In a phase 3 randomized trial of 1307 patients with rheumatoid arthritis receiving background methotrexate, the oral JAK1 and JAK2 inhibitor baricitinib showed superior efficacy to placebo and to the ...anti–tumor necrosis factor α monoclonal antibody adalimumab.
Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammatory synovitis and progressive joint destruction, which are associated with severe disability and increased mortality. Progress in treatment with the use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and biologic DMARDs that target tumor necrosis factor (TNF) has made clinical remission a realistic target.
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Activated Janus kinases (JAKs) play pivotal roles in intracellular signaling from cell-surface receptors for multiple cytokines implicated in the pathologic processes of rheumatoid arthritis.
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Baricitinib, an orally available small molecule, provides reversible inhibition of JAK1 and JAK2 and has shown clinical efficacy in studies . . .
The world population has doubled over the last half century. Yet, research on the psychological effects of human population density, once a popular topic, has decreased over the past few decades. ...Applying a fresh perspective to an old topic, we draw upon life history theory to examine the effects of population density. Across nations and across the U.S. states (Studies 1 and 2), we find that dense populations exhibit behaviors corresponding to a slower life history strategy, including greater future-orientation, greater investment in education, more long-term mating orientation, later marriage age, lower fertility, and greater parental investment. In Studies 3 and 4, experimentally manipulating perceptions of high density led individuals to become more future-oriented. Finally, in Studies 5 and 6, experimentally manipulating perceptions of high density seemed to lead to life-stage-specific slower strategies, with college students preferring to invest in fewer rather than more relationship partners, and an older MTurk sample preferring to invest in fewer rather than more children. This research sheds new insight on the effects of density and its implications for human cultural variation and society at large.
Hybridization occurs differentially across the genome in a balancing act between selection and migration. With the unprecedented resolution of contemporary sequencing technologies, selection and ...migration can now be effectively quantified such that researchers can identify genetic elements involved in introgression. Furthermore, genomic patterns can now be associated with ecologically relevant phenotypes, given availability of annotated reference genomes. We do so in North American box turtles (Terrapene) by deciphering how selection affects hybrid zones at the interface of species boundaries and identifying genetic regions potentially under selection that may relate to thermal adaptations. Such genes may impact physiological pathways involved in temperature‐dependent sex determination, immune system functioning and hypoxia tolerance. We contrasted these patterns across inter‐ and intraspecific hybrid zones that differ temporally and biogeographically. We demonstrate hybridization is broadly apparent in Terrapene, but with observed genomic cline patterns corresponding to species boundaries at loci potentially associated with thermal adaptation. These loci display signatures of directional introgression within intraspecific boundaries, despite a genome‐wide selective trend against intergrades. In contrast, outlier loci for interspecific comparisons exhibited evidence of being under selection against hybrids. Importantly, adaptations coinciding with species boundaries in Terrapene overlap with climatic boundaries and highlight the vulnerability of these terrestrial ectotherms to anthropogenic pressures.
The persistence of an invasive species is influenced by its reproductive ecology, and a successful control program must operate on this premise. However, the reproductive ecology of invasive species ...may be enigmatic due to factors that also limit their management, such as cryptic coloration and behavior. We explored the mating and reproductive ecology of the invasive Brown Treesnake (BTS: Boiga irregularis) by reconstructing a multigenerational genomic pedigree based on 654 single nucleotide polymorphisms for a geographically closed population established in 2004 on Guam (N = 426). The pedigree allowed annual estimates of individual mating and reproductive success to be inferred for snakes in the study population over a 14‐year period. We then employed generalized linear mixed models to gauge how well phenotypic and genomic data could predict sex‐specific annual mating and reproductive success. Average snout–vent length (SVL), average body condition index (BCI), and trappability were significantly related to annual mating success for males, with average SVL also related to annual mating success for females. Male and female annual reproductive success was positively affected by SVL, BCI, and trappability. Surprisingly, the degree to which individuals were inbred had no effect on annual mating or reproductive success. When juxtaposed with current control methods, these results indicate that baited traps, a common interdiction tool, may target fecund BTS in some regards but not others. Our study emphasizes the importance of reproductive ecology as a focus for improving BTS control and promotes genomic pedigree reconstruction for such an endeavor in this invasive species and others.
Our study details the use of genomic tools (i.e., double‐digest restriction site‐associated DNA sequencing) to develop novel genomic resources (>6,000 SNPs) for a high‐profile and invasive vertebrate pest (i.e., Brown Treesnake). We used a subset of these SNPs to reconstruct a multigenerational genomic pedigree for a wild population of Brown Treesnakes from which we inferred patterns and predictors of annual mating and reproductive success, and we juxtaposed phenotypes of individuals with high annual mating and reproductive success against those of commonly trapped individuals to assess existing management efficacy. Our results promote the use of genomic pedigree reconstruction to elucidate the reproductive ecology of invasive species with cryptic coloration and behaviors, so as to inform and improve management.
Summary Background In a phase 2 study, dexpramipexole (25–150 mg twice daily) was well tolerated for up to 9 months and showed a significant benefit at the high dose in a combined assessment of ...function and mortality in patients with amyotrophic lateral sclerosis. We aimed to assess efficacy and safety of dexpramipexole in a phase 3 trial of patients with familial or sporadic disease. Methods In our randomised, double-blind, placebo-controlled phase 3 trial (EMPOWER), we enrolled participants aged 18–80 years (with first amyotrophic lateral sclerosis symptom onset 24 months or less before baseline) at 81 academic medical centres in 11 countries. We randomly allocated eligible participants (1:1) with a centralised voice–interactive online system to twice-daily dexpramipexole 150 mg or matched placebo for 12–18 months, stratified by trial site, area of disease onset (bulbar vs other areas), and previous use of riluzole. The primary endpoint was the combined assessment of function and survival (CAFS) score, based on changes in amyotrophic lateral sclerosis functional rating scale–revised (ALSFRS-R) total scores and time to death up to 12 months. We assessed the primary endpoint in all participants who received at least one dose and had at least one post-dose ALSFRS-R measurement or died. We monitored adverse events in all participants. This study is registered with ClinicalTrials.gov , number NCT01281189. Findings Between March 28, 2011, and Sept 30, 2011, we enrolled 943 participants (474 randomly allocated dexpramipexole, 468 randomly allocated placebo, and one withdrew). Least-square mean CAFS scores at 12 months did not differ between participants in the dexpramipexole group (score 441·76, 95% CI 415·43–468·08) and those in the placebo group (438·84, 412·81–464·88; p=0·86). At 12 months, we noted no differences in mean change from baseline in ALSFRS-R total score (–13·34 in the dexpramipexole group vs −13·42 in the placebo group; p=0·90) or time to death (74 16% vs 79 17%; hazard ratio 1·03 0·75–1·43; p=0·84). 37 (8%) participants in the dexpramipexole group developed neutropenia compared with eight (2%) participants in the placebo group, and incidence of other adverse events was similar between groups. Interpretation Dexpramipexole was generally well tolerated but did not differ from placebo on any prespecified efficacy endpoint measurement. Our trial can inform the design of future clinical research strategies in amyotrophic lateral sclerosis. Funding Biogen Idec.
To assess the association of low- vs. guideline-recommended high-intensity cystoscopic surveillance with outcomes among patients with high-risk non-muscle invasive bladder cancer (NMIBC).
A ...retrospective cohort study of Veterans Affairs patients diagnosed with high-risk NMIBC between 2005 and 2011 with follow-up through 2014. Patients were categorized by number of surveillance cystoscopies over two years following diagnosis: low- (1-5) vs. high-intensity (6 or more) surveillance. Propensity score adjusted regression models were used to assess the association of low-intensity cystoscopic surveillance with frequency of transurethral resections, and risk of progression to invasive disease and bladder cancer death.
Among 1,542 patients, 520 (33.7%) underwent low-intensity cystoscopic surveillance. Patients undergoing low-intensity surveillance had fewer transurethral resections (37 vs. 99 per 100 person-years; p<0.001). Risk of death from bladder cancer did not differ significantly by low (cumulative incidence CIn 8.4% 95% CI 6.5-10.9) at 5 years) vs. high-intensity surveillance (CIn 9.1% 95% CI 7.4-11.2) at 5 years, p = 0.61). Low vs. high-intensity surveillance was not associated with increased risk of bladder cancer death among patients with Ta (CIn 5.7% vs. 8.2% at 5 years p = 0.24) or T1 disease at diagnosis (CIn 10.2% vs. 9.1% at 5 years, p = 0.58). Among patients with Ta disease, low-intensity surveillance was associated with decreased risk of progression to invasive disease (T1 or T2) or bladder cancer death (CIn 19.3% vs. 31.3% at 5 years, p = 0.002).
Patients with high-risk NMIBC undergoing low- vs. high-intensity cystoscopic surveillance underwent fewer transurethral resections, but did not experience an increased risk of progression or bladder cancer death. These findings provide a strong rationale for a clinical trial to determine whether low-intensity surveillance is comparable to high-intensity surveillance for cancer control in high-risk NMIBC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies argue that cross-country labor productivity differences are much larger in agriculture than in the aggregate. We reexamine the agricultural productivity data underlying this conclusion ...using new evidence from disaggregate sources. We find that for the world's staple grains-maize, rice, and wheat-cross-country differences in the quantity of grain produced per worker are enormous according to both micro- and macrosources. Our findings validate the idea that understanding agricultural productivity is at the heart of understanding world income inequality.
Background Unilateral pulmonary edema (UPE) has been reported after mitral operations performed through the right side of the chest. The clinical presentation is compatible with an ...ischemia-reperfusion injury. This report describes modifications to robotic mitral valve operations that were designed to reduce UPE. Methods We reviewed 15 patients with UPE after robotic mitral valve operations from 2006 through 2012. Technique modifications to reduce right lung ischemia were used from 2013 through June 2015. Modifications included alterations in patient position, ventilation, and perfusion factors. The incidence of UPE before and after modifications was determined, as was perfusion factors and outcomes in a higher-risk patient subgroup with pulmonary hypertension and prolonged bypass procedures. Results The incidence of UPE was 1.4% (n = 15) in 1,059 consecutive robotic mitral valve procedures using the standard technique and 0.0% in 435 consecutive procedures using the modified technique ( p < 0.02). All patients with UPE had pulmonary hypertension and bypass times of greater than 120 minutes. Patients in the higher-risk subgroup had significantly lower systemic temperature (31°C range, 30°–32°C versus 34°C range, 33°–34°C; p < 0.01) and higher mean perfusion pressure (67mm Hg range 62-72 mm Hg versus 54 mm Hg range, 52–57 mm Hg; p < 0.01) on bypass using the modified technique. The incidence of UPE in higher-risk patients was significantly reduced using the modified technique (0% versus 5.6%; p < 0.01) without any increase in overall morbidity or mortality. Conclusions The incidence of UPE in patients undergoing robotic mitral valve operations has been significantly reduced using a modified technique, without increasing the perioperative complication rate. Further work is necessary to validate this protocol and understand the pathophysiology of postoperative UPE.
Multiple methods have been developed to estimate narrow-sense heritability, h
, using single nucleotide polymorphisms (SNPs) in unrelated individuals. However, a comprehensive evaluation of these ...methods has not yet been performed, leading to confusion and discrepancy in the literature. We present the most thorough and realistic comparison of these methods to date. We used thousands of real whole-genome sequences to simulate phenotypes under varying genetic architectures and confounding variables, and we used array, imputed, or whole genome sequence SNPs to obtain 'SNP-heritability' estimates. We show that SNP-heritability can be highly sensitive to assumptions about the frequencies, effect sizes, and levels of linkage disequilibrium of underlying causal variants, but that methods that bin SNPs according to minor allele frequency and linkage disequilibrium are less sensitive to these assumptions across a wide range of genetic architectures and possible confounding factors. These findings provide guidance for best practices and proper interpretation of published estimates.
Global climate change is apparent within the Arctic and the south‐western deserts of North America, with record drought in the latter reflected within 640 000 km2 of the Colorado River Basin. To ...discern the manner by which natural and anthropogenic drivers have compressed Basin‐wide fish biodiversity, and to establish a baseline for future climate effects, the Stream Hierarchy Model (SHM) was employed to juxtapose fluvial topography against molecular diversities of 1092 Bluehead Sucker (Catostomus discobolus). MtDNA revealed three geomorphically defined evolutionarily significant units (ESUs): Bonneville Basin, upper Little Colorado River and the remaining Colorado River Basin. Microsatellite analyses (16 loci) reinforced distinctiveness of the Bonneville Basin and upper Little Colorado River, but subdivided the Colorado River Basin into seven management units (MUs). One represents a cline of three admixed gene pools comprising the mainstem and its lower‐gradient tributaries. Six others are not only distinct genetically but also demographically (i.e. migrants/generation <9.7%). Two of these (i.e. Grand Canyon and Canyon de Chelly) are defined by geomorphology, two others (i.e. Fremont‐Muddy and San Raphael rivers) are isolated by sharp declivities as they drop precipitously from the west slope into the mainstem Colorado/Green rivers, another represents an isolated impoundment (i.e. Ringdahl Reservoir), while the last corresponds to a recognized subspecies (i.e. Zuni River, NM). Historical legacies of endemic fishes (ESUs) and their evolutionary potential (MUs) are clearly represented in our data, yet their arbiter will be the unrelenting natural and anthropogenic water depletions that will precipitate yet another conservation conflict within this unique but arid region.
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