Corrigendum: Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis.

[This corrects the article DOI: 10.3389/fimmu.2022.1009016.].

Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis.

Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of Mycobacterium tuberculosis (Mtb)-specific T cells in pericardial fluid and peripheral blood in patients with pericardial TB (PCTB). Whole blood and pericardial fluid (PCF) samples were collected at the time of diagnostic sampling, with repeat blood sampling after completion of anti-tubercular treatment (ATT) in 16 PCTB patients, most of them being HIV-1 infected (n=14). These samples were stimulated ex vivo and the phenotypic and functional cellular profile of PCF and blood was assessed by flow cytometry. We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-α producing Mtb-specific granulocytes and Mtb-specific CD4 T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFNγ, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1ß production was lower in the PCF T cells. Bacterial loads were not associated with alterations in the phenotype or function of Mtb-specific CD4 T cells. Upon ATT completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using an ex vivo assay to compare the immune response towards Mtb in PCF and in blood, we identified significant difference in the phenotypic profile of Mtb-specific CD4 T response between these two compartments. Moreover, we show that the activation profile of peripheral Mtb-specific CD4 T cells could be used to monitor treatment response in PCTB.

Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.

BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).

Health trends, inequalities and opportunities in South Africa's provinces, 1990-2019: findings from the Global Burden of Disease 2019 Study.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990-2007, largely due to differences in HIV/AIDS, then decreased over 2007-2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study.

BACKGROUND: Heart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans. METHOD: The African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study. CONCLUSION: The IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.

Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. METHODS: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. RESULTS: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). CONCLUSIONS: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

N-terminal pro BNP and galectin-3 are prognostic biomarkers of acute heart failure in sub-Saharan Africa: lessons from the BAHEF trial.

AIMS: The relationship between N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and galectin-3 and outcomes has not been studied in African patients with acute heart failure (AHF). The current analysis sought to describe the association between plasma levels of NT-pro-BNP and galectin-3 and cardiovascular (CV) death or heart failure (HF) hospitalization, as well as their associations with symptoms and echocardiography markers of left and right ventricular remodelling among AHF patientsv in sub-Saharan Africa. METHODS AND RESULTS: In a subset of 80 patients with complete data in a study assessing the effects of hydralazine and nitrates in patients with AHF (BAHEF trial; NCT01822808), NT-pro-BNP and galectin-3 analyses were performed, and the association with various characteristics and outcome measures assessed. The mean age of the patients for whom the aforementioned biomarkers were measured was 52.6 years, with 52.5% women. Galectin-3 at baseline predicted changes (Week 24 to baseline) in left ventricular ejection fraction, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and tricuspid annular plane systolic excursion. Biomarkers and their changes were not associated with changes in 6 min walk test at 24 weeks. Baseline galectin-3 and change in NT-pro-BNP were associated with improvements in dyspnoea at 24 weeks. Nine patients had an HF readmission or died of CV causes through 24 weeks (11.6%). Both biomarkers at baseline predicted combined CV death or HF hospitalization through Week 24 (P-values = 0.0328 and 0.0001, respectively). CONCLUSIONS: In a cohort of patients with AHF from sub-Saharan Africa, NT-pro-BNP and galectin-3 at baseline and their changes were associated with some changes in dyspnoea, echocardiographic remodelling, and CV death or HF hospitalization through Week 24. These tests have potential of being used for risk stratification of AHF patients in sub-Saharan Africa where resources are scarce.

The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation.

BACKGROUND: Rheumatic heart disease (RHD) is a neglected disease affecting 33 million people, mainly in low and middle income countries. Yet very few large trials or registries have been conducted in this population. The INVICTUS program of research in RHD consists of a randomized-controlled trial (RCT) of 4500 patients comparing rivaroxaban with vitamin K antagonists (VKA) in patients with RHD and atrial fibrillation (AF), a registry of 17,000 patients to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. This paper describes the rationale, design, organization and baseline characteristics of the RCT and a summary of the design of the registry and its sub-study. Patients with RHD and AF are considered to be at high risk of embolic strokes, and oral anticoagulation with VKAs is recommended for stroke prevention. But the quality of anticoagulation with VKA is poor in developing countries. A drug which does not require monitoring, and which is safe and effective for preventing stroke in patients with valvular AF, would fulfill a major unmet need. METHODS: The INVestIgation of rheumatiC AF Treatment Using VKAs, rivaroxaban or aspirin Studies (INVICTUS-VKA) trial is an international, multicentre, randomized, open-label, parallel group trial, testing whether rivaroxaban 20 mg given once daily is non-inferior (or superior) to VKA in patients with RHD, AF, and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo-contrast or thrombus, or a CHA2DS2VASc score ≥2). The primary efficacy outcome is a composite of stroke or systemic embolism and the primary safety outcome is the occurrence of major bleeding. The trial has enrolled 4565 patients from 138 sites in 23 countries from Africa, Asia and South America. The Registry plans to enroll an additional 17,000 patients with RHD and document their treatments, and their clinical course for at least 2 years. The pregnancy sub-study will document the clinical course of pregnant women with RHD. CONCLUSION: INVICTUS is the largest program of clinical research focused on a neglected cardiovascular disease and will provide new information on the clinical course of patients with RHD, and approaches to anticoagulation in those with concomitant AF.

Exploring how a genetic attribution to disease relates to stigma experiences of Xhosa patients with schizophrenia in South Africa.

BACKGROUND: Over the past three decades, a range of international stakeholders have highlighted the possibility that genomic research may impact stigma associated with psychiatric disorders. Limited research has been conducted in Africa to investigate this relation. METHOD: In the present study, using focus group discussions, we explored the relation between genetic attribution and stigma among 36 Xhosa people with schizophrenia. We addressed three main questions: (1) What causal beliefs do Xhosa people with schizophrenia use to explain their illness and to what extent do genetic explanations play a role in these beliefs? (2) What are the internalised stigma experiences of Xhosa people with schizophrenia? (3) How do genetic explanations relate to stigma experiences, if at all? RESULTS: Most participants were able to define genetics and some linked genetics to disease causation. Despite adequate knowledge of genetics and an emphasis on genetic explanations of schizophrenia in the study, most participants held a multitude of causal explanations including: psychosocial, environmental, and cultural. Moreover, participants rarely mentioned disease cause when describing their stigma experiences. DISCUSSION: For this population group, there was no straight-forward relation between a genetic attribution and stigma. Therefore, we did not find evidence that genetic attribution may significantly increase stigma. Although North American and European literature provides conflicting evidence regarding this relation, there is increased consensus that biomedical explanations for psychiatric disorders may reduce blame. This study found evidence supporting that consensus. This study provides an empirical foundation to inform ongoing work on the psychosocial implications of psychiatric genomics research in non-Western contexts.

Regional Patterns and Association Between Obesity and Hypertension in Africa: Evidence From the H3Africa CHAIR Study.

Hypertension and obesity are the most important modifiable risk factors for cardiovascular diseases, but their association is not well characterized in Africa. We investigated regional patterns and association of obesity with hypertension among 30 044 continental Africans. We harmonized data on hypertension (defined as previous diagnosis/use of antihypertensive drugs or blood pressure [BP]≥140/90 mmHg/BP≥130/80 mmHg) and obesity from 30 044 individuals in the Cardiovascular H3Africa Innovation Resource across 13 African countries. We analyzed data from population-based controls and the Entire Harmonized Dataset. Age-adjusted and crude proportions of hypertension were compared regionally, across sex, and between hypertension definitions. Logit generalized estimating equation was used to determine the independent association of obesity with hypertension (P value <5%). Participants were 56% women; with mean age 48.5±12.0 years. Crude proportions of hypertension (at BP≥140/90 mmHg) were 47.9% (95% CI, 47.4-48.5) for Entire Harmonized Dataset and 42.0% (41.1-42.7) for population-based controls and were significantly higher for the 130/80 mm Hg threshold at 59.3% (58.7-59.9) in population-based controls. The age-adjusted proportion of hypertension at BP≥140/90 mmHg was the highest among men (33.8% [32.1-35.6]), in western Africa (34.7% [33.3-36.2]), and in obese individuals (43.6%; 40.3-47.2). Obesity was independently associated with hypertension in population-based controls (adjusted odds ratio, 2.5 [2.3-2.7]) and odds of hypertension in obesity increased with increasing age from 2.0 (1.7-2.3) in younger age to 8.8 (7.4-10.3) in older age. Hypertension is common across multiple countries in Africa with 11.9% to 51.7% having BP≥140/90 mmHg and 39.5% to 69.4% with BP≥130/80 mmHg. Obese Africans were more than twice as likely to be hypertensive and the odds increased with increasing age.

Prevalence of group A Streptococcal infection in Africa to inform GAS vaccines for rheumatic heart disease: A systematic review and meta-analysis.

BACKGROUND: The prevalence of group A streptococcal (GAS) disease is estimated at >18.1 million cases with an incidence of >1.78 million cases per year. While a significant cause of mortality and morbidity on the global scale, the burden of GAS disease in Africa is unknown. We conducted a systematic review on the prevalence of GAS disease among children and adults in Africa and the frequency and distribution of emm types among isolates. METHODS: We performed a comprehensive literature search in a number of databases, using an African search filter. Two reviewers independently selected articles meeting pre-specified criteria and extracted relevant data as per a data extraction form. We applied the random-effects meta-analysis model to aggregate GAS prevalence estimates with 95% CI for GAS prevalence, incorporating the Freeman-Tukey transformation to account for between-study variability. RESULTS: Twenty-five studies were included. Invasive GAS disease prevalence ranged from 0.6% to 10.8% in samples from normally-sterile sites including blood, CSF and soft tissue. A single study reported a prevalence of 74% in skin infections. Prevalence of emm types varied with up to 88 different strains reported, corresponding to a vaccine coverage of 28% to 65%. The pooled prevalence of GAS in persons presenting with pharyngitis was 21% (95% CI, 17% to 26%). CONCLUSIONS: The prevalence of GAS remains high among symptomatic individuals residing in Africa. Data on molecular strain characterisation of GAS in Africa is largely non-existent, thus the need for further studies is warranted to inform current prevention efforts including vaccine development.

Prevalence and progression of rheumatic heart disease: a global systematic review and meta-analysis of population-based echocardiographic studies.

This systematic review and meta-analysis aimed to provide a contemporaneous estimate of the global burden of rheumatic heart disease (RHD) from echocardiographic population-based studies. We searched multiple databases between January 01, 1996 and October 17, 2017. Random-effect meta-analysis was used to pool data. We included 82 studies (1,090,792 participant) reporting data on the prevalence of RHD and 9 studies on the evolution of RHD lesions. The pooled prevalence of RHD was 26.1‰ (95%CI 19.2-33.1) and 11.3‰ (95%CI 7.2-16.2) for studies which used the World Heart Federation (WHF) and World Health Organization (WHO) criteria, respectively. The prevalence of RHD varied inversely with the level of a country's income, was lower with the WHO criteria compared to the WHF criteria, and was lowest in South East Asia. Definite RHD progressed in 7.5% (95% CI 1.5-17.6) of the cases, while 60.7% (95% CI 42.4-77.5) of cases remained stable over the course of follow-up. The proportion of cases borderline RHD who progressed to definite RHD was 11.3% (95% CI 6.9-16.5). The prevalence of RHD across WHO regions remains high. The highest prevalence of RHD was noted among studies which used the WHF diagnostic criteria. Definite RHD tends to progress or remain stable over time.

Burden of non-communicable diseases in sub-Saharan Africa, 1990-2017: results from the Global Burden of Disease Study 2017.

BACKGROUND: Although the burden of disease in sub-Saharan Africa continues to be dominated by infectious diseases, countries in this region are undergoing a demographic transition leading to increasing prevalence of non-communicable diseases (NCDs). To inform health system responses to these changing patterns of disease, we aimed to assess changes in the burden of NCDs in sub-Saharan Africa from 1990 to 2017. METHODS: We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to analyse the burden of NCDs in sub-Saharan Africa in terms of disability-adjusted life-years (DALYs)-with crude counts as well as all-age and age-standardised rates per 100 000 population-with 95% uncertainty intervals (UIs). We examined changes in burden between 1990 and 2017, and differences across age, sex, and regions. We also compared the observed NCD burden across countries with the expected values based on a country's Socio-demographic Index. FINDINGS: All-age total DALYs due to NCDs increased by 67·0% between 1990 (90·6 million [95% UI 81·0-101·9]) and 2017 (151·3 million [133·4-171·8]), reflecting an increase in the proportion of total DALYs attributable to NCDs (from 18·6% [95% UI 17·1-20·4] to 29·8% [27·6-32·0] of the total burden). Although most of this increase can be explained by population growth and ageing, the age-standardised DALY rate (per 100 000 population) due to NCDs in 2017 (21 757·7 DALYs [95% UI 19 377·1-24 380·7]) was almost equivalent to that of communicable, maternal, neonatal, and nutritional diseases (26 491·6 DALYs [25 165·2-28 129·8]). Cardiovascular diseases were the second leading cause of NCD burden in 2017, resulting in 22·9 million (21·5-24·3) DALYs (15·1% of the total NCD burden), after the group of disorders categorised as other NCDs (28·8 million [25·1-33·0] DALYs, 19·1%). These categories were followed by neoplasms, mental disorders, and digestive diseases. Although crude DALY rates for all NCDs have decreased slightly across sub-Saharan Africa, age-standardised rates are on the rise in some countries (particularly those in southern sub-Saharan Africa) and for some NCDs (such as diabetes and some cancers, including breast and prostate cancer). INTERPRETATION: NCDs in sub-Saharan Africa are posing an increasing challenge for health systems, which have to date largely focused on tackling infectious diseases and maternal, neonatal, and child deaths. To effectively address these changing needs, countries in sub-Saharan Africa require detailed epidemiological data on NCDs. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Centre (Australia).

Marked variation in heritability estimates of left ventricular mass depending on modality of measurement.

Left ventricular (LV) hypertrophy is a strong risk factor for heart failure and cardiovascular death. ECG measures of LV mass are estimated as heritable in twin and family-based analyses and heritability estimates of LV mass measured by echocardiography are lower. We hypothesised that CMR-derived measurements, being more precise than echocardiographic measurements, would advance our understanding of heritable LV traits. We phenotyped 116 British families (427 individuals) by CMR and ECG, and undertook heritability analyses using variance-components (QTDT) and GWAS SNP-based (GCTA-GREML) methods. ECG-based traits such as LV mass and Sokolow-Lyon duration showed substantial estimates of heritability (60%), whereas CMR-derived LV mass was only modestly heritable (20%). However, the ECG LV mass was positively correlated with the lateral diameter of the chest (rho = 0.67), and adjustment for this attenuated the heritability estimate (42%). Finally, CMR-derived right ventricular mass showed considerable heritability (44%). Heritability estimates of LV phenotypes show substantial variation depending on the modality of measurement, being greater when measured by ECG than CMR. This may reflect the differences between electrophysiological as opposed to anatomical hypertrophy. However, ECG LV hypertrophy traits are likely to be influenced by genetic association with anthropometric measures, inflating their overall measured heritability.

Detectable prednisolone is delayed in pericardial fluid, compared with plasma of patients with tuberculous pericarditis: A pilot study.

BACKGROUND: In patients with tuberculous pericarditis [TBP] adjunctive prednisolone reduces the incidence of constrictive pericarditis. It is unknown whether prednisolone permeates adequately into pericardial fluid. Drug measurements in pericardial fluid require invasive procedures, and thus less invasive methods are needed to perform full pharmacokinetic characterization of prednisolone in large numbers of patients. We sought to evaluate the relationship between prednisolone concentrations in pericardial fluid, plasma, and saliva. METHODS: Plasma, pericardial fluid, and saliva samples were collected at 7 time points from TBP patients randomized to 120 mg prednisolone or placebo. Compartmental pharmacokinetic parameters, peak concentration [Cmax], and 0-24 h area under the concentration-time curve [AUC0-24] were identified in plasma, saliva and pericardial fluid. RESULTS: There were five patients each in the prednisolone and placebo groups. Prednisolone concentrations were best described using a one compartment model. The absorption half-life into plasma was 1 h, while that into pericardial fluid was 9.4 h, which led to a median time-to-maximum concentration in plasma of 2.0 h versus 5.0 h in pericardial fluid [p = 0.048]. The concentration-time profiles in pericardial fluid versus plasma exhibited system hysteresis. The pericardial fluid-to-plasma Cmax peak concentration ratio was 0.28 (p = 0.032), while the AUC0-24 ratio was 0.793. The concentration-time profiles in saliva had a similar shape to those in plasma, but the saliva-to-plasma Cmax was 0.59 [p = 0.032]. CONCLUSION: The prednisolone AUC0-24 achieved in pericardial fluid approximates that in plasma, but the Cmax is low due to delayed absorption. Saliva can be used as surrogate sampling site for pericardial fluid prednisolone.

Comparison of Dual Therapies for Lowering Blood Pressure in Black Africans.

BACKGROUND: The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established. METHODS: In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or was taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months. RESULTS: The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, -3.14 mm Hg; 95% confidence interval [CI], -5.90 to -0.38; P = 0.03; and -3.00 mm Hg; 95% CI, -5.8 to -0.20; P = 0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was -0.14 mm Hg (95% CI, -2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups. CONCLUSIONS: These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months. (Funded by GlaxoSmithKline Africa Noncommunicable Disease Open Lab; CREOLE ClinicalTrials.gov number, NCT02742467.).

Use of broad consent and related procedures in genomics research: Perspectives from research participants in the Genetics of Rheumatic Heart Disease (RHDGen) study in a University Teaching Hospital in Zambia.

The use of broad consent for genomics research raises important ethical questions for the conduct of genomics research, including relating to its acceptability to research participants and comprehension of difficult scientific concepts. To explore these and other challenges, we conducted a study using qualitative methods with participants enrolled in an H3Africa Rheumatic Heart Disease genomics study (the RHDGen network) in Zambia to explore their views on broad consent, sample and data sharing and secondary use. In-depth interviews were conducted with RHDGen participants (n = 18), study staff (n = 5) and with individuals who refused to participate (n = 3). In general, broad consent was seen to be reasonable if reasons for storing the samples for future research use were disclosed. Some felt that broad consent should be restricted by specifying planned future studies and that secondary research should ideally relate to original disease for which samples were collected. A few participants felt that broad consent would delay the return of research results to participants. This study echoes findings in other similar studies in other parts of the continent that suggested that broad consent could be an acceptable consent model in Africa if careful thought is given to restrictions on re-use.

Digoxin and clinical outcomes in the Global Rheumatic Heart Disease Registry.

OBJECTIVE: Digoxin is widely used in patients with rheumatic heart disease (RHD) despite a lack of data on its impact on clinical outcomes. We aimed to determine the association of digoxin use on clinical outcomes in patients with RHD. METHODS: We performed a retrospective analysis of the association of digoxin use with mortality at 2 years in a large RHD registry. Secondary outcomes were recurrent heart failure (HF) and hospitalisation for any cause. We assessed associations using multivariable logistic regression in the entire cohort and in subgroups of patients with atrial fibrillation (AF) and HF. We also estimated average treatment effects from propensity-adjusted analyses using inverse probability treatment weighting. RESULTS: Information on digoxin use at baseline was available for 98.7% (3298/3343) of patients. In the overall population, digoxin was significantly associated with mortality (OR 1.63, 95% CI 1.30 to 2.04, p<0.0001) and recurrent HF (OR 1.48, 95% CI 1.07 to 2.04, p=0.019). On propensity-weighted analyses, this effect was markedly attenuated (OR 1.05, 95% CI 1.01 to 1.09, p=0.005). Patients in sinus rhythm without HF had a higher propensity-adjusted odds of death with digoxin use (OR 1.06, 95% CI 1.01 to 1.12, p=0.015), but those with both AF and HF had lower mortality (OR 0.88, 95% CI 0.80 to 0.98, p=0.019). CONCLUSION: Digoxin use is associated with higher mortality in patients with RHD, but this is greatly attenuated on propensity adjustment, indicating the presence of substantial treatment bias. The adjusted estimates may therefore not be reliable, and large randomised trials are needed to determine the true effect of digoxin in patients with RHD.