Structure-function analysis of MmpL7-mediated lipid transport in mycobacteria

Mycobacterial membrane protein Large (MmpL7) is a Resistance-Nodulation-Division (RND) family transporter required for the export of the virulence lipid, phthiocerol dimycocerosate (PDIM), in Mycobacterium tuberculosis. Using a null mutant of the related, vaccine strain Mycobacterium bovis BCG, we show that MmpL7 is also involved in the transport of the structurally related phenolic glycolipid (PGL), which is also produced by the hypervirulent M. tuberculosis strain HN878, but absent in M. tuberculosis H37Rv. Furthermore, we generated an in silico model of M. tuberculosis MmpL7 that revealed MmpL7 as a functional outlier within the MmpL-family, missing a canonical proton-relay signature sequence, suggesting that it employs a yet-unidentified mechanism for energy coupling for transport. In addition, our analysis demonstrates that the periplasmic porter domain 2 insert (PD2-insert), which doesn't share any recognisable homology, is highly alpha-helical in nature, suggesting an organisation similar to that seen in the hopanoid PD3/4 domains. Using the M. bovis BCG mmpL7 mutant for functional complementation with mutated alleles of mmpL7, we were able to identify residues present in the transmembrane domains TM4 and TM10, and the PD2 domain insert that play a crucial role in PDIM transport, and in certain cases, biosynthesis of PDIM

High HIV prevalence in an early cohort of hospital admissions with COVID-19 in Cape Town, South Africa

Background. South Africa (SA) has a high prevalence of HIV and tuberculosis. Cape Town was the SA metropole most affected in the early stages of the COVID-19 pandemic. Early observational data from Africa may provide valuable insight into what can be expected as the pandemic expands across the continent.Objectives. To describe the prevalence, clinical features, comorbidities and outcome of an early cohort of HIV-positive and HIV-negative patients admitted with COVID-19.Methods. This was a descriptive observational study of an early cohort of adults with COVID-19 pneumonia admitted from 25 March to 11 May 2020.Results. Of 116 patients (mean age 48 years, 61% female) admitted, 24 were HIV-positive (21%). The most common symptoms reported were cough (n=88; 73%), shortness of breath (n=78; 69%), fever (n=67; 59%), myalgia (n=29; 25%) and chest pain (n=22; 20%). The most common comorbidities were hypertension (n=46; 41%), diabetes mellitus (n=43; 38%), obesity (n=32; 28%) and HIV (n=24; 21%). Mortality was associated with older age (mean (standard deviation) 55 (12) years v. 46 (14) years; p<0.01); the presence of hypertension or hypertension along with diabetes and/or obesity; lower partial pressure of arterial oxygen to fraction of inspired oxygen ratio; and higher urea level, white cell count, neutrophil count, and C-reactive protein, lactate dehydrogenase and ferritin levels, and high neutrophil to lymphocyte ratio. The overall survival rate for all hospital admissions was 86/116 (73%). In this early cohort, survival was similar in patients with HIV (n=18; 75%) compared with those without HIV (n=67; 75%) (p=1). Of the 74 patients admitted to the wards, 63 (85%) survived, whereas 22 of 42 (52%) admitted to the intensive care unit survived.Conclusions. Patients with HIV infection represented a large proportion of all COVID-19 admissions. The presentation and outcome of patients with HIV did not differ significantly from those of patients without HIV

A point-prevalence study of body mass indices in HIV-positive and HIV-negative patients admitted to hospital with COVID-19 in South Africa

Background. Obesity is now well recognised as a risk factor for severe COVID‐19, but the true prevalence of obesity in hospitalised adults with COVID‐19 remains unclear because formal body mass indices (BMIs) are not routinely measured on admission. Objectives. To describe the true prevalence of obesity measured by the BMI, and associated comorbidities, in patients hospitalised with severe COVID‐19, including people with HIV (PWH). Methods. We conducted a point‐prevalence study of measured BMI in consecutive patients with severe COVID‐19 admitted to the medical COVID‐19 wards in a tertiary academic hospital in Cape Town, South Africa (SA). Patients were enrolled over a 2‐week period during the peak of the first COVID‐19 wave in SA. Results. We were able to measure the BMI in 122 of the 146 patients admitted during the study period. The prevalence of HIV was 20% (n=24/122). Most of the participants were overweight or obese (n=104; 85%), and 84 (68.9%) met criteria for obesity. The mean (standard deviation) BMI was 33 (7.5), and 34.5 (9.1) in PWH. Of PWH, 83% (n=20/24) were overweight or obese and 75% (n=18) met criteria for obesity. Multimorbidity was present in 22 (92%) of PWH. Conclusion. We found that most patients, including PWH, met criteria for being overweight or obese. The high prevalence of obesity in PWH and severe COVID‐19 reinforces the need for targeted management of non‐communicable diseases, including obesity, in PWH

High HIV prevalence in an early cohort of hospital admissions with COVID-19 in Cape Town, South Africa

CITATION: Parker, A. et al. 2020. High HIV prevalence in an early cohort of hospital admissions with COVID-19 in Cape Town, South Africa. South African Medical Journal, doi:10.7196/SAMJ.2020.v110i10.15067.The original publication is available at http://www.samj.org.zaBackground. South Africa (SA) has a high prevalence of HIV and tuberculosis. Cape Town was the SA metropole most affected in the early stages of the COVID-19 pandemic. Early observational data from Africa may provide valuable insight into what can be expected as the pandemic expands across the continent. Objectives. To describe the prevalence, clinical features, comorbidities and outcome of an early cohort of HIV-positive and HIV-negative patients admitted with COVID-19. Methods. This was a descriptive observational study of an early cohort of adults with COVID-19 pneumonia admitted from 25 March to 11 May 2020. Results. Of 116 patients (mean age 48 years, 61% female) admitted, 24 were HIV-positive (21%). The most common symptoms reported were cough (n=88; 73%), shortness of breath (n=78; 69%), fever (n=67; 59%), myalgia (n=29; 25%) and chest pain (n=22; 20%). The most common comorbidities were hypertension (n=46; 41%), diabetes mellitus (n=43; 38%), obesity (n=32; 28%) and HIV (n=24; 21%). Mortality was associated with older age (mean (standard deviation) 55 (12) years v. 46 (14) years; p<0.01); the presence of hypertension or hypertension along with diabetes and/or obesity; lower partial pressure of arterial oxygen to fraction of inspired oxygen ratio; and higher urea level, white cell count, neutrophil count, and C-reactive protein, lactate dehydrogenase and ferritin levels, and high neutrophil to lymphocyte ratio. The overall survival rate for all hospital admissions was 86/116 (73%). In this early cohort, survival was similar in patients with HIV (n=18; 75%) compared with those without HIV (n=67; 75%) (p=1). Of the 74 patients admitted to the wards, 63 (85%) survived, whereas 22 of 42 (52%) admitted to the intensive care unit survived. Conclusions. Patients with HIV infection represented a large proportion of all COVID-19 admissions. The presentation and outcome of patients with HIV did not differ significantly from those of patients without HIV.http://www.samj.org.za/index.php/samj/article/view/13054Publisher's versio

Border crossings in the African travel narratives of Ibn Battuta, Richard Burton and Paul Theroux

This article compares the representation of African borders in the 14th-century travelogue of Ibn Battuta, the 19th-century travel narrative of Richard Burton and the 21st-century travel writing of Paul Theroux. It examines the mutually constitutive relationship between conceptions of literal territorial boundaries and the figurative boundaries of the subject that ventures across borders in Africa. The border is seen as a liminal zone which paradoxically separates and joins spaces. Accounts of border crossings in travel writing from different periods suggest the historicity and cultural specificity of conceptions of geographical borders, and the way they index the “boundaries” of the subjects who cross them. Tracing the transformations in these conceptions of literal and metaphorical borders allows one to chart the emergence of the dominant contemporary idea of “Africa” as the inscrutable, savage continent

The G1613A Mutation in the HBV Genome Affects HBeAg Expression and Viral Replication through Altered Core Promoter Activity

Infection of hepatitis B virus (HBV) causes acute and chronic hepatitis and is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we demonstrated that the G1613A mutation in the HBV negative regulatory element (NRE) is a hotspot mutation in HCC patients. In this study, we further investigated the functional consequences of this mutation in the context of the full length HBV genome and its replication. We showed that the G1613A mutation significantly suppresses the secretion of e antigen (HBeAg) and enhances the synthesis of viral DNA, which is in consistence to our clinical result that the G1613A mutation associates with high viral load in chronic HBV carriers. To further investigate the molecular mechanism of the mutation, we performed the electrophoretic mobility shift assay with the recombinant RFX1 protein, a trans-activator that was shown to interact with the NRE of HBV. Intriguingly, RFX1 binds to the G1613A mutant with higher affinity than the wild-type sequence, indicating that the mutation possesses the trans-activating effect to the core promoter via NRE. The trans-activating effect was further validated by the enhancement of the core promoter activity after overexpression of RFX1 in liver cell line. In summary, our results suggest the functional consequences of the hotspot G1613A mutation found in HBV. We also provide a possible molecular mechanism of this hotspot mutation to the increased viral load of HBV carriers, which increases the risk to HCC

Transforming Growth Factor-β1 Suppresses Hepatitis B Virus Replication by the Reduction of Hepatocyte Nuclear Factor-4α Expression

Several studies have demonstrated that cytokine-mediated noncytopathic suppression of hepatitis B virus (HBV) replication may provide an alternative therapeutic strategy for the treatment of chronic hepatitis B infection. In our previous study, we showed that transforming growth factor-beta1 (TGF-β1) could effectively suppress HBV replication at physiological concentrations. Here, we provide more evidence that TGF-β1 specifically diminishes HBV core promoter activity, which subsequently results in a reduction in the level of viral pregenomic RNA (pgRNA), core protein (HBc), nucleocapsid, and consequently suppresses HBV replication. The hepatocyte nuclear factor 4alpha (HNF-4α) binding element(s) within the HBV core promoter region was characterized to be responsive for the inhibitory effect of TGF-β1 on HBV regulation. Furthermore, we found that TGF-β1 treatment significantly repressed HNF-4α expression at both mRNA and protein levels. We demonstrated that RNAi-mediated depletion of HNF-4α was sufficient to reduce HBc synthesis as TGF-β1 did. Prevention of HNF-4α degradation by treating with proteasome inhibitor MG132 also prevented the inhibitory effect of TGF-β1. Finally, we confirmed that HBV replication could be rescued by ectopic expression of HNF-4α in TGF-β1-treated cells. Our data clarify the mechanism by which TGF-β1 suppresses HBV replication, primarily through modulating the expression of HNF-4α gene

Features of home and neighbourhood and the liveability of older South Africans

While older people live in developing countries, little is known about the relative importance of features of their communities in influencing their liveability. We examinecomponents of home and neighbourhood among older South Africans. Linear regression analyses revealed that features of home (basic amenities, household composition, financial status and safety) and neighbourhood (ability to shop for groceries, participate in organizations and feel safe from crime) are significantly associated with life satisfaction. Approaches to liveability that are person-centred and also set within contexts beyond home and neighbourhood are needed to addressboundaries between home and neighbourhood; incorporate personal resources into liveability models and import broader environmental contexts such as health and social policy

11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn’t met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700