strategies is crucial to achieving epidemic control. However, little is known about the reach and effect of these strategies in some communities.

With the goal of eliminating new HIV infections, UNAIDS set the ambitious 90-90-90 targets to be achieved by 2020. We assessed whether these targets are being met among participants of the HIV Incidence Provincial Surveillance System (HIPSS) in a high-burden district of South Africa.

Background We assessed whether women who acquired HIV during tenofovir gel prophylaxis trials can be safely and effectively treated with tenofovir-containing anti-retroviral therapy (ART).Methods Between May 2011 and October 2014, HIV seroconvertors from two tenofovir gel trials were recruited when eligible for ART (CD4+T-cell count <350 cells/ml, pregnancy or AIDS-defining illness). Women were randomized to tenofovir-containing (tenofovir + lamivudine/emtricitabine + efavirenz) or tenofovir-sparing (zidovudine + lamivudine/emtricitabine + efavirenz) antiretroviral treatment regimens. The proportion with virological suppression, adverse events and drug switches were compared.Results Fifty-nine women were enrolled and followed-up for median 18 months (IQR 6–24). Twenty-nine women (7 tenofovir gel exposed, 22 tenofovir gel unexposed) were randomized to a tenofovir-containing and 30 (9 tenofovir gel exposed, 21 tenofovir gel unexposed) to a tenofovir-sparing regimen. Median baseline CD4+T-cell count and viral load (VL) were 345 cells/ml (IQR 280–423) and 4.5 log copies/ml (sd0.79), and did not differ by ART assignment. Overall VL suppression rates were 88.0% and 78.3% at 6 months (P=0.454) and 85.7% and 79.0% at 12 months (P=0.689) in women on the tenofovir-containing and tenofovir-sparing regimens, respectively. Toxicity-related drug switches were more frequent in women on the tenofovir-sparing than tenofovir-containing regimen (36.7% versus 0.0%, P<0.001).Conclusions Preliminary data show that tenofovir-containing ART was effective and more tolerable in HIV seroconvertors from tenofovir gel prophylaxis trials and may be considered for use in women with prior tenofovir gel exposure. Clinical trials.gov NCT01387022.

The incidence of HIV infection in young women in Africa is very high. We did a large-scale community-wide phylogenetic study to examine the underlying HIV transmission dynamics and the source and consequences of high rates of HIV infection in young women in South Africa.

Community-acquired pneumonia is a leading cause of morbidity and mortality among children and adults worldwide. Adult pneumonia surveillance remains limited in many low- and middle-income settings, resulting in the disease burden being largely unknown.

Few studies have assessed the potential indirect effects of childhood pneumococcal conjugate vaccine (PCV) programs on the adult pneumonia burden in resource-limited settings. We evaluated the impact of childhood PCV13 immunisation on adult all-cause pneumonia following a phased program introduction from 2016.

Oxycodone is a frequently used opioid in cancer. Opioid-induced constipation (OIC) is common. Oxycodone/Naloxone Prolonged Release (OXN PR) contains naloxone, which mitigates OIC. Trials have either focused on non-cancer pain, or conducted before significant experience of using OXN PR. This trial aims to: demonstrate (1) analgesic equivalence between OXN PR and Oxycodone Prolonged Release (Oxy PR), and (2) superiority of constipation outcomes in OXN PR compared to Oxy PR in cancer pain. Unlike other trials, it will only include patients with at least moderate pain scores (≥4/10), allow usual laxatives, and exclude potential liver dysfunction.

Introduction:Secondary antibiotic prophylaxis improves outcomes for children diagnosed with latent rheumatic heart disease (RHD). However, many children with latent RHD show improvement without prescription of prophylaxis. The objective of this study was to determine if specific sociodemographic or echocardiographic features are associated with progression of latent RHD.Methods:This is a retrospective analysis of the GOAL Trial, a randomized controlled trial of secondary antibiotic prophylaxis in children with latent RHD conducted in Uganda. Sociodemographic and echocardiographic variables were collected at trial entry. Progression was defined by a change in echocardiographic category according to the World Heart Federation Criteria (WHF; normal, borderline RHD, mild definite RHD, moderate/severe RHD), determined by consensus of a blinded 4-member adjudication panel. The association of risk factors with progression were calculated as odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models adjusted for the randomized treatment arm and the stratification variable (definite/borderline RHD).Results:Outcomes for the 799 children who completed the GOAL Trial were included in this analysis. Female sex (OR 2.6, 95% CI 1.19-5.68, p=0.016) and poorer socioeconomic conditions (WAMI Index 0-1 with 1 being the least deprived, OR 0.48 for every 0.10-point increase) were associated with progression. There was no difference in risk of progression or regression between those with borderline RHD or mild definite RHD.Conclusions:Females and those living in less advantaged conditions were more likely to show progression of latent RHD. The strength of these associations was relatively low and does not warrant restricting prophylaxis to subgroups based on risk factors. The lack of difference in progression risk between those with borderline and those with definite RHD may impact revisions of the World Heart Federation Criteria for latent RHD diagnosis and calls into question the use of the term ‘borderline RHD’.

Background Tenofovir gel, used vaginally before and after coitus, reduced women's acquisition of HIV by 39%. This is a safety assessment of tenofovir gel, including renal, bone, gastrointestinal, genital and haematological parameters.Methods In the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, a double-blind, randomized placebo-controlled trial, 445 of the 889 eligibly enrolled women were assigned to tenofovir gel. All participants were advised to use the gel vaginally only, with one dose of gel within 12 h before and a second dose as soon as possible after sex, with no more than two doses in 24 h. Clinical and laboratory safety data were collected at monthly and quarterly visits, respectively. Genital assessments were undertaken at enrolment and quarterly thereafter, or as indicated.Results Women assigned to tenofovir gel were exposed to an average monthly vaginal dose of 240 mg of tenofovir (six applications). In total, six women, three in each group, had mild creatinine elevations, all of which occurred in July/ August 2008. The incidence of anaemia was 3.5 and 3.8 per 100 women-years in tenofovir and placebo groups, respectively (P=0.80). Of the six women (four tenofovir and two placebo) experiencing bone fractures, none were associated with abnormal phosphate or calcium values. The proportion of women with diarrhoea was higher in the tenofovir gel group (17% versus 11%; P=0.026). There was no significant increase of any genital adverse event in the tenofovir group.Conclusions No significant renal, haematological, genital or bone effects were associated with the use of tenofovir gel. Aside from a puzzling increase in diarrhoea, tenofovir gel has an excellent safety profile.

Background Although recent World Health Organization (WHO) guidelines recommend withdrawing stavudine (d4T) from first-line antiretroviral therapy (ART), it remains commonly used in resource-limited settings. In 2006, WHO recommended decreasing the dose of d4T from 40 mg to 30 mg to mitigate toxicities. We compared the incidence and severity of peripheral neuropathy by d4T dose in a retrospective cohort study.Methods Patients’ charts from an ART-naive population at a rural clinic in KwaZulu-Natal, South Africa, were retrospectively reviewed for signs and symptoms of incident peripheral neuropathy and were graded for severity using the DAIDS scale. Patients enrolled prior to the WHO guideline change were included in the study if they were on d4T 40 mg for =6 months. After the guideline change all patients were initiated on d4T 30 mg.Results A total of 475 patients were analysed, including 235 in the 40 mg cohort (152.7 person-years [py]) and 240 in the 30 mg cohort (244.7 py). Incidence of peripheral neuropathy was 90.4/100 py (95% CI 75.9, 106.8) in the 40 mg cohort versus 40.5/100 py (95% CI 32.9, 49.3) in the 30 mg group (incidence rate ratio 0.45; P<0.0001). There was no difference in proportion of severe peripheral neuropathy cases (grade 3/4) between the cohorts: 8.3% in the 40 mg group and 8.9% in the 30 mg group (P=1.0). In a multivariate analysis, risk of peripheral neuropathy was associated with increasing age (hazard ratio [HR] 1.65, 95% CI 1.24, 2.19), 40 mg dose (HR 2.1, 95% CI 1.61, 2.74) and concurrent tuberculosis therapy (HR 1.41, 95% CI 1.06, 1.87).Conclusions Incidence of peripheral neuropathy in the 40 mg cohort was extremely high and, although lower, the rate in the 30 mg cohort was nonetheless unacceptably high.

Introduction:Rheumatic heart disease affects 40.5 million people globally and causes 306,000 annual deaths. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. However, it is unknown if secondary antibiotic prophylaxis is effective at preventing progression of latent rheumatic heart disease.Methods:We conducted a randomized controlled trial of secondary antibiotic prophylaxis among Ugandan children (5-17 years) with latent rheumatic heart disease. We randomized children to receive either 4-weekly injections of benzathine benzylpenicillin G or no prophylaxis. All children underwent echocardiography at baseline and 2 years after randomization. Changes from baseline were adjudicated by a panel blinded to treatment allocation. The primary outcome was rheumatic heart disease progression. The trial was registered at ClinicalTrials.org (NCT03346525) on November 17, 2017.Results:818 were included in the modified intention to treat analysis and 799 participants (97.7%) reached study completion. Three participants in the prophylaxis group (0.8%) demonstrated echocardiographic progression, compared to 33 (8.3%) in the control group (risk difference -7.5%, 95%CI, -10.2 to -4.7, p<0.001). The number of children with latent rheumatic heart disease needed to receive prophylaxis to prevent one child from developing progression was 13 (95%CI, 10 to 21). There were 2 serious adverse events in the prophylaxis group, including one episode of a mild anaphylactic reaction (0.01% of all treatment doses).Conclusions:Secondary antibiotic prophylaxis reduces the risk of latent rheumatic heart disease progression at 2 years. These data provide new information for our understanding of the role of screening for latent rheumatic heart disease. Further research is needed before the implementation of population-level screening can be recommended.

This study was conducted to identify predictors of mathematics achievement among grade 9 learners of a random sample of five township schools. A series of regression analyses were performed for boys and girls separately to obtain Cohen's (1992) effect size estimate (uniquely explained criterion variance expressed as a proportion of unexplained criterion variance) for various predictor variables. Cognitive predictors were verbal and non-verbal General Scholastic Aptitude Test scores. Non-cognitive variables included the hierarchical levels of self-concept: Global (Rosenberg Self-Esteem Scale), and academic and mathematics self-concept (relevant scales of Brookover, Erickson and Joiner). Socio-economic predictors included home-related variables (parental education, parental occupation, family size) and school-related factors (class size, teacher's qualification, teacher's experience). Gender differences favouring boys were found. Non-verbal and verbal scholastic aptitude and teacher's general training correlated significantly with mathematics achievement for boys and girls, with nonverbal scholastic aptitude showing the highest correlation and effect size estimate for girls and teacher's general training occupying this position for boys. Teacher's mathematics training and class size showed correlations in excess of 0.35 for boys but not for girls. The negative corrrelation obtained for teacher's general training suggested that learners whose teachers held a three-year teaching diploma performed better in mathematics than did learners whose teachers held a degree and a teacher's diploma.

The statistical results from a clinical trial rely on the accuracy and completeness of the database used to generate the results. The quality of the database depends on the quality of the data collection methods and the data management procedures. As part of the data management-biostatistics team, a statistician can ensure that a protocol is written in such a manner as to enhance data management; a statistician's input into the subsequent design of the case report form can facilitate the collection of appropriate and complete data. A statistician can contribute to the accuracy and validity of a database by providing input into the design of both the database structure and data plausibility checks, and the quality control procedures performed to evaluate the integrity of a database. Finally, performing a statistical review on the database prior to database lock can detect anomalies that would otherwise only show up during analysis.

The statistical results from a clinical trial rely on the accuracy and completeness of the database used to generate the results. The quality of the database depends on the quality of the data collection methods and the data management procedures. As part of the data management-biostatistics team, a statistician can ensure that a protocol is written in such a manner as to enhance data management; a statistician’s input into the subsequent design of the case report form can facilitate the collection of appropriate and complete data. A statistician can contribute to the accuracy and validity of a database by providing input into the design of both the database structure and data plausibility checks, and the quality control procedures performed to evaluate the integrity of a database. Finally, performing a statistical review on the database prior to database lock can detect anomalies that would otherwise only show up during analysis.