In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in ...patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3.
We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy.
Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval CI, 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia.
Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).
Development of a precise theory of the electroweak interaction was a great achievement of Twentieth Century physics. The next generation of colliders will address a deeper understanding of underlying ...principles of Nature. The Large Hadron Collider (LHC) will soon begin operations at CERN and confront the limits of theory at the Terascale. Anticipated new physics will illuminate the fundamental particle properties and the relationships between the observed forces. New symmetries, extra dimensions, and the source of the mysterious dark matter of the cosmos are possible discoveries. The International Linear Collider (ILC) will bring complementary vision to exploration of the Terascale, enabled by the special advantages of an electron-positron collider. This paper presents examples of the physics opportunities of the ILC, describes the advantages of the linear collider experimental environment, and presents some detector developments aimed at enabling this experimental program.
The Collider Detector at Fermilab (CDF) pursues a broad physics program at Fermilab's Tevatron collider. Between Run II commissioning in early 2001 and the end of operations in September 2011, the ...Tevatron delivered 12fb−1 of integrated luminosity of pp¯ collisions at s=1.96TeV. The physics at CDF includes precise measurements of the masses of the top quark and W boson, measurement of CP violation and Bs mixing, and searches for Higgs bosons and new physics signatures, all of which require heavy flavor tagging with large charged particle tracking acceptance. To realize these goals, in 2001 CDF installed eight layers of silicon microstrip detectors around its interaction region. These detectors were designed for 2–5 years of operation, radiation doses up to 2Mrad (0.02Gy), and were expected to be replaced in 2004. The sensors were not replaced, and the Tevatron run was extended for several years beyond its design, exposing the sensors and electronics to much higher radiation doses than anticipated. In this paper we describe the operational challenges encountered over the past 10 years of running the CDF silicon detectors, the preventive measures undertaken, and the improvements made along the way to ensure their optimal performance for collecting high quality physics data. In addition, we describe the quantities and methods used to monitor radiation damage in the sensors for optimal performance and summarize the detector performance quantities important to CDF's physics program, including vertex resolution, heavy flavor tagging, and silicon vertex trigger performance.
•We have operated the CDF II silicon detector system well beyond its design lifetime.•We describe design of each component, its performance parameters and resource needs.•A history of operational experience and mitigation of encountered problems is given.•Novel methods were found to mitigate wirebond resonance and cooling system corrosion.•Radiation aging effects on silicon sensors from a decade long exposure are presented.
To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.
In this Phase 2b double-blind, ...placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients.
Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups.
The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4.
NCT01125189.
We survey 336 chief financial officers (CFOs) to compare practice to theory in the areas of initial public offering (IPO) motivation, timing, underwriter selection, underpricing, signaling, and the ...decision to remain private. We find the primary motivation for going public is to facilitate acquisitions. CFOs base IPO timing on overall market conditions, are well informed regarding expected underpricing, and feel underpricing compensates investors for taking risk. The most important positive signal is past historical earnings, followed by underwriter certification. CFOs have divergent opinions about the IPO process depending on firm-specific characteristics. Finally, we find the main reason for remaining private is to preserve decision-making control and ownership.
The use of CCDs in future linear collider experiments will require immunity to large neutron fluences, in excess of 10/sup 9//cm/sup 2//year. The effects on charge transfer efficiency of neutron ...induced bulk damage are presented along with a demonstration of a technique to fill the traps with sacrificial charge. Operation is then possible at fluences in excess of 10/sup 10//cm/sup 2/.
Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who ...were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.
We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.
Overall, 32.2% (95% CI, 30.8-33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2-42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24-25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85-13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70-13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42-16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0-78.3%) agreed to be treated and multivariable analysis showed that persons >/=50 yr of age (OR = 1.37; 95% CI, 1.07-1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08-1.93) were more likely to decline treatment.
The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.
Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the ...interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials.
In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo.
Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval CI, 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94).
In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).
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