Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an ...estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.
ABSTRACT
We use the large homogeneous sample of late M dwarfs, M7–M9.5, of Ahmed & Warren (2019) matched to Gaia DR2, to measure the relation between absolute magnitude and spectral type, and to ...infer the multiplicity fraction of the population, and the distribution of mass ratios in the binary systems. Binaries are identified photometrically as overluminous sources. In order to define a sample that is unbiased with respect to multiplicity we use distance limits that are a function of G − J colour to define a volume-complete sample of 2706 systems. The G − J colours are very precise, with random errors all less than 0.02. We measure absolute magnitudes MJ that are on average 0.5 mag brighter than previous determinations. We find evidence that the discrepancies arise from differences in spectral types in different samples. The measured binary fraction is $16.5\pm 0.8{{\ \rm per\ cent}}$, of which $98{{\ \rm per\ cent}}$ are unresolved: both values are consistent with results of previous studies. The distribution of excess flux in the binaries, compared to the singles, is used to infer the mass ratio distribution f(q)∝qγ, where q = Ms/Mp. We infer a very steep distribution over this spectral range, with γ > 10 ($99{{\ \rm per\ cent}}$ probability). This says that unresolved ultracool M dwarf binaries reside almost exclusively in equal mass systems, and implies that the spectral types of the unresolved binaries match to with 0.5 spectral subtypes. The intrinsic scatter in absolute magnitude MJ for ultracool M dwarfs at fixed G − J colour is measured to be 0.21 mag.
Low- and high-energy proton experimental data and error rate predictions are presented for many bulk Si and SOI circuits from the 20-90 nm technology nodes to quantify how much low-energy protons ...(LEPs) can contribute to the total on-orbit single-event upset (SEU) rate. Every effort was made to predict LEP error rates that are conservatively high; even secondary protons generated in the spacecraft shielding have been included in the analysis. Across all the environments and circuits investigated, and when operating within 10% of the nominal operating voltage, LEPs were found to increase the total SEU rate to up to 4.3 times as high as it would have been in the absence of LEPs. Therefore, the best approach to account for LEP effects may be to calculate the total error rate from high-energy protons and heavy ions, and then multiply it by a safety margin of 5. If that error rate can be tolerated then our findings suggest that it is justified to waive LEP tests in certain situations. Trends were observed in the LEP angular responses of the circuits tested. Grazing angles were the worst case for the SOI circuits, whereas the worst-case angle was at or near normal incidence for the bulk circuits.
ABSTRACT
We present a systematic analysis of the constraints σγ on the mass profile slope γ obtainable when fitting a singular power-law ellipsoid model to a typical strong lensing observation of an ...extended source. These results extend our previous analysis of circular systems, Paper I. We draw our results from 676 mock observations covering a range of image configurations, each created with a fixed signal to noise ratio S = 100 in the images. We analyse the results using a combination of theory and a simplified model which identifies the contribution to the constraints of the individual fluxes and positions in each of the lensed images. The main results are: 1. For any lens ellipticity, the constraints σγ for two image systems are well described by the results of Paper I, transformed to elliptical coordinates; 2. We derive an analytical expression for σγ for systems with the source aligned with the axis of the lens; 3. For both two-image systems and aligned systems, σγ is limited by the flux uncertainties; 4. The constraints for off-axis four-image systems are a factor of two to eight better, depending on source size, than for two-image systems, and improve with increasing lens ellipticity. We show that the constraints on γ in these systems derive from the complementary positional information of the images alone, without using flux. The complementarity improves as the offset of the source from the axis increases, such that the best constraints σγ < 0.01, for S = 100, occur when the source approaches the caustic.
Background Recent studies demonstrate a potentially critical role of matrix metalloproteinases (MMPs) and their inhibitors in the pathophysiology
of rotator cuff tears.
Hypothesis ...Doxycycline-mediated MMP inhibition after rotator cuff repair will improve tendon-to-bone healing.
Study Design Controlled laboratory study.
Methods Rats (n = 183) underwent acute detachment and repair of the supraspinatus tendon and the animals were divided into 4 groups:
In controls (n = 66), the supraspinatus was repaired to its anatomical footprint. In experimental groups, an identical surgery
was performed with doxycycline (130 mg/kg/d) administered orally at (1) preoperative day 1 (n = 66), (2) postoperative day
(POD) 5 (n = 28), or (3) POD 14 (n = 23). Animals were sacrificed at 5 days, 8 days, 2 weeks, and 4 weeks. Tendon-bone interface
was evaluated with histomorphometry. Enzyme-linked immunosorbent assay for local MMP-13 activity was performed at 8 days and
4 weeks. Biomechanical testing of the healing enthesis was performed at 8 days, 2 weeks, and 4 weeks. Serum doxycycline levels
were measured at sacrifice. Statistical analysis was performed using unpaired t tests and 2-way analysis of variance ( P < .05).
Results Serum doxycycline levels were significantly higher in all treated groups compared with controls (1830 ± 835 vs 3 ± 3 ng/mL,
respectively; P < .001). Doxycycline-treated animals demonstrated greater metachromasia and improved collagen organization at the healing
enthesis at POD 5 ( P < .06), POD 8 ( P < .03), and 2 weeks ( P < .04). The MMP-13 activity was significantly reduced in doxycycline-treated compared with control animals at POD 8 (6740
± 2770 vs 10400 ± 2930 relative fluorescent units RFU, respectively; P < .02) but not at 4 weeks (3600 ± 3280 vs 4530 ± 2720 RFU, respectively). The healing enthesis of animals started on doxycycline
preoperatively or at POD 5 had an increased load to failure compared to controls at 2 weeks (13.6 ± 1.8 and 13.2 ± 1.94 N
vs 9.1 ± 2.5 N, respectively; P < .01).
Conclusion/Clinical Relevance Modulation of MMP-13 activity after rotator cuff repair may offer a novel biological pathway to augment tendon-to-bone healing.
Summary
Background
The phase III reSURFACE 1 and reSURFACE 2 (NCT01722331/NCT01729754) trials of the anti‐interleukin‐23p19 monoclonal antibody tildrakizumab (TIL) for psoriasis treatment are ...complete.
Objectives
We present 5‐year pooled data from reSURFACE 1 and reSURFACE 2.
Methods
reSURFACE 1 and reSURFACE 2 were double‐blind, randomized, controlled studies with optional long‐term extensions. Adults with moderate‐to‐severe chronic plaque psoriasis were randomized 2 : 2 : 1 to TIL 100 mg (TIL 100) or 200 mg (TIL 200) or placebo at weeks 0 and 4, and every 12 weeks thereafter reSURFACE 2 included an etanercept (ETN) arm. Efficacy outcomes included proportions of patients achieving absolute and relative improvement from baseline Psoriasis Area and Severity Index (PASI) score through week 244 in TIL responders (≥ 75% improvement from baseline PASI; PASI 75 response) continuously receiving the same dose and ETN partial responders and nonresponders (PASI < 75 response) switched to TIL 200 at week 28. Safety was assessed from adverse events (AEs) in all patients as treated.
Results
Efficacy analyses included 329 and 227 week 28 responders to TIL 100 and TIL 200, respectively, and 121 ETN partial responders/nonresponders switched to TIL 200 at week 28. Of TIL 100 or TIL 200 responders and ETN partial responders/nonresponders entering the extensions, 235/302, 176/213 and 85/107, respectively, were evaluated at week 244, and 88·7%, 92·5% and 81·3%, respectively, achieved PASI 75 response. Exposure‐adjusted rates of serious AEs were 6·3 and 6·0 patients with events per 100 patient‐years of TIL 100 and TIL 200, respectively.
Conclusions
TIL treatment provided sustained disease control over 5 years in week 28 TIL responders and ETN partial responders/nonresponders, with a reassuring safety profile.
What’s already known about this topic?
Tildrakizumab (TIL) is approved for treatment of moderate‐to‐severe psoriasis, and 3‐year data have been previously published.
Long‐term efficacy and safety data of biological therapies is crucial to inform clinical practice.
What does this study add?
TIL is the first anti‐interleukin‐23p19 treatment for which 5‐year efficacy and safety data are reported from two phase III studies, reSURFACE 1 and reSURFACE 2.
These data provide evidence of sustained efficacy in TIL responders and in patients switched from etanercept to TIL at week 28, and a favourable long‐term safety profile with total TIL exposure of over 5400 patient‐years.
Linked Comment: C.G. Purvis et al. Br J Dermatol 2021; 185:242–243.
Plain language summary available online
Abstract
In this series of papers, we develop a formalism for constraining mass profiles in strong gravitational lenses with extended images, using fluxes in addition to positional information. We ...start in this paper with a circular power-law profile and show that the slope γ is uniquely determined by only two observables: the flux ratio f1/f2 and the image position ratio θ1/θ2 of the two images. We derive an analytic expression relating these two observables to the slope, a result that does not depend on the Einstein angle or the structure or brightness of the source. We then find an expression for the uncertainty on the slope σγ that depends only on the position ratio θ1/θ2 and the total signal-to-noise ratio (S/N) in the images. For example, in a system with position ratio θ1/θ2 = 0.5, S/N = 100, and γ = 2 we find that γ is constrained to a precision of ±0.03. We then test these results against a series of mock observations. We invert the images and fit an 11-parameter model, including ellipticity and position angle for both lens and source and measure the uncertainty on γ. We find agreement with the theoretical estimate for all mock observations. In future papers, we will examine the radial range of the galaxy over which the constraint on the slope applies, and extend the analysis to elliptical lenses.
Photometric brown-dwarf classification Skrzypek, N; Warren, S J; Faherty, J K ...
Astronomy and astrophysics (Berlin),
2/2015, Letnik:
574
Journal Article
Recenzirano
Odprti dostop
Aims. We present a method, named photo-type, to identify and accurately classify L and T dwarfs onto the standard spectral classification system using photometry alone. This enables the creation of ...large and deep homogeneous samples of these objects efficiently, without the need for spectroscopy. Methods. We created a catalogue of point sources with photometry in 8 bands, ranging from 0.75 to 4.6 mum, selected from an area of 3344 deg super(2), by combining SDSS, UKIDSS LAS, and WISE data. Sources with 13.0 <J< 17.5, and Y -J> 0.8, were then classified by comparison against template colours of quasars, stars, and brown dwarfs. The L and T templates, spectral types L0 to T8, were created by identifying previously known sources with spectroscopic classifications, and fitting polynomial relations between colour and spectral type. Results. Of the 192 known L and T dwarfs with reliable photometry in the surveyed area and magnitude range, 189 are recovered by our selection and classification method. We have quantified the accuracy of the classification method both externally, with spectroscopy, and internally, by creating synthetic catalogues and accounting for the uncertainties. We find that, brighter than J = 17.5, photo-type classifications are accurate to one spectral sub-type, and are therefore competitive with spectroscopic classifications. The resultant catalogue of 1157 L and T dwarfs will be presented in a companion paper.
Objectives To characterize the rate of decline of forced expiratory volume in 1 second (FEV1 ) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated ...with FEV1 decline. Study design The rate of decline in FEV1 % predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeated-measures, mixed-model regression. Results Mean (±SD) baseline FEV1 % predicted was 88.4% ± 20.5% for 6- to 8-year-olds (n = 1811), 85.3% ± 20.8% for 9- to 12-year-olds (n = 1696), and 78.4% ± 22.0% for 13- to 17-year-olds (n = 1359). Decline in FEV1 % predicted/year was −1.12, −2.39, and −2.34, respectively. High baseline FEV1 and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age groups. Conclusions This study identifies risk factors for FEV1 decline in children and adolescents with cystic fibrosis. Clinicians should not be reassured by high lung function, particularly in young children, because this factor, among others, is independently associated with steeper decline in FEV1.
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