Niraparib is an oral poly(adenosine diphosphate ADP-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of ...niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer.
In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival.
Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval CI, 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications.
Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).
Despite the eradication of smallpox as a naturally occurring disease, concern persists over its potential use as a bioterrorist agent. The development of a new-generation smallpox vaccine represents ...an important contribution to a cogent biodefense strategy. We conducted a phase 2 randomized, double-blind, controlled trial at four sites in the United States to determine whether a clonal smallpox vaccine manufactured in cell culture, ACAM2000, is equivalent to the standard calf-lymph vaccine, Dryvax
®, in terms of cutaneous response rate, antibody responses and safety. Subjects received either Dryvax
® or one of four dose levels of ACAM2000 administered percutaneously using a bifurcated needle. All subjects in the highest ACAM2000 dose group and the Dryvax
® group experienced a successful vaccination. Dilution doses of ACAM2000 were associated with success rates below the 90% threshold established for efficacy. There were no differences in the proportion of subjects who developed neutralizing antibody: 94% in the highest ACAM2000 dose group (95% CI, 84–99) and 96% in the Dryvax
® group (95% CI, 86–100). No significant differences were seen between the effective ACAM2000 and Dryvax
® groups regarding the occurrence of adverse events. One subject who received ACAM2000 developed myopericarditis. In healthy, primary vaccines ACAM2000 has a similar vaccination success rate, antibody response, and safety profile to Dryvax.
Abstract
The Southern H
ii
Region Discovery Survey (SHRDS) is a 900 hr Australia Telescope Compact Array 4–10 GHz radio continuum and radio recombination line (RRL) survey of Galactic H
ii
regions ...and infrared-identified H
ii
region candidates in the southern sky. For this data release, we reprocess all previously published SHRDS data and include an additional ∼450 hr of observations. The search for new H
ii
regions is now complete over the range 259° <
ℓ
< 346°, ∣
b
∣ < 4° for H
ii
region candidates with predicted 6 GHz continuum peak brightnesses ≳30 mJy beam
−1
. We detect radio continuum emission toward 730 targets altogether including previously known nebulae and H
ii
region candidates. By averaging ∼18 RRL transitions, we detect RRL emission toward 206 previously known H
ii
regions and 436 H
ii
region candidates. Including the northern sky surveys, over the last decade the H
ii
Region Discovery Surveys have more than doubled the number of known Galactic H
ii
regions. The census of H
ii
regions in the Wide-field Infrared Survey Explorer (WISE) Catalog of Galactic H
ii
Regions is now complete for nebulae with 9 GHz continuum flux densities ≳250 mJy. We compare the RRL properties of the newly discovered SHRDS nebulae with those of all previously known H
ii
regions. The median RRL FWHM line width of the entire WISE Catalog H
ii
region population is 23.9 km s
−1
and is consistent between Galactic quadrants. The observed Galactic longitude–velocity asymmetry in the population of H
ii
regions probably reflects underlying spiral structure in the Milky Way.
The census of Galactic H ii regions is vastly incomplete in the southern sky. We use the Australia Telescope Compact Array to observe 4-10 radio continuum and hydrogen radio recombination line (RRL) ...emission from candidate H ii regions in the Galactic zone . In this first data release, we target the brightest H ii region candidates and observe 282 fields in the direction of at least one previously known or candidate H ii region. We detect radio continuum emission and RRL emission in 275 (97.5%) and 258 (91.5%) of these fields, respectively. We catalog the ∼7 GHz radio continuum peak flux densities and positions of 80 previously known and 298 candidate H ii regions. After averaging ∼18 RRL transitions, we detect 77 RRL velocity components toward 76 previously known H ii regions and 267 RRL velocity components toward 256 H ii region candidates. The discovery of RRL emission from these nebulae increases the number of known Galactic H ii regions in the surveyed zone by 82% to 568 nebulae. In the fourth quadrant, we discover 50 RRLs with positive velocities, placing those sources outside the solar circle. Including the pilot survey, the Southern H ɪɪ Region Discovery Survey has now discovered 295 Galactic H ii regions. In the next data release, we expect to add ∼200 fainter and more distant nebulae.
Abstract
We investigate the kinematic properties of Galactic H
ii
regions using radio recombination line (RRL) emission detected by the Australia Telescope Compact Array at 4–10 GHz and the Jansky ...Very Large Array at 8–10 GHz. Our H
ii
region sample consists of 425 independent observations of 374 nebulae that are relatively well isolated from other, potentially confusing sources and have a single RRL component with a high signal-to-noise ratio. We perform Gaussian fits to the RRL emission in position-position–velocity data cubes and discover velocity gradients in 178 (42%) of the nebulae with magnitudes between 5 and 200
m
s
−
1
arcsec
−
1
. About 15% of the sources also have an RRL width spatial distribution that peaks toward the center of the nebula. The velocity gradient position angles appear to be random on the sky with no favored orientation with respect to the Galactic plane. We craft H
ii
region simulations that include bipolar outflows or solid body rotational motions to explain the observed velocity gradients. The simulations favor solid body rotation since, unlike the bipolar outflow kinematic models, they are able to produce both the large, >40
m
s
−
1
arcsec
−
1
, velocity gradients and also the RRL width structure that we observe in some sources. The bipolar outflow model, however, cannot be ruled out as a possible explanation for the observed velocity gradients for many sources in our sample. We nevertheless suggest that most H
ii
region complexes are rotating and may have inherited angular momentum from their parent molecular clouds.
Yellow fever is a lethal viral hemorrhagic fever occurring in Africa and South America. A highly effective live vaccine (17D) is widely used for travelers to and residents of areas in which yellow ...fever is endemic, but the vaccine can cause serious adverse events, including viscerotropic disease, which is associated with a high rate of death. A safer, nonreplicating vaccine is needed.
In a double-blind, placebo-controlled, dose-escalation, phase 1 study of 60 healthy subjects between 18 and 49 years of age, we investigated the safety and immunogenicity of XRX-001 purified whole-virus, β-propiolactone-inactivated yellow fever vaccine produced in Vero cell cultures and adsorbed to aluminum hydroxide (alum) adjuvant. On two visits 21 days apart, subjects received intramuscular injections of vaccine that contained 0.48 μg or 4.8 μg of antigen. Levels of neutralizing antibodies were measured at baseline and on days 21, 31, and 42.
The vaccine induced the development of neutralizing antibodies in 100% of subjects receiving 4.8 μg of antigen in each injection and in 88% of subjects receiving 0.48 μg of antigen in each injection. Antibody levels increased by day 10 after the second injection, at which time levels were significantly higher with the 4.8-μg formulation than with the 0.48-μg formulation (geometric mean titer, 146 vs. 39; P<0.001). Three adverse events occurred at a higher incidence in the two vaccine groups than in the placebo group: mild pain, tenderness, and (much less frequently) itching at the injection site. One case of urticaria was observed on day 3 after the second dose of 4.8 μg of vaccine.
A two-dose regimen of the XRX-001 vaccine, containing inactivated yellow fever antigen with an alum adjuvant, induced neutralizing antibodies in a high percentage of subjects. XRX-001 has the potential to be a safer alternative to live attenuated 17D vaccine. (Funded by Xcellerex; ClinicalTrials.gov number, NCT00995865.).
We have found that when suprathreshold cathodal stimuli were applied to the epicardium of canine ventricle, impulse propagation originated at a "virtual cathode" with dimensions greater than those of ...the physical cathode. We report the two-dimensional geometry of the virtual cathode as a function of stimulus strength; the results are compared with the predictions of an anisotropic, bidomain model of cardiac conduction recently developed in our laboratories. Data were collected in six pentobarbital-anesthetized dogs by using a small plaque electrode sewn to the left ventricular epicardium. Arrival times at closely spaced bipolar electrodes oriented radially around a central cathode were obtained as a function of stimulus strength and fiber orientation. The dimensions of the virtual cathode were determined by linear back-extrapolation of arrival times to the time of stimulation. The directional dependence of the conduction velocity was consistent with previous reports: at 1 mA, longitudinal (0 degree) and transverse (90 degrees) velocities were 0.60 +/- 0.03 and 0.29 +/- 0.02 m/sec, respectively. At 7 mA, the longitudinal velocity was 0.75 +/- 0.05 m/sec, whereas there was no significant change in the transverse velocity. In contrast to conduction velocity, the virtual cathode was smallest in the longitudinal orientation and largest between 45 degrees and 60 degrees. Virtual cathode size was dependent on both orientation and stimulus strength: at 0 degree, the virtual cathode was small (approximately 1 mm) and relatively constant over the range of 1-7 mA; at oblique orientations (45 degrees-90 degrees), it displayed a roughly logarithmic dependence on stimulus strength, approximately 1 mm at 1 mA and approximately 3 mm at 7 mA. The bidomain, anisotropic model reproduced both the stimulus strength and the fiber-orientation dependence of the virtual cathode geometry when the intracellular and extracellular anisotropies were 10:1 and 4:1, respectively, but not when the two anisotropies were equal. We suggest that the virtual cathode provides a direct measure of the determinants of cardiac activation; its complex geometry appears to reflect the bidomain, anisotropic nature of cardiac muscle.
Interferon-γ release assays have significant advantages over tuberculin skin testing in many clinical situations. However, recent studies have called into question their reliability in serial testing ...of healthcare workers because of reportedly high rates of positivity and high conversion/reversion rates on retesting.
To define the performance characteristics of the T-SPOT.TB test, an interferon-γ release assay, during serial screening programs of healthcare workers at 19 U.S. hospitals.
A total of 42,155 T-SPOT.TB test results from healthcare workers at 19 geographically diverse hospitals obtained for routine tuberculosis screening programs were analyzed to determine the rates of positivity, reversion, and conversion in serial testing data.
In 19,630 evaluable serial pairs from 16,076 healthcare workers, the mean test positivity rate was 2.3% (range, 0.0-27.4%). The mean conversion rate was 0.8% (range, 0.0-2.5%), and the mean reversion rate was 17.6%. Positivity and conversion rates correlated with known tuberculosis risk factors including age and sex. The observed specificity of the T-SPOT.TB test was at least 98.6%.
The high concordance and test completion rates in this study suggest that the T-SPOT.TB test is a reliable tool for healthcare worker serial screening. As expected, the observed positivity rates were lower compared with the tuberculin skin test, likely reflecting the higher specificity of this test. Furthermore, the observed rates of conversion were low and significantly correlated with the geographic incidence of tuberculosis. Our findings suggest that the T-SPOT.TB test is an accurate and reliable way to screen healthcare workers.
The electrophysiologic effects of high concentrations of the opioid agonists, fentanyl and sufentanil, on isolated canine cardiac Purkinje fibers were studied. Changes in action potential parameters ...were examined at the following concentrations: fentanyl 94.6 nM, 0.19 microM, and 0.95 microM; sufentanil 8.6 nM, 86.4 nM, 0.17 microM, and 0.26 microM. Naloxone 5.5 microM was administered after maximal changes were induced by fentanyl in order to explore the possibility of an opioid receptor interaction. Action potential parameters measured were Vmax of phase 0, amplitude, overshoot, maximum diastolic potential, action potential duration at 50%, and 90% repolarization and membrane responsiveness. Fentanyl 0.19 microM and sufentanil-0.17 microM caused a significant lengthening of action potential duration at 50 and 90% repolarization, 6.4% and 7.3%, and 10.2% and 12.4%, respectively, P less than 0.05. Other action potential parameters were not significantly affected by the opioids. Naloxone 5.5 microM alone did not alter action potential characteristics and failed to reverse action potential prolongation produced by fentanyl. The authors suggest that fentanyl and sufentanil prolong action potential duration in canine cardiac Purkinje fibers via direct membrane actions.
PDF
