Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources in the Western Cape, South Africa (2007-2021).

BACKGROUND: Routinely collected population-wide health data are often used to understand mortality trends including child mortality, as these data are often available more readily or quickly and for lower geographic levels than population-wide mortality data. However, understanding the completeness and accuracy of routine health data sources is essential for their appropriate interpretation and use. This study aims to assess the accuracy of diagnostic coding for public sector in-facility childhood (age < 5 years) infectious disease deaths (lower respiratory tract infections [LRTI], diarrhoea, meningitis, and tuberculous meningitis [TBM]) in routine hospital information systems (RHIS) through comparison with causes of death identified in a child death audit system (Child Healthcare Problem Identification Programme [Child PIP]) and the vital registration system (Death Notification [DN] Surveillance) in the Western Cape, South Africa and to calculate admission mortality rates (number of deaths in admitted patients per 1000 live births) using the best available data from all sources. METHODS: The three data sources: RHIS, Child PIP, and DN Surveillance are integrated and linked by the Western Cape Provincial Health Data Centre using a unique patient identifier. We calculated the deduplicated total number of infectious disease deaths and estimated admission mortality rates using all three data sources. We determined the completeness of Child PIP and DN Surveillance in identifying deaths recorded in RHIS and the level of agreement for causes of death between data sources. RESULTS: Completeness of recorded in-facility infectious disease deaths in Child PIP (23/05/2007-08/02/2021) and DN Surveillance (2010-2013) was 70% and 69% respectively. The greatest agreement in infectious causes of death were for diarrhoea and LRTI: 92% and 84% respectively between RHIS and Child PIP, and 98% and 83% respectively between RHIS and DN Surveillance. In-facility infectious disease admission mortality rates decreased significantly for the province: 1.60 (95% CI: 1.37-1.85) to 0.73 (95% CI: 0.56-0.93) deaths per 1000 live births from 2007 to 2020. CONCLUSION: RHIS had accurate causes of death amongst children dying from infectious diseases, particularly for diarrhoea and LRTI, with declining in-facility admission mortality rates over time. We recommend integrating data sources to ensure the most accurate assessment of child deaths.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

Using longitudinal targeted maximum likelihood estimation in complex settings with dynamic interventions.

Longitudinal targeted maximum likelihood estimation (LTMLE) has very rarely been used to estimate dynamic treatment effects in the context of time-dependent confounding affected by prior treatment when faced with long follow-up times, multiple time-varying confounders, and complex associational relationships simultaneously. Reasons for this include the potential computational burden, technical challenges, restricted modeling options for long follow-up times, and limited practical guidance in the literature. However, LTMLE has desirable asymptotic properties, ie, it is doubly robust, and can yield valid inference when used in conjunction with machine learning. It also has the advantage of easy-to-calculate analytic standard errors in contrast to the g-formula, which requires bootstrapping. We use a topical and sophisticated question from HIV treatment research to show that LTMLE can be used successfully in complex realistic settings, and we compare results to competing estimators. Our example illustrates the following practical challenges common to many epidemiological studies: (1) long follow-up time (30 months); (2) gradually declining sample size; (3) limited support for some intervention rules of interest; (4) a high-dimensional set of potential adjustment variables, increasing both the need and the challenge of integrating appropriate machine learning methods; and (5) consideration of collider bias. Our analyses, as well as simulations, shed new light on the application of LTMLE in complex and realistic settings: We show that (1) LTMLE can yield stable and good estimates, even when confronted with small samples and limited modeling options; (2) machine learning utilized with a small set of simple learners (if more complex ones cannot be fitted) can outperform a single, complex model, which is tailored to incorporate prior clinical knowledge; and (3) performance can vary considerably depending on interventions and their support in the data, and therefore critical quality checks should accompany every LTMLE analysis. We provide guidance for the practical application of LTMLE.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.

BACKGROUND: Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients. PATIENTS AND METHODS: This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics. RESULTS: Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use. CONCLUSIONS: These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.

BACKGROUND: Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs). PATIENTS AND METHODS: Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing. RESULTS: Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing. CONCLUSIONS: In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling.

Salicylic acid deposition from wash-off products: comparison of in vivo and porcine deposition models.

OBJECTIVE: Salicylic acid (SA) is a widely used active in anti-acne face wash products. Only about 1-2% of the total dose is actually deposited on skin during washing, and more efficient deposition systems are sought. The objective of this work was to develop an improved method, including data analysis, to measure deposition of SA from wash-off formulae. METHODS: Full fluorescence excitation-emission matrices (EEMs) were acquired for non-invasive measurement of deposition of SA from wash-off products. Multivariate data analysis methods - parallel factor analysis and N-way partial least-squares regression - were used to develop and compare deposition models on human volunteers and porcine skin. RESULTS: Although both models are useful, there are differences between them. First, the range of linear response to dosages of SA was 60 µg cm(-2) in vivo compared to 25 µg cm(-2) on porcine skin. Second, the actual shape of the SA band was different between substrates. CONCLUSION: The methods employed in this work highlight the utility of the use of EEMs, in conjunction with multivariate analysis tools such as parallel factor analysis and multiway partial least-squares calibration, in determining sources of spectral variability in skin and quantification of exogenous species deposited on skin. The human model exhibited the widest range of linearity, but porcine model is still useful up to deposition levels of 25 µg cm(-2) or used with nonlinear calibration models.

Lower respiratory tract infection admissions and deaths among children under 5 years in public sector facilities in the Western Cape Province, South Africa, before and during the COVID-19 pandemic (2019 - 2021).

BACKGROUND: The COVID-19 pandemic resulted in the implementation of strict public health and social measures (PHSMs) (including mobility restrictions, social distancing, mask-wearing and hand hygiene), limitations on non-essential healthcare services, and public fear of COVID-19 infection, all of which potentially affected transmission and healthcare use for other diseases such as lower respiratory tract infections (LRTIs). OBJECTIVE: To determine changes in LRTI hospital admissions and in-facility mortality in children aged <5 years in the Western Cape Province during the pandemic. METHODS: We conducted a retrospective analysis of LRTI admissions and in-facility deaths from January 2019 to November 2021. We estimated changes in rates and trends of LRTI admissions during the pandemic compared with pre-pandemic period using interrupted time series analysis, adjusting for key characteristics. RESULTS: There were 36 277 children admitted for LRTIs during the study period, of whom 58% were male and 51% were aged 28 days - 1 year. COVID-19 restrictions were associated with a 13% step reduction in LRTI admissions compared with the pre-COVID-19 period (incidence rate ratio (IRR) 0.87, 95% confidence interval (CI)) 0.80 - 0.94). The average LRTI admission trend increased on average by 2% per month during the pandemic (IRR 1.02, 95% CI 1.02 - 1.04). CONCLUSIONS: The COVID-19 surges and their associated measures were linked to declining LRTI admissions and in-facility deaths, likely driven by a combination of reduced infectious disease transmission and reduced use of healthcare services, with effects diminishing over time. These findings may inform future pandemic response policies.

Cadmium level in pregnancy, influence on neonatal birth weight and possible amelioration by some essential trace elements.

Cadmium (Cd) is currently of great concern in rapidly industrializing countries-India, China. Their products consumed especially due to increase demand in many developing countries like Nigeria can result in adverse effects. Cd is a ubiquitous environmental pollutant and toxicant and humans are continually exposed to the toxic effects of Cd primarily through food as well as from environmental pollution through industrial activities. Maternal exposure to Cd has been associated with the delivery of low-birth weight babies and an increase incidence of spontaneous abortion. Cd a toxic metal can displace zinc (Zn) an essential element necessary for normal fetal development and growth. With this consideration, 160 subjects comprising of 125 pregnant and 35 non-pregnant subjects as controls were recruited for this study. The pregnant subjects were classified according to the three trimesters of pregnancy as followed; 35, 35, and 55 from the first to the third trimesters respectively. The third trimester subjects were followed-up until after delivery where neonatal parameters (birth weight, head circumference, and length) of babies were measured. 32 (58%) of the women delivered babies with normal birth weight, 19 women (35%) delivered babies with low-birth weight while four women (7%) delivered babies with high- birth weight. Subject who delivered low-birth weight babies had significantly higher Cd concentration and lower Zn concentration and body mass index when compared with those with normal weight babies. These results suggest that Cd indeed has some toxic effects on neonatal birth weight.

A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity.

BACKGROUND: Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. METHODS: A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. RESULTS: A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. CONCLUSION: This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

Antimicrobial stewardship in the Western Cape: A situational analysis of existing facility-level initiatives.

BACKGROUND: Antimicrobial resistance (AMR) is a growing problem worldwide. With the current occurrence of pan-resistant bacterial infections and a paucity of novel antimicrobials in development, the world has entered a post-antibiotic era, in which previously treatable, common infections can become fatal. Antimicrobial stewardship (AMS), defined as 'co-ordinated interventions to ensure appropriate and rational use of antimicrobials', aims to decrease rates of AMR. OBJECTIVES: To co-ordinate AMS in Western Cape Province. The National Department of Health (NDoH) has identified AMS as a key strategic objective, and the Western Cape has formed a provincial AMS committee. However, not much is known regarding current AMS activities in health facilities in the province. METHODS: A self-administered, email questionnaire was sent to specific staff at all district, regional and tertiary hospitals in the 6 health districts of the Western Cape - 47 facilities in total, of which 35 (74.4%) responded. Respondents included pharmacists, managers, doctors, nurses, infection prevention and control practitioners, as well as quality assurance practitioners. The number of facilities implementing AMS were determined, as well as the composition of AMS committees and the nature and frequency of team activities. Barriers to facility-level AMS were explored. Support and outreach activities were assessed, as well as facilities' needs and expectations of the provincial AMS committee. RESULTS: Approximately half of all responding hospitals (n=19; 54.3%) had active AMS committees. Double the proportion of metropolitan (83.3%) than rural facilities (39.1%) had committees. Stewardship activities included antimicrobial prescription chart reviews and audits, AMS ward rounds, antimicrobial restriction policies and training. Most committees included a pharmacist and an infection prevention and control practitioner. More than a third of hospitals (36.1%) did not review their antimicrobial consumption data on a regular basis. Just over half of the hospitals (n=18; 51.4%) did not review AMR patterns. CONCLUSIONS: Despite the need for effective AMS, there is limited information on AMS in South Africa. Most assistance is required in rural areas and smaller hospitals with low numbers of staff and greater numbers of transient rotating junior staff. Information management support, multidisciplinary teamwork and clinical governance are required to enable regular and ongoing AMS in facilities. Rural and smaller facilities require greater support to establish effectively functioning AMS committees.

Asymptomatic COVID-19 in South Africa - implications for the control of transmission.

Asymptomatic COVID-19 may contribute significantly to the pandemic trajectory based on global biological, epidemiological and modelling evidence. A retrospective analysis was done to determine the proportion of asymptomatic COVID-19 in the workplace during the lockdown period from 27 March to 31 May 2020. We found that nearly 45% of cases were asymptomatic at the time of the first test. This high proportion of asymptomatic COVID-19 cases has implications for interventions, such as enforcing quarantine of all close contacts of COVID-19 cases regardless of symptoms.

Le COVID-19 a symptomatique pourrait contribuer significativement à la trajectoire de la pandémie en se basant sur des preuves mondiales, biologique et épidémiologiques, et en modélisant les preuves. Une analyse rétrospective a été réalisée afin de décrire la proportion d'infections asymptomatiques de SARS-CoV-2 parmi les clusters essentiels sur les lieux de travail en Afrique du Sud où des investigations de flambée ont été réalisées durant la période de confinement très restrictive du 27 mars au 31 mai 2020. Près de 45% des cas étaient asymptomatique lors du premier test. Cette proportion élevée des cas de COVID-19 asymptomatiques a des implications en ce qui concerne les interventions nonpharmaceutique comme le renforcement de la quarantaine de tous les contacts étroits des cas de SARS-CoV-2 sans tenir compte des symptômes.

Hard choices: Ethical challenges in phase 1 of COVID-19 vaccine roll-out in South Africa.

Access to COVID-19 vaccines has raised concerns globally. Despite calls for solidarity and social justice during the pandemic, vaccine nationalism, stockpiling of limited vaccine supplies by high-income countries and profit-driven strategies of global pharmaceutical manufacturers have brought into sharp focus global health inequities and the plight of low- and middle-income countries (LMICs) as they wait in line for restricted tranches of vaccines. Even in high-income countries that received vaccine supplies first, vaccine roll-out globally has been fraught with logistic and ethical challenges. South Africa (SA) is no exception. Flawed global institutional strategies for vaccine distribution and delivery have undermined public procurement platforms, leaving LMICs facing disproportionate shortages necessitating strict criteria for vaccine prioritisation. In anticipation of our first consignment of vaccines, deliberations around phase 1 roll-out were intense and contentious. Although the first phase focuses on healthcare personnel (HCP), the devil is in the detail. Navigating the granularity of prioritising different categories of risk in healthcare sectors in SA is complicated by definitions of risk in personal and occupational contexts. The inequitable public-private divide that characterises the SA health system adds another layer of complexity. Unlike other therapeutic or preventive interventions that are procured independently by the private health sector, COVID-19 vaccine procurement is currently limited to the SA government only, leaving HCP in the private sector dependent on central government allocation. Fair distribution among tertiary, secondary and primary levels of care is another consideration. Taking all these complexities into account, procedural and substantive ethical principles supporting a prioritisation approach are outlined. Within the constraints of suboptimal global health governance, LMICs must optimise progressive distribution of scarce vaccines to HCP at highest risk.

The HIV cascade of care among serodiscordant couples in four high HIV prevalence settings in sub-Saharan Africa.

BACKGROUND:  HIV-serodiscordant couples are at high risk of HIV transmission. In sub-Saharan Africa, HIV-serodiscordant couples contribute ~30% of all new infections in the region. OBJECTIVES: To quantify the prevalence of HIV-serodiscordant couples and evaluate steps of the HIV cascade of care among people living with HIV in serodiscordant relationships in four high-prevalence settings in sub-Saharan Africa. METHODS:  Four HIV prevalence surveys were conducted: in Ndhiwa (Kenya) in 2012, in Chiradzulu (Malawi) in 2013, and in Gutu (Zimbabwe) and Nsanje (Malawi) in 2016. Eligible individuals aged 15 - 59 years were asked to participate in voluntary rapid HIV testing. Viral load and CD4 counts were measured on those who tested HIV-positive. A couple was defined as a man and a woman who reported being married or cohabiting and were living together in the same household. RESULTS: Among 4 385 couples, the prevalence of HIV serodiscordancy was 10.9% (95% confidence interval (CI) 10.2 - 11.5) overall, ranging from 6.7% (95% CI 5.6 - 7.9) in Nsanje to 15.8% (95% CI 14.5 - 17.3) in Ndhiwa. Men were the HIV-positive partner in 62.7% of the serodiscordant couples in Ndhiwa, in 60.4% in Gutu, in 48.8% in Chiradzulu and in 50.9% in Nsanje. Status awareness among HIV-positive partners in serodiscordant couples ranged from 45.4% in Ndhiwa to 70.7% in Gutu. Viral load suppression (VLS) ranged from 33.9% in Ndhiwa to 68.5% in Nsanje. VLS was similar by sex in three settings, Ndhiwa (37.8% (men) v. 27.8% (women); p=0.16), Nsanje (60.7% v. 76.9%; p=0.21) and Gutu (48.2% v. 55.6%; p=0.63), and dissimilar by sex in Chiradzulu (44.4% v. 62.7%; p=0.03). CONCLUSIONS: Low HIV status awareness and poor VLS among HIV-positive partners are major gaps in preventing transmission among serodiscordant couples. Intensifying programmes that target couples to test for HIV and timely antiretroviral therapy initiation could increase VLS and reduce HIV transmission.

The treatment gap for mental disorders in adults enrolled in HIV treatment programmes in South Africa: a cohort study using linked electronic health records.

AIMS: Mental disorders are common in people living with HIV (PLWH) but often remain untreated. This study aimed to explore the treatment gap for mental disorders in adults followed-up in antiretroviral therapy (ART) programmes in South Africa and disparities between ART programmes regarding the provision of mental health services. METHODS: We conducted a cohort study using ART programme data and linked pharmacy and hospitalisation data to examine the 12-month prevalence of treatment for mental disorders and factors associated with the rate of treatment for mental disorders among adults, aged 15-49 years, followed-up from 1 January 2012 to 31 December 2017 at one private care, one public tertiary care and two pubic primary care ART programmes in South Africa. We calculated the treatment gap for mental disorders as the discrepancy between the 12-month prevalence of mental disorders in PLWH (aged 15-49 years) in South Africa (estimated based on data from the Global Burden of Disease study) and the 12-month prevalence of treatment for mental disorders in ART programmes. We calculated adjusted rate ratios (aRRs) for factors associated with the treatment rate of mental disorders using Poisson regression. RESULTS: In total, 182 285 ART patients were followed-up over 405 153 person-years. In 2017, the estimated treatment gap for mental disorders was 40.5% (95% confidence interval [CI] 19.5-52.9) for patients followed-up in private care, 96.5% (95% CI 95.0-97.5) for patients followed-up in public primary care and 65.0% (95% CI 36.5-85.1) for patients followed-up in public tertiary care ART programmes. Rates of treatment with antidepressants, anxiolytics and antipsychotics were 17 (aRR 0.06, 95% CI 0.06-0.07), 50 (aRR 0.02, 95% CI 0.01-0.03) and 2.6 (aRR 0.39, 95% CI 0.35-0.43) times lower in public primary care programmes than in the private sector programmes. CONCLUSIONS: There is a large treatment gap for mental disorders in PLWH in South Africa and substantial disparities in access to mental health services between patients receiving ART in the public vs the private sector. In the public sector and especially in public primary care, PLWH with common mental disorders remain mostly untreated.

Repeat injuries in childhood.

BACKGROUND: Injury remains a leading cause of childhood morbidity and mortality in the developing world. The probability of injury occurrence is influenced by agent, host and environmental factors. Studies of repeat injuries in childhood therefore provide insight into factors in the epidemiological triad predisposing children to injury. OBJECTIVES: To determine the proportion of children and the factors associated with repeat presentations to the Red Cross War Memorial Children's Hospital Trauma Unit (RCWMCH TU) in Cape Town, South Africa, for all non-transport-related injuries in childhood. METHODS: This was a retrospective cohort study using data from the RCWMCH TU. We included children aged 0 - 10 years with first presentation from January 1997 to June 2013 and followed up until the earlier of age 13 years or June 2016. We assessed individual and population-level factors associated with repeat injury using multilevel Poisson regression analysis. Child dependency ratios were derived from the 2011 National Census. RESULTS: Between 1997 and 2013, 72 490 children aged <10 years (59% male) presented to the RCWMCH TU for the first time with injuries. After the initial injury, 9 417 (13%) presented with a repeat injury by 2016 and before age 13 years. After adjusting for health subdistrict, distance from RCWMCH TU and age at first presentation, factors associated with reduced repeat presentation were injury identified as due to abuse (adjusted incidence rate ratio (aIRR) 0.6; 95% confidence interval (CI) 0.4 - 0.7), fluid burn (aIRR 0.6; 95% CI 0.6 - 0.7), foreign body ingestion (aIRR 0.7; 95% CI 0.7 - 0.9), and moderate and severe (v. minor) initial injury (aIRR 0.9; 95% CI 0.8 - 0.9 and aIRR 0.7; 95% CI 0.6 - 0.8, respectively), while boys were more likely to have repeat injury presentations (aIRR 1.4; 95% CI 1.4 - 1.5). CONCLUSIONS: Repeat presentations were substantial and associated with male gender. They occurred less commonly after fluid burn injuries, foreign body ingestion and moderate to severe injuries. Children with intentional injuries were also less likely to have a repeat presentation. Further research is indicated for childhood injuries with greater propensity to repeat, including non-height falls and sport-related injuries. Secondary injury prevention education should not neglect patients with unintentional and minor injuries. These results strengthen the hypothesis that injuries arise as a result of sustained exposure to agent, host and environmental risk factors.