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

Sleep duration in preschool age and later behavioral and cognitive outcomes:an individual participant data meta-analysis in five European cohorts

Data de publicació electrònica: 07-02-2023Short sleep duration has been linked to adverse behavioral and cognitive outcomes in schoolchildren, but few studies examined this relation in preschoolers. We aimed to investigate the association between parent-reported sleep duration at 3.5 years and behavioral and cognitive outcomes at 5 years in European children. We used harmonized data from five cohorts of the European Union Child Cohort Network: ALSPAC, SWS (UK); EDEN, ELFE (France); INMA (Spain). Associations were estimated through DataSHIELD using adjusted generalized linear regression models fitted separately for each cohort and pooled with random-effects meta-analysis. Behavior was measured with the Strengths and Difficulties Questionnaire. Language and non-verbal intelligence were assessed by the Wechsler Preschool and Primary Scale of Intelligence or the McCarthy Scales of Children's Abilities. Behavioral and cognitive analyses included 11,920 and 2981 children, respectively (34.0%/13.4% of the original sample). In meta-analysis, longer mean sleep duration per day at 3.5 years was associated with lower mean internalizing and externalizing behavior percentile scores at 5 years (adjusted mean difference: - 1.27, 95% CI [- 2.22, - 0.32] / - 2.39, 95% CI [- 3.04, - 1.75]). Sleep duration and language or non-verbal intelligence showed trends of inverse associations, however, with imprecise estimates (adjusted mean difference: - 0.28, 95% CI [- 0.83, 0.27] / - 0.42, 95% CI [- 0.99, 0.15]). This individual participant data meta-analysis suggests that longer sleep duration in preschool age may be important for children's later behavior and highlight the need for larger samples for robust analyses of cognitive outcomes. Findings could be influenced by confounding or reverse causality and require replication.Open Access funding enabled and organized by Projekt DEAL. This research (LifeCycle Project ID: ECCNLC201914) was funded by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement N: 733206, LifeCycle project. Kathrin Guerlich was granted a LifeCycle Fellowship (Grant Agreement N: 733206, LifeCycle project). Berthold Koletzko is the Else Kröner Seniorprofessor of Paediatrics at LMU – University of Munich, financially supported by Else Kröner-Fresenius-Foundation, LMU Medical Faculty and LMU University Hospital. Deborah A Lawlor and Ahmed Elhakeem work in a Unit that receives support from the University of Bristol and UK Medical Research Council (MC_UU_00011/6). Deborah A Lawlor is a British Heart Foundation Chair (CH/F/20/90003) and a National Institute of Health Research Senior Investigator (NF-0616–10102). Mònica Guxens is funded by a Miguel Servet II fellowship (CPII18/00018) awarded by the Spanish Institute of Health Carlos III. Jordi Julvez holds Miguel Servet-II contract (CPII19/00015) awarded by the Instituto de Salud Carlos III (Co-funded by European Social Fund "Investing in your future"). Tim Cadman was funded a Marie Sklodowska-Curie Individual Fellowship. Funding details for each cohort are provided in Online Resource 1. No funder had any influence on the study design, data collection, statistical analyses or interpretation of findings. The views expressed in this paper are those of the authors and not necessarily of any funders

Tackling barriers to COVID-19 vaccine uptake in London: a mixed-methods evaluation

BACKGROUND: In response to the COVID-19 pandemic, the first vaccine was administered in December 2020 in England. However, vaccination uptake has historically been lower in London than in other English regions. METHODS: Mixed-methods: This comprised an analysis of cumulative percentage uptake across London between 8 December 2020 and 6 June 2021 by vaccine priority cohorts and ethnicity. We also undertook thematic analyses of uptake barriers, interventions to tackle these and key learning from a qualitative survey of 27 London local authority representatives, vaccine plans from London's five Integrated Care Systems and interviews with 38 London system representatives. RESULTS: Vaccine uptake was lower in Black ethnic (57-65% uptake) compared with the White British group (90% uptake). Trust was a critical issue, including mistrust in the vaccine itself and in authorities administering or promoting it. The balance between putative costs and benefits of vaccination created uptake barriers for zero-hour and shift workers. Intensive, targeted and 'hyper-local' initiatives, which sustained community relationships and were not constrained by administrative boundaries, helped tackle these barriers. CONCLUSIONS: The success of the national vaccination programme depended on conceding local autonomy, investing in responsive and long-term partnerships to engender trust through in-depth understanding of communities' beliefs

Lived experience of Silver-Russell syndrome: Implications for management during childhood and into adulthood

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objective There is limited information on the psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by slow growth in utero leading to short stature in adulthood. Such information could aid families in making difficult treatment decisions and guide management strategies for health professionals. We aimed to explore the lived experience of people with SRS across the lifespan. Design/setting/patients In-depth, semi-structured interviews were conducted between January 2015 and October 2016 with a sample of 15 adults (six women) with genetically confirmed SRS from the UK. Qualitative interviews were transcribed and coded to identify similarities and differences: codes were then grouped to form overarching themes. Results Four themes were identified from participant accounts: (1) appearance-related concerns extending beyond height; (2) strategies to deal with real and perceived threats; (3) women's experiences of pain, disability and feeling older than their years; and (4) feeling overlooked in romantic relationships. These themes show that other factors, beyond short stature, affect patient well-being and indicate a mismatch between patient need and healthcare provision. Conclusions Challenges in SRS during childhood and adolescence were central to the psychosocial impact of SRS, and were not limited to height. These challenges, as well as symptoms such as pain and fatigue for women, have not previously been documented. To help individuals with SRS develop strategies to manage psychosocial issues, we recommend clinicians incorporate psychological services as an integral part of multidisciplinary teams managing individuals with SRS during childhood, adolescence and adulthood

Associations of Maternal Educational Level, Proximity to Green Space During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood:A Proof-of-Concept Federated Analysis in 18 Birth Cohorts

International sharing of cohort data for research is important and challenging. We explored the feasibility of multicohort federated analyses by examining associations between 3 pregnancy exposures (maternal education, exposure to green vegetation, and gestational diabetes) and offspring body mass index (BMI) from infancy to age 17 years. We used data from 18 cohorts (n = 206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13, and 14-17 years. Associations were estimated using linear regression via 1-stage individual participant data meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z score comparing low with high education, at age 2-3 years = 0.03 (95% confidence interval (CI): 0.00, 0.05), at 4-7 years = 0.16 (95% CI: 0.14, 0.17), and at 8-13 years = 0.24 (95% CI: 0.22, 0.26)). Gestational diabetes was positively associated with BMI from age 8 years (BMI z score difference = 0.18, 95% CI: 0.12, 0.25) but not at younger ages; however, associations attenuated towards the null when restricted to cohorts that measured gestational diabetes via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age 1 year but not at older ages. Opportunities of cross-cohort federated analyses are discussed.</p

Associations of Maternal Educational Level, Proximity to Green Space During Pregnancy, and Gestational Diabetes With Body Mass Index From Infancy to Early Adulthood:A Proof-of-Concept Federated Analysis in 18 Birth Cohorts

International sharing of cohort data for research is important and challenging. We explored the feasibility of multicohort federated analyses by examining associations between 3 pregnancy exposures (maternal education, exposure to green vegetation, and gestational diabetes) and offspring body mass index (BMI) from infancy to age 17 years. We used data from 18 cohorts (n = 206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13, and 14-17 years. Associations were estimated using linear regression via 1-stage individual participant data meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z score comparing low with high education, at age 2-3 years = 0.03 (95% confidence interval (CI): 0.00, 0.05), at 4-7 years = 0.16 (95% CI: 0.14, 0.17), and at 8-13 years = 0.24 (95% CI: 0.22, 0.26)). Gestational diabetes was positively associated with BMI from age 8 years (BMI z score difference = 0.18, 95% CI: 0.12, 0.25) but not at younger ages; however, associations attenuated towards the null when restricted to cohorts that measured gestational diabetes via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age 1 year but not at older ages. Opportunities of cross-cohort federated analyses are discussed.</p

Tackling barriers to COVID-19 vaccine uptake in London: a mixed-methods evaluation.

BACKGROUND: In response to the COVID-19 pandemic, the first vaccine was administered in December 2020 in England. However, vaccination uptake has historically been lower in London than in other English regions. METHODS: Mixed-methods: This comprised an analysis of cumulative percentage uptake across London between 8 December 2020 and 6 June 2021 by vaccine priority cohorts and ethnicity. We also undertook thematic analyses of uptake barriers, interventions to tackle these and key learning from a qualitative survey of 27 London local authority representatives, vaccine plans from London's five Integrated Care Systems and interviews with 38 London system representatives. RESULTS: Vaccine uptake was lower in Black ethnic (57-65% uptake) compared with the White British group (90% uptake). Trust was a critical issue, including mistrust in the vaccine itself and in authorities administering or promoting it. The balance between putative costs and benefits of vaccination created uptake barriers for zero-hour and shift workers. Intensive, targeted and 'hyper-local' initiatives, which sustained community relationships and were not constrained by administrative boundaries, helped tackle these barriers. CONCLUSIONS: The success of the national vaccination programme depended on conceding local autonomy, investing in responsive and long-term partnerships to engender trust through in-depth understanding of communities' beliefs

The LifeCycle Project-EU Child Cohort Network : a federated analysis infrastructure and harmonized data of more than 250,000 children and parents

Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with individual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.Peer reviewe

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: insights from the LUNG SAFE study

Contains fulltext : 218568.pdf (publisher's version ) (Open Access)BACKGROUND: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. METHODS: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 >/= 0.60 during hyperoxemia). RESULTS: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). CONCLUSIONS: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. TRIAL REGISTRATION: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073