An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Methods: Open label randomized controlled trial. Participants received standard care – amphotericin combined with fluconazole for the first 2 weeks – or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) – the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031. Results: Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (−0.48log10 colony-forming units/mL/CSF control arm versus −0.49 tamoxifen arm, difference −0.005log10CFU/ml/day, 95% CI: −0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation. Conclusions: High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. Funding: The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA

Metals as chemical tracers to discriminate ecological populations of threatened Franciscana dolphins (Pontoporia blainvillei) from Argentina

Franciscana dolphins are the most impacted small cetacean in the Southwestern Atlantic Ocean, classified as Vulnerable A3d by IUCN. Essential (Fe, Mo, Mn, Cr, Ni, Co) and non-essential (Ag, Pb, Sn) trace elements (TEs) were measured in liver, kidney, and brain samples of by-catch Franciscana dolphins that were living in estuarine (n = 21) and marine (n = 21) habitats (1) to assess whether TEs posed a threat and (2) to evaluate the suitability of TEs for discriminating ecological populations of this species in Argentinean waters. Essential TEs showed little variation in tissues from both groups in agreement with levels reported for other cetaceans and suggesting that these concentrations correspond to normal physiological levels. Non-essential TEs were higher in estuarine juveniles and adults dolphins than in marine specimens. These results suggest anthropogenic sources associated with estuarine area and that Franciscana dolphins are good sentinels of the impact of the environment. The difference in the concentrations of TEs beetwen ecological populations appeared to be related to distinct exposures in both geographical areas, and it is suggested that Ag and Sn concentrations in adults are good chemical tracers of anthropogenic input of TEs. These results provide additional information for improved management and regulatory policy.Fil: Romero, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Polizzi, Paula Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Chiodi Boudet, Leila Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Robles, Alicia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; ArgentinaFil: Das, Kalyan. Université de Liège; BélgicaFil: Gerpe, Marcela Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentin