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Background: Type 2 diabetes mellitus (T2DM) may be a long-term sequela of infection with Mycobacterium tuberculosis ( Mtb ) by mechanisms that remain to be fully explained. We evaluated the association between Mtb sensitization and T2DM and, via mediation analysis, the extent to which it is mediated by insulin resistance and/or β-cell failure., Methods: Adults were assessed for T2DM by fasting plasma glucose, 2-hour oral glucose tolerance testing, and hemoglobin A 1c ; β-cell dysfunction and insulin resistance by homoeostasis model assessment 2; and Mtb sensitization by tuberculin skin testing. Associations between Mtb sensitization and T2DM were modeled with probit regression and decomposed into indirect effects of β-cell dysfunction and insulin resistance. Analyses were adjusted for sociodemographic, behavioral, and clinical characteristics., Results: We included 1843 adults. Individuals with Mtb sensitization were older than those without Mtb (median [IQR], 54 [39-64] vs 47 [33-62] years). As compared with being uninfected, Mtb sensitization was associated with T2DM (adjusted absolute risk difference, 9.34% [95% CI, 2.38%-15.0%]; P < .001) and increased insulin resistance (adjusted median difference, 0.16 [95% CI, .03-.29]; P = .014) but not β-cell dysfunction (adjusted median difference, -3.1 [95% CI, -10.4 to 4.3]; P = .42). In mediation analyses, insulin resistance mediated 18.3% (95% CI, 3.29%-36.0%; P = .020) of the total effect of the association between Mtb sensitization and T2DM., Conclusions: Definitive prospective studies examining incident T2DM following tuberculosis are warranted. Notwithstanding, our findings suggest that exposure to Mtb may be a novel risk factor for T2DM, likely driven by an increase in insulin resistance., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Few data exist on myocardial fibrosis and inflammation in youth with HIV., Methods: We performed cardiovascular magnetic resonance (CMR) on a cross section of South African youth: youth with perinatally acquired HIV (YPHIV) undergoing antiretroviral therapy (ART), youth with nonperinatally acquired HIV (YNPHIV) receiving ART, and youth without HIV. Quantile regression models were fit to assess the association between HIV status and CMR outcomes: subclinical fibrosis (late gadolinium enhancement [LGE] mass and fraction, native T1, extracellular volume) and inflammation (native T1, T2 mapping)., Results: Of 464 youth, 287 were YPHIV, 87 were YNPHIV, and 90 were HIV seronegative. The median age was 16 years (range, 11-24). LGE mass was higher in YPHIV and YNPHIV than in youth who were HIV seronegative (1.85 vs 2.00 vs 1.41 g, respectively), as was fraction (5.8% vs 6.4% vs 4.5%); native T1 was highest in YNPHIV. In adjusted analyses, when compared with youth with HIV seronegativity, YPHIV and YNPHIV exhibited higher LGE mass (β = 0.468, P = .001; β = 0.544, P = .002) and LGE fraction (β = 1.587, P < .001; β = 1.781, P < .001). CMR outcomes were similar between YPHIV and YNPHIV., Conclusions: Despite ART use, YPHIV and YNPHIV appear to have higher subclinical myocardial fibrosis than youth who are HIV seronegative and healthy adults in South Africa and may benefit from early screening/monitoring for cardiovascular disease., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: Access to MRI in low- and middle-income countries (LMICs) remains among the poorest in the world. The lack of skilled MRI personnel exacerbates access gaps, reinforcing long-standing health disparities. The Scan With Me (SWiM) program aims to sustainably create a network of highly skilled MRI technologists in LMICs who will facilitate the transfer of MRI knowledge and skills to their peers and contribute to the implementation of highly valuable imaging protocols for effective clinical and research use., Methods: The program introduces a case-based curriculum designed using a novel train-the-trainer approach, integrated with peer-collaborative learning to upskill practicing MRI technologists in LMICs. The 6-week curriculum uses the teach-try-use approach, which combines self-paced didactic lectures covering the basics of MR image acquisition (teach) with hands-on expert-guided scanning experience (try) and the implementation of protocols tailored to provide the best possible images on their infrastructures (use). Each program includes research translation skills training using an established advanced MRI technique relevant to LMICs. A pilot program focused on cardiac MRI (CMR) was conducted to assess the program's curriculum, delivery, and evaluation methods., Results: Forty-three MRI technologists from 16 LMICs participated in the pilot CMR program and, over the course of the training, implemented optimized CMR protocols that reduced acquisition times while improving image quality. The training resources and scanner-specific standardized protocols are published openly for public use in an online repository. In general, at the end of the program, learners reported considerable improvements in CMR knowledge and skills. All respondents to the program evaluation survey agreed to recommend the program to their colleagues, while 87% indicated interest in returning to help train others., Conclusions: The SWiM program is the first master class in MRI acquisition for practicing imaging technologists in LMICs. The program holds the potential to help reduce disparities in MRI expertise and access. The support of the MRI community, imaging societies, and funding agencies will increase its reach and further its impact in democratizing MRI., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05335928., Competing Interests: S. Heymans receives personal fees for independent scientific advice on early development in the field of heart failure for AstraZeneca, Ribocure, and CSL Behring, and receives research support from AstraZeneca and CSL Behring.

The global disparity of magnetic resonance imaging (MRI) is a major challenge, with many low- and middle-income countries (LMICs) experiencing limited access to MRI. The reasons for limited access are technological, economic and social. With the advancement of MRI technology, we explore why these challenges still prevail, highlighting the importance of MRI as the epidemiology of disease changes in LMICs. In this paper, we establish a framework to develop MRI with these challenges in mind and discuss the different aspects of MRI development, including maximising image quality using cost-effective components, integrating local technology and infrastructure and implementing sustainable practices. We also highlight the current solutions-including teleradiology, artificial intelligence and doctor and patient education strategies-and how these might be further improved to achieve greater access to MRI., (© 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Whether, and how, cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) vary with age at treatment initiation is unknown. We used magnetic resonance imaging to compare cardiac status between APHIV initiated on ART at < 5 years of age (early ART, n = 37) and ≥ 5 years of age (delayed ART, n = 34) versus HIV-uninfected peers (n = 21), reporting z-score mean differences adjusted for confounders. Relative to HIV-uninfected adolescents, APHIV with early ART had higher left ventricular (LV) global circumferential strain (GCS) [adjusted mean (95%CI) z-score: 0.53 (0.13, 0.92)] and maximum indexed left atrium volume (LAVi) [adjusted z-score: 0.55 (0.08, 1.02)]. In contrast, APHIV with delayed ART had greater indexed LV end-diastolic volume (LVEDVi) [adjusted z-score: 0.47 (0.09, 0.86)] and extracellular volume fraction [adjusted z-score: 0.79 (0.20, 1.37)], but lower GCS [adjusted z-score: -0.51 (-0.91, -0.10)] than HIV-uninfected peers. APHIV had distinct albeit subclinical cardiac phenotypes depending on ART initiation age. Changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined., (© 2024. The Author(s).)

Introduction: Rheumatic heart disease (RHD), degenerative aortic stenosis (AS), and congenital valve diseases are prevalent in sub-Saharan Africa. Many knowledge gaps remain in understanding disease mechanisms, stratifying phenotypes, and prognostication. Therefore, we aimed to characterise patients through clinical profiling, imaging, histology, and molecular biomarkers to improve our understanding of the pathophysiology, diagnosis, and prognosis of RHD and AS., Methods: In this cross-sectional, case-controlled study, we plan to recruit RHD and AS patients and compare them to matched controls. Living participants will undergo clinical assessment, echocardiography, CMR and blood sampling for circulatory biomarker analyses. Tissue samples will be obtained from patients undergoing valve replacement, while healthy tissues will be obtained from cadavers. Immunohistology, proteomics, metabolomics, and transcriptome analyses will be used to analyse circulatory- and tissue-specific biomarkers. Univariate and multivariate statistical analyses will be used for hypothesis testing and identification of important biomarkers. In summary, this study aims to delineate the pathophysiology of RHD and degenerative AS using multiparametric CMR imaging. In addition to discover novel biomarkers and explore the pathomechanisms associated with RHD and AS through high-throughput profiling of the tissue and blood proteome and metabolome and provide a proof of concept of the suitability of using cadaveric tissues as controls for cardiovascular disease studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mutithu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: COVID-19 cardiovascular research from Africa is limited. This study describes cardiovascular risk factors, manifestations, and outcomes of patients hospitalised with COVID-19 in the African region, with an overarching goal to investigate whether important differences exist between African and other populations, which may inform health policies., Methods: A multinational prospective cohort study was conducted on adults hospitalised with confirmed COVID-19, consecutively admitted to 40 hospitals across 23 countries, 6 of which were African countries. Of the 5,313 participants enrolled globally, 948 were from African sites (n = 9). Data on demographics, pre-existing conditions, clinical outcomes in hospital (major adverse cardiovascular events (MACE), renal failure, neurological events, pulmonary outcomes, and death), 30-day vitality status and re-hospitalization were assessed, comparing African to non-African participants., Results: Access to specialist care at African sites was significantly lower than the global average (71% vs. 95%), as were ICU admissions (19.4% vs. 34.0%) and COVID-19 vaccination rates (0.6% vs. 7.4%). The African cohort was slightly younger than the non-African cohort (55.0 vs. 57.5 years), with higher rates of hypertension (48.8% vs. 46.9%), HIV (5.9% vs. 0.3%), and Tuberculosis (3.6% vs. 0.3%). In African sites, a higher proportion of patients suffered cardiac arrest (7.5% vs. 5.1%) and acute kidney injury (12.7% vs. 7.2%), with acute kidney injury (AKI) appearing to be one of the strongest predictors of MACE and death in African populations compared to other populations. The overall mortality rate was significantly higher among African participants (18.2% vs. 14.2%)., Conclusions: Overall, hospitalised African patients with COVID-19 had a higher mortality despite a lower mean age, contradicting literature that had previously reported a lower mortality attributed to COVID-19 in Africa. African sites had lower COVID-19 vaccination rates and higher AKI rates, which were positively associated with increased mortality. In conclusion, African patients were hospitalized with more severe COVID-19 cases and had poorer outcomes., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Background: High-flow nasal oxygen (HFNO) is an accepted treatment for severe COVID-19-related acute hypoxaemic respiratory failure (AHRF)., Objectives: To determine whether treatment outcomes at Groote Schuur Hospital, Cape Town, South Africa, during the third COVID-19 wave would be affected by increased institutional experience and capacity for HNFO and more restrictive admission criteria for respiratory high-care wards and intensive care units., Methods: We included consecutive patients with COVID-19-related AHRF treated with HFNO during the first and third COVID-19 waves. The primary endpoint was comparison of HFNO failure (composite of the need for intubation or death while on HFNO) between waves., Results: A total of 744 patients were included: 343 in the first COVID-19 wave and 401 in the third. Patients treated with HFNO in the first wave were older (median (interquartile range) age 53 (46 - 61) years v. 47 (40 - 56) years; p<0.001), and had higher prevalences of diabetes (46.9% v. 36.9%; p=0.006), hypertension (51.0% v. 35.2%; p<0.001), obesity (33.5% v. 26.2%; p=0.029) and HIV infection (12.5% v. 5.5%; p<0.001). The partial pressure of arterial oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio at HFNO initiation and the ratio of oxygen saturation/FiO 2 to respiratory rate within 6 hours (ROX-6 score) after HFNO commencement were lower in the first wave compared with the third (median 57.9 (47.3 - 74.3) mmHg v. 64.3 (51.2 - 79.0) mmHg; p=0.005 and 3.19 (2.37 - 3.77) v. 3.43 (2.93 - 4.00); p<0.001, respectively). The likelihood of HFNO failure (57.1% v. 59.6%; p=0.498) and mortality (46.9% v. 52.1%; p=0.159) did not differ significantly between the first and third waves., Conclusion: Despite differences in patient characteristics, circulating viral variant and institutional experience with HFNO, treatment outcomes were very similar in the first and third COVID-19 waves. We conclude that once AHRF is established in COVID-19 pneumonia, the comorbidity profile and HFNO provider experience do not appear to affect outcome., Study Synopsis: What the study adds. This study adds to the body of evidence demonstrating the utility of high-flow nasal oxygen (HFNO) in avoiding invasive mechanical ventilation (IMV) in patients with severe COVID-19 hypoxaemic respiratory failure, and shows that this utility remained consistent across different waves of the COVID-19 pandemic. Implications of the study. In resource-constrained settings, HFNO is a feasible non-invasive alternative to IMV and can be employed with favourable and consistent outcomes outside traditional critical care wards. It also confirms that the degree of gas exchange abnormality, and not pre-existing patient-related factors, circulating wave variant or provider experience, is the main predictor of HFNO failure., (Copyright © 2023, Audley et al.)

Background: Cardiomyopathy is an important cause of heart failure, however, there is notable lack of data on causes and manifestations of cardiomyopathy in Africa., Aims: The African Cardiomyopathy and Myocarditis Registry Program (IMHOTEP) aims to address the knowledge gap on etiology, treatment, and outcomes of cardiomyopathy in sub-Saharan Africa., Methods and Results: We conducted a single-center pilot study to delineate the clinical and cardiovascular magnetic resonance (CMR) phenotypes of cardiomyopathy in South African patients. Assessment of the first 99 adult incident cases [mean age 36.8 ± 12.5 years; females 53.5%] enrolled in IMHOTEP showed that dilated cardiomyopathy (n = 77) was commonest, followed by hypertrophic (n = 13), restrictive (n = 5) and arrhythmogenic (n = 4) cardiomyopathies. A broad range of etiologies were encountered with secondary causes identified in 42% of patients. Onset of symptoms in the peripartum period was observed in 47% of women, and peripartum cardiomyopathy was diagnosed in 32.1% of women recruited. In addition to electrocardiography and echocardiography, CMR was performed in 67 cases and contributed diagnostically in a third of cases. Acute inflammation was rarely observed [2%] on CMR, however, late gadolinium enhancement (LGE) was noted in 92% of cases., Conclusion: We report a diverse spectrum of causes of cardiomyopathy in the South African population, with secondary, potentially treatable, etiologies in a significant proportion of cases. CMR was useful in delineating specific phenotypes and etiologies, influencing clinical care. A higher-than-expected burden of LGE was observed in this young patient cohort - the implications of which are yet to be determined., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosures None.

Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T cell immune memory is critical for continued protection against severe COVID-19. We examined T cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T cell memory responses in healthcare workers in South Africa (n = 39) who were vaccinated and experienced at least one SARS-CoV-2 infection. Spike-specific T cells are highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant nucleocapsid and membrane-specific T cells are detectable in most participants. The bulk of SARS-CoV-2-specific T cell responses have an early-differentiated phenotype, explaining their persistent nature. Overall, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants., Competing Interests: Declaration of interests A.S. is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. A.G. is a consultant for Pfizer. L.J.I. has filed for patent protection for various aspects of T cell epitope and vaccine design work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Youth living with perinatally acquired HIV infection (YLPHIV) are at risk of developing atherosclerotic cardiovascular disease., Methods: We determined the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries (CA) and abdominal aorta (AA) risk scores among YLPHIV who are ≥15 years old in Cape Town Adolescent and Antiretroviral Cohort. PDAY score was calculated using non-high-density lipoprotein, high-density lipoprotein cholesterol, hyperglycemia, hypertension, obesity, and smoking; a score ≥1 was considered elevated. HIV viremia was categorized as sustained (SV) = viral load (VL) >50 copies/mL, transient (TV) = mix of VL >50 and ≤50 copies/mL, or sustained-virologic suppression = VL <50 copies/mL throughout the study. Among YLPHIV, logistic models were fit to assess factors associated with elevated PDAY., Results: Overall, 218 YLPHIV [median age 16.8 (interquartile range: 15.9-17.8) years, male 47%] were included. Among YLPHIV, 8% (n = 17) had SV, and 54% (n = 118) had TV. Median antiretroviral therapy (ART) duration was 12 (interquartile range: 8-14) years. Among YLPHIV, 30.3% and 18.4% had elevated PDAY for CA and AA, respectively.Among YLPHIV, SV [adjusted odds ratio (aOR) = 18.4, P < 0.01] and TV (aOR = 2.10, P = 0.04) compared with virologic suppression and ART duration in years (aOR = 1.12, P = 0.03) were associated with elevated CA. Male sex was associated with both elevated CA and AA (aOR = 2.14, P = 0.02, and aOR = 3.43, P = 0.01, respectively) and association of SV with elevated AA (aOR = 3.24, P = 0.09)., Conclusions: A substantial proportion of YLPHIV have PDAY scores reflecting increased aggregate atherosclerotic risk. Among YLPHIV, viremia, lifetime ART duration, and male sex contribute to this risk, highlighting the importance of HIV control and the need to monitor cardiometabolic health., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The emergence of genetic variants of SARS-CoV-2 was associated with changing epidemiological characteristics throughout coronavirus disease 2019 (COVID-19) pandemic in population-based studies. Individual-level data on the clinical characteristics of infection with different SARS-CoV-2 variants in African countries is less well documented., Objectives: To describe the evolving clinical differences observed with the various SARS-CoV-2 variants of concern and compare the Omicron-driven wave in infections to the previous Delta-driven wave., Method: We performed a retrospective observational cohort study among patients admitted to a South African referral hospital with COVID-19 pneumonia. Patients were stratified by epidemiological wave period, and in a subset, the variants associated with each wave were confirmed by genomic sequencing. Outcomes were analysed by Cox proportional hazard models., Results: We included 1689 patients were included, representing infection waves driven predominantly by ancestral, Beta, Delta and Omicron BA1/BA2 & BA4/BA5 variants. Crude 28-day mortality was 25.8% (34/133) in the Omicron wave period versus 37.1% (138/374) in the Delta wave period (hazard ratio [HR] 0.68 [95% CI 0.47-1.00] p = 0.049); this effect persisted after adjustment for age, gender, HIV status and presence of cardiovascular disease (adjusted HR [aHR] 0.43 [95% CI 0.28-0.67] p < 0.001). Hospital-wide SARS-CoV-2 admissions and deaths were highest during the Delta wave period, with a decoupling of SARS-CoV-2 deaths and overall deaths thereafter., Conclusion: There was lower in-hospital mortality during Omicron-driven waves compared with the prior Delta wave, despite patients admitted during the Omicron wave being at higher risk., Contribution: This study summarises clinical characteristics associated with SARS-CoV-2 variants during the COVID-19 pandemic at a South African tertiary hospital, demonstrating a waning impact of COVID-19 on healthcare services over time despite epidemic waves driven by new variants. Findings suggest the absence of increasing virulence from later variants and protection from population and individual-level immunity., Competing Interests: The authors have declared that no competing interest exists., (© 2023. The Authors.)

SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on SARS-CoV-2 antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4 + T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4 + T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4 + T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children., Competing Interests: The authors have no competing interests., (© 2023 The Authors.)

Background: Despite treatment with combination antiretroviral therapy (cART), persons living with HIV (PLWH) are at higher risk of cardiac structural abnormalities that may presage clinical heart failure, including myocardial fibrosis. This study assessed whether circulating cellular and soluble protein markers of immune activation cross-sectionally associate with myocardial fibrosis among cART-treated PLWH in South Africa., Methods: Participants were enrolled in Khayelitsha township near Cape Town, SA. Cardiac magnetic resonance imaging was performed. Plasma protein biomarkers were measured using enzyme-linked immunoassays and monocyte phenotypes were evaluated using flow cytometry. Associations were assessed using multivariable linear and logistic regression., Results: Among 69 cART-treated PLWH, mean (SD) age was 48 (10) years, 71% were female, and time since HIV diagnosis was 9 (6) years. Evidence of left ventricular fibrosis by late gadolinium enhancement was present in 74% of participants and mean (SD) extracellular volume fraction (ECV) was 30.9 (5.9)%. Degree of myocardial fibrosis/inflammation measured by ECV was positively associated with percentages of circulating non-classical and intermediate monocyte phenotypes reflecting inflammation and tissue injury., Conclusion: These data generate hypotheses on possible immune mechanisms of HIV-associated non-ischemic myocardial disease, specifically among cART-treated PLWH in sub-Saharan Africa, where the majority of the HIV burden exists globally., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Moyo-Gwete et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rheumatic heart disease (RHD) is a neglected tropical disease despite the substantial global health burden. In this study, we aimed to develop a lower cost method of modeling aortic blood flow using subject-specific velocity profiles, aiding our understanding of RHD's consequences on the structure and function of the ascending aorta. Echocardiography and cardiovascular magnetic resonance (CMR) are often used for diagnosis, including valve dysfunction assessments. However, there is a need to further characterize aortic valve lesions to improve treatment options and timing for patients, while using accessible and affordable imaging strategies. Here, we simulated effects of RHD aortic valve lesions on the aorta using computational fluid dynamics (CFD). We hypothesized that inlet velocity distribution and wall shear stress (WSS) will differ between RHD and non-RHD individuals, as well as between subject-specific and standard Womersley velocity profiles. Phase-contrast CMR data from South Africa of six RHD subjects with aortic stenosis and/or regurgitation and six matched controls were used to estimate subject-specific velocity inlet profiles and the mean velocity for Womersley profiles. Our findings were twofold. First, we found WSS in subject-specific RHD was significantly higher (p < 0.05) than control subject simulations, while Womersley simulation groups did not differ. Second, evaluating spatial velocity differences (ΔSV) between simulation types revealed that simulations of RHD had significantly higher ΔSV than non-RHD (p < 0.05), these results highlight the need for implementing subject-specific input into RHD CFD, which we demonstrate how to accomplish through accessible methods., (Copyright © 2023 by ASME.)

Introduction: Differences in class or molecule-specific effects between renin-angiotensin-aldosterone system (RAAS) inhibitors have not been conclusively demonstrated. This study used South African data to assess clinical and cost outcomes of antihypertensive therapy with the three most common RAAS inhibitors: perindopril, losartan and enalapril., Methods: Using a large, South African private health insurance claims database, we identified patients with a hypertension diagnosis in January 2015 receiving standard doses of perindopril, enalapril or losartan, alone or in combination with other agents. From claims over the subsequent 5 years, we calculated the risk-adjusted rate of the composite primary outcome of myocardial infarction, ischaemic heart disease, heart failure or stroke; rate of all-cause mortality; and costs per life per month (PLPM), with adjustments based on demographic characteristics, healthcare plan and comorbidity., Results: Overall, 32,857 individuals received perindopril, 16,693 losartan and 13,939 enalapril. Perindopril-based regimens were associated with a significantly lower primary outcome rate (205 per 1000 patients over 5 years) versus losartan (221; P < 0.0001) or enalapril (223; P < 0.0001). The risk-adjusted all-cause mortality rate was lower with perindopril than enalapril (100 vs. 139 deaths per 1000 patients over 5 years; P = 0.007), but not losartan (100 vs. 94; P = 0.650). Mean (95% confidence interval) overall risk-adjusted cost PLPM was Rands (ZAR) 1342 (87-8973) for perindopril, ZAR 1466 (104-9365) for losartan (P = 0.0044) and ZAR 1540 (77-10,546) for enalapril (P = 0.0003)., Conclusion: In South African individuals with private health insurance, a perindopril-based antihypertensive regimen provided better clinical and cost outcomes compared with other regimens., (© 2023. The Author(s).)

Background: Left ventricular (LV) remodeling and its transitions from compensatory adaptations to LV dysfunction have not been examined in adolescents with perinatally acquired HIV infection (PHIV). We used cardiovascular magnetic resonance (CMR) in a cross-sectional study to characterize PHIV-related progressive LV remodeling in adolescents in South Africa., Methods: Adolescents with PHIV on antiretroviral treatment and their HIV uninfected peers completed 3 T CMR examination. We defined LV remodeling by LV mass/volume (M/V) ratio, modelling progressive LV remodeling as increasing M/V ratio. Linear regression models were applied to estimate the correlates of progressive LV remodeling., Results: Overall, 71 adolescents with PHIV [mean age: 15.2 years; 54% male] and 36 HIV uninfected [15.1 years; 42% male] peers were enrolled. Adolescents with PHIV had lower mean LV M/V ratio (0.68 vs. 0.75 g/mL; p = 0.004) than HIV uninfected peers, without LV hypertrophy in either group. Among adolescents with PHIV, increasing M/V ratio was accompanied by increasing interstitial volume [adjusted mean change (AMC) per 0.1 g/mL M/V ratio: 1.75 mL, p < 0.001] with no change in global circumferential strain (GCS) [AMC per 0.1 g/mL M/V ratio: -0.21%, p = 0.48]. However, in HIV uninfected individuals, increasing M/V ratio was accompanied by increasing peak GCS [AMC per 0.1 g/mL M/V ratio: -1.25%, p = 0.039] with no change in interstitial volume (AMC per 0.1 g/mL M/V ratio: 1.16 mL, p = 0.32]., Conclusions: Successfully treated PHIV is associated with less severe LV remodeling in adolescence when compared to HIV uninfected controls. LV remodeling in PHIV is associated with disproportionate expansion of the non-contractile interstitium not accompanied by improved GCS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Itai M. Magodoro reports financial support was provided by National Institutes of Health. Itai M. Magodoro reports financial support was provided by AIDS Healthcare Foundation. Heather Zar reports financial support was provided by National Institutes of Health. Heather Zar reports financial support was provided by South African Medical Research Council. Mark J. Siedner reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the memory B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. Participants were either naïve to SARS-CoV-2 or had been infected before vaccination. SARS-CoV-2-specific memory B-cells expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a significant reduction in expression of the germinal center chemokine receptor CXCR5, and increased class switching. These B cell features correlated with neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). Vaccination-induced effective neutralization of the D614G variant in both infected and naïve participants but boosted neutralizing antibodies against the Beta and Omicron variants only in participants with prior infection. In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell expression of the lung-homing receptor CXCR3, which was sustained in the previously infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the response to vaccination can provide insight into the impact of prior infection on memory B cell homing, CSM, cTfh, and neutralization activity. These data can provide early signals to inform studies of vaccine boosting, durability, and co-morbidities., (© 2023. Springer Nature Limited.)

Competing Interests: L-GB reports personal fees from Merck, ViiV Healthcare, and Gilead Sciences outside the submitted work. PS and NABN declare no competing interests.

High-throughput metabolomics techniques are a useful tool to understand many disease conditions including cardiovascular disease such as valvular heart disease(s) (VHD). VHD involves damage to heart valves, mostly presenting as stenosis, regurgitation or prolapse and can be classified into degenerative, rheumatic, congenital, or prosthetic valve disease. Gaps remain in our understanding of the pathogenesis of the common VHD. It is now fitting to place into perspective the contribution of metabolomics in the mechanism of development, diagnosis, and prognosis of VHD. A structured search for metabolomics studies centred on human VHD was undertaken. Biomarkers associated with the pathogenesis of bicuspid aortic valve disease, mitral valve disease, rheumatic heart disease, and degenerative aortic valve stenosis are reviewed and discussed. In addition, metabolic biomarkers reported to prognosticate patient outcomes of post-valve repair or replacement are highlighted. Finally, we also review the pitfalls and limitations to consider when designing metabolomics studies, especially from a clinician's viewpoint. In the future, reliable and simple metabolic biomarker(s) may supplement the existing diagnostic tools in the early diagnosis of VHD., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Despite advances in our understanding of the pathophysiology of many cardiovascular diseases (CVDs) and expansion of available therapies, the global burden of CVD-associated morbidity and mortality remains unacceptably high. Important gaps remain in our understanding of the mechanisms of CVD and determinants of disease progression. In the past decade, much research has been conducted on the human microbiome and its potential role in modulating CVD. With the advent of high-throughput technologies and multiomics analyses, the complex and dynamic relationship between the microbiota, their 'theatre of activity' and the host is gradually being elucidated. The relationship between the gut microbiome and CVD is well established. Much less is known about the role of disruption (dysbiosis) of the oral microbiome; however, interest in the field is growing, as is the body of literature from basic science and animal and human investigations. In this Review, we examine the link between the oral microbiome and CVD, specifically coronary artery disease, stroke, peripheral artery disease, heart failure, infective endocarditis and rheumatic heart disease. We discuss the various mechanisms by which oral dysbiosis contributes to CVD pathogenesis and potential strategies for prevention and treatment., (© 2023. Springer Nature Limited.)

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic that has affected nearly 600 million people to date across the world. While COVID-19 is primarily a respiratory illness, cardiac injury is also known to occur. Cardiovascular magnetic resonance (CMR) imaging is uniquely capable of characterizing myocardial tissue properties in-vivo, enabling insights into the pattern and degree of cardiac injury. The reported prevalence of myocardial involvement identified by CMR in the context of COVID-19 infection among previously hospitalized patients ranges from 26 to 60%. Variations in the reported prevalence of myocardial involvement may result from differing patient populations (e.g. differences in severity of illness) and the varying intervals between acute infection and CMR evaluation. Standardized methodologies in image acquisition, analysis, interpretation, and reporting of CMR abnormalities across would likely improve concordance between studies. This consensus document by the Society for Cardiovascular Magnetic Resonance (SCMR) provides recommendations on CMR imaging and reporting metrics towards the goal of improved standardization and uniform data acquisition and analytic approaches when performing CMR in patients with COVID-19 infection., (© 2023. The Author(s).)

Objective: Inflammation is key in the pathogenesis of atherosclerotic coronary artery disease (CAD). Distinct sex-specific inflammatory mechanisms may contribute to CAD in sub-Saharan Africa (SSA), where environmental and biological determinants of systemic inflammation may differ from those in high-income settings., Approach and Results: We investigated sex differences in inflammatory markers and CAD in a 2-year prospective cohort of Ugandan adults enriched for cardiometabolic risk factors (RFs) and HIV. Seven plasma biomarkers were quantified at the baseline visit among 125 females and 75 males (50% with HIV) at least 45 years old at enrollment with one or more major cardiovascular RF. In year 2, coronary CT angiography (CCTA) was performed in 82 females and 50 males returning for follow-up (52% with HIV). In sex-specific models adjusted for cardiovascular RFs and HIV, tumor necrosis factor-alpha (TNF-α) RII and sCD163 predicted subsequent CAD in females, while only fibrinogen was predictive in males ( P  < 0.05). Interleukin-6 (IL-6) and sCD14 were inversely associated with CAD in males ( P  < 0.05). Sex modified the associations of TNF-α RII, sCD14, and sCD163 with CAD ( P  < 0.05 for interaction). In multivariable multiple imputation models applied to missing year 2 CCTA data to test associations between serum biomarkers in the baseline cohort ( n  = 200) and subsequent CAD, higher sCD163 was predictive in females only ( P  < 0.05)., Conclusions: The positive link between inflammation and subclinical CAD was stronger among females than males in Uganda. Mechanisms by which sex modulates the relationship between inflammation and CAD should be further investigated in SSA., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The COVID-19 pandemic continues to affect individuals across the globe, with some individuals experiencing more severe disease than others. The relatively high frequency of re-infections and breakthrough infections observed with SARS-CoV-2 highlights the importance of extending our understanding of immunity to COVID-19. Here, we aim to shed light on the importance of antibody titres and epitope utilization in protection from re-infection. Health care workers are highly exposed to SARS-CoV-2 and are therefore also more likely to become re-infected. We utilized quantitative, multi-antigen, multi-epitope SARS-CoV-2 protein microarrays to measure IgG and IgA titres against various domains of the nucleocapsid and spike proteins. Potential re-infections in a large, diverse health care worker cohort (N = 300) during the second wave of the pandemic were identified by assessing the IgG anti-N titres before and after the second wave. We assessed epitope coverage and antibody titres between the 'single infection' and 're-infection' groups. Clear differences were observed in the breadth of the anti-N response before the second wave, with the epitope coverage for both IgG ( p = 0.019) and IgA ( p = 0.015) being significantly increased in those who did not become re-infected compared to those who did. Additionally, the IgG anti-N ( p = 0.004) and anti-S titres ( p = 0.018) were significantly higher in those not re-infected. These results highlight the importance of the breadth of elicited antibody epitope coverage following natural infection in protection from re-infection and disease in the COVID-19 pandemic.

Objectives: We aimed to compare the clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection., Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between May 01-May 21, 2022 (BA.4/BA.5 wave) and equivalent previous wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination, and previous infection., Results: Among 3793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves, the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95% confidence interval [CI] 0.93; 1.34). Both Omicron waves had a lower risk of severe outcomes than previous waves. Previous infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for at least three doses vs no vaccine) were protective., Conclusion: Disease severity was similar among diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to previous infection and vaccination, both of which were strongly protective., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4 and BA.5 variants caused major waves of infections. Here, we assess the sensitivity of BA.4 to binding, neutralization, and antibody-dependent cellular cytotoxicity (ADCC) potential, measured by FcγRIIIa signaling, in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high-level neutralization resistance regardless of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to ADCC is reduced compared with other variants but with smaller fold losses compared with neutralization and similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity may contribute to observed protection from severe disease., Competing Interests: Declaration of interests P.L.M. is a member of the advisory board for Cell Reports Medicine., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures, from infection or vaccination, can potently boost spike antibody responses. Less is known about the impact of repeated exposures on T cell responses. Here, we compare the prevalence and frequency of peripheral SARS-CoV-2-specific T cell and immunoglobulin G (IgG) responses in 190 individuals with complex SARS-CoV-2 exposure histories. As expected, an increasing number of SARS-CoV-2 spike exposures significantly enhances the magnitude of IgG responses, while repeated exposures improve the number of T cell responders but have less impact on SARS-CoV-2 spike-specific T cell frequencies in the circulation. Moreover, we find that the number and nature of exposures (rather than the order of infection and vaccination) shape the spike immune response, with spike-specific CD4 T cells displaying a greater polyfunctional potential following hybrid immunity compared with vaccination only. Characterizing adaptive immunity from an evolving viral and immunological landscape may inform vaccine strategies to elicit optimal immunity as the pandemic progress., Competing Interests: Declaration of interests A. Sette is a consultant for Gritstone Bio, Flow Pharma, Moderna, AstraZeneca, Qiagen, Avalia, Fortress, Gilead, Sanofi, Merck, RiverVest, MedaCorp, Turnstone, NA Vaccine Institute, Gerson Lehrman Group, and Guggenheim. La Jolla Institute for Immunology has filed for patent protection for various aspects of T cell epitope and vaccine design work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis., (© 2023. The Author(s).)

This JACC Focus Seminar provides an overview of and highlights recently published research on cardiomyopathies and nutritional heart disease that have a higher prevalence in tropical regions. The development of tropical cardiomyopathies and nutritional cardiovascular disease (CVD) is complicated by high rates of poverty, fragmented health care systems, and suboptimal access to health care because of socioeconomic inequalities, leading to the fact that children, adolescents, and young adults are disproportionally affected. Such tropical cardiomyopathies and nutritional CVD that have not been prevalent in high-income countries in the past decades are now reemerging. When treating migrants or refugees, it is important for attending physicians to consider the burden of endemic diseases in the countries of origin and the likelihood that such patients might be affected. In this review, the authors propose an approach for adequate diagnostic work-up leading to appropriate care for those with suspected or confirmed tropical cardiomyopathies and nutritional CVD., Competing Interests: Funding Support and Author Disclosures Support for the Cape Heart Institute was provided by the following funding bodies: the University of Cape Town, the South African Medical Research Council, the National Research Foundation SA, and the Hippocrate Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, several variants of concern (VOCs) have arisen which are defined by multiple mutations in their spike proteins. These VOCs have shown variable escape from antibody responses and have been shown to trigger qualitatively different antibody responses during infection. By studying plasma from individuals infected with either the original D614G, Beta, or Delta variants, we showed that the Beta and Delta variants elicit antibody responses that are overall more cross-reactive than those triggered by D614G. Patterns of cross-reactivity varied, and the Beta and Delta variants did not elicit cross-reactive responses to each other. However, Beta-elicited plasma was highly cross-reactive against Delta Plus (Delta+), which differs from Delta by a single K417N mutation in the receptor binding domain, suggesting that the plasma response targets the N417 residue. To probe this further, we isolated monoclonal antibodies from a Beta-infected individual with plasma responses against Beta, Delta+, and Omicron, which all possess the N417 residue. We isolated an N417-dependent antibody, 084-7D, which showed similar neutralization breadth to the plasma. The 084-7D MAb utilized the IGHV3-23*01 germ line gene and had somatic hypermutations similar to those of previously described public antibodies which target the 417 residue. Thus, we have identified a novel antibody which targets a shared epitope found on three distinct VOCs, enabling their cross-neutralization. Understanding antibodies targeting escape mutations, such as K417N, which repeatedly emerge through convergent evolution in SARS-CoV-2 variants, may aid in the development of next-generation antibody therapeutics and vaccines. IMPORTANCE The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring various immune escape profiles. These variable mutations also influence the cross-reactivity of the antibody response mounted by individuals infected with each of these variants. This study sought to understand the antibody responses elicited by different SARS-CoV-2 variants and to define shared epitopes. We show that Beta and Delta infections resulted in antibody responses that were more cross-reactive than the original D614G variant, but they had differing patterns of cross-reactivity. We further isolated an antibody from Beta infection which targeted the N417 site, enabling cross-neutralization of Beta, Delta+, and Omicron, all of which possess this residue. The discovery of antibodies which target escape mutations common to multiple variants highlights conserved epitopes to target in future vaccines and therapeutics.