European Union's Horizon Research Articles

Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy.

Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives? We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene. Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Despite being a common early pregnancy complication, the genetic predisposition to this condition remains understudied and no large scale genetic studies have been performed so far. A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study. We identified ectopic pregnancy cases from national registers by ICD (International Classification of Disease) codes (ICD-10 O00), and all remaining women were considered controls. We carried out standard GWAS meta-analysis and additionally annotated GWAS signals, analysed co-localization with quantitative trait loci, estimated genetic correlations and identified associated phenotypes to characterize the genetic signals, as well as to analyse the genetic and phenotypic relationships with the condition. We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P = 5.32×10-9) and 10 (rs11598956, P = 2.41×10-8) potentially associated with ectopic pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein with an important role in barrier function, as the most likely candidate gene for the association on chromosome 1. We also characterize the phenotypic and genetic correlations with other phenotypes, identifying a genetic correlation with smoking and diseases of the (genito)urinary and gastrointestinal system, and phenotypic correlations with various reproductive health diagnoses, reflecting the previously known epidemiological associations. The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883). The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes. Additionally, further larger meta-analysis or independent studies are needed to validate these findings. This study encourages the use of large-scale genetic datasets to unravel genetic factors linked to ectopic pregnancy, which is difficult to study in experimental settings. Increased sample size might bring additional genetic factors associating with ectopic pregnancy and inform its heritability. Altogether, our results provide more insight into the biology of ectopic pregnancy and, accordingly, the biological processes governing embryo implantation. N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 813707. This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of University of Tartu. The authors declare no competing interests.

Delving into vaccine hesitancy through multicentre studies: VAX-TRUST and INF-ACT projects’ insights

Abstract Vaccine hesitancy is a wide and varied phenomenon and represents a challenge for healthcare professionals (HCPs), who may encounter obstacles in building trusting relationships with parents and patients. Depicting the multifaceted aspects of hesitancy and finding effective tools that could help HCPs in addressing this issue are major public health priorities. This presentation will provide insights about two multicentre research initiatives that aim to respond to these needs. The “VAX-TRUST - Addressing Vaccine Hesitancy in Europe” project (funding from European Union's Horizon 2020 research and innovation program under Grant Agreement No. 965280) involves several institutions across Finland, Belgium, Poland, the Czech Republic, Italy, Portugal, and the UK. One of the goals of VAX-TRUST is to assist HCPs in dealing with hesitancy by implementing tailored interventions, specific for each target region. The process of development of interventions, starting from data supporting the planning up to the final intervention framework, will be discussed. The INF-ACT project (Next Generation EU funding within the MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases, Project no. PE00000007) is a multicentre collaboration including universities and institutions throughout Italy. Within this project, the EPI-MOD node will contribute to realize novel monitoring methods to gather information on human behaviours during outbreaks and evaluate vaccine hesitancy levels and determinants. Among the main objectives, EPI-MOD will examine features and applications of immunization registries and will delve into vaccine hesitancy through a broad Italian nationwide survey, profiling subgroups of population at high risk for vaccine hesitancy. Overall, the results of these two large projects will allow to integrate novel data into information for action by identifying interventions that could be used to support HCPs and vulnerable groups that may require additional attention.

Humanizing science: seven actions for PhD students to become next generation, future-proof scientists.

PhD students, also referred to as the early stage researchers (ESRs), that were participating in the European Union's Horizon 2020 consortium, OrganoVIR, have the ambition to become top scientists in virology with innovative, animal-free, research models; organoids. To achieve this ambition, developing more self-confidence and resilience was used to strengthen personal leadership needed in such professional role. Towards this purpose, seven actions have been selected that guide the ESRs through their PhD journey and help them elevate their career perspectives and employability in the international labor market. In this essay, we share the seven personal development actions that have been carried out by the ESRs in the OrganoVIR H2020 Innovative Training Network (ITN) project, with the goal of demonstrating how training human skills can contribute to innovation and collaboration in European research. This article is an effort by OrganoVIR's Training and Education Committee to provide views on personal growth and leadership awareness.

A systematic analysis of the human immune response to Plasmodium vivax.

BACKGROUNDThe biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence.METHODSParticipants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA sequencing, and cytometry by time of flight, and temporal changes in the host response to P. vivax were quantified by linear regression. Comparative analyses with P. falciparum were then undertaken using analogous data sets derived from prior controlled human malaria infection studies.RESULTSP. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. This acute-phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at RNA and protein levels), leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation were significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and autoinflammatory disease.CONCLUSIONP. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03797989.FUNDINGThe European Union's Horizon 2020 Research and Innovation programme, the Wellcome Trust, and the Royal Society.

Safety and infectivity of female cercariae in Schistosoma-naïve, healthy participants: a controlled human Schistosoma mansoni infection study

A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently, we established CHI-S model using single-sex male-only Schistosoma mansoni (Sm) cercariae in Schistosoma-naïve individuals. Given important differences in antigenic profile and human immune responses to schistosomes of different sex, we pioneered a single-sex female-only CHI-S model for future use in vaccine development. We exposed 13 healthy, Schistosoma-naïve adult participants to 10 (n=3) or 20 (n=10) female cercariae and followed for 20 weeks, receiving treatment with praziquantel (PZQ) 60mg/kg at week 8 and 12 after exposure. The majority (11/13) participants reported rash and/or itch at the site of exposure, 5/13 had transient symptoms of acute schistosomiasis. Exposure to 20 cercariae led to detectable infection, defined as serum circulating anodic antigen levels >1.0pg/mL, in 6/10 participants. Despite two rounds of PZQ treatment, 4/13 participants showed signs of persistent infection. Additional one- or three-day PZQ treatment (1×60mg/kg and 3×60mg/kg) or artemether did not result in cure, but over time three participants self-cured. Antibody, cellular, and cytokine responses peaked at week 4 post infection, with a mixed Th1, Th2, and regulatory profile. Cellular responses were (most) discriminative for symptoms. Female-only infections exhibit similar clinical and immunological profiles as male-only infections but are more resistant to PZQ treatment. This limits future use of this model and may have important implications for disease control programs. European Union's Horizon 2020 (grant no. 81564).

Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial

In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. European Union Horizon 2020 and Global Alliance for Chronic Diseases.

Geographical Indications, public goods and sustainable development goals: A methodological proposal

Geographical Indications (GIs) are examples of food production that leans towards sustainability through management rules laid down by consortia and a Code of Specifications (CoS) that guides good practices. The objective of this paper is to develop a methodology grounded in the European union horizon 2020 Strength2food (S2F) project, which can measure the extent to which GI production systems contribute to the fulfilment of Sustainable Development Goals (SDGs). The analysis comprises three stages. The first two use the S2F methodology: i) the identification of the benefits that the activities codified in the GI CoS bring to the territory, and ii) the definition of indicators for measuring such benefits, classed as public goods (PGs), and their evaluation criteria. The third stage represents this study's contribution to the methodology, that is, iii) establishing connections between the identified PGs and SDGs. To this end, we discuss a Protected Designation of Origin Parmigiano Reggiano hard cheese case study. Our methodology aims to provide policymakers, operators, and managers of GI value chains with a tool to define which good practices in GI production systems should be supported over time to better achieve the SDGs.

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death

We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR).

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

P11.75.B PSEUDOPROGRESSION IN A REAL-WORLD GLIOBLASTOMA COHORT: INCIDENCE, MANAGEMENT, PROGNOSTIC IMPACT, AND ASSOCIATED FACTORS

Abstract BACKGROUND Radiotherapy remains a cornerstone in glioblastoma (GBM) management. A continued and unmet need in neuro-oncology is efficient non-invasive methods to differentiate post-radiation magnetic resonance imaging (MRI) changes from progressive disease (PD) in GBM patients. The clinical challenge is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed incidence, management, prognostic impact, and associated factors with PsP in a real-world GBM patient cohort. MATERIAL AND METHODS Adult (≥18 years) GBM patients diagnosed in the South-Eastern Health Region of Norway from 2015 to 2018, had received radiotherapy, and follow-up MRIs were included. Patient, tumor, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at three and six months post-radiation using response assessment in neuro-oncology criteria. RESULTS PsP incidences at three and six months post-radiation were 20% and 8%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and absence of neurological deterioration were associated with PsP at both three (p&amp;lt;0.001 and p=0.04, respectively) and six months (p=0.003 and p=0.04, respectively) post-radiation. Patients with PsP at MRI three months post-radiation had a median OS of 24.8 months compared to 11.4 months for patients with PD and 18.7 months in patients with stable disease (SD); the difference was significant only when comparing patients with PsP and PD (p&amp;lt;0.001). There was no survival benefit of treatment change for patients retrospectively evaluated as PD three months post-radiation (p=0.8). Median OS for patients in the PsP group was 31.8 months and thus longer than in the PD group (13.1 months) and the SD group (24.1 months). The difference was only significant when comparing patients with PsP and PD (p&amp;lt;0.001). CONCLUSION PsP incidence in this retrospective material was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that the absence of neurological deterioration significantly correlated to PsP. Continuation of temozolomide courses did not compromise survival for patients with PD at three months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings. Funding: European Union's Horizon 2020 Programme European Research Council Grant 758657-ImPRESS.

An Open-Source Continuum Model for Anion-Exchange Membrane Water Electrolysis

Anion-exchange membrane (AEM) electrolysis has the potential to produce green hydrogen at low cost by combining the advantages of conventional alkaline electrolysis and proton-exchange membrane electrolysis. The alkaline environment in AEM electrolysis enables the use of less expensive catalysts such as nickel, whereas the use of a solid polymer electrolyte enables differential pressure operation. Recent advancements in AEM performance and lifetime have spurred interest in AEM electrolysis, but many open research areas remain, such as understanding the impacts of water transport in the membrane and salt content in the electrolyte on cell performance and degradation. Furthermore, integrating electrolyser systems into renewable energy grids necessitates dynamic operation of the electrolyser cell, which introduces additional challenges. Computational modelling of AEM electrolysis is ideally suited to tackle many of these open questions by providing insight into the transport processes and electrochemical reactions occurring in the cell under dynamic conditions.In this work, an open-source, transient continuum modelling framework for anion-exchange membrane (AEM) electrolysis is presented and applied to study electrolyzer cell dynamic performance. The one-dimensional cell model contains coupled equations for multiphase flow in the porous transport layers, a parameterized solution property model for potassium hydroxide electrolytes, and coupled ion and water transport equations to account for water activity gradients within the AEM. The model is validated with experimental results from an AEM electrolyser cell. We find that pH gradients develop within the electrolyte due to the production and consumption of hydroxide, which can lead to voltage losses and cell degradation. The influence of these pH gradients on potential catalyst dissolution mechanisms is explored and discussed. Finally, initial studies of transient operation will be presented.This work has been performed in the frame of the CHANNEL project. This project has received funding from the Fuel Cells and Hydrogen 2 Joint Undertaking (now Clean Hydrogen Partnership) under grant agreement No 875088. This Joint undertaking receives support from the European Union's Horizon 2020 Research and Innovation program, Hydrogen Europe and Hydrogen Europe Research. Some of this work has been performed within the MODELYS project "Electrolyzer 2030 – Cell and stack designs" financially supported by the Research Council of Norway under project number 326809.

Preterm birth and the risk of multimorbidity in adolescence: a multiregister-based cohort study

Multimorbidity affects people of all ages, but the risk factors of multimorbidity in adolescence are unclear. The aim of this study was to examine preterm birth (<37 weeks) as a shared risk factor for multiple health outcomes and the role of gestational age (degree of prematurity) in the development of increasingly complex multimorbidity (two, three, or four health outcomes) in adolescence (age 10-18 years). We used population-wide data from Finland (1 187 610 adolescents born 1987-2006) and Norway (555 431 adolescents born 1998-2007). Gestational age at birth was ascertained from medical birth registers and categorised as 23-27 weeks (extremely preterm), 28-31 weeks (very preterm), 32-33 weeks (moderately preterm), 34-36 weeks (late preterm), 37-38 weeks (early term), 39-41 weeks (term, reference category) and 42-44 weeks (post-term). Children who died or emigrated before their 10th birthday, and those with missing or implausible data on gestational age, birthweight, or covariates, were excluded. Health outcomes at age 10-18 years were ascertained from specialised health care and mortality registers. We calculated hazard ratios (HRs) and population attributable fractions (PAFs) with 95% CIs for multiple health outcomes during adolescence. Individuals were followed up from age 10 to 18 years (mean follow-up: 6 years, SD: 3 years). Preterm birth was associated with increased risks of 20 hospital-treated malignant, cardiovascular, endocrinological, neuropsychiatric, respiratory, genitourinary, and congenital health outcomes, after correcting for multiple testing and ignoring small effects (HR <1·2). Confounder-adjusted HRs comparing preterm with term-born adolescents were 2·29 (95% CI 2·19-2·39) for two health outcomes (PAF 9·0%; 8·3-9·6), and 4·22 (3·66-4·87) for four health outcomes (PAF 22·7%; 19·4-25·8) in the Finnish data. Results in the Norwegian data showed a similar pattern. We observed a consistent dose-response relationship between an earlier gestational age and elevated risks of increasingly complex multimorbidity in both datasets. Preterm birth is associated with increased risks of diverse multimorbidity patterns at age 10-18 years. Adolescents with a preterm-born background could benefit from diagnostic vigilance directed at multimorbidity and a multidisciplinary approach to health care. European Union Horizon 2020, Academy of Finland, Foundation for Pediatric Research, Sigrid Jusélius Foundation, Signe and Ane Gyllenberg Foundation.

Utilization of healthcare prior to endometriosis diagnosis: a Danish case-control study.

Do women with endometriosis have higher utilization of primary and secondary healthcare prior to diagnosis compared to women without endometriosis? Women with a hospital-based diagnosis of endometriosis had an overall higher utilization of both primary and secondary healthcare in all 10 years prior to diagnosis. Endometriosis is associated with a diagnostic delay, but only a few studies have investigated the potential consequences of this delay with regard to the utilization of healthcare. To the best of our knowledge, no study has investigated it in a period corresponding to the estimated diagnostic delay. This national Danish registry-based case-control study included 129 696 women. Cases were women with a first-time hospital-based diagnosis of endometriosis between 1 January 2000 and 31 December 2017. We identified 21 616 cases using density sampling. Each case was matched on age at the date of diagnosis (index date) to five women without diagnosed endometriosis (n = 108 080). The utilization of healthcare was assessed for the 10 years before the index. Cases had significantly higher use of healthcare in all 10 years preceding the index. The mean number of yearly contacts with the GP was 9.99 for cases and 7.85 for controls, with an adjusted incidence rate ratio of 1.28 (1.27; 1.29). For hospital contacts, the association increased slightly in the first 9 years and was most profound in the last year preceding index when the adjusted incidence rate ratio was 2.26 (95% CI 2.28; 2.31). We were not able to include women with an endometriosis diagnosis from the general practitioner or private gynaecologist. Therefore, our results are only applicable to hospital-based diagnoses of endometriosis. We do not have information on the specific reasons for contacting the healthcare providers and we can therefore only speculate that the higher utilization of healthcare among cases was related to endometriosis. This study is in agreement with the other known studies on the subject. Future studies should include specific reasons for contacting the healthcare system and thereby identify any specific contact patterns for women with endometriosis. With this knowledge, healthcare professionals could be better at relating certain healthcare seeking behaviour to endometriosis earlier and thereby reduce the time from onset of symptoms to diagnosis. This study is supported by grants from the project 'Finding Endometriosis using Machine Learning' (FEMaLe/101017562), which has received funding from The European Union's Horizon 2020 research and innovation program and Helsefonden (21-B-0141). K.Z. report grants from Bayer AG, Roche Inc. and Volition, royalties from Oxford-Bayer scientific collaboration in gynaecological therapies, non-financial collaboration with the World Endometriosis Society and World Endometriosis Research Foundation and is a Wellbeing of Women research advisory committee member. All this is outside the submitted work. The other authors have no conflict of interest to declare. N/A.

Investigation of European Union Horizon 2020 Information and Communication Technology Projects with the Social Network Analysis Method

This study aims to examine the partnerships of the projects accepted in the Horizon 2020 grant support program, which supports innovative Research and Development (R&amp;D) projects of the European Union, using social network analysis according to criteria such as participant countries, the project subjects in which they participate, and the number of funds they receive. Social network analysis can be used in many different areas, as well as in the analysis of collaborations and partnerships. Turkey's partnership has not been examined in detail for such international multi-partner collaborations. While taking advantage of the opportunity to follow the trend of technology by conducting innovative R&amp;D studies with leading organizations in many different strategic fields, the interest and participation rate of Turkey is increasing day by day in such programs, offering opportunities to obtain grant incentives. Examining the network of collaborations established so far in this field can provide various inferences and suggestions for strategic partnerships.

Exposures to perfluoroalkyl substances and asthma phenotypes in childhood: an investigation of the COPSAC2010 cohort.

Exposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown. In the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age ½, 1½ and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics. Higher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes. Prenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis. All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764); The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B); and The Capital Region Research Foundation have provided core support to the COPSAC research center. COPSAC acknowledges the National Facility for Exposomics (SciLifeLab, Sweden) for supporting calibration of the untargeted metabolomics PFAS data. BC and AS has received funding for this project from the European Union's Horizon 2020 research and innovation programme (BC: grant agreement No. 946228 DEFEND; AS: grant agreement No. 864764 HEDIMED).

What makes nurses flourish at work? How the perceived clinical work environment relates to nurse motivation and well-being: A cross-sectional study

BackgroundLiterature shows that the work environment is a main determinant of nurses' well-being and psychological strain; yet, the (psychological) mechanisms underlying this relationship remain understudied. ObjectiveThis study explored the underlying (psychological) mechanisms (why) and boundary conditions (when) by which characteristics present in the clinical work environment influence nurses' well-being. We investigated the mediating role of intrinsic motivation in the relationship of job demands and job resources with burnout vs. work engagement. In addition, we examined if job resources strengthen the relationship of job demands with intrinsic motivation and burnout. DesignA cross-sectional survey study. Setting(s)General acute care hospitals in Belgium (n = 14). ParticipantsDirect care nurses (n = 1729). MethodsData were collected by means of online questionnaires between October 2020 and July 2021. Study variables included burnout, work engagement, intrinsic motivation and a set of different job demands (workload, role conflicts, emotional demands, red tape) and job resources (performance feedback, autonomy, skill use, opportunity for growth, and value congruence). All variables were obtained using self-report measures. The central hypotheses were tested using structural equation modeling. ResultsJob resources appeared to be a crucial factor for nurses' health showing positive associations with work motivation (β = 0.513) and work engagement (β = 0.462) and negative associations with burnout (β = −0.216). Job demands remained an essential factor that harms psychological health and is associated with increased burnout (β = 0.489). Our results confirmed that intrinsic motivation mediated the relationship of job resources with work engagement (β = 0.170) and burnout (β = −0.135). In addition, job resources moderated the relationship of job demands with burnout (β = −0.039). Against our expectations, we found no associations between job demands and intrinsic motivation or a moderation effect of job resources on the respective relationship. ConclusionsA highly demanding work environment can be a source of significant stress which may put nurses' health at severe risk. Nurses who perceive sufficient job resources such as feedback, autonomy and opportunities for growth and development, are likely to feel intrinsically motivated at work. In addition, it will foster their work engagement and prevent them from burning out, particularly when job demands are high. RegistrationThe study described herein is funded under the European Union's Horizon 2020 Research and Innovation program from 2020 to 2023 (Grant Agreement 848031). The protocol of Magnet4Europe is registered in the ISRCTN registry (ISRCTN10196901). Tweetable abstractProviding nurses with sufficient resources will not only increase their motivation and engagement at work but also reduce their feelings of burnout.

The HighNESS Project at the European Spallation Source: Current Status and Future Perspectives

The European Spallation Source (ESS), presently under construction in Lund, Sweden, is a multidisciplinary international laboratory that, once completed at full specifications, will operate the world’s most powerful pulsed neutron source. Supported by a 3 M Euro Research and Innovation Action within the European Union Horizon 2020 program, a design study (HighNESS) is now underway to develop a second neutron source located below the spallation target. Compared to the first source, which is located above the spallation target and designed for high cold and thermal brightness, the new source is being optimized to deliver higher intensity and a shift to longer wavelengths in the spectral regions of cold neutrons (CNs) (2 to 20 Å), very cold neutrons (VCNs) (10 to 120 Å), and ultracold neutrons (UCNs) ( > 500 Å). The second source consists of a large liquid deuterium moderator to deliver CNs and serve secondary VCN and UCN sources, for which different options are under study. These new sources will boost several areas of condensed matter research and will provide unique opportunities in fundamental physics. The HighNESS project is now entering its last year, and we are working toward the Conceptual Design Report of the ESS upgrade. In this paper, results obtained in the first 2 years, ongoing developments, and future perspectives are described.

Income inequalities beyond access to mental health care: a Dutch nationwide record-linkage cohort study of baseline disease severity, treatment intensity, and mental health outcomes

Existing literature shows low and unequal access to mental health treatment globally, resulting in policy efforts to promote access for vulnerable groups. Yet, there is little evidence about how inequalities develop once individuals start treatment. The greater use of mental health care among individuals with low income, such as in the Dutch system, might be driven by differences in need and might not necessarily lead to better treatment outcomes. In this study, we aimed to examine income inequalities in four stages of the mental health treatment pathway while adjusting for need. We constructed a nationwide retrospective cohort study, examining all patients aged older than 18 years with a first specialist mental health treatment record in the Netherlands between 2011 and 2016, excluding those who did not receive any treatment minutes. We linked patient-level data from treatment records to administrative data on income, demographics from municipal registries, and health insurance claims. We used multivariate models to estimate adjusted associations between household income quintile (standardised for household size) and outcomes characterising four stages of mental health treatment: severity at baseline assessment based on the Global Assessment of Functioning (GAF) score, treatment minutes received, functional improvement by the end of the initial record, and additional treatment in a subsequent record. Estimates were adjusted for patient need (97 categories of primary diagnosis and severity at baseline assessment measured by GAF) and demographic covariates. Our study population consisted of 951 530 adults with a first specialist mental health treatment record in the Netherlands between Jan 1, 2011, and Dec 31, 2016. Patients in our cohort were on average aged 45·0 years (range 19-107) and mostly female (529 859 [55·7%] women and 421 671 [44·3%] men; no ethnicity data were available). First, we found that patients with the lowest income had the greatest initial therapist-assessed disease severity (5·545 GAF points), which was 0·353 GAF points (95% CI 0·347-0·360) lower than those in the highest income quintile. Second, we found that the negative association between income and treatment minutes was reversed once we adjusted for diagnosis and severity at baseline, with patients with the lowest income receiving 1·8% fewer treatment minutes (95% CI 1·1-2·4) than those in the highest quintile. Third, those in the highest income quintile were 17·3 percentage points (95% CI 17·0-17·6) more likely to have functional improvements by the end of the initial record, compared with 25·8% of patients with an improvement in the lowest income quintile. Fourth, while 35·7% of patients in the lowest income quintile received additional treatment in a subsequent record, this was only 3·0 percentage points (95% CI 2·7-3·3) lower for those in the highest quintile. None of these patterns were explained by diagnosis, severity at baseline, or treatment minutes received. Disparities favourable to patients with a higher income persist through the different stages of mental health treatment. These differences highlight the limitations of solely focusing on improving access to care to reduce the mental health gap. Our findings call for a better understanding of the role of social environment and quality of care as complementary mechanisms explaining inequalities during mental health treatment. Erasmus Initiative Smarter Choices for Better Health (Erasmus University Rotterdam), European Union's Horizon 2020, and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Dutch Research Council). For the Dutch translation of the abstract see Supplementary Materials section.

Diastolic dysfunction inhibits mechanical dyssynchrony in cardiac resynchronization therapy patients: a combined clinical-computational study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This work was supported by the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie grant agreement No. 860745. Background In heart failure patients treated with cardiac resynchronization therapy (CRT), both the presence of typical left bundle branch block (LBBB) mechanics and a relatively preserved diastolic function are associated with better clinical outcomes. However, the mechanistic interaction between both phenomena has never been investigated. Aim In this combined clinical-computational study, we explored the potential interaction between LBBB mechanics and the severity of diastolic dysfunction. Methods In 219 CRT candidates, left atrial pressure (LAP) was retrospectively estimated using the multiparametric guideline approach, where patients were classified into elevated (eLAP, 49%), normal (nLAP, 40%) and undetermined (uLAP, 11%) LAP. nLAP and uLAP were together referred to as non-elevated LAP (non-eLAP, 51%). Typical LBBB mechanical behavior was quantified using two speckle-tracking echocardiography-based indices, being systolic stretch index (SSI) and global myocardial wasted work (GWW). Both indices positively correlate with the mechanical interaction between septal and lateral walls in typical LBBB as previously shown. CRT response was quantified as change of LV end-systolic volume (LVESV) at follow-up (12±6 months) relative to baseline. We used the CircAdapt computer model of the human heart and circulation to investigate the effects of eccentric remodeling and diastolic dysfunction (i.e. myocardial stiffening) on SSI and GWW in virtual hearts with a constant LBBB-like septal-to-lateral conduction delay, i.e. a 25-ms and 75-ms mechanical activation delay of the septum and LV free wall with respect to the right ventricular free wall. Results Before CRT, patients with non-eLAP showed more typical LBBB mechanical behavior (Fig. 1), as suggested by higher SSI and higher GWW compared to patients with non-eLAP (SSI: 4.6±3.2 vs 3.4±3.5 %, P=0.02, GWW: 368±131 vs 309±127 mmHg*%, P=0.03). At follow-up, patients with eLAP showed significantly less LV reverse remodeling compared to patients with non-eLAP (relative decrease of LVESV: 30±26% vs 46±34 P=0.001). Our simulations (Fig. 2) revealed that eccentric remodeling amplifies mechanical dyssynchrony, characterized by increased septal rebound stretch (second row) and increased wasted work (third and bottom rows), while LAP remained normal (top row). In contrast, increasing myocardial stiffness led to elevated LAP (top row), but a pronounced reduction of mechanical dyssynchrony (second, third and bottom rows). Conclusion The presented combination of clinical data and virtual patient simulations revealed that diastolic dysfunction, in particular myocardial stiffening, inhibits mechanical dyssynchrony induced by LBBB. In contrast, eccentric remodeling amplifies the LBBB mechanical substrate. These data further explain why baseline dyssynchrony measures like septal rebound stretch and wasted work are well associated with reverse remodeling and clinical outcome after CRT.

The clinical profile of individuals with symptoms of knee osteoarthritis referred to secondary care in Denmark: Across-sectional study of 282 people.

The clinical profile of individuals with symptoms of knee osteoarthritis referred to secondary care in Denmark: Across-sectional study of 282 people.