We describe a search underway for periodic gravitational waves from the central compact object in the supernova remnant Cassiopeia A. The object is the youngest likely neutron star in the Galaxy. Its ...position is well known, but the object does not pulse in any electromagnetic radiation band and thus presents a challenge in searching the parameter space of frequency and frequency derivatives. We estimate that a fully coherent search can, with a reasonable amount of time on a computing cluster, achieve a sensitivity at which it is theoretically possible (though not likely) to observe a signal even with the initial LIGO noise spectrum. Cassiopeia A is only the second object after the Crab pulsar for which this is true. The search method described here can also obtain interesting results for similar objects with current LIGO sensitivity.
Objectives: Many studies have shown consistent associations between evident indoor dampness or mold and respiratory or allergic health effects, but causal links remain unclear. Findings on measured ...microbiologie factors have received little review. We conducted an updated, comprehensive review on these topics. Data Sources: We reviewed eligible peer-reviewed epidemiologic studies or quantitative metaanalyses, up to late 2009, on dampness, mold, or other microbiologie agents and respiratory or allergic effects. Data Extraction: We evaluated evidence for causation or association between qualitative/subjective assessments of dampness or mold (considered together) and specific health outcomes. We separately considered evidence for associations between specific quantitative measurements of microbiologie factors and each health outcome. Data Synthesis: Evidence from epidemiologic studies and meta-analyses showed indoor dampness or mold to be associated consistently with increased asthma development and exacerbation, current and ever diagnosis of asthma, dyspnea, wheeze, cough, respiratory infections, bronchitis, allergic rhinitis, eczema, and upper respiratory tract symptoms. Associations were found in allergic and nonallergic individuals. Evidence strongly suggested causation of asthma exacerbation in children. Suggestive evidence was available for only a few specific measured microbiologic factors and was in part equivocal, suggesting both adverse and protective associations with health. Conclusions: Evident dampness or mold had consistent positive associations with multiple allergic and respiratory effects. Measured microbiologic agents in dust had limited suggestive associations, including both positive and negative associations for some agents. Thus, prevention and remediation of indoor dampness and mold are likely to reduce health risks, but current evidence does not support measuring specific indoor microbiologic factors to guide health-protective actions.
Limited evidence associates inadequate classroom ventilation rates (VRs) with increased illness absence (IA). We investigated relationships between VRs and IA in California elementary schools over ...two school years in 162 3rd–5th‐grade classrooms in 28 schools in three school districts: South Coast (SC), Bay Area (BA), and Central Valley (CV). We estimated relationships between daily IA and VR (estimated from two year daily real‐time carbon dioxide in each classroom) in zero‐inflated negative binomial models. We also compared IA benefits and energy costs of increased VRs. All school districts had median VRs below the 7.1 l/s‐person California standard. For each additional 1 l/s‐person of VR, IA was reduced significantly (p<0.05) in models for combined districts (−1.6%) and for SC (−1.2%), and nonsignificantly for districts providing less data: BA (−1.5%) and CV (−1.0%). Assuming associations were causal and generalizable, increasing classroom VRs from the California average (4 l/s‐person) to the State standard would decrease IA by 3.4%, increase attendance‐linked funding to schools by $33 million annually, and increase costs by only $4 million. Further increasing VRs would provide additional benefits. These findings, while requiring confirmation, suggest that increasing classroom VRs above the State standard would substantially decrease illness absence and produce economic benefits.
Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), ...where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid—PS—controls the movement of another lipid—cholesterol—between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.
To assess whether school environments can adversely affect academic performance, we review scientific evidence relating indoor pollutants and thermal conditions, in schools or other indoor ...environments, to human performance or attendance. We critically review evidence for direct associations between these aspects of indoor environmental quality (IEQ) and performance or attendance. Secondarily, we summarize, without critique, evidence on indirect connections potentially linking IEQ to performance or attendance. Regarding direct associations, little strongly designed research was available. Persuasive evidence links higher indoor concentrations of NO(2) to reduced school attendance, and suggestive evidence links low ventilation rates to reduced performance. Regarding indirect associations, many studies link indoor dampness and microbiologic pollutants (primarily in homes) to asthma exacerbations and respiratory infections, which in turn have been related to reduced performance and attendance. Also, much evidence links poor IEQ (e.g. low ventilation rate, excess moisture, or formaldehyde) with adverse health effects in children and adults and documents dampness problems and inadequate ventilation as common in schools. Overall, evidence suggests that poor IEQ in schools is common and adversely influences the performance and attendance of students, primarily through health effects from indoor pollutants. Evidence is available to justify (i) immediate actions to assess and improve IEQ in schools and (ii) focused research to guide IEQ improvements in schools.
There is more justification now for improving IEQ in schools to reduce health risks to students than to reduce performance or attendance risks. However, as IEQ-performance links are likely to operate largely through effects of IEQ on health, IEQ improvements that benefit the health of students are likely to have performance and attendance benefits as well. Immediate actions are warranted in schools to prevent dampness problems, inadequate ventilation, and excess indoor exposures to substances such as NO(2) and formaldehyde. Also, siting of new schools in areas with lower outdoor pollutant levels is preferable.
Objective
To continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy ...(DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).
Methods
Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.
Results
At 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.
Interpretation
Over 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271
Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly ...transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.
Data from published studies were combined and analyzed to develop best-fit equations and curves quantifying the change in sick building syndrome (SBS) symptom prevalence in office workers with ...ventilation rate. For each study, slopes were calculated, representing the fractional change in SBS symptom prevalence per unit change in ventilation rate per person. Values of ventilation rate, associated with each value of slope, were also calculated. Linear regression equations were fitted to the resulting data points, after weighting by study size. Integration of the slope-ventilation rate equations yielded curves of relative SBS symptom prevalence vs. ventilation rate. Based on these analyses, as the ventilation rate drops from 10 to 5 l/s-person, relative SBS symptom prevalence increases approximately 23% (12% to 32%), and as ventilation rate increases from 10 to 25 l/s-person, relative prevalence decreases approximately 29% (15% to 42%). Variations in SBS symptom types, building features, and outdoor air quality may cause the relationship of SBS symptom prevalence with ventilation rate in specific situations to differ from the average relationship predicted in this paper.
On average, providing more outdoor air ventilation will reduce prevalence rates of sick building syndrome (SBS) symptoms. However, given the costs of energy use, including increased risks of climate change, it is important to balance the benefits and risks of increased ventilation. This paper provides initial estimates of how the incremental health benefits per unit of increased ventilation diminish at higher levels of ventilation.
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