Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.

Summary The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.

In southern Vietnam, a four-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter). The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's nine-year-old sister had died from a similar syndrome two weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis. Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought.

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BackgroundRegional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.Methods and FindingsWe reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.ConclusionsMost TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance...

BACKGROUND: Active surveillance (AS) is an attempt to avoid overtreatment of clinically insignificant prostate cancer (PCa); however, patient selection remains controversial. Multiparametric prostate magnetic resonance imaging (MP-MRI) may help better select AS candidates. METHODS: We reviewed a cohort of men who underwent MP-MRI with MRI=Ultrasound fusion-guided prostate biopsy and selected potential AS patients at entry using Johns Hopkins criteria. MP-MRI findings were assessed, including number of lesions, dominant lesion diameter, total lesion volume, prostate volume, and lesion density (calculated as total lesion volume=prostate volume). Lesions were assigned a suspicion score for cancer by MRI. AS criteria were reapplied based on the confirmatory biopsy, and accuracy of MP-MRI in predicting AS candidacy was assessed. Logistic regression modeling and chi-square statistics were used to assess associations between MP-MRI interpretation and biopsy results. RESULTS: Eighty-five patients qualified for AS with a mean age of 60.2 years and mean prostate-specific antigen level of 4.8 ng=mL. Of these, 25 patients (29%) were reclassified as not meeting AS criteria based on confirmatory biopsy. Number of lesions, lesion density, and highest MRI lesion suspicion were significantly associated with confirmatory biopsy AS reclassification. These MRI-based factors were combined to create a nomogram that generates a probability for confirmed AS candidacy. CONCLUSION: As clinicians counsel patients with PCa, MP-MRI may contribute to the decision-making process when considering AS. Three MRI-based factors (number of lesions, lesion suspicion, and lesion density) were associated with confirmatory biopsy outcome and reclassification. A nomogram using these factors has promising predictive accuracy for which future validation is necessary.

SUMMARYPerformance engineering of parallel and distributed applications is a complex task that iterates through various phases, ranging from modeling and prediction, to performance measurement, experiment management, data collection, and bottleneck analysis. There is no evidence so far that all of these phases should/can be integrated into a single monolithic tool. Moreover, the emergence of computational Grids as a common single wide-area platform for high-performance computing raises the idea to provide tools as interacting Grid services that share resources, support interoperability among different users and tools, and, most importantly, provide omnipresent services over the Grid. We have developed the ASKALON tool set to support performance-oriented development of parallel and distributed (Grid) applications. ASKALON comprises four tools, coherently integrated into a service-oriented architecture. SCALEA is a performance instrumentation, measurement, and analysis tool of parallel and distributed applications. ZENTURIO is a general purpose experiment management tool with advanced support for multi-experiment performance analysis and parameter studies. AKSUM provides semi-automatic highlevel performance bottleneck detection through a special-purpose performance property specification language. The PerformanceProphet enables the user to model and predict the performance of parallel applications at the early stages of development. In this paper we describe the overall architecture of the ASKALON tool set and outline the basic functionality of the four constituent tools. The structure of each tool is based on the composition and sharing of remote Grid services, thus enabling tool interoperability. In addition, a data repository allows the tools to share the common application performance and output data that have been derived by the individual tools. A service repository is used to store common portable Grid service implementations. A general-purpose Factory service is employed to create service instances on arbitrary remote Grid sites. Discovering and dynamically binding to existing remote services is achieved through registry services. The ASKALON visualization diagrams support both online and postmortem visualization of performance and output data. We demonstrate the usefulness and effectiveness of ASKALON by applying the tools to real-world applications.

Purpose of this paperThis survey aims at studying and analyzing current techniques and methods for context-aware Web service systems, discussing future trends and proposing further steps on making Web services systems being context-aware.Design/methodology/approach We analyzed and compared existing context-aware Web servicebased systems based on techniques they support, such as context information modeling, context sensing, distribution, security and privacy, and adaptation techniques. Existing systems are also examined in terms of application domains, system type, mobility support, multi-organization support and level of Web services implementation. FindingsSupporting context-aware Web service-based systems is increasing. It is hard to find a truly context-aware Web service-based system that is interoperable and secure, and operates on multiorganizational environments. Various issues, such as distributed context management, context-aware service modeling and engineering, context reasoning and quality of context, security and privacy issues have not been well addressed. Research limitations/implications (if applicable)The number of systems analyzed is limited. Furthermore, the survey is based on published papers. Therefore, up-to-date information and development might not be taken into account.What is original/value of paper Existing surveys do not focus on context-awareness techniques for Web services. This paper helps to understand the state of the art in context-aware techniques for Web services that can be employed in the future of services which is built around, amongst other, mobile devices, Web services, and pervasive environments.A previous version of this paper was published, as an invited paper, in the International Journal of Web Information Systems, 5(