bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol design and preliminary evaluation of the REAL-Health Triple Aim, an open-cohort CVD-care optimisation initiative
Authors: Rison S C G , Dostal I , Ahmed Z , Raisi-Estabragh Z , Carvalho C , Lobo M , Patel R , Antoniou M , Boomla K , McManus R J , Robson J P 
Published: October 2021

Abstract

Introduction
Effective treatment of cardiovascular disease (CVD) in primary care could be improved. We aim to assess the efficacy of a scalable treatment optimisation programme in unselected community populations in South East England, with the triple aim of improved blood pressure control in people with hypertension, increased high-intensity statin use in people with CVD and reduced gastrointestinal bleeding in patients on antithrombotic medication.

Method
This observational study comprises an open cohort of approximately 200,000 adults at high cardiovascular risk registered with general practitioners in five South East England Clinical Commissioning Groups (CCGs). An intervention programme is planned in four of these CCGs with a further non-intervention CCG acting as a control group. The intervention will consist of: clinical guidelines and educational outreach; virtual patient-reviews software; peer-performance “dashboards” and, where available, financial incentives.
The study will examine 3 primary outcomes: 1. Diagnosed hypertension with a blood pressure &lt;140/90mmHg; 2. Diagnosed CVD on a high-intensity statin; 3. A cardiovascular indication for antithrombotic therapy with one or more factors for increased risk of gastrointestinal bleeding (e.g. age ≥65) on gastroprotection. A further 17 secondary outcomes related to these three aims will be assessed.

Analysis
We will use an interrupted time series analysis over 18 months, representing the pre-implementation, implementation and the post-implementation phases with comparison to the control CCG and applicable national Quality and Outcomes Framework and national prescribing statistics (e.g. OpenPrescribing). Secondary outcomes include an equity impact analysis with results stratified by age, gender, ethnic group and index of deprivation.

Preliminary data
We present preliminary data on Key Performance Indicators (KPIs) collected from 191 GP practices including [percentage achievement on 01/09/2019, on 01/09/2020]: 1. Patients with hypertension and most recent blood pressure ≤140/90mmHg [68.7%, 60.6%]. 2. Patients eligible for treatment with a high-intensity statin on such treatment [53.8%, 55.8%]. 3. Patients on antithrombotics with ≥1 risk factors for gastrointestinal bleeding on gastroprotection [59.0%, 60.1%]. We also present our virtual patient-review software tool and outcome visualisation dashboard.

Conclusion
The REAL-Health Triple Aim initiative is a large-scale primary care cardiovascular risk reduction initiative which was launched almost contemporaneously with the United Kingdom's first SARS-CoV-2 related lockdown. Preliminary data justify the need for the Triple Aim initiative and give us an insight on the impact of the pandemic on its implementation.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): Barts CharityBritish Heart Foundation
Increase of serum cyclophilin C levels in the follow-up of coronary artery disease: a biomarker and possible clinical predictor
Authors: Gonzalez Juanatey C , Bayon J , Ocaranza-Sanchez R , Santas-Alvarez M , Abellas-Sequeiros A , Alfonso A , Botana L 
Published: October 2021

Abstract

Background
Traditional cardiovascular risk factors and a large number of biomarkers are well known in their association with the diagnosis and prognosis of coronary artery disease (CAD). Cyclophilin C (CypC) is a subfamily of immunophilins that modulates macrophage activation and redox homeostasis.

Purpose
This study is aimed at investigating the changes in serum CypC levels and their relationship with cardiovascular events at 12 months of follow-up in CAD patients.

Methods
The study included a total of 125 subjects (40 patients with acute CAD, 40 patients with chronic CAD and 45 control volunteers). We analyzed plasma CypC levels from baseline to 6 and 12 months for a better understanding of its behaviour in atherosclerosis.

Results
Serum CypC levels were shown to be gradually increased in CAD patients [(30.63 pg/mL ± 3.77 at baseline, 38.70 pg/mL ± 6.41 at 6 months (p=0.25) and 47.27 pg/mL ± 5.65 at 12 months (p=0.007)]. In addition, serum CypC levels during the follow-up were a significant predictor of CAD (c- statistic 0.76 at 6 months and 0.89 at 12 months; p&lt;0.001). Despite it, there was no significant association between CypC and cardiovascular events, but serum CypC levels tended to be higher in patients suffering cardiovascular events during the follow-up (29.02 pg/mL ± 6.39 vs 79.96 pg/mL ± 22.18; p=0.029). In this regard, plasma levels of hsCRP &gt;2.3 mg/L plus NT-proBNP &gt;300pg/mL together were significant predictors of cardiovascular events during the follow-up in CAD patients with CypC levels &gt;17.5 pg/mL (p=0.048).

Conclusions
Taken together, our results suggest that serum CypC levels increase during the follow-up in CAD patients and could be a novel biomarker with a possible prognostic value in combination with hsCRP and NT-proBNP.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III. Spain
LncRNA Bigheart stimulates Regulator of calcineurin 1 (Rcan1) expression in an auto-amplification loop that stimulates calcineurin-NFAT signalling in heart failure
Authors: Mangraviti N , Ruhle F , Martens L , Kinet V , Hegenbarth J C , Seyer S , Olieslagers S , Stoll M , De Windt L J 
Published: October 2021

Abstract

Background
Cardiac hypertrophy precedes many heart diseases and understanding its molecular basis remains one of the greatest challenges in cardiovascular medicine. Recent studies highlighted the sporadic involvement of long noncoding RNAs (lncRNAs) in cardiac development and disease but our understanding of lncRNAs in heart failure is still limited.

Results
Expression profiling of lncRNAs in failing mouse hearts revealed dysregulation of “Bigheart”, a novel lncRNA that is evolutionary conserved. Bigheart overexpressed using a serotype 9 adeno-associated virus (AAV) in neonatal rat cardiomyocytes (NRCMs) induced spontaneous hypertrophy, while silencing this lncRNA with specific siRNAs blunted the hypertrophic response in agonist-stimulated cardiomyocytes. GapmeR-mediated silencing of Bigheart prevented transverse aortic constriction (TAC)-induced pathological cardiac remodeling in the mouse in vivo. Mechanistically, analysis of the Bigheart genomic locus revealed several binding sites for the transcription factor nuclear factor of activated T-cells (NFAT), a downstream transcription factor of the pro-hypertrophic calcineurin-NFAT signaling cascade. The sensitivity of Bigheart transcriptional induction for calcineurin-NFAT signalling was further demonstrated by luciferase assays using a Bigheart promoter-luciferase construct. Finally, RNA-sequencing of Gapmer-silenced mouse hearts and chromatin isolation by RNA purification (ChIRP) coupled to mass spectrometry (MS), revealed that Bigheart interacts with heterogeneous nuclear ribonucleoproteins (hnRNPs) and High Mobility Group Box 1 (HMGB1) acts in trans to stimulate the transcription of Regulator of calcineurin 1 (Rcan1), a facilitator of calcineurin-NFAT signaling.

Conclusions
These results indicate that lncRNA Bigheart constitutes a positive feedforward loop in hypertrophic signaling and a promising target to attenuate maladaptive cardiac hypertrophy

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): Maastricht university
Smooth muscle cell specific ablation of CXCL12 downregulates endothelial CXCR7 leading to defective coronary arteries and cardiac hypertrophy
Authors: Messner M , Ghadge S K , Seiringer H , Maurer T , Staggl S , Zeller T , Mueller C , Wenninger W J , Geyer S H , Sopper S , Krogsdam A , Poelzl G , Bauer A , Zaruba M M 
Published: October 2021

Abstract

Aims
The chemokine CXCL12 plays a fundamental role in cardiovascular development, cell trafficking, and myocardial repair. Human genome-wide association studies even have identified novel loci downstream of the CXCL12 gene locus associated with coronary artery disease and myocardial infarction. Nevertheless, cell and tissue specific effects of CXCL12 are barely understood. Since we detected high expression of CXCL12 in smooth muscle (SM) cells, we generated a SM22-alpha-Cre driven mouse model to ablate CXCL12 (SM-CXCL12−/−).

Methods and results
SM-CXCL12−/− mice revealed high embryonic lethality (50%) with developmental defects, including aberrant topology of coronary arteries. Postnatally, SM-CXCL12−/− mice developed severe cardiac hypertrophy associated with fibrosis, apoptotic cell death, impaired heart function, and severe coronary vascular defects characterized by thinned and dilated arteries. Transcriptome analyses showed specific upregulation of pathways associated with hypertrophic cardiomyopathy, collagen protein network, heart-related proteoglycans, and downregulation of the M2 macrophage modulators. CXCL12 mutants showed endothelial downregulation of the CXCL12 co-receptor CXCR7. Treatment of SM-CXCL12−/− mice with the CXCR7 agonist TC14012 attenuated cardiac hypertrophy associated with increased pERK signaling.

Conclusion
Our data suggest a critical role of smooth muscle-specific CXCL12 in arterial development, vessel maturation, and cardiac hypertrophy. Pharmacological stimulation of CXCR7 might be a promising target to attenuate adverse hypertrophic remodeling.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FWF-Austria
SIRT1 protects the heart against doxorubicin-induced cardiotoxicity by mediating the DNA damage response via deacetylation of histone H2AX
Authors: Kuno A , Hosoda R , Horio Y 
Published: October 2021

Abstract

Background
Doxorubicin induces DNA damage not only in tumor cells but also in the cardiomyocyte, and accumulation of damaged DNA has been implicated in doxorubicin-induced cardiotoxicity. We previously found that cardiomyocyte-specific deletion of SIRT1, a NAD+-dependent histone/protein deacetylase, worsens doxorubicin-induced cardiotoxicity in mice. However, its molecular mechanism remains unclear. Phosphorylation of histone H2AX at Ser139 catalyzed by ATM (mutated in ataxia-telangiectasia) at the sites of DNA damage is a critical mediator for DNA repair.

Purpose
Here, we tested the hypothesis that deacetylation of H2AX by SIRT1 mediates DNA damage response to counteract doxorubicin-induced cardiotoxicity.

Methods and results
Wild-type (WT) mice and tamoxifen-inducible cardiomyocyte-specific SIRT1 knockout (SIRT1-cKO) mice at 3 month of age received doxorubicin (4 IP injections of 5 mg/kg/week) or a vehicle. Immunoblotting of myocardial lysates from mice 1 week after final doxorubicin showed that doxorubicin increased phospho-Ser139-H2AX level by 1.6-fold in WT, but such a response was blunted in SIRT1-cKO. Ser1981-phosphorylations of ATM induced by doxorubicin were similar in WT and SIRT1-cKO. DNA fragmentation evaluated by TUNEL staining revealed that the increase in TUNEL-positive nuclei by doxorubicin was more in SIRT1-cKO (0.13% to 0.38%) than those in WT (0.07% to 0.19%), suggesting higher DNA damage in SIRT1-cKO.
In H9c2 cardiomyocytes, knockdown of SIRT1 also abolished the doxorubicin-induced Ser139-phosphorylation of H2AX without changing phospho-ATM levels. Increases in DNA damage evaluated by comet assay and cleavage of caspase-3 by doxorubicin were also enhanced in SIRT1-knockdown cells. Immunostaining for acetyl-Lys5-H2AX in the heart sections revealed that acetyl-Lys5-H2AX levels were increased in SIRT1-cKO by 58% compared with those in WT. In H9c2 cells, acetyl-Lys5-H2AX level was also increased by SIRT1 knockdown and reduced by expression of wild-type SIRT1. To test the role of the increased acetyl-Lys5-H2AX level under SIRT1 inhibition, we generated a mutant in which Lys5 was substituted to glutamine (K5Q H2AX) as a mimic of acetylated Lys5. In COS7 cells expressing WT or K5Q H2AX, Ser139-phosphorylation induced by doxorubicin was suppressed in K5Q mutant. In addition, doxorubicin-induced cleavage of caspase-3 was enhanced in H9c2 cells expressing K5Q H2AX as well as S139A H2AX, that cannot be phosphorylated at Ser139, compared with cells expressing WT H2AX.

Conclusions
These findings suggest that the increased Lys5 acetylation of H2AX via SIRT1 inhibition interferes Ser139 phosphorylation, leading to accumulation of damaged DNA and promotion of the apoptotic response. Such regulation of the DNA damage response contributes to protection by SIRT1 against doxorubicin-induced cardiotoxicity.

Funding Acknowledgement
Type of funding sources: None.
Activated myofibroblasts promote cardiac hypertrophy and systolic dysfunction independently of cardiac fibrosis in experimental autoimmune myocarditis
Authors: Tkacz K , Jazwa-Kusior A , Rolski F , Dzialo E , Weglarczyk K , Czepiel M , Siedlar M , Kania G , Blyszczuk P 
Published: October 2021

Abstract

Background/Introduction
Heart-specific inflammation – myocarditis is a common cause dilated cardiomyopathy which is characterized by pathological tissue remodeling, ventricular stiffening, cardiomyopathy and heart failure. In experimental autoimmune myocarditis (EAM) susceptible mice immunized with alpha myosin heavy chain (αMyHC) and complete Freund's adjuvant (CFA) develop acute myocarditis driven by autoreactive CD4+ T cells that is followed by progressive fibrosis, cardiomyopathy and systolic dysfunction.

Purpose
The aim of the study was to investigate the role of cardiac fibroblasts and myofibroblasts in myocarditis and post-inflammatory dilated cardiomyopathy in mouse model of EAM.

Methods
EAM was induced in BALB/c mice by immunization with αMyHC/CFA. We used reporter mice expressing EGFP under collagen type I promoter (Coll-EGFP) and RFP under a control of α-smooth muscle actin (αSMA) promoter (αSMA-RFP) and transgenic αSMA-TK mice with ganciclovir-inducible ablation of proliferating myofibroblasts. Cardiac cells were quantified using flow cytometry. Cardiac fibroblasts (CD45-CD31-EGFP+) were sorted from healthy and myocarditis-positive (day 21) mice using BD FACSAria™ II Cell Sorter and analyzed for the whole genome transcriptomics by RNA sequencing. Echocardiography was performed on Vevo 2100 Imaging System. Cardiac fibrosis was assessed by Trichrome Massons's staining and hydroxyproline assay, whereas cardiac hypertrophy by analysing cross-sectional cardiomyocyte area. Profibrotic gene expression was assessed by qRT-PCR.

Results
The total number of cardiac fibroblasts (CD45-CD31-EGFP+) and the subset of myofibroblasts (CD45-CD31-EGFP+RFP+) remained unchanged at inflammatory (d21) and fibrotic stages (d40). Analysis of differentially expressed genes (min. 2x fold change, p value &lt;0.05) pointed out activation of immune processes (mainly chemokine production), response to stress, cytoskeletal and extracellular matrix re-organization in cardiac fibroblasts in response to myocarditis. αSMA-TK mice treated with ganciclovir (from day 21) showed comparable percent of fibrotic area, but significantly reduced heart weight, decreased cardiomyocyte hypertrophy and improved ejection fraction and cardiac output at day 40 comparing to PBS-treated mice. Ganciclovir-treated mice showed also attenuated cardiac Acta2 and Srf but markedly enhanced Mmp2 expression.

Conclusions
In EAM model cardiac fibroblasts actively participate in proinflammatory and profibrotic responses, while activated myofibroblasts contribute to dilated cardiomyopathy development independently of cardiac fibrosis.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre (Poland)
1.A. Workshop: Public health, climate change and strategic litigation
Authors:   Organised by: EUPHA-LAW, EUPHA-ENV, Global Health Law Groningen (Netherlands), PETRA,   Chair persons: David Patterson (Netherlands), Vlatka Matkovic Puljic (Belgium)
Published: October 2021

Abstract

There is ample and growing evidence of the damage to human and planetary health from environmental pollution and climate change. National and international legal frameworks provide opportunities for strategic legal challenges to government inaction (whether as the primary polluter or for a failure to regulate a third-party polluter) and to industry polluters. Public health professionals need to understand how litigation can be used as a public health tool to advance policies to address environmental and health challenges. [Parmet, W.E. and Daynard, R.A., 2000. The new public health litigation. Annual Review of Public Health, 21(1), pp.437-454; Laaser U. and Beluli F. A Global Public Health Curriculum. South Eastern European Journal of Public Health. 2nd Edition (2016); Foldspang, A. ed., 2018. ASPHER's European List of Core Competences for the Public Health Professional. Sage Publications.]
A positive court decision can require governments to take immediate and long-term action or require polluters to cease, clean up and compensate. Successful national court decisions also provide precedents for legal action in other countries. If action in national courts fails or is not possible, legal action may be taken in European and international courts and tribunals. When legal action fails, or there is no decision, strategic litigation can still focus national and international media coverage and draw public attention to real or potential harms caused by government or industry action or inaction. Public health, environmental and human rights advocates can make better use of strategic litigation to address environmental harms and advance climate change mitigation and adaptation. Most European countries have already seen some strategic litigation on climate change. Litigation based on international and European human rights frameworks is also gaining ground. The workshop will examine the elements of strategic litigation and current cases in European courts. The workshop will follow a planned pre-conference webinar on public health, climate change and strategic litigation sponsored by EUPHA in October 2021.

Key messages
Strategic litigation supported by effective interdisciplinary collaboration can strengthen government resolve and stimulate action to address environmental and climate goals. Strategic litigation can advance public health objectives even without a favourable court decision. Its value includes the publicity and awareness generated and engagement of multiple stakeholders.
COVID-19 as a syndemic: from inequalities to biological embodiment
Authors: Vineis Paolo 
Published: October 2021

Abstract
Different determinants play a role in the health and wellbeing of people, population groups, communities, and the society as a whole. During the COVID-19 epidemic (and beyond) the direct and indirect impact of such determinants has become yet more evident. Individual proximal factors such as age, ethnicity, socioeconomic position, underlying comorbidities have concurred to increase individual risk of acquiring the infection as well as of developing severe disease complications, including death. The concept of COVID-19 as a syndemic has been proposed on this ground, whereby socioeconomic determinants of disease have catalyzed health worse outcomes.
Did the COVID-19 pandemic impact population’s mental health?
Authors: Forgeot C , Pontais I , Khirredine I , Gillaizeau I , Du Roscoat E , Fouillet A , Bauchet E , Caserio-Schonemann C 
Published: October 2021

Abstract

Background
Sanitary, societal and economic effects due to the COVID-19 pandemic could lead to an impact on population's mental health. Santé publique France (SpF), the French public health agency set up a specific monitoring based on emergency department (ED) and GP's associations (GPs) SOS Médecins (SOSMed) data to early assess the impact of COVID-19 pandemic on mental health.

Methods
Since 2004, SpF daily collects data from ED participating to the OSCOUR® network (93% of French emergency attendances) and from SOSMed network. For both data sources, visits for several mental health disorders were analyzed for different age groups in 2020 and 2021 (until Week 16) and compared to years 2018 and 2019 (mean) with a focus on the two lockdown periods (resp W11 to W19-2020 and W45 to W51-2020)

Results
During the first lockdown period, while a major decrease of all-cause activity was observed in both networks, the number of SOSMed visits for anxiety increased in adults with a peak of + 115% in W13-2020 compared to 2018-19 and remained higher than the 2 previous years until W12-2021. An increase in ED visits for mood disorders (including depression) for children (especially 11-17yo) were also observed from W36 (back to school) and reinforced at the beginning of the 2nd lockdown period to reach +111% in W12-2021 compared to 2018-19. 11-17yo children were also concerned by an increase in ED visits for suicide ideation since W36 (peak of + 170% in W12-2021) and suicide attempt from W04-2021 to W12-2021 (peaks of + 45% and +41% in W05 and W10-2021).

Discussion
ED and SOSMed visits are the most reactive data sources to assess the impact of COVID-19 pandemic on the mental health of French population. These results confirm that the impact concerns all age groups. For children, the condition seems to worsen in 2021 and highlight the need of a close follow-up of the situation and the reinforcement of preventive measures in order to prevent long-term impacts.

Key messages
Results confirm an impact of COVID-19 pandemic on populations mental health. Impact of COVID-19 on mental health: a long-term issue for children?