Phenotype and predictors of insulin independence in adults presenting with diabetic ketoacidosis: a prospective cohort study.

AIMS/HYPOTHESIS: The aim of this work was to describe the phenotype of adults presenting with a first episode of diabetic ketoacidosis (DKA) in Cape Town, South Africa, and identify predictors of insulin independence at 12 and 60 months after presentation. METHODS: A prospective, descriptive cohort study of all individuals, 18 years or older, presenting for the first time with DKA to four public-sector hospitals of the Groote Schuur Academic Health Complex was performed. Clinical, biochemical and laboratory data including GAD antibody and C-peptide status were collected at baseline. Insulin was systematically weaned and stopped in individuals who achieved normoglycaemia within the months after DKA. Individuals were followed for 12 months and then annually until 5 years after initial presentation with ketoacidosis. RESULTS: Eighty-eight individuals newly diagnosed with diabetes when presenting with DKA were included and followed for 5 years. The mean ± SD age was 35±10 years and the median (IQR) BMI at diagnosis was 28.5 (23.3-33.4) kg/m2. Overall, 46% were insulin independent 12 months after diagnosis and 26% remained insulin independent 5 years after presentation. Forty-one participants (47%) tested negative for anti-GAD and anti-IA-2 antibodies and had C-peptide levels >0.3 nmol/l; in this group, 68% were insulin independent at 12 months and 37% at 5 years after diagnosis. The presence of acanthosis nigricans was strongly associated with insulin independence (OR 27.1 [95% CI 7.2, 102.2]; p<0.001); a positive antibody status was associated with a lower likelihood of insulin independence at 12 months (OR 0.10 [95% CI 0.03, 0.36]; p<0.001). On multivariable analysis only acanthosis (OR 11.5 [95% CI 2.5, 53.2]; p=0.004) was predictive of insulin independence 5 years after diagnosis. CONCLUSIONS/INTERPRETATION: The predominant phenotype of adults presenting with a first episode of DKA in Cape Town, South Africa, was that of ketosis-prone type 2 diabetes. These individuals presented with obesity, acanthosis nigricans, negative antibodies and normal C-peptide and could potentially be weaned off insulin at follow-up. Classic type 1 diabetes (lower weight, antibody positivity, low or unrecordable C-peptide levels and long-term insulin dependence) was less common. The simple clinical sign of acanthosis nigricans is a strong predictor of insulin independence at 12 months and 5 years after initial presentation.

Routine health data describe adherence and persistence patterns for oral diabetes medication for a virtual cohort in the Khayelitsha sub-district of Cape Town, South Africa.

Type 2 diabetes mellitus (T2DM) is managed with combined lifestyle modifications and antidiabetic drugs, but people on treatment often fail to reach glycaemic control. Adherence is important for achieving optimal glycaemic control, and management of diabetes with drugs is a lifelong process, so understanding adherence through analysis of longitudinal medications data is important. Using retrospective routine health data and metformin dispensing records as a proxy for medication use, we describe longitudinal persistence and adherence to oral diabetes medication in a virtual cohort of 10541 people with diabetes (PLWD) in Khayelitsha subdistrict, Cape Town. Adherence was measured in 120-day sliding windows over two years and used to estimate metformin adherence trajectories. Multinomial logistic regression identified factors influencing these trajectories. Analysis of pharmacy dispensing records showed varying medication refill patterns: while some PLWD refilled prescriptions consistently, others had treatment gaps with periods of non-persistence and multiple treatment episodes-from one to five per individual across two years. There was a general trend of decreasing adherence over time across all sliding windows in the two-year period, with only 25% of the study population achieved medication adherence (> = 80% adherence) after two years. Four adherence trajectories; 'low adherence gradual decline (A), 'high adherence rapid decline' (B), 'low adherence gradual increase (C) and 'adherent' (D) were identified. Only trajectory D represented participants who were adherent at treatment start and remained adherent after two years. Taking HIV antiretroviral treatment before or concurrently with diabetes treatment and taking metformin in combination with sulphonylurea and/or insulin were associated with the long-term adherence (trajectory D). Routine data shows real life medication implementation patterns which might not be seen under controlled study conditions. This study illustrates the utility of these data in describing longitudinal adherence patterns at both an individual and population level.

A description of the elevation of pericardial cortisol: cortisone ratio in patients with tuberculous pericarditis.

Pulmonary tuberculosis is an inflammatory disease associated with an elevated cortisol/cortisone ratio at the site of infection and an array of cytokine changes. Tuberculous pericarditis is a less common but more lethal form of tuberculosis and has a similar inflammatory process in the pericardium. As the pericardium is largely inaccessible, the effect of tuberculous pericarditis on pericardial glucocorticoids is largely unknown. We wished to describe pericardial cortisolcortisone ratio in relation to plasma and saliva cortisol/cortisone ratios and the associated changes in cytokine concentrations. The median (interquartile range) of plasma, pericardial, and saliva cortisol concentration was 443 (379-532), 303 (257-384), and 20 (10-32) nmol/L, respectively, whereas the median (interquartile range) of plasma, pericardial, and saliva cortisone concentrations was 49 (35-57), 15.0 (0.0-21.7), and 37 (25-55) nmol/L, respectively. The cortisol/cortisone ratio was highest in pericardium with median (interquartile range) of 20 (13-445), followed by plasma of 9.1 (7.4-12.1) and saliva of 0.4 (0.3-0.8). The elevated cortisol/cortisone ratio was associated with elevated pericardial, interferon gamma, tumor necrosis factor-alpha, interleukin-6, interleukin-8, and induced protein 10. Administration of a single dose of 120 mg of prednisolone was associated with the suppression of pericardial cortisol and cortisone within 24 h of administration. The cortisol/cortisone ratio was highest at the site of infection, in this case, the pericardium. The elevated ratio was associated with a differential cytokine response. The observed pericardial cortisol suppression suggests that 120 mg of prednisolone was sufficient to evoke an immunomodulatory effect in the pericardium.

Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa.

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

A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.

BACKGROUND: Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design. METHODS: We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM. Participants were randomized (1.4:1:1) to 3 treatment arms (1, standard of care [SOC]; 2, SOC + additional rifampicin [up to 35 mg/kg/d] + linezolid 1200 mg/d reducing after 28 days to 600 mg/d; 3, as per arm 2 + aspirin 1000 mg/d) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. RESULTS: A total of 52 participants with HIV-associated TBM were randomized; 59% had mild disease (British Medical Research Council (MRC) grade 1) vs 39% (grade 2) vs 2% (grade 3). AESI or death occurred in 10 of 16 (63%; arm 3) vs 4 of 14 (29%; arm 2) vs 6 of 20 (30%; arm 1; P = .083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (P = .04); however, only 1 event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) between arms. CONCLUSIONS: High-dose rifampicin and adjunctive linezolid can safely be added to the standard of care in HIV-associated TBM. Larger studies are required to determine whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit. CLINICAL TRIALS REGISTRATION: NCT03927313.

Adherence to a care bundle for Staphylococcus aureus bacteraemia: A retrospective cohort study.

Background: Staphylococcus aureus bacteraemia is associated with high hospital mortality. Improvements in outcome have been described with standardised bundles of care. Objectives: To study the adherence of a standardised bundle of care (BOC) recommendations using a consultation pro forma, for all patients admitted with S. aureus bacteraemia to Groote Schuur Hospital over a year. The study further aimed to describe the 90-day mortality in these patients and to assess for an association between adherence to the bundle of care and outcome. Method: A retrospective audit of all unsolicited infectious disease consultations for patients with S. aureus bacteraemia admitted to Groote Schuur Hospital during 2018. Adherence to recommendations of a standard bundle of care was audited. Results: A total of 86 patients were included in the study: 61 (71%) with hospital-associated infection and 25 (29%) with community-associated infection. Over 80% of adherence to treatment recommendations was achieved regarding antibiotic (including vancomycin) usage, source control and use of echocardiography as required. In-hospital mortality was 16%, while the overall 90-day mortality was 18%, with only age as an independent predictor of mortality. No association between adherence to the bundle of care and outcome was found. Conclusion: Adherence to a simple, structured bundle of care was good when using standardised pro forma as communication tools for advice and a structured antibiotic chart for vancomycin administration. Although adherence was not associated with outcome, the overall mortality for S. aureus bacteraemia was improving in the institution under study. Contribution: Our findings support feasibility and ongoing use of bundles of care for S. aureus bacteraemia in similar settings.

Dulaglutide and cardiovascular and heart failure outcomes in patients with and without heart failure: a post-hoc analysis from the REWIND randomized trial.

AIMS: People with diabetes are at high risk for cardiovascular events including heart failure (HF). We examined the effect of the glucagon-like peptide 1 agonist dulaglutide on incident HF events and other cardiovascular outcomes in those with or without prior HF in the randomized placebo-controlled Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. METHODS AND RESULTS: The REWIND major adverse cardiovascular event (MACE) outcome was the first occurrence of a composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes). In this post-hoc analysis, a HF event was defined as an adjudication-confirmed hospitalization or urgent evaluation for HF. Of the 9901 participants studied over a median follow-up of 5.4 years, 213/4949 (4.3%) randomly assigned to dulaglutide and 226/4952 (4.6%) participants assigned to placebo experienced a HF event (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.77-1.12; p = 0.456). In the 853 (8.6%) participants with HF at baseline, there was no change in either MACE or HF events with dulaglutide as compared to participants without HF (p = 0.44 and 0.19 for interaction, respectively). Combined cardiovascular death and HF events were marginally reduced with dulaglutide compared to placebo (HR 0.88, 95% CI 0.78-1.00; p = 0.050) but unchanged in patients with and without HF at baseline (p = 0.31). CONCLUSIONS: Dulaglutide was not associated with a reduction in HF events in patients with type 2 diabetes regardless of baseline HF status over 5.4 years of follow-up.

A novel kidney disease index reflecting both the albumin-to-creatinine ratio and estimated glomerular filtration rate, predicted cardiovascular and kidney outcomes in type 2 diabetes.

BACKGROUND: The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. METHODS: 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. RESULTS: A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. CONCLUSIONS: The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952.

Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa.

Objective: We aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. Results: Among 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95% confidence interval [CI] 0.93; 1.34). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for boosted vs. no vaccine) were protective. Conclusion: Disease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective.

A Delphi study to guide the development of a clinical indicator tool for palliative care in South Africa.

BACKGROUND:  The South African National Policy Framework and Strategy on Palliative Care (NPFSPC) recommends that when integrating palliative care (PC) into the health system, a PC indicators tool should be used to guide clinicians to recognise a patient who should receive PC. The policy document recommends 'a simple screening tool developed for use in South Africa that would assist healthcare professionals (HCPs) to recognise patients who may have unmet palliative care needs'. AIM:  This research study sought to develop South African consensus on indicators for PC to assist clinicians to recognise a patient in need of PC. SETTING:  The South African healthcare setting. METHODS:  A Delphi study was considered suitable as a methodology to develop consensus. The methodology was based on the Conducting and REporting of DElphi studies (CREDES) guidance on Delphi studies to ensure rigour and transparency in conducting and reporting. Six different Delphi rounds were used to develop consensus. Each round allowed participants to anonymously rate statements with predefined rating scales. RESULTS:  Cognisant of the disparities in healthcare provision and access to equitable healthcare in South Africa, the expert advisory group recommended, especially for South Africa, that 'this tool is for deteriorating patients with an advanced life-limiting illness where all available and appropriate management for underlying illnesses and reversible complications has been offered'. The expert advisory group felt that disease-specific indicators should be described before the general indicators in the South African indicators tool, so all users of the tool orientate themselves to the disease categories first. This study included three new domains to address the South African context: trauma, infectious diseases and haematological diseases. General indicators for PC aligned with the original Supportive and Palliative Care Indicators Tool (SPICT) tool. CONCLUSION:  The Supportive and Palliative Care Indicators Tool for South Africa (SPICTTM-SA) is a simple screening tool for South Africa that may assist HCPs to recognise patients who may have unmet PC needs.

Novel Indices of Cognitive Impairment and Incident Cardiovascular Outcomes in the REWIND Trial.

CONTEXT: Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown. METHODS: Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (N = 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSST ≥ 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that was ≥ 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed. RESULTS: Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; P = 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; P < 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; P < 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; P < 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors. CONCLUSION: Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial.

Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa.

OBJECTIVES: The objective was to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, assess the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection and determine whether protection against severe disease conferred by prior infection and/or vaccination was maintained. METHODS: In this cohort study, we included public sector patients aged ≥20 years with a laboratory-confirmed COVID-19 diagnosis between 14 November and 11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalisation or death and any hospitalisation or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. RESULTS: We included 5144 patients from wave four and 11,609 from prior waves. The risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted hazard ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR: 0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). CONCLUSIONS: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for a modest reduction in risk of severe hospitalisation or death compared to the Delta-driven wave.

Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diagnostic PCR proxy marker of RdRp target delay to distinguish between Omicron and Delta infections - a survival analysis.

BACKGROUND: At present, it is unclear whether the extent of reduced risk of severe disease seen with SARS-Cov-2 Omicron variant infection is caused by a decrease in variant virulence or by higher levels of population immunity. METHODS: RdRp target delay (RTD) in the Seegene AllplexTM 2019-nCoV PCR assay is a proxy marker for the Delta variant. The absence of this proxy marker in the transition period was used to identify suspected Omicron infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene AllplexTM assay from November 1 to December 14, 2021 in the Western Cape Province, South Africa, in the public sector. Adjustments were made for vaccination status and prior diagnosis of infection. RESULTS: A total of 150 cases with RTD and 1486 cases without RTD were included. Cases without RTD had a lower hazard of admission (adjusted hazard ratio [aHR], 0.56; 95% confidence interval [CI], 0.34-0.91). Complete vaccination was protective against admission, with an aHR of 0.45 (95% CI, 0.26-0.77). CONCLUSION: Omicron has resulted in a lower risk of hospital admission compared with contemporaneous Delta infection, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant remains a challenge to accurately assessing variant virulence.

Dulaglutide and incident atrial fibrillation or flutter in patients with type 2 diabetes: A post hoc analysis from the REWIND randomized trial.

AIM: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo. MATERIALS AND METHODS: Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. RESULTS: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. CONCLUSION: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes.

Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa.

OBJECTIVES: We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. METHODS: In this cohort study, we included public sector patients aged ≥20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. RESULTS: We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). CONCLUSIONS: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta.

Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy: a cross-sectional study.

Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant's disease severity in other settings, particularly in an African context, and when compared to the Beta variant. Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene Allplex TM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status. Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95% confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95%CI: 0.11-0.92) as was vaccination (aOR [95%CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]). Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.

One-year mortality after hospital admission as an indicator of palliative care need: A retrospective cohort study.

BACKGROUND: Globally there is increasing awareness of the need for end-of-life care and palliative care in hospitalised patients who are in their final year of life. Limited data are available on palliative care requirements in low- and middle-income countries, hindering the design and implementation of effective policies and health services for these patients. OBJECTIVES: To determine the proportion of patients who die within 1 year of their date of admission to public hospitals in South Africa (SA), as a proxy for palliative care need in SA. METHODS: This was a retrospective cohort study using record linkage of admission and mortality data. The setting was 46 acute-care public hospitals in Western Cape Province, SA. RESULTS: Of 10 761 patients (median (interquartile range (IQR)) age 44 (31 - 60) years) admitted to the 46 hospitals over a 2-week period in March 2012, 1 570 (14.6%) died within 1 year, the majority within the first 3 months. Mortality rose steeply with age. The median (IQR) age of death was 57.5 (45 - 70) years. A greater proportion of patients admitted to medical beds died within 1 year (21.3%) compared with those admitted to surgical beds (7.7%). CONCLUSIONS: Despite a median age <60 years at admission, a substantial percentage of patients admitted to public sector hospitals in SA are in the final year of their lives. This finding should be seen in the context of SA's high communicable and non-communicable disease burden and resource-limited public health system, and highlights the need for policy development, planning and implementation of end-of-life and palliative care strategies for hospitals and patients.

Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM].

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019).

Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin / Desfechos cardiovasculares semelhantes em pacientes com diabetes e risco estabelecido ou alto para doença vascular coronariana tratada com dulaglutida com e sem linha de base metformina

Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. Results Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81­1.05) vs. 0.78 (CI 0.61­0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. Conclusion This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.

Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial.

BACKGROUND: Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes. METHODS: The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006). INTERPRETATION: Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes. FUNDING: Eli Lilly and Company.