The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design

Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdon: multicentre cohort study

Objectives: To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. Design: Multicentre cohort study. Setting: Six large HIV treatment centres in southeast England. Participants: All individuals seen for care between 1 January 1996 and 31 December 2002. Main outcome measures: Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. Results: Information is available on 16 593 individuals (13 378 (80.6%) male patients, 10 340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16 593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of “viral load failure” with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. Conclusions: The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients

Toward High-Precision Measures of Large-Scale Structure

I review some results of estimation of the power spectrum of density fluctuations from galaxy redshift surveys and discuss advances that may be possible with the Sloan Digital Sky Survey. I then examine the realities of power spectrum estimation in the presence of Galactic extinction, photometric errors, galaxy evolution, clustering evolution, and uncertainty about the background cosmology.Comment: 24 pages, including 11 postscript figures. Uses crckapb.sty (included in submission). To appear in ``Ringberg Workshop on Large-Scale Structure,'' ed D. Hamilton (Kluwer, Amsterdam), p. 39

Multiple Start Modifications of Ant Colony Algorithm for Multiversion Software Design

The paper discusses the use of an optimization algorithm based on the behaviour of the ant colony to solve the problem of forming the composition of a multiversion fault-tolerant software package. A model for constructing a graph for the implementation of the ant algorithm for the selected task is proposed. The modifications of the basic algorithm for both the ascending and the descending design styles of software systems are given. When optimizing for downstream design, cost, reliability, and evaluation of the successful implementation of each version with the specified characteristics are taken into account. When optimizing for up-stream design, reliability and resource intensity indicators are taken into account, as there is a selection from already implemented software modules. A method is proposed for increasing the efficiency of the ant algorithm, which consists in launching a group of “test” ants, choosing the best solution from this group and further calculating on the basis of it. A software system that implements both modifications of the basic ant algorithm for both design styles, as well as the possibility of applying the proposed multiple start technique to both modifications, is considered. The results of calculations obtained using the proposed software tool are considered. The results confirm the applicability of ant algorithms to the problem of forming a multiversion software package, and show the effectiveness of the proposed method

Protecting eyewitness evidence: Examining the efficacy of a self-administered interview tool

Given the crucial role of eyewitness evidence, statements should be obtained as soon as possible after an incident. This is not always achieved due to demands on police resources. Two studies trace the development of a new tool, the Self-Administered Interview (SAI), designed to elicit a comprehensive initial statement. In Study 1, SAI participants reported more correct details than participants who provided a free recall account, and performed at the same level as participants given a Cognitive Interview. In Study 2, participants viewed a simulated crime and half recorded their statement using the SAI. After a delay of 1 week, all participants completed a free recall test. SAI participants recalled more correct details in the delayed recall task than control participants

Sprint interval and moderate-intensity continuous training have equal benefits on aerobic capacity, insulin sensitivity, muscle capillarisation and endothelial eNOS/NAD(P)Hoxidase protein ratio in obese men

Sprint interval training (SIT) has been proposed as a time efficient alternative to moderate-intensity continuous training (MICT), leading to similar improvements in skeletal muscle capillary density and microvascular function in young healthy humans. In this study we made the first comparisons of the muscle microvascular response to SIT and MICT in an obese population. Sixteen young obese men (age 25±1 yr, BMI 34.8±0.9 kg.m-2) were randomly assigned to 4 weeks of MICT (40-60 min cycling at ~65% VO2peak, 5 times per wk.) or constant load SIT (4-7 constant workload intervals of 200% Wattmax 3 times per wk.). Muscle biopsies were taken before and after training from the m. vastus lateralis to measure muscle microvascular endothelial eNOS content, eNOS serine1177 phosphorylation, NOX2 content and capillarization using quantitative immunofluorescence microscopy. Maximal aerobic capacity (VO2peak), whole body insulin sensitivity and arterial stiffness were also assessed. SIT and MICT increased skeletal muscle microvascular eNOS content and eNOS ser1177 phosphorylation in terminal arterioles and capillaries (P<0.05), but the later effect was eliminated when normalised to eNOS content (P = 0.217). SIT and MICT also reduced microvascular endothelial NOX2 content (P<0.05) and both increased capillary density and capillary-fibre-perimeter exchange index (P<0.05). In parallel, SIT and MICT increased VO2peak (P<0.05), whole body insulin sensitivity (P<0.05) and reduced central artery stiffness (P<0.05). As no significant differences were observed between SIT and MICT it is concluded that SIT is a time efficient alternative to MICT to improve aerobic capacity, insulin sensitivity and muscle capillarisation and endothelial eNOS/NAD(P)Hoxidase protein ratio in young obese men

Switching the World's Salt Supply—Learning from Iodization to Achieve Potassium Enrichment

Sodium is an essential dietary component, but excess sodium intake can lead to high blood pressure and an increased risk of cardiovascular disease. Many national and international bodies, including the World Health Organization, have advocated for population-wide sodium reduction interventions. Most have been unsuccessful due to inadequate sodium reduction by food industry and difficulties in persuading consumers to add less salt to food. Recent research highlights potassium-enriched salt as a new, feasible, acceptable, and scalable approach to reducing the harms caused by excess sodium and inadequate potassium consumption. Modeling shows that a global switch from regular salt to potassium-enriched salt has the potential to avert millions of strokes, heart attacks, and premature deaths worldwide each year. There will be many challenges in switching the world's salt supply to potassium-enriched salt, but the success of universal salt iodization shows that making a global change to the manufacture and use of salt is a tractable proposition. This in-depth review of universal salt iodization identified the importance of a multisectoral effort with strong global leadership, the support of multilateral organizations, engagement with the salt industry, empowered incountry teams, strong participation of national governments, understanding the salt supply chain, and a strategic advocacy and communication plan. Key challenges to the implementation of the iodization program were costs to government, industry, and consumers, industry concerns about consumer acceptability, variance in the size and capabilities of salt producers, inconsistent quality control, ineffective regulation, and trade-related regulatory issues. Many of the opportunities and challenges to universal salt iodization will likely also be applicable to switching the global salt supply to iodized and potassium-enriched salt

Evaluation of Microwave Steam Bags for the Decontamination of Filtering Facepiece Respirators

Reusing filtering facepiece respirators (FFRs) has been suggested as a strategy to conserve available supplies for home and healthcare environments during an influenza pandemic. For reuse to be possible, used FFRs must be decontaminated before redonning to reduce the risk of virus transmission; however, there are no approved methods for FFR decontamination. An effective method must reduce the microbial threat, maintain the function of the FFR, and present no residual chemical hazard. The method should be readily available, inexpensive and easily implemented by healthcare workers and the general public. Many of the general decontamination protocols used in healthcare and home settings are unable to address all of the desired qualities of an efficient FFR decontamination protocol. The goal of this study is to evaluate the use of two commercially available steam bags, marketed to the public for disinfecting infant feeding equipment, for FFR decontamination. The FFRs were decontaminated with microwave generated steam following the manufacturers' instructions then evaluated for water absorption and filtration efficiency for up to three steam exposures. Water absorption of the FFR was found to be model specific as FFRs constructed with hydrophilic materials absorbed more water. The steam had little effect on FFR performance as filtration efficiency of the treated FFRs remained above 95%. The decontamination efficacy of the steam bag was assessed using bacteriophage MS2 as a surrogate for a pathogenic virus. The tested steam bags were found to be 99.9% effective for inactivating MS2 on FFRs; however, more research is required to determine the effectiveness against respiratory pathogens

Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas

INTRODUCTION: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity. MATERIALS AND METHODS: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment. RESULTS: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care. CONCLUSION: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management

A Unifying Framework for Evaluating the Predictive Power of Genetic Variants Based on the Level of Heritability Explained

An increasing number of genetic variants have been identified for many complex diseases. However, it is controversial whether risk prediction based on genomic profiles will be useful clinically. Appropriate statistical measures to evaluate the performance of genetic risk prediction models are required. Previous studies have mainly focused on the use of the area under the receiver operating characteristic (ROC) curve, or AUC, to judge the predictive value of genetic tests. However, AUC has its limitations and should be complemented by other measures. In this study, we develop a novel unifying statistical framework that connects a large variety of predictive indices together. We showed that, given the overall disease probability and the level of variance in total liability (or heritability) explained by the genetic variants, we can estimate analytically a large variety of prediction metrics, for example the AUC, the mean risk difference between cases and non-cases, the net reclassification improvement (ability to reclassify people into high- and low-risk categories), the proportion of cases explained by a specific percentile of population at the highest risk, the variance of predicted risks, and the risk at any percentile. We also demonstrate how to construct graphs to visualize the performance of risk models, such as the ROC curve, the density of risks, and the predictiveness curve (disease risk plotted against risk percentile). The results from simulations match very well with our theoretical estimates. Finally we apply the methodology to nine complex diseases, evaluating the predictive power of genetic tests based on known susceptibility variants for each trait