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New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial

Background: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. Methods: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18–50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. Findings: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73–99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73–99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64–95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65–95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67–97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64–95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. Interpretation: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. Funding: Drugs for Neglected Diseases initiative (DNDi). Translation: For the Spanish translation of the abstract see Supplementary Materials section.Fil: Torrico, Faustino. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; Bolivia. Universidad Mayor de San Simón; BoliviaFil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España. Universidad de Barcelona; EspañaFil: Barreira, Fabiana. DNDi Latin America; BrasilFil: Blum, Bethania. DNDi Latin America; BrasilFil: Almeida, Igor C. University of Texas at El Paso; Estados UnidosFil: Alonso Vega, Cristina. DNDi Latin America; Brasil. Instituto de Salud Global de Barcelona; EspañaFil: Barboza, Tayná. DNDi Latin America; BrasilFil: Bilbe, Graeme. Drugs For Neglected Diseases Initiative; SuizaFil: Correia, Erika. DNDi Latin America; BrasilFil: Garcia, Wilson. Universidad Mayor de San Simón; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente ; BoliviaFil: Ortiz, Lourdes. Universidad Autónoma Juan Misael Saracho; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; BoliviaFil: Parrado, Rudy. Universidad Mayor de San Simón; BoliviaFil: Ramirez Gomez, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaFil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Vaillant, Michel. Luxembourg Institute Of Health; LuxemburgoFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. DNDi Latin America; Brasi

Interventions to prevent youth violence in Latin America: a systematic review

Objectives: This review aims to summarise evidence on the effectiveness of interventions to prevent youth violence in Latin America. Methods: A systematic search on 13 academic databases was conducted to locate studies evaluating a primary or secondary prevention intervention in Latin America. Studies could use any type of quantitative design to assess outcomes related to youth violence. A search of websites, references and citation searching was also carried out. The quality of each study was assessed. Results: Nine studies were identified. Most documented positive effects of the interventions on the perception of youth violence present in the community/school. Evidence was found of a reduction in homicides and juvenile crimes in three studies, two of which evaluated a community-based intervention. There were mixed results for the self-report of participation on violent acts. The majority of the studies lacked of a rigorous design. Conclusions: Most of the interventions had some promising results, including the reduction of homicides within communities. Community-based programmes were the most consistent regarding an effectiveness to prevent violence. However, the evidence for Latin America is still scarce and relies on non-rigorously designed studies

A prognostic tool to identify adolescents at high risk of becoming daily smokers

<p>Abstract</p> <p>Background</p> <p>The American Academy of Pediatrics advocates that pediatricians should be involved in tobacco counseling and has developed guidelines for counseling. We present a prognostic tool for use by health care practitioners in both clinical and non-clinical settings, to identify adolescents at risk of becoming daily smokers.</p> <p>Methods</p> <p>Data were drawn from the Nicotine Dependence in Teens (NDIT) Study, a prospective investigation of 1293 adolescents, initially aged 12-13 years, recruited in 10 secondary schools in Montreal, Canada in 1999. Questionnaires were administered every three months for five years. The prognostic tool was developed using estimated coefficients from multivariable logistic models. Model overfitting was corrected using bootstrap cross-validation. Goodness-of-fit and predictive ability of the models were assessed by R², the c-statistic, and the Hosmer-Lemeshow test.</p> <p>Results</p> <p>The 1-year and 2-year probability of initiating daily smoking was a joint function of seven individual characteristics: age; ever smoked; ever felt like you needed a cigarette; parent(s) smoke; sibling(s) smoke; friend(s) smoke; and ever drank alcohol. The models were characterized by reasonably good fit and predictive ability. They were transformed into user-friendly tables such that the risk of daily smoking can be easily computed by summing points for responses to each item. The prognostic tool is also available on-line at <url>http://episerve.chumontreal.qc.ca/calculation_risk/daily-risk/daily_smokingadd.php</url>.</p> <p>Conclusions</p> <p>The prognostic tool to identify youth at high risk of daily smoking may eventually be an important component of a comprehensive tobacco control system.</p

Antibodies That Induce Phagocytosis of Malaria Infected Erythrocytes: Effect of HIV Infection and Correlation with Clinical Outcomes

HIV infection increases the burden of disease of malaria in pregnancy, in part by impairing the development of immunity. We measured total IgG and phagocytic antibodies against variant surface antigens of placental-type CS2 parasites in 187 secundigravidae (65% HIV infected). In women with placental malaria infection, phagocytic antibodies to CS2VSA were decreased in the presence of HIV (p = 0.011) and correlated positively with infant birth weight (coef = 3.57, p = 0.025), whereas total IgG to CS2VSA did not. Phagocytic antibodies to CS2VSA are valuable tools to study acquired immunity to malaria in the context of HIV co-infection. Secundigravidae may be an informative group for identification of correlates of immunity

Prevalence of dementia subtypes in a developing country: a clinicopathological study

OBJECTIVES: To assess the distribution of dementia subtypes in Brazil using a population-based clinicopathological study. METHOD: Brains from deceased individuals aged ≥50 years old were collected after the next of kin signed an informed consent form and provided information through standardized questionnaires. Post-mortem clinical diagnoses were established in consensus meetings, and only cases with moderate or severe dementia or without cognitive impairment were included in the analysis. Immunohistochemical neuropathological examinations were performed following the universally accepted guidelines. A diagnosis of Alzheimer's disease was made when there were at least both a moderate density of neuritic plaques (Consortium to Establish a Register for Alzheimer's disease B or C) and Braak stage III for neurofibrillary tangle distribution. For the diagnosis of vascular dementia, at least three zones or strategic areas had to be affected by infarcts, lacunae, or microinfarcts. RESULTS: From 1,291 subjects, 113 cases were classified as having moderate or severe dementia, and 972 cases were free of cognitive impairment. The neuropathological diagnoses of the dementia sub-group were Alzheimer's disease (35.4%), vascular dementia (21.2%), Alzheimer's disease plus vascular dementia (13.3%), and other causes of dementia (30.1%). Small-vessel disease, which alone was not considered sufficient for a vascular dementia diagnosis, was present in 38.9% of all of the dementia cases and in 16.8% of the group without cognitive impairment (odds ratio = 2.91; 95% confidence interval, 1.53-5.51), adjusted for age, sex, and education. CONCLUSIONS: The relatively high frequencies of vascular dementia and small-vessel disease in the dementia sub-group constitute relevant findings for public health initiatives because control of vascular risk factors could decrease the prevalence of dementia in developing countries

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200

Improving the sensitivity to gravitational-wave sources by modifying the input-output optics of advanced interferometers

We study frequency dependent (FD) input-output schemes for signal-recycling interferometers, the baseline design of Advanced LIGO and the current configuration of GEO 600. Complementary to a recent proposal by Harms et al. to use FD input squeezing and ordinary homodyne detection, we explore a scheme which uses ordinary squeezed vacuum, but FD readout. Both schemes, which are sub-optimal among all possible input-output schemes, provide a global noise suppression by the power squeeze factor, while being realizable by using detuned Fabry-Perot cavities as input/output filters. At high frequencies, the two schemes are shown to be equivalent, while at low frequencies our scheme gives better performance than that of Harms et al., and is nearly fully optimal. We then study the sensitivity improvement achievable by these schemes in Advanced LIGO era (with 30-m filter cavities and current estimates of filter-mirror losses and thermal noise), for neutron star binary inspirals, and for narrowband GW sources such as low-mass X-ray binaries and known radio pulsars. Optical losses are shown to be a major obstacle for the actual implementation of these techniques in Advanced LIGO. On time scales of third-generation interferometers, like EURO/LIGO-III (~2012), with kilometer-scale filter cavities, a signal-recycling interferometer with the FD readout scheme explored in this paper can have performances comparable to existing proposals. [abridged]Comment: Figs. 9 and 12 corrected; Appendix added for narrowband data analysi

The \u3cem\u3eChlamydomonas\u3c/em\u3e Genome Reveals the Evolution of Key Animal and Plant Functions

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the ∼120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella