Meta-analysis of genome-wide association studies of stable warfarin dose in patients of African ancestry.

ABSTRACT: Warfarin dose requirements are highly variable because of clinical and genetic factors. Although genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWASs) in 4 African cohorts from Uganda, South Africa, and Zimbabwe, totaling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included 2 African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n = 316) and the University of Alabama at Birmingham (n = 199). After the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci in chromosomes 10 and 16. The genome-wide significance threshold was set at P < 5 × 10-8. The meta-analysis, comprising 1504 participants, identified 242 significant SNPs across 3 genomic loci, with 99.6% of these located within known loci on chromosomes 10 (top SNP: rs58800757, P = 4.27 × 10-13) and 16 (top SNP: rs9925964, P = 9.97 × 10-16). Adjustment for the VKORC1 SNP -1639G>A revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P = 3.64 × 10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, we reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements, and identified a new locus (MALL), that still requires direct evidence of biological plausibility.

Diagnostic performance of an albuminuria point-of-care test in screening for chronic kidney disease among young people living with HIV in Uganda: a cross-sectional study.

OBJECTIVES: The main aim was to determine the diagnostic performance of an albuminuria point-of-care test (POC) for diagnosis of chronic kidney disease among young people living with HIV (YPLHIV) in Uganda. DESIGN: We conducted a cross-sectional study comparing the diagnostic performance of MicroalbuPHAN (Erba Lachema, Czech Republic), an albuminuria POC test against the laboratory-measured albumin and creatinine as the reference standard. SETTING: The study was set in seven HIV clinics in Kampala, Uganda that provide antiretroviral therapy to adults and children living with HIV. The study took place from April to August 2023. PARTICIPANTS: 497 YPLHIV aged 10-24 years who were diagnosed with HIV before 10 years of age were randomly selected from the HIV clinics. Pregnant YPLHIV were excluded. PROCEDURES: Participants provided a spot urine sample that was tested for albumin and creatinine using the POC and in the laboratory and proteinuria using urine dipstick. The sensitivity, specificity, negative and positive predictive values (NPV, PPV) of the POC versus the laboratory test were calculated, and factors associated with having a positive POC test were estimated using logistic regression. OUTCOME MEASURES: The primary outcome was a diagnosis of albuminuria defined as an albumin creatinine ratio above 30 mg/g. RESULTS: Of the 497 participants enrolled, 278 (55.9%) were female and 331 (66.8%) were aged 10-17 years. The POC test had a sensitivity of 74.5% (95% CI 70.6% to 78.4%) and specificity of 68.1% (95% CI 63.9% to 72.3%). The PPV was 21.5% (95% CI 17.8% to 25.1%) and the NPV was 95.8% (95% CI 94.0% to 97.6%), with an accuracy of 68.8%. There was strong evidence that a positive POC test was associated with having proteinuria (OR 2.82; 95% CI 1.89 to 4.22, p<0.001); body mass index <19.5 (OR 1.69 95% CI 1.17 to 2.45, p=0.005) and being male (OR 1.48; 95% CI 1.02 to 2.14, p=0.04). CONCLUSIONS: The albuminuria POC test had low sensitivity and specificity. However, it can be used to exclude kidney disease given its high NPV. It should be validated against the 24-hour urinary excretion rate to further determine its diagnostic performance.

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

[This corrects the article DOI: 10.5334/gh.1313.].

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.

High intracardiac clot burden in a young mother with peripartum cardiomyopathy in Uganda.

Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy presenting with a reduction in left ventricular systolic function towards the end of pregnancy or in the months after delivery. It is a life-threatening condition with a substantial mortality rate ranging from six to 25%, commonly due to heart failure or sudden cardiac death. Pregnancy is a prothrombotic state. Due to poor systolic function, women with PPCM are prone to intracardiac thrombi and a high risk of thromboembolic events. Early diagnosis with echocardiography and treatment plays a critical role. We describe a case of a woman with PPCM and biventricular thrombi, with the aim of creating awareness for early echocardiographic screening for thrombi and appropriate implementation of care.

The Echocardiographic Diagnosis of Rheumatic Heart Disease: A Review of the Performance of the World Heart Federation Criteria 2012-2023.

Background: The World Heart Federation (WHF) published the first evidence-based guidelines on the echocardiographic diagnosis of rheumatic heart disease (RHD) in 2012. These guidelines have since been applied internationally in research and clinical practice. Substantial research has assessed the utility of the 2012 WHF criteria, including its applicability in low-resource settings. This article summarises the evidence regarding the performance of the guidelines. Methods: A scoping review assessing the performance of the guidelines was performed. Cochrane, Embase, Medline, PubMed Lilacs, Sielo, and Portal BVS databases were searched for studies on the performance of the guidelines between January 2012-March 2023, and 4047 manuscripts met the search criteria, of which 34 were included. This included papers assessing the specificity, inter-rater reliability, application using hand-carried ultrasound, and modification of the criteria for simplicity. The review followed the PRISMA Extension for Scoping Reviews guideline. Results: The WHF 2012 criteria were 100% specific for definite RHD when applied in low-prevalence populations. The criteria demonstrated substantial and moderate inter-rater reliability for detecting definite and borderline RHD, respectively. The inter-rater reliability for morphological features was lower than for valvular regurgitation. When applied to hand-carried ultrasound performed by an expert, modified versions of the criteria demonstrated a sensitivity and specificity range of 79-90% and 87-93% respectively for detecting any RHD, performing best for definite RHD. The sensitivity and the specificity were reduced when performed in task-sharing but remains moderately accurate. Conclusion: The WHF 2012 criteria provide clear guidance for the echocardiographic diagnosis of RHD that is reproducible and applicable to a range of echocardiographic technology. Furthermore, the criteria are highly specific and particularly accurate for detecting definite RHD. There are limitations in applying all aspects of the criteria in specific settings, including task-sharing. This summary of evidence can inform the updated version of the WHF guidelines to ensure improved applicability in all RHD endemic regions.

Intramuscular versus enteral penicillin prophylaxis to prevent progression of rheumatic heart disease: Study protocol for a noninferiority randomized trial (the GOALIE trial).

BACKGROUND: Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. METHODS/DESIGN: The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. DISCUSSION: The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05693545.

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.

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.

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.