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Rubeshan Perumal,1,2 Azraa Khan,1 Kogieleum Naidoo,1,2 Senamile L Ngema,1 Louansha Nandlal,1,2 Nesri Padayatchi,1,2 Navisha Dookie1,2 1Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu Natal, South Africa; 2South African Medical Research Council (SAMRC) – CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Durban, KwaZulu Natal, South AfricaCorrespondence: Rubeshan Perumal, Doris Duke Medical Research Institute (2nd Floor), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X7, Congella, Durban, 4013, South Africa, Tel +27 31 260 4555, Fax +27 31 260 4566, Email Rubeshan.perumal@caprisa.orgBackground: Understanding Mycobacterium tuberculosis (Mtb) intra-host evolution of drug resistance is important for successful drug-resistant tuberculosis (DR-TB) treatment and control strategies. This study aimed to characterise the acquisition of genetic mutations and low-frequency variants associated with treatment-emergent Mtb drug resistance in longitudinally profiled clinical isolates from patients who experienced DR-TB treatment failure.Patients and Methods: We performed deep Whole Genome Sequencing on 23 clinical isolates obtained longitudinally across nine timepoints from five patients who experienced DR-TB treatment failure enrolled in the CAPRISA 020 InDEX study. The minimum inhibitory concentrations (MICs) were established on the BACTEC™ MGIT 960™ instrument on 15/23 longitudinal clinical isolates for eight anti-TB drugs (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, linezolid, clofazimine, bedaquiline).Results: In total, 22 resistance associated mutations/variants were detected. We observed four treatment-emergent mutations in two out of the five patients. Emerging resistance to the fluoroquinolones was associated with 16- and 64-fold elevated levofloxacin (2– 8 mg/L) and moxifloxacin (1– 2 mg/L) MICs, respectively, resulting from the D94G/N and A90V variants in the gyrA gene. We identified two novel mutations associated with elevated bedaquiline MICs (> 66-fold): an emerging frameshift variant (D165) on the Rv0678 gene and R409Q variant on the Rv1979c gene present from baseline.Conclusion: Genotypic and phenotypic resistance to the fluoroquinolones and bedaquiline was acquired in two out of five patients who experienced DR-TB treatment failure. Deep sequencing of multiple longitudinal clinical isolates for resistance-associated mutations coupled with phenotypic MIC testing confirmed intra-host Mtb evolution.Keywords: tuberculosis, phenotypic resistance, drug resistance acquisition, whole genome sequencing, emerging mutations, bedaquiline

Post COVID-19 condition (PCC), as defined by WHO, refers to a wide range of new, returning, or ongoing health problems in people who have had COVID-19, and it represents a rapidly emerging public health priority. We aimed to establish how this developing condition has affected patients in South Africa and which population groups are at risk.In this prospective cohort study, we used the DATCOV national hospital surveillance system to identify participants aged 18 years or older who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection in South Africa. Participants underwent telephone follow-up assessment at 1 month and 3 months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life, and occupational status. We used negative binomial regression models to determine factors associated with PCC.Of 241 159 COVID-19 admissions reported to DATCOV between Dec 1, 2020, and Aug 23, 2021, 8309 were randomly selected for enrolment. Of the 3094 patients that we were able to contact, 2410 (77·9%) consented to participate in the study at 1 month after discharge. Of these, 1873 (77·7%) were followed up at 3 months after hospital discharge. Participants had a median age of 52 years (IQR 41-62) and 960 (51·3%) were women. At 3 months of follow-up, 1249 (66·7%) of 1873 participants reported new or persistent COVID-19-related symptoms, compared with 1978 (82·1%) of 2410 at 1 month after hospital discharge. The most common symptoms reported at 3 months were fatigue (50·3%), shortness of breath (23·4%), confusion or lack of concentration (17·5%), headaches (13·8%), and problems seeing or blurred vision (10·1%). On multivariable analysis, the factors associated with persistent symptoms after acute COVID-19 were being female (adjusted incident rate ratio 1·20, 95% CI 1·04-1·38) and admission to an intensive care unit (1·17, 1·01-1·37).Most participants in this cohort of individuals previously hospitalised with COVID-19 reported persistent symptoms 3 months after hospital discharge and a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health-care workers for identifying, assessing, and caring for patients affected by PCC; establishment of multidisciplinary health services; and provision of information and support to people who have PCC.BillMelinda Gates Foundation, UK Foreign, CommonwealthDevelopment Office, and Wellcome.

The recognition that drug-resistant tuberculosis (DR-TB) poses a major threat to global tuberculosis (TB) control efforts has catalysed the development of new and urgently needed TB diagnostics. The full beneficial impact of the subsequent flood of new TB diagnostic tests into the market can only be realised if these diagnostic tests are readily accessible to TB programs and contribute to improved patient outcomes. Although phenotypic drug-susceptibility testing remains the gold standard, an improved understanding of the relationship between mutations and different levels of drug resistance coupled with the advantages of molecular diagnostics could result in rapid molecular diagnostic tests replacing phenotypic drug-susceptibility testing. Successful diagnostics need to diagnose all forms of drug-resistant TB prevalent in each geographic region. Given the finite number and often limited availability of effective drugs for DR-TB, the diagnostic test must be able to detect all clinically important types of resistance to available anti-TB drugs. However, less comprehensive resistance profiling may be sufficient in settings where extensively drug-resistant TB (XDR-TB) and pre-XDR are absent. Rapid molecular diagnostic tests for DR-TB detection suitable for DR-TB endemic settings should be accurate, inexpensive, suitable to be performed on an easily accessible sample, detect prevalent circulating drug-resistant strains, and provide results within a short turnaround time to enable timely treatment initiation. In this review, we appraise the wide range of molecular diagnostics for DR-TB endorsed by the World Health Organisation, discuss the challenges in the development and rollout of rapid molecular DR-TB tests in low- and middle-income countries, and highlight user perspectives and cost-effectiveness factors that influence their utility.

The global tuberculosis burden remains substantial, with more than 10 million people newly ill per year. Nevertheless, tuberculosis incidence has slowly declined over the past decade, and mortality has decreased by almost a third in tandem. This positive trend was abruptly reversed by the COVID-19 pandemic, which in many parts of the world has resulted in a substantial reduction in tuberculosis testing and case notifications, with an associated increase in mortality, taking global tuberculosis control back by roughly 10 years. Here, we consider points of intersection between the tuberculosis and COVID-19 pandemics, identifying wide-ranging approaches that could be taken to reverse the devastating effects of COVID-19 on tuberculosis control. We review the impact of COVID-19 at the population level on tuberculosis case detection, morbidity and mortality, and the patient-level impact, including susceptibility to disease, clinical presentation, diagnosis, management, and prognosis. We propose strategies to reverse or mitigate the deleterious effects of COVID-19 and restore tuberculosis services. Finally, we highlight research priorities and major challenges and controversies that need to be addressed to restore and advance the global response to tuberculosis.

BackgroundClinical bedaquiline resistance predominantly involves mutations inmmpR5(Rv0678). However,mmpR5resistance-associated variants (RAVs) have a variable relationship with phenotypicM. tuberculosisresistance. We performed a systematic review to (1) assess the maximal sensitivity of sequencing bedaquiline resistance-associated genes and (2) evaluate the association between RAVs and phenotypic resistance, using traditional and machine-based learning techniques.MethodsWe screened public databases for articles published until October 2022. Eligible studies performed sequencing of at leastmmpR5andatpEon clinically-sourcedM. tuberculosisisolates and measured bedaquiline minimum inhibitory concentrations (MICs). We performed genetic analysis for identification of phenotypic resistance and determined the association of RAVs with resistance. Machine-based learning methods were employed to define test characteristics of optimised sets of RAVs, andmmpR5mutations were mapped to the protein structure to highlight mechanisms of resistance.ResultsEighteen eligible studies were identified, comprising 975M. tuberculosisisolates containing ≥1 potential RAV (mutation inmmpR5, atpE, atpBorpepQ), with 201 (20.6%) demonstrating phenotypic bedaquiline resistance. 84/285 (29.5%) resistant isolates had no candidate gene mutation. Sensitivity and positive predictive value of taking an ‘any mutation’ approach was 69% and 14% respectively. Thirteen mutations, all inmmpR5, had a significant association with a resistant MIC (adjusted pDiscussionSequencing candidate genes is insufficiently sensitive to diagnose clinical bedaquiline resistance, but where identified a limited number of mutations should be assumed to be associated with resistance. Genomic tools are most likely to be effective in combination with rapid phenotypic diagnostics.

Background Undiagnosed asymptomatic subclinical tuberculosis (TB) remains a significant threat to global TB control, accounting for a substantial proportion of cases among people living with human immunodeficiency virus (HIV)/AIDS (PLWHA). We determined incidence, progression, and outcomes of subclinical TB in antiretroviral therapy (ART)–accessing PLWHA with known previous TB in South Africa. Methods A total of 402 adult PLWHA previously treated for TB were enrolled in the prospective Centre for the AIDS Programme of Research in South Africa TRuTH (TB Recurrence Upon TB and HIV treatment) Study. Participants were screened for TB with quarterly clinical and bacteriologic evaluation and biannual chest radiographs over 36 months. Those with suspected or confirmed TB were referred to the National TB Programme. Participants received HIV services, including ART. Incidence rate of TB was estimated using Poisson regression and descriptive statistical analyses summarized data. Results A total of 48 of 402 (11.9%) bacteriologically confirmed incident recurrent TB cases were identified, comprising 17 of 48 (35.4%) subclinical TB cases and 31 of 48 (64.5%) clinical TB cases. Age, sex, and body mass index were similar among subclinical, clinical, and no TB groups. Incidence rates (95% Confidence Interval [CI]) of recurrent TB overall, in clinical and subclinical TB groups were 2.3 (1.7-3.0), 1.5 (1.1-2.2), and 0.9 (0.5-1.4) per 100 person-years, respectively. In the subclinical TB group, 14 of 17 (82.4%) were diagnosed by TB culture only, 11 of 17 (64.7%) received TB treatment, and 6 of 17 (35.3%) resolved TB spontaneously. Conclusions High incidence rates of recurrent subclinical TB in PLWHA highlight inadequacies of symptom-based TB screening in high TB–HIV burden settings.

Drug-resistant tuberculosis (DR-TB) remains a global crisis due to the increasing incidence of drug-resistant forms of the disease, gaps in detection and prevention, models of care, and limited treatment options. The DR-TB treatment landscape has evolved over the last 10 years. Recent developments include the remarkable activity demonstrated by the newly approved anti-TB drugs bedaquiline and pretomanid against Mycobacterium tuberculosis. Hence, treatment of DR-TB has drastically evolved with the introduction of the short-course regimen for multidrug-resistant TB (MDR-TB), transitioning to injection-free regimens and the approval of the 6-month short regimens for rifampin-resistant TB and MDR-TB. Moreover, numerous clinical trials are under way with the aim to reduce pill burden and shorten the DR-TB treatment duration. While there have been apparent successes in the field, some challenges remain. These include the ongoing inclusion of high-dose isoniazid in DR-TB regimens despite a lack of evidence for its efficacy and the inclusion of ethambutol and pyrazinamide in the standard short regimen despite known high levels of background resistance to both drugs. Furthermore, antimicrobial heteroresistance, extensive cavitary disease and intracavitary gradients, the emergence of bedaquiline resistance, and the lack of biomarkers to monitor DR-TB treatment response remain serious challenges to the sustained successes. In this review, we outline the impact of the new drugs and regimens on patient treatment outcomes, explore evidence underpinning current practices on regimen selection and duration, reflect on the disappointments and pitfalls in the field, and highlight key areas that require continued efforts toward improving treatment approaches and rapid biomarkers for monitoring treatment response.

IntroductionCotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries.Methods and analysisThis is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled.Ethics and disseminationThe University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.Trial registration numberClinicaltrials.gov; Trial registration number:NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789)

BackgroundPost COVID-19 Condition (PCC) as defined by WHO refers to a wide range of new, returning, or ongoing health problems experienced by COVID-19 survivors, and represents a rapidly emerging public health priority. We aimed to establish how this developing condition has impacted patients in South Africa and which population groups are at risk.MethodsIn this prospective cohort study, participants ≥18 years who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection during the second and third wave between December 2020 and August 2021 underwent telephonic follow-up assessment up at one-month and three-months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life and occupational status. Multivariable logistic regression models were used to determine factors associated with PCC.FindingsIn total, 1,873 of 2,413 (78%) enrolled hospitalised COVID-19 participants were followed up at three-months after hospital discharge. Participants had a median age of 52 years (IQR 41-62) and 960 (51.3%) were women. At three-months follow-up, 1,249 (66.7%) participants reported one or more persistent COVID-related symptom(s), compared to 1,978/2,413 (82.1%) at one-month post-hospital discharge. The most common symptoms reported were fatigue (50.3%), shortness of breath (23.4%), confusion or lack of concentration (17.5%), headaches (13.8%) and problems seeing/blurred vision (10.1%). On multivariable analysis, factors associated with new or persistent symptoms following acute COVID-19 were age ≥65 years [adjusted odds ratio (aOR) 1.62; 95%confidence interval (CI) 1.00-2.61]; female sex (aOR 2.00; 95% CI 1.51-2.65); mixed ethnicity (aOR 2.15; 95% CI 1.26-3.66) compared to black ethnicity; requiring supplemental oxygen during admission (aOR 1.44; 95% CI 1.06-1.97); ICU admission (aOR 1.87; 95% CI 1.36-2.57); pre-existing obesity (aOR 1.44; 95% CI 1.09-1.91); and the presence of ≥4 acute symptoms (aOR 1.94; 95% CI 1.19-3.15) compared to no symptoms at onset.InterpretationThe majority of COVID-19 survivors in this cohort of previously hospitalised participants reported persistent symptoms at three-months from hospital discharge, as well as a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health care workers, in identifying, assessing and caring for patients affected by PCC, establishment of multidisciplinary national health services, and provision of information and support to people who suffer from PCC.

Background Incorrect inhaler use is associated with poorer health outcomes, reduced quality of life, and higher healthcare utilisation in patients with asthma and COPD. Methods We performed an observational study of pressurized metered-dose inhaler technique in patients with asthma or COPD. Patients were assessed using a six-point inhaler checklist to identify common critical inhaler technique errors. An inadequate inhaler technique was defined as the presence of one or more critical errors. A multivariate logistic regression model was used to determine the odds of an inadequate inhaler technique. Results During the 14-month study period, 357 patients were enrolled. At least one critical error was executed by 66.7% of participants, and 24.9% made four or more critical errors. The most common errors were failure to exhale completely prior to pMDI activation and inhalation (49.6%), failure to perform a slow, deep inhalation following device activation (48.7%), and failure to perform a breath-hold at the end of inspiration (47.3%). The risk of a critical error was higher in COPD patients (aOR 2.25, 95% CI 1.13-4.47). Prior training reduced error risk specifically when trained by a doctor (aOR 0.08, 95% CI 0.1-0.57) or a pharmacist (aOR 0.02, 95% CI 0.01-0.26) compared to those with no training. Previous clinical trial participation significantly reduced error risk and rate

Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, n = 2727; RR 1.73, 95%CI 1.10–2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, n = 2753; RR 1.40, 95%CI 0.91–2.16), whereas low concentrations of INH (10 studies, n = 2640; RR 1.32, 95%CI 0.66–2.63) and EMB (4 studies, n = 551; RR 1.12, 95%CI 0.41–3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.

Community-acquired pneumonia (CAP) is associated with significant mortality and morbidity, and high costs globally. The epidemiology of CAP demonstrates high regional and geographic variability with regard to age, risk factors, disease severity and causative pathogens.

Summary: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles

Background: Improving treatment outcomes, reducing drug toxicity, eliminating the need for injectable agents, and shortening the treatment duration to 6-months (the same as rifampicin-susceptible tuberculosis) remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Methods: We conducted a multicentre randomised controlled trial in adults with MDR/RR-TB (i.e. without resistance to fluoroquinolones or aminoglycosides). Participants were randomly assigned (1:1 ratio) to a 6-month all-oral regimen that included levofloxacin, bedaquiline and linezolid, or the standard-of-care ≥ 9-month WHO-approved injectable-based regimen. The primary endpoint was a favourable WHO-defined treatment outcome 24 months after treatment initiation. Findings: 93 of 111 participants randomised were included in the modified intention-to-treat analysis; 51 (55%) were HIV co-infected (median CD4 count 158 cells/ml). Participants in the intervention arm were 2·2 times more likely to experience a favourable 24-month outcome ( 95% CI) than participants in the standard-of-care arm [RR 2·2 (1·2–4·1); p=0·006]. They were also less likely, over a 24-month period, to experience an unfavourable outcome event than participants in the standard-of-care arm [HR 0·4, (0·2–0·6), p

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Background Incorrect inhaler use is associated with poorer health outcomes, reduced quality of life, and higher healthcare utilisation in patients with asthma and COPD. Methods We performed an observational study of pressurized metered-dose inhaler technique in patients with asthma or COPD. Patients were assessed using a six-point inhaler checklist to identify common critical inhaler technique errors. An inadequate inhaler technique was defined as the presence of one or more critical errors. A multivariate logistic regression model was used to determine the odds of an inadequate inhaler technique. Results During the 14-month study period, 357 patients were enrolled. At least one critical error was executed by 66.7% of participants, and 24.9% made four or more critical errors. The most common errors were failure to exhale completely prior to pMDI activation and inhalation (49.6%), failure to perform a slow, deep inhalation following device activation (48.7%), and failure to perform a breath-hold at the end of inspiration (47.3%). The risk of a critical error was higher in COPD patients (aOR 2.25, 95% CI 1.13–4.47). Prior training reduced error risk specifically when trained by a doctor (aOR 0.08, 95% CI 0.1–0.57) or a pharmacist (aOR 0.02, 95% CI 0.01–0.26) compared to those with no training. Previous clinical trial participation significantly reduced error risk and rate

Background: During magnetic resonance cholangiopancreatography (MRCP), the pancreatobiliary ducts can be obscured by the high-intensity signal from the stomach and duodenum. Pineapple juice may be an alternative to commercially available negative contrast agents, but has not been evaluated locally. Objectives: To evaluate the efficacy of a local, off-the-shelf pineapple juice preparation as a negative oral contrast agent for MRCP. Method: An observational, analytical study was conducted during January–December 2017. A 1.5 Tesla MRCP sequence was performed immediately before and after ingestion of 250 mL of a local, commercially-available pineapple juice preparation. Image evaluation was performed by two radiologists with independent, blind assessment of gastric/duodenal signal intensity and biliary /pancreatic duct visibility, before and after pineapple juice. Results: Fifty adult patients (F = 44, 88%) with median age 44 years (IQR: 34.75, 57) were included. After pineapple juice administration, there was significant measured (1661.51 vs. 1409.94, p < 0.01) and perceived (2.16 vs. 2.72, p < 0.01) duodenal signal reduction but no significant change in measured (1081.17 vs. 1044.38, p = 0.34) or perceived (2.73 vs. 2.84, p = 0.14) gastric signal intensity. Visibility of the common bile duct was significantly improved (3.67 vs. 3.86, p < 0.01), whilst that of the main pancreatic duct showed no significant change (2.92 vs. 2.86, p = 0.44). Conclusion: The local pineapple juice preparation used in this study is an effective, affordable and natural negative oral contrast agent for enhancement of MRCP images, and specifically improves visualisation of the common bile duct.

Background: Bronchoalveolar lavage (BAL) is indicated for medical evaluation of complex cases of lung disease. There is limited data on the performance of tuberculosis (TB) microbiologic tests on BAL in such patients, particularly in human immunodeficiency virus (HIV) and TB endemic areas. Methods: We evaluated the performance of Mycobacterium tuberculosis (Mtb) culture and up to two simultaneous Xpert MTB/RIF tests on BAL fluid against a consensus clinical diagnosis in 98 medically complex patients undergoing bronchoscopy over a two-year period in Durban, South Africa. Results: TB was the most frequently diagnosed lung disease, found in 19 of 98 participants (19%) and was microbiologically proven in 14 of these (74%); 9 (47%) were culture positive and 5 were positive on at least one Xpert MTB/RIF assay. Immunosuppression prevalence was high (26% HIV-infected, 29% on immunosuppressive therapy and 4% on chemotherapy). Xpert MTB/RIF had low sensitivity (45%) and high specificity (99%) when assessed against the consensus clinical diagnosis. Compared to TB culture, a single Xpert MTB/RIF increased the diagnostic yield by 11% and a second Xpert MTB/RIF by a further 16%. Conclusion: Although Xpert MTB/RIF had a low sensitivity, sending two tests improved the microbiologically-proven diagnostic yield of bronchoscopy from 47% to 74% compared to culture alone.

Pericardial and myopericardial diseases are common cardiac presentations in people living with HIV, and may occur at all stages of HIV disease. There are a vast number of aetiologies, the relative likelihood of which is dependent on a complex interplay between host, pathogenic, and environmental factors. The convergence of HIV and tuberculosis in many settings has resulted in an increased prevalence of tuberculous pericardial disease associated with significant morbidity and mortality. The introduction of antiretroviral therapy has resulted in a reduced incidence of viral, bacterial, neoplastic, and idiopathic pericarditis in people living with HIV, but tuberculous pericarditis remains a challenge. The clinical presentation of the pericardial and myopericardial disease may reflect the extent of cardiac involvement, and further investigation should be guided by risk stratification. There is limited evidence to guide the treatment of myopericarditis; however, the principles of treatment are now well established in guidelines. A high index of suspicion for tuberculous pericarditis in high tuberculosis–HIV burden settings, and the appropriate use of empiric tuberculosis treatment may be warranted. While tuberculous pericardial disease continues to confer a high risk of mortality, most other causes of pericardial and myopericardial diseases bear a good prognosis.

BACKGROUND: Given the global shortage of N95 filtering facepiece respirators (FFP2 in Europe) during the COVID-19 pandemic, KN95 masks (Chinese equivalent of the N95 and FFP2) were imported and distributed in South Africa (SA). However, there are hardly any published independent safety data on KN95 masks. OBJECTIVES: To evaluate the seal, fit and filtration efficiency of several brands of KN95 masks marketed for widespread use in SA healthcare facilities, using standardised testing protocols. METHODS: The verifiability of manufacturer and technical details was first ascertained, followed by evaluation of the number of layers comprising the mask material. The testing protocol involved a directly observed positive and negative pressure user seal check, which if passed was followed by qualitative fit testing (sodium saccharin) in healthy laboratory or healthcare workers. Quantitative fit testing (3M) was used to validate the qualitative fit testing method. The filtration efficacy and integrity of the mask filter material were evaluated using a particle counter-based testing rig utilising aerosolised saline (expressed as filtration efficacy of 0.3 µm particles). Halyard FLUIDSHIELD 3 N95 and 3M 1860 N95 masks were used as controls. RESULTS: Twelve KN95 mask brands (total of 36 masks) were evaluated in 7 participants. The mask type and manufacturing details were printed on only 2/12 brands (17%) as per National Institute of Occupational Safety and Health and European Union regulatory requirements. There was considerable variability in the number of KN95 mask layers (between 3 and 6 layers in the 12 brands evaluated). The seal check pass rate was significantly lower in KN95 compared with N95 masks (1/36 (3%) v. 12/12 (100%); p99% for the N95 masks at the 0.3 µm particle size). CONCLUSIONS: The KN95 masks tested failed the stipulated safety thresholds associated with protection of healthcare workers against airborne pathogens such as SARS-CoV-2. These preliminary data have implications for the regulation of masks and their distribution to healthcare workers and facilities in SA.

Medical education is evolving from a heavily hierarchical and paternalistic approach to a more developmental and student-centred paradigm. In addition, there has been a greater focus on decentralised medical education, taking medical students closer to the lowest tiers of the healthcare system and allowing for a more immersive experience within the communities of their patients. This paper presents the experience of an enlightening rural experience, in which the benefits of such a model to medical education are explored. Furthermore, it presents the highly personal and developmental journey that decentralised and, in particular, rural medical training can offer. A new concept of a ‘home-stay’ model has now been introduced as part of the rural medicine experience, where students are hosted by a family within the community in which they work. This is a transformative project in which the most fundamental principles of medical training and the art of medical practice can be honed. The convergence of clinical training, public health enlightenment, and family practice are highlighted.

Background The substitution of moxifloxacin for ethambutol produced promising results for improved tuberculosis treatment outcomes. Methods We conducted an open-label, randomized trial to test whether a moxifloxacin-containing treatment regimen was superior to the standard regimen for the treatment of recurrent tuberculosis. The primary and secondary outcomes were the sputum culture conversion rate at the end of 8 weeks and the proportion of participants with a favorable outcome, respectively. Results We enrolled 196 participants; 69.9% were male and 70.4% were co-infected with human immunodeficiency virus (HIV). There was no significant difference between the study groups in the proportion of patients achieving culture conversion at the end of 8 weeks (83.0% [moxifloxacin] vs 78.5% [control]; P = .463); however, the median time to culture conversion was significantly shorter (6.0 weeks, interquartile range [IQR] 4.0–8.3) in the moxifloxacin group than the control group (7.9 weeks, IQR 4.0– 11.4; P = .018). A favorable end-of-treatment outcome was reported in 86 participants (87.8%) in the moxifloxacin group and 93 participants (94.9%) in the control group, for an adjusted absolute risk difference of −5.5 (95% confidence interval −13.8 to 2.8; P = .193) percentage points. There were significantly higher proportions of participants with Grade 3 or 4 adverse events (43.9% [43/98] vs 25.5% [25/98]; P = .01) and serious adverse events (27.6% [27/98] vs 12.2% [12/98]; P = .012) in the moxifloxacin group. Conclusions The replacement of ethambutol with moxifloxacin did not significantly improve either culture conversion rates at the end of 8 weeks or treatment success, and was associated with a higher incidence of adverse events. Clinical Trials Registration NCT02114684.

Achieving the targets set by UNAIDS for the year 2020 will enable the world to end the AIDS epidemic by 2030. Combination antiretroviral treatment (ART) is key to success of this goal and expanding access to all who need it, an imperative. Human immunodeficiency virus (HIV), ART, and traditional cardiovascular risk factors have all been implicated in the pathogenesis of cardiovascular disease in HIV-infected patients, either separately or collectively. The HIV replication in infected patients without ART is associated with an increase in cardiovascular disease risk, which seems to reduce with ART. Proinflammatory cytokines maintained with HIV infection and associated with endothelial activation leading to a proatherogenic profile appear to improve with ART. Associations between protease inhibitors and increased triglycerides, low-density lipoprotein, and total cholesterol have been demonstrated. Although ART use has been associated with an increased cardiovascular risk in HIV-1-infected patients, the overall mortality benefit of ART seems to outweigh the cardiovascular risk. In the context of ART, traditional risk factors have been shown to be strong predictors of cardiovascular disease. Emphasis should be placed on assessment for and management of traditional risk factors. ART with less cardiovascular toxicity should be selected. Early initiation of ART is now recommended.

Background The intersection of HIV and drug-resistant (DR) tuberculosis (TB) presents the challenge of managing convergent drug toxicities. Methods We conducted a retrospective study of adult patients with DR-TB treated with a kanamycin/capreomycin-based (KM) regimen, with or without concomitant antiretroviral therapy (ART). We estimated the incidence of nephrotoxicity (defined as an increase in serum creatinine greater than 26.5 µmol, or an increase in serum creatinine to 1.5 times the baseline value, or a decline in glomerular filtration rate to less than 60 mL/min/1.73 m), and evaluated the association between reported drug use and nephrotoxicity using Kaplan-Meier plots. Results A total of 215 patients with DR-TB were treated with a kanamycin/capreomycin-based regimen, with or without concomitant ART. The incidence rate of nephrotoxicity was 3.6 [95% confidence interval (CI): 1.4 to 7.3], 6.9 (95% CI: 5.2 to 9.0), and 12 (95% CI: 3.3 to 30.9) cases per 100 person-months of follow-up in the KM only group (n = 42), the KM + TDF (tenofovir disoproxil fumarate) group (n = 163), and the KM + Other ART group (n = 10), respectively. Using the KM only group as a reference, the hazard ratio was 2.06 (95% CI: 0.92 to 4.63) in the KM + TDF group, and 4.09 (95% CI: 1.17 to 14.25) in the KM + Other ART group. Advancing age was an independent predictor of nephrotoxicity (adjusted hazard ratio 1.29, 95% CI: 1.14 to 1.46). Conclusions Our findings provide evidence of a significant risk of nephrotoxicity during treatment with a kanamycin/capreomycin-based DR-TB regimen, with or without concurrent treatment with ART. This study lends further support to calls for the substitution of TDF during the intensive phase of DR-TB treatment and for close monitoring of renal function during DR-TB treatment, especially in settings where the use of kanamycin/capreomycin is unavoidable.

Thrombotic thrombocytopenic purpura is a catastrophic disease and may occur in the presence of other confounding diseases. We present a case of TTP in a patient with connective tissue disease and HIV infection, in whom the diagnosis and management of TTP was challenging. It is important to understand the various underlying mechanisms that drive TTP in the presence of these comorbid diseases, so that an appropriate treatment strategy can be initiated. Our patient failed an initial trial of plasma infusion alone, but responded well to plasma exchange.

Background: Process analysis and expert consultation help streamline and optimise processes, but these are underutilised. The World Health Organisation (WHO) recommends migration to electronic data collection by 2015, partly in response to multidrug-resistant tuberculosis (MDR-TB). We explore the influence of process analysis and iterative expert consultation, on shaping health information solutions to MDR-TB programmes. Methods: The study employs a two phase design. Phase one involves a process analysis of the South African National Tuberculosis Programme and an electronic medical records (EMR) solution and the generation of a detailed process model grounded in the fit between individual task and technology (FITT) theoretical framework using ‘business process modelling notation’. Phase two involves a two round Delphi study in the clinical management of tuberculosis and implementers of EMR solutions. Expert opinion is analysed according to emergent thematic content. Analyses and graphical model representation are performed using Microsoft Excel ® and Visio ® software. Results: A detailed process model is constructed which reveals 54 break points, 12 gaps, 3 risks, 5 wastes. Five participants are included in the Delphi study which support the findings of the process analysis. Thematic analysis identifies five themes: the individual, the process, technology, capacity, and collaboration. The opportunity to include synergistic relations across programmes emerges as a strong theme. Conclusions: Overall, the findings highlight inefficiencies, risk and gaps in the current process and the need for an operational excellence intervention. The study demonstrated the value of process engineering with iterative expert consultation toward developing a meaningful EMR solution consultation in a resource constrained, developing world context.

Background. Expanded HIV surveillance in TB patients forms part of the World Health Organization framework for strategic collaborative activity. Surveillance helps understand the epidemiology of the local dual epidemic and enables design of a tailored response to these challenges. Methods. We conducted an observational, cross-sectional study of anonymous unlinked HIV testing for 741 consecutive TB suspects attending an urban TB facility during a seven-week period in 2008. Results. A total of 512 patients were found to have TB. The mean age was 35.7 years, and 63% were male. The prevalence of HIV was 72.2% (95% CI: 68.2–75.9) in all TB cases, 69.8% (95% CI: 65.3–74.2) in pulmonary tuberculosis (PTB), 81.6% (95% CI: 72.9–90.3) in extrapulmonary disease, and 66.8% (95% CI: 60.7–72.9) in those without TB disease. HIV prevalence in TB patients was higher in females than males and in younger age groups (18–29 years). The sex ratio of PTB patients correlated with the sex ratio of the prevalence of HIV in the respective age groups P<0.05. Conclusion. The use of a rapid HIV test performed on sputum anonymously provides an opportunity for HIV surveillance in this high-burdened setting, which has the potential to lend valuable insight into the coepidemics.

Amidst the seeming desolation here, I feel inspired each morning when I wake up to the sound of the cock crowing, and the morning star twinkling above the mountain backdrop. This feeling has been matched only by the sense of opportunity I perceive at the hospital every day. There might be a lot more hospital now than some 20 years ago, but there is still so much that can and must be done here. It is not surprising that the revolutionary work of Sydney Kark, and many others, emanated from their experiences in this very setting. Necessity is, after all, the mother of invention.