Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

Trial protocol: a multicentre randomised trial of first-line treatment pathways for newly diagnosed immune thrombocytopenia: standard steroid treatment versus combined steroid and mycophenolate. The FLIGHT trial

Introduction Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia-related bleeding. Current first-line ITP treatment is with high-dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate mofetil (MMF) is often used as the next treatment with efficacy in 50%–80% of patients and good tolerability but can take up to 2 months to work. Objective To test the hypothesis that MMF combined with corticosteroid is a more effective first-line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone. Design Multicentre, UK-based, open-label, randomised controlled trial. Setting Haematology departments in secondary care. Participants We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30x109/L who require first-line treatment. Patients will be followed up for a minimum of 12 months following randomisation. Primary outcome Time from randomisation to treatment failure defined as platelets <30x109/L and a need for second-line treatment. Secondary outcomes Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient-reported outcomes (quality of life, fatigue, impact of bleeding, care costs). Analysis The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as an HR with 95% CI, median time to event if more than 50% have had an event and illustrated with Kaplan-Meier curves. Cost-effectiveness will be based on the first 12 months from diagnosis

African American Emerging Adult Perspectives on Unintended Pregnancy and Meeting Their Needs With Mobile Technology: Mixed Methods Qualitative Study

Background: In the United States, a disproportionate number of unintended pregnancies occur among African Americans, particularly those in their later teenage years and early 20s. Mobile technology is becoming more ubiquitous as a method for health promotion; however, relatively little research has been done with this population to determine their perspectives about unintended pregnancy, the potential of successfully using mobile technology to prevent unintended pregnancy, and the content of such programs. Objective: The purpose of this study was to obtain the perspectives of African American emerging adults about unintended pregnancy and the use of mobile technology to reduce unintended pregnancy rates. Methods: Focus groups and interviews were conducted with 83 African Americans, aged 18-21 years. Data were analyzed using an open coding process. Emergent codes were then added as needed, and themes and subthemes were identified. Results: Participants cited the social environment and lack of education as primary reasons for disproportionate rates of unintended pregnancy. They noted that unintended pregnancy is an important issue and that they desire more sexual health information. They enthusiastically supported mobile technology as a means to communicate unintended pregnancy prevention programming and offered many suggestions for program content, look, and feel. Conclusions: Young and emerging adult African Americans want and need sexual health resources, and a mobile-based platform could be widely accepted and address needs to lower disproportionate rates of unintended pregnancy. An essential next step is to use these findings to inform the development of a mobile-based unintended pregnancy prevention and sexual health program prototype to determine feasibility

Pion absorption in ^4He

This paper presents a large solid angle measurement of the positive pion absorption cross section on ^4He and its decomposition into partial channels. A large fraction of the absorption cross section at incident pion kinetic energies of T_π+ =70, 118, 162, 239, and 330 MeV is due to multinucleon channels

Multinucleon emission following the pion absorption in N, Ar and Xe

Positive pion absorption was studied in an almost 4p geometry allowing simultaneous measurements of various charge and neutral multiplicities. Total absorption cross sections and its decomposition into the most important channels is determined. The results are presented for N, Ar and Xe nuclei at incident pion energies of 118,162 and 239 MeV. The role of multinucleon emission in the absorption process is emphasized

Energy Resolution Performance of the CMS Electromagnetic Calorimeter

The energy resolution performance of the CMS lead tungstate crystal electromagnetic calorimeter is presented. Measurements were made with an electron beam using a fully equipped supermodule of the calorimeter barrel. Results are given both for electrons incident on the centre of crystals and for electrons distributed uniformly over the calorimeter surface. The electron energy is reconstructed in matrices of 3 times 3 or 5 times 5 crystals centred on the crystal containing the maximum energy. Corrections for variations in the shower containment are applied in the case of uniform incidence. The resolution measured is consistent with the design goals

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Severe early onset preeclampsia: short and long term clinical, psychosocial and biochemical aspects

Preeclampsia is a pregnancy specific disorder commonly defined as de novo hypertension and proteinuria after 20 weeks gestational age. It occurs in approximately 3-5% of pregnancies and it is still a major cause of both foetal and maternal morbidity and mortality worldwide1. As extensive research has not yet elucidated the aetiology of preeclampsia, there are no rational preventive or therapeutic interventions available. The only rational treatment is delivery, which benefits the mother but is not in the interest of the foetus, if remote from term. Early onset preeclampsia (<32 weeks’ gestational age) occurs in less than 1% of pregnancies. It is, however often associated with maternal morbidity as the risk of progression to severe maternal disease is inversely related with gestational age at onset2. Resulting prematurity is therefore the main cause of neonatal mortality and morbidity in patients with severe preeclampsia3. Although the discussion is ongoing, perinatal survival is suggested to be increased in patients with preterm preeclampsia by expectant, non-interventional management. This temporising treatment option to lengthen pregnancy includes the use of antihypertensive medication to control hypertension, magnesium sulphate to prevent eclampsia and corticosteroids to enhance foetal lung maturity4. With optimal maternal haemodynamic status and reassuring foetal condition this results on average in an extension of 2 weeks. Prolongation of these pregnancies is a great challenge for clinicians to balance between potential maternal risks on one the eve hand and possible foetal benefits on the other. Clinical controversies regarding prolongation of preterm preeclamptic pregnancies still exist – also taking into account that preeclampsia is the leading cause of maternal mortality in the Netherlands5 - a debate which is even more pronounced in very preterm pregnancies with questionable foetal viability6-9. Do maternal risks of prolongation of these very early pregnancies outweigh the chances of neonatal survival? Counselling of women with very early onset preeclampsia not only comprises of knowledge of the outcome of those particular pregnancies, but also knowledge of outcomes of future pregnancies of these women is of major clinical importance. This thesis opens with a review of the literature on identifiable risk factors of preeclampsia

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good