Exploring the accessibility of primary health care data in Europe's COVID-19 response: developing key indicators for managing future pandemics (Eurodata study).

BACKGROUND: Primary Health Care (PHC) plays a crucial role in managing the COVID-19 pandemic, with only 8% of cases requiring hospitalization. However, PHC COVID-19 data often goes unnoticed on European government dashboards and in media discussions. This project aims to examine official information on PHC patient care during the COVID-19 pandemic in Europe, with specific objectives: (1) Describe PHC's clinical pathways for acute COVID-19 cases, including long-term care facilities, (2) Describe PHC COVID-19 pandemic indicators, (3) Develop COVID-19 PHC activity indicators, (4) Explain PHC's role in vaccination strategies, and (5) Create a PHC contingency plan for future pandemics. METHODS: A mixed-method study will employ two online questionnaires to gather retrospective PHC data on COVID-19 management and PHC involvement in vaccination strategies. Validation will occur through focus group discussions with medical and public health (PH) experts. A two-wave Delphi survey will establish a European PHC indicators dashboard for future pandemics. Additionally, a coordinated health system action plan involving PHC, secondary care, and PH will be devised to address future pandemic scenarios. ANALYSIS: Quantitative data will be analysed using STATA v16.0 for descriptive and multivariate analyses. Qualitative data will be collected through peer-reviewed questionnaires and content analysis of focus group discussions. A Delphi survey and multiple focus groups will be employed to achieve consensus on PHC indicators and a common European health system response plan for future pandemics. The Eurodata research group involving researchers from 28 European countries support the development. DISCUSSION: While PHC manages most COVID-19 acute cases, data remains limited in many European countries. This study collects data from numerous countries, offering a comprehensive perspective on PHC's role during the pandemic in Europe. It pioneers the development of a PHC dashboard and health system plan for pandemics in Europe. These results may prove invaluable in future pandemics. However, data may have biases due to key informants' involvement and may not fully represent all European GP practices. PHC has a significant role in the management of the COVID-19 pandemic, as most of the cases are mild or moderate and only 8% needed hospitalization. However, PHC COVID-19 activity data is invisible on governments' daily dashboards in Europe, often overlooked in media and public debates.

Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model.

Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.NEW & NOTEWORTHY Apelin levels decline with age. This study demonstrates that in trained mice, apelin deficiency results in a switch from fast type II myofibers to slow oxidative type I myofibers. This is associated with a concomitant change in gene expression profile toward fatty acid utilization, indicating an aged-muscle phenotype in exercised apelin-deficient mice. These data are of importance in the design of exercise programs for aging individuals and could offer therapeutic target to maintain muscle mass.

Primary care indicators for disease burden, monitoring and surveillance of COVID-19 in 31 European countries: Eurodata Study.

BACKGROUND: During the COVID-19 pandemic, the majority of patients received ambulatory treatment, highlighting the importance of primary health care (PHC). However, there is limited knowledge regarding PHC workload in Europe during this period. The utilization of COVID-19 PHC indicators could facilitate the efficient monitoring and coordination of the pandemic response. The objective of this study is to describe PHC indicators for disease surveillance and monitoring of COVID-19's impact in Europe. METHODS: Descriptive, cross-sectional study employing data obtained through a semi-structured ad hoc questionnaire, which was collectively agreed upon by all participants. The study encompasses PHC settings in 31 European countries from March 2020 to August 2021. Key-informants from each country answered the questionnaire. Main outcome: the identification of any indicator used to describe PHC COVID-19 activity. RESULTS: Out of the 31 countries surveyed, data on PHC information were obtained from 14. The principal indicators were: total number of cases within PHC (Belarus, Cyprus, Italy, Romania and Spain), number of follow-up cases (Croatia, Cyprus, Finland, Spain and Turkey), GP's COVID-19 tests referrals (Poland), proportion of COVID-19 cases among respiratory illnesses consultations (Norway and France), sick leaves issued by GPs (Romania and Spain) and examination and complementary tests (Cyprus). All COVID-19 cases were attended in PHC in Belarus and Italy. CONCLUSIONS: The COVID-19 pandemic exposes a crucial deficiency in preparedness for infectious diseases in European health systems highlighting the inconsistent recording of indicators within PHC organizations. PHC standardized indicators and public data accessibility are urgently needed, conforming the foundation for an effective European-level health services response framework against future pandemics.

The role of primary health care in long-term care facilities during the COVID-19 pandemic in 30 European countries: a retrospective descriptive study (Eurodata study).

BACKGROUND AND AIM: Primary health care (PHC) supported long-term care facilities (LTCFs) in attending COVID-19 patients. The aim of this study is to describe the role of PHC in LTCFs in Europe during the early phase of the pandemic. METHODS: Retrospective descriptive study from 30 European countries using data from September 2020 collected with an ad hoc semi-structured questionnaire. Related variables are SARS-CoV-2 testing, contact tracing, follow-up, additional testing, and patient care. RESULTS: Twenty-six out of the 30 European countries had PHC involvement in LTCFs during the COVID-19 pandemic. PHC participated in initial medical care in 22 countries, while, in 15, PHC was responsible for SARS-CoV-2 test along with other institutions. Supervision of individuals in isolation was carried out mostly by LTCF staff, but physical examination or symptom's follow-up was performed mainly by PHC. CONCLUSION: PHC has participated in COVID-19 pandemic assistance in LTCFs in coordination with LTCF staff, public health officers, and hospitals.

Clinical pathway of COVID-19 patients in primary health care in 30 European countries: Eurodata study.

BACKGROUND: Most COVID-19 patients were treated in primary health care (PHC) in Europe. OBJECTIVES: To demonstrate the scope of PHC workflow during the COVID-19 pandemic emphasising similarities and differences of patient's clinical pathways in Europe. METHODS: Descriptive, cross-sectional study with data acquired through a semi-structured questionnaire in PHC in 30 European countries, created ad hoc and agreed upon among all researchers who participated in the study. GPs from each country answered the approved questionnaire. Main variable: PHC COVID-19 acute clinical pathway. All variables were collected from each country as of September 2020. RESULTS: COVID-19 clinics in PHC facilities were organised in 8/30. Case detection and testing were performed in PHC in 27/30 countries. RT-PCR and lateral flow tests were performed in PHC in 23/30, free of charge with a medical prescription. Contact tracing was performed mainly by public health authorities. Mandatory isolation ranged from 5 to 14 days. Sick leave certification was given exclusively by GPs in 21/30 countries. Patient hotels or other resources to isolate patients were available in 12/30. Follow-up to monitor the symptoms and/or new complementary tests was made mainly by phone call (27/30). Chest X-ray and phlebotomy were performed in PHC in 18/30 and 23/30 countries, respectively. Oxygen and low-molecular-weight heparin were available in PHC (21/30). CONCLUSION: In Europe PHC participated in many steps to diagnose, treat and monitor COVID-19 patients. Differences among countries might be addressed at European level for the management of future pandemics.

Countrywide survey on utilization of medical devices by GPs in Hungary: advantages of the cluster-practice model.

BACKGROUND: Expectations towards general practitioners (GPs) are continuously increasing to provide a more systematic preventive- and definitive-based care, a wider range of multidisciplinary team-based services and to integrate state-of-the-art digital solutions into daily practice. Aided by development programmes, Hungarian primary care is facing the challenge to fulfil its role as the provider of comprehensive, high quality, patient-centred, preventive care, answering the challenges caused by non-communicable diseases (NCDs). AIM: The article aims to provide an insight into the utilization of simple, digital, medical devices. We show the relationship between the primary health care (PHC) practice models and the used types of devices. We point at further development directions of GP practices regarding the utilization of evidence-based medical technologies and how such devices support the screening and chronic care of patients with NCDs in everyday practice. METHODS: Data were collected using an online self-assessment questionnaire from 1800 Hungarian GPs registered in Hungary. Descriptive statistics, Wilcoxon's test and χ2 test were applied to analyze the ownership and utilization of 32 types of medical devices, characteristics of the GP practices and to highlight the differences between traditional and cluster-based operating model. FINDINGS: Based on the responses from 27.7% of all Hungarian GPs, the medical device infrastructure was found to be limited especially in single GP-practices. Those involved in development projects of GP's clusters in the last decade reported a wider range and significantly more intensive utilization of evidence-based technologies (average number of devices: 5.42 versus 7.56, P<.001), but even these GPs are not using some of their devices (e.g., various point of care testing devices) due to the lack of financing. In addition, GPs involved in GPs-cluster development model programmes showed significantly greater willingness for sharing relatively expensive, extra workforce-demanding technologies (χ2 = 24.5, P<.001).

Introducing the National Institute for Sports Medicine in Hungary: a complex sports medical healthcare and screening system.

The Hungarian National Institute for Sports Medicine (NISM) was founded in 1952 to provide medical coverage for national teams, screening and periodic health evaluation (PHE) for all Hungarian athletes. The system of 'all in one and ASAP' evolved by now to a specific state-funded healthcare provider with complex sports medical and sport-related services available for athletes. The NISM created a countrywide network to make health clearance available for all athletes close to their place of residency. This centralised system guarantees the uniformity and financial independence of the network, as it is directly financed by the government and free for every competitive athlete. Thus, it leaves no chance for conflict of interest in evaluating athletes' eligibility. In 2013, NISM established an online registry for preparticipation screening and PHE. This made the registry available for sports physicians and certain data for both sports physicians and athletes themselves. Furthermore, NISM created a nationwide, centrally coordinated, out of turn care with central coordination for elite athletes nationwide. Outpatient and inpatient clinics of NISM provide sports-specific care. Most of the minimally invasive techniques used at the Department of Sports Surgery are applied only here in the country. The medical staff of NISM has special experience in Sports Medicine and sport-related conditions. All tasks are managed within the same system, within institutional frames by professionals at Sports Medicine, which guarantees institutional expertise, competence and responsibility. Our aim is to introduce the complex system, the services and the recent achievements of the Hungarian NISM.

Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart.

The G protein-coupled apelin receptor regulates important processes of the cardiovascular homeostasis, including cardiac development, cardiac contractility, and vascular tone. Most recently, a novel endogenous peptide ligand for the apelin receptor was identified in zebrafish, and it was named apela/elabela/toddler. The peptide was originally considered as an exclusively embryonic regulator, and so far its function in the adult organism remains elusive. We show here that apela is predominantly expressed in the non-cardiomyocyte fraction in the adult rodent heart. We also provide evidence that apela binds to apelin receptors in the heart. Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Pharmacological inhibition of ERK1/2 activation markedly attenuates the apela-induced inotropy. Analysis of samples from infarcted mouse hearts showed that expression of both apela and apelin receptor is induced in failing mouse hearts and correlate with left ventricular ejection fraction. Hence, we conclude that apela is present in the adult heart, is upregulated in post-infarction cardiac remodeling, and increases cardiac contractility in an ERK1/2-dependent manner.

[Role of reactive oxygen species in the regulation of cardiac function]. / Reaktívoxigén-származékok szerepe a szívmuködés szabályozásában.

Increased production of reactive oxygen species has been implicated in the pathogenesis of congestive heart failure. However, emerging evidence suggests a role for reactive oxygen species in regulating various physiological cellular processes in the myocardium. The authors summarize the current understanding of involvement of reactive oxygen species in the regulation of cardiac contractility under physiological conditions.

Apelin increases cardiac contractility via protein kinase Cε- and extracellular signal-regulated kinase-dependent mechanisms.

BACKGROUND: Apelin, the endogenous ligand for the G protein-coupled apelin receptor, is an important regulator of the cardiovascular homoeostasis. We previously demonstrated that apelin is one of the most potent endogenous stimulators of cardiac contractility; however, its underlying signaling mechanisms remain largely elusive. In this study we characterized the contribution of protein kinase C (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2) and myosin light chain kinase (MLCK) to the positive inotropic effect of apelin. METHODS AND RESULTS: In isolated perfused rat hearts, apelin increased contractility in association with activation of prosurvival kinases PKC and ERK1/2. Apelin induced a transient increase in the translocation of PKCε, but not PKCα, from the cytosol to the particulate fraction, and a sustained increase in the phosphorylation of ERK1/2 in the left ventricle. Suppression of ERK1/2 activation diminished the apelin-induced increase in contractility. Although pharmacological inhibition of PKC attenuated the inotropic response to apelin, it had no effect on ERK1/2 phosphorylation. Moreover, the apelin-induced positive inotropic effect was significantly decreased by inhibition of MLCK, a kinase that increases myofilament Ca2+ sensitivity. CONCLUSIONS: Apelin increases cardiac contractility through parallel and independent activation of PKCε and ERK1/2 signaling in the adult rat heart. Additionally MLCK activation represents a downstream mechanism in apelin signaling. Our data suggest that, in addition to their role in cytoprotection, modest activation of PKCε and ERK1/2 signaling improve contractile function, therefore these pathways represent attractive possible targets in the treatment of heart failure.

p38α regulates SERCA2a function.

cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38. PLB phosphorylation was enhanced in cardiomyocytes by chemical p38 inhibition, by overexpression of dominant negative p38α and by p38α RNAi, but not with dominant negative p38ß. Treatment of cardiomyocytes with dominant negative p38α significantly decreased Ca(2+)-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca(2+)-ATPase function and increased cardiomyocyte contractility. Analysis of signaling mechanisms involved showed that inhibition of p38 decreased the activity of protein phosphatase 2A, which renders protein phosphatase inhibitor-1 phosphorylated and thereby inhibits PP1. In conclusion, inhibition of p38α enhances PLB phosphorylation and diastolic Ca(2+) uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition.

Neuronostatin, a novel peptide encoded by somatostatin gene, regulates cardiac contractile function and cardiomyocyte survival.

Neuronostatin, a recently discovered peptide encoded by somatostatin gene, is involved in regulation of neuronal function, blood pressure, food intake, and drinking behavior. However, the biological effects of neuronostatin on cardiac myocytes are not known, and the intracellular signaling mechanisms induced by neuronostatin remain unidentified. We analyzed the effect of neuronostatin in isolated perfused rat hearts and in cultured primary cardiomyocytes. Neuronostatin infusion alone had no effect on left ventricular (LV) contractile function or on isoprenaline- or preload-induced increase in cardiac contractility. However, infusion of neuronostatin significantly decreased the positive inotropic response to endothelin-1 (ET-1). This was associated with an increase in phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK). Treatment of both neonatal and adult cardiomyocytes with neuronostatin resulted in reduced cardiomyocyte viability. Inhibition of JNK further increased the neuronostatin-induced cell death. We conclude that neuronostatin regulates cardiac contractile function and cardiomyocyte survival. Receptors for neuronostatin need to be identified to further characterize the biological functions of the peptide.

Role of reactive oxygen species in the regulation of cardiac contractility.

Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of contractile dysfunction in heart failure. However, it is unclear whether ROS can regulate physiological cellular processes in the myocardium. Here, we characterized the role of endogenous ROS production in the acute regulation of cardiac contractility in the intact rat heart. In isolated perfused rat hearts, endothelin-1 (ET-1, 1nmol/L) stimulated ROS formation in the left ventricle, which was prevented by the antioxidant N-acetylcysteine and the NAD(P)H oxidase inhibitor apocynin. N-acetylcysteine, the superoxide dismutase mimetic MnTMPyP, and apocynin significantly attenuated ET-1-mediated inotropic effect, which was accompanied by inhibition of extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Moreover, the mitochondrial K(ATP) channel blocker 5-HD, and the mitochondrial large conductance calcium activated potassium channel blocker paxilline, but not the sarcolemmal K(ATP) channel blocker HMR 1098 attenuated the inotropic response to ET-1. However, ET-1-induced ROS generation was not abolished by inhibiting mitochondrial K(ATP) channel opening. In contrast to ET-1 stimulation, the positive inotropic effect of ß(1)-adrenergic receptor agonist dobutamine (250nmol/L) was significantly augmented by N-acetylcysteine and apocynin. Moreover, dobutamine-induced phospholamban phosphorylation was markedly enhanced by apocynin. In conclusion, NAD(P)H oxidase-derived ROS play a physiological role in the acute regulation of cardiac contractility in the intact rat heart. Our results reveal that ET-1-induced increase in cardiac contractility is partially dependent on enhanced ROS generation, which in turn, activates the ERK1/2 pathway. On the other hand, ß-adrenergic receptor-induced positive inotropic effect and phospholamban phosphorylation is enhanced by NAD(P)H oxidase inhibition.

Prolactin-releasing peptide regulates cardiac contractility.

High levels of specific prolactin-releasing peptide (PrRP) binding sites have been found in the myocardium; however, the functional importance of PrRP in the regulation of cardiac function is unknown. In isolated perfused rat hearts, infusion of PrRP (1-100 nM) induced a dose-dependent positive inotropic effect. Inhibition of cAMP catabolism by IBMX, a phosphodiesterase inhibitor, failed to augment the contractile effect of PrRP. The protein phosphatase (PP1/PP2A) inhibitor calyculin A increased the inotropic response to PrRP, whereas the PP2A inhibitor okadaic acid had no effect. Ro32-0432, a protein kinase C alpha (PKC alpha) inhibitor, significantly enhanced the inotropic effect of PrRP as well as the phosphorylation of phospholamban at Ser-16. In conclusion, the present data define a hitherto unrecognized role for PrRP in the regulation of cardiovascular system by showing that PrRP exerts a direct positive inotropic effect. Moreover, our results suggest that the cAMP-independent inotropic response to PrRP is suppressed by concurrent activation of PKC alpha and PP1.