Protocol for a cluster-randomised non-inferiority trial of one versus two doses of ivermectin for the control of scabies using a mass drug administration strategy (the RISE study).

INTRODUCTION: Scabies is a significant contributor to global morbidity, affecting approximately 200 million people at any time. Scabies is endemic in many resource-limited tropical settings. Bacterial skin infection (impetigo) frequently complicates scabies infestation in these settings. Community-wide ivermectin-based mass drug administration (MDA) is an effective control strategy for scabies in island settings, with a single round of MDA reducing population prevalence by around 90%. However, current two-dose regimens present a number of barriers to programmatic MDA implementation. We designed the Regimens of Ivermectin for Scabies Elimination (RISE) trial to investigate whether one-dose MDA may be as effective as two-dose MDA in controlling scabies in high-prevalence settings. METHODS AND ANALYSIS: RISE is a cluster-randomised non-inferiority trial. The study will be conducted in 20 isolated villages in Western Province of Solomon Islands where population prevalence of scabies is approximately 20%. Villages will be randomly allocated to receive either one dose or two doses of ivermectin-based MDA in a 1:1 ratio. The primary objective of the study is to determine if ivermectin-based MDA with one dose is as effective as MDA with two doses in reducing the prevalence of scabies after 12 months. Secondary objectives include the effect of ivermectin-based MDA on impetigo prevalence after 12 and 24 months, the prevalence of scabies at 24 months after the intervention, the impact on presentation to health facilities with scabies and impetigo, and the safety of one-dose and two-dose MDA. ETHICS AND DISSEMINATION: This trial has been approved by the ethics review committees of the Solomon Islands and the Royal Children's Hospital, Australia. Results will be disseminated in peer-reviewed publications and in meetings with the Solomon Islands Ministry of Health and Medical Services and participating communities. TRIAL REGISTRATION DETAILS: Australian New Zealand Clinical Trials Registry: ACTRN12618001086257. Date registered: 28 June 2018

Health-related quality of life impact of scabies in the Solomon Islands.

BACKGROUND: Scabies causes intense itching and skin lesions. A small number of studies have shown that scabies impacts health-related quality of life (HRQoL), but no studies have been conducted in the Pacific region. We assessed the impact of scabies on HRQoL in a high-prevalence setting using the Children's Dermatology Life Quality Index (CDLQI) and Dermatology Life Quality Index (DLQI). We also assessed the validity of these tools in a Pacific Island population. METHODS: The study was conducted in the Solomon Islands. Participants with and without skin disease were randomly selected. HRQoL indices were scored on a scale of 0-30. RESULTS: We surveyed 1051 adults (91 with scabies) and 604 children (103 with scabies). Scabies had a small impact on HRQoL, with a median DLQI score of 2 (interquartile range [IQR] 0-6) and a CDLQI score of 2 (IQR 0-4). Scores increased linearly with severity. The greatest impact on QoL was due to itch, sleep disturbance and impacts on education and employment. CONCLUSIONS: Scabies has a small but measurable impact on HRQoL. The DLQI and CDLQI scores were discriminated between the skin-related QoL of patients with scabies and the control group, indicating that these tools are appropriate to measure skin-related QoL in the Solomon Islands

Defining the need for public health control of scabies in Solomon Islands.

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

Estimation of scabies prevalence using simplified criteria and mapping procedures in three Pacific and southeast Asian countries

BACKGROUND: Scabies causes considerable morbidity in disadvantaged populations. The International Alliance for the Control of Scabies (IACS) published consensus criteria in 2020 to standardize scabies diagnosis. However, these criteria are complex, and a WHO informal consultation proposed simplified criteria for mapping, to identify regions of high prevalence as targets for mass drug administration. We aimed to investigate the accuracy of simplified criteria in determining scabies prevalence, compared to the 2020 IACS criteria. METHODS: We obtained data relating to demographics, relevant history and skin lesions from all-age prevalence surveys from Fiji (n = 3365) and Solomon Islands (n = 5239), as well as school-aged children in Timor-Leste (n = 1043). We calculated prevalence using the 2020 IACS criteria and simplified criteria and compared these disease estimates. RESULTS: There was no significant difference in the pooled prevalence using the two methods (2020 IACS criteria: 16.6%; simplified criteria: 15.6%; difference = 0.9, [95% CI -0.1, 2.0]). In Timor-Leste, the prevalence using simplified criteria was lower (26.5% vs 33.8%). Simplified criteria had a sensitivity of 82.3% (95% CI 80.2, 84.2) and specificity of 97.6% (95% CI 97.2, 97.9) compared to the 2020 IACS criteria. CONCLUSIONS: The scabies prevalence estimation using simplified criteria was similar to using the 2020 IACS criteria in high prevalence, tropical countries. The prevalence estimation was lower in the school-based survey in Timor-Leste. Mapping using simplified criteria may be a feasible and effective public health tool to identify priority regions for scabies control. Further work assessing use of simplified criteria for mapping in a field setting should be conducted

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

One versus two doses of ivermectin-based mass drug administration for the control of scabies: A cluster randomised non-inferiority trial.

BackgroundMass 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.MethodsRISE 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.ResultsWe 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.ConclusionsThere 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 registrationRegistered with Australian New Zealand Clinical Trials Registry ACTRN12618001086257

Aging-Related Comorbidity Burden Among Women and Men With or At-Risk for HIV in the US, 2008-2019

This cross-sectional study of US adults compares the burden of non-AIDS comorbidities between persons with HIV and those without by age and sex