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Context: Missing data are common in hospice/palliative care randomized trials due to high drop-out because of the demographic of interest. It can introduce bias in the estimate of the treatment effect and its precision.Objectives: The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) released updated guidance on statistical principles for clinical trials introducing the estimand framework to align trial objectives, trial conduct, statistical analysis and interpretation of results. Our objective is to present how the estimand framework can be used to guide the handling of missing data in palliative care trials.Methods: We outline the estimand framework by highlighting the five elements of an estimand: treatment, population, variable, summary measure and intercurrent event handling. We list common intercurrent events in palliative care trials and present the five strategies for handling intercurrent events outlined in the ICH guidance.Results: We describe common intercurrent events in palliative care trials and discuss and justify what analytic strategies could be followed with each. We provide an example using a palliative care trial comparing two opioids for pain relieve in participants with cancer pain.Conclusion: When planning a palliative care trial, the estimand should be explicitly stated, including how intercurrent events will be handled in the analysis. This should be informed by the scientific objectives of the trial. The estimand guides the handling of missing data during the conduct and analysis of the trial. Defining an estimand is not a statistical activity, but a multi-disciplinary process involving all stakeholders. [ABSTRACT FROM AUTHOR]

Rationale and objective: Hypericum perforatum (St John's wort) is used to treat depression, but the effectiveness has not been established. Recent guidelines described the analysis of clinical trials with missing data, inspiring the reanalysis of this trial using proper missing data methods. The objective was to determine whether hypericum was superior to placebo in treating major depression. Methods: A placebo-controlled, randomized clinical trial was conducted for 8 weeks to determine the effectiveness of hypericum or sertraline in reducing depression, measured using the Hamilton depression scale. We performed sensitivity analyses under different assumptions about the missing data process. Results: Three hundred forty participants were randomized, with 28 % lost to follow-up. The missing data mechanism was not missing completely at random. Under missing at random assumptions, some sensitivity analyses found no difference between either treatment arm and placebo, while some sensitivity analyses found a significant difference from baseline to week 8 between sertraline and placebo (−1.28, 95 % credible interval [−2.48; −0.08]), but not between hypericum and placebo (0.56, [−0.64;1.76]). The results were similar when the missing data process was assumed to be missing not at random. Conclusions: There is no difference between hypericum and placebo, regardless of the assumption about the missing data process. There is a significant difference between sertraline and placebo with some statistical methods used. It is important to conduct an analysis that takes account of missing data using valid statistically principled methods. The assumptions about the missing data process could influence the results. [ABSTRACT FROM AUTHOR]

Two-arm time-to-event (or survival) trials are powered to continue until a required number of events is reached. The authors discuss how the required number of events should be defined for a study with three or more arms with various pairwise comparisons and a common control arm. They advocate stopping one active arm when the required number of events is observed in the applicable pairwise comparison but continuing with the other active arm and the control arm until the required number of events is observed in that pairwise comparison, thereby ensuring that the study continues until enough events are observed in each pairwise comparison. This article is the result of considerations during the design of a three-arm microbicide trial. [ABSTRACT FROM AUTHOR]

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 non-verbal 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 correlation 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Understanding early-life relationships between the Ideal Cardiovascular Health (ICVH) score and vascular phenotypes could inform likely effectiveness and timing of cardiovascular disease prevention strategies. We aimed to describe associations between ICVH scores and vascular phenotypes in 11- to 12-year-old children and their parents. Methods and results Cross-sectional ICVH scores (range 0–7, higher indicating better health), derived by summing dichotomized metrics for cholesterol, glucose, blood pressure (BP), body mass index (BMI), diet, physical activity and smoking, were constructed for 1235 adults (89% female, mean age 43 years) and 1028 children (48% female, 12 years). The median scores were 4 and 5 for adults and children respectively. Child ICVH scores were associated with parent scores (0.18 higher child score per additional point in parent's score, 95% CI 0.12 to 0.22, P < 0.001). Each additional point in the adult ICVH score was associated with slower carotid-femoral pulse wave velocity (PWV, −0.32 m/s, 95% CI −0.37 to −0.27), greater carotid elasticity (0.017%/mm Hg, 95% CI 0.014 to 0.020) and reduced carotid intima-media thickness (IMT, −7.3 μm, 95% CI −12.0 to −2.5). An additional point in the child score was associated with functional phenotypes (PWV −0.07 m/s, 95% CI −0.11 to −0.03; carotid elasticity 0.009%/mm Hg, 95% CI 0.004 to 0.015) but not structural phenotypes (IMT −1.8 μm, 95% CI −5.2 to 1.5). Conclusion Few Australian children and even fewer parents have ideal cardiovascular health. Lower ICVH scores were associated with adverse adult vascular phenotypes and adverse child vascular function. Family-based interventions optimizing ICVH metrics may delay onset and progression of subclinical atherosclerosis and later cardiovascular disease. Highlights • Lower child Ideal Cardiovascular Health scores predicted poorer vascular function. • In their parents, lower scores predicted poorer vascular function and structure. • Parent attainment of ideal health predicted their child's attainment in each metric. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: In several subgroups of South Africa, the percentage of HIV-positive individuals aware of their status falls well below the UNAIDS 90% target. This study examined the impact that home-based HIV testing services (HBHTS) had on knowledge of status in a hyperendemic area of South Africa. Methods: We analysed data from the second cross-sectional HIV Incidence Provincial Surveillance System survey (2015/2016), a representative sample (n = 10,236) of individuals aged 15–49 years. Participants completed a questionnaire, provided blood samples for laboratory testing (used to estimate HIV prevalence), and were offered HBHTS. The proportion of people living with HIV (n = 3870) made aware of their status through HBHTS was measured, and factors associated with HBHTS uptake were identified. Results: Knowledge of HIV-positive status at the time of the survey was 62.9% among men and 73.4% among women. Through HBHTS, the percentage of HIV-positive men and women who knew their status rose to 74.2% and 80.5%, respectively. The largest impact was observed among youth (15–24 years). Knowledge of status increased from 36.6% to 59.3% and from 50.8% to 64.8% among young men and women, respectively. In addition, 51.4% of those who had previously never tested received their first test. Key reasons for declining HBHTS among undiagnosed HIV-positive individuals included fear and self-report of an HIV-negative status. Conclusions: HBHTS was effective in increasing awareness of HIV-positive status, particularly among youth, men, and those who had never tested. HBHTS could have a marked impact on progress toward the UNAIDS 90-90-90 targets within these subgroups. [ABSTRACT FROM AUTHOR]

Background: Mental health problems, such as behavioural and emotional problems, are prevalent in children. These problems can have long lasting, detrimental effects on the child, their parents and society. Most children with a mental health problem do not receive professional help. Those that do get help can face long wait times. While waiting, parents want to learn how they can help their child. To address this need, we co-designed a new website to help parents find ways of helping their child's mental health problem while waiting to get specialist help. Objectives: To assess the acceptability and feasibility of a new co-designed website, FindWays, through a pilot randomised controlled trial. The protocol is registered with ISRCTN (ISRCTN64605513). Methods: This study will recruit up to 60 parents of children aged two-twelve years old referred to a paediatrician for behavioural and/or emotional problems. Participants will be randomly allocated by computer generated number sequence to either the intervention or control group. Intervention group participants will receive access to the FindWays website to help them manage their child's mental health problem while they wait to see the paediatrician. Acceptability and feasibility will be assessed over the 4-month intervention through mixed methods including: recruitment, adherence, retention, net promoter score (quantitative measures) and semi-structured interviews to gain an in-depth understanding of parents' experience and potential adverse effects (qualitative measure). Secondary outcomes measured by parent survey at 4-months post randomisation include child mental health, parent mental health, impact of the child's mental health problem on their functioning and family, and health service use and associated costs. Results: Recruitment commenced June 2022 with publication expected in October 2023. Conclusion: This study will provide novel data on the acceptability and feasibility of a new website co-designed with parents to help them find ways of managing their child's behaviour and emotions. [ABSTRACT FROM AUTHOR]

Background: Mass drug administration (MDA) based on two doses of ivermectin, one week apart, substantially reduces prevalence of both scabies and impetigo. The Regimens of Ivermectin for Scabies Elimination (RISE) trial assessed whether one-dose ivermectin-based MDA would be as effective. Methods: RISE was a cluster-randomised trial in Solomon Islands. We assigned 20 villages in a 1:1 ratio to one- or two-dose ivermectin-based MDA. We planned to test whether the impact of one dose on scabies prevalence at 12 and 24 months was non-inferior to two, at a 5% non-inferiority margin. Results: We deferred endpoint assessment to 21 months due to COVID-19. We enrolled 5239 participants in 20 villages at baseline and 3369 at 21 months from an estimated population of 5500. At baseline scabies prevalence was similar in the two arms (one-dose 17·2%; two-dose 13·2%). At 21 months, there was no reduction in scabies prevalence (one-dose 18·7%; two-dose 13·4%), and the confidence interval around the difference included values substantially greater than 5%. There was however a reduction in prevalence among those who had been present at the baseline assessment (one-dose 15·9%; two-dose 10·8%). Additionally, we found a reduction in both scabies severity and impetigo prevalence in both arms, to a similar degree. Conclusions: There was no indication of an overall decline in scabies prevalence in either arm. The reduction in scabies prevalence in those present at baseline suggests that the unexpectedly high influx of people into the trial villages, likely related to the COVID-19 pandemic, may have compromised the effectiveness of the MDA. Despite the lack of effect there are important lessons to be learnt from this trial about conducting MDA for scabies in high prevalence settings. Trial registration: Registered with Australian New Zealand Clinical Trials Registry ACTRN12618001086257. Author summary: We conducted a trial of one versus two doses of ivermectin based mass drug administration (MDA) for the control of scabies. We found that no reduction in scabies prevalence in either the one or two dose arms. However there was a reduction in the severity of scabies and prevalence of impetigo in both arms, to a similar degree. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Keywords: child; rheumatic heart disease; risk EN child rheumatic heart disease risk 1848 1850 3 06/09/23 20230613 NES 230613 The GOAL trial (Determining the Impact of Penicillin in Latent RHD; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03346525) was a randomized controlled trial of secondary antibiotic prophylaxis (SAP) compared with no prophylaxis among Ugandan children with latent, or screen-detected, rheumatic heart disease (RHD).[1],[2] SAP resulted in a significant reduction in RHD progression (worsening of diagnostic category) versus no prophylaxis (0.8% versus 8.3%; I P i <0.001), whereas nearly half of the children, regardless of SAP administration, regressed (improvement in diagnostic category) over 2 years.[2] Understanding risk factors for progression and regression of latent RHD at the time of screening echocardiogram could refine approaches to SAP in RHD, which would have both individual and health system benefit. In contrast, participants were more likely to regress if they were older at diagnosis and if they had borderline RHD, as compared with definite RHD. These data begin to unravel level of risk of RHD progression, with both sociodemographic and echocardiographic risk factors incorporated into the analyses. [Extracted from the article]

Background: Anaemia is a common clinical finding in HIV infected women and has been associated with advanced disease. The use of antiretroviral drugs such as Zidovudine (ZDV) either for prevention of mother to child transmission (MTCT) of HIV or used in combination with other antiretrovirals have been implicated in the development or increased severity of anaemia. We report the prevalence, type, severity and incidence of anaemia in a cohort of HIV infected women who initiated antiretroviral prophylaxis or treatment during pregnancy. Methods and Materials: This is a retrospective cohort data analysis of 408 HIV infected pregnant women who participated in a breastfeeding intervention study (HPTN 046 Study, ClinicalTrials.gov NCT 00074412) in South Africa. Women initiated zidovudine prophylaxis for PMTCT or triple antiretroviral treatment in pregnancy according to the standard of care. Laboratory and clinical data in pregnancy, <72 hours and 2 weeks postdelivery were extracted from the main database and analysed. Results: The mean Hb concentration was 10.6 g/dL at baseline and 262/408 (64.2%) women were diagnosed with anaemia (Hb<11 g/dL) in pregnancy, 48/146 (32.9%) subsequently developed anaemia intrapartum or postpartum and 89/310 (28.7%) of all cases of anaemia remained unresolved by 2 weeks postdelivery. In a univariate analysis, CD4 count and gravidity were significant risk factors for anaemia in pregnancy, RR 1.41; 1.23–1.61 (p<0.001) and 1.10; 1.01–1.18 (p = 0.02) respectively. After adjusting for antiretroviral regimen, age and gravidity in a multivariable analysis, only the CD4 count remains a significant risk factor for anaemia in pregnancy and postdelivery. Conclusion: In conclusion, anaemia was most common among women in the advanced stage of HIV infection (CD4<200 cells/mm3). There was no evidence of an association between ZDV or triple ARVs and anaemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. Methods: We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. Results: At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006). Conclusions: Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.) [ABSTRACT FROM PUBLISHER]

Background: The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial. Methods: In an open-label, randomized, controlled trial in Durban, South Africa, we assigned 642 patients with both tuberculosis and HIV infection to start antiretroviral therapy either during tuberculosis therapy (in two integrated-therapy groups) or after the completion of such treatment (in one sequential-therapy group). The diagnosis of tuberculosis was based on a positive sputum smear for acid-fast bacilli. Only patients with HIV infection and a CD4+ cell count of less than 500 per cubic millimeter were included. All patients received standard tuberculosis therapy, prophylaxis with trimethoprim–sulfamethoxazole, and a once-daily antiretroviral regimen of didanosine, lamivudine, and efavirenz. The primary end point was death from any cause. Results: This analysis compares data from the sequential-therapy group and the combined integrated-therapy groups up to September 1, 2008, when the data and safety monitoring committee recommended that all patients receive integrated antiretroviral therapy. There was a reduction in the rate of death among the 429 patients in the combined integrated-therapy groups (5.4 deaths per 100 person-years, or 25 deaths), as compared with the 213 patients in the sequential-therapy group (12.1 per 100 person-years, or 27 deaths); a relative reduction of 56% (hazard ratio in the combined integrated-therapy groups, 0.44; 95% confidence interval, 0.25 to 0.79; P=0.003). Mortality was lower in the combined integrated-therapy groups in all CD4+ count strata. Rates of adverse events during follow-up were similar in the two study groups. Conclusions: The initiation of antiretroviral therapy during tuberculosis therapy significantly improved survival and provides further impetus for the integration of tuberculosis and HIV services. (ClinicalTrials.gov number, NCT00398996.) N Engl J Med 2010;362:697-706. [ABSTRACT FROM AUTHOR]

Background: The high prevalence of anaemia and the increased morbidity and mortality associated with anaemia during AIDS has been well described yet there has been little information about anaemia and changes in haemoglobin levels during acute and early HIV-1 infection. Methods: HIV-negative women (n = 245) were enrolled into an observational cohort as part of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Acute Infection Study. Acute infection was diagnosed following a positive HIV RNA PCR in the absence of antibodies, or detection of HIV-1 antibodies within 3 months of a previously negative antibody test. Haemotologic parameters were assessed before infection and at regular intervals in the first twelve months of HIV infection. Results: Fifty-seven participants with acute HIV infection were identified at a median of 14.5 days post-infection (range 10-81) and were enrolled in the CAPRISA Acute Infection cohort at a median of 41 days post-infection (range 15-104). Mean haemoglobin prior to HIV-1 infection was 12.7 g/dL, with a mean decline of 0.46 g/dL following infection. The prevalence of anaemia increased from 25.0% prior to HIV-1 infection to 52.6% at 3 months post-infection, 61.1% at 6 months postinfection, and 51.4% at 12 months post-infection. Conclusions: Haematologic derangements and anaemia with a trend towards iron deficiency are common with acute HIV-1 subtype C infection in this small cohort. The negative impact of anaemia concurrent with established HIV infection upon morbidity and mortality has been well documented but the prognostic potential and long-term effects of anaemia during acute HIV-1 infection remain unknown. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (β: 2.4, 95% CI: - 6.2, 11.0), light physical activity (β: 1.4, 95% CI: - 5.7, 8.5) or MVPA (β: -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. [ABSTRACT FROM AUTHOR]

Pacific Island countries have a high burden of scabies and impetigo. Understanding of the epidemiology of these diseases is needed to target public health interventions such as mass drug administration (MDA). The aim of this study is to determine the prevalence of scabies and impetigo in Solomon Islands as well as the relationship between them and their distribution. We conducted a prevalence study in 20 villages in Western Province in Solomon Islands. All residents of the village were eligible to participate. Nurses conducted clinical assessments including history features and skin examination. Diagnosis of scabies was made using the 2020 International Alliance for the Control of Scabies diagnostic criteria. Assessments were completed on 5239 participants across 20 villages. Overall scabies prevalence was 15.0% (95%CI 11.8–19.1). There was considerable variation by village with a range of 3.3% to 42.6%. There was a higher prevalence of scabies in males (16.7%) than females (13.5%, adjusted relative risk 1.2, 95%CI 1.1–1.4). Children aged under two years had the highest prevalence (27%). Overall impetigo prevalence was 5.6% (95%CI 4.2–7.3), ranging from 1.4% to 19% by village. The population attributable risk of impetigo associated with scabies was 16.1% (95% CI 9.8–22.4). The prevalence of scabies in our study is comparable to previous studies in Solomon Islands, highlighting a persistent high burden of disease in the country, and the need for public health strategies for disease control. Author summary: Scabies is a skin disease caused by infestation with the mite Sarcoptes scabiei var. hominis. The mite burrows under the skin causing intense itch. Scabies lesions are commonly infected with bacteria, causing impetigo. Pacific Island countries have a high burden of scabies due to overcrowding, the tropical environment and limited access to treatment. We aimed to assess the prevalence of scabies and impetigo in 20 villages in Western Province of Solomon Islands. We used the International Alliance for the Control of Scabies 2020 diagnostic criteria to diagnoses scabies. We found that 15% of the 5239 people surveyed had scabies, and 5.6% had impetigo. While the prevalence of scabies was comparable to other studies there were fewer cases of impetigo than observed previously. The burden of disease was highest among children. Mass drug administration, where the whole community is given treatment for a condition regardless of whether they have symptoms of the disease, has been shown to reduce the prevalence of scabies. This study supports the need for mass drug administration for scabies in Solomon Islands. [ABSTRACT FROM AUTHOR]

BACKGROUND: Poor mental health is recognized as one of the greatest global burdens of disease. Maternal mental health is crucial for the optimal health of mothers and their children. We examined the effects of an Australian Nurse Home Visiting (NHV) program (right@home), offered to pregnant women experiencing adversity, on maternal mental health and well-being at child age 3 years. METHODS: A randomized controlled trial of NHV delivered via universal child and family health services (2013-2016). Pregnant women experiencing adversity (≥2 of 10 risk factors) were recruited from 10 antenatal clinics across 2 states. Intervention comprised 25 home visits until child age 2 years. The outcomes assessed 1-year postintervention completion were maternal self-report of mental health symptoms (Depression Anxiety Stress Scales) and positive aspects of mental health (personal well-being and self-efficacy). RESULTS: Of the 722 women enrolled in the trial, 255 of 363 (70%) intervention and 240 of 359 (67%) control group women provided data at 3 years. Compared with controls, the intervention group reported better mental health (reverse Depression Anxiety Stress Scales scores): effect sizes of 0.25 (depression; 95% confidence interval [CI]: 0.08 to 0.32), 0.20 (anxiety; 95% CI: 0.05 to 0.30), 0.17 (stress; 95% CI: 0.09 to 0.37), and 0.23 (total score; 95% CI: 0.12 to 0.38); 0.16 (95% CI: 0.04 to 0.29) for personal well-being; and an odds ratio of 1.60 (95% CI: 1.19 to 2.16) for self-efficacy. CONCLUSIONS: An NHV designed to support mothers experiencing adversity can lead to later maternal mental health benefits, even after the program ends. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases. Author summary: Lymphatic filariasis is a parasitic infection that is spread between humans by mosquitos. The adult worms can live up to 6 years in humans causing chronic irreversible damage to lymphatic vessels resulting in permanent limb swelling known as elephantiasis. The filariasis worm is susceptible to three different drugs: ivermectin, diethylcarbamazine and albendazole. They have been used in two drug combinations globally in communities at risk of filariasis infection, including Fiji, for over a decade. In an attempt to improve efficacy of the treatment with the ultimate goal of eliminating the infection, the three drugs are now being used in the one administration. In this study, the safety of the triple combination in Fiji was proven to be as safe as the standard two drug treatment. Two other common infections that will be affected by the new treatment, scabies and intestinal worms, did not impact on the frequency of adverse events. The use of the triple combination in Fiji has the potential to improve the control of common neglected diseases without excess side effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS) is a highly-adapted and human-restricted pathogen responsible for a high global burden of disease across a diverse clinical spectrum. Vaccine development has been impeded by scientific, regulatory, and commercial obstacles. Human infection studies (HIS) are increasingly contributing to drug, diagnostics, and vaccine development, reducing uncertainty at early stages, especially for pathogens with animal models that incompletely reproduce key elements of human disease. We review the small number of historical GAS HIS and present the study protocol for a dose-ranging inpatient study in healthy adults. The primary objective of the study is to establish a new GAS pharyngitis HIS with an attack rate of at least 60% as a safe and reliable platform for vaccine evaluation and pathogenesis research. According to an adaptive dose-ranging study design, emm 75 GAS doses manufactured in keeping with principles of Good Manufacturing Practice will be directly applied by swab to the pharynx of carefully screened healthy adult volunteers at low risk of severe complicated GAS disease. Participants will remain as closely monitored inpatients for up to six days, observed for development of the primary outcome of acute symptomatic pharyngitis, as defined by clinical and microbiological criteria. All participants will be treated with antibiotics and followed as outpatients for six months. An intensive sampling schedule will facilitate extensive studies of host and organism dynamics during experimental pharyngitis. Ethics approval has been obtained and the study has been registered at ClinicalTrials.gov (NCT03361163). [ABSTRACT FROM AUTHOR]

Pro-inflammatory diet may be a modifiable risk factor for cardiovascular disease. We examine associations of two inflammatory diet scores with preclinical cardiovascular phenotypes at two life course stages. Participants: 1771 children (49% girls) aged 11–12 years and 1793 parents (87% mothers, mean age 43.7 (standard deviation 5.2) years) in the Child Health CheckPoint Study. Measures: 23 items in the Australian National Secondary Students' Diet and Activity (NaSSDA) survey were used to derive two inflammatory diet scores based on: 1) published evidence of associations with C-reactive protein (literature-derived score), and 2) empirical associations with CheckPoint's inflammatory biomarker (glycoprotein acetyls, GlycA-derived score). Cardiovascular phenotypes assessed vascular structure (carotid intima-media thickness, retinal vessel calibre) and function (pulse wave velocity, blood pressure). Analyses: Linear regression models were conducted, adjusted for age, sex, socioeconomic position and child pubertal status, plus a sensitivity analysis also including BMI (z-score for children). In adults, both inflammatory diet scores showed small associations with adverse cardiovascular function and microvascular structure. Per standard deviation higher GlycA-derived diet score, pulse wave velocity was 0.17 m/s faster (95% CI 0.11 to 0.22), mean arterial pressure was 1.85 mmHg (1.34–2.37) higher, and retinal arteriolar calibre was 1.29 μm narrower (−2.10 to −0.49). Adding BMI to models attenuated associations towards null. There was little evidence of associations in children. Our findings support cumulative adverse effects of a pro-inflammatory diet on preclinical cardiovascular phenotypes across the life course. Associations evident by mid-life were not present in childhood, when preventive measures should be instituted. Image 1 • Pro-inflammatory diet may be a modifiable risk factor for cardiovascular disease. • In adults, a pro-inflammatory diet was associated with cardiovascular phenotypes. • Associations in adults were seen for vascular function and microvascular structure. • There was little evidence of associations in children. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: We describe the overall accuracy and performance of a serial rapid HIV testing algorithm used in community-based HIV testing in the context of a population-based household survey conducted in two sub-districts of uMgungundlovu district, KwaZulu-Natal, South Africa, against reference fourth-generation HIV-1/2 antibody and p24 antigen combination immunoassays. We discuss implications of the findings on rapid HIV testing programmes. Methods: Cross-sectional design: Following enrolment into the survey, questionnaires were administered to eligible and consenting participants in order to obtain demographic and HIV-related data. Peripheral blood samples were collected for HIV-related testing. Participants were offered community-based HIV testing in the home by trained field workers using a serial algorithm with two rapid diagnostic tests (RDTs) in series. In the laboratory, reference HIV testing was conducted using two fourth-generation immunoassays with all positives in the confirmatory test considered true positives. Accuracy, sensitivity, specificity, positive predictive value, negative predictive value and false-positive and false-negative rates were determined. Results: Of 10,236 individuals enrolled in the survey, 3740 were tested in the home (median age 24 years (interquartile range 19-31 years), 42.1% males and HIV positivity on RDT algorithm 8.0%). From those tested, 3729 (99.7%) had a definitive RDT result as well as a laboratory immunoassay result. The overall accuracy of the RDT when compared to the fourth-generation immunoassays was 98.8% (95% confidence interval (CI) 98.5-99.2). The sensitivity, specificity, positive predictive value and negative predictive value were 91.1% (95% CI 87.5-93.7), 99.9% (95% CI 99.8-100), 99.3% (95% CI 97.4-99.8) and 99.1% (95% CI 98.8-99.4) respectively. The false-positive and false-negative rates were 0.06% (95% CI 0.01-0.24) and 8.9% (95% CI 6.3-12.53). Compared to true positives, false negatives were more likely to be recently infected on limited antigen avidity assay and to report antiretroviral therapy (ART) use. Conclusions: The overall accuracy of the RDT algorithm was high. However, there were few false positives, and the sensitivity was lower than expected with high false negatives, despite implementation of quality assurance measures. False negatives were associated with recent (early) infection and ART exposure. The RDT algorithm was able to correctly identify the majority of HIV infections in community-based HIV testing. Messaging on the potential for false positives and false negatives should be included in these programmes. [ABSTRACT FROM AUTHOR]

Introduction: We describe the overall accuracy and performance of a serial rapid HIV testing algorithm used in communitybased HIV testing in the context of a population-based household survey conducted in two sub-districts of uMgungundlovu district, KwaZulu-Natal, South Africa, against reference fourth-generation HIV-1/2 antibody and p24 antigen combination immunoassays. We discuss implications of the findings on rapid HIV testing programmes. Methods: Cross-sectional design: Following enrolment into the survey, questionnaires were administered to eligible and consenting participants in order to obtain demographic and HIV-related data. Peripheral blood samples were collected for HIV-related testing. Participants were offered community-based HIV testing in the home by trained field workers using a serial algorithm with two rapid diagnostic tests (RDTs) in series. In the laboratory, reference HIV testing was conducted using two fourth-generation immunoassays with all positives in the confirmatory test considered true positives. Accuracy, sensitivity, specificity, positive predictive value, negative predictive value and false-positive and false-negative rates were determined. Results: Of 10,236 individuals enrolled in the survey, 3740 were tested in the home (median age 24 years (interquartile range 19-31 years), 42.1% males and HIV positivity on RDT algorithm 8.0%). From those tested, 3729 (99.7%) had a definitive RDT result as well as a laboratory immunoassay result. The overall accuracy of the RDT when compared to the fourth-generation immunoassays was 98.8% (95% confidence interval (CI) 98.5-99.2). The sensitivity, specificity, positive predictive value and negative predictive value were 91.1% (95% CI 87.5-93.7), 99.9% (95% CI 99.8-100), 99.3% (95% CI 97.4-99.8) and 99.1% (95% CI 98.8-99.4) respectively. The false-positive and false-negative rates were 0.06% (95% CI 0.01-0.24) and 8.9% (95% CI 6.3-12.53). Compared to true positives, false negatives were more likely to be recently infected on limited antigen avidity assay and to report antiretroviral therapy (ART) use. Conclusions: The overall accuracy of the RDT algorithm was high. However, there were few false positives, and the sensitivity was lower than expected with high false negatives, despite implementation of quality assurance measures. False negatives were associated with recent (early) infection and ART exposure. The RDT algorithm was able to correctly identify the majority of HIV infections in community-based HIV testing. Messaging on the potential for false positives and false negatives should be included in these programmes. [ABSTRACT FROM AUTHOR]

Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial.Two major vaginal bacterial community types—one dominated by Lactobacillus (59.2%) and the other where Gardnerella vaginalis predominated with other anaerobic bacteria (40.8%)—were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61%(P = 0.013) in Lactobacillus-dominant women but only 18% (P = 0.644) in women with non-Lactobacillus bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non-Lactobacillus women, negatively correlating with G. vaginalis and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism. [ABSTRACT FROM AUTHOR]

The Victorian COVID-19 Cancer Network (VCCN) Telehealth Expert Working Group aimed to evaluate the telehealth (TH) experience for cancer patients, carers and clinicians with the rapid uptake of TH in early 2020 during the COVID-19 pandemic.We conducted a prospective multi-centre cross-sectional survey involving eight Victorian regional and metropolitan cancer services and three consumer advocacy groups. Patients or their carers and clinicians who had TH consultations between 1 July 2020 and 31 December 2020 were invited to participate in patient and clinician surveys, respectively. These surveys were opened from September to December 2020.The acceptability of TH via both video (82.9%) and phone (70.4%) were high though acceptability appeared to decrease in older phone TH users. Video was associated with higher satisfaction compared to phone (87.1% vs 79.7%) even though phone was more commonly used. Various themes from the qualitative surveys highlighted barriers and enablers to rapid TH implementation.The high TH acceptability supports this as a safe and effective strategy for continued care and should persist beyond the pandemic environment, where patient preferences are considered and clinically appropriate. Ongoing support to health services for infrastructure and resources, as well as expansion of reimbursement eligibility criteria for patients and health professionals, including allied health and nursing, are crucial for sustainability. [ABSTRACT FROM AUTHOR]

The article presents a study on the use of tenofovir gel in preventing herpes simplex virus type 2 infections. Topics include the global strategy to prevent and control sexually transmitted diseases of the World Health Organization, the participation of women at the Centre for the AIDS Programme of Research in South Africa (CAPRISA), and the use of the Western blot assay in testing.

Background: Women in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group. Methods: Twelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1á, IL-1â, IL-6, tumor necrosis factor-á, IL-8, interferon-ã inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1á, MIP-1â), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial. Results: HIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1á, MIP-1â, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3-7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines. Conclusions: Elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women. [ABSTRACT FROM AUTHOR]

Background Precise knowledge of the prevalence and spectrum of skin diseases in a population allows for effective planning for provision of dermatology services and distribution of resources. There are no published data on the epidemiology of skin disorders in Durban, KwaZulu-Natal. Objective We investigated the prevalence of skin diseases in black African patients attending a predominantly black private healthcare facility and profiled the patients. Methods Clinical charts of all black African patients seen between January 2003 and December 2010 in a private practice in Durban were reviewed. The diseases seen were described and the prevalence calculated. Results A total of 6664 patient charts were reviewed. The five most common conditions were acne, eczemas, dyschromias, infections, and hair disorders. These data agree with reports from other parts of the world. Limitations Selection bias was presented by a single private practice, thus data may not be fully representative of our population. Conclusion Acne, eczemas, dyschromias, infections, and hair disorders are, in that order, the five most common disorders encountered. [ABSTRACT FROM AUTHOR]

Background The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide posttrial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. Methods/design This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. Discussion This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scaleup of microbicides within the public health system of South Africa. [ABSTRACT FROM AUTHOR]

Objective Adolescents in southern African high schools are a key population for HIV prevention interventions. We report on the prevalence of HIV, HSV-2 and pregnancy as indicators of high-risk sexual behaviour among high school students in rural KwaZulu-Natal. Design Bio-behavioural cross-sectional survey. Methods Students completed a self-administered structured, standardised demographic and sexual behavioural questionnaire. Dried blood spot specimens were collected for HIV and HSV-2 testing. Urine specimens were used for pregnancy testing in female students. Results A total of 2675 (1423 females, 1252 males) consenting students were enrolled from 14 high schools between September and November 2010. The median age of students was 16 years (IQR 15-18). HIV prevalence was 1.4% (95% CI 0.9 to 1.9) in males and 6.4% (95% CI 4.6 to 8.3) in females ( p<0.001). HSV-2 prevalence was 2.6% (95% CI 1.6 to 3.7) in males and 10.7% (95% CI 8.8 to 12.6) in females ( p<0.001). Pregnancy prevalence was 3.6% (95% CI 2.6 to 4.5). Risk factors for prevalent HIV infection in female students included being over 18 years of age (adjusted OR (aOR)=2.67, 95% CI 1.67 to 4.27; p<0.001), prevalent HSV-2 infection (aOR=4.35, 95% CI 2.61 to 7.24; p<0.001), previous pregnancy (aOR=1.66, 95% CI 1.10 to 2.51; p=0.016) and experience of two or more deaths in the household in the previous year (aOR=1.97, 95% CI 1.13 to 3.44; p=0.016). Conclusions The high prevalence of HIV, HSV-2 and pregnancy underscore the need for school-based sexual and reproductive health services, and provide further impetus for the inclusion of adolescents in behavioural and biomedical trials with HIV incidence endpoints. [ABSTRACT FROM AUTHOR]

Background Skin-lightening products are commonly used by black communities in South Africa and worldwide. This practice has deep historical and cultural roots and is associated with adverse cutaneous effects. Methods A cross-sectional survey of 579 African and Indian women aged 18–70 years was conducted in two large public hospitals in Durban, South Africa. Results There were 292 Africans and 287 Indians included in the survey sample. Of these 32.3% had used skin-lightening products (60% of Africans and 40% of Indians). Most of those who had used skin lighteners (85 of Africans and 76% of Indians) claimed awareness of the adverse effects of the products, although this did not appear to inform knowledge of the product, how it was used, nor the decision to use the product. Most users (90%) expressed satisfaction with results achieved but 32% reported adverse events. Conclusion Skin-lightening products are used by a third of African and Indian women in South Africa Cultural and historical perceptions equating a fairer skin with social advantage are pervasive and strongly reinforced by the media. There is a poor understanding of the risks associated with the use of these products. Public education campaigns are required to teach consumers about these risks and the importance of concomitant use of sunscreens with these products. [ABSTRACT FROM AUTHOR]

Background Precise knowledge of the prevalence and spectrum of skin diseases in a population allows for effective planning for provision of dermatology services and distribution of resources. There are no published data on the epidemiology of skin disorders in Durban, KwaZulu-Natal. Objective We investigated the prevalence of skin diseases in black African patients attending a predominantly black private healthcare facility and profiled the patients. Methods Clinical charts of all black African patients seen between January 2003 and December 2010 in a private practice in Durban were reviewed. The diseases seen were described and the prevalence calculated. Results A total of 6664 patient charts were reviewed. The five most common conditions were acne, eczemas, dyschromias, infections, and hair disorders. These data agree with reports from other parts of the world. Limitations Selection bias was presented by a single private practice, thus data may not be fully representative of our population. Conclusion Acne, eczemas, dyschromias, infections, and hair disorders are, in that order, the five most common disorders encountered. [ABSTRACT FROM AUTHOR]

Background. Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women.Methods. HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly.Results. Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5–7.2)], clinical symptoms were not.Conclusions. Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not. [ABSTRACT FROM AUTHOR]

Introduction: Young women are at disproportionate risk of HIV infection in South Africa. Understanding risk behaviors and factors associated with ability to negotiate safe sex and condom use is likely to be key in curbing the spread of HIV. Traditionally prevention efforts have focused on creating behavioral changes by increasing knowledge about HIV/AIDS. Methods: This was a cross-sectional analysis from a prospective observational cohort study of 245 women at a high-risk of HIV infection in KwaZulu-Natal, South Africa. Results: Participants demonstrated a high level of HIV/AIDS knowledge. Overall, 60.3% of participants reported condom use. Reported condom use at last sexual encounter varied slightly by partner type (57.0% with steady versus 64.4% with casual partners), and self-perceived ability to choose to use a condom was significantly lower with steady partners compared to casual partners (p<0.01). In multivariate analysis, women who had high school education were more likely to use condoms at their last sex encounter compared to those with only primary school education (RR of 1.36 (95% Confidence Interval (CI) 1.06-1.75) and 1.46 (95% CI 1.13-1.88) for grades 8-10 and 11-12, respectively). Those who used condoms as a contraceptive method were twice as likely to use condoms compared to women who did not report using them as a contraceptive method. Greater perceived ability to choose to use condoms was associated with higher self-reported condom use at last encounter, irrespective of partner type (RR = 2.65 (95% CI 2.15-32.5). Discussion: Self-perceived ability to use condoms, level of formal education and condom use as a contraceptive were all significantly associated with self-reported condom use at last sexual encounter. These findings suggest that that gender inequality and access to formal education, as opposed to lack of HIV/AIDS knowledge, prevent safer sexual practices in South Africa. [ABSTRACT FROM AUTHOR]

The article highlights a workshop on strengthening biostatistics resources in sub-Saharan Africa (SSA) on September 30, 2009. The major driving forces behind the increase in biomedical research in low- to mid-income countries were noted including HIV/AIDS pandemic, the re-emergence of malaria and tuberculosis, and other emerging infections. The workshop included capacity-building discussions among researchers form the U.S. and SSA.

Background: Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use. Purpose: This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa. Methods: This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables. Results: HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001). [ABSTRACT FROM AUTHOR]

The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use. [ABSTRACT FROM AUTHOR]

This study explores the influence of baseline factors on first-month adherence to highly active antiretroviral therapy (HAART) among adults. The study design involved a review of routinely collected patient information in the CAPRISA AIDS Treatment (CAT) programme, at a rural and an urban clinic in KwaZulu-Natal Province, South Africa. The records of 688 patients enrolled in the CAT programme between June 2004 and September 2006 were analysed. Adherence was calculated from pharmacy records (pill counts) and patients were considered adherent if they had taken at least 95% of their prescribed drugs. Logistic regression was used to analyse the data and account for confounding factors. During the first month of therapy, 79% of the patients were adherent to HAART. HAART adherence was negatively associated with a higher baseline CD4 count. Women had better adherence if they attended voluntarily testing and counselling or if they had taken an HIV test because they were unwell, while men had higher adherence if they were tested due to perceived risk of HIV infection. HAART adherence was positively associated with higher age among patients who possessed cell phones and among patients who provided a source of income in the urban setting, but not in the rural setting. Though long-term data from this cohort is required to fully evaluate the impact of non-adherence in the first month of treatment, this study identifies specific groups of patients at higher risk for whom adherence counselling should be targeted and tailored. For example, first-month HAART adherence can be improved by targeting patients initiated on treatment with a high CD4 count. [ABSTRACT FROM AUTHOR]