Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection

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Alphacoronaviruses in New World Bats: Prevalence, Persistence, Phylogeny, and Potential for Interaction with Humans

Bats are reservoirs for many different coronaviruses (CoVs) as well as many other important zoonotic viruses. We sampled feces and/or anal swabs of 1,044 insectivorous bats of 2 families and 17 species from 21 different locations within Colorado from 2007 to 2009. We detected alphacoronavirus RNA in bats of 4 species: big brown bats (Eptesicus fuscus), 10% prevalence; long-legged bats (Myotis volans), 8% prevalence; little brown bats (Myotis lucifugus), 3% prevalence; and western long-eared bats (Myotis evotis), 2% prevalence. Overall, juvenile bats were twice as likely to be positive for CoV RNA as adult bats. At two of the rural sampling sites, CoV RNAs were detected in big brown and long-legged bats during the three sequential summers of this study. CoV RNA was detected in big brown bats in all five of the urban maternity roosts sampled throughout each of the periods tested. Individually tagged big brown bats that were positive for CoV RNA and later sampled again all became CoV RNA negative. Nucleotide sequences in the RdRp gene fell into 3 main clusters, all distinct from those of Old World bats. Similar nucleotide sequences were found in amplicons from gene 1b and the spike gene in both a big-brown and a long-legged bat, indicating that a CoV may be capable of infecting bats of different genera. These data suggest that ongoing evolution of CoVs in bats creates the possibility of a continued threat for emergence into hosts of other species. Alphacoronavirus RNA was detected at a high prevalence in big brown bats in roosts in close proximity to human habitations (10%) and known to have direct contact with people (19%), suggesting that significant potential opportunities exist for cross-species transmission of these viruses. Further CoV surveillance studies in bats throughout the Americas are warranted

Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes

Transcriptome Analysis of the Desert Locust Central Nervous System: Production and Annotation of a Schistocerca gregaria EST Database

) displays a fascinating type of phenotypic plasticity, designated as ‘phase polyphenism’. Depending on environmental conditions, one genome can be translated into two highly divergent phenotypes, termed the solitarious and gregarious (swarming) phase. Although many of the underlying molecular events remain elusive, the central nervous system (CNS) is expected to play a crucial role in the phase transition process. Locusts have also proven to be interesting model organisms in a physiological and neurobiological research context. However, molecular studies in locusts are hampered by the fact that genome/transcriptome sequence information available for this branch of insects is still limited. EST information is highly complementary to the existing orthopteran transcriptomic data. Since many novel transcripts encode neuronal signaling and signal transduction components, this paper includes an overview of these sequences. Furthermore, several transcripts being differentially represented in solitarious and gregarious locusts were retrieved from this EST database. The findings highlight the involvement of the CNS in the phase transition process and indicate that this novel annotated database may also add to the emerging knowledge of concomitant neuronal signaling and neuroplasticity events. EST data constitute an important new source of information that will be instrumental in further unraveling the molecular principles of phase polyphenism, in further establishing locusts as valuable research model organisms and in molecular evolutionary and comparative entomology

Measuring the population burden of injuries-implications for global and national estimates: A multicentre prospective UK longitudinal study

Current methods of measuring the population burden of injuries rely on many assumptions and limited data available to the global burden of diseases (GBD) studies. The aim of this study was to compare the population burden of injuries using different approaches from the UK Burden of Injury (UKBOI) and GBD studies.The UKBOI was a prospective cohort of 1,517 injured individuals that collected patient-reported outcomes. Extrapolated outcome data were combined with multiple sources of morbidity and mortality data to derive population metrics of the burden of injury in the UK. Participants were injured patients recruited from hospitals in four UK cities and towns: Swansea, Nottingham, Bristol, and Guildford, between September 2005 and April 2007. Patient-reported changes in quality of life using the EQ-5D at baseline, 1, 4, and 12 months after injury provided disability weights used to calculate the years lived with disability (YLDs) component of disability adjusted life years (DALYs). DALYs were calculated for the UK and extrapolated to global estimates using both UKBOI and GBD disability weights. Estimated numbers (and rates per 100,000) for UK population extrapolations were 750,999 (1,240) for hospital admissions, 7,982,947 (13,339) for emergency department (ED) attendances, and 22,185 (36.8) for injury-related deaths in 2005. Nonadmitted ED-treated injuries accounted for 67% of YLDs. Estimates for UK DALYs amounted to 1,771,486 (82% due to YLDs), compared with 669,822 (52% due to YLDs) using the GBD approach. Extrapolating patient-derived disability weights to GBD estimates would increase injury-related DALYs 2.6-fold.The use of disability weights derived from patient experiences combined with additional morbidity data on ED-treated patients and inpatients suggests that the absolute burden of injury is higher than previously estimated. These findings have substantial implications for improving measurement of the national and global burden of injury

Neutrinos

229 pages229 pages229 pagesThe Proceedings of the 2011 workshop on Fundamental Physics at the Intensity Frontier. Science opportunities at the intensity frontier are identified and described in the areas of heavy quarks, charged leptons, neutrinos, proton decay, new light weakly-coupled particles, and nucleons, nuclei, and atoms

The impact of injuries study. Multicentre study assessing physical, psychological, social and occupational functioning post injury - a protocol

Background: Large numbers of people are killed or severely injured following injuries each year and these injuries place a large burden on health care resources. The majority of the severely injured are not fully recovered 12-18 months later. Psychological disorders are common post injury and are associated with poorer functional and occupational outcomes. Much of this evidence comes from countries other than the UK, with differing health care and compensation systems. Early interventions can be effective in treating psychological morbidity, hence the scale and nature of the problem and its impact of functioning in the UK must be known before services can be designed to identify and manage psychological morbidity post injury. Methods/Design : A longitudinal multi-centre study of 680 injured patients admitted to hospital in four areas across the UK: Nottingham, Leicester/Loughborough, Bristol and Surrey. A stratified sample of injuries will ensure a range of common and less common injuries will be included. Participants will complete a baseline questionnaire about their injury and pre-injury quality of life, and follow-up questionnaires 1, 2, 4, and 12 months post injury. Measures will include health and social care utilisation, perceptions of recovery, physical, psychological, social and occupational functioning and health-related quality of life. A nested qualitative study will explore the experiences of a sample of participants, their carers and service providers to inform service design. Discussion: This study will quantify physical, psychological, social and occupational functioning and health and social care utilisation following a range of different types of injury and will assess the impact of psychological disorders on function and health service use. The findings will be used to guide the development of interventions to maximise recovery post injury

Influence of provider experience on antiretroviral adherence and viral suppression

Michael A Horberg,1,2 Leo B Hurley,2,3 William J Towner,4 Michael W Allerton,3 Beth T Tang,5 Sheryl L Catz,6 Michael J Silverberg,2,3 Charles P Quesenberry31Mid-Atlantic Permanente Research Institute, Rockville, MD, USA; 2HIV Initiative, Kaiser Permanente, Oakland, CA, USA; 3Kaiser Permanente Northern California, Oakland, CA, USA; 4Kaiser Permanente Southern California, Los Angeles, CA, USA; 5Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA; 6Group Health Research Institute, Seattle, WA, USABackground and aim: Early in the combination antiretroviral therapy (cART) era, provider experience (as measured by panel size) was associated with improved outcomes. We explored that association and other characteristics of provider experience.Methods: We performed a retrospective cohort analysis in Kaiser Permanente California (an integrated health care system in the United States), examining all human immunodeficiency virus seropositive (HIV+) patients initiating a first cART regimen (antiretroviral therapy [ART]-naïve, N = 7071) or initiating a second or later cART regimen (ART-experienced, N = 3730) from 1996–2006. We measured ART adherence through 12 months (pharmacy fill and refill records) and determined HIV viral load levels below limits of quantification at 12 months. Provider experience, updated annually, was measured as (1) HIV panel size (0–10 patients as reference strata), (2) years treating HIV (less than 1 year as reference), and (3) specialty (noninfectious disease specialty, non-HIV expert as reference). We assessed associations by utilizing mixed modeling analyses (clustered by provider and medical center), controlling for patient age, sex, race/ethnicity, HIV risk behavior, hepatitis C coinfection, ART regimen class, and calendar year.Results: Among the ART-experienced, improved adherence was associated with greater years experience (mean increase 3.1% 2–5 years experience; 3.7% 5–10 years; 2.7% 11–20 years; P = 0.07, categorical). In adjusted analyses, viral suppression among ART-naïve was positively associated with panel size (odds ratio 26–50 patients: 1.31, P = 0.03, categorical), but negatively associated with years experience (18% less for greater than 100 patients; P = 0.003). No provider characteristic was significantly associated with improved adherence among ART-naïve or odds of maximal viral suppression among ART-experienced in adjusted analysis.Conclusions: Except for panel size and years experience among ART-naïve, provider characteristics did not significantly influence ART adherence or likelihood of viral suppression.Keywords: antiretroviral therapy, adherence, provider-level factors, HIV-related outcome