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LJ Zühlke¹, ME Engel²¹Western Cape Paediatric Cardiac Services, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa; ²Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South AfricaWe would like to applaud the authors of the article "The worldwide epidemiology of acute rheumatic fever (ARF) and rheumatic heart disease (RHD)"¹ for highlighting this important disease which continues needlessly to kill people living in poverty while being largely ignored by the developed world.² We would however like to address some key issues.The authors state that: the evidence of serologic infection is based on one of "a pharyngeal swab culture positive for GABHS, positive rapid GABHS antigen test or rising serologic antibody titers". Very few countries in highly affected regions of the world utilize routine rapid antigen or microbiological testing due to the cost involved. Furthermore, the delay involved in repeat serological testing before a diagnosis can be made, will result in missed diagnoses and tragic consequences. We recommend therefore that elevated serological markers of previous GABHS infection, together with major and minor criteria, are sufficient for a diagnosis of ARF.

Background: There is concern regarding the increasing resistance of Group A streptococcus (GAS) to routinely used antibiotics. GAS is a common cause of bacterial pharyngitis and more severe invasive infections such as septicaemia. Furthermore, GAS pharyngitis is the antecedent for serious conditions such as rheumatic fever and rheumatic heart disease. The study aimed to determine the antimicrobial susceptibility patterns of GAS cultured from patients with invasive and non-invasive infections from Cape Town, as part of the AFRO Strep Registry., Methods: Samples were provided by the AFRO Strep Registry, a continental endeavour aiming to document Streptococcus pyogenes infection in Africa and create the first biorepository of its kind. Ninety-five GAS isolates (invasive, n = 40; non-invasive, n = 55) were evaluated for resistance to a panel of 20 antibiotics using the Sensititre® STP6F system with MICs interpreted by CLSI break points., Results: Amongst all isolates, highest levels of resistance were observed with respect to tetracycline (8.33 %), followed by azithromycin (1.04 %) and erythromycin (1.04 %). No resistance to the remaining antibiotics was detected amongst all isolates. No differences with regard to MIC values were observed between isolates from invasive and non-invasive infections (p-value >0.05 for all antibiotics)., Conclusion: GAS remains susceptible to routine-antimicrobial agents used in our low-resourced setting. Eight percent of the GAS isolates were resistant to tetracycline, and we did not observe macrolide resistance as reported in high income countries. This is the first study to report on the antimicrobial patterns of GAS in South Africa. These results address a critical gap in the available data on GAS in Africa and specifically South Africa and, thus, aid in avoiding therapeutic failures., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: It is currently unclear what the role of Group A streptococcus (GAS) virulence factors (VFs) is in contributing to the invasive potential of GAS. This work investigated the evidence for the association of GAS VFs with invasive disease., Methods: We employed a broad search strategy for studies reporting the presence of GAS VFs in invasive and non-invasive GAS disease. Data were independently extracted by two reviewers, quality assessed, and meta-analyzed using Stata®., Results: A total of 32 studies reported on 45 putative virulence factors [invasive (n = 3,236); non-invasive (n = 5,218)], characterized by polymerase chain reaction (PCR) (n = 30) and whole-genome sequencing (WGS) (n = 2). The risk of bias was rated as low and moderate, in 23 and 9 studies, respectively. Meta-,analyses of high-quality studies (n = 23) revealed a significant association of speM [OR, 1.64 (95%CI, 1.06; 2.52)] with invasive infection. Meta-analysis of WGS studies demonstrated a significant association of hasA [OR, 1.91 (95%CI, 1.36; 2.67)] and speG [OR, 2.83 (95%CI, 1.63; 4.92)] with invasive GAS (iGAS). Meta-analysis of PCR studies indicated a significant association of speA [OR, 1.59 (95%CI, 1.10; 2.30)] and speK [OR, 2.95 (95%CI, 1.81; 4.80)] with invasive infection. A significant inverse association was observed between prtf1 [OR, 0.42 (95%CI, 0.20; 0.87)] and invasive infection., Conclusion: This systematic review and genomic meta-analysis provides evidence of a statistically significant association with invasive infection for the hasA gene, while smeZ , ssa , pnga3 , sda1 , sic , and NaDase show statistically significantly inverse associations with invasive infection. SpeA , speK , and speG are associated with GAS virulence; however, it is unclear if they are markers of invasive infection. This work could possibly aid in developing preventative strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rampersadh, Salie, Engel, Moodley, Zühlke and Engel.)

Background: The prevalence of tuberculosis (TB)-associated pulmonary hypertension (PH) has not previously been quantified, resulting in an underappreciated burden of disease. We aimed to estimate the prevalence of PH in post-TB and active TB populations., Methods: In this systematic review and meta-analysis, we searched PubMed/Medline, Cochrane Library, EBSCOhost, Scopus, African Journals Online and Google Scholar, with no language restriction, for available literature published after 1950. Eligible studies described adult participants (≥16 years), with documented evidence of active or prior TB, diagnosed with PH. Study quality was assessed using a risk of bias tool specifically developed for prevalence studies. Aggregate prevalence estimates with 95% confidence intervals were synthesised using a random-effects meta-analysis model, incorporating the Freeman-Tukey transformation. Subgroup analysis was conducted to ascertain prevalence estimates in specific patient populations., Results: We identified 1452 unique records, of which 34 met our inclusion criteria. 23 studies, with an acceptable risk of bias and where PH was diagnosed at right heart catheterisation or echocardiography, were included in the meta-analysis. In post-TB studies (14/23), the prevalence of PH was 67.0% (95% CI 50.8-81.4) in patients with chronic respiratory failure, 42.4% (95% CI 31.3-54.0) in hospitalised or symptomatic patients and 6.3% (95% CI 2.3-11.8) in nonhealthcare-seeking outpatients (I 2 =96%). There was a lower estimated prevalence of PH in studies of populations with active TB (9.4%, 95% CI 6.3-13.0), I 2 =84%)., Conclusion: Our results highlight the significant burden of PH in post-TB and active TB populations. We emphasise the need for increased recognition of TB-associated PH and additional high-quality prevalence data., Competing Interests: Conflicts of interest: None to declare., (Copyright ©The authors 2024.)

Background: Sexually transmitted infections are among the most commonly occurring infections globally, with countries in sub-Saharan Africa exhibiting disproportionately higher prevalence rates. Numerous reports indicate the need for accurate detection, epidemiological characterisation, and appropriate management of these infections. This prospective observational laboratory study sought to determine the occurrence of STI, using a validated molecular assay as a diagnostic and surveillance tool in our setting., Methods: Urogenital swabs from symptomatic and asymptomatic patients, submitted to the National Health Laboratory Service, at Groote Schuur Hospital, from 04 August 2021-03 February 2022, for routine microbiological investigations, were subjected to the Allplex™ STI Essential Assay (Seegene Inc, South Korea) to determine the distribution of STI pathogens in our setting. This multiplex assay includes C. trachomatis, Mycoplasma genitalium, Mycoplasma hominis, N. gonorrhoeae, Trichomonas vaginalis, Ureaplasma parvum, and Ureaplasma urealyticum. Correlations between detected organisms and participant age and clinical indications for testing were determined using Stata® software., Results: A total of 148 urogenital swabs (91.2% from women) were included in the analysis, of which 56/148 (37.84%) were from symptomatic patients. Up to 83.8% of the samples tested positive for ≥1 organism, with all seven target organisms detected in at least one sample. Ureaplasma parvum was the most common organism detected, followed by N. gonorrhoeae, M. hominis, U. urealyticum, T. vaginalis, C. trachomatis, with M. genitalium being the least detected. All 25 samples submitted for routine antenatal Group B Streptococcal screening were positive for at least one STI organism, and one sample from sexual non-accidental injury tested positive for five different organisms., Conclusions: STIs comprise a variety of organisms in our setting, with many patients exhibiting coinfection with multiple organisms. This suggests the need for a critical evaluation of current syndromic testing and treatment guidelines so as to stem inadvertent spread of STI organisms and the development of resistance. The use of molecular testing methods may improve detection, especially in resource limited settings, providing speedy results, and thus allowing for guided therapy in only infected patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Moodley 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.)

Primary prevention of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) encompasses the timely diagnosis and adequate treatment of the superficial group A Streptococcus (GAS) infections pharyngitis and impetigo. GAS is the only known inciting agent in the pathophysiology of the disease. However, sufficient evidence indicates that the uptake and delivery of primary prevention approaches in RHD-endemic regions are significantly suboptimal. This report presents expert deliberations on priority research and implementation opportunities for primary prevention of ARF/RHD that were developed as part of a workshop convened by the US National Heart, Lung, and Blood Institute in November 2021. The opportunities identified by the Primary Prevention Working Group encompass epidemiological, laboratory, clinical, implementation and dissemination research domains and are anchored on five pillars including: (A) to gain a better understanding of superficial GAS infection epidemiology to guide programmes and policies; (B) to improve diagnosis of superficial GAS infections in RHD endemic settings; (C) to develop scalable and sustainable models for delivery of primary prevention; (D) to understand potential downstream effects of the scale-up of primary prevention and (E) to develop and conduct economic evaluations of primary prevention strategies in RHD endemic settings. In view of the multisectoral stakeholders in primary prevention strategies, we emphasise the need for community co-design and government engagement, especially in the implementation and dissemination research arena. We present these opportunities as a reference point for research organisations and sponsors who aim to contribute to the increasing momentum towards the global control and prevention of RHD., Competing Interests: Competing interests: ABeaton, AS, CSY and NS received funding support from the National Institutes of Health. ABeaton, AS and MEE received funding support from American Heart Association. ABeaton received funding support from Leducq Foundation, Edwards Lifesciences—Every Heartbeat Matters, The Philips Foundation and Thrasher Pediatric Research Fund. CSY received consultation fees from the WHO. JD received consulting fees from Variation Biotechnology. MEE received funding support from South African Research Council. ABowen receives funding support from the National Health and Medical Research Council of Australia., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Polygenic risk scores (PRS) identify at-risk individuals for many common diseases. A discussion of strengths and limitations is carried out in this review. PRS complement traditional genetic testing and have shown utility in establishing a proper diagnosis and guiding primary and secondary prevention. Some individuals with high PRS have risks similar to those with monogenic predisposition. Limitations include potential misinterpretations, problems with application across ancestries, and limited usefulness in low-heritability traits. Despite its shortcomings PRS are predicted to play major roles in the future of personal medicine and genetic testing., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Retrospective studies on artificial intelligence (AI) in screening for diabetic retinopathy (DR) have shown promising results in addressing the mismatch between the capacity to implement DR screening and increasing DR incidence. This review sought to evaluate the diagnostic test accuracy (DTA) of AI in screening for referable diabetic retinopathy (RDR) in real-world settings. We searched CENTRAL, PubMed, CINAHL, Scopus, and Web of Science on 9 February 2023. We included prospective DTA studies assessing AI against trained human graders (HGs) in screening for RDR in patients with diabetes. Two reviewers independently extracted data and assessed methodological quality against QUADAS-2 criteria. We used the hierarchical summary receiver operating characteristics (HSROC) model to pool estimates of sensitivity and specificity and, forest plots and SROC plots to visually examine heterogeneity in accuracy estimates. From our initial search results of 3899 studies, we included 15 studies comprising 17 datasets. Meta-analyses revealed a sensitivity of 95.33% (95%CI: 90.60-100%) and specificity of 92.01% (95%CI: 87.61-96.42%) for patient-level analysis (10 datasets, N = 45,785) while, for the eye-level analysis, sensitivity was 91.24% (95%CI: 79.15-100%) and specificity, 93.90% (95%CI: 90.63-97.16%) (7 datasets, N = 15,390). Subgroup analyses did not provide variations in the diagnostic accuracy of country classification and DR classification criteria. However, a moderate increase was observed in diagnostic accuracy in the primary-level healthcare settings: sensitivity of 99.35% (95%CI: 96.85-100%), specificity of 93.72% (95%CI: 88.83-98.61%) and, a minimal decrease in the tertiary-level healthcare settings: sensitivity of 94.71% (95%CI: 89.00-100%), specificity of 90.88% (95%CI: 83.22-98.53%). Sensitivity analyses did not show any variations in studies that included diabetic macular edema in the RDR definition, nor studies with ≥3 HGs. This review provides evidence, for the first time from prospective studies, for the effectiveness of AI in screening for RDR in real-world settings. The results may serve to strengthen existing guidelines to improve current practices., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Uy 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.)

There is limited information on the human immune response following infection with group A Streptococcus (Strep A). Animal studies have shown, in addition to the M protein, that shared Strep A antigens elicit protective immunity. This study aimed to investigate the kinetics of antibody responses against a panel of Strep A antigens in a cohort of school-aged children in Cape Town, South Africa. Participants provided serial throat cultures and serum samples at two-monthly follow-up visits. Strep A recovered were emm -typed, and serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) to assess immune responses to thirty-five Strep A antigens (10-shared and 25-M peptides). Serologic evaluations were performed on serial serum samples from 42 selected participants (from 256 enrolled) based on the number of follow-up visits, the frequency of visits, and throat culture results. Among these, there were 44 Strep A acquisitions, 36 of which were successfully emm -typed. Participants were grouped into three clinical event groups based on culture results and immune responses. A preceding infection was most convincingly represented by a Strep A-positive culture with an immune response to at least one shared antigen and M peptide (11 events) or a Strep A-negative culture with antibody responses to shared antigens and M peptides (9 events). More than a third of participants demonstrated no immune response despite a positive culture. This study provided important information regarding the complexity and variability of human immune responses following pharyngeal acquisition of Strep A, as well as demonstrating the immunogenicity of Strep A antigens currently under consideration as potential vaccine candidates. IMPORTANCE There is currently limited information regarding the human immune response to group A streptococcal throat infection. An understanding of the kinetics and specificity of antibody responses against a panel of Group A Streptococcus (GAS) antigens will serve to refine diagnostic approaches and contribute to vaccine efforts, which together will serve to reduce the burden of rheumatic heart disease, a major source of morbidity and mortality especially in the developing world. This study, utilizing an antibody-specific assay, uncovered three patterns of response profiles following GAS infection, among 256 children presenting with sore throat to local clinics. Overall, the response profiles were complex and variable. Of note, a preceding infection was most convincingly represented by a GAS-positive culture with an immune response to at least one shared antigen and M peptide. Also, more than a third of participants demonstrated no immune response despite a positive culture. All antigens tested were immunogenic, providing guidance for future vaccine development., Competing Interests: The authors declare a conflict of interest. James B. Dale is the inventor of certain technologies related to the development of group A streptococcal vaccines. The intellectual property is held by the University of Tennessee Research Foundation.

Introduction: Rheumatic heart disease (RHD) is responsible for a significant burden of cardiovascular morbidity and mortality, and remains the most common cause of acquired heart disease among children and young adults in low-income and middle-income countries. Additionally, the global COVID-19 pandemic has forced the emergency restructuring of many health systems, which has had a broad impact on health in general, including cardiovascular disease. Despite significant cost to the health system and estimates from 2015 indicating both high incidence and prevalence of RHD in South Africa, no cohesive national strategy exists. An updated review of national burden of disease estimates, as well as literature on barriers to care for patients with RHD, will provide crucial information to assist in the development of a national RHD programme., Methods and Analysis: Using predefined search terms that capture relevant disease processes from Group A Streptococcal (GAS) infection through to the sequelae of RHD, a search of PubMed, Scopus, ISI Web of Science, Sabinet African Journals, SA Heart and Current and Completed Research databases will be performed. All eligible studies on RHD, acute rheumatic fever and GAS infection published from April 2014 to December 2022 will be included. Vital registration data for the same period from Statistics South Africa will also be collected. A standardised data extraction form will be used to capture results for both quantitative and qualitative analyses. All studies included in burden of disease estimates will undergo quality assessment using standardised tools. Updated estimates on mortality and morbidity as well as a synthesis of work on primary, secondary and tertiary prevention of RHD will be reported., Ethics and Dissemination: No ethics clearance is required for this study. Findings will be disseminated in a peer-reviewed journal and submitted to national stakeholders in RHD., Prospero Registration Number: CRD42023392782., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries., Methods: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway., Results: Participants were enrolled into RHDGen between December 2012 and March 2018. For GWAS, 2548 RHD cases and 2261 controls (3301 women [69%]; mean age [SD], 37 [16.3] years) were available. RHD cases were predominantly Black (66%), Admixed (24%), and other ethnicities (10%). Among RHD cases, 34% were asymptomatic, 26% had prior valve surgery, and 23% had atrial fibrillation. The trio family replication arm included 116 RHD trio probands and 232 parents., Conclusions: RHDGen presents a rare opportunity to identify relevant patterns of genetic factors and biomarkers in Africans that may be associated with differential RHD risk. Furthermore, the RHDGen Network provides a platform for further work on fully elucidating the causes and mechanisms associated with RHD susceptibility and development.

Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1's demethylase and scaffolding functions during embryogenesis are not known. Here, we analyze two independent zebrafish lsd1/kdm1a mutant lines and show Lsd1 is required to repress primitive hematopoietic stem cell gene expression. Lsd1 rescue constructs containing point mutations that selectively abrogate its demethylase or scaffolding capacity demonstrate the scaffolding function of Lsd1, not its demethylase activity, is required for repression of gene expression in vivo . Lsd1's SNAG-binding domain mediates its scaffolding function and reinforces a negative feedback loop to repress the expression of SNAG-domain-containing genes during embryogenesis, including gfi1 and snai1/2 . Our findings reveal a model in which the SNAG-binding and scaffolding function of Lsd1, and its associated negative feedback loop, provide transient and reversible regulation of gene expression during hematopoietic development., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Author(s).)

Background: COVID-19 has proven to be challenging to manage for many reasons, including its high infection rate. One of the potential ways to limit its spread is by limiting international travel. The objective of this systematic review was to identify, critically appraise and summarise evidence on international air travel-related control measures for COVID-19., Methods: This review is based on the Cochrane review: International travel-related control measures to contain the COVID-19 pandemic and followed the same methods. In brief, we searched for clinical and modelling studies in general health and COVID-19-specific bibliographic databases. The primary outcome categories were (i) cases avoided, (ii) a shift in epidemic development and, (iii) cases detected., Results: From 6,202 citations identified by the search strategy, we included 22 new studies (modelling = 9, observational = 13) in addition to the 62 studies identified in the Cochrane review. Studies suggest that quarantine or microbial detection or a combination may avoid further cases. Similarly, these interventions may produce a positive shift in epidemic development and case detection may improve. Most studies were evaluated as having a moderate to critical risk of bias. The studies did not change the main conclusions of the Cochrane review nor the quality of the evidence (very low certainty); however, they added to the evidence base for most outcomes., Conclusions: Weak evidence supports the use of international air travel-related control measures to limit the spread of COVID-19 via air travel. More real-world studies are required to support these conclusions., (© 2022 The Authors.)

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Invasive group A streptococcal (Strep A) infections occur when Streptococcus pyogenes , also known as beta-hemolytic group A Streptococcus , invades a normally sterile site in the body. This article provides guidelines for establishing surveillance for invasive Strep A infections. The primary objective of invasive Strep A surveillance is to monitor trends in rates of infection and determine the demographic and clinical characteristics of patients with laboratory-confirmed invasive Strep A infection, the age- and sex-specific incidence in the population of a defined geographic area, trends in risk factors, and the mortality rates and rates of nonfatal sequelae caused by invasive Strep A infections. This article includes clinical descriptions followed by case definitions, based on clinical and laboratory evidence, and case classifications (confirmed or probable, if applicable) for invasive Strep A infections and for 3 Strep A syndromes: streptococcal toxic shock syndrome, necrotizing fasciitis, and pregnancy-associated Strep A infection. Considerations of the type of surveillance are also presented, noting that most people who have invasive Strep A infections will present to hospital and that invasive Strep A is a notifiable disease in some countries. Minimal surveillance necessary for invasive Strep A infection is facility-based, passive surveillance. A resource-intensive but more informative approach is active case finding of laboratory-confirmed Strep A invasive infections among a large (eg, state-wide) and well defined population. Participant eligibility, surveillance population, and additional surveillance components such as the use of International Classification of Disease diagnosis codes, follow-up, period of surveillance, seasonality, and sample size are discussed. Finally, the core data elements to be collected on case report forms are presented., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aims: Peripartum cardiomyopathy (PPCM) remains a major contributor to maternal morbidity and mortality worldwide. The disease is associated with various complications occurring mainly early during its course. Reported adverse outcomes include decompensated heart failure, thromboembolic complications, arrhythmias and death. We sought to systematically and comprehensively review published literature on the management and outcome of women with PPCM across different geographical regions and to identify possible predictors of adverse outcomes., Methods and Results: We performed a comprehensive search of relevant literature (2000 to June 2021) across a number of electronic databases. Cohort, case-control and cross-sectional studies, as well as control arms of randomized controlled trials reporting on 6- and/or 12-month outcomes of PPCM were considered eligible (PROSPERO registration: CRD42021255654). Forty-seven studies (4875 patients across 60 countries) met the inclusion criteria. Haemodynamic and echocardiographic parameters were similar across all continents. All-cause mortality was 8.0% (95% confidence interval [CI] 5.5-10.8, I 2  = 79.1%) at 6 months and 9.8% (95% CI 6.2-14.0, I 2  = 80.5%) at 12 months. All-cause mortality was highest in Africa and Asia/Pacific. Overall, 44.1% (95% CI 36.1-52.2, I 2  = 91.7%) of patients recovered their left ventricular (LV) function within 6 months and 58.7% (95% CI 48.1-68.9, I 2  = 75.8%) within 12 months. Europe and North America reported the highest prevalence of LV recovery. Frequent prescription of beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and bromocriptine/cabergoline were associated with significantly lower all-cause mortality and better LV recovery., Conclusion: We identified significant global differences in 6- and 12-month outcomes in women with PPCM. Frequent prescription of guideline-directed heart failure therapy was associated with better LV recovery and lower all-cause mortality. Timely initiation and up-titration of heart failure therapy should therefore be strongly encouraged to improve outcome in PPCM., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Integrase strand transfer inhibitors (InSTIs) decrease HIV plasma viral load faster than other antiretroviral classes. More rapid viral load decline has been associated with higher risk of immune reconstitution inflammatory syndrome (IRIS). There are conflicting reports on the association between InSTI and IRIS. We performed a systematic review and meta-analysis to compare the risk of IRIS among treatment-naive HIV-positive patients starting InSTI versus non-InSTI regimens., Methods: We searched PubMed, Scopus, Web of Science, Africa-Wide, and Cochrane databases from earliest available date to 26 November 2021, for randomized controlled trials (RCTs) having intervention arms with InSTI versus control arms without InSTI in patients initiating first-line antiretroviral therapy. The primary outcome was relative risk (RR) of IRIS, whereas the secondary outcome was RR of paradoxical tuberculosis-associated IRIS (TB-IRIS). Data were combined by random-effects meta-analysis according to the Mantel-Haenszel method. The protocol for this study is registered with PROSPERO, CRD42020213976., Results: We included 14 RCTs comprising 8696 participants from 6 continents for the primary outcome of IRIS and a subset of 674 participants (from 3 RCTs) for the secondary outcome of paradoxical TB-IRIS. Risk of IRIS was similar between InSTI and non-InSTI regimens (RR, 0.93; 95% confidence interval: 0.75 to 1.14). There was a trend towards a lower risk of paradoxical TB-IRIS with InSTI versus efavirenz regimens that was not statistically significant (RR, 0.64; 95% confidence interval: 0.34 to 1.19)., Conclusions: In this meta-analysis among treatment-naive patients commencing first-line antiretroviral therapy, InSTI regimens were not associated with higher risk of IRIS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Growth factor independence-1 (GFI1) is a transcriptional repressor and master regulator of normal and malignant hematopoiesis. Repression by GFI1 is attributable to recruitment of LSD1-containing protein complexes via its SNAG domain. However, the full complement of GFI1 partners in transcriptional control is not known. We show that in T-acute lymphoblastic leukemia (ALL) cells, GFI1 and IKAROS are transcriptional partners that co-occupy regulatory regions of hallmark T-cell development genes. Transcriptional profiling reveals a subset of genes directly transactivated through the GFI1-IKAROS partnership. Among these is NOTCH3, a key factor in T-ALL pathogenesis. Surprisingly, NOTCH3 expression by GFI1 and IKAROS requires the GFI1 SNAG domain but occurs independent of SNAG-LSD1 binding. GFI1 variants deficient in LSD1 binding fail to activate NOTCH3, but conversely, small molecules that disrupt the SNAG-LSD1 interaction while leaving the SNAG primary structure intact stimulate NOTCH3 expression. These results identify a noncanonical transcriptional control mechanism in T-ALL which supports GFI1-mediated transactivation in partnership with IKAROS and suggest competition between LSD1-containing repressive complexes and others favoring transactivation., Implications: Combinatorial diversity and cooperation between DNA binding proteins and complexes assembled by them can direct context-dependent transcriptional outputs to control cell fate and may offer new insights for therapeutic targeting in cancer., (©2022 American Association for Cancer Research.)

Background: Rheumatic heart disease (RHD) remains a major source of morbidity and mortality in developing countries. A deeper insight into the pathogenetic mechanisms underlying RHD could provide opportunities for drug repurposing, guide recommendations for secondary penicillin prophylaxis, and/or inform development of near-patient diagnostics., Methods: We performed quantitative proteomics using Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectrometry (SWATH-MS) to screen protein expression in 215 African patients with severe RHD, and 230 controls. We applied a machine learning (ML) approach to feature selection among the 366 proteins quantifiable in at least 40% of samples, using the Boruta wrapper algorithm. The case-control differences and contribution to Area Under the Receiver Operating Curve (AUC) for each of the 56 proteins identified by the Boruta algorithm were calculated by Logistic Regression adjusted for age, sex and BMI. Biological pathways and functions enriched for proteins were identified using ClueGo pathway analyses., Results: Adiponectin, complement component C7 and fibulin-1, a component of heart valve matrix, were significantly higher in cases when compared with controls. Ficolin-3, a protein with calcium-independent lectin activity that activates the complement pathway, was lower in cases than controls. The top six biomarkers from the Boruta analyses conferred an AUC of 0.90 indicating excellent discriminatory capacity between RHD cases and controls., Conclusions: These results support the presence of an ongoing inflammatory response in RHD, at a time when severe valve disease has developed, and distant from previous episodes of acute rheumatic fever. This biomarker signature could have potential utility in recognizing different degrees of ongoing inflammation in RHD patients, which may, in turn, be related to prognostic severity., (© 2022. The Author(s).)

Introduction: Peripartum cardiomyopathy (PPCM) remains a major contributor to maternal morbidity and mortality worldwide. The disease is associated with various complications, which occur predominantly during the early stages of the disease. Adverse outcomes include decompensated heart failure, thromboembolic complications, arrhythmias and death. We present a protocol for a systematic review and meta-analysis to summarise the available data on the complications and outcomes of women with PPCM., Methods and Analysis: A comprehensive search of all articles published between 2000 (the year in which the first universal definition of PPCM was used) and 1 June 2021 will be performed on PubMed/MEDLINE, Web of Science, Scopus and EBSCO Host, including Academic Search Premier, Africa-Wide Information, Cumulative Index to Nursing and Allied Health Literature. All cohort and cross-sectional studies, as well as control arms of randomised control trials (RCTs) reporting on the complications and outcomes of PPCM will be included in the review. Methodological quality assessment of included studies will be done by assessing the risk of bias. Heterogeneity of the data will be tested by visual inspection of the forest plot and I 2 and χ 2 tests. This study will report the burden of complications occurring around the time of diagnosis as well as the 6-month or 12-month outcomes of women with PPCM. A summarised description in form of a pooled analysis of across multiple centres, regions and continents would help us to better understand the estimates of complications and outcomes of women with PPCM., Ethics and Dissemination: As this research is a systematic review of published literature, ethical approval is not required. The results will be reported according to the latest guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement, and will be submitted to a peer-reviewed journal., Prospero Registration Number: CRD42021255654., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations., Objective: To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death., Design, Setting, and Participants: This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021., Exposures: Focal 22q11.22 deletions., Main Outcomes and Measures: Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VPREB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040)., Results: This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05)., Conclusions and Relevance: This cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.

Competing Interests: I declare no competing interests.

Importance: Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD., Objective: To identify common genetic loci associated with RHD susceptibility in Black African individuals., Design, Setting, and Participants: This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021., Main Outcomes and Measures: Genetic associations with RHD., Results: This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10-8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10-3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10-5) in Black African individuals., Conclusions and Relevance: This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.

Various samples of the Eastern oyster, Crassostrea virginica, were collected from five harvest bay areas in the Gulf of Mexico coastal waters of Florida (FL), Louisiana (LA) and Texas (TX). Cadmium and lead concentrations from the extracted whole-body soft tissues were analyzed by inductively coupled plasma-mass spectrometry (ICP-MS), and bulk δ13C and δ15N isotope ratios and amino-acid-specific δ13C values were analyzed via isotope ratio mass-spectrometry (IRMS). The combined data was subjected to multivariate statistical analysis to assess whether oysters could be linked to their harvest area. Results indicate that discriminant analysis using the δ13C values of five amino acids-serine, glycine, valine, lysine and phenylalanine-could discriminate oysters from two adjacent harvesting in Florida with 90% success rate, using leave-one-out cross validation. The combination of trace elements and isotope ratios could also predict geographic provenance of oysters with a success rate superior to the isolated use of each technique. The combinatory approach proposed in this study is a proof-of-concept that compound specific stable isotope analysis is a potential tool for oyster fisheries managers, wildlife, and food safety enforcement officers, as well as to forensics and ecology research areas, although significantly more work would need to be completed to fully validate the approach and achieve more reliable statistical results.

Introduction: Human papillomavirus (HPV) is an established risk factor for oropharyngeal squamous cell carcinoma, regardless of a history of other known risk factors such as alcohol and tobacco. While cases of HPV-related oral squamous cell carcinoma (OSSC) are increasing in the USA, Europe and South Central Asian countries, little is known about the impact of the disease on the African continent., Methods and Analysis: We describe a protocol for a systematic review to synthesise the best current evidence to assess the disease burden in Africa. Electronic databases including EBSCOhost, MEDLINE, CINAHL, ACADEMIC SEARCH COMPLETE, ScienceDirect, Web of Science, Scopus, SciCENTRAL, Cochrane Library, International Prospective Register of Systematic Reviews) and WorldCAT will be comprehensively searched for studies reporting on the defined outcomes, in Africa, published from 1985 (when HPV was first reported) to the latest current entries, with no language restriction. Supplemental handsearching of grey literature, conference abstract proceedings, reference lists of included studies and citations in Google Scholar will be conducted. Authors will be contacted, where necessary, to assist with missing data. A customised data extraction form, with specified criteria, will be used for data extraction. Overall study quality assessment will be done using an appropriate risk of bias tool suited to the study design. Where available, qualitative data from studies reporting on the outcomes will be captured on the data extraction form. Using Stata software, we will apply the random-effects meta-analysis model to aggregate prevalence estimates with 95% CI, incorporating the Freeman-Tukey transformation to account for between-study variability. A narrative report of the findings will be presented where data are insufficient in terms of the outcome/s. Subgroup analysis will be done subject to sufficient available data., Ethics and Dissemination: Ethics approval or written consent is not required as the review will be conducted using published data. The findings will be distributed through a peer-review publication and conference presentation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Group A Streptococcus (Strep A) is an important cause of mortality and morbidity globally. This bacterium is responsible for a range of different infections and post-infectious sequelae. Summarising the current knowledge of Strep A transmission to humans will address gaps in the evidence and inform prevention and control strategies. The objective of this study is to evaluate the modes of transmission and attack rates of group A streptococcal infection in human populations., Methods: This systematic review protocol was prepared according to the Preferred Reporting Items for Systematic reviews and Meta-analysis Protocols (PRISMA-P) 2015 Statement. Using a comprehensive search strategy to identify any transmission studies that have been published in English since 1980, full-text articles will be identified and considered for inclusion against predefined criteria. We will include all studies reporting on Strep A transmission, who have identified a mode of transmission, and who reported attack rates. Risk of bias will be appraised using an appropriate tool. Our results will be described narratively and where feasible and appropriate, a meta-analysis utilizing the random-effects model will be used to aggregate the incidence proportions (attack rates) for each mode of transmission. In addition, we will also evaluate the emm genotype variants of the M protein causing Strep A infection and the association with transmission routes and attack rates, if any, by setting, socioeconomic background and geographical regions., Discussion: We anticipate that this review will contribute to elucidating Strep A modes of transmission which in turn, will serve to inform evidence-based strategies including environmental health activities to reduce the transmission of Strep A in populations at risk of severe disease., Trial Registration: Systematic review registration: PROSPERO ( CRD42019138472 ).

The collapse of the Fundão Dam, in Southeastern Brazil, caused about 50 million m³ of iron ore tailings to sluice down the mountain to Rio Doce, in what is considered the greatest environmental disaster in Brazilian history. The fluvial system received an intense and sudden mudflow that was transported for more than 650 km, before reaching the Atlantic Ocean. Because the area was already impacted by the mineral activities in the region, it becomes essential to evaluate the environmental conditions before the disaster to correctly assess the disaster real damage. This study compares the concentration of trace metals in the sediments of the Rio Doce alluvial plain, before and after the dam collapse, as well as the newly deposited iron ore tailings that became part of the sedimentary framework. The data indicate that the fine particles deposited have since been incorporated into the sandy river sediments. The cadmium and arsenic contents in the sediments increased to levels above the National Environment Council thresholds. The comparison between the levels of trace metals in the situations before and after disaster shows that the mining mud is the source of cadmium while the arsenic was present before the environmental disaster, and its concentration increased due to sediment remobilization. The iron ore tailings deposited on the alluvial sediments also affected the physical parameters since the formed ferruginous crusts waterproofed the ground surface and may, gradually, release toxic metals when exposed to weathering and river reworking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Group A streptococcal (GAS) pharyngitis has traditionally been considered the sole precursor of acute rheumatic fever (ARF). Evidence from Australia, however, suggests that GAS skin infections may contribute to the pathogenesis of ARF. A missing piece of evidence is the incidence of sore throat and GAS pharyngitis in this setting. We conducted a systematic review and meta-analysis of the incidence of sore throat and GAS pharyngitis in all children at risk of developing ARF., Methods: Databases were systematically searched for studies reporting on the incidence of pharyngitis among children from low to upper-middle income countries, and Indigenous children living in high-income countries. Studies were subjected to data extraction by two independent reviewers. Following an assessment of the methodological quality of the studies, we extracted incidence rates (IRs) and conducted a meta-analysis. This systematic review is registered on PROSPERO (CRD42019113019)., Results: From 607 titles identified by the search, 11 articles met the predetermined inclusion criteria; ten studies reported IRs while for the remaining study, the incidence was calculated. The pooled incidence estimated for sore throat was 82.5 per 100 child-years (95% confidence interval [CI], 6.5 to 1044.4 per 100 child-years, I2 = 100%) and GAS pharyngitis was 10.8 per 100 child-years (95% CI, 2.3 to 50.0 per 100 child-years, I2 = 99.9%)., Conclusions: The pooled IRs for sore throat in children at risk of developing ARF were higher than rates reported in developed nations (32.70-40 per 100 child-years) and similar for GAS pharyngitis (12.8-14 per 100 years). The limited Australian data lend support to the need for further studies to inform the role of GAS pharyngitis in the development of ARF in Australian Indigenous children, so as to inform local primary prevention strategies for ARF and Rheumatic Heart Disease (RHD)., Competing Interests: The authors have declared that no competing interest exists.

Objective: To summarise the accuracy of handheld echocardiography (HAND) which, if shown to be sufficiently similar to that of standard echocardiography (STAND), could usher in a new age of rheumatic heart disease (RHD) screening in endemic areas., Design: Systematic review and meta-analysis., Data Sources: PubMed, Scopus, EBSCOHost and ISI Web of Science were initially searched on 27 September 2017 and again on 3 March 2020 for studies published from 2012 onwards., Eligibility Criteria: Studies assessing the accuracy of HAND compared with STAND when performed by an experienced cardiologist in conjunction with the 2012 World Heart Federation criteria among populations of children and adolescents living in endemic areas were included., Data Extraction and Synthesis: Two reviewers independently extracted data and assessed the methodological quality of included studies against review-specific Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 criteria. A meta-analysis using the hierarchical summary receiver operating characteristic model was conducted to produce summary results of sensitivity and specificity. Forest plots and scatter plots in receiver operating characteristic space in combination with subgroup analyses were used to investigate heterogeneity. Publication bias was not investigated., Results: Six studies (N=4208) were included in the analysis. For any RHD detection, the pooled results from six studies were as follows: sensitivity: 81.56% (95% CI 76.52% to 86.61%) and specificity: 89.75% (84.48% to 95.01%). Meta-analytical results from five of the six included studies were as follows: sensitivity: 91.06% (80.46% to 100%) and specificity: 91.96% (85.57% to 98.36%) for the detection of definite RHD only and sensitivity: 62.01% (31.80% to 92.22%) and specificity: 82.33% (65.15% to 99.52%) for the detection of borderline RHD only., Conclusions: HAND displayed good accuracy for detecting definite RHD only and modest accuracy for detecting any RHD but demonstrated poor accuracy for the detection of borderline RHD alone. Findings from this review provide some evidence for the potential of HAND to increase access to echocardiographic screening for RHD in resource-limited and remote settings; however, further research into feasibility and cost-effectiveness of wide-scale screening is still needed., Prospero Registration Number: CRD42016051261., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: National and international political commitments have been made recently on rheumatic heart disease (RHD), a preventable heart condition that is endemic in low-resource countries. To inform best practice and identify evidence gaps, we assessed the effectiveness of RHD prevention and control programmes and the extent and nature of their integration into local health systems., Methods: We conducted a systematic review and meta-analysis using a previously published protocol that included electronic and manual searches for studies published between January 1990 and July 2019 reporting on prevention and control programmes for populations at risk for streptococcal pharyngitis, rheumatic fever, and/or RHD. We analysed programme integration according to a previously published framework and programme effectiveness using a results-chain framework. We meta-analysed secondary prophylaxis adherence using random-effects models. Study quality was assessed using peer-reviewed checklists (CASP and PRISM). PROSPERO registration: CRD42017076307., Findings: Five observational studies met with the inclusion criteria. Studies were similar in extent and nature of integration into health systems; no programme was completely integrated or non-integrated. A single study reported on programme impact. Secondary prophylaxis adherence improved among partially integrated RHD programmes (RR, 1.18 [95% CI, 1.03 to 1.36], 3 studies, n = 618). Risk of bias was low in two studies, and indeterminable in the remaining three studies., Interpretation: There is evidence that partially integrated RHD programmes are beneficial for a range of intermediate health outcomes. This review provides a starting point for the design and implementation of future RHD programmes by outlining current best practice for integration and identifying key gaps in knowledge., Funding: National Research Foundation of South Africa., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Background: An effective vaccine against Bordetella pertussis was introduced into the Expanded Programme on Immunisation (EPI) by WHO in 1974, leading to a substantial global reduction in pertussis morbidity and mortality. In low- and middle-income countries (LMICs), however, the epidemiology of pertussis remains largely unknown. This impacts negatively on pertussis control strategies in these countries. This study aimed to systematically and comprehensively review published literature on the burden of laboratory-confirmed pertussis in LMICs over the 45 years of EPI., Methods: Electronic databases were searched for relevant literature (1974 to December 2018) using common and MeSH terms for pertussis. Studies using PCR, culture or paired serology to confirm Bordetella pertussis and parapertussis in symptomatic individuals were included if they had clearly defined numerators and denominators to determine prevalence and mortality rates., Results: Eighty-two studies (49,167 participants) made the inclusion criteria. All six WHO regions were represented with most of the studies published after 2010 and involving mainly upper middle-income countries (n = 63; 77%). PCR was the main diagnostic test after the year 2000. The overall median point prevalence of PCR-confirmed Bordetella pertussis was 11% (interquartile range (IQR), 5-27%), while culture-confirmed was 3% (IQR 1-9%) and paired serology a median of 17% (IQR 3-23%) over the period. On average, culture underestimated prevalence by 85% (RR = 0.15, 95% CI, 0.10-0.22) compared to PCR in the same studies. Risk of pertussis increased with HIV exposure [RR, 1.4 (95% CI, 1.0-2.0)] and infection [RR, 2.4 (95% CI, 1.1-5.1)]. HIV infection and exposure were also related to higher pertussis incidences, higher rates of hospitalisation and pertussis-related deaths. Pertussis mortality and case fatality rates were 0.8% (95% CI, 0.4-1.4%) and 6.5% (95% CI, 4.0-9.5%), respectively. Most deaths occurred in infants less than 6 months of age., Conclusions: Despite the widespread use of pertussis vaccines, the prevalence of pertussis remains high in LMIC over the last three decades. There is a need to increase access to PCR-based diagnostic confirmation in order to improve surveillance. Disease control measures in LMICs must take into account the persistent significant infant mortality and increased disease burden associated with HIV infection and exposure.

An emm -cluster based system was proposed as a standard typing scheme to facilitate and enhance future studies of group A Streptococcus (GAS) epidemiological surveillance, M protein function, and vaccine development strategies. We provide an evidence-based distribution of GAS emm clusters in Africa and assess the potential coverage of the new 30-valent vaccine in terms of an emm cluster-based approach. Two reviewers independently assessed studies retrieved from a comprehensive search and extracted relevant data. Meta-analyses were performed (random-effects model) to aggregate emm cluster prevalence estimates. Eight studies ( n  = 1,595 isolates) revealed the predominant emm clusters as E6 (18%; 95% confidence interval [CI], 12.6% to 24.0%), followed by E3 (14%; 95% CI, 11.2% to 17.4%) and E4 (13%; 95% CI, 9.5% to 16.0%). There was negligible variation in emm clusters with regard to regions, age, and socioeconomic status across the continent. Considering an emm cluster-based vaccine strategy, which assumes cross-protection within clusters, the 30-valent vaccine currently in clinical development would provide hypothetical coverage to 80.3% of isolates in Africa. This systematic review indicates the most predominant GAS emm cluster in Africa is E6 followed by E3, E4, and D4. The current 30-valent vaccine would provide considerable coverage across the diversity of emm cluster types in Africa. Future efforts could be directed toward estimating the overall potential coverage of the new 30-valent vaccine based on cross-opsonization studies with representative panels of GAS isolates from populations at highest risk for GAS diseases. IMPORTANCE Low vaccine coverage is of grave public health concern, particularly in developing countries where epidemiological data are often absent. To inform vaccine development for group A Streptococcus (GAS), we report on the epidemiology of the M protein emm clusters from GAS infections in Africa, where GAS-related illnesses and their sequelae, including rheumatic fever and rheumatic heart disease, are of a high burden. This first report of emm clusters across the continent indicates a high probably of coverage by the M protein-based vaccine currently undergoing testing were an emm -cluster based approach to be used., (Copyright © 2020 Salie et al.)

Congenital heart disease (CHD) is the most common birth defect globally and coarctation of the aorta (CoA) is one of the commoner CHD conditions, affecting around 1/1800 live births. CoA is considered a CHD of critical severity. Unfortunately, the prognosis for a child born in a low and lower-middle income country (LLMICs) with CoA is far worse than in a high-income country. Reduced diagnostic and interventional capacities of specialists in these regions lead to delayed diagnosis and treatment, which in turn lead to more cases presenting at an advanced stage. Computational fluid dynamics (CFD) is an important tool in this context since it can provide additional diagnostic data in the form of hemodynamic parameters. It also provides an in silico framework, both to test potential procedures and to assess the risk of further complications arising post-repair. Although this concept is already in practice in high income countries, the clinical infrastructure in LLMICs can be sparse, and access to advanced imaging modalities such as phase contrast magnetic resonance imaging (PC-MRI) is limited, if not impossible. In this study, a pipeline was developed in conjunction with clinicians at the Red Cross War Memorial Children's Hospital, Cape Town and was applied to perform a patient-specific CFD study of CoA. The pipeline uses data acquired from CT angiography and Doppler transthoracic echocardiography (both much more clinically available than MRI in LLMICs), while segmentation is conducted via SimVascular and simulation is realized using OpenFOAM. The reduction in cost through use of open-source software and the use of broadly available imaging modalities makes the methodology clinically feasible and repeatable within resource-constrained environments. The project identifies the key role of Doppler echocardiography, despite its disadvantages, as an intrinsic component of the pipeline if it is to be used routinely in LLMICs., (Copyright © 2020 Swanson, Owen, Keshmiri, Deyranlou, Aldersley, Lawrenson, Human, De Decker, Fourie, Comitis, Engel, Keavney, Zühlke, Ngoepe and Revell.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

Objectives: Group A β-hemolytic Streptococcus (GAS), also known as Streptococcus pyogenes, is responsible for an annual 600 million cases of acute pharyngitis globally, with 92% of those infections occurring in low-resource settings. Further knowledge of the acute streptococcal pharyngitis burden in low-resource settings is essential if serious post-streptococcal complications - rheumatic fever (RF) and its long-term sequel rheumatic heart disease (RHD) - are to be prevented., Methods: Two studies were conducted in school-aged children (5-16 years): a cross-sectional study of streptococcal pharyngeal carriage followed by a prospective cohort study of streptococcal sore throat over 4 weeks from March to April 2017., Results: The cross-sectional study revealed an overall prevalence of GAS carriage of 15.9% (79/496, 95% confidence interval 12.8-19.5%). Among 532 children enrolled in the prospective cohort study, 358 (67%) reported 528 sore throats, with 221 (41.1%) experiencing at least one GAS-positive sore throat. The overall GAS-positive rate for sore throat was 41.8% (221/528)., Conclusions: The GAS pharyngeal carriage rates seen in Uganda (15.9%, 95% confidence interval 12.8-19.5%) are higher than the most recent pooled results globally, at 12% (range 6-28%). Additionally, pilot data suggest a substantially higher percentage of sore throat that was GAS-positive (41.8%) compared to pooled global rates when active recruitment is employed., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Genetic association studies in rheumatic heart disease (RHD) have the potential to contribute toward our understanding of the pathogenetic mechanism, and may shed light on controversies about RHD etiology. Furthermore, genetic association studies may uncover biomarkers that can be used to identify susceptible individuals, and contribute toward developing vaccine and novel therapeutic targets. Genetic predisposition to rheumatic fever and RHD has been hypothesized by findings from familial studies and observed associations between genes located in the human leukocyte antigens on chromosome 6p21.3 and elsewhere in the genome. We sought to summarize, from published Genetic association studies in RHD, evidence on genetic variants implicated in RHD susceptibility. Using HuGENet™ systematic review methods, we evaluated 66 studies reporting on 42 genes. Existing meta-analyses of candidate gene studies suggest that TGF-β1 [rs1800469], and IL-1β [rs2853550] single nucleotide polymorphisms (SNPs) contribute to susceptibility to RHD, whereas the TNF-α [rs1800629 and rs361525], TGF-β1 [rs1800470 and rs4803457], IL-6 [rs1800795], IL-10 [rs1800896] were not associated with RHD. However, candidate gene studies in RF/RHD are relatively small, thus lacking statistical power to identify reliable and reproducible findings, emphasizing the need for large-scale multicenter studies with different populations., (© 2020 Wiley Periodicals, Inc.)

Introduction: A common concern in African genomic research is that such work may cause, or increase, stigma associated with particular diseases or population groups. While there is some evidence suggesting that genetic attribution of disease might impact stigma, there exists no evidence for the situation in African populations. With increasing genomic research in African populations, questions about the effect of genetic attribution on disease-related stigma are salient for stakeholders involved in implementation and regulation. To understand better the relationship between stigma and genetic attribution, we interviewed people with Rheumatic Heart Disease (RHD) in the Western Cape of South Africa., Method: We conducted 11 focus group discussions with RHD patients of mixed-ancestry in the Western Cape, exploring the impact of genetic attribution on stigma. Participants had previously consented to participate in genomic research, attending information sessions on genetics. We explored the impact of genetic attribution by introducing both genetic and environmental causes to RHD and by specifically probing how these various causes would likely impact selected features of disease stigma., Results: Participants reported varying experiences of stigma relating to RHD, such as labelling, social exclusion and discrimination at the workplace. They had some understanding of genetics, either in general, or in relation to their illness. Participants' understanding depicted multiple causal models to explain RHD including genetic, environmental and bacterial causation. Overall, participants did not make a connection between genetics as a cause of RHD and their experiences of stigma., Discussion: In this study we found no support for the concern that genetic attribution of RHD, understood by participants in our study as a genetic predisposition to developing the disease, would impact stigma associated with it. Our findings provide some reassurance that genomic research may be unlikely to cause an increase in disease-related stigma in the South African context., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: It remains unclear whether computer-assisted instruction (CAI) is more effective than other teaching methods in acquiring and retaining ECG competence among medical students and residents., Design: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Data Sources: Electronic literature searches of PubMed, databases via EBSCOhost, Scopus, Web of Science, Google Scholar and grey literature were conducted on 28 November 2017. We subsequently reviewed the citation indexes for articles identified by the search., Eligibility Criteria: Studies were included if a comparative research design was used to evaluate the efficacy of CAI versus other methods of ECG instruction, as determined by the acquisition and/or retention of ECG competence of medical students and/or residents., Data Extraction and Synthesis: Two reviewers independently extracted data from all eligible studies and assessed the risk of bias. After duplicates were removed, 559 papers were screened. Thirteen studies met the eligibility criteria. Eight studies reported sufficient data to be included in the meta-analysis., Results: In all studies, CAI was compared with face-to-face ECG instruction. There was a wide range of computer-assisted and face-to-face teaching methods. Overall, the meta-analysis found no significant difference in acquired ECG competence between those who received computer-assisted or face-to-face instruction. However, subanalyses showed that CAI in a blended learning context was better than face-to-face teaching alone, especially if trainees had unlimited access to teaching materials and/or deliberate practice with feedback. There was no conclusive evidence that CAI was better than face-to-face teaching for longer-term retention of ECG competence., Conclusion: CAI was not better than face-to-face ECG teaching. However, this meta-analysis was constrained by significant heterogeneity amongst studies. Nevertheless, the finding that blended learning is more effective than face-to-face ECG teaching is important in the era of increased implementation of e-learning., Prospero Registration Number: CRD42017067054., Competing Interests: Competing interests: RSM is a lecturer and host of the AO Memorial Advanced ECG and Arrhythmia Course and receives an honorarium from Medtronic Africa., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Group A streptococcus (GAS) is responsible for a wide range of noninvasive group A streptococcal (non- i GAS) and invasive group A streptococcal ( i GAS) infections. Information about the emm type variants of the M protein causing GAS disease is important to assess potential vaccine coverage of a 30-valent vaccine under development, particularly with respect to how they compare and contrast with non -i GAS isolates, especially in regions with a high burden of GAS. We conducted a prospective passive surveillance study of samples from patients attending public health facilities in Cape Town, South Africa. We documented demographic data and clinical presentation. emm typing was conducted using CDC protocols. GAS was commonly isolated from pus swabs, blood, deep tissue, and aspirates. Clinical presentations included wound infections (20%), bacteremia (15%), abscesses (9%), and septic arthritis (8%). Forty-six different emm types were identified, including M76 (16%), M81 (10%), M80 (6%), M43 (6%), and M183 (6%), and the emm types were almost evenly distributed between non- i GAS and i GAS isolates. There was a statistically significant association with M80 in patients presenting with noninvasive abscesses. Compared to the 30-valent vaccine under development, the levels of potential vaccine coverage for non- i GAS and i GAS infection were 60% and 58%, respectively, notably lower than the coverage in developed countries; five of the most prevalent emm types, M76, M81, M80, M43, and M183, were not included. The emm types from GAS isolated from patients with invasive disease did not differ significantly from those from noninvasive disease cases. There is low coverage of the multivalent M protein vaccine in our setting, emphasizing the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high. IMPORTANCE The development of a vaccine for group A streptococcus (GAS) is of paramount importance given that GAS infections cause more than 500,000 deaths annually across the world. This prospective passive surveillance laboratory study evaluated the potential coverage of the M protein-based vaccine currently under development. While a number of GAS strains isolated from this sub-Sahara African study were included in the current vaccine formulation, we nevertheless report that potential vaccine coverage for GAS infection in our setting was approximately 60%, with four of the most prevalent strains not included. This research emphasizes the need to reformulate the vaccine to improve coverage in areas where the burden of disease is high., (Copyright © 2019 Barth et al.)

Background: Globally, rheumatic heart disease (RHD) is a major contributor to the burden of cardiovascular disease. Major gaps in RHD prevention and treatment have been documented at all levels of health systems in low- and middle-income countries. Task sharing is an approach that could prove effective in remediating bottlenecks in RHD-related care., Objectives: This study conducted a systematic review to assess the state of the evidence for the use of task sharing in the diagnosis, prevention, and management of RHD., Methods: Guided by a previously published protocol, we searched various databases using a systematic search strategy including MeSH and free-text terms for (1) group A streptococcus, acute rheumatic fever, and RHD and (2) strategies of task sharing in limited-resource settings. Two investigators independently screened the search outputs, selected the studies, extracted the data, and assessed the risk of bias, resolving discrepancies by discussion and consensus., Results: The publications search yielded 212 records, of which 18 articles were deemed as potentially eligible for inclusion. None of the studies, however, met with the inclusion criteria., Conclusions: There is a lack of evidence for the use of task-sharing approaches in scaling up RHD prevention and treatment services in limited-resource settings. Considering the persistent burden of group A streptococcus, acute rheumatic fever, and RHD in low- and middle-income countries, this work highlights the urgent need to develop and test models of RHD-related care utilizing an evidence-based approach to task sharing. [Task Sharing in the Diagnosis, Prevention, and Management of Rheumatic Heart Disease: A Systematic Review; CRD42017072989]., (Copyright © 2019 World Heart Federation (Geneva). Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to summarise the results from existing studies reporting on the effectiveness of the introduction of violence and injury observatories (VIOs)., Design: This is a systematic review and meta-analysis study., Data Sources: We searched multiple electronic databases including but not limited to PubMed, PsycINFO, SCOPUS, Cochrane Collaboration, Campbell Collaboration and Web of Knowledge., Eligibility Criteria: We included non-randomised controlled trials, quasi-experimental designs, prospective and retrospective cohort studies, controlled before-and-after studies and cross-sectional studies. We sought to include studies performed in any country and published in any language. The primary outcome was homicide, while the secondary outcome was assault., Data Extraction and Synthesis: We searched a number of databases, supplemented by searches in grey literature including technical reports. Searches comprised studies from January 1990 to October 2018., Results: Of 3105 potentially relevant unique citations from all literature searches, 3 empirical studies and 4 technical reports met our inclusion criteria. Studies were conducted in the UK (n=3), Colombia (n=2), Brazil (n=1) and Uruguay (n=1). Subgroup analyses according to the two types of models implemented, the VIO and the injury surveillance system (ISS), provided evidence for an association between implementing the VIO model and a reduction in homicide count in high-violence settings (incidence rate ratio (IRR)=0.06; 95% CI 0.02 to 0.19; four studies), while the introduction of ISS showed significant results in reducing assault (IRR=0.80; 95% CI 0.71 to 0.91; three studies)., Conclusion: This systematic review provides the best evidence available for the effectiveness of the introduction of VIOs and ISSs in reducing violence outcomes in adults in high-violence settings. The implementation of VIOs should be considered in high-violence communities where reduction in homicide rates is desired., Prospero Registration Number: CRD42014009818., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Rheumatic heart disease (RHD) is a preventable chronic condition affecting the valves of the heart. RHD prevention and care programmes have historically originated in more developed countries, implemented in a targeted (or vertical) manner and evaluated using non-controlled approaches. Taking a broad view of the integration of RHD activities within the whole system is critical for health planning in low-income regions with a high burden of RHD and less robust health systems. Therefore, we propose to conduct a systematic review to assess RHD programme models in order to gain a better understanding of the extent of integration within relevant health systems., Methods and Analysis: A predefined search strategy will be used to search for relevant articles published in English from January 1990 to December 2017. Electronic databases PubMed, Scopus, Web of Science, Africa Wide, CINAHL, Cochrane Central Register of Controlled Trials, Google Scholar and Global Index Medicus will be searched, as well as reference lists of relevant articles published. A standardised data extraction form will be used to obtain information for analysis from the included studies. The quality, reliability and risk of bias of included studies will be assessed using design-specific criteria. Programme integration will be analysed according to stewardship and governance, financing, planning, service delivery, monitoring and evaluation, and demand generation. Programme inputs, outputs and impact will also be described., Ethics and Dissemination: No ethical approval is required. Findings will be disseminated in a peer-review journal in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines., Prospero Registration Number: CRD42017076307., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)