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Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines.In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality.From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38·7%) individuals received a flucytosine-containing regimen and 943 (61·3%) received another regimen. The median age was 36 years (IQR 32-43) and 906 (58·9%) participants were male and 633 (41·1%) were female. The crude in-hospital case-fatality ratio was 23·9% (95% CI 20·0-27·0; 143 of 596) in those treated with flucytosine-containing regimens and 37·2% (95% CI 34·0-40·0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1·95 [95% CI 1·53-2·48]; p0·0001) and those who were antiretroviral treatment-experienced (aOR 1·30 [1·02-1·67]; p=0·033) were more likely to receive flucytosine. After adjusting for relevant confounders, flucytosine treatment was associated with a 53% reduction in mortality (aOR 0·47 [95% CI 0·35-0·64]; p0·0001). Among survivors, the median length of hospital admission in the flucytosine group was 11 days (IQR 8-15) versus 17 days (13-21) in the comparison group (p=0·0010).In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit.National Institute for Communicable Diseases, a Division of the National Health Laboratory Service.For the Zulu translation of the abstract see Supplementary Materials section.

Humanitarian aid and development is a multibillion-dollar sector, representing millions of organisations, with hundreds of millions of employees and volunteers operating worldwide. The community is, by its very nature, drawn towards danger, supporting vulnerable parties in high-risk areas. In the face of complex global health emergencies, natural disasters and deteriorating security conditions, the imperative for individuals to deploy to, or work in, increasingly fragile and hostile environments is growing. At the same time, expectations regarding the sector's duty of care are mounting, and employees, families, donors and governments are holding organisations increasingly accountable for their actions. Where an organisation fails - or is perceived to have failed - the people it is supposed to protect, it can face catastrophic litigation and reputational harm. Hostile environment awareness training is part of the duty-of-care strategy for those working in, or travelling to, high to extreme-risk environments. It addresses tactical-level risks by raising the awareness and competency of the individual in identifying, controlling and reacting to security and safety risks. In doing so, it concurrently reduces enterprise-level risks to the organisation. This paper discusses what drives the increasing need for hostile environment awareness training (HEAT), the value it brings in terms of duty of care and organisational resilience, what technical content and immersive learning should be included within a HEAT curriculum, and the challenges organisations face when implementing instruction programme at the global and multicultural level.

Background In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. Methods Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. Findings Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, andfabG promoter combined (isoniazid resistance), 54% (39-68) for pucA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. Interpretation Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. Copyright (C) 2018 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

This study aimed to test the null hypothesis that platelet-rich fibrin (PRF), as an immediate postextraction graft material, produces bone that is histomorphometrically no different than bone derived from healing without intervention. The authors compared split-mouth human bone biopsy specimens derived from PRF with bone that had healed without intervention. Eight human bone biopsies were successfully harvested from four patients. The mean ± standard deviation (SD) percent of newly formed osteoid was 9.9% ± 5.9% for specimens derived from PRF, and 4% ± 2.1% for specimens derived from the control sites (P = .089; 95% confidence interval [CI] 4.5-18.1 and 1.6-6.6, respectively). Mean ± SD percent of new mineralized bone was 40.8% ± 10.3% for the PRF specimens and 43.9% ± 16.8% for the control specimens (P = .72, 95% CI, 33.4-55.6 and 19.3-55.5, respectively). Newly formed bone to fibrovascular tissue ratios for specimens in the PRF and control groups were 51%:49% and 48%:52%, respectively. Within the limitations of this study, the null hypothesis could not be rejected. Bone derived from PRF histologically did not differ from bone that healed without intervention.