Systematic study of constitutive cyclo-oxygenase-2 expression: role of NFκB and NFAT transcriptional pathways

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system

Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study

OBJECTIVE Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician’s Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568

Safety and clinical activity of atacicept in the long-term extension of the Phase IIb ADDRESS II study in systemic lupus erythematosus

Objectives: Atacicept reduced SLE disease activity in the Phase IIb ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. Methods: In the 24-week, randomised, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary end point. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. Results: 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4–93.2%). 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. Conclusion: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy

Exclusive neuronal expression of SUCLA2 in the human brain

SUCLA2 encodes the ATP-forming subunit (A-SUCL-) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL- immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming subunit (G-SUCL-) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL- immunoreactivity that was however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex

Adapting the Marine Stewardship Council risk-based framework to estimate impacts on seabirds, marine mammals, marine turtles and sea snakes

This is the final version. Available from Elsevier via the DOI in this record. Information available on impacts of fisheries on target or bycatch species varies greatly, requiring development of risk assessment tools to determine potentially unacceptable levels. Seabirds, marine mammals, marine turtles and sea snakes are particularly vulnerable given their extreme life histories, and data are often lacking on their populations or bycatch rates with which to quantify fisheries impacts. The Marine Stewardship Council (MSC) use a semi-quantitative Productivity Susceptibility Analysis (PSA) that is applicable to all species, target and non-target, to calculate risk of impact and to provide a score for relevant Performance Indicators for fisheries undertaking certification. The most recent MSC Fisheries Standard Review provided an opportunity to test the appropriateness of using this tool and whether it was sufficiently precautionary for seabirds, marine mammals and reptiles . The existing PSA was tested on a range of species and fisheries and reviewed in relation to literature on these species groups. New taxa-specific PSAs were produced and then reviewed by taxa-specific experts and other relevant stakeholders (e.g., assessors, fisheries managers, non-governmental conservation organizations). The conclusions of the Fishery Standard Review process were that the new taxa-specific PSAs were more appropriate than the existing PSA for assessing fisheries risk for seabirds, marine mammals and reptiles, and that, as intended, they resulted in precautionary outcomes. The taxa-specific PSAs provide useful tools for true data-deficient fisheries to assess relative risk of impact. Where some data are available, the MSC could consider developing or adapting other approaches to support robust and relevant risk assessments.Marine Stewardship Counci

Linear viscoelasticity - bone volume fraction relationships of bovine trabecular bone

Trabecular bone has been previously recognized as time-dependent (viscoelastic) material, but the relationships of its viscoelastic behaviour with bone volume fraction (BV/TV) have not been investigated so far. Therefore, the aim of the present study was to quantify the time-dependent viscoelastic behaviour of trabecular bone and relate it to BV/TV. Uniaxial compressive creep experiments were performed on cylindrical bovine trabecular bone samples ([Formula: see text] ) at loads corresponding to physiological strain level of 2000 [Formula: see text] . We assumed that the bone behaves in a linear viscoelastic manner at this low strain level and the corresponding linear viscoelastic parameters were estimated by fitting a generalized Kelvin–Voigt rheological model to the experimental creep strain response. Strong and significant power law relationships ([Formula: see text] ) were found between time-dependent creep compliance function and BV/TV of the bone. These BV/TV-based material properties can be used in finite element models involving trabecular bone to predict time-dependent response. For users’ convenience, the creep compliance functions were also converted to relaxation functions by using numerical interconversion methods and similar power law relationships were reported between time-dependent relaxation modulus function and BV/TV

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Effectiveness of skills-based training using the Drink-less package to increase family practitioner confidence in intervening for alcohol use disorders

BACKGROUND: Misuse of alcohol is second only to tobacco as a leading cause of preventable death in Australia. There is an opportunity in family practice to detect problems and intervene with people at risk of alcohol-related harm before complications occur. However, family practitioners (FPs) report low levels of confidence in managing patients with drinking problems. The aim of this study was to determine whether the interactive training session using the 'Drink-less' package led to improvement in FPs' self-reported level of confidence in detecting and providing interventions for risky alcohol consumption. METHOD: FPs in urban and rural New South Wales were invited to training sessions in their local area. An introductory overview preceded a practical skills- based session, using the Drink-less package. Participants completed before and after evaluation forms. RESULTS: While 49% (CI 43 – 55) of the attending FPs indicated at baseline that they felt confident in identifying at-risk drinkers, this proportion rose to 90% (95% CI: 87 – 93) post-session, and they also reported increases in confidence from 36% (95% CI: 31 – 41) to 90% in their ability to advise patients. Urban FPs reported lower levels of confidence than rural FPs, both pre- and post-session. CONCLUSION: Training sessions in the Drink-less intervention resulted in increased self-reported confidence in detection and brief intervention for alcohol problems. Further research is needed to determine the duration of this effect and its influence on practice behaviour

Immediate effect of the COVID-19 pandemic on patient health, health-care use, and behaviours : results from an international survey of people with rheumatic diseases

Funding Information: We would like to thank all the clinicians, health-care providers, and patient organisations who helped to develop and disseminate this survey. A full list of all the contributors can be found in the appendix (pp 44?45). Preliminary results were presented at the American College of Rheumatology 2020 conference. The views expressed here are those of the authors and participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent the views of the American College of Rheumatology, the European League Against Rheumatism, the UK National Health Service, the National Institute for Health Research, the UK Department of Health, or any other organisation. Funding Information: JSH reports grants from Childhood Arthritis and Rheumatology Research Alliance and Rheumatology Research Alliance; and personal fees from Novartis, Pfizer, and Biogen, outside of the submitted work. JWL reports grants from Pfizer, outside of the submitted work. JAS reports grants and personal fees from Bristol-Myers Squibb; and personal fees from Gilead, Inova Diagnostics, Optum, and Pfizer, outside of the submitted work. CH reports personal fees from AstraZeneca and Aurinia Pharmaceuticals, outside of the submitted work. MJL reports grants from American College of Rheumatology during the conduct of the study and consulting fees from AbbVie, Amgen, Actelion, Boehringer Ingelheim, BMS, Celgene, Gilead, Johnson & Johnson, Mallinckrodt, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi, and UCB, outside of the submitted work. SES is supported by the Vasculitis Clinical Research Consortium and Vasculitis Foundation outside of the submitted work. KLD reports grants from Novartis, Sobi, National Institutes of Health, and Horizon Bio, outside of the submitted work. EFM reports that the Liga Portuguesa Contra as Doenças Reumaticas received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal SA, MSD, Celgene, Medac, Pharmakern, GAfPA, AMGEN, A Menarini Portugal; grants and non-financial support from Pfizer; and non-financial support from Grünenthal GmbH and Tilray, outside of the submitted work. DPR is the volunteer Vice President of the Canadian Arthritis Patient Alliance, which is primarily supported by independent grants from pharmaceutical companies. DPR reports consulting fees from NovoNordisk Canada and speaking fees and an honoraria from Eli Lilly Canada, outside of the submitted work. DPR also lives with rheumatoid arthritis. SB reports personal fees from Novartis, AbbVie, Pfizer, and Horizon Pharma, outside of the submitted work. RG reports personal fees from AbbVie New Zealand, Cornerstones, Janssen New Zealand; and personal fees and non-financial support from Pfizer New Zealand, (all <$10 000) outside of the submitted work. PMM reports personal fees from Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and grants and personal fees from Orphazyme, outside of the submitted work. PCR reports personal fees from Abbvie, Gilead, Lilly, and Roche; grants and personal fees from Novartis, UCB Pharma, Janssen, and Pfizer; and non-financial support from BMS, outside of the submitted work. PS reports honoraria from being a social media editor for @ACR_Journals, outside of the submitted work. ZSW reports grants from National Institutes of Health, BMS, and Sanofi; and personal fees from Viela Bio and MedPace, outside of the submitted work. JY reports personal fees from Pfizer and Eli Lilly, and grants and personal fees from Astra Zeneca, outside of the submitted work. ES is a Board Member of the Canadian Arthritis Patient Alliance, which is a patient-run, volunteer-based organisation whose activities are primarily supported by independent grants from pharmaceutical companies. All other authors declare no competing interests. Publisher Copyright: © 2021 Elsevier LtdBackground: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. Methods: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. Findings: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjögren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). Interpretation: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. Funding: American College of Rheumatology.publishersversionPeer reviewe

Site Fidelity in Space Use by Spider Monkeys (Ateles geoffroyi) in the Yucatan Peninsula, Mexico

Animal home ranges may vary little in their size and location in the short term but nevertheless show more variability in the long term. We evaluated the degree of site fidelity of two groups of spider monkeys (Ateles geoffroyi) over a 10- and 13-year period, respectively, in the northeastern Yucatan peninsula, Mexico. We used the Local Convex Hull method to estimate yearly home ranges and core areas (defined as the 60% probability contour) for the two groups. Home ranges varied from 7.7 to 49.6 ha and core areas varied from 3.1 to 9.2 ha. We evaluated the degree of site fidelity by quantifying the number of years in which different areas were used as either home ranges or core areas. Large tracts were used only as home ranges and only for a few years, whereas small areas were used as either core area or home range for the duration of the study. The sum of the yearly core areas coincided partially with the yearly home ranges, indicating that home ranges contain areas used intermittently. Home ranges, and especially core areas, contained a higher proportion of mature forest than the larger study site as a whole. Across years and only in one group, the size of core areas was positively correlated with the proportion of adult males in the group, while the size of home ranges was positively correlated with both the proportion of males and the number of tree species included in the diet. Our findings suggest that spider monkey home ranges are the result of a combination of long-term site fidelity and year-to-year use variation to enable exploration of new resources