Outcomes and care quality metrics for people living with rheumatic heart disease and atrial fibrillation in Uganda.

Background: Atrial fibrillation (AF) is a common complication of rheumatic heart disease (RHD) and is challenging to treat in lower-resourced settings in which RHD remains endemic. Objective: We characterized demographics, treatment outcomes, and factors leading to care retention for participants with RHD and AF in Uganda. Methods: We conducted a retrospective analysis of the Uganda national RHD registry between June 2009 and May 2018. Participants with AF or atrial flutter were included. Demographics, survival, and care metrics were compared with participants without AF. Multivariable logistic regression was used to identify factors associated with retention in care among participants with AF. Results: A total of 1530 participants with RHD were analyzed and 293 (19%) had AF. The median age was 24 (interquartile range 14-38) years. Mortality was similar in both groups (adjusted hazard ratio 1.183, P = .77) over a median follow-up of 203 (interquartile range 98-275) days. A total of 79% of AF participants were prescribed anticoagulation, and 43% were aware of their target international normalized ratio. Retention in care was higher in participants with AF (18% vs 12%, P < .01). Factors associated with decreased retention in care include New York Heart Association functional class III/IV (adjusted odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30-0.76) and distance to nearest health center (adjusted OR 0.94, 95% CI 0.90-0.99). Anticoagulation prescription was associated with enhanced care retention (adjusted OR 1.86, 95% CI 1.24-2.79). Conclusion: Participants with RHD and AF in Uganda do not experience higher mortality than those without AF. Anticoagulation prescription rates are high. Although retention in care is poor among RHD participants, those with concurrent AF are more likely to be retained.

Global Assessment of Palliative Care Need: Serious Health-Related Suffering Measurement Methodology.

CONTEXT: Inequities and gaps in palliative care access are a serious impediment to health systems especially in low- and middle-income countries and the accurate measurement of need across health conditions is a critical step to understanding and addressing the issue. Serious Health-related Suffering (SHS) is a novel methodology to measure the palliative care need and was originally developed by The Lancet Commission on Global Access to Palliative Care and Pain Relief. In 2015, the first iteration - SHS 1.0 - was estimated at over 61 million people worldwide experiencing at least 6 billion days of SHS annually as a result of life-limiting and life-threatening conditions. OBJECTIVES: In this paper, an updated methodology - SHS 2.0 - is presented building on the work of the Lancet Commission and detailing calculations, data requirements, limitations, and assumptions. METHODS AND RESULTS: The updates to the original methodology focus on measuring the number of people who die with (decedents) or live with (non-decedents) SHS in a given year to assess the number of people in need of palliative care across health conditions and populations. Detail on the methodology for measuring the number of days of SHS that was pioneered by the Lancet Commission, is also shared, as this second measure is essential for determining the health system responses that are necessary to address palliative care need and must be a priority for future methodological work on SHS. CONCLUSIONS: The methodology encompasses opportunities for applying SHS to future policy making assessment of future research priorities particularly in light of the dearth of data from low- and middle-income countries, and sharing of directions for future work to develop SHS 3.0.

Health and economic burden of insufficient physical activity in Saudi Arabia.

BACKGROUND: Insufficient physical activity (PA) was estimated to cause 4.8% of deaths and 2.6% of disability-adjusted life-years (DALYs) due to noncommunicable diseases in Saudi Arabia in 2019. While Saudi Arabia is already achieving great improvements, we predict the health and economic burden of insufficient PA up to 2040 to present a case for policy makers to invest more in the uptake of PA. METHODS: Using a population health model to estimate avoidable health loss, we identified four causes of health loss related to low PA (cardiovascular diseases, diabetes, breast cancer, and colorectal cancer) and estimated the deaths and DALYs from these causes. We projected the expected disease burden until 2040 under alternative assumptions about future PA levels and trends by using three health scenarios: baseline (no change in 2019 PA levels), intervention (81% of the population achieving sufficient PA levels), and ideal (65% of population: moderate PA, 30%: high PA, and 5%: inactive). We applied an "intrinsic value" approach to estimate the economic impact of each scenario. RESULTS: Overall, we estimate that between 2023 and 2040, about 80,000 to 110,000 deaths from all causes and 2.0 million to 2.9 million DALYs could be avoided by increasing PA levels in Saudi Arabia. The average annual economic loss from insufficient PA is valued at 0.49% to 0.68% of the current gross domestic product, with an average of US$5.4 billion to US$7.6 billion annually till 2040. The most avoidable disease burden and economic losses are expected among males and because of ischemic heart disease. CONCLUSIONS: This study highlights that low PA levels will have considerable health and economic impacts in Saudi Arabia if people remain inactive and do not start following interventions. There is an urgent need to develop innovative programs and policies to encourage PA among all age and sex groups.

Scaling-up and scaling-out the Systems Analysis and Improvement Approach to optimize the hypertension diagnosis and care cascade for HIV infected individuals (SCALE SAIA-HTN): a stepped-wedge cluster randomized trial.

BACKGROUND: Undiagnosed and untreated hypertension is a main driver of cardiovascular disease and disproportionately affects persons living with HIV (PLHIV) in low- and middle-income countries. Across sub-Saharan Africa, guideline application to screen and manage hypertension among PLHIV is inconsistent due to poor service readiness, low health worker motivation, and limited integration of hypertension screening and management within HIV care services. In Mozambique, where the adult HIV prevalence is over 13%, an estimated 39% of adults have hypertension. As the only scaled chronic care service in the county, the HIV treatment platform presents an opportunity to standardize and scale hypertension care services. Low-cost, multi-component systems-level strategies such as the Systems Analysis and Improvement Approach (SAIA) have been found effective at integrating hypertension and HIV services to improve the effectiveness of hypertension care delivery for PLHIV, reduce drop-offs in care, and improve service quality. To build off lessons learned from a recently completed cluster randomized trial (SAIA-HTN) and establish a robust evidence base on the effectiveness of SAIA at scale, we evaluated a scaled-delivery model of SAIA (SCALE SAIA-HTN) using existing district health management structures to facilitate SAIA across six districts of Maputo Province, Mozambique. METHODS: This study employs a stepped-wedge design with randomization at the district level. The SAIA strategy will be "scaled up" with delivery by district health supervisors (rather than research staff) and will be "scaled out" via expansion to Southern Mozambique, to 18 facilities across six districts in Maputo Province. SCALE SAIA-HTN will be introduced over three, 9-month waves of intensive intervention, where technical support will be provided to facilities and district managers by study team members from the Mozambican National Institute of Health. Our evaluation of SCALE SAIA-HTN will be guided by the RE-AIM framework and will seek to estimate the budget impact from the payer's perspective. DISCUSSION: SAIA packages user-friendly systems engineering tools to support decision-making by frontline health workers and to identify low-cost, contextually relevant improvement strategies. By integrating SAIA delivery into routine management structures, this pragmatic trial will determine an effective strategy for national scale-up and inform program planning. TRIAL REGISTRATION: ClinicalTrials.gov NCT05002322 (registered 02/15/2023).

Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652-3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer.

PURPOSE: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. EXPERIMENTAL DESIGN: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib.

The economic costs of orthopaedic services: a health system cost analysis of tertiary hospitals in a low-income country.

BACKGROUND: Traumatic injuries are rising globally, disproportionately affecting low- and middle-income countries, constituting 88% of the burden of surgically treatable conditions. While contributing to the highest burden, LMICs also have the least availability of resources to address this growing burden effectively. Studies on the cost-of-service provision in these settings have concentrated on the most common traumatic injuries, leaving an evidence gap on other traumatic injuries. This study aimed to address the gap in understanding the cost of orthopaedic services in low-income settings by conducting a comprehensive costing analysis in two tertiary-level hospitals in Malawi. METHODS: We used a mixed costing methodology, utilising both Top-Down and Time-Driven Activity-Based Costing approaches. Data on resource utilisation, personnel costs, medicines, supplies, capital costs, laboratory costs, radiology service costs, and overhead costs were collected for one year, from July 2021 to June 2022. We conducted a retrospective review of all the available patient files for the period under review. Assumptions on the intensity of service use were based on utilisation patterns observed in patient records. All costs were expressed in 2021 United States Dollars. RESULTS: We conducted a review of 2,372 patient files, 72% of which were male. The median length of stay for all patients was 9.5 days (8-11). The mean weighted cost of treatment across the entire pathway varied, ranging from $195 ($136-$235) for Supracondylar Fractures to $711 ($389-$931) for Proximal Ulna Fractures. The main cost components were personnel (30%) and medicines and supplies (23%). Within diagnosis-specific costs, the length of stay was the most significant cost driver, contributing to the substantial disparity in treatment costs between the two hospitals. CONCLUSION: This study underscores the critical role of orthopaedic care in LMICs and the need for context-specific cost data. It highlights the variation in cost drivers and resource utilisation patterns between hospitals, emphasising the importance of tailored healthcare planning and resource allocation approaches. Understanding the costs of surgical interventions in LMICs can inform policy decisions and improve access to essential orthopaedic services, potentially reducing the disease burden associated with trauma-related injuries. We recommend that future studies focus on evaluating the cost-effectiveness of orthopaedic interventions, particularly those that have not been analysed within the existing literature.

The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.

Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B12 metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), "compounds"), and four c.271dupA homozygotes ("homozygotes"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 µM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 µM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.

Service readiness for the management of non-communicable diseases in publicly financed facilities in Malawi: findings from the 2019 Harmonised Health Facility Assessment census survey.

INTRODUCTION: Non-communicable diseases (NCDs) are rising in low-income and middle-income countries, including Malawi. To inform policy-makers and planners on the preparedness of the Malawian healthcare system to respond to NCDs, we estimated NCD service readiness in publicly financed healthcare facilities in Malawi. METHODS: We analysed data from 564 facilities surveyed in the 2019 Harmonised Health Facility Assessment, including 512 primary healthcare (PHC) and 52 secondary and tertiary care (STC) facilities. To characterise service readiness, applying the law of minimum, we estimated the percentage of facilities with functional equipment and unexpired medicines required to provide NCD services. Further, we estimated permanently unavailable items to identify service readiness bottlenecks. RESULTS: Fewer than 40% of PHC facilities were ready to deliver services for each of the 14 NCDs analysed. Insulin and beclomethasone inhalers had the lowest stock levels at PHC facilities (6% and 8%, respectively). Only 17% of rural and community hospitals (RCHs) have liver and kidney diagnostics. STC facilities had varying service readiness, ranging from 27% for managing acute diabetes complications to 94% for chronic type 2 diabetes management. Only 38% of STC facilities were ready to manage chronic heart failure. Oral pain medicines were widely available at all levels of health facilities; however, only 22% of RCHs and 29% of STCs had injectable morphine or pethidine. Beclomethasone was never available at 74% of PHC and 29% of STC facilities. CONCLUSION: Publicly financed facilities in Malawi are generally unprepared to provide NCD services, especially at the PHC level. Targeted investments in PHC can substantially improve service readiness for chronic NCD conditions in local communities and enable STC to respond to acute NCD complications and more complex NCD cases.

Effectiveness of conservation messages to reduce households' GHG emissions: A serious-gaming experiment.

Households play a critical role in reducing greenhouse gas emissions. However, there have been few studies of household conservation from the perspective of the nexus of food, energy, and water (FEW) consumption. This study's objective is to understand the effects of different types of intervention messages for inducing conservation of FEW resources and reducing carbon emissions at the household level in the U.S. Employing a serious-gaming approach, we developed the HomeRUN (Home Role-play for Understanding the Nexus) game, which allows players to act as homeowners and take behavioral and technological upgrade actions in a computer-simulation setting. The types of messages tested include social comparisons and resource-reduction measures across FEW sectors as well as information about the health, economic, and environmental impacts of FEW consumption. A game experiment with U.S. university students finds that social-comparison messages on food and energy consumption, but not on water, lead to significant reductions in household carbon emissions. In addition, messages associated with each type of FEW resource tend to lead to an immediate action corresponding to the particular FEW domain. These insights support a prioritization of intervention messaging for coordinated FEW conservation efforts at a household level.

User-Centered Design to Develop Automated Short Message Service Messaging for Patient Support of Rheumatic Heart Disease Secondary Antibiotic Prophylaxis.

BACKGROUND: The Active Community Case Management Platform is a cloud-based technology developed to facilitate rheumatic heart disease case management by health care providers. This study aimed to design and pilot an automated short message service (SMS) intervention to support secondary prophylaxis adherence. METHODS AND RESULTS: We developed a concise library of messages to support secondary antibiotic prophylaxis. The SMS intervention used TextIT, an interface that enables users to send out interactive SMS messages at scale. The message bank was piloted in a cohort of 50 patients with rheumatic heart disease randomized into 2 groups. Group 1 received standard support (nurse-led/Active Community Case Management Platform). Group 2 received standard support plus SMS intervention for 2 months in the Lira and Gulu districts of Northern Uganda. We collected qualitative data on participants' experiences and assessed treatment adherence. Using a sequential user-centered process consisting of 4 phases (phases 1-4), we developed a message bank (n=43) deployed during our pilot study. There were no between-group differences in treatment adherence or acceptance. Interviews of participants indicated that the intervention was viewed positively. A total of 75% of SMS recipients responded to the messages, and 25% called the study staff to acknowledge receipt of text messages. CONCLUSIONS: This study has successfully developed a bank of SMS messages to support secondary antibiotic prophylaxis adherence. We have demonstrated the feasibility and acceptability of SMS technology in rheumatic heart disease care management. Future work will include integrating automated SMS into the Active Community Case Management Platform and a larger study of integrated SMS to reduce health care worker burden for patient support and improve adherence to secondary antibiotic prophylaxis.

Growth requirement for methionine in human melanoma-derived cell lines with different levels of MMACHC expression and methylation.

Methionine dependence, the inability to grow in culture when methionine in the medium is replaced by its metabolic precursor homocysteine, occurs in many tumor cell lines. In most affected lines, the cause of methionine dependence is not known. An exception is the melanoma-derived cell line MeWo-LC1, in which hypermethylation of the MMACHC gene is associated with decreased MMACHC expression. Decreased expression results in decreased provision of the methylcobalamin cofactor required for activity of methionine synthase and thus decreased conversion of homocysteine to methionine. Analysis of data in the Cancer Cell Line Encyclopedia Archive demonstrated that MMACHC hypermethylation and decreased MMACHC expression occurred more frequently in melanoma cell lines when compared to other tumor cell lines. We further investigated methionine dependence and aspects of MMACHC function in a panel of six melanoma lines, including both melanoma lines with known methionine dependence status (MeWo, which is methionine independent, and A375, which is methionine dependent). We found that the previously unclassified melanoma lines HMCB, Colo829 and SH-4 were methionine dependent, while SK-Mel-28 was methionine independent. However, despite varying levels of MMACHC methylation and expression, none of the tested lines had decreased methylcobalamin and adenosylcobalamin synthesis as seen in MeWo-LC1, and the functions of both cobalamin-dependent enzymes methionine synthase and methylmalonyl-CoA mutase were intact. Thus, while melanoma lines were characterized by relatively high levels of MMACHC methylation and low expression, the defect in metabolism observed in MeWo-LC1 was unique, and decreased MMACHC expression was not a cause of methionine dependence in the other melanoma lines.

The Role of HTA for Essential Health Benefit Package Design in Low or Middle-Income Countries.

This Commentary explores the relationship between Health Technology Assessment (HTA) and Health Benefits Package (HBP) design to achieve Universal Health Coverage (UHC) in low- and middle-income countries. It emphasizes that while HTA evaluates individual healthcare interventions, HBP reform aims to create comprehensive service sets considering overall population health needs and available resources. Challenges in LMICs include limited local data and technical capacity, leading to reliance on cost-effectiveness estimates from other settings. We suggest a practical approach by combining HTA and HBP elements through a hybrid or compartmentalized method. This approach sets differentiated cost-effectiveness thresholds for specific healthcare platforms or programs (e.g., primary care or essential surgery), aligning priority-setting with organizational considerations, ethics, and implementation strategies. Strong institutions and academic support are vital for evidence-informed priority-setting processes. In summary, HTA can play a pivotal role in designing HBPs for UHC in LMICs, and a compartmentalized approach can enhance priority-setting while considering budget constraints and equity.

Homotypic antibodies target novel E glycoprotein domains after natural DENV 3 infection/vaccination.

The envelope (E) glycoprotein is the primary target of type-specific (TS) neutralizing antibodies (nAbs) after infection with any of the four distinct dengue virus serotypes (DENV1-4). nAbs can be elicited to distinct structural E domains (EDs) I, II, or III. However, the relative contribution of these domain-specific antibodies is unclear. To identify the primary DENV3 nAb targets in sera after natural infection or vaccination, chimeric DENV1 recombinant encoding DENV3 EDI, EDII, or EDIII were generated. DENV3 EDII is the principal target of TS polyclonal nAb responses and encodes two or more neutralizing epitopes. In contrast, some were individuals vaccinated with a DENV3 monovalent vaccine-elicited serum TS nAbs targeting each ED in a subject-dependent fashion, with an emphasis on EDI and EDIII. Vaccine responses were also sensitive to DENV3 genotypic variation. This DENV1/3 panel allows the measurement of serum ED TS nAbs, revealing differences in TS nAb immunity after natural infection or vaccination.

Development and User Testing of a Dynamic Tool for Rheumatic Heart Disease Management.

OBJECTIVE: Most rheumatic heart disease (RHD) registries are static and centralized, collecting epidemiological and clinical data without providing tools to improve care. We developed a dynamic cloud-based RHD case management application with the goal of improving care for patients with RHD in Uganda. METHODS: The Active Community Case Management Tool (ACT) was designed to improve community-based case management for chronic disease, with RHD as the first test case. Global and local partner consultation informed selection of critical data fields and prioritization of application functionality. Multiple stages of review and revision culminated in user testing of the application at the Uganda Heart Institute. RESULTS: Global and local partners provided feedback of the application via survey and interview. The application was well received, and top considerations included avenues to import existing patient data, considering a minimum data entry form, and performing a situation assessment to tailor ACT to the health system setup for each new country. Test users completed a postuse survey. Responses were favorable regarding ease of use, desire to use the application in regular practice, and ability of the application to improve RHD care in Uganda. Concerns included appropriate technical skills and supports and potential disruption of workflow. CONCLUSION: Creating the ACT application was a dynamic process, incorporating iterative feedback from local and global partners. Results of the user testing will help refine and optimize the application. The ACT application showed potential for utility and integration into existing care models in Uganda.

Research priorities for the secondary prevention and management of acute rheumatic fever and rheumatic heart disease: a National Heart, Lung, and Blood Institute workshop report.

Secondary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) involves continuous antimicrobial prophylaxis among affected individuals and is recognised as a cornerstone of public health programmes that address these conditions. However, several important scientific issues around the secondary prevention paradigm remain unresolved. This report details research priorities for secondary prevention that were developed as part of a workshop convened by the US National Heart, Lung, and Blood Institute in November 2021. These span basic, translational, clinical and population science research disciplines and are built on four pillars. First, we need a better understanding of RHD epidemiology to guide programmes, policies, and clinical and public health practice. Second, we need better strategies to find and diagnose people affected by ARF and RHD. Third, we urgently need better tools to manage acute RF and slow the progression of RHD. Fourth, new and existing technologies for these conditions need to be better integrated into healthcare systems. We intend for this document to be a reference point for research organisations and research sponsors interested in contributing to the growing scientific community focused on RHD prevention and control.

Evaluating the implementation of a dynamic digital application to enable community-based decentralisation of rheumatic heart disease case management in Uganda: protocol for a hybrid type III effectiveness-implementation study.

INTRODUCTION: Rheumatic heart disease (RHD) affects over 39 million people worldwide, the majority in low-income and middle-income countries. Secondary antibiotic prophylaxis (SAP), given every 3-4 weeks can improve outcomes, provided more than 80% of doses are received. Poor adherence is strongly correlated with the distance travelled to receive prophylaxis. Decentralising RHD care has the potential to bridge these gaps and at least maintain or potentially increase RHD prophylaxis uptake. A package of implementation strategies was developed with the aim of reducing barriers to optimum SAP uptake. METHODS AND ANALYSIS: A hybrid implementation-effectiveness study type III was designed to evaluate the effectiveness of a package of implementation strategies including a digital, cloud-based application to support decentralised RHD care, integrated into the public healthcare system in Uganda. Our overarching hypothesis is that secondary prophylaxis adherence can be maintained or improved via a decentralisation strategy, compared with the centralised delivery strategy, by increasing retention in care. To evaluate this, eligible patients with RHD irrespective of their age enrolled at Lira and Gulu hospital registry sites will be consented for decentralised care at their nearest participating health centre. We estimated a sample size of 150-200 registrants. The primary outcome will be adherence to secondary prophylaxis while detailed implementation measures will be collected to understand barriers and facilitators to decentralisation, digital application tool adoption and ultimately its use and scale-up in the public healthcare system. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board (IRB) at Cincinnati Children's Hospital Medical Center (IRB 2021-0160) and Makerere University School of Medicine Research Ethics Committee (Mak-SOMREC-2021-61). Participation will be voluntary and informed consent or assent (>8 but <18) will be obtained prior to participation. At completion, study findings will be communicated to the public, key stakeholders and submitted for publication.

Burden of disease and barriers to comprehensive care for rheumatic heart disease in South Africa: an updated systematic review protocol.

INTRODUCTION: Rheumatic heart disease (RHD) is responsible for a significant burden of cardiovascular morbidity and mortality, and remains the most common cause of acquired heart disease among children and young adults in low-income and middle-income countries. Additionally, the global COVID-19 pandemic has forced the emergency restructuring of many health systems, which has had a broad impact on health in general, including cardiovascular disease. Despite significant cost to the health system and estimates from 2015 indicating both high incidence and prevalence of RHD in South Africa, no cohesive national strategy exists. An updated review of national burden of disease estimates, as well as literature on barriers to care for patients with RHD, will provide crucial information to assist in the development of a national RHD programme. METHODS AND ANALYSIS: Using predefined search terms that capture relevant disease processes from Group A Streptococcal (GAS) infection through to the sequelae of RHD, a search of PubMed, Scopus, ISI Web of Science, Sabinet African Journals, SA Heart and Current and Completed Research databases will be performed. All eligible studies on RHD, acute rheumatic fever and GAS infection published from April 2014 to December 2022 will be included. Vital registration data for the same period from Statistics South Africa will also be collected. A standardised data extraction form will be used to capture results for both quantitative and qualitative analyses. All studies included in burden of disease estimates will undergo quality assessment using standardised tools. Updated estimates on mortality and morbidity as well as a synthesis of work on primary, secondary and tertiary prevention of RHD will be reported. ETHICS AND DISSEMINATION: No ethics clearance is required for this study. Findings will be disseminated in a peer-reviewed journal and submitted to national stakeholders in RHD. PROSPERO REGISTRATION NUMBER: CRD42023392782.