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Abstract Background Mitochondrial carriers (MCs) can deeply affect the intracellular flux distribution of metabolic pathways. The manipulation of their expression level, to redirect the flux toward the production of a molecule of interest, is an attractive target for the metabolic engineering of eukaryotic microorganisms. The non-conventional yeast Yarrowia lipolytica is able to use a wide range of substrates. As oleaginous yeast, it directs most of the acetyl-CoA therefrom generated towards the synthesis of lipids, which occurs in the cytoplasm. Among them, the odd-chain fatty acids (OCFAs) are promising microbial-based compounds with several applications in the medical, cosmetic, chemical and agricultural industries. Results In this study, we have identified the MC involved in the Carnitine/Acetyl-Carnitine shuttle in Y. lipolytica, YlCrc1. The Y. lipolytica Ylcrc1 knock-out strain failed to grow on ethanol, acetate and oleic acid, demonstrating the fundamental role of this MC in the transport of acetyl-CoA from peroxisomes and cytoplasm into mitochondria. A metabolic engineering strategy involving the deletion of YlCRC1, and the recombinant expression of propionyl-CoA transferase from Ralstonia eutropha (RePCT), improved propionate utilization and its conversion into OCFAs. These genetic modifications and a lipogenic medium supplemented with glucose and propionate as the sole carbon sources, led to enhanced accumulation of OCFAs in Y. lipolytica. Conclusions The Carnitine/Acetyl-Carnitine shuttle of Y. lipolytica involving YlCrc1, is the sole pathway for transporting peroxisomal or cytosolic acetyl-CoA to mitochondria. Manipulation of this carrier can be a promising target for metabolic engineering approaches involving cytosolic acetyl-CoA, as demonstrated by the effect of YlCRC1 deletion on OCFAs synthesis.

Abstract Background In Europe, data on population health is fragmented, difficult to access, project-based and prone to health information inequalities in terms of availability, accessibility and especially in quality between and within countries. This situation is further exacerbated and exposed by the recent COVID-19 pandemic. The Joint Action on Health Information (InfAct) that builds on previous works of the BRIDGE Health project, carried out collaborative action to set up a sustainable infrastructure for health information in the European Union (EU). The aim of this paper is to present InfAct’s proposal for a sustainable research infrastructure, the Distributed Infrastructure on Population Health (DIPoH), which includes the setup of a Health Information Portal on population health to be maintained beyond InfAct’s time span. Methods The strategy for the proposal was based on three components: scientific initiatives and proposals to improve Health Information Systems (HIS), exploration of technical acceptability and feasibility, and finally obtaining high-level political support.. The technical exploration (Technical Dialogues—TD) was assumed by technical experts proposed by the countries, and political guidance was provided by the Assembly of Members (AoM), which gathered representatives from Ministries of Health and Science of EU/EEA countries. The results from the AoM and the TD were integrated in the sustainability plan compiling all the major outputs of InfAct. Results The InfAct sustainability plan was organized in three main sections: a proposal of a new research infrastructure on population health (the DIPoH), new health information tools and innovative proposals for HIS, and a comprehensive capacity building programme. These activities were carried out in InfAct and are being further developed in the Population Health Information Research Infrastructure (PHIRI). PHIRI is a practical rollout of DIPoH facilitating and generating the best available evidence for research on health and wellbeing of populations as impacted by COVID-19. Conclusions The sustainability plan received wide support from Member States and was recognized to have an added value at EU level. Nevertheless, there were several aspects which still need to be considered for the near future such as: (i) a commitment of stable financial and political support by Member States (MSs), (ii) the availability of resources at regional, national and European level to deal with innovations, and (iii) a more direct involvement from EU and international institutions such as the European Centre for Disease Prevention and Control (ECDC), the World Health Organization (WHO) and the Organisation for Economic Cooperation and Development OECD for providing support and sustainable contributions.

Abstract Background Patients hospitalised for COVID-19 may present with or acquire bacterial or fungal infections that can affect the course of the disease. The aim of this study was to describe the microbiological characteristics of laboratory-confirmed infections in hospitalised patients with severe COVID-19. Methods We reviewed the hospital charts of a sample of patients deceased with COVID-19 from the Italian National COVID-19 Surveillance, who had laboratory-confirmed bacterial or fungal bloodstream infections (BSI) or lower respiratory tract infections (LRTI), evaluating the pathogens responsible for the infections and their antimicrobial susceptibility. Results Among 157 patients with infections hospitalised from February 2020 to April 2021, 28 (17.8%) had co-infections (≤ 48 h from admission) and 138 (87.9%) had secondary infections (> 48 h). Most infections were bacterial; LRTI were more frequent than BSI. The most common co-infection was pneumococcal LRTI. In secondary infections, Enterococci were the most frequently recovered pathogens in BSI (21.7% of patients), followed by Enterobacterales, mainly K. pneumoniae, while LRTI were mostly associated with Gram-negative bacteria, firstly Enterobacterales (27.4% of patients, K. pneumoniae 15.3%), followed by A. baumannii (19.1%). Fungal infections, both BSI and LRTI, were mostly due to C. albicans. Antibiotic resistance rates were extremely high in Gram-negative bacteria, with almost all A. baumannii isolates resistant to carbapenems (95.5%), and K. pneumoniae and P. aeruginosa showing carbapenem resistance rates of 59.5% and 34.6%, respectively. Conclusions In hospitalised patients with severe COVID-19, secondary infections are considerably more common than co-infections, and are mostly due to Gram-negative bacterial pathogens showing a very high rate of antibiotic resistance.

Abstract Background Health-related data are collected from a variety of sources for different purposes, including secondary use for population health monitoring (HM) and health system performance assessment (HSPA). Most of these data sources are not included in databases of international organizations (e.g., WHO, OECD, Eurostat), limiting their use for research activities and policy making. This study aims at identifying and describing collection methods, quality assessment procedures, availability and accessibility of health data across EU Member States (MS) for HM and HSPA. Methods A structured questionnaire was developed and administered through an online platform to partners of the InfAct consortium form EU MS to investigate data collections applied in HM and HSPA projects, as well as their methods and procedures. A descriptive analysis of the questionnaire results was performed. Results Information on 91 projects from 18 EU MS was collected. In these projects, data were mainly collected through administrative sources, population health interview or health examination surveys and from electronic medical records. Tools and methods used for data collection were mostly mandatory reports, self-administered questionnaires, or record linkage of various data sources. One-third of the projects shared data with EU research networks and less than one-third performed quality assessment of their data collection procedures using international standardized criteria. Macrodata were accessible via open access and reusable in 22 projects. Microdata were accessible upon specific request and reusable in 15 projects based on data usage licenses. Metadata was available for the majority of the projects, but followed reporting standards only in 29 projects. Overall, compliance to FAIR Data principles (Findable, Accessible, Interoperable, and Reusable) was not optimal across the EU projects. Conclusions Data collection and exchange procedures differ across EU MS and research data are not always available, accessible, comparable or reusable for further research and evidence-based policy making. There is a need for an EU-level health information infrastructure and governance to promote and facilitate sharing and dissemination of standardized and comparable health data, following FAIR Data principles, across the EU.

Abstract Background Research networks offer multidisciplinary expertise and promote information exchange between researchers across Europe. They are essential for the European Union’s (EU) health information system as providers of health information and data. The aim of this mapping exercise was to identify and analyze EU research networks in terms of health data collection methods, quality assessment, availability and accessibility procedures. Methods A web-based search was performed to identify EU research networks that are not part of international organizations (e.g., WHO-Europe, OECD) and are involved in collection of data for health monitoring or health system performance assessment. General characteristics of the research networks (e.g., data sources, representativeness), quality assessment procedures, availability and accessibility of health data were collected through an ad hoc extraction form. Results Fifty-seven research networks, representative at national, international or regional level, were identified. In these networks, data are mainly collected through administrative sources, health surveys and cohort studies. Over 70% of networks provide information on quality assessment of their data collection procedures. Most networks share macrodata through articles and reports, while microdata are available from ten networks. A request for data access is required by 14 networks, of which three apply a financial charge. Few networks share data with other research networks (8/49) or specify the metadata-reporting standards used for data description (9/49). Conclusions Improving health information and availability of high quality data is a priority in Europe. Research networks could play a major role in tackling health data and information inequalities by enhancing quality, availability, and accessibility of health data and data sharing across European networks.

Abstract Background Non-Communicable diseases (NCD) are the main contributors to mortality and burden of disease. There is no infrastructure in Europe that could provide health information (HI) on Public Health monitoring and Health Systems Performance (HSP) for research and evidence-informed decision-making. Moreover, there was no EU and European Economic Area Member States (EU/EEA MSs) general consensus, on developing this initiative and guarantee its sustainability. The aim of this study is to analyze the integration of technical and political views made by the Joint Action on Health Information (InfAct; Information for Action) and the results obtained from those activities, in terms of advice and national and institutional support to develop an integrated and sustainable European Distributed Infrastructure on Population Health (DIPoH) for research and evidence-informed policy-making. Methods InfAct established two main boards, the Technical Dialogues (TDs) and the Assembly of Members (AoM), to provide a platform for discussion with EU/EEA MSs to establish a sustainable infrastructure for HI: 1) The TDs were composed by national technical experts (NTE) with the aim to discuss and provide feedback about scientific aspects, feasibility and EU-added value of the infrastructure proposed by InfAct. 2) The AoM gathered country representatives from Ministries of Health and Research at the highest political level, with the aim of providing policy-oriented advice for the future political acceptance, support, implementation, and development of InfAct’s outcomes including DIPoH. The documentation provided for the meetings consisted in Fact-Sheets, where the main results, new methods and proposals were clearly exposed for discussion and assessment; altogether with more extended information of the DIPoH. The documentation was provided to national representatives within one more before each TD and AoM meeting. The Agenda and methodological approaches for each TD and AoM meeting consisted in the presentations of the InfAct outcomes extending the information provided in the Fact-Sheets; followed by a non-structured interaction, exchange of information, discussion and suggestions by the MSs representatives. The outcomes of the non-structured discussions were collected in Minutes of the TD and AoM meetings, and the final version was obtained with the consensus of all participants. Additionally, structured letters of political support were provided to the AoM representatives, for them to consider providing their MS written support for DIPoH. Results NTE, within the TDs, considered that DIPoH was useful for technical mutual learning and cooperation among and within countries; although they considered that the technical feasibility to uptake InfAct deliverables at the national and EU level was complex. The AoM focused on political support, resources, and expected MSs returns. The AoM representatives agreed in the interest of setting up an integrated and sustainable HI infrastructure and they considered DIPoH to be well-articulated and defined; although, some of them, expressed some barriers for providing DIPoH political support. The AoM representatives stated that the AoM is the most suitable way to inform EU MSs/ACs about future advances of DIPoH. Both boards provided valuable feedback to develop this infrastructure. Eleven countries and sixteen institutions supported the proposal, either by letters of political support or by signing the Memorandum of Understandings (MoU) and three countries, additionally, provided expression of financial commitment, for DIPoH to be added to the ESFRI 2021 roadmap. Conclusions TDs and AoM were key forums to develop, advise, advocate and provide support for a sustainable European research infrastructure for Population Health.

Abstract Background Information for Action! is a Joint Action (JA-InfAct) on Health Information promoted by the EU Member States and funded by the European Commission within the Third EU Health Programme (2014–2020) to create and develop solid sustainable infrastructure on EU health information. The main objective of this the JA-InfAct is to build an EU health information system infrastructure and strengthen its core elements by a) establishing a sustainable research infrastructure to support population health and health system performance assessment, b) enhancing the European health information and knowledge bases, as well as health information research capacities to reduce health information inequalities, and c) supporting health information interoperability and innovative health information tools and data sources. Methods Following a federated analysis approach, JA-InfAct developed an ad hoc federated infrastructure based on distributing a well-defined process-mining analysis methodology to be deployed at each participating partners’ systems to reproduce the analysis and pool the aggregated results from the analyses. To overcome the legal interoperability issues on international data sharing, data linkage and management, partners (EU regions) participating in the case studies worked coordinately to query their real-world healthcare data sources complying with a common data model, executed the process-mining analysis pipeline on their premises, and shared the results enabling international comparison and the identification of best practices on stroke care. Results The ad hoc federated infrastructure was designed and built upon open source technologies, providing partners with the capacity to exploit their data and generate dashboards exploring the stroke care pathways. These dashboards can be shared among the participating partners or to a coordination hub without legal issues, enabling the comparative evaluation of the caregiving activities for acute stroke across regions. Nonetheless, the approach is not free of a number of challenges that have been solved, and new challenges that should be addressed in the eventual case of scaling up. For that eventual case, 12 recommendations considering the different layers of interoperability have been provided. Conclusion The proposed approach, when successfully deployed as a federated analysis infrastructure, such as the one developed within the JA-InfAct, can concisely tackle all levels of the interoperability requirements from organisational to technical interoperability, supported by the close collaboration of the partners participating in the study. Any proposal for extension, should require further thinking on how to deal with new challenges on interoperability.

Abstract Background Metabolic syndrome (MetS) is a public health problem in Europe, affecting all age groups. Several MetS definitions are available. The aim of this study was to compare four different MetS definitions in the Finnish adult population, to assess their agreement and to evaluate the impact of the choice of the definition on the prevalence of MetS. Methods Data from FinHealth 2017, a cross-sectional national population health survey, focusing on adults aged 25 years or older were used in the analysis (n=5687). Measured data on anthropometrics, blood pressure and biomarkers together with questionnaire data were used to classify the participants into the MetS categories according to the four definitions. The definitions chosen for the comparison were those by the World Health Organization (WHO) (1998), National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (2004), International Diabetes Federation (IDF) (2005), and Joint Interim Statement (JIS) (2009). Results The four MetS definitions resulted in substantially different MetS prevalence: 17.7% by WHO, 33.3% by NCEP-ATP III, 41.5% by IDF, and 43.0% by JIS. Regardless of the definition used, the prevalence of MetS increased with age. The prevalence of the different components varied between the definitions, depending on the different cut-off points adopted. Out of all participants, only 13.6% were identified to have MetS according to all four definitions. Agreement between participants recognised by different MetS definitions, estimated through kappa coefficients, was almost perfect for IDF vs. JIS (0.97), strong for JIS vs. NCEP-ATP III (0.80), moderate for IDF vs. NCEP-ATP III (0.76) and weak for WHO vs. NCEP-ATP III (0.42), WHO vs. IDF (0.41) and WHO vs. JIS (0.40). Conclusions Differences between observed prevalence of MetS in Finnish men and women using different MetS definitions were large. For cross-country comparisons, as well as for trend analyses within a country, it is essential to use the same MetS definition to avoid discrepancies in classification due to differences in used definitions.

Abstract Background Health reporting shall provide up-to-date health-related data to inform policy-makers, researchers and the public. To this end, health reporting formats should be tailored to the needs and competencies of the target groups and provide comparable and high-quality information. Within the Joint Action on Health Information ‘InfAct’, we aimed at gaining an overview of health reporting practices in the EU Member States and associated countries, and developed quality criteria for the preparation of public health reports. The results are intended to facilitate making health information adequately available while reducing inequalities in health reporting across the EU. Methods A web-based desk research was conducted among EU Member States and associated countries to generate an overview of different formats of national health reporting and their respective target groups. To identify possible quality criteria for public health reports, an exploratory literature review was performed and earlier projects were analysed. The final set of criteria was developed in exchange with experts from the InfAct consortium. Results The web-based desk research showed that public health reports are the most frequently used format across countries (94%), most often addressed to scientists and researchers (51%), politicians and decision-makers (41%). However, across all reporting formats, the general public is the most frequently addressed target group. With regards to quality criteria for public health reports, the literature review has yielded few results. Therefore, two earlier projects served as main sources: the ‘Evaluation of National and Regional Public Health Reports’ and the guideline ‘Good Practice in Health Reporting‘from Germany. In collaboration with experts, quality criteria were identified and grouped into eight categories, ranging from topic selection to presentation of results, and compiled in a checklist for easy reference. Conclusion Health reporting practices in the EU are heterogeneous across Member States. The assembled quality criteria are intended to facilitate the preparation, dissemination and access to better comparable high-quality public health reports as a basis for evidence-based decision-making. A comprehensive conceptual and integrative approach that incorporates the policy perspective would be useful to investigate which dissemination strategies are the most suitable for specific requirements of the targeted groups.

Abstract Background Health indicators are used to monitor the health status and determinants of health of the population and population sub-groups, identify existing or emerging health problems which would require prevention and health promotion activities, help to target health care resources in the most adequate way as well as for evaluation of the success of public health actions both at the national and international level. The quality and validity of the health indicator depends both on available data and used indicator definition. In this study we will evaluate existing knowledge about comparability of different data sources for definition of health indicators, compare how selected health indicators presented in different international databases possibly differ, and finally, present the results from a case study from Finland on comparability of health indicators derived from different data sources at national level. Methods For comparisons, four health indicators were selected that were commonly available in international databases and available for the Finnish case study. These were prevalence of obesity, hypertension, diabetes, and asthma in the adult populations. Our evaluation has three parts: 1) a scoping review of the latest literature, 2) comparison of the prevalences presented in different international databases, and 3) a case study using data from Finland. Results Literature shows that comparability of estimated outcomes for health indicators using different data sources such as self-reported questionnaire data from surveys, measured data from surveys or data from administrative health registers, varies between indicators. Also, the case study from Finland showed that diseases which require regular health care visits such as diabetes, comparability is high while for health outcomes which can remain asymptomatic for a long time such as hypertension, comparability is lower. In different international health related databases, country specific results differ due to variations in the used data sources but also due to differences in indicator definitions. Conclusions Reliable comparison of the health indicators over time and between regions within a country or across the countries requires common indicator definitions, similar data sources and standardized data collection methods.

Abstract Background Among the unknowns posed by the coronavirus disease 2019 (COVID-19) outbreak, the role of biological sex to explain disease susceptibility and progression is still a matter of debate, with limited sex-disaggregated data available. Methods A retrospective analysis was performed to assess if sex differences exist in the clinical manifestations and transitions of care among hospitalized individuals dying with laboratory-confirmed SARS-CoV-2 infection in Italy (February 27–June 11, 2020). Clinical characteristics and the times from symptoms’ onset to admission, nasopharyngeal swab, and death were compared between sexes. Adjusted multivariate analysis was performed to identify the clinical features associated with male sex. Results Of the 32,938 COVID-19-related deaths that occurred in Italy, 3517 hospitalized and deceased individuals with COVID-19 (mean 78 ± 12 years, 33% women) were analyzed. At admission, men had a higher prevalence of ischemic heart disease (adj-OR = 1.76, 95% CI 1.39–2.23), chronic obstructive pulmonary disease (adj-OR = 1.7, 95% CI 1.29–2.27), and chronic kidney disease (adj-OR = 1.48, 95% CI 1.13–1.96), while women were older and more likely to have dementia (adj-OR = 0.73, 95% CI 0.55–0.95) and autoimmune diseases (adj-OR = 0.40, 95% CI 0.25–0.63), yet both sexes had a high level of multimorbidity. The times from symptoms’ onset to admission and nasopharyngeal swab were slightly longer in men despite a typical acute respiratory illness with more frequent fever at the onset. Men received more often experimental therapy (adj-OR = 2.89, 95% CI 1.45–5.74) and experienced more likely acute kidney injury (adj-OR = 1.47, 95% CI 1.13–1.90). Conclusions Men and women dying with COVID-19 had different clinical manifestations and transitions of care. Identifying sex-specific features in individuals with COVID-19 and fatal outcome might inform preventive strategies.

Abstract Background The availability of data generated from different sources is increasing with the possibility to link these data sources with each other. However, linked administrative data can be complex to use and may require advanced expertise and skills in statistical analysis. The main objectives of this study were to describe the current use of data linkage at the individual level and artificial intelligence (AI) in routine public health activities, to identify the related estimated health indicators (i.e., outcome and intervention indicators) and health determinants of non-communicable diseases and the obstacles to linking different data sources. Method We performed a survey across European countries to explore the current practices applied by national institutes of public health, health information and statistics for innovative use of data sources (i.e., the use of data linkage and/or AI). Results The use of data linkage and AI at national institutes of public health, health information and statistics in Europe varies. The majority of European countries use data linkage in routine by applying a deterministic method or a combination of two types of linkages (i.e., deterministic & probabilistic) for public health surveillance and research purposes. The use of AI to estimate health indicators is not frequent at national institutes of public health, health information and statistics. Using linked data, 46 health outcome indicators, 34 health determinants and 23 health intervention indicators were estimated in routine. The complex data regulation laws, lack of human resources, skills and problems with data governance, were reported by European countries as obstacles to routine data linkage for public health surveillance and research. Conclusions Our results highlight that the majority of European countries have integrated data linkage in their routine public health activities but only a few use AI. A sustainable national health information system and a robust data governance framework allowing to link different data sources are essential to support evidence-informed health policy development. Building analytical capacity and raising awareness of the added value of data linkage in national institutes is necessary for improving the use of linked data in order to improve the quality of public health surveillance and monitoring activities.