Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non‐OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low‐dose SclAb (TRL, 2.5 μg/mL), or high‐dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt‐related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone‐forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients’ genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision‐making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/2/jbm410377_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/1/jbm410377.pd

Ethnic inequalities and pathways to care in psychosis in England: a systematic review and meta-analysis

© The Author(s). 2018Background: As part of a national programme to tackle ethnic inequalities, we conducted a systematic review and meta-analysis of research on ethnic inequalities in pathways to care for adults with psychosis living in England and/or Wales. Methods: Nine databases were searched from inception to 03.07.17 for previous systematic reviews, including forward and backward citation tracking and a PROSPERO search to identify ongoing reviews. We then carried forward relevant primary studies from included reviews (with the latest meta-analyses reporting on research up to 2012), supplemented by a search on 18.10.17 in MEDLINE, Embase, PsycINFO and CINAHL for primary studies between 2012 and 2017 that had not been covered by previous meta-analyses. Results: Forty studies, all conducted in England, were included for our updated meta-analyses on pathways to care. Relative to the White reference group, elevated rates of civil detentions were found for Black Caribbean (OR = 3.43, 95% CI = 2.68 to 4.40, n = 18), Black African (OR = 3.11, 95% CI = 2.40 to 4.02, n = 6), and South Asian patients (OR = 1.50, 95% CI 1.07 to 2.12, n = 10). Analyses of each Mental Health Act section revealed significantly higher rates for Black people under (civil) Section 2 (OR = 1.53, 95% CI = 1.11 to 2.11, n = 3). Rates in repeat admissions were significantly higher than in first admission for South Asian patients (between-group difference p < 0.01). Some ethnic groups had more police contact (Black African OR = 3.60, 95% CI = 2.15 to 6.05, n = 2; Black Caribbean OR = 2.64, 95% CI = 1.88 to 3.72, n = 8) and criminal justice system involvement (Black Caribbean OR = 2.76, 95% CI = 2.02 to 3.78, n = 5; Black African OR = 1.92, 95% CI = 1.32 to 2.78, n = 3). The White Other patients also showed greater police and criminal justice system involvement than White British patients (OR = 1.49, 95% CI = 1.03 to 2.15, n = 4). General practitioner involvement was less likely for Black than the White reference group. No significant variations over time were found across all the main outcomes. Conclusions: Our updated meta-analyses reveal persisting but not significantly worsening patterns of ethnic inequalities in pathways to psychiatric care, particularly affecting Black groups. This provides a comprehensive evidence base from which to inform policy and practice amidst a prospective Mental Health Act reform. Trial registration: CRD42017071663Peer reviewedFinal Published versio

Removal of Lattice Imperfections that Impact the Optical Quality of Ti:Sapphire using Advanced Magnetorheological Finishing Techniques

Ti:sapphire has become the premier lasing medium material for use in solid-state femtosecond high-peak power laser systems because of its wide wavelength tuning range. With a tuneable range from 680 to 1100 nm, peaking at 800 nm, Ti:sapphire lasing crystals can easily be tuned to the required pump wavelength and provide very high pump brightness due to their good beam quality and high output power of typically several watts. Femtosecond lasers are used for precision cutting and machining of materials ranging from steel to tooth enamel to delicate heart tissue and high explosives. These ultra-short pulses are too brief to transfer heat or shock to the material being cut, which means that cutting, drilling, and machining occur with virtually no damage to surrounding material. Furthermore, these lasers can cut with high precision, making hairline cuts of less than 100 microns in thick materials along a computer-generated path. Extension of laser output to higher energies is limited by the size of the amplification medium. Yields of high quality large diameter crystals have been constrained by lattice distortions that may appear in the boule limiting the usable area from which high quality optics can be harvested. Lattice distortions affect the transmitted wavefront of these optics which ultimately limits the high-end power output and efficiency of the laser system, particularly when operated in multi-pass mode. To make matters even more complicated, Ti:sapphire is extremely hard (Mohs hardness of 9 with diamond being 10) which makes it extremely difficult to accurately polish using conventional methods without subsurface damage or significant wavefront error. In this presentation, we demonstrate for the first time that Magnetorheological finishing (MRF) can be used to compensate for the lattice distortions in Ti:sapphire by perturbing the transmitted wavefront. The advanced MRF techniques developed allow for precise polishing of the optical inverse of lattice distortions with magnitudes of about 70 nm in optical path difference onto one or both of the optical surfaces to produce high quality optics from otherwise unusable Ti:sapphire crystals. The techniques include interferometric, software, and machine modifications to precisely locate and polish sub-millimeter sites onto the optical surfaces that can not be polished into the optics conventionally. This work may allow extension of Ti:sapphire based systems to peak powers well beyond one petawatt

Production Summary for Extended Barrel Module Fabrication at Argonne for the Atlas Tile Calorimeter.

The Tile Calorimeter is one of the main hadronic calorimeters to be used in the ATLAS experiment at CERN [1,2]. It is a steel/scintillator sampling calorimeter which is built by stacking 64 segments in azimuth and 3 separate cylinders to provide a total structure whose length is approximately 12m and whose diameter is a little over 8.4m. It has a total weight of about 2630 metric tons. Important features of this calorimeter are: A minimum gap (1.5mm) between modules in azimuth; Pockets in the structure to hold the scintillator tiles; Recessed channels at the edges of the module into which the readout fibers will sit; and Holes in the structure through which a radioactive source will pass. The mechanical structure for one of the 3 calorimeter sections, the Extended Barrel (EBA) was constructed at Argonne. A schematic of the calorimeter sampling structure and the layout of one of the 64 segments, termed a module, are shown in figure 1. Each module comprises mechanically of a precision machined, structural girder to which 10 submodules are bolted. One of these submodules, the ITC, has a customized shape to accommodate services for other detector elements. Each submodule weighs 850Kg and the assembled mechanical structure of the module weighs approximately 9000Kg (a fully instrumented Extended Barrel modules weighs {approx}9600Kg). A crucial issue for the tile calorimeter assembly is the minimization of the un-instrumented gap between modules when they are stacked on top of each other during final assembly. The design goal was originally 1mm gap which was eventually relaxed to 1.5mm following a careful evaluation of all tolerances in the construction and assembly process as shown in figure 2 [3]. Submodules for this assembly were produced at 4 locations [4] using tooling and procedures which were largely identical [5]. An important issue was the height of each submodule on the stacking fixture on which they were fabricated as this defines the length along the girder for installation, with a design gap between submodules on the girder of 0.3mm. During production we relaxed this tolerance to +0.3, -1.5mm. The height summary for submodules used at Argonne is shown in Appendix I. About 10 submodules fell outside the positive height envelope (due to the raw plate thickness being out of specification) and we constructed some custom short submodules to allow their use in module assembly. The structural girders were produced commercially following the Quality Control plan agreed to with the Tile Calorimeter collaboration and shipped to Argonne. The crucial tolerances on the girder are the key into which submodules are placed as well as the flatness of the key surface which are used in aligning submodules such that the azimuthal surface lies wholly an envelope of +0.75mm from nominal [6]. Another important characteristic of the girder are clearance holes through which the wavelength shift fibers pass to couple the light to photomultipliers located inside the girder, as described in [2]. Since these fiber bundles must be located to high precision, rather than position the holes in the steel to this precision, tooling was developed by which the precision pieces are glued into the girder [7]. This is shown in figure 3. More details on the pieces used to accomplish this interface to the readout electronics are discussed in [2]

Innovation, low energy buildings and intermediaries in Europe: systematic case study review

As buildings throughout their lifecycle account for circa 40% of total energy use in Europe, reducing energy use of the building stock is a key task. This task is, however, complicated by a range of factors, including slow renewal and renovation rates of buildings, multiple non- coordinated actors, conservative building practices, and limited competence to innovate. Drawing from academic literature published during 2005-2015, this article carries out a systematic review of case studies on low energy innovations in the European residential building sector, analysing their drivers. Specific attention is paid to intermediary actors in facilitating innovation processes and creating new opportunities. The study finds that qualitative case study literature on low energy building innovation has been limited, particularly regarding the existing building stock. Environmental concerns, EU, national and local policies have been the key drivers; financial, knowledge and social sustainability and equity drivers have been of modest importance; while design, health and comfort, and market drivers have played a minor role. Intermediary organisations and individuals have been important through five processes: (1) facilitating individual building projects, (2) creating niche markets, (3) implementing new practices in social housing stock, (4) supporting new business model creation, and (5) facilitating building use post construction. The intermediaries have included both public and private actors, while local authority agents have acted as intermediaries in several cases

Discovery and Creation: Alternative Theories of Entrepreneurial Action

As oportunidades empreendedoras existem, independentemente, das percepções dos empreendedores, esperando apenas para serem descobertas? Ou, estas oportunidades são criadas pelas ações dos empreendedores? Duas teorias, internamente, consistentes com as oportunidades empreendedoras são: teoria da criação e teoria da descoberta- as quais serão descritas. Enquanto, será sempre possível, descrever a formação de uma oportunidade particular, como exemplo, de um processo da descoberta ou da criação de oportunidade, estas duas teorias têm implicações importantes para a eficácia de uma variedade ampla de ações empreendedoras em contextos diferentes. As implicações destas teorias para sete destas ações serão descritas, acompanhadas de uma discussão sobre algumas das implicações teóricas mais amplas destas duas teorias para os campos do empreendimento e do gerenciamento estratégico

Estimates of linkage disequilibrium and effective population size in rainbow trout

<p>Abstract</p> <p>Background</p> <p>The use of molecular genetic technologies for broodstock management and selective breeding of aquaculture species is becoming increasingly more common with the continued development of genome tools and reagents. Several laboratories have produced genetic maps for rainbow trout to aid in the identification of loci affecting phenotypes of interest. These maps have resulted in the identification of many quantitative/qualitative trait loci affecting phenotypic variation in traits associated with albinism, disease resistance, temperature tolerance, sex determination, embryonic development rate, spawning date, condition factor and growth. Unfortunately, the elucidation of the precise allelic variation and/or genes underlying phenotypic diversity has yet to be achieved in this species having low marker densities and lacking a whole genome reference sequence. Experimental designs which integrate segregation analyses with linkage disequilibrium (LD) approaches facilitate the discovery of genes affecting important traits. To date the extent of LD has been characterized for humans and several agriculturally important livestock species but not for rainbow trout.</p> <p>Results</p> <p>We observed that the level of LD between syntenic loci decayed rapidly at distances greater than 2 cM which is similar to observations of LD in other agriculturally important species including cattle, sheep, pigs and chickens. However, in some cases significant LD was also observed up to 50 cM. Our estimate of effective population size based on genome wide estimates of LD for the NCCCWA broodstock population was 145, indicating that this population will respond well to high selection intensity. However, the range of effective population size based on individual chromosomes was 75.51 - 203.35, possibly indicating that suites of genes on each chromosome are disproportionately under selection pressures.</p> <p>Conclusions</p> <p>Our results indicate that large numbers of markers, more than are currently available for this species, will be required to enable the use of genome-wide integrated mapping approaches aimed at identifying genes of interest in rainbow trout.</p

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks