Gravitational Waves From Known Pulsars: Results From The Initial Detector Era

We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom

Impact of Upadacitinib on laboratory parameters and related adverse events in patients with RA: Integrated data up to 6.5 years

Introduction: Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. Methods: Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30 mg once daily (QD), adalimumab (ADA) 40 mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. Results: A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30 mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5 years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1–4.3 and 1.7–5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15 mg and UPA 30 mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30 mg QD, respectively. Conclusions: The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA

A blood RNA signature for tuberculosis disease risk: a prospective cohort study.

BACKGROUND: Identification of blood biomarkers that prospectively predict progression of Mycobacterium tuberculosis infection to tuberculosis disease might lead to interventions that combat the tuberculosis epidemic. We aimed to assess whether global gene expression measured in whole blood of healthy people allowed identification of prospective signatures of risk of active tuberculosis disease. METHODS: In this prospective cohort study, we followed up healthy, South African adolescents aged 12-18 years from the adolescent cohort study (ACS) who were infected with M tuberculosis for 2 years. We collected blood samples from study participants every 6 months and monitored the adolescents for progression to tuberculosis disease. A prospective signature of risk was derived from whole blood RNA sequencing data by comparing participants who developed active tuberculosis disease (progressors) with those who remained healthy (matched controls). After adaptation to multiplex quantitative real-time PCR (qRT-PCR), the signature was used to predict tuberculosis disease in untouched adolescent samples and in samples from independent cohorts of South African and Gambian adult progressors and controls. Participants of the independent cohorts were household contacts of adults with active pulmonary tuberculosis disease. FINDINGS: Between July 6, 2005, and April 23, 2007, we enrolled 6363 participants from the ACS study and 4466 from independent South African and Gambian cohorts. 46 progressors and 107 matched controls were identified in the ACS cohort. A 16 gene signature of risk was identified. The signature predicted tuberculosis progression with a sensitivity of 66·1% (95% CI 63·2-68·9) and a specificity of 80·6% (79·2-82·0) in the 12 months preceding tuberculosis diagnosis. The risk signature was validated in an untouched group of adolescents (p=0·018 for RNA sequencing and p=0·0095 for qRT-PCR) and in the independent South African and Gambian cohorts (p values <0·0001 by qRT-PCR) with a sensitivity of 53·7% (42·6-64·3) and a specificity of 82·8% (76·7-86) in the 12 months preceding tuberculosis. INTERPRETATION: The whole blood tuberculosis risk signature prospectively identified people at risk of developing active tuberculosis, opening the possibility for targeted intervention to prevent the disease. FUNDING: Bill & Melinda Gates Foundation, the National Institutes of Health, Aeras, the European Union, and the South African Medical Research Council

Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis.

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease.Objectives: We investigated biosignatures with predictive ability for incident TB.Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated.Measurements and Main Results: A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-α variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events.Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs

Orexin-A and Orexin-B During the Postnatal Development of the Rat Brain

Orexin-A and orexin-B are hypothalamic neuropeptides isolated from a small group of neurons in the hypothalamus, which project their axons to all major parts of the central nervous system. Despite the extensive information about orexin expression and function at different parts of the nervous system in adults, data about the development and maturation of the orexin system in the brain are a bit contradictory and insufficient. A previous study has found expression of orexins in the hypothalamus after postnatal day 15 only, while others report orexins detection at embryonic stages of brain formation. In the present study, we investigated the distribution of orexin-A and orexin-B neuronal cell bodies and fibers in the brain at three different postnatal stages: 1-week-, 2-week-old and adult rats. By means of immunohistochemical techniques, we demonstrated that a small subset of cells in the lateral hypothalamus, and the perifornical and periventricular areas were orexin-A and orexin-B positive not only in 2-week-old and adult rats but also in 1-week-old animals. In addition, orexin-A and orexin-B expressing neuronal varicosities were found in many other brain regions. These results suggest that orexin-A and orexin-B play an important role in the early postnatal brain development. The widespread distribution of orexinergic projections through all these stages may imply an involvement of the two neurotransmitters in a large variety of physiological and behavioral processes also including higher brain functions like learning and memory

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

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE

Abstract Introduction This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228 weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase 3 SELECT-COMPARE study. Methods Patients with non-response or incomplete response to initially prescribed upadacitinib 15 mg once daily or adalimumab 40 mg every other week were switched to the alternate therapy by week 26. Efficacy was evaluated through 228 weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week 264. Results Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week 26. Clinically relevant improvements in all efficacy measures were observed through 228 weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Conclusion Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. Trial Registration NCT02629159

miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling

We investigated whether microRNAs could regulate AMPA receptor expression during activity blockade. miR-92a strongly repressed the translation of GluA1 receptors by binding the 3' untranslated region of rat GluA1 (also known as Gria1) mRNA and was downregulated in rat hippocampal neurons after treatment with tetrodotoxin and AP5. Deleting the seed region in GluA1 or overexpressing miR-92a blocked homeostatic scaling, indicating that miR-92a regulates the translation and synaptic incorporation of new GluA1-containing AMPA receptors