Decentralization and Integration of Advanced Cardiac Care for the World's Poorest Billion Through the PEN-Plus Strategy for Severe Chronic Non-Communicable Disease.

Rheumatic and congenital heart disease, cardiomyopathies, and hypertensive heart disease are major causes of suffering and death in low- and lower middle-income countries (LLMICs), where the world's poorest billion people reside. Advanced cardiac care in these counties is still predominantly provided by specialists at urban tertiary centers, and is largely inaccessible to the rural poor. This situation is due to critical shortages in diagnostics, medications, and trained healthcare workers. The Package of Essential NCD Interventions - Plus (PEN-Plus) is an integrated care model for severe chronic noncommunicable diseases (NCDs) that aims to decentralize services and increase access. PEN-Plus strategies are being initiated by a growing number of LLMICs. We describe how PEN-Plus addresses the need for advanced cardiac care and discuss how a global group of cardiac organizations are working through the PEN-Plus Cardiac expert group to promote a shared operational strategy for management of severe cardiac disease in high-poverty settings.

Outcomes of rheumatic fever in Uganda: a prospective cohort study.

BACKGROUND: Rheumatic heart disease is the largest contributor to cardiac-related mortality in children worldwide. Outcomes in endemic settings after its antecedent illness, acute rheumatic fever, are not well understood. We aimed to describe 3-5 year mortality, acute rheumatic fever recurrence, changes in carditis, and correlates of mortality after acute rheumatic fever. METHODS: We conducted a prospective cohort study of Ugandan patients aged 4-23 years who were diagnosed with definite acute rheumatic fever using the modified 2015 Jones criteria from July 1, 2017, to March 31, 2020, enrolled at three rheumatic heart disease registry sites in Uganda (in Mbarara, Mulago, or Lira), and followed up for at least 1 year after diagnosis. Patients with congenital heart disease were excluded. Patients underwent annual review, most recently in August, 2022. We calculated rates of mortality and acute rheumatic fever recurrence, tabulated changes in carditis, performed Kaplan-Meier survival analyses, and used Cox regression models to identify correlates of mortality. FINDINGS: Data were collected between Sept 1 and Sept 30, 2022. Of 182 patients diagnosed with definite acute rheumatic fever, 156 patients were included in the analysis. Of these 156 patients (77 [49%] male and 79 (51%) female; data on ethnicity not collected), 25 (16%) died, 21 (13%) had a cardiac-related death, and 17 (11%) had recurrent acute rheumatic fever over a median of 4·3 (IQR 3·0-4·8) years. 16 (24%) of the 25 deaths occurred within 1 year. Among 131 (84%) of 156 survivors, one had carditis progression by echo. Moderate-to-severe carditis (hazard ratio 12·7 [95% CI 3·9-40·9]) and prolonged PR interval (hazard ratio 4·4 [95% CI 1·7-11·2]) at acute rheumatic fever diagnosis were associated with increased cardiac-related mortality. INTERPRETATION: These are the first contemporary data from sub-Saharan Africa on medium-term acute rheumatic fever outcomes. Mortality rates exceeded those reported elsewhere. Most decedents already had chronic carditis at initial acute rheumatic fever diagnosis, suggesting previous undiagnosed episodes that had already compounded into rheumatic heart disease. Our data highlight the large burden of undetected acute rheumatic fever in these settings and the need for improved awareness of and diagnostics for acute rheumatic fever to allow earlier detection. FUNDING: Strauss Award at Cincinnati Children's Hospital, American Heart Association, and Wellcome Trust.

Using Artificial Intelligence for Rheumatic Heart Disease Detection by Echocardiography: Focus on Mitral Regurgitation.

BACKGROUND: Identification of children with latent rheumatic heart disease (RHD) by echocardiography, before onset of symptoms, provides an opportunity to initiate secondary prophylaxis and prevent disease progression. There have been limited artificial intelligence studies published assessing the potential of machine learning to detect and analyze mitral regurgitation or to detect the presence of RHD on standard portable echocardiograms. METHODS AND RESULTS: We used 511 echocardiograms in children, focusing on color Doppler images of the mitral valve. Echocardiograms were independently reviewed by an expert adjudication panel. Among 511 cases, 229 were normal, and 282 had RHD. Our automated method included harmonization of echocardiograms to localize the left atrium during systole using convolutional neural networks and RHD detection using mitral regurgitation jet analysis and deep learning models with an attention mechanism. We identified the correct view with an average accuracy of 0.99 and the correct systolic frame with an average accuracy of 0.94 (apical) and 0.93 (parasternal long axis). It localized the left atrium with an average Dice coefficient of 0.88 (apical) and 0.9 (parasternal long axis). Maximum mitral regurgitation jet measurements were similar to expert manual measurements (P value=0.83) and a 9-feature mitral regurgitation analysis showed an area under the receiver operating characteristics curve of 0.93, precision of 0.83, recall of 0.92, and F1 score of 0.87. Our deep learning model showed an area under the receiver operating characteristics curve of 0.84, precision of 0.78, recall of 0.98, and F1 score of 0.87. CONCLUSIONS: Artificial intelligence has the potential to detect RHD as accurately as expert cardiologists and to improve with more data. These innovative approaches hold promise to scale echocardiography screening for RHD.

Outcomes of latent rheumatic heart disease: External validation of a simplified score in patients with and without secondary prophylaxis.

BACKGROUND: Secondary antibiotic prophylaxis reduces progression of latent rheumatic heart disease (RHD) but not all children benefit. Improved risk stratification could refine recommendations following positive screening. We aimed to evaluate the performance of a previously developed echocardiographic risk score to predict mid-term outcomes among children with latent RHD. METHODS: We included children who completed the GOAL, a randomized trial of secondary antibiotic prophylaxis among children with latent RHD in Uganda. Outcomes were determined by a 4-member adjudication panel. We applied the point-based score, consisting of 5 variables (mitral valve (MV) anterior leaflet thickening (3 points), MV excessive leaflet tip motion (3 points), MV regurgitation jet length ≥ 2 cm (6 points), aortic valve focal thickening (4 points) and any aortic regurgitation (5 points)), to panel results. Unfavorable outcome was defined as progression of diagnostic category (borderline to definite, mild definite to moderate/severe definite), worsening valve involvement or remaining with mild definite RHD. RESULTS: 799 patients (625 borderline and 174 definite RHD) were included, with median follow-up of 24 months. At total 116 patients (14.5%) had unfavorable outcome per study criteria, 57.8% not under prophylaxis. The score was strongly associated with unfavorable outcome (HR = 1.26, 95% CI 1.16-1.37, p < 0.001). Unfavorable outcome rates in low (≤6 points), intermediate (7-9 points) and high-risk (≥10 points) children at follow-up were 11.8%, 30.4%, and 42.2%, (p < 0.001) respectively (C-statistic = 0.64 (95% CI 0.59-0.69)). CONCLUSIONS: The simple risk score provided an accurate prediction of RHD status at 2-years, showing a good performance in a population with milder RHD phenotypes.

Lifting all boats: strategies to promote equitable bidirectional research training opportunities to enhance global health reciprocal innovation.

Inequities in global health research are well documented. For example, training opportunities for US investigators to conduct research in low-income and middle-income countries (LMIC) have exceeded opportunities for LMIC investigators to train and conduct research in high-income countries. Reciprocal innovation addresses these inequities through collaborative research across diverse global settings.The Fogarty International Center of the US National Institutes of Health (NIH) promotes research capacity building in LMICs. Fogarty K-grants for mentored career development in global health are available for both US and LMIC investigators, whereas the D43 is the standard grant to support institutional training programmes in LMIC. Other NIH institutes fund T32 training grants to support biomedical research training in the USA, but very few have any global health component. Most global health training partnerships have historically focused on research conducted solely in LMIC, with few examples of bidirectional training partnerships. Opportunities may exist to promote global health reciprocal innovation (GHRI) research by twinning K-awardees in the USA with those from LMIC or by intentionally creating partnerships between T32 and D43 training programmes.To sustain independent careers in GHRI research, trainees must be supported through the path to independence known as the K (mentored grantee)-to-R (independent grantee) transition. Opportunities to support this transition include comentorship, research training at both LMIC and US institutions and protected time and resources for research. Other opportunities for sustainability include postdoctoral training before and after the K-award period, absorption of trained researchers into home institutions, South-South training initiatives and innovations to mitigate brain drain.

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.

Tertiary prevention and treatment of rheumatic heart disease: a National Heart, Lung, and Blood Institute working group summary.

Although entirely preventable, rheumatic heart disease (RHD), a disease of poverty and social disadvantage resulting in high morbidity and mortality, remains an ever-present burden in low-income and middle-income countries (LMICs) and rural, remote, marginalised and disenfranchised populations within high-income countries. In late 2021, the National Heart, Lung, and Blood Institute convened a workshop to explore the current state of science, to identify basic science and clinical research priorities to support RHD eradication efforts worldwide. This was done through the inclusion of multidisciplinary global experts, including cardiovascular and non-cardiovascular specialists as well as health policy and health economics experts, many of whom also represented or closely worked with patient-family organisations and local governments. This report summarises findings from one of the four working groups, the Tertiary Prevention Working Group, that was charged with assessing the management of late complications of RHD, including surgical interventions for patients with RHD. Due to the high prevalence of RHD in LMICs, particular emphasis was made on gaining a better understanding of needs in the field from the perspectives of the patient, community, provider, health system and policy-maker. We outline priorities to support the development, and implementation of accessible, affordable and sustainable interventions in low-resource settings to manage RHD and related complications. These priorities and other interventions need to be adapted to and driven by local contexts and integrated into health systems to best meet the needs of local communities.

2023 World Heart Federation guidelines for the echocardiographic diagnosis of rheumatic heart disease.

Rheumatic heart disease (RHD) is an important and preventable cause of morbidity and mortality among children and young adults in low-income and middle-income countries, as well as among certain at-risk populations living in high-income countries. The 2012 World Heart Federation echocardiographic criteria provided a standardized approach for the identification of RHD and facilitated an improvement in early case detection. The 2012 criteria were used to define disease burden in numerous epidemiological studies, but researchers and clinicians have since highlighted limitations that have prompted a revision. In this updated version of the guidelines, we incorporate evidence from a scoping review, an expert panel and end-user feedback and present an approach for active case finding for RHD, including the use of screening and confirmatory criteria. These guidelines also introduce a new stage-based classification for RHD to identify the risk of disease progression. They describe the latest evidence and recommendations on population-based echocardiographic active case finding and risk stratification. Secondary antibiotic prophylaxis, echocardiography equipment and task sharing for RHD active case finding are also discussed. These World Heart Federation 2023 guidelines provide a concise and updated resource for clinical and research applications in RHD-endemic regions.

Clinical Profile and Outcomes of Rheumatic Heart Disease Patients Undergoing Surgical Valve Procedures in Uganda.

Background: Chronic valvular heart disease is a well-known, long-term complication of acute rheumatic fever (ARF), which remains a major public health problem in low- and middle-income countries. Access to surgical management remains limited. Outcomes of the minority proportion of patients that access surgery have not been described in Uganda. Objectives: To describe the volume and type of rheumatic heart disease (RHD) valvular interventions and the outcomes of operated patients in the Uganda RHD registry. Methods: We performed a retrospective cohort study of all valve surgery procedures identified in the Uganda RHD registry through December 2021. Results: Three hundred and sixty-seven surgical procedures were performed among 359 patients. More than half were among young (55.9% were ≤20 years of age), female (59.9%) patients. All patients were censored at 15 years. The median (IQR) follow up period was 43 (22,79) months. Nearly half of surgeries (46.9%) included interventions on multiple valves, and most valvular operations were replacements with mechanical prostheses (96.6%). Over 70% of the procedures were sponsored by charity organizations. The overall mortality of patients who underwent surgery was 13% (47/359), with over half of the mortalities occurring within the first year following surgery (27/47; 57.4%). Fifteen-year survival or freedom from re-operation was not significantly different between those receiving valve replacements and those receiving valve repair (log-rank p = 0.76). Conclusions: There has been increasing access to valve surgery among Ugandan patients with RHD. Post-operative survival is similar to regionally reported rates. The growing cohort of patients living with prosthetic valves necessitates national expansion and decentralization of post-operative care services. Major reliance on charity funding of surgery is unsustainable, thus calling for locally generated and controlled support mechanisms such as a national health insurance scheme. The central illustration (Figure 1) provides a summary of our findings and recommendations.

Long COVID in Uganda: Electrographic findings among patients at risk.

Background: COVID-19 has a significant cardiovascular involvement. Electrocardiographic (ECG) abnormalities among people at a risk of Long COVID in Uganda was investigated. Methods: A cross-sectional study was conducted from February to June 2022 at the post COVID - 19 clinic in Mulago National Specialized Hospital, Kampala. A standard resting ECG was performed on individuals at least 2 months following acute COVID-19, with a negative SARS-CoV-2 reverse-transcription polymerase chain reaction. Sociodemographic and clinical characteristics as well as vital signs were recorded for all study participants. Results: Of the 244 study participants, 117 (47.9%) were female. The median age of all the participants was 33.0 (interquartile range: 26.0 - 43.5) years. Twenty-five (10.2%) participants had a history of smoking while 117 (48%) had a history of alcohol intake. In total, 46 (18.9%) had abnormal ECG findings (95% Confidence Interval (CI): 14.39 - 24.29) and non-specific T-wave inversion (n = 16, 34%) was the most frequent ECG abnormality. The proportion of participants with ECG abnormalities was 48% lower among females (adjusted prevalence ratio (aPR): 0.52, 95% CI: 0.28 - 0.96, p value < 0.05) and 2-fold greater for those with a history of smoking (aPR: 2.03, 95% CI:1.096 - 3.776, p value < 0.05). Conclusion: One in five Ugandans who were checked at the clinic at a risk of Long COVID showed ECG abnormalities. ECG screening is suggested to be integrated into the follow-up care of those at a risk of Long COVID.

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.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

BACKGROUND: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. OBJECTIVE: This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. METHODS: Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. RESULTS: We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. CONCLUSIONS: We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46710.