Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31–1·57]), were male compared with female (1·38 [1·05–1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23–1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50–3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49–3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry.

OBJECTIVE: To investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA). METHODS: We analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders. RESULTS: Of 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity. CONCLUSIONS: People with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people

Association between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death among Patients with Immune-Mediated Inflammatory Disease and COVID-19

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P =.006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P =.001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P <.001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P =.004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P =.33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs

Phenanthrene and nitrite effects on juvenile sea bass, Dicentrarchus labrax, using hepatic biotransformation enzymes, biliary fluorescence, and micronuclei as biomarkers

Aquatic organisms may absorb organic compounds mainly from water and by ingestion of contaminated food. The toxicity of such compounds may be intensified by the presence of certain inorganic compounds such as nitrite (NO2–). In order to evaluate the effect of phenanthrene (PHE), a polycyclic aromatic hydrocarbon, in the presence and absence of NO2–, juvenile sea bass, Dicentrarchus labrax L, were exposed to PHE i.p. and to NO2– in water, and several endpoints were measured at days 1, 3, and 6 of exposure. Sea bass exposed to PHE exhibited lower hepatic 7-ethoxyresorufin O-deethylase (EROD) activity as compared to the control group. The activity of the phase II enzyme, glutathione S-transferase (GST), was similar in all the groups of fish. The concentration of PHE metabolites, determined as fluorescent aromatic compounds, was nearly 14 times higher both in the presence and absence of NO2–, showing that even at low EROD activities this PAH is metabolized. The presence of micronuclei was observed to be significantly higher only in sea bass treated with PHE alone, suggesting that different PHE metabolites, without genotoxic properties, were formed in the presence of NO2–.

Deep Extragalactic VIsible Legacy Survey (DEVILS): evolution of the σSFR–M⋆ relation and implications for self-regulated star formation

We present the evolution of the star formation dispersion&ndash;stellar mass relation (&sigma;SFR&ndash;M⋆) in the DEVILS D10 region using new measurements derived using the&nbsp;PROSPECT&nbsp;spectral energy distribution fitting code. We find that &sigma;SFR&ndash;M⋆&nbsp;shows the characteristic &lsquo;U-shape&rsquo; at intermediate stellar masses from 0.1 &lt;&nbsp;z&nbsp;&lt; 0.7 for a number of metrics, including using the deconvolved intrinsic dispersion. A physical interpretation of this relation is the combination of stochastic star formation and stellar feedback causing large scatter at low stellar masses and AGN feedback causing asymmetric scatter at high stellar masses. As such, the shape of this distribution and its evolution encodes detailed information about the astrophysical processes affecting star formation, feedback and the lifecycle of galaxies. We find that the stellar mass that the minimum &sigma;SFR&nbsp;occurs evolves linearly with redshift, moving to higher stellar masses with increasing lookback time and traces the turnover in the star-forming sequence. This minimum &sigma;SFR&nbsp;point is also found to occur at a fixed specific star formation rate (sSFR) at all epochs (sSFR &sim; 10&minus;9.6&thinsp;Gyr&minus;1). The physical interpretation of this is that there exists a maximum sSFR at which galaxies can internally self-regulate on the tight sequence of star formation. At higher sSFRs, stochastic stellar processes begin to cause galaxies to be pushed both above and below the star-forming sequence leading to increased SFR dispersion. As the Universe evolves, a higher fraction of galaxies will drop below this sSFR threshold, causing the dispersion of the low stellar mass end of the star-forming sequence to decrease with time.</p

Characterization of diphtheria toxin's catalytic domain interaction with lipid membranes.

In response to a low environmental pH and with the help of the B fragment (DTB) the catalytic domain of diphtheria toxin (DTA) crosses the endosomal membrane to inhibit protein synthesis. In this study, we investigated the interaction of DTA with lipid membranes by biochemical and biophysical approaches. Data obtained from proteinase K and trypsin digestion experiments of membrane-inserted DTA suggested that residues 134-157 may adopt a transmembrane orientation and residues 77-100 could be membrane-associated, adopting either a surface or a transmembrane orientation. Fourier transform infrared spectroscopy analysis (FTIR) was used to characterize the secondary and tertiary structure of DTA along its pathway, from the native secreted form at pH 7.2 to the refolded structure at neutral pH after interaction with and desorption from a lipid membrane. We found that the association of DTA with lipid membranes at low pH was characterized by an increase of beta-sheet structures and that the refolded structure at neutral pH after interaction with the membrane was identical to the native structure at the same pH. We also investigated the desorption of DTA from the membrane at neutral pH as a function of temperature. Although a complete desorption was observed at 37 degrees C, no desorption took place at 4 degrees C. A model of translocation involving the possibility that DTA might insert one or several transient transmembrane domains during translocation is discussed.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Intentionality, Cognitive Integration and the Continuity Thesis

Naturalistic philosophers ought to think that the mind is continuous with the rest of the world and should not, therefore, be surprised by the findings of the extended mind, cognitive integration and enactivism. Not everyone is convinced that all mental phenomena are continuous with the rest of the world. For example, intentionality is often formulated in a way that makes the mind discontinuous with the rest of the world. This is a consequence of Brentano’s formulation of intentionality, I suggest, and can be overcome by revealing that the concept of intentional directedness as he receives it from the Scholastics is quite consistent with the continuity thesis. It is only when intentional directedness is conjoined with intentional inexistence that intentionality and content are consistent with a discontinuity thesis (such as Brentano’s thesis). This makes room to develop an account of intentional directedness that is consistent with the continuity thesis in the form of Peirce’s representational principle. I also argue against a form of the discontinuity thesis in the guise of the derived/underived content distinction. Having shown that intentionality is consistent with the continuity thesis I argue that we should focus on intentionality and representation as bodily enacted. I conclude that we would be better off focussing on representation and intentionality in action rather than giving abstract functional accounts of extended cognition