Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non-mTOR-mediated etiologies.

The present study was designed to examine the potential cellular antiseizure mechanisms of everolimus, a mechanistic target of rapamycin (mTOR) pathway blocker, in pediatric epilepsy cases. Cortical tissue samples obtained from pediatric patients (n = 11, ages 0.67-6.75 years) undergoing surgical resections for the treatment of their pharmacoresistant epilepsy were examined electrophysiologically in ex vivo slices. The cohort included mTOR-mediated pathologies (tuberous sclerosis complex [TSC] and severe cortical dysplasia [CD]) as well as non-mTOR-mediated pathologies (tumor and perinatal infarct). Bath application of everolimus (2 μm) had practically no effect on spontaneous inhibitory postsynaptic activity. In contrast, long-term application of everolimus reduced spontaneous excitatory postsynaptic activity, burst discharges induced by blockade of γ-aminobutyric acid A (GABAA) receptors, and epileptiform activity generated by 4-aminopyridine, a K+ channel blocker. The antiseizure effects were more pronounced in TSC and CD cases, whereas in non-mTOR-mediated pathologies, the effects were subtle at best. These results support further clinical trials of everolimus in mTOR pathway-mediated pathologies and emphasize that the effects require sustained exposure over time

Physical Activity and Quality of Life in Retinitis Pigmentosa

Purpose. Aerobic exercise has been found to be neuroprotective in animal models of retinal degeneration. This study aims to report physical activity levels in patients with RP and investigate the relationship between physical activity and vision-related quality-of-life (QOL). Materials and Methods. A retrospective study of adult patients with RP examined in 2005–2014. Physical activity levels were assessed using the Godin Exercise Questionnaire. The NEI-Visual Function Questionaire-25 (VFQ-25), SF-36 General Health survey, and Pepper Assessment Tool for Disability (PAT-D) were administered. Results. 143 patients participated. 81 (56.6%) patients were classified as “active” and 62 (43.4%) as “insufficiently active” by Godin score. VFQ-25 revealed statistically significant differences between the active and insufficiently active patients, including overall visual function (53.3 versus 45.1, p=0.010), color vision (73.8 versus 52.9, p<0.001), and peripheral vision (34.3 versus 23.8, p=0.021). The physical component of the SF-36 and the PAT-D survey also demonstrated statistically significant differences (47.2 versus 52.9, p=0.002; 24.3 versus 30.0, p=0.010). Active patients had a higher initial Goldmann visual field (GVF) score (74.8 versus 60.1 degrees, p=0.255) and final GVF score (78.7 versus 47.1 degrees, p=0.069) but did not reach statistical significance. Conclusions. In RP, increased physical activity is associated with greater self-reported visual function and QOL

Generalized Tests for Selection Effects in GRB High-Energy Correlations

Several correlations among parameters derived from modelling the high-energy properties of GRBs have been reported. We show that well-known examples of these have common features indicative of strong contamination by selection effects. We focus here on the impact of detector threshold truncation on the spectral peak versus isotropic equivalent energy release ($E_{\rm pk}$-$E_{\rm iso}$) relation, extended to a large sample of 218 Swift and 56 HETE-2 GRBs with and without measured redshift. The existence of faint Swift events missing from pre-Swift surveys calls into question inferences based on pre-Swift surveys which must be subject to complicated incompleteness effects. We demonstrate a generalized method for treating data truncation in correlation analyses and apply this method to Swift and pre-Swift data. Also, we show that the $E_{\rm pk}$-$E_{\gamma}$ ("Ghirlanda") correlation is effectively independent of the GRB redshifts, which suggests its existence has little to do with intrinsic physics. We suggest that a physically-based correlation, manifest observationally, must show significantly reduced scatter in the rest frame relative to the observer frame and must not persist if the assumed redshifts are scattered. As with the $E_{\rm pk}$-$E_{\gamma}$ correlation, we find that the pre-Swift, bright GRB $E_{\rm pk}$-$E_{\rm iso}$ correlation of \citet{amati06} does not rigorously satisfy these conditions.Comment: 8 pages, 4 figures, ApJ Accepte

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Physician Characteristics Associated With Ordering 4 Low-Value Screening Tests in Primary Care

Importance: Efforts to reduce low-value tests and treatments in primary care are often ineffective. These efforts typically target physicians broadly, most of whom order low-value care infrequently. Objectives: To measure physician-level use rates of 4 low-value screening tests in primary care to investigate the presence and characteristics of primary care physicians who frequently order low-value care. Design, Setting, and Participants: A retrospective cohort study was conducted using administrative health care claims collected between April 1, 2012, and March 31, 2016, in Ontario, Canada. This study measured use of 4 low-value screening tests-repeated dual-energy x-ray absorptiometry (DXA) scans, electrocardiograms (ECGs), Papanicolaou (Pap) tests, and chest radiographs (CXRs)-among low-risk outpatients rostered to a common cohort of primary care physicians. Exposures: Physician sex, years since medical school graduation, and primary care model. Main Outcomes and Measures: This study measured the number of tests to which a given physician ranked in the top quintile by ordering rate. The resulting cross-test score (range, 0-4) reflects a physician's propensity to order low-value care across screening tests. Physicians were then dichotomized into infrequent or isolated frequent users (score, 0 or 1, respectively) or generalized frequent users for 2 or more tests (score, ≥2). Results: The final sample consisted of 2394 primary care physicians (mean [SD] age, 51.3 [10.0] years; 50.2% female), who were predominantly Canadian medical school graduates (1701 [71.1%]), far removed from medical school graduation (median, 25.3 years; interquartile range, 17.3-32.3 years), and reimbursed via fee-for-service in a family health group (1130 [47.2%]), far removed from medical school graduation (median, 25.3 years; interquartile range, 17.3-32.3 years), and reimbursed via fee-for-service in a family health group (1130 [47.2%). They ordered 302 509 low-value screening tests (74 167 DXA scans, 179 855 ECGs, 19 906 Pap tests, and 28 581 CXRs) after 3 428 557 ordering opportunities. Within the cohort, generalized frequent users represented 18.4% (441 of 2394) of physicians but ordered 39.2% (118 665 of 302 509) of all low-value screening tests. Physicians who were male (odds ratio, 1.29; 95% CI, 1.01-1.64), further removed from medical school graduation (odds ratio, 1.03; 95% CI, 1.02-1.04), or in an enhanced fee-for-service payment model (family health group) vs a capitated payment model (family health team) (odds ratio, 2.04; 95% CI, 1.42-2.94) had increased odds of being generalized frequent users. Conclusions and Relevance: This study identified a group of primary care physicians who frequently ordered low-value screening tests. Tailoring future interventions to these generalized frequent users might be an effective approach to reducing low-value care

Discovery of a Cosmological, Relativistic Outburst via its Rapidly Fading Optical Emission

We report the discovery by the Palomar Transient Factory (PTF) of the transient source PTF11agg, which is distinguished by three primary characteristics: (1) bright (R_peak = 18.3 mag), rapidly fading (ΔR = 4 mag in Δt = 2 days) optical transient emission; (2) a faint (R = 26.2 ± 0.2 mag), blue (g' – R = 0.17 ± 0.29 mag) quiescent optical counterpart; and (3) an associated year-long, scintillating radio transient. We argue that these observed properties are inconsistent with any known class of Galactic transients (flare stars, X-ray binaries, dwarf novae), and instead suggest a cosmological origin. The detection of incoherent radio emission at such distances implies a large emitting region, from which we infer the presence of relativistic ejecta. The observed properties are all consistent with the population of long-duration gamma-ray bursts (GRBs), marking the first time such an outburst has been discovered in the distant universe independent of a high-energy trigger. We searched for possible high-energy counterparts to PTF11agg, but found no evidence for associated prompt emission. We therefore consider three possible scenarios to account for a GRB-like afterglow without a high-energy counterpart: an "untriggered" GRB (lack of satellite coverage), an "orphan" afterglow (viewing-angle effects), and a "dirty fireball" (suppressed high-energy emission). The observed optical and radio light curves appear inconsistent with even the most basic predictions for off-axis afterglow models. The simplest explanation, then, is that PTF11agg is a normal, on-axis long-duration GRB for which the associated high-energy emission was simply missed. However, we have calculated the likelihood of such a serendipitous discovery by PTF and find that it is quite small (≈2.6%). While not definitive, we nonetheless speculate that PTF11agg may represent a new, more common (>4 times the on-axis GRB rate at 90% confidence) class of relativistic outbursts lacking associated high-energy emission. If so, such sources will be uncovered in large numbers by future wide-field optical and radio transient surveys

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest