High response diversity and conspecific density-dependence, not species interactions, drive dynamics of coral reef fish communities.

Species-to-species and species-to-environment interactions are key drivers of community dynamics. Disentangling these drivers in species-rich assemblages is challenging due to the high number of potentially interacting species (the 'curse of dimensionality'). We develop a process-based model that quantifies how intraspecific and interspecific interactions, and species' covarying responses to environmental fluctuations, jointly drive community dynamics. We fit the model to reef fish abundance time series from 41 reefs of Australia's Great Barrier Reef. We found that fluctuating relative abundances are driven by species' heterogenous responses to environmental fluctuations, whereas interspecific interactions are negligible. Species differences in long-term average abundances are driven by interspecific variation in the magnitudes of both conspecific density-dependence and density-independent growth rates. This study introduces a novel approach to overcoming the curse of dimensionality, which reveals highly individualistic dynamics in coral reef fish communities that imply a high level of niche structure.

Developing accessible speech technology with users with dysarthric speech.

The Voiceitt app is designed for people with dysarthric speech, to support vocal communication and access to voice-driven technologies. Sixty-six participants were recruited to test the Voiceitt app and share feedback with developers. Most had physical, sensory, or cognitive impairments in addition to atypical speech. The project team liaised with individuals, their families and local support teams to provide access to the app and associated equipment. Testing was user-led, with participants asked to identify and test use cases most relevant to their daily lives over three months or more. Ongoing technical support and training were provided remotely and in-person throughout their testing. Semi-structured interviews were used to collect feedback on users' experiences, with delivery adapted to individuals' needs and preferences. Informal feedback was collected through ongoing contact between participants, their families and support teams and the project team. User feedback has led to improvements to the user interface and functionality, including faster voice training, simplified navigation, the introduction of game-style features and of switch access as an alternative to touchscreen access. This work offers a case-study in meaningful engagement with diverse disabled users of assistive technology in commercial software development.

Late-onset Tay-Sachs disease presenting with a neuromuscular phenotype-a case series.

BACKGROUND AND PURPOSE: Tay-Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in ß-hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms. CASES: A case series of four unrelated patients of non-Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients. CONCLUSION: This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders.

Disturbance-Induced Changes in Population Size Structure Promote Coral Biodiversity.

AbstractReef-building coral assemblages are typically species rich, yet the processes maintaining high biodiversity remain poorly understood. Disturbance has long been thought to promote coral species coexistence by reducing the strength of competition (i.e., the intermediate disturbance hypothesis [IDH]). However, such disturbance-induced effects are insufficient to inhibit competitive exclusion. Nevertheless, there are other mechanisms by which disturbance and, more generally, environmental variation can favor coexistence. Here, we develop a size-structured, stochastic coral competition model calibrated with field data from two common colony morphologies to investigate the effects of hydrodynamic disturbance on community dynamics. We show that fluctuations in wave action can promote coral species coexistence but that this occurs via interspecific differences in size-dependent mortality rather than solely via stochastic fluctuations in competition (i.e., free space availability). While this mechanism differs from that originally envisioned in the IDH, it is nonetheless a mechanism by which intermediate levels of disturbance do promote coexistence. Given the sensitivity of coexistence to disturbance frequency and intensity, anthropogenic changes in disturbance regimes are likely to affect coral assemblages in ways that are not predictable from single-population models.

Sustainable reference points for multispecies coral reef fisheries.

Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to lack research and monitoring capacity, preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for >2000 coral reefs, we estimate site-specific sustainable reference points for coral reef fisheries and use these and available catch estimates to assess the status of global coral reef fish stocks. We reveal that >50% of sites and jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the world's coral reef fisheries.

Subcutaneous abatacept for the treatment of rheumatoid arthritis in routine clinical practice in Germany, Austria, and Switzerland: 2-year retention and efficacy by treatment line and serostatus.

INTRODUCTION/OBJECTIVES: The ASCORE study on treatment for rheumatoid arthritis (RA) showed better retention and clinical response rates for abatacept as first-line versus later-line therapy. This post hoc analysis of ASCORE assessed 2-year retention, efficacy, and safety of subcutaneous (SC) abatacept in Germany, Austria, and Switzerland. METHODS: Adults with RA who initiated SC abatacept 125 mg once weekly were assessed. Primary endpoint was abatacept retention rate at 2 years. Secondary endpoints: proportions of patients with low disease activity (LDA)/remission per Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (≤ 3.2), Simplified Disease Activity Index (≤ 11), and Clinical Disease Activity Index (≤ 10). Outcomes were analyzed by treatment line and serostatus. RESULTS: For the pooled cohort, the 2-year abatacept retention rate was 47.6%; retention was highest in biologic-naïve patients (50.5% [95% confidence interval 44.9, 55.9]). Patients seropositive for both anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF; + / +) at baseline had a higher 2-year abatacept retention rate than patients with single seropositivity for either APCA or RF or double-seronegativity (- / -), irrespective of treatment line. At 2 years, a higher proportion of patients who were biologic-naïve were in LDA/remission than patients with one or ≥ two prior biologics. CONCLUSION: A higher proportion of patients with + / + RA (compared with - / - RA) had abatacept retention after 2 years. Early identification of patients with seropositive RA may facilitate a precision-medicine approach to RA treatment, leading to a higher proportion of patients in LDA/remission. TRIAL REGISTRATION NUMBER: NCT02090556; date registered: March 18, 2014 (retrospectively registered). Key Points • This post hoc analysis of a German-speaking subset of European patients with RA from the global ASCORE study (NCT02090556) showed that retention of SC abatacept within this subset was 47.6%, with good clinical outcomes after 2 years. • Patients with double-seropositive RA (ACPA and RF positive) had higher retention of abatacept than patients with double-seronegative RA (ACPA and RF negative). Retention and clinical responses were highest for patients who were biologic-naïve compared with patients who had one or ≥ two prior biologic treatments. • These real-world data may be useful for clinicians in informing individualized treatment pathways for patients with RA, and fostering superior disease control and clinical outcomes.

The trajectory of clinical responses in patients with early rheumatoid arthritis who achieve sustained remission in response to abatacept: subanalysis of AVERT-2, a randomized phase IIIb study.

BACKGROUND: AVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy. METHODS: During the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP]) < 2.6, were assessed. For patients achieving early sustained SDAI remission at weeks 24/40/52, flow between disease activity categories and individual trajectories was evaluated; flow was also evaluated for later remitters (weeks 40/52 but not week 24). RESULTS: Among patients treated with abatacept + methotrexate (n/N = 451/752) at IP week 24, 22% achieved SDAI remission, 17% achieved Boolean remission, and 42% achieved DAS28 (CRP) < 2.6; of these, 56%, 58%, and 74%, respectively, sustained a response throughout IP weeks 40/52. Among patients with a sustained response at IP weeks 24/40/52, 82% (14/17) on weekly abatacept + methotrexate, 81% (13/16) on abatacept monotherapy, 63% (12/19) who de-escalated/withdrew abatacept, and 65% (11/17) on abatacept placebo + methotrexate were in SDAI remission at end of the DE period; rates were higher than for later remitters in all arms except abatacept placebo + methotrexate. CONCLUSIONS: A high proportion of individual patients achieving clinical endpoints at IP week 24 with abatacept + methotrexate sustained their responses through week 52. Of patients achieving early and sustained SDAI remission through 52 weeks, numerically more maintained remission during the DE period if weekly abatacept treatment continued. TRIAL REGISTRATION: NCT02504268 (ClinicalTrials.gov), registered July 21, 2015.

Six years of demography data for 11 reef coral species.

Scleractinian corals are colonial animals with a range of life-history strategies, making up diverse species assemblages that define coral reefs. We tagged and tracked ~30 colonies from each of 11 species during seven trips spanning 6 years (2009-2015) to measure their vital rates and competitive interactions on the reef crest at Trimodal Reef, Lizard Island, Australia. Pairs of species were chosen from five growth forms in which one species of the pair was locally rare (R) and the other common (C). The sampled growth forms were massive (Goniastrea pectinata [R] and G. retiformis [C]), digitate (Acropora humilis [R] and A. cf. digitifera [C]), corymbose (A. millepora [R] and A. nasuta [C]), tabular (A. cytherea [R] and A. hyacinthus [C]) and arborescent (A. robusta [R] and A. intermedia [C]). An extra corymbose species with intermediate abundance, A. spathulata was included when it became apparent that A. millepora was too rare on the reef crest, making the 11 species in total. The tagged colonies were visited each year in the weeks prior to spawning. During visits, two or more observers each took two or three photographs of each tagged colony from directly above and on the horizontal plane with a scale plate to track planar area. Dead or missing colonies were recorded and new colonies tagged to maintain ~30 colonies per species throughout the 6 years of the study. In addition to tracking tagged corals, 30 fragments were collected from neighboring untagged colonies of each species for counting numbers of eggs per polyp (fecundity); and fragments of untagged colonies were brought into the laboratory where spawned eggs were collected for biomass and energy measurements. We also conducted surveys at the study site to generate size structure data for each species in several of the years. Each tagged colony photograph was digitized by at least two people. Therefore, we could examine sources of error in planar area for both photographers and outliners. Competitive interactions were recorded for a subset of species by measuring the margins of tagged colony outlines interacting with neighboring corals. The study was abruptly ended by Tropical Cyclone Nathan (Category 4) that killed all but nine of the more than 300 tagged colonies in early 2015. Nonetheless, these data will be of use to other researchers interested in coral demography and coexistence, functional ecology, and parametrizing population, community, and ecosystem models. The data set is not copyright restricted, and users should cite this paper when using the data.

Sustained Remission and Outcomes with Abatacept plus Methotrexate Following Stepwise Dose De-escalation in Patients with Early Rheumatoid Arthritis.

INTRODUCTION: One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. METHODS: The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. PRIMARY ENDPOINT: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). RESULTS: Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. CONCLUSIONS: The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB).

Patients with rheumatoid arthritis (RA) experience inflamed and damaged joints. RA is an autoimmune disease in which proteins called autoantibodies, particularly anti-citrullinated protein autoantibodies, target the patient's own joint tissue and organs by mistake, leading to symptomatic inflammation. Successful treatment can decrease the disease's activity to a state known as remission. Patients in remission may experience little or no symptoms and it may be possible for some to then be able to decrease their treatment. Here, we report the results of a large, international study that looked at two treatments, abatacept and methotrexate, in patients with RA and anti-citrullinated protein autoantibodies. The study had two parts. Firstly, to see how many patients had success (remission) with weekly abatacept and/or methotrexate treatment, and secondly, to see if remission was maintained when treatment was either continued or decreased and stopped. The study showed that the number of patients in remission 6 months after treatment started was not greatly different between patients treated with both abatacept and methotrexate and those treated with just methotrexate. Those taking abatacept and methotrexate together had better remission rates 1 year later. More patients also stayed in remission when they continued to receive both abatacept and methotrexate compared with those who were just treated with abatacept or when their abatacept treatment was decreased and stopped. More patients stayed in remission when abatacept was decreased than when it was stopped. The results from this study may help determine possible future treatment reduction and/or withdrawal plans for some patients with RA.

Benthic composition changes on coral reefs at global scales.

Globally, ecosystems are being reconfigured by a range of intensifying human-induced stressors. Coral reefs are at the forefront of this environmental transformation, and if we are to secure their key ecosystem functions and services, it is important to understand the likely configuration of future reefs. However, the composition and trajectory of global coral reef benthic communities is currently unclear. Here our global dataset of 24,468 observations spanning 22 years (1997-2018) revealed that particularly marked declines in coral cover occurred in the Western Atlantic and Central Pacific. The data also suggest that high macroalgal cover, widely regarded as the major degraded state on coral reefs, is a phenomenon largely restricted to the Western Atlantic. At a global scale, the raw data suggest decreased average (± standard error of the mean) hard coral cover from 36 ± 1.4% to 19 ± 0.4% (during a period delineated by the first global coral bleaching event (1998) until the end of the most recent event (2017)) was largely associated with increased low-lying algal cover such as algal turfs and crustose coralline algae. Enhanced understanding of reef change, typified by decreased hard coral cover and increased cover of low-lying algal communities, will be key to managing Anthropocene coral reefs.

Net effects of life-history traits explain persistent differences in abundance among similar species.

Life-history traits are promising tools to predict species commonness and rarity because they influence a population's fitness in a given environment. Yet, species with similar traits can have vastly different abundances, challenging the prospect of robust trait-based predictions. Using long-term demographic monitoring, we show that coral populations with similar morphological and life-history traits show persistent (decade-long) differences in abundance. Morphological groups predicted species positions along two, well known life-history axes (the fast-slow continuum and size-specific fecundity). However, integral projection models revealed that density-independent population growth (λ) was more variable within morphological groups, and was consistently higher in dominant species relative to rare species. Within-group λ differences projected large abundance differences among similar species in short timeframes, and were generated by small but compounding variation in growth, survival, and reproduction. Our study shows that easily measured morphological traits predict demographic strategies, yet small life-history differences can accumulate into large differences in λ and abundance among similar species. Quantifying the net effects of multiple traits on population dynamics is therefore essential to anticipate species commonness and rarity.

Baseline serum levels of cross-linked carboxy-terminal telopeptide of type I collagen predict abatacept treatment response in methotrexate-naive, anticitrullinated protein antibody-positive patients with early rheumatoid arthritis.

OBJECTIVE: To investigate correlations between biomarkers of bone remodelling and extracellular matrix turnover with baseline disease activity and treatment response in patients with early rheumatoid arthritis (RA). METHODS: Assessing Very Early Rheumatoid arthritis Treatment-2 (AVERT-2; NCT02504268) included disease-modifying antirheumatic drug-naive, anti-citrullinated protein antibody (ACPA)-positive patients randomised to weekly subcutaneous abatacept+methotrexate (MTX) or abatacept placebo+MTX for 56 weeks. This post hoc exploratory subanalysis assessed the association between baseline disease activity and eight biomarkers (Spearman's correlation coefficient), and whether baseline biomarkers (continuous or categorical variables) could predict treatment response at weeks 24 and 52 (logistic regression). RESULTS: Patient characteristics were similar between overall (n=752) and biomarker subgroup (n=535) populations and across treatments. At baseline, neoepitopes of matrix metalloproteinase-mediated degradation products of types III and IV collagen and of C reactive protein (CRP) showed the greatest correlations with disease activity; cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) showed weak correlation. Only CTX-I predicted treatment response; baseline CTX-I levels were significantly associated with achieving Simplified Disease Activity Index remission and Disease Activity Score in 28 joints (DAS28 (CRP)) <2.6 (weeks 24 and 52), and American College of Rheumatology 70 response (week 52), in patients treated with abatacept+MTX but not abatacept placebo+MTX. CTX-I predicted significant differential response between arms for DAS28 (CRP) <2.6 (week 24). Treatment differences were greater for abatacept+MTX in patients with medium/high versus low baseline CTX-I. CONCLUSION: In MTX-naive, ACPA-positive patients with early RA, baseline CTX-I predicted treatment response to abatacept+MTX but not abatacept placebo+MTX.

Social Determinants of Cardiovascular Health in US Adolescents: National Health and Nutrition Examination Surveys 1999 to 2014.

Background Cardiovascular health (CVH) is suboptimal in US adolescents. Social determinants of health (SDOH) may affect CVH. We examined SDOH by race and ethnicity and assessed for associations between SDOH and CVH among US adolescents. Methods and Results We analyzed data from the National Health and Nutrition Examination Survey for 3590 participants aged 12 to 19 years from 1999 to 2014. SDOH variables were chosen and an SDOH score assigned (range, 0-7 points; higher=more favorable). CVH was classified according to American Heart Association criteria. We estimated population prevalence and used multivariable linear and polytomous logistic regression for associations between SDOH and CVH. SDOH varied by group, with the non-Hispanic White group (n=1155) having a higher/better mean SDOH score compared with non-Hispanic Black (n=1223) and Mexican American groups (n=1212). Associations between SDOH and CVH differed between racial and ethnic groups (interaction P<0.0001). For the non-Hispanic White group, each additional favorable SDOH variable was associated with a CVH score higher/better by 0.3 points (ß, 0.3, P<0.0001), 20% higher odds for moderate (versus low) CVH (odds ratio [OR], 1.2 [95% CI, 1.1-1.4]), and 80% higher odds for high/favorable (versus low) CVH (1.8 [1.5-2.1]). Associations between SDOH and CVH were more modest among the Mexican American group (ß, 0.12, P=0.001; OR 1.1 [1.0-1.2] for moderate CVH; OR, 1.3 [1.1-1.6] for high CVH) and were not significant among the non-Hispanic Black group (ß, 0.07; P=0.464). Conclusions SDOH and CVH were more favorable for non-Hispanic White adolescents compared with non-Hispanic Black and Mexican American adolescents. SDOH were strongly associated with CVH among the non-Hispanic White group. Racially and culturally sensitive public policy approaches may improve CVH in US adolescents.

Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity.

Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase ß subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.

Volatility in coral cover erodes niche structure, but not diversity, in reef fish assemblages.

The world's coral reefs are experiencing increasing volatility in coral cover, largely because of anthropogenic environmental change, highlighting the need to understand how such volatility will influence the structure and dynamics of reef assemblages. These changes may influence not only richness or evenness but also the temporal stability of species' relative abundances (temporal beta-diversity). Here, we analyzed reef fish assemblage time series from the Great Barrier Reef to show that, overall, 75% of the variance in abundance among species was attributable to persistent differences in species' long-term mean abundances. However, the relative importance of stochastic fluctuations in abundance was higher on reefs that experienced greater volatility in coral cover, whereas it did not vary with drivers of alpha-diversity. These findings imply that increased coral cover volatility decreases temporal stability in relative abundances of fishes, a transformation that is not detectable from static measures of biodiversity.

ACPA-negative and ACPA-positive RA patients achieving disease resolution demonstrate distinct patterns of MRI-detected joint-inflammation.

OBJECTIVES: Although sustained DMARD-free remission (SDFR; sustained absence of clinical-synovitis after DMARD-discontinuation) is increasingly achievable in RA, prevalence differs between ACPA-negative (40%) and ACPA-positive RA (5-10%). Additionally, early DAS remission (DAS4months<1.6) is associated with achieving SDFR in ACPA-negative, but not in ACPA-positive RA. Based on these differences, we hypothesized that longitudinal patterns of local tissue inflammation (synovitis/tenosynovitis/osteitis) also differ between ACPA-negative and ACPA-positive RA patients achieving SDFR. With the ultimate aim being to increase understanding of disease resolution in RA, we studied MRI-detected joint inflammation over time in relation to SDFR development in ACPA-positive RA and ACPA-negative RA. METHODS: A total of 198 RA patients (94 ACPA-negative, 104 ACPA-positive) underwent repeated MRIs (0/4/12/24 months) and were followed on SDFR development. The course of MRI-detected total inflammation, and synovitis/tenosynovitis/osteitis individually were compared between RA patients who did and did not achieve SDFR, using Poisson mixed models. In total, 174 ACPA-positive RA patients from the AVERT-1 were studied as ACPA-positive validation population. RESULTS: In ACPA-negative RA, baseline MRI-detected inflammation levels of patients achieving SDFR were similar to patients without SDFR but declined 2.0 times stronger in the first year of DMARD treatment [IRR 0.50 (95% CI; 0.32, 0.77); P < 0.01]. This stronger decline was seen in tenosynovitis/synovitis/osteitis. In contrast, ACPA-positive RA-patients achieving SDFR, had already lower inflammation levels (especially synovitis/osteitis) at disease presentation [IRR 0.45 (95% CI; 0.24, 0.86); P = 0.02] compared with patients without SDFR, and remained lower during subsequent follow-up (P = 0.02). Similar results were found in the ACPA-positive validation population. CONCLUSION: Compared with RA patients without disease resolution, ACPA-positive RA patients achieving SDFR have less severe joint inflammation from diagnosis onwards, while ACPA-negative RA patients present with similar inflammation levels but demonstrate a stronger decline in the first year of DMARD therapy. These different trajectories suggest different mechanisms underlying resolution of RA chronicity in both RA subsets.

Retention of subcutaneous abatacept for the treatment of rheumatoid arthritis: real-world results from the ASCORE study: an international 2-year observational study.

OBJECTIVES: To evaluate retention, efficacy, and safety of subcutaneous (SC) abatacept over 2 years in patients with moderate-to-severe RA in the Abatacept SubCutaneOus in Routine clinical practicE (ASCORE) study. METHODS: Patients with RA who initiated SC abatacept 125 mg once weekly were enrolled in the international, observational, prospective multicentre ASCORE study into biologic-naïve or ≥ 1 prior biologic failure cohorts. PRIMARY ENDPOINT: abatacept retention rate at 2 years. Secondary endpoints: proportion of patients with good/moderate EULAR response rates based on DAS28 (ESR), low disease activity and/or remission according to DAS28 (ESR; ≤ 3.2/ < 2.6), SDAI (≤ 11/ ≤ 3.3), CDAI (≤ 10/ ≤ 2.8), and Boolean criteria. Retention rate by baseline serostatus was evaluated post hoc. RESULTS: Overall, 47% of patients remained on abatacept for 2 years, irrespective of treatment line. Higher abatacept retention rates were associated with lower prior biologic exposure. Generally, clinical outcomes showed that the proportion of patients with low disease activity/remission was higher in biologic-naïve patients (vs biologic-failure) and similar in those with 1 and ≥ 2 prior biologic failures. In patients on treatment at 2 years, good/moderate EULAR response rates of ~ 80% were consistently noted irrespective of prior biologic exposure. Across treatment lines, retention was greater in patients with seropositive (vs seronegative) RA. Patients with rheumatoid factor/anti-citrullinated protein antibody single-positive RA who were bio-naïve had higher retention than patients who were bio-experienced. CONCLUSIONS: In the ASCORE study, SC abatacept retention was 47% at 2 years with good clinical outcomes and was well-tolerated in the real-world setting. Abatacept retention and clinical response rates were higher in patients who received abatacept as an earlier- versus later-line biologic drug treatment and in those with seropositive RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02090556.

Interactive effects of multiple stressors vary with consumer interactions, stressor dynamics and magnitude.

Predicting the impacts of multiple stressors is important for informing ecosystem management but is impeded by a lack of a general framework for predicting whether stressors interact synergistically, additively or antagonistically. Here, we use process-based models to study how interactions generalise across three levels of biological organisation (physiological, population and consumer-resource) for a two-stressor experiment on a seagrass model system. We found that the same underlying processes could result in synergistic, additive or antagonistic interactions, with interaction type depending on initial conditions, experiment duration, stressor dynamics and consumer presence. Our results help explain why meta-analyses of multiple stressor experimental results have struggled to identify predictors of consistently non-additive interactions in the natural environment. Experiments run over extended temporal scales, with treatments across gradients of stressor magnitude, are needed to identify the processes that underpin how stressors interact and provide useful predictions to management.

Implementation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System in a randomized phase IIb study of abatacept in psoriatic arthritis.

OBJECTIVES: To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA. METHODS: We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365. MRIs at baseline and days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, osteitis, tenosynovitis, periarticular inflammation, bone erosions, joint space narrowing and bone proliferation were assessed using the PsAMRIS. A novel total inflammation score was tested. RESULTS: MRIs for 123 patients were included. On day 169, ABA10 and ABA30/10 significantly reduced MRI synovitis and tenosynovitis, respectively, vs placebo [differences -0.966 (P = 0.039) and -1.652 (P = 0.014), respectively]. Synovitis in the placebo group increased non-significantly from baseline to day 169, total inflammation and tenosynovitis decreased non-significantly and all measures improved significantly after a switch to ABA10 [-1.019, -0.940, -2.275 (P < 0.05), respectively, day 365 vs day 169]. Structural outcomes changed minimally across groups. CONCLUSION: Adults with PsA receiving ABA10 and ABA30/10 demonstrated significant resolution of inflammatory components of disease, confirmed by MRI, with synovitis and tenosynovitis improvements consistent with previously reported clinical responses for these doses. Results indicate that a reduction in OMERACT PsAMRIS inflammation scores may provide proof of tissue-level efficacy in PsA clinical trials. REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00534313.