Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in ...BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after≥36-month follow-up for all living patients.
This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150mg twice daily) plus trametinib (2mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.
Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n= 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and<3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.
These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.
Carotid-artery stenting and carotid endarterectomy are both options for treating carotid-artery stenosis, an important cause of stroke.
We randomly assigned patients with symptomatic or asymptomatic ...carotid stenosis to undergo carotid-artery stenting or carotid endarterectomy. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization.
For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P=0.84) or sex (P=0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P=0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P=0.01), and for myocardial infarction (1.1% vs. 2.3%, P=0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85).
Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)
•We model world fossil fuel production by country including unconventional sources.•Four countries, China, USA, Canada and Australia modelled by state/province level.•Three ultimately recouverable ...resources applied, that range from 48.4 to 121.5 ZJ.•Scenarios suggest coal production peaks before 2025 due to China.•Results suggest lack of fossil fuels to deliver high IPCC scenarios: A1Fl, RCP8.5.
Detailed projections of world fossil fuel production including unconventional sources were created by country and fuel type to estimate possible future fossil fuel production. Four critical countries (China, USA, Canada and Australia) were examined in detail with projections made on the state/province level. Ultimately Recoverable Resources (URR) for fossil fuels were estimated for three scenarios: Low=48.4 ZJ, Best Guess (BG)=75.7 ZJ, High=121.5 ZJ. The scenarios were developed using Geologic Resources Supply-Demand Model (GeRS-DeMo). The Low and Best Guess (BG) scenarios suggest that world fossil fuel production may peak before 2025 and decline rapidly thereafter. The High scenario indicates that fossil fuels may have a strong growth till 2025 followed by a plateau lasting approximately 50years before declining. All three scenarios suggest that world coal production may peak before 2025 due to peaking Chinese production and that only natural gas could have strong growth in the future. In addition, by converting the fossil fuel projections to greenhouse gas emissions, the projections were compared to IPCC scenarios which indicated that based on current estimates of URR there are insufficient fossil fuels to deliver the higher emission IPCC scenarios A1Fl and RCP8.5.
The Blanco Cosmology Survey (BCS) is a 60 night imaging survey of ~80 deg super(2) of the southern sky located in two fields: (alpha, delta) = (5 hr, -55degrees) and (23 hr, -55degrees). The survey ...was carried out between 2005 and 2008 in griz bands with the Mosaic2 imager on the Blanco 4 m telescope. The primary aim of the BCS survey is to provide the data required to optically confirm and measure photometric redshifts for Sunyaev-Zel'dovich effect selected galaxy clusters from the South Pole Telescope and the Atacama Cosmology Telescope. We process and calibrate the BCS data, carrying out point-spread function-corrected model-fitting photometry for all detected objects. The median 10sigma galaxy (point-source) depths over the survey in griz are approximately 23.3 (23.9), 23.4 (24.0), 23.0 (23.6), and 21.3 (22.1), respectively. The astrometric accuracy relative to the USNO-B survey is ~45 mas. We calibrate our absolute photometry using the stellar locus in grizJ bands, and thus our absolute photometric scale derives from the Two Micron All Sky Survey, which has ~2% accuracy. The scatter of stars about the stellar locus indicates a systematic floor in the relative stellar photometric scatter in griz that is ~1.9%, ~2.2%, ~2.7%, and ~2.7%, respectively. A simple cut in the AstrOmatic star-galaxy classifier spread_model produces a star sample with good spatial uniformity. We use the resulting photometric catalogs to calibrate photometric redshifts for the survey and demonstrate scatter deltaz/(1 + z) = 0.054 with an outlier fraction eta < 5% to z ~ 1. We highlight some selected science results to date and provide a full description of the released data products.
The FOCUS smartphone intervention was developed to provide automated real-time/real-place illness management support to individuals with schizophrenia. The system was specifically designed to be ...usable by people with psychotic disorders who may have cognitive impairment, psychotic symptoms, negative symptoms, and/or low reading levels. FOCUS offers users both prescheduled and on-demand resources to facilitate symptom management, mood regulation, medication adherence, social functioning, and improved sleep. In this study, 33 individuals with schizophrenia or schizoaffective disorder used FOCUS over a 1-month period in their own environments. Participants were able to learn how to use the intervention independently, and all but one participant completed the trial successfully and returned the smartphones intact. Completers used the system on 86.5% of days they had the device, an average of 5.2 times a day. Approximately 62% of use of the FOCUS intervention was initiated by the participants, and 38% of use was in response to automated prompts. Baseline levels of cognitive functioning, negative symptoms, persecutory ideation, and reading level were not related to participants' use of the intervention. Approximately 90% of participants rated the intervention as highly acceptable and usable. Paired samples t tests found significant reductions in psychotic symptoms, depression, and general psychopathology, after 1 month of FOCUS use. This study demonstrated the feasibility, acceptability, and preliminary efficacy of the FOCUS intervention for schizophrenia and introduces a new treatment model which has promise for extending the reach of evidence-based care beyond the confines of a physical clinic using widely available technologies.
We present measurements as part of the Southern Oxidant and Aerosol Study (SOAS) during which atmospheric aerosol particles were comprehensively characterized. We present results utilizing a Filter ...Inlet for Gases and AEROsol coupled to a chemical ionization mass spectrometer (CIMS). We focus on the volatility and composition of isoprene derived organic aerosol tracers and of the bulk organic aerosol. By utilizing the online volatility and molecular composition information provided by the FIGAERO–CIMS, we show that the vast majority of commonly reported molecular tracers of isoprene epoxydiol (IEPOX) derived secondary organic aerosol (SOA) is derived from thermal decomposition of accretion products or other low volatility organics having effective saturation vapor concentrations <10–3 μg m–3. In addition, while accounting for up to 30% of total submicrometer organic aerosol mass, the IEPOX-derived SOA has a higher volatility than the remaining bulk. That IEPOX-SOA, and more generally bulk organic aerosol in the Southeastern U.S. is comprised of effectively nonvolatile material has important implications for modeling SOA derived from isoprene, and for mechanistic interpretations of molecular tracer measurements. Our results show that partitioning theory performs well for 2-methyltetrols, once accretion product decomposition is taken into account. No significant partitioning delays due to aerosol phase or viscosity are observed, and no partitioning to particle-phase water or other unexplained mechanisms are needed to explain our results.
The INT/WFC Photometric H... Survey of the Northern Galactic Plane (IPHAS) is a 1800 deg... imaging survey covering Galactic latitudes |b| < 5... and longitudes ... = 30...-215... in the r, i, and Hα ...filters using the Wide Field Camera (WFC) on the 2.5-m Isaac Newton Telescope (INT) in La Palma. We present the first quality-controlled and globally calibrated source catalogue derived from the survey, providing single-epoch photometry for 219 million unique sources across 92 per cent of the footprint. The observations were carried out between 2003 and 2012 at a median seeing of 1.1 arcsec (sampled at 0.33 arcsec pixel...) and to a mean 5... depth of 21.2 (r), 20.0 (i), and 20.3 (Hα) in the Vega magnitude system. We explain the data reduction and quality control procedures, describe and test the global re-calibration, and detail the construction of the new catalogue. We show that the new calibration is accurate to 0.03 mag (root mean square) and recommend a series of quality criteria to select accurate data from the catalogue. Finally, we demonstrate the ability of the catalogue's unique (r - Hα,...r - i) diagram to (i) characterize stellar populations and extinction regimes towards different Galactic sightlines and (ii) select and quantify Hα emission-line objects. IPHAS is the first survey to offer comprehensive CCD photometry of point sources across the Galactic plane at visible wavelengths, providing the much-needed counterpart to recent infrared surveys. (ProQuest: ... denotes formulae/symbols omitted.)
The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes ...coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting.
We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose).
The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval CI, 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely.
The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).
A phenomenological ductile fracture initiation model for metals is developed for predicting ductile fracture in industrial practice. Its formulation is based on the assumption that the onset of ...fracture is imminent with the formation of a primary or secondary band of localization. The results from a unit cell analysis on a Levy–von Mises material with spherical defects revealed that a Mohr–Coulomb type of model is suitable for predicting the onset of shear and normal localization. To improve the agreement of the model predictions with experimental results, an extended Mohr–Coulomb criterion is proposed which makes use of the Hosford equivalent stress in combination with the normal stress acting on the plane of maximum shear. A fracture initiation model is obtained by transforming the localization criterion from stress space to the space of equivalent plastic strain, stress triaxiality and Lode angle parameter using the material’s isotropic hardening law. Experimental results are presented for three different advanced high strength steels. For each material, the onset of fracture is characterized for five distinct stress states including butterfly shear, notched tension, tension with a central hole and punch experiments. The comparison of model predictions with the experimental results demonstrates that the proposed Hosford–Coulomb model can predict the instant of ductile fracture initiation in advanced high strength steels with good accuracy.
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