Efficacy and safety of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup

Background Lumacaftor/ivacaftor combination therapy demonstrated clinical benefits inpatients with cystic fibrosis homozygous for the Phe508del CFTR mutation.Pretreatment lung function is a confounding factor that potentially impacts the efficacyand safety of lumacaftor/ivacaftor therapy. Methods Two multinational, randomised, double-blind, placebo-controlled, parallelgroupPhase 3 studies randomised patients to receive placebo or lumacaftor (600 mgonce daily [qd] or 400 mg every 12 hours [q12h]) in combination with ivacaftor (250 mgq12h) for 24 weeks. Prespecified analyses of pooled efficacy and safety data by lungfunction, as measured by percent predicted forced expiratory volume in 1 second(ppFEV1), were performed for patients with baseline ppFEV1 <40 (n=81) and ≥40(n=1016) and screening ppFEV1 <70 (n=730) and ≥70 (n=342). These studies wereregistered with ClinicalTrials.gov (NCT01807923 and NCT01807949). Findings The studies were conducted from April 2013 through April 2014.Improvements in the primary endpoint, absolute change from baseline at week 24 inppFEV1, were observed with both lumacaftor/ivacaftor doses in the subgroup withbaseline ppFEV1 <40 (least-squares mean difference versus placebo was 3∙7 and 3.3percentage points for lumacaftor 600 mg qd/ivacaftor 250 mg q12h and lumacaftor 400mg q12h/ivacaftor 250 mg q12h, respectively [p<0∙05] and in the subgroup with baselineppFEV1 ≥40 (3∙3 and 2∙8 percentage points, respectively [p<0∙001]). Similar absoluteimprovements versus placebo in ppFEV1 were observed in subgroups with screening 4ppFEV1 <70 (3∙3 and 3∙3 percentage points for lumacaftor 600 mg qd/ivacaftor 250 mgq12h and lumacaftor 400 mg q12h/ivacaftor 250 mg q12h, respectively [p<0∙001]) and≥70 (3∙3 and 1∙9 percentage points, respectively [p=0.002] and [p=0∙079]). Increases inBMI and reduction in number of pulmonary exacerbation events were observed in bothLUM/IVA dose groups vs placebo across all lung function subgroups. Treatment wasgenerally well tolerated, although the incidence of some respiratory adverse events washigher with active treatment than with placebo. Interpretation Lumacaftor/ivacaftor combination therapy benefits patients homozygousfor Phe508del CFTR who have varying degrees of lung function impairment. Funding Vertex Pharmaceuticals Incorporated.

Exploring molecular variation in Schistosoma japonicum in China

Schistosomiasis is a neglected tropical disease that affects more than 200 million people worldwide. The main disease-causing agents, Schistosoma japonicum, S. mansoni and S. haematobium, are blood flukes that have complex life cycles involving a snail intermediate host. In Asia, S. japonicum causes hepatointestinal disease (schistosomiasis japonica) and is challenging to control due to a broad distribution of its snail hosts and range of animal reservoir hosts. In China, extensive efforts have been underway to control this parasite, but genetic variability in S. japonicum populations could represent an obstacle to eliminating schistosomiasis japonica. Although a draft genome sequence is available for S. japonicum, there has been no previous study of molecular variation in this parasite on a genome-wide scale. In this study, we conducted the first deep genomic exploration of seven S. japonicum populations from mainland China, constructed phylogenies using mitochondrial and nuclear genomic data sets, and established considerable variation between some of the populations in genes inferred to be linked to key cellular processes and/or pathogen-host interactions. Based on the findings from this study, we propose that verifying intraspecific conservation in vaccine or drug target candidates is an important first step toward developing effective vaccines and chemotherapies against schistosomiasis.

Agricultural show awards : a brief exploration of their role marketing food products

The Effect of Supportive Social Interaction Priming on Children's Prosocial Comforing Responses to Distressed Others

The ability to sensitively care for others’ wellbeing develops early in ontogeny and is an important developmental milestone for healthy social, emotional, and moral development. One facet of care for others, prosocial comforting, has been linked with important social outcomes such as peer acceptance and friendship quality, underscoring the importance of determining factors involved in the ability to comfort. Although social support has been linked with a number of important social outcomes, no study has directly examined whether felt social support can foster children’s positive behavior toward others. The purpose of the current investigation was to use an experimental priming paradigm to demonstrate that felt social support a) enhances children’s ability to respond prosocially to the distress of others and b) decreases children’s expressions of personal distress when faced with the distress of another person. Participants were 94 4-year-old children (M = 53.56 months, SD = 3.38 months; 52 girls). Children were randomly assigned to either view pictures of mothers and children in close, personal interactions (supportive social interaction condition), happy women and children in separate pictures, presented side-by-side (happy control condition), or pictures of colorful overlapping shapes (neutral control condition). Each set of 20 pictures was presented in the context of a categorization computer game that participants played 4 times throughout the course of the study. Immediately following the first three computer games, children were given the opportunity to comfort someone who was distressed; twice it was the adult experimenter working with the child, and once it was an unseen infant crying over a monitor that participants had been trained to use. Comforting behaviors and distress/arousal were coded in 10-second time segments and yielded a global comforting score and a distress proportion score for each task. Results indicated that priming condition had no effect on either prosocial comforting behavior or expressions of personal distress. I discuss these null findings in light of the available literatures on priming mental representations in children and on prosocial comforting, and suggest some future directions for continued investigation in both fields.

The spectral albedo of sea ice and salt crusts on the tropical ocean of Snowball Earth: II. Optical modeling

During the Snowball Earth events of the Neoproterozoic, tropical regions of the ocean could have developed a precipitated salt lag deposit left behind by sublimating sea ice. The major salt would have been hydrohalite, NaCl•2H2O. The crystals in such a deposit can be small and highly scattering, resulting in an allwave albedo similar to that of snow. The snow-free sea ice from which such a crust could develop has a lower albedo, around 0.5, so the development of a crust would substantially increase the albedo of tropical regions on Snowball Earth. Hydrohalite crystals are much less absorptive than ice in the near- infrared part of the solar spectrum, so their presence at the surface would increase the overall albedo as well as altering its spectral distribution. In this paper, we use laboratory measurements of the spectral albedo of a hydrohalite lag deposit, in combination with a radiative transfer model, to infer the inherent optical properties of hydrohalite as functions of wavelength. Using this result, we model mixtures of hydrohalite and ice representing both artificially created surfaces in the laboratory and surfaces relevant to Snowball Earth. The model is tested against sequences of laboratory measurements taken during the formation and the dissolution of a lag deposit of hydrohalite. We present a parameterization for the broadband albedo of cold, sublimating sea ice as it forms and evolves a hydrohalite crust, for use in climate models of Snowball Earth.

“Albedo dome”: a method for measuring spectral flux-reflectance in a laboratory for media with long optical paths

A method is presented for accurate measurement of spectral flux-reflectance (albedo) in a laboratory, for media with long optical path lengths, such as snow and ice. The approach uses an acrylic hemispheric dome, which, when placed over the surface being studied, serves two functions: (i) it creates an overcast “sky” to illuminate the target surface from all directions within a hemisphere, and (ii) serves as a platform for measuring incident and backscattered spectral radiances, which can be integrated to obtain fluxes. The fluxes are relative measurements and because their ratio is used to determine flux-reflectance, no absolute radiometric calibrations are required. The dome and surface must meet minimum size requirements based on the scattering properties of the surface. This technique is suited for media with long photon path lengths since the backscattered illumination is collected over a large enough area to include photons that reemerge from the domain far from their point of entry because of multiple scattering and small absorption. Comparison between field and laboratory albedo of a portable test surface demonstrates the viability of this method.

Hydrohalite in cold sea ice: Laboratory observations of single crystals, surface accumulations, and migration rates under a temperature gradient, with application to “Snowball Earth"

When NaCl precipitates out of a saturated solution, it forms anhydrous crystals of halite at temperatures above +0.11?C, but at temperatures below this threshold it instead precipitates as the dihydrate ‘‘hydrohalite,’’ NaCl * 2H2O. When sea ice is cooled, hydrohalite begins to precipitate within brine inclusions at about -23C. In this work, hydrohalite crystals are examined in laboratory experiments: their formation, their shape, and their response to warming and desiccation. Sublimation of a sea ice surface at low temperature leaves a lag deposit of hydrohalite, which has the character of a fine powder. The precipitation of hydrohalite in brine inclusions raises the albedo of sea ice, and the subsequent formation of a surface accumulation further raises the albedo. Although these processes have limited climatic importance on the modern Earth, they would have been important in determining the surface types present in regions of net sublimation on the tropical ocean in the cold phase of a Snowball Earth event. However, brine inclusions in sea ice migrate downward to warmer ice, so whether salt can accumulate on the surface depends on the relative rates of sublimation and migration. The migration rates are measured in a laboratory experiment at temperatures from -2C to -32C; the migration appears to be too slow to prevent formation of a salt crust on Snowball Earth.

UW Modern Music Ensemble presents Steve Reich An 80th Birthday Celebration with special guests UW Percussion Ensemble December 6, 2016

Concert Program

Iberian and Latin American Music Scholarship on the Ascent: Reflections from the United States

In the early twentieth century, musicology was established as an academic discipline in the United States. Nonetheless, with the exception of Iberian medieval and Renaissance repertories, U.S. scholars largely overlooked the music of the Spanish- and Portuguese- speaking world. Why should this have been the case, especially in light of Spain’s strong historical presence in the United States? This autobiographical essay examines this question by tracing the career of an individual musicologist, the Hispanist musicologist Carol A. Hess. Evaluated here are disciplinary shifts in U.S. musicology —methodological, philosophical, and ideological— over the past thirty years. These transformations have combined to make this repertory a viable field of study today. Musicologists in the United States can now make their careers by specializing in Iberian and Latin American music, as well as the music of the Hispanic diaspora. They research topics ranging from the avant-garde composer Llorenç Barber to the rapper Nach Scratch or the popular bandleader Xavier Cugat and his U.S. audiences of the 1940s, while others also pursue the time-tested areas of medieval and Renaissance music. Iberian and Latin American music is regularly offered in postsecondary institutions while instructors now have a variety of textbooks and other pedagogical resources from which to choose. All add up to a disciplinary freedom that would have been unthinkable only a few decades ago.