A Six-Planet System Around the Star HD 34445

We present a new precision radial velocity dataset that reveals a multi-planet system orbiting the G0V star HD 34445. Our 18-year span consists of 333 precision radial velocity observations, 56 of which were previously published, and 277 which are new data from Keck Observatory, Magellan at Las Campanas Observatory, and the Automated Planet Finder at Lick Observatory. These data indicate the presence of six planet candidates in Keplerian motion about the host star with periods of 1057, 215, 118, 49, 677, and 5700 days, and minimum masses of 0.63, 0.17, 0.1, 0.05, 0.12 and 0.38 Jupiter masses respectively. The HD 34445 planetary system, with its high degree of multiplicity, its long orbital periods, and its induced stellar radial velocity half-amplitudes in the range $2 \,{\rm m\, s^{-1}} \lesssim K \lesssim 5\,{\rm m\, s^{-1}}$ is fundamentally unlike either our own solar system (in which only Jupiter and Saturn induce significant reflex velocities for the Sun), or the Kepler multiple-transiting systems (which tend to have much more compact orbital configurations)Comment: 10 pages, 11 figure

A Randomised Trial to Compare the Safety, Tolerability and Efficacy of Three Drug Combinations for Intermittent Preventive Treatment in Children

BACKGROUND: Results from trials of intermittent preventive treatment (IPT) in infants and children have shown that IPT provides significant protection against clinical malaria. Sulfadoxine-pyrimethamine (SP) given alone or in combination with other drugs has been used for most IPT programmes. However, SP resistance is increasing in many parts of Africa. Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ) and dihydroartemisinin (DHA) plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission. METHODS: During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ), SP plus piperaquine (PQ) or dihydroartemisinin (DHA) plus PQ at monthly intervals on three occasions during the peak malaria transmission season. To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed. To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages. Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season. RESULTS: All three treatment regimens showed good safety profiles. No severe adverse event related to IPT was reported. The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite. Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group. The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22), 0.06 (95% CI: 0.022, 0.16) and 0.06 (95% CI: 0.02, 0.15) respectively. The incidence of malaria in the control group was 0.79 cases per child year (0.58, 1.08). CONCLUSION: All the three regimens of IPT in children were safe and highly efficacious TRIAL REGISTRATION: ClinicalTrials.gov NCT00561899

Cost-eff ectiveness of diff erent strategies to monitor adults on antiretroviral treatment: a combined analysis of three mathematical models

Background WHO’s 2013 revisions to its Consolidated Guidelines on antiretroviral drugs recommend routine viral load monitoring, rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most costeff ective use of resources in view of other competing priorities such as expansion of antiretroviral therapy coverage. We assessed the cost-eff ectiveness of alternative patient monitoring strategies. Methods We evaluated a range of monitoring strategies, including clinical, CD4 cell count, and viral load monitoring, alone and together, at diff erent frequencies and with diff erent criteria for switching to second-line therapies. We used three independently constructed and validated models simultaneously. We estimated costs on the basis of resource use projected in the models and associated unit costs; we quantifi ed impact as disability-adjusted life years (DALYs) averted. We compared alternatives using incremental cost-eff ectiveness analysis. Findings All models show that clinical monitoring delivers signifi cant benefi t compared with a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefi t over clinical monitoring alone, at an incremental cost that makes it aff ordable in more settings than viral load monitoring, which is currently more expensive. Viral load monitoring without CD4 cell count every 6–12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing antiretroviral therapy coverage or expanding antiretroviral therapy eligibility. Interpretation The priority for HIV programmes should be to expand antiretroviral therapy coverage, fi rstly at CD4 cell count lower than 350 cells per μL, and then at a CD4 cell count lower than 500 cells per μL, using lower-cost clinical or CD4 monitoring. At current costs, viral load monitoring should be considered only after high antiretroviral therapy coverage has been achieved. Point-of-care technologies and other factors reducing costs might make viral load monitoring more aff ordable in future

Elevated Plasma IL-6 Associates with Increased Risk of Advanced Fibrosis and Cholangiocarcinoma in Individuals Infected by Opisthorchis viverrini

Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and increasing risk of advanced fibrosis and bile duct cancer; for example, in age and sex adjusted analyses, individuals with the highest quartiles of plasma IL-6 had a 19 times greater risk of developing advanced periductal fibrosis and a 150 times greater risk of developing of bile duct cancer than individuals with no detectable level of plasma IL-6. Finally, we show that a single plasma IL-6 measurement has excellent positive predictive value for the detection of both advanced bile duct fibrosis and bile duct cancer in regions with high O. viverrini transmission. These data support our hypothesis that common mechanisms drive bile duct fibrosis and bile duct tumorogenesis from chronic O. viverrini infection. Our study also adds a unique aspect to the literature on circulating levels of IL-6 as an immune marker of hepatobiliary pathology by showing that high levels of circulating IL-6 in plasma are not related to infection with O. viverrini, but to the development of the advanced and often lethal pathologies resulting from chronic O. viverrini infection

Protection from annual flooding is correlated with increased cholera prevalence in Bangladesh: a zero-inflated regression analysis

<p>Abstract</p> <p>Background</p> <p>Alteration of natural or historical aquatic flows can have unintended consequences for regions where waterborne diseases are endemic and where the epidemiologic implications of such change are poorly understood. The implementation of flood protection measures for a portion of an intensely monitored population in Matlab, Bangladesh, allows us to examine whether cholera outcomes respond positively or negatively to measures designed to control river flooding.</p> <p>Methods</p> <p>Using a zero inflated negative binomial model, we examine how selected covariates can simultaneously account for household clusters reporting no cholera from those with positive counts as well as distinguishing residential areas with low counts from areas with high cholera counts. Our goal is to examine how residence within or outside a flood protected area interacts with the probability of cholera presence and the effect of flood protection on the magnitude of cholera prevalence.</p> <p>Results</p> <p>In Matlab, living in a household that is protected from annual monsoon flooding appears to have no significant effect on whether the household experiences cholera, net of other covariates. However, counter-intuitively, among households where cholera is reported, living within the flood protected region significantly increases the number of cholera cases.</p> <p>Conclusions</p> <p>The construction of dams or other water impoundment strategies for economic or social motives can have profound and unanticipated consequences for waterborne disease. Our results indicate that the construction of a flood control structure in rural Bangladesh is correlated with an increase in cholera cases for residents protected from annual monsoon flooding. Such a finding requires attention from both the health community and from governments and non-governmental organizations involved in ongoing water management schemes.</p

Unlocking the Transcriptomes of Two Carcinogenic Parasites, Clonorchis sinensis and Opisthorchis viverrini

The two parasitic trematodes, Clonorchis sinensis and Opisthorchis viverrini, have a major impact on the health of tens of millions of humans throughout Asia. The greatest impact is through the malignant cancer ( = cholangiocarcinoma) that these parasites induce in chronically infected people. Therefore, both C. sinensis and O. viverrini have been classified by the World Health Organization (WHO) as Group 1 carcinogens. Despite their impact, little is known about these parasites and their interplay with the host at the molecular level. Recent advances in genomics and bioinformatics provide unique opportunities to gain improved insights into the biology of parasites as well as their relationships with their hosts at the molecular level. The present study elucidates the transcriptomes of C. sinensis and O. viverrini using a platform based on next-generation (high throughput) sequencing and advanced in silico analyses. From 500,000 sequences, >50,000 sequences were assembled for each species and categorized as biologically relevant based on homology searches, gene ontology and/or pathway mapping. The results of the present study could assist in defining molecules that are essential for the development, reproduction and survival of liver flukes and/or that are linked to the development of cholangiocarcinoma. This study also lays a foundation for future genomic and proteomic research of C. sinensis and O. viverrini and the cancers that they are known to induce, as well as novel intervention strategies

A Comparative Chemogenomics Strategy to Predict Potential Drug Targets in the Metazoan Pathogen, Schistosoma mansoni

Schistosomiasis is a prevalent and chronic helmintic disease in tropical regions. Treatment and control relies on chemotherapy with just one drug, praziquantel and this reliance is of concern should clinically relevant drug resistance emerge and spread. Therefore, to identify potential target proteins for new avenues of drug discovery we have taken a comparative chemogenomics approach utilizing the putative proteome of Schistosoma mansoni compared to the proteomes of two model organisms, the nematode, Caenorhabditis elegans and the fruitfly, Drosophila melanogaster. Using the genome comparison software Genlight, two separate in silico workflows were implemented to derive a set of parasite proteins for which gene disruption of the orthologs in both the model organisms yielded deleterious phenotypes (e.g., lethal, impairment of motility), i.e., are essential genes/proteins. Of the 67 and 68 sequences generated for each workflow, 63 were identical in both sets, leading to a final set of 72 parasite proteins. All but one of these were expressed in the relevant developmental stages of the parasite infecting humans. Subsequent in depth manual curation of the combined workflow output revealed 57 candidate proteins. Scrutiny of these for ‘druggable’ protein homologs in the literature identified 35 S. mansoni sequences, 18 of which were homologous to proteins with 3D structures including co-crystallized ligands that will allow further structure-based drug design studies. The comparative chemogenomics strategy presented generates a tractable set of S. mansoni proteins for experimental validation as drug targets against this insidious human pathogen

The LCES HIRES/Keck Precision Radial Velocity Exoplanet Survey

This document is the Accepted Manuscript version of the following article: R. Paul Butler, et al, The LCES HIRES/Keck Precision Radial Velocity Exoplanet Survey, The Astronomical Journal, Vol 153 (5), 19 pp., published 13 April 2017. The Version of Record is available online at doi: https://doi.org/10.3847/1538-3881/aa66ca. Paper data available at: http://home.dtm.ciw.edu/ebps/data/. © 2017. The American Astronomical Society. All rights reserved.We describe a 20-year survey carried out by the Lick-Carnegie Exoplanet Survey Team (LCES), using precision radial velocities from HIRES on the Keck-I telescope to find and characterize extrasolar planetary systems orbiting nearby F, G, K, and M dwarf stars. We provide here 60,949 precision radial velocities for 1,624 stars contained in that survey. We tabulate a list of 357 significant periodic signals that are of constant period and phase, and not coincident in period and/or phase with stellar activity indices. These signals are thus strongly suggestive of barycentric reflex motion of the star induced by one or more candidate exoplanets in Keplerian motion about the host star. Of these signals, 225 have already been published as planet claims, 60 are classified as significant unpublished planet candidates that await photometric follow-up to rule out activity-related causes, and 54 are also unpublished, but are classified as "significant" signals that require confirmation by additional data before rising to classification as planet candidates. Of particular interest is our detection of a candidate planet with a minimum mass of 3.9 Earth masses and an orbital period of 9.9 days orbiting Lalande 21185, the fourth-closest main sequence star to the Sun. For each of our exoplanetary candidate signals, we provide the period and semi-amplitude of the Keplerian orbital fit, and a likelihood ratio estimate of its statistical significance. We also tabulate 18 Keplerian-like signals that we classify as likely arising from stellar activity.Peer reviewedFinal Accepted Versio

A Computational Approach to Finding Novel Targets for Existing Drugs

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects