Select committees : an examination of factors determining their influence on the policy process.

In 2 volsSIGLEAvailable from British Library Document Supply Centre- DSC:DX179432 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Asymptotic Scaling and Infrared Behavior of the Gluon Propagator

The Landau gauge gluon propagator for the pure gauge theory is evaluated on a 32^3x64 lattice with a physical volume of (3.35^3x6.7)fm^4. Comparison with two smaller lattices at different lattice spacings allows an assessment of finite volume and finite lattice spacing errors. Cuts on the data are imposed to minimize these errors. Scaling of the gluon propagator is verified between beta=6.0 and beta=6.2. The tensor structure is evaluated and found to be in good agreement with the Landau gauge form, except at very small momentum values, where some small finite volume errors persist. A number of functional forms for the momentum dependence of the propagator are investigated. The form D(q^2)=D_ir+D_uv, where D_ir(q^2) ~ (q^2+M^2)^-\eta and D_uv is an infrared regulated one-loop asymptotic form, is found to provide an adequate description of the data over the entire momentum region studied - thereby bridging the gap between the infrared confinement region and the ultraviolet asymptotic region. The best estimate for the exponent \eta is 3.2(+0.1/-0.2)(+0.2/-0.3), where the first set of errors represents the uncertainty associated with varying the fitting range, while the second set of errors reflects the variation arising from different choices of infrared regulator in D_uv. Fixing the form of D_uv, we find that the mass parameter M is (1020+/-100)MeV.Comment: 37 pages, RevTeX, 16 postscript figures, 7 gif figures. Revised version accepted for publication in Phys. Rev. D. Model functions and discussion of asymptotic behaviour modified; all model fits have been redone. This paper, including postscript version of all figures, can be found at http://www.physics.adelaide.edu.au/~jskuller/papers

A prospective study comparing tendon-to-bone interface healing using an interposition bioresorbable scaffold with a vented anchor for primary rotator cuff repair in sheep.

BACKGROUND: The purpose of this study was to evaluate the biomechanical and histologic properties of rotator cuff repairs using a vented anchor attached to a bioresorbable interpositional scaffold composed of aligned PLGA (poly(l-lactide-co-glycoside)) microfibers in an animal model compared to standard anchors in an ovine model. METHODS: Fifty-six (n = 56) skeletally mature sheep were randomly assigned to a repair of an acute infraspinatus tendon detachment using a innovative anchor-PLGA scaffold device (Treatment) or a similar anchor without the scaffold (Control). Animals were humanely euthanized at 7 and 12 weeks post repair. Histologic and biomechanical properties of the repairs were evaluated and compared. RESULTS: The Treatment group had a significantly higher fibroblast count at 7 weeks compared to the Control group. The tendon bone repair distance, percentage perpendicular fibers, new bone formation at the tendon-bone interface, and collagen type III deposition was significantly greater for the Treatment group compared with the Control group at 12 weeks (P ≤ .05). A positive correlation was identified in the Treatment group between increased failure loads at 12 weeks and the following parameters: tendon-bone integration, new bone formation, and collagen type III. No statistically significant differences in biomechanical properties were identified between Treatment and Control Groups (P \u3e .05). CONCLUSIONS: Use of a vented anchor attached to a bioresorbable interpositional scaffold composed of aligned PLGA microfibers improves the histologic properties of rotator cuff repairs in a sheep model. Improved histology was correlated with improved final construct strength at the 12-week time point

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570