Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Feasibility and acceptability of a Community Outpatient Psychotherapy Engagement Service for Self-harm (COPESS):A randomised controlled trial

Background: Self-harm is widespread and often occurs in the community without resulting in hospital presentation. Individuals with depressive symptoms are at elevated risk. There are limited self-harm interventions designed for community, primary care settings. The Community Outpatient Psychological Engagement Service for Self-Harm (COPESS) is a brief talking therapy intervention for self-harm based in community settings. Aim: To assess the feasibility of evaluating the COPESS intervention in a community setting in relation to participant recruitment, retention, data collection, and the acceptability of the intervention.Method: A mixed-method approach, using a single-blind randomised controlled trial (RCT) design with 1:1 allocation to COPESS plus Treatment-As-Usual (TAU) or TAU alone, was used. Adults with depressive symptoms and self-harm in the past 6 months were recruited from GP practices. Secondary outcome measures were assessed at baseline, 1-month, 2-months, and 3-months after randomisation.Results: Fifty-five people were randomised (out of an initial target of 60). Retention rates at follow-up assessments were high (&gt;75%). Attendance by all participants for all therapy sessions was high (93%). At three months there were trends towards lower levels of self-harm urges, depressive symptoms, and distress in the COPESS group compared to control. Fidelity to the manualised COPESS therapy was moderate to high.Conclusion: All progression criteria were met supporting further evaluation of the intervention in a full-scale efficacy/cost effectiveness trial. These findings add to the growing evidence base supporting the utility of brief psychological interventions for self-harm. COPESS has potential as a brief primary-care based intervention for those struggling with self-harm. <br/

Feasibility and acceptability of the Community Outpatient Psychotherapy Engagement Service for Self-harm (COPESS): randomised controlled trial.

BackgroundSelf-harm is widespread and often occurs in the community without resulting in hospital presentation. Individuals with depressive symptoms are at elevated risk. There are limited self-harm interventions designed for community and primary care settings. The Community Outpatient Psychological Engagement Service for Self-harm (COPESS) is a brief talking therapy intervention for self-harm based in community settings.AimsTo assess the feasibility of evaluating the COPESS intervention in a community setting in relation to participant recruitment, retention, data collection and the acceptability of the intervention.MethodWe used a mixed-method approach and a single-blind randomised controlled trial design with 1:1 allocation to either COPESS plus treatment as usual or treatment as usual alone. Adults with depressive symptoms and self-harm in the past 6 months were recruited from general practices. Secondary outcome measures were assessed at baseline and 1 month, 2 months and 3 months after randomisation. The trial was pre-registered on clinicaltrials.gov (NCT04191122) on 9 December 2019.ResultsFifty-five people were randomised (of an initial target of 60). Retention rates at follow-up assessments were high (>75%), as was attendance by all participants for all therapy sessions (93%). At 3 months, there were trends towards lower levels of self-harm urges, depressive symptoms and distress in the COPESS group compared with controls. Fidelity to the manualised COPESS therapy was moderate to high.ConclusionsAll progression criteria were met, supporting further evaluation of the intervention in a full-scale efficacy and/or cost-effectiveness trial. These findings add to the growing evidence base supporting the utility of brief psychological interventions for self-harm. COPESS has potential as a brief primary-care-based intervention for those struggling with self-harm

Distinct components of cardiovascular health are linked with age-related differences in cognitive abilities

Cardiovascular ageing contributes to cognitive impairment. However, the unique and synergistic contributions of multiple cardiovascular factors to cognitive function remain unclear because they are often condensed into a single composite score or examined in isolation. We hypothesized that vascular risk factors, electrocardiographic features and blood pressure indices reveal multiple latent vascular factors, with independent contributions to cognition. In a population-based deep-phenotyping study (n = 708, age 18–88), path analysis revealed three latent vascular factors dissociating the autonomic nervous system response from two components of blood pressure. These three factors made unique and additive contributions to the variability in crystallized and fluid intelligence. The discrepancy in fluid relative to crystallized intelligence, indicative of cognitive decline, was associated with a latent vascular factor predominantly expressing pulse pressure. This suggests that higher pulse pressure is associated with cognitive decline from expected performance. The effect was stronger in older adults. Controlling pulse pressure may help to preserve cognition, particularly in older adults. Our findings highlight the need to better understand the multifactorial nature of vascular aging

Genome-Wide Analyses of Vocabulary Size in Infancy and Toddlerhood:Associations With Attention-Deficit/Hyperactivity Disorder, Literacy, and Cognition-Related Traits

Background: The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta–genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). Methods: We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15–18 months), late-phase expressive (toddlerhood, 24–38 months), and late-phase receptive (toddlerhood, 24–38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism–based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models. Results: Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08–0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = −0.74), highlighting developmental heterogeneity. Conclusions: The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.</p

MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages

Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine considered to exert wide-ranging, proinflammatory effects on the immune system. Recently, members of this gene family have been discovered in a number of invertebrate species, including parasitic helminths. However, chronic helminth infections are typically associated with a Th2-dominated, counter-inflammatory phenotype, in which alternatively activated macrophages (AAMs) are prominent. To resolve this apparent paradox, we have analyzed the activity of two helminth MIF homologues from the filarial nematode Brugia malayi, in comparison with the canonical MIF from the mouse. We report that murine MIF (mMIF) and Brugia MIF proteins induce broadly similar effects on bone marrow-derived mouse macrophages, eliciting a measured release of proinflammatory cytokines. In parallel, MIF was found to induce up-regulation of IL-4R on macrophages, which when treated in vitro with MIF in combination with IL-4, expressed markers of alternative activation [arginase, resistin-like molecule α (RELM-α) or found in inflammatory zone 1, Ym-1, murine macrophage mannose receptor] and differentiated into functional AAMs with in vitro-suppressive ability. Consistent with this finding, repeated in vivo administration of Brugia MIF induced expression of alternative macrophage activation markers. As mMIF did not induce RELM-α or Ym-1 in vivo, alternative activation may require components of the adaptive immune response to Brugia MIF, such as the production of IL-4. Hence, MIF may accentuate macrophage activation according to the polarity of the environment, thus promoting AAM differentiation in the presence of IL-4-inducing parasitic helminths

Improved Measurement of CP Violation Parameters in Bs0→J/ψK+K− Decays in the Vicinity of the φ(1020) Resonance

The decay-time-dependent CP asymmetry in Bs0→J/ψ(→μ+μ-)K+K- decays is measured using proton-proton collision data, corresponding to an integrated luminosity of 6 fb-1, collected with the LHCb detector at a center-of-mass energy of 13 TeV. Using a sample of approximately 349 000 Bs0 signal decays with an invariant K+K- mass in the vicinity of the φ(1020) resonance, the CP-violating phase φs is measured, along with the difference in decay widths of the light and heavy mass eigenstates of the Bs0-B ̄s0 system, ΔΓs, and the difference of the average Bs0 and B0 meson decay widths, Γs-Γd. The values obtained are φs=-0.039±0.022±0.006 rad, ΔΓs=0.0845±0.0044±0.0024 ps-1, and Γs-Γd=-0.056-0.0015+0.0013±0.0014 ps-1, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements to date and are consistent with expectations based on the Standard Model and with the previous LHCb analyses of this decay. These results are combined with previous independent LHCb measurements. The phase φs is also measured independently for each polarization state of the K+K- system and shows no evidence for polarization dependence