Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study

BACKGROUND: Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT. METHODS: In this prospective, multicentre, open-label, single-arm cohort study, patients with stage 1 or early stage 2 g-HAT were recruited from eight treatment centres in the Democratic Republic of the Congo. Primary inclusion criteria included being older than 15 years, being able to ingest at least one complete meal per day (or at least one sachet of Plumpy'Nut®), a Karnofsky score higher than 50, evidence of trypanosomes in the blood or lymph but no evidence of trypanosomes in the CSF, willingness to be admitted to hospital to receive treatment, having a permanent address, and being able to comply with the follow-up visit schedule. Exclusion criteria included severe malnutrition, inability to take medication orally, pregnant or breastfeeding women, any clinically important medical condition that could jeopardise patient safety or participation in the study, severely deteriorated general status, any contraindication to imidazole drugs, HAT treatment in the past 2 years, previous enrolment in the study or previous intake of fexinidazole, abnormalities on electrocardiogram that did not return to normal in pretreatment repeated assessments or were considered clinically important, QT interval corrected using Fridericia's formula of at least 450 ms, and patients not tested for malaria or not having received appropriate treatment for malaria or for soil-transmitted helminthiasis. Patients were classified into stage 1 or early stage 2 g-HAT groups following evidence of trypanosomes in the blood, lymph, and absence in CSF, and using white-blood-cell count in CSF. Patients received 1800 mg fexinidazole once per day on days 1-4 then 1200 mg fexinidazole on days 5-10. Patients were observed for approximately 19 months in total. Study participants were followed up on day 5 and day 8 during treatment, at end of treatment on day 11, at end of hospitalisation on days 11-18, at week 9 for a subset of patients, and after 6 months, 12 months, and 18 months. The primary endpoint was treatment success at 12 months. Safety was assessed through routine monitoring. Analyses were done in the intention-to-treat population. The acceptable success rate was defined as treatment efficacy in more than 80% of patients. This study is completed and registered with ClinicalTrials.gov (NCT02169557). FINDINGS: Patients were enrolled between April 30, 2014, and April 25, 2017. 238 patients were recruited: 195 (82%) patients with stage 1 g-HAT and 43 (18%) with early stage 2 g-HAT. 189 (97%) of 195 patients with stage 1 g-HAT and 41 (95%) of 43 patients with early stage 2 g-HAT were finally included and completed the 10 day treatment period. Three patients with stage 1 g-HAT died after the 10 day treatment period and before the 12 month primary follow-up visit, considered as treatment failure and were withdrawn from the study. Treatment was effective at 12 months for 227 (99%) of 230 patients (95% CI 96·2-99·7): 186 (98%) of 189 patients (95·4-99·7) with stage 1 and 41 (100%) of 41 patients (91·4-100·0) with early stage 2, indicating that the primary study endpoint was met. No new safety issues were observed. The most frequent adverse events were headache and vomiting. In total, 214 (93%) of 230 patients had treatment-emergent adverse events, mainly common-terminology criteria for adverse events grades 1 to 3. None led to treatment discontinuation. INTERPRETATION: Fexinidazole is a valuable first-line treatment option in the early stages of g-HAT. FUNDING: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation, the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (also known as DGIS; Netherlands), the Norwegian Agency for Development Cooperation (also known as Norad; Norway), the Federal Ministry of Education and Research (also known as BMBF) through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the HAT campaign

Response of groundnut (Arachis hypogaea L.) in sole crop and in intercrop with cassava (Manihot esculenta Crantz) to lime in an Ultisol in Bas Zaire

Field trials were carried out in M'Vuazi, Bas Zaire, to test the response of groundnuts (cv P43), planted sole or intercropped with cassava (cv Kinuani), to lime application. Groundnuts responded significantly to low rates of lime (250-500 kg ha-1). Maximum cost, benefit ratio of 1:7 was obtained when 500 kg lime ha-1was applied. Whether it was planted sole or intercropped with cassava, critical soil Ca level for groundnuts was estimated at 0.6 cmol kg-1. There was no cassava root yield response to the lime application at a soil Ca level of 0.11 cmol kg-1. Lime application below 2000 kg ha-1 did not significantly change the surface soil pH and did not affect the subsoil chemical properties. The main effects of lime on groundnuts were, therefore, to supply adequate Ca to: (1) produce maximum number of mature pods and (2) diminish the incidence of unfilled pods

Multi-accent acoustic modelling of South African English

Although English is spoken throughout South Africa it is most often used as a second or third language, resulting in several prevalent accents within the same population. When dealing with multiple accents in this under-resourced environment, automatic speech recognition (ASR) is complicated by the need to compile multiple, accent-specific speech corpora. We investigate how best to combine speech data from five South African accents of English in order to improve overall speech recognition performance. Three acoustic modelling approaches are considered: separate accent-specific models, accent-independent models obtained by pooling training data across accents, and multi-accent models. The latter approach extends the decision-tree clustering process normally used to construct tied-state hidden Markov models (HMMs) by allowing questions relating to accent. We find that multi-accent modelling outperforms accent-specific and accent-independent modelling in both phone and word recognition experiments, and that these improvements are statistically significant. Furthermore, we find that the relative merits of the accent-independent and accent-specific approaches depend on the particular accents involved. Multi-accent modelling therefore offers a mechanism by which speech recognition performance can be optimised automatically, and for hard decisions regarding which data to pool and which to separate to be avoided. © 2012 Elsevier B.V. All rights reserved

Synthetic routes to NEtXaa(4)-cyclosporin A derivatives as potential anti-HIV I drugs

An efficient synthesis in 10 steps and overall yields up to 27% of NEtXaa(4)-cyclosporin A derivatives (Xaa = Leu, Val, Ile, Thr) starting from cyclosporin A is described. Biological activities of the new analogues show promising results for the design of cyclosporin derivatives exhibiting non-immunosuppressive and anti-HIV activity. (C) 2000 Elsevier Science Ltd. All rights reserved