The full health, economic, and social benefits of prospective Strep A vaccination.

Recent research has documented a wide range of health, economic, and social benefits conferred by vaccination, beyond the direct reductions in morbidity, mortality, and future healthcare costs traditionally captured in economic evaluations. In this paper, we describe the societal benefits that would likely stem from widespread administration of safe and effective vaccines against Streptococcus pyogenes (Strep A), which was estimated to be the fifth-leading cause of infectious disease deaths globally prior to the COVID-19 pandemic. We then estimate the global societal gains from prospective Strep A vaccination through a value-per-statistical-life approach. Estimated aggregate lifetime benefits for 30 global birth cohorts range from $1.7 to $5.1 trillion, depending on the age at which vaccination is administered and other factors. These results suggest that the benefits of Strep A vaccination would be large and justify substantial investment in the vaccines' development, manufacture, and delivery.

The potential global cost-effectiveness of prospective Strep A vaccines and associated implementation efforts.

Group A Streptococcus causes a wide range of diseases from relatively mild infections including pharyngitis to more severe illnesses such as invasive diseases and rheumatic heart disease (RHD). Our aim is to estimate the cost-effectiveness of a hypothetical Strep A vaccine on multiple disease manifestations at the global-level. Cost-effectiveness analyses were carried out by building on the potential epidemiological impact of vaccines that align with the WHO's Preferred Product Characteristics for Strep A vaccines. Maximum vaccination costs for a cost-effective vaccination strategy were estimated at the thresholds of 1XGDP per capita and health opportunity costs. The maximum cost per fully vaccinated person for Strep A vaccination to be cost-effective was $385-$489 in high-income countries, $213-$312 in upper-income-income countries, $74-$132 in lower-middle-income countries, and $37-$69 in low-income countries for routine vaccination at birth and 5 years of age respectively. While the threshold costs are sensitive to vaccine characteristics such as efficacy, and waning immunity, a cost-effective Strep A vaccine will lower morbidity and mortality burden in all income settings.

Modalities of group A streptococcal prevention and treatment and their economic justification.

Infection by group A Streptococcus (Strep A) results in a diverse range of clinical conditions, including pharyngitis, impetigo, cellulitis, necrotising fasciitis, and rheumatic heart disease. In this article, we outline the recommended strategies for Strep A treatment and prevention and review the literature for economic evaluations of competing treatment and prevention strategies. We find that most economic evaluations focus on reducing the duration of illness or risk of rheumatic fever among people presenting with sore throat through diagnostic and/or treatment strategies. Few studies have evaluated strategies to reduce the burden of Strep A infection among the general population, nor have they considered the local capacity to finance and implement strategies. Evaluation of validated costs and consequences for a more diverse range of Strep A interventions are needed to ensure policies maximise patient outcomes under budget constraints. This should include attention to basic public health strategies and emerging strategies such as vaccination.

A Systematic Framework for Prioritizing Burden of Disease Data Required for Vaccine Development and Implementation: The Case for Group A Streptococcal Diseases.

Vaccine development and implementation decisions need to be guided by accurate and robust burden of disease data. We developed an innovative systematic framework outlining the properties of such data that are needed to advance vaccine development and evaluation, and prioritize research and surveillance activities. We focus on 4 objectives-advocacy, regulatory oversight and licensure, policy and post-licensure evaluation, and post-licensure financing-and identify key stakeholders and specific requirements for burden of disease data aligned with each objective. We apply this framework to group A Streptococcus, a pathogen with an underrecognized global burden, and give specific examples pertinent to 8 clinical endpoints. This dynamic framework can be adapted for any disease with a vaccine in development and can be updated as vaccine candidates progress through clinical trials. This framework will also help with research and innovation priority setting of the Immunization Agenda 2030 (IA2030) and accelerate development of future vaccines.

Photoredox-Catalyzed Oxidation of Anions for the Atom-Economical Hydro-, Amido-, and Dialkylation of Alkenes.

Photoredox catalysis has become a powerful method to generate free radical intermediates in organic synthesis. This report describes the use of photoredox catalysis to directly oxidize common nucleophilic anions to access electrophilic 1,3-dicarbonyl and amidyl radical intermediates. First, conjugate bases of 1,3-dicarbonyls were oxidized to neutral radical species for intramolecular hydro- and dialkylation of alkenes. This overall redox-neutral process provided cyclopentanone products in excellent yields (up to 96%). The scope included a variety of styrene radical acceptors and products with newly formed vicinal quaternary carbons. This process was then extended to the synthesis of pyrrolidinones by alkene amidoalkylation that proceeded via N-aryl amidyl radical intermediates in good yield (up to 85%). These reactions were characterized by their mild conditions, high atom economy, and the absence of stoichiometric byproducts. Mechanistic and computational studies supported a stepwise proton-coupled electron transfer mechanism, where an "electron borrowing" photocatalyst oxidizes an anion and reduces a benzylic radical after bond formation.

The economic and health burdens of diseases caused by group A Streptococcus in New Zealand.

OBJECTIVES: In preparation for the future arrival of a group A Streptococcus (GAS) vaccine, this study estimated the economic and health burdens of GAS diseases in New Zealand (NZ). METHODS: The annual incidence of GAS diseases was based on extrapolation of the average number of primary healthcare episodes managed each year in general practices (2014-2016) and on the average number of hospitalizations occurring each year (2005-2014). Disease incidence was multiplied by the average cost of diagnosing and managing an episode of disease at each level of care to estimate the annual economic burden. RESULTS: GAS affected 1.5% of the population each year, resulting in an economic burden of 29.2 million NZ dollars (2015 prices) and inflicting a health burden of 2373 disability-adjusted life years (DALYs). Children <5 years of age were the most likely age group to present for GAS-related healthcare. Presentations for superficial throat and skin infections (predominantly pharyngitis and impetigo) were more common than other GAS diseases. Cellulitis contributed the most to the total economic and health burdens. Invasive and immune-mediated diseases disproportionately contributed to the total economic and health burdens relative to their frequency of occurrence. CONCLUSION: Preventing GAS diseases would have substantial economic and health benefits in NZ and globally.

Contemporary Incidence and Prevalence of Rheumatic Fever and Rheumatic Heart Disease in Australia Using Linked Data: The Case for Policy Change.

Background In 2018, the World Health Organization prioritized control of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), including disease surveillance. We developed strategies for estimating contemporary ARF/RHD incidence and prevalence in Australia (2015-2017) by age group, sex, and region for Indigenous and non-Indigenous Australians based on innovative, direct methods. Methods and Results This population-based study used linked administrative data from 5 Australian jurisdictions. A cohort of ARF (age <45 years) and RHD cases (<55 years) were sourced from jurisdictional ARF/RHD registers, surgical registries, and inpatient data. We developed robust methods for epidemiologic case ascertainment for ARF/RHD. We calculated age-specific and age-standardized incidence and prevalence. Age-standardized rate and prevalence ratios compared disease burden between demographic subgroups. Of 1425 ARF episodes, 72.1% were first-ever, 88.8% in Indigenous people and 78.6% were aged <25 years. The age-standardized ARF first-ever rates were 71.9 and 0.60/100 000 for Indigenous and non-Indigenous populations, respectively (age-standardized rate ratio=124.1; 95% CI, 105.2-146.3). The 2017 Global Burden of Disease RHD prevalent counts for Australia (<55 years) underestimate the burden (1518 versus 6156 Australia-wide extrapolated from our study). The Indigenous age-standardized RHD prevalence (666.3/100 000) was 61.4 times higher (95% CI, 59.3-63.5) than non-Indigenous (10.9/100 000). Female RHD prevalence was double that in males. Regions in northern Australia had the highest rates. Conclusions This study provides the most accurate estimates to date of Australian ARF and RHD rates. The high Indigenous burden necessitates urgent government action. Findings suggest RHD may be underestimated in many high-resource settings. The linked data methods outlined here have potential for global applicability.

SToP (See, Treat, Prevent) skin sores and scabies trial: study protocol for a cluster randomised, stepped-wedge trial for skin disease control in remote Western Australia.

INTRODUCTION: Skin is important in Australian Aboriginal culture informing kinship and identity. In many remote Aboriginal communities, scabies and impetigo are very common. Untreated skin infections are painful, itchy and frequently go untreated due to under-recognition and lack of awareness of their potential serious complications. We hypothesise that the skin infection burden in remote Aboriginal communities can be reduced by implementing streamlined training and treatment pathways integrated with environmental health and health promotion activities, tested in the See, Treat, Prevent (SToP skin sores and scabies) trial. METHODS AND ANALYSIS: SToP will evaluate a skin control programme using a stepped-wedge, cluster randomised trial design with three intervention components (the 'SToP activities'): (1) seeing skin infections (development of training resources implemented within a community dermatology model); (2) treating skin infections (employing the latest evidence for impetigo, and scabies treatment); and (3) preventing skin infections (embedded, culturally informed health promotion and environmental health activities). Four community clusters in the remote Kimberley region of Western Australia will participate. Following baseline data collection, two clusters will be randomly allocated to the SToP activities. At 12 months, the remaining two clusters will transition to the SToP activities. The primary outcome is the diagnosis of impetigo in children (5-9 years) at school-based surveillance. Secondary outcome measures include scabies diagnosis, other child health indicators, resistance to cotrimoxazole in circulating pathogenic bacteria, determining the economic burden of skin disease and evaluating the cost effectiveness of SToP activities. ETHICS AND DISSEMINATION: This study protocol was approved by the health ethics review committees at the Child and Adolescent Health Service (Approval number RGS0000000584), the Western Australian Aboriginal Health Ethics Committee (Reference number: 819) and the University of Western Australia (Reference RA/4/20/4123). Study findings will be shared with community members, academic and medical communities via publications and presentations, and in reports to funders. Authorship for all publications based on this study will be determined in line with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals published by the International Committee of Medical Journal Editors. Sharing results with organisations and communities who contributed to the study is paramount. The results of the SToP trial will be shared with participants in a suitable format, such as a single summary page provided to participants or presentations to communities, the Kimberly Aboriginal Health Planning Forum Research Subcommittee and other stakeholders as appropriate and as requested. Communication and dissemination will require ongoing consultation with Aboriginal communities to determine appropriate formats. TRIAL REGISTRATION NUMBER: ACTRN12618000520235.

Comparing adolescent and parent reports of externalizing problems: A longitudinal population-based study.

Adolescent and parent reports of adolescent mental health problems often correlate poorly, and understanding this discrepancy has clinical importance. Yet contextual factors have only been inconsistently explained. At the 14- and 17-year follow-ups of the Western Australian Pregnancy Cohort (Raine) Study, 1,596 parent-child dyads completed the parent-reported Child Behaviour Checklist (CBCL) and the adolescent-rated Youth Self-Report (YSR). Maternal, family, adolescent, and parent factors were examined as potential predictors of discrepancies. When adolescent YSR scores were in the clinical range but parents' CBCL ratings were not, adolescents were more likely to report alcohol intoxication in the last 6 months, illicit drug use, low school motivation, and depression. When parents reported externalizing behaviour in the clinical range but adolescents did not, the characteristics associated with this were a younger maternal age, receiving social security benefit, stress related to parenting, depression, and poor family functioning. These new results will inform clinical management and research with adolescents who present with behavioural disorders. Statement of contribution What is already known on this subject? We know that adolescent and parent reports of adolescent mental health problems often correlate poorly, but little is known about which contextual factors lead to disagreement. Understanding the factors that influence agreement is clinically relevant for predicting and identifying externalizing behavioural disorders. This is a large-scale study with the ability to assess the impact of numerous psychosocial factors on instrument disagreement. What the present study adds We found that substance use, depression and low school motivation impacted on discrepancy in externalizing behaviour scores for 14-year-old male adolescents and their parents. Parental depression, stress, low family income, and family dysfunction also led to a higher likelihood of discrepancy in scores.

An economic case for a vaccine to prevent group A streptococcus skin infections.

BACKGROUND: Group A streptococcus (GAS) causes an exceptionally diverse range of diseases, raising questions about the optimal product characteristics of a commercially viable vaccine. The objectives of this study were to (1) estimate the current health and economic burdens caused by 24 diseases attributable to GAS each year in Australia and (2) use these estimates to explore the value of a GAS vaccine for different clinical indications, age schedules, and population groups. METHODS: For objective 1, we estimated the population heath and economic burdens by synthesising data from administrative databases, nationally representative surveys, literature reviews, public reimbursement schedules, and expert opinion. For objective 2, we modelled the prospective lifetime burden of GAS for all infants from birth, for children from 5 years of age, and for adults from 65 years of age. A vaccine was assumed to reduce each GAS disease by 70% for a period of 10 years, and the difference in outcomes between vaccinated and non-vaccinated cohorts were used to calculate the cost-effective value of vaccination. RESULTS: The annual health and economic burdens of GAS diseases totalled 23,528 disability-adjusted life years and AU$185.1 million in healthcare costs respectively; approximately half of each measure was due to cellulitis, followed by other skin infections and throat infections. Reducing the incidence of throat infections, skin infections, and cellulitis in non-Indigenous cohorts resulted in 30%, 33%, and 28% of the total vaccine value for an infant schedule (cost-effective vaccine price AU$260 per course); 47%, 26%, and 22% of the value for a child schedule (AU$289); and 2%, 15% and 74% for an adult schedule (AU$489). CONCLUSIONS: A vaccine that prevents GAS cellulitis and other skin infections, in addition to throat infections, would maximise its value and commercial viability, with a cost-effective price in line with other recently-licensed and funded vaccines in Australia.

Echocardiographic Screening for Rheumatic Heart Disease in Indigenous Australian Children: A Cost-Utility Analysis.

BACKGROUND: Rheumatic heart disease (RHD) remains a leading cause of cardiovascular morbidity and mortality in children and young adults in disadvantaged populations. The emergence of echocardiographic screening provides the opportunity for early disease detection and intervention. Using our own multistate model of RHD progression derived from Australian RHD register data, we performed a cost-utility analysis of echocardiographic screening in indigenous Australian children, with the dual aims of informing policy decisions in Australia and providing a model that could be adapted in other countries. METHODS AND RESULTS: We simulated the outcomes of 2 screening strategies, assuming that RHD could be detected 1, 2, or 3 years earlier by screening. Outcomes included reductions in heart failure, surgery, mortality, disability-adjusted life-years, and corresponding costs. Only a strategy of screening all indigenous 5- to 12-year-olds in half of their communities in alternate years was found to be cost-effective (incremental cost-effectiveness ratio less than AU$50 000 per disability-adjusted life-year averted), assuming that RHD can be detected at least 2 years earlier by screening; however, this result was sensitive to a number of assumptions. Additional modeling of improved adherence to secondary prophylaxis alone resulted in dramatic reductions in heart failure, surgery, and death; these outcomes improved even further when combined with screening. CONCLUSIONS: Echocardiographic screening for RHD is cost-effective in our context, assuming that RHD can be detected ≥2 years earlier by screening. Our model can be adapted to any other setting but will require local data or acceptable assumptions for model parameters.

Cost effectiveness of universal umbilical cord blood gas and lactate analysis in a tertiary level maternity unit.

OBJECTIVE: There is an increasing body of literature supporting universal umbilical cord blood gas analysis (UCBGA) into all maternity units. A significant impediment to UCBGA's introduction is the perceived expense of the introduction and associated ongoing costs. Consequently, this study set out to conduct the first cost-effectiveness analysis of introducing universal UCBGA. METHODS: Analysis was based on 42,100 consecutive deliveries ≥23 weeks of gestation at a single tertiary obstetric unit. Within 4 years of UCBGA's introduction there was a 45% reduction in term special care nursery (SCN) admissions >2499 g. Incurred costs included initial and ongoing costs associated with universal UCBGA. Averted costs were based on local diagnosis-related grouping costs for reduction in term SCN admissions. Incremental cost-effectiveness ratio (ICER) and sensitivity analysis results were reported. RESULTS: Under the base-case scenario, the adoption of universal UCBGA was less costly and more effective than selective UCBGA over 4 years and resulted in saving of AU$641,532 while adverting 376 SCN admissions. Sensitivity analysis showed that UCBGA was cost-effective in 51.8%, 83.3%, 99.6% and 100% of simulations in years 1, 2, 3 and 4. These conclusions were not sensitive to wide, clinically possible variations in parameter values for neonatal intensive care unit and SCN admissions, magnitude of averted SCN admissions, cumulative delivery numbers, and SCN admission costs. CONCLUSIONS: Universal UCBGA is associated with significant initial and ongoing costs; however, potential averted costs (due to reduced SCN admissions) exceed incurred costs in most scenarios.