Bolaamphiphile analogues of 12-bis-THA Cl2 are potent antimicrobial therapeutics with distinct mechanisms of action against bacterial, mycobacterial, and fungal pathogens.

12-Bis-THA Cl2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro, but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study) : results from a single-arm, open-label, phase 3B, implementation study

DATA SHARING : Individual participant data will not be made available. Study protocol, statistical analysis plan, and analytical code will be available from the time of publication in response to any reasonable request to the corresponding author.BACKGROUND : We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS : In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 x 10¹⁰ viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS : Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0–51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75–89) to prevent COVID-19-related deaths, 75% (69–82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62–71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42–76] and during delta wave was 67% [62–71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57–100] and during delta wave was 82% [74–89]). INTERPRETATION : The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally.National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.http;//thelancet.comam2023Paediatrics and Child HealthSchool of Health Systems and Public Health (SHSPH

South African Paediatric Surgical Outcomes Study : a 14-day prospective, observational cohort study of paediatric surgical patients

BACKGROUND : Children comprise a large proportion of the population in sub-Saharan Africa. The burden of paediatric surgical disease exceeds available resources in Africa, potentially increasing morbidity and mortality. There are few prospective paediatric perioperative outcomes studies, especially in low- and middle-income countries (LMICs). METHODS : We conducted a 14-day multicentre, prospective, observational cohort study of paediatric patients (aged <16 yrs) undergoing surgery in 43 government-funded hospitals in South Africa. The primary outcome was the incidence of in-hospital postoperative complications. RESULTS : We recruited 2024 patients at 43 hospitals. The overall incidence of postoperative complications was 9.7% [95% confidence interval (CI): 8.4–11.0]. The most common postoperative complications were infective (7.3%; 95% CI: 6.2–8.4%). In-hospital mortality rate was 1.1% (95% CI: 0.6–1.5), of which nine of the deaths (41%) were in ASA physical status 1 and 2 patients. The preoperative risk factors independently associated with postoperative complications were ASA physcial status, urgency of surgery, severity of surgery, and an infective indication for surgery. CONCLUSIONS : The risk factors, frequency, and type of complications after paediatric surgery differ between LMICs and high-income countries. The in-hospital mortality is 10 times greater than in high-income countries. These findings should be used to develop strategies to improve paediatric surgical outcomes in LMICs, and support the need for larger prospective, observational paediatric surgical outcomes research in LMICs. CLINICAL TRIAL REGISTRATION : NCT03367832.Jan Pretorius Research Fund; Discipline of Anaesthesiology and Critical Care, Nelson R Mandela School of Medicine, University of KwaZulu-Natal; Department of Anaesthesia and Perioperative Medicine, Groote Schuur Hospital and University of Cape Town; Department of Anaesthesia, University of the Witwatersrand; and the Paediatric Anaesthesia Community of South Africa (PACSA).https://bjanaesthesia.org2020-02-01gl2019Anaesthesiolog

Managing the impacts of drought: the role of cultural beliefs in small-scale farmers’ responses to drought in Gaza Province, southern Mozambique

Drought has had a harsh impact on small-scale farmers' agricultural activities, livestock production, and well-being, so that even droughts dating back to 1947 remain memorable. These memories, experiences, and knowledge of the impacts frame farmers' awareness of the need to respond to drought, and they therefore implement an array of responses collectively to tackle its causes, and individually to reduce its impacts. Farmers' collective responses, comprised of prayers or traditional rainmaking ceremonies, are directly framed by their enduring cultural beliefs of the causes of drought and appropriate responses to address them. Farmers’ individual responses involve dependence on help, activities which generate income or secure immediate food needs. Cultural beliefs indirectly influence these individual responses by determining the timing and order of their implementation because farmers usually implement first collective responses. Thus, farmers tend to implement short-term, reactive coping strategies, which are often insufficient to feed their large families. Although cultural beliefs do not necessarily help farmers to adapt to drought, the enduring collective responses bind farmers together in solidarity during times of drought, since they are driven by their common need of rainfall for agricultural activities. Thus, acting as a psychological support system to deal with the causes, maintain their livelihoods, recover from the hardship and survive. Therefore, we conclude that it is important to account for these direct and indirect influences of cultural beliefs as they may affect the level of engagement, endorsement and position that farmers will (consciously or unconsciously) attribute to the implementation of drought-related adaptation strategies