Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide ...drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.
We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.
In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants 41% vs. 0 of 27 0%, P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants 51% vs. 0 of 37 0%), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.
Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
In this work, we report the discovery with Fermi/LAT of γ-ray emission from three radio-loud narrow-line Seyfert 1 galaxies: PKS 1502+036 (z = 0.409), 1H 0323+342 (z = 0.061), and PKS 2004 – 447 (z = ...0.24). In addition to PMN J0948+0022 (z = 0.585), the first source of this type to be detected in γ rays, they may form an emerging new class of γ-ray active galactic nuclei (AGNs). Lastly, these findings can have strong implications on our knowledge about relativistic jets and the unified model of the AGN.
We present cosmological results from a combined analysis of galaxy clustering and weak gravitational lensing, using 1321 deg2 of griz imaging data from the first year of the Dark Energy Survey (DES ...Y1). We combine three two-point functions: (i) the cosmic shear correlation function of 26 million source galaxies in four redshift bins, (ii) the galaxy angular autocorrelation function of 650,000 luminous red galaxies in five redshift bins, and (iii) the galaxy-shear cross-correlation of luminous red galaxy positions and source galaxy shears. To demonstrate the robustness of these results, we use independent pairs of galaxy shape, photometric-redshift estimation and validation, and likelihood analysis pipelines. To prevent confirmation bias, the bulk of the analysis was carried out while “blind” to the true results; we describe an extensive suite of systematics checks performed and passed during this blinded phase. The data are modeled in flat ΛCDM and wCDM cosmologies, marginalizing over 20 nuisance parameters, varying 6 (for ΛCDM) or 7 (for wCDM) cosmological parameters including the neutrino mass density and including the 457×457 element analytic covariance matrix. We find consistent cosmological results from these three two-point functions and from their combination obtain S8≡σ8(Ωm/0.3)0.5=0.773−0.020+0.026 and Ωm=0.267−0.017+0.030 for ΛCDM; for wCDM, we find S8=0.782−0.024+0.036, Ωm=0.284−0.030+0.033, and w=−0.82−0.20+0.21 at 68% C.L. The precision of these DES Y1 constraints rivals that from the Planck cosmic microwave background measurements, allowing a comparison of structure in the very early and late Universe on equal terms. Although the DES Y1 best-fit values for S8 and Ωm are lower than the central values from Planck for both ΛCDM and wCDM, the Bayes factor indicates that the DES Y1 and Planck data sets are consistent with each other in the context of ΛCDM. Combining DES Y1 with Planck, baryonic acoustic oscillation measurements from SDSS, 6dF, and BOSS and type Ia supernovae from the Joint Lightcurve Analysis data set, we derive very tight constraints on cosmological parameters: S8=0.802±0.012 and Ωm=0.298±0.007 in ΛCDM and w=−1.00−0.04+0.05 in wCDM. Upcoming Dark Energy Survey analyses will provide more stringent tests of the ΛCDM model and extensions such as a time-varying equation of state of dark energy or modified gravity.
We measure the clustering of DES year 1 galaxies that are intended to be combined with weak lensing samples in order to produce precise cosmological constraints from the joint analysis of large-scale ...structure and lensing correlations. Two-point correlation functions are measured for a sample of 6.6×105 luminous red galaxies selected using the redMaGiC algorithm over an area of 1321 square degrees, in the redshift range 0.15<z<0.9, split into five tomographic redshift bins. The sample has a mean redshift uncertainty of σz/(1+z)=0.017. We quantify and correct spurious correlations induced by spatially variable survey properties, testing their impact on the clustering measurements and covariance. We demonstrate the sample’s robustness by testing for stellar contamination, for potential biases that could arise from the systematic correction, and for the consistency between the two-point auto- and cross-correlation functions. We show that the corrections we apply have a significant impact on the resultant measurement of cosmological parameters, but that the results are robust against arbitrary choices in the correction method. We find the linear galaxy bias in each redshift bin in a fiducial cosmology to be b(σ8/0.81)|z=0.24=1.40±0.07, b(σ8/0.81)|z=0.38=1.60±0.05, b(σ8/0.81)|z=0.53=1.60±0.04 for galaxies with luminosities L/L*>0.5, b(σ8/0.81)|z=0.68=1.93±0.04 for L/L*>1 and b(σ8/0.81)|z=0.83=1.98±0.07 for L/L*>1.5, broadly consistent with expectations for the redshift and luminosity dependence of the bias of red galaxies. We show these measurements to be consistent with the linear bias obtained from tangential shear measurements.
Summary
Patients with epilepsy may be subject to an increased risk of premature death from the underlying cause, or from the epilepsy intself. The extent and nature of this risk has been ...insufficiently investigated. Standard mortality ratios (SMRs) of patients with newly diagnosed epilepsy were determined in a prospective national population-based study. 1091 patients with newly diagnosed or suspected epilepsy were ascertained who were attending one of 275 UK general practices from 1984-1987.
1091 patients were classified after 6 months as definite epilepsy (564), possible epilepsy (228), febrile seizures (220), or not epilepsy (79). Over a median follow up of 6·9 years the SMR for patients with definite or possible epilepsy was 2·5 (95% Cl 2·1-2·9), and 3·0 (2·5-3·7) for definite epilepsy. The SMR was highest during the first year after diagnosis 5·1 (3·8-6·5), declined to 2·5 (1·5-3·9) at 3 years, and 1·3 (0·7-2·0) at 5 years. The commonest causes of death were pneumonia (SMR 7·2), cancer (3·5), and stroke (3·7). The SMR for patients with idiopathic epilepsy was 1·6 (1·0-2·4), remote symptomatic epilepsy 4·3 (3·3-5·5), and acute symptomatic epilepsy 2·9 (1·7-4·5).
Mortality in patients with newly-diagnosed epilepsy was high, mainly due to the underlying cause. The SMR for idiopathic epilepsy was also raised, suggesting that epilepsy per se may carry a small risk of death.
Analysis of RNA expression using techniques like real-time PCR has traditionally used reference or housekeeping genes to control for error between samples. This practice is being questioned as it ...becomes increasingly clear that some housekeeping genes may vary considerably in certain biological samples. We used real-time reverse transcription PCR (RT-PCR) to assess the levels of 13 housekeeping genes expressed in peripheral blood mononuclear cell culture and whole blood from healthy individuals and those with tuberculosis. Housekeeping genes were selected from conventionally used ones and from genes reported to be invariant in human T cell culture. None of the commonly used housekeeping genes e.g., glyceraldehyde-phosphate-dehydrogenase (GAPDH) were found to be suitable as internal references, as they were highly variable (>30-fold maximal variability). Furthermore, genes previously found to be invariant in human T cell culture also showed large variation in RNA expression (>34-fold maximal variability). Genes that were invariant in blood were highly variable in peripheral blood mononuclear cell culture. Our data show that RNA specifying human acidic ribosomal protein was the most suitable housekeeping gene for normalizing mRNA levels in human pulmonary tuberculosis. Validations of housekeeping genes are highly specific for a particular experimental model and are a crucial component in assessing any new model.
Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain.
To assess the major health benefits and ...risks of the most commonly used combined hormone preparation in the United States.
Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998.
Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102).
The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals CIs) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years.
Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
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