bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zfhx3 decreases expression of cardiac Nav1.5 channels and inhibits sodium current
Authors: Caballero R , Camara-Checa A , Rubio-Alarcon M , Crespo-Garcia T , Dago M , Nieto-Marin P , Marin M , Salguero R , Toquero J , Tamargo J , Cebrian J , Delpon E ,   ITACA Consortium
Published: October 2021

Abstract

Background
Zfhx3 (zinc finger homeobox 3) is a transcription factor (TF) encoded by the ZFHX3 gene. GWAS and gene-based association studies showed that ZFHX3 is one of the major atrial fibrillation (AF) susceptibility-conferring genes. The sodium current (INa), carried by Nav1.5 channels encoded by SCN5A, is responsible for atrial and ventricular action potential depolarization and determines cardiac excitability. Zfhx3 interacts with other TFs, such as Tbx5 and Pitx2c that increase and decrease INa, respectively. However, the effects of Zfhx3 on cardiac INa are currently unknown.

Purpose
We aimed to determine the effects of Zfhx3 on the INa on HL-1 cardiomyocytes.

Methods
cDNAs encoding human Zfhx3 together or not with Pitx2c or Tbx5 were transfected in HL-1 cells. Endogenous Zfhx3 expression in HL-1 cells was silenced by means of siRNAs. INa was recorded at room temperature using the whole-cell patch-clamp and luciferase reporter assays, qPCR and Western-blot (WB) analyses were also conducted.

Results
Expression analysis of RNA-seq data from human ventricular (n=432) samples (GTEx) demonstrated that Zfhx3 mRNA can be detected in the adult working myocardium. Transfection of Zfhx3 strongly reduced peak INa density (from −75.0±6.6 to −30.9±2.9 pA/pF; n≥26, P&lt;0.001). In contrast, Zfhx3 silencing augmented INa density compared to cells transfected with scrambled siRNA (from −65.9±8.9 to −104.6±10.8 pA/pF; n≥8, P&lt;0.05). Neither Zfhx3 expression nor silencing modified time and voltage dependence of activation and inactivation or the reactivation kinetics. Zfhx3 significantly reduced transcriptional activity of human SCN5A, PITX2 and TBX5 minimal promoters and, consequently, the mRNA and protein expression levels of Nav1.5, Pitx2c, and Tbx5 were diminished (n≥6, P&lt;0.05). In cells transfected with Zfhx3 together with Pitx2c, but not with Tbx5, INa density was significantly smaller than in cells expressing WT Zfhx3 alone (n≥15, P&lt;0.05). Further WB experiments demonstrated that Zfhx3 increased the expression of Nedd4–2 ubiquitin-protein ligase, which ubiquitinates Nav1.5 channels and favors their proteasomal degradation.

Conclusions
Zfhx3 inhibits INa as a result of a direct repressor effect on the SCN5A promoter, the modulation of Tbx5-increasing and Pitx2-decreasing effects on the INa, and the enhancement of Nav1.5 channel degradation. We propose a novel and complex mechanism that regulates the expression of sodium channels and the density of the INa, which are critical for the control of cardiac excitability.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de Economía y CompetitividadComunidad Autόnoma de Madrid
Kynurenic acid- a key metabolite protecting the heart from an ischemic damage
Authors: Entin-Meer M , Bigelman E B , Pasmanik-Chor M P C , Dassa B D , Gross A G , Itkin M I , Malitsky S M , Dorot O D , Pichinuk E P , Dezorell N M , Keren G K 
Published: October 2021

Abstract

Background
Myocardial ischemia is a major cause of death in patients with renal dysfunction. In order to identify a key metabolite which may protect cardiac function following renal injury, we have recently performed a metabolomics profiling analysis of LV lysates and plasma samples derived from animals that underwent an acute kidney injury (AKI) 1 or 7 days earlier, versus sham-operated controls. The analysis revealed that the kynurenic acid (kynurenate, KYNA) metabolite levels are highly elevated in all tested experimental samples relative to control.

Purpose
We wished to analyze whether KYNA may protect cardiomyocytes' survival and cardiac function upon an ischemic event and if so, to characterize whether the protecting effect may be linked to better preservation of the cardiac mitochondria.

Methods
Cellular viability of H9C2 rat cardiac myoblasts grown under normoxic or anoxic conditions with or without KYNA was determined by flow cytometry following Annexin-PI staining. The mitochondrial structure of the cells was determined by live cell staining with green (FITC) and deep red (Cy5) mito-tracker dyes. The potential effect of the metabolite on cardiac function following acute MI was tested in a murine model by echocardiography followed by histological staining of the cardiac sections with Picro Sirius Red.

Results
KYNA given at 10 mM concentration hardly affected the viability of H9C2 grown under normoxia, however the metabolite rescued the viability of the anoxic cells by 63% and largely improved their mitochondrial structure. Moreover, KYNA diluted in the drinking water of post-MI animals (250mg/ml), highly enhanced their cardiac recovery compared to untreated-animals as determined by echocardiography and collagen staining.

Conclusions
1. KYNA may represent a key metabolite absorbed by the heart following AKI.
2. KYNA can enhance cardiac cell viability following an ischemic event both in vitro and in vivo in a mechanism which is mediated, at least in part, by protection of the cardiac mitochondria.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Weizmann Institute-Tel-Aviv Sourasky Medical Center joint research grant KYNA's protection of cardiac cells
The effect of canakinumab on COVID19-associated cardiomyocyte contractile dysfunction and arrhythmias
Authors: Dimai S , Semmler L , Stachelscheid H , Pieske B M , Heinzel F R , Hohendanner F 
Published: October 2021

Abstract

Background
Cardiac injury associated with cytokine release occurs in almost 20% of SARS-CoV-2 positive patients during hospitalization and mortality is particularly high in these patients. Cardiac enzyme (e.g. troponin or creatinine kinase (CK)) elevations are a frequently reported finding, indicating myocardial damage and arrhythmias are the cause for ICU transfer in up to 12% of patients. However, the mechanistic role of COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. In addition, the role of anti-inflammatory therapy approaches to mitigate this cardiac dysfunction remains elusive.

Methods
We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPSc-CM). Moreover, we evaluated the therapeutic potential of the IL1-beta antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy.

Results
Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 plasma from intensive care unit patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Cardiomyocytes showed decreased Ca2+ transient amplitudes and altered baseline Ca2+ concentrations leading to impaired cellular contractile function upon electrical field-stimulation and exposure to patient plasma (n=276 control and 359 COVID19 cells; Fura). In addition, we used iPSc-CM to explore the long-term effect of patient plasma on cardiac electrical and mechanical function in a translational setting (24h incubation; Fluo). In iPSc, spontaneous Ca2+ release events (i.e. Ca2+ waves and Ca2+ sparks) were more likely to occur upon incubation with COVID19 plasma and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling but influenced cellular automaticity upon prolonged electrical stimulation.

Conclusion
Plasma derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Chronic co-incubation with Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling.

Funding Acknowledgement
Type of funding sources: None.
Influence of highest dominant frequency area on fibrillation dynamics and frequency spectrum on electrograms
Authors: Sanchez De La Nava A M , Rios-Munoz G R , Gomez-Cid L , Grigorian-Shamagian L , Fernandez-Santos M E , Arenal A , Atienza F , Fernandez-Aviles F 
Published: October 2021

Abstract

Introduction
Highest Dominant Frequency (HDF) has been extensively described as one of the descriptors for Atrial Fibrillation (AF) and some studies also describe the total area activating at this frequency. However, the influence of this area on the registered power spectrum of the electrogram is usually not explained.

Objective
To describe the role of the highest Dominant Frequency Area (DFA) on the electrogram signal.

Methods
HL1 cell line monolayers were used as AF in vitro model and cultured on p35 plates (N=15) until confluence was reached. Optical mapping was performed to evaluate the electrophysiological activity of the samples employing Ca2+ transient quantification and activation frequency (Hz). Pseudo electrograms were calculated from the recorded signals and their frequency spectrum was evaluated.

Results
Two different groups were identified during the study: a group in which the DFA was higher than 0.2% of the total area (hDFA) and a group in which it was lower (lDFA). For hDFA cultures, the ratio between the DF of the catheter and the culture was significantly higher in the hDFA group (0.90±0.18; 0.47±0.13; p-value &lt;0.0001), indicating that more complex scenarios lead to dissociation between the HDF of the tissue and HDF registered on the electrogram. This relation is identified in Figure 1, where the R2 values for both cases are 0.99 and 0.62 respectively. Figure 2 shows two examples with different DFA and the respective Ca2+ signals, electrograms, and power spectrum density of both signals, exemplifying how lDFA cases can lead to a mismatch between the power spectrum density of the optical mapping signal and the electrogram.

Conclusions
Complex arrhythmic scenarios identified as lDFA present a low correlation between the power spectrum registered on the culture and the electrogram, whereas samples in which the DFA is large, the DF from the catheter presents high correlation ratios among both signals, suggesting that clinical scenarios with high variability on the electrophysiological substrate may be difficult to interpret.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III and Ministerio de Ciencia Innovaciόn y Universidades Figure 1. HDF from tissue vs EGM-HDFFigure 2. Example of two cultures
What is strategic litigation?
Authors: Hesselmann Marlies 
Published: October 2021

Abstract
This presentation is an introduction to strategic litigation for public health professionals. It will review the opportunities offered by legal action on environmental issues, with examples from past successes. It will consider opportunities in Europe for legal action in both national courts and in international courts and tribunals. Procedural issues affecting the choice of forum will be discussed, such as ‘standing' (the right to initiate a legal action or participate in the proceedings), admissible evidence, the possible orders available if the case is successful, and the costs and risks involved. What if we don't win? Was it still worth it? Broader public engagement and advocacy opportunities will be noted.
Preventive and risky health behavior of Swiss university students during the COVID-19 pandemic
Authors: Zysset A , Volken T , Dratva J ,   on behalf of the HES-C Study group
Published: October 2021

Abstract

Background
Young adults are not considered a risk group for contracting COVID-19, but they are disproportionately affected by pandemic containment measures compared to other age groups. University students were confronted with abrupt changes both in their personal and academic lives. The “Health in Students during the Corona pandemic” study (HES-C) investigated the health and health behavior, concerns and views in students of the Zurich University of Applied Sciences. In the current analyses, we focused on COVID-19 related preventive behaviors, alcohol and marijuana consumption during the pandemic.

Methods
All students of the Zurich University of Applied Sciences (N = 12,429) were invited to a voluntary repeated cross-sectional open cohort survey which took place from the April 3 2020 (T0) to January 25 (T5), covering two university semesters with overall 6 surveys. Participation rates varied from T0 20% to T5 13%.

Results
While overall adherence to containment measures was high, men yielded lower adjusted odds (OR; 95%-CI) of adherence regarding the following measures: social distancing (0.68; 0.53-0.87), non-utilization of public transport (0.74; 0.56-0.97), 5-person limit for social gatherings (0.47; 0.35-0.64) and the stay at home rule (0.64; 0.51-0.82). In addition to gender, factors associated with adherence were information source and perceived susceptibility to the virus. Out of 80% who reported having drunk alcohol during the last 30 days at T0, 31% engaged at least once in binge drinking (&gt;5 beverages) and 18% consumed more than usual. Marijuana was consumed by 11%, of which 27% reported higher use during the lock-down than before. Longitudinal data on risk behavior and factors associated with risk behavior and changes in behavior are currently being analyzed and will be presented.

Conclusions
Public health communication targeting university students should not only address pandemic related preventive behavior but also risk behavior during the pandemic.

Key messages
The pandemic has led to increased risky health behavior among certain students. Public health communication targeting university students should not only address pandemic related preventive behavior but also risk behavior during the pandemic.
Climate Change in Wales and its health impact: Who is vulnerable and how?
Authors: Green L , Edmonds N 
Published: October 2021

Abstract
In April 2019, Wales declared a climate emergency. Public Health Wales commissioned a Health Impact Assessment (HIA) to be carried out to assess the potential impact of Climate Change (CCh) on the population of Wales and inform key strategic decision makers to understand/plan for the potential differential health and inequalities impacts that may occur from CCh. A comprehensive mixed-method HIA was conducted over a 6 month period in 2019/2020. A review of peer-reviewed evidence on the potential impact of CCh/climate change events on health and population groups and a review of grey literature on direct impacts such as the environment, mental wellbeing and health care settings was conducted. 2 stakeholder workshops, qualitative interviews, a community health profile utilising sources such as the National Survey for Wales were also carried out. All findings were analysed, synthesized and collated into a report. Vulnerability is a critical aspect of population health and the HIA findings identified a range of positive and negative impacts on specific population groups which highlights their vulnerability to climate change. This includes children and young people; older people; coastal and rural communities and those on low incomes. These are often not explicitly highlighted in other environmentally focused assessments. The HIA also indicated significant potential impacts across the determinants of health including excess heat/cold; flooding; economy; access to services; mental well-being; and community resilience. The findings have informed decision-makers to prepare for CCh plans/policies using an evidence-informed approach and particularly to address who may be disproportionately negatively affected. The work has demonstrated the importance of HIA to assess significant, complex policies by mobilising a range of evidence through a transparent process, explicitly considering the impact on vulnerable groups, resulting in transferrable learning for others.
Risk communication during COVID-19: a comparative analysis of four countries
Authors: Weishaar H , Geurts B , Mari-Saez A , Delamou A , Jegede AS , Legido-Quigley H , Cristea F , Rocha C , Boklage E , El-Bcheraoui C 
Published: October 2021

Abstract

Background
Risk communication (RC) is fundamental to ensuring public engagement in public health emergencies. Existing studies describe the mechanisms that integrate RC into emergency responses, but knowledge about which governing structures and policies are needed to ensure effective RC in public health emergencies is lacking. We compare RC across four epidemiological, socio-political, and geo-economic settings and identify key structural factors that can lead to effective RC in public health emergencies.

Methods
A multisite international study was implemented using qualitative research methods in Germany, Guinea, Nigeria, and Singapore. We mapped and assessed RC governing structures, drawing on a document review and semi-structured key informant interviews with 155 stakeholders involved in the design and implementation of RC strategies at national and sub-national levels.

Results
A comparative analysis of the content, process, actors, and context of the distinct RC structures in the four countries as well as related strengths and weaknesses are presented. Early integration of RC into preparedness and response plans alongside the use of previous experiences and structures are key to effective implementation of RC during public health emergencies. A lack of coordination increases the risk of parallel structures, missed opportunities, duplication of resources, and public confusion due to a cacophony of messages. Building on previous experiences of outbreaks and on existing structures and relationships can help governments to more quickly mobilise effective RC strategies during pandemics.

Conclusions
RC is key to effective pandemic responses and can help to reduce infection and transmission. Yet, considerable potential exists for countries to improve RC in public health emergencies. Learning from mistakes and successes during COVID-19 can help improve RC strategies and governing structures and prepare for future pandemics.

Key messages
Strengthening RC preparedness and response enables governments to more effectively implement the International Health Regulations. COVID-19 provides ample learning opportunities to improve communication in public health emergencies.
Design, protocol, and perspectives of the MADRE-REA study
Authors: Maugeri A , Barchitta M , Magnano San Lio R , La Rosa MC , Favara G , Guarnera L , Riela PM , Battiato S , Agodi A 
Published: October 2021

Abstract

Background
Unhealthy diet during pregnancy poses serious risks for both mothers and children, representing an important Public Health issue. Although Epigenetics offers a plausible explanation of the transgenerational pathway from mother to child, it is still necessary to understand if maternal epigenetic aging increases the risk for adverse outcomes in newborns. In this scenario, the “MAternal Diet, Risks and Epigenetic age during pregnancy: a Real-world Ecological momentary Assessment” (MADRE-REA) study aims to evaluate the relationship between maternal diet, epigenetic age and risk for adverse pregnancy outcomes in a mother-child cohort.

Methods
We will develop a smartphone-based ecological momentary assessment (EMA) of dietary, behavioral, physical, and sociopsychological information of 400 pregnant women recruited by the “Mamma & Bambino” cohort (Catania, Italy). Women will be asked to complete 6 waves of EMA during the 2nd and 3rd trimesters of pregnancy, and 3, 6, 9 and 12 months after delivery. Each wave consists of a 7-day assessment based on a signal-contingent approach, which prompts participants to record dietary consumption and other information. We will also examine maternal epigenetic age at recruitment and at delivery, using the DNAm PhenoAge.

Results
The novelty of the MADRE-REA study lies in the opportunity to apply a smartphone-based EMA to capture the complexity of dietary intake during and after pregnancy. Moreover, expected findings will help to understand if maternal behaviors and other exposures might affect epigenetic age, and hence if the eventual accelerated biological aging might be associated with health and disease in newborns.

Conclusions
This study could disentangle the relationship between maternal diet, epigenetic aging, and adverse outcomes, laying the foundation for future strategies to reduce the burden of disease in newborns throughout their life. The study is funded by the Italian Ministry of Health (Bando Ricerca Finalizzata 2019).

Key messages
The application of a smartphone-based tool could overcome limitations of traditional methods to assess dietary behaviors in the periconceptional period. Uncovering the relationship between maternal diet and epigenetic aging could provide the molecular basis for future strategies against adverse pregnancy outcomes.
1.I. Workshop: Capturing access challenges in health care: can the vignette methodology help?
Authors:   Organised by: European Observatory,   Chair persons: Dimitra Panteli (Belgium), Ewout Van Ginneken (Germany)
Published: October 2021

Abstract

Access to health care is a key performance dimension for health systems. Around 3% of the EU27 population experienced unmet need for health services in 2019 (Eurostat 2021). However, this average hides significant differences across and within countries, between income groups, levels of education and socio-economic categories. While some of the reasons for unmet need are more personal (no time, fear of doctor, etc.), the most common factors are health system-related. Although self-reported unmet need and other existing indicators, including catastrophic spending and impoverishing out-of-pocket spending, provide a general picture of the state of accessibility in EU Member States in relation to factors such as age, income or education, they do not necessarily reveal specific gaps in access or coverage that are linked to other characteristics or specific services. This workshop discusses a new method to measure access to health care, which was developed by the Observatory on Health Systems and Policies to support the European Commission's DG SANTE and the Expert Group on Health Performance Assessment (HSPA) in developing their work on more refined performance measures for health care system access across Europe. The work builds on the findings of a 2019 survey by the Observatory and its Health System and Policy Monitor (HSPM) network on “Gaps in Coverage and Access in the European Union”, which identified a range of vulnerable groups facing access hurdles. The overall goal is to provide a ‘proof of concept' to see whether a vignette approach could add to existing indicators, particularly regarding the differentiation between population coverage and realised access to care. A vignette is a short case study of an individual designed to simulate key features of a real-world scenario, which is then presented to relevant professionals to solicit their hypothetical response. Our workshop first discusses the vignette method developed for this purpose (presentation 1) before sharing the interpretation of results of two of the four vignette pilots that were carried out, that is, the vignette on stroke (presentation 2) and the vignette on palliative care for cancer patients (Presentation 3). The workshop will conclude with a moderated audience discussion about the pros and cons of the vignette method as opportunities to scale up the vignette approach.

Key messages
The vignette approach can identify gaps in coverage and access as well as differences in treatment and quality not identified by other indicators. The vignette approach can help explain how access contributed to suboptimal health outcomes, enabling the formulation of targeted policies.