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Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

(1) Background: infective endocarditis (IE) is a significant health concern associated with important morbidity and mortality. Only limited, often monocentric, retrospective data on IE in Belgium are available. This prospective study sought to assess the clinical characteristics and outcomes of Belgian IE patients in the ESC EORP European endocarditis (EURO-ENDO) registry; (2) Methods: 132 IE patients were identified based on the ESC 2015 criteria and included in six tertiary hospitals in Belgium; (3) Results: The average Belgian IE patient was male and 62.8 ± 14.9 years old. The native valve was most affected (56.8%), but prosthetic/repaired valves (34.1%) and intracardiac device-related (5.3%) IE are increasing. The most frequently identified microorganisms were S. aureus (37.2%), enterococci (15.5%), and S. viridans (15.5%). The most frequent complications were acute renal failure (36.2%) and embolic events (23.6%). Cardiac surgery was effectively performed when indicated in 71.7% of the cases. In-hospital mortality occurred in 15.7% of patients. Predictors of mortality in the multivariate analysis were S. aureus (HR = 2.99 [1.07–8.33], p = 0.036) and unperformed cardiac surgery when indicated (HR = 19.54 [1.91–200.17], p = 0.012). (4) Conclusion: This prospective EURO-ENDO ancillary analysis provides valuable contemporary insights into the profile, treatment, and clinical outcomes of IE patients in Belgium., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Primary care is a critical partner for antimicrobial stewardship efforts given its high human antibiotic usage. Peer comparison audit and feedback (A&F) is often used to reduce inappropriate antibiotic prescribing. The design and implementation of A&F may impact its effectiveness. There are no best practice guidelines for peer comparison A&F in antibiotic prescribing in primary care. Objective To develop best practice guidelines for peer comparison A&F for antibiotic prescribing in primary care in high income countries by leveraging international expertise via the Joint Programming Initiative on Antimicrobial Resistance—Primary Care Antibiotic Audit and Feedback Network. Methods We used a modified Delphi process to achieve convergence of expert opinions on best practice statements for peer comparison A&F based on existing evidence and theory. Three rounds were performed, each with online surveys and virtual meetings to enable discussion and rating of each best practice statement. A five-point Likert scale was used to rate consensus with a median threshold score of 4 to indicate a consensus statement. Results The final set of guidelines include 13 best practice statements in four categories: general considerations (n = 3), selecting feedback recipients (n = 1), data and indicator selection (n = 4), and feedback delivery (n = 5). Conclusion We report an expert-derived best practice recommendations for designing and evaluating peer comparison A&F for antibiotic prescribing in primary care. These 13 statements can be used by A&F designers to optimize the impact of their quality improvement interventions, and improve antibiotic prescribing in primary care., BACKGROUND: Primary care is a critical partner for antimicrobial stewardship efforts given its high human antibiotic usage. Peer comparison audit and feedback (A&F) is often used to reduce inappropriate antibiotic prescribing. The design and implementation of A&F may impact its effectiveness. There are no best practice guidelines for peer comparison A&F in antibiotic prescribing in primary care. OBJECTIVE: To develop best practice guidelines for peer comparison A&F for antibiotic prescribing in primary care in high income countries by leveraging international expertise via the Joint Programming Initiative on Antimicrobial Resistance-Primary Care Antibiotic Audit and Feedback Network. METHODS: We used a modified Delphi process to achieve convergence of expert opinions on best practice statements for peer comparison A&F based on existing evidence and theory. Three rounds were performed, each with online surveys and virtual meetings to enable discussion and rating of each best practice statement. A five-point Likert scale was used to rate consensus with a median threshold score of 4 to indicate a consensus statement. RESULTS: The final set of guidelines include 13 best practice statements in four categories: general considerations (n = 3), selecting feedback recipients (n = 1), data and indicator selection (n = 4), and feedback delivery (n = 5). CONCLUSION: We report an expert-derived best practice recommendations for designing and evaluating peer comparison A&F for antibiotic prescribing in primary care. These 13 statements can be used by A&F designers to optimize the impact of their quality improvement interventions, and improve antibiotic prescribing in primary care.

Background Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries. Methods Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed. Results The healthcare payers' expected ICERs of oseltamivir were euro22,459 per QALY gained in adults/adolescents and euro13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is euro8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged euro1-euro35 per patient). Conclusion Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained > euro22,459) and cost-saving in adults/adolescents from a societal perspective.

The last years have seen an increase in Man-at-the-End (MATE) attacks against software applications, both in number and severity. However, software protection, which aims at mitigating MATE attacks, is dominated by fuzzy concepts and security-through-obscurity. This paper presents a rationale for adopting and standardizing the protection of software as a risk management process according to the NIST SP800-39 approach. We examine the relevant constructs, models, and methods needed for formalizing and automating the activities in this process in the context of MATE software protection. We highlight the open issues that the research community still has to address. We discuss the benefits that such an approach can bring to all stakeholders. In addition, we present a Proof of Concept (PoC) decision support system that instantiates many of the discussed construct, models, and methods and automates many activities in the risk analysis methodology for the protection of software. Despite being a prototype, the PoC's validation with industry experts indicated that several aspects of the proposed risk management process can already be formalized and automated with our existing toolbox and that it can actually assist decision-making in industrially relevant settings., Comment: Preprint submitted to Computers & Security. arXiv admin note: substantial text overlap with arXiv:2011.07269

Study Objectives: International guidelines recommend using benzodiazepine receptor agonists (BZRA) for maximally four weeks. Nevertheless, long-term use for chronic insomnia disorder remains a common practice. This study aimed to test the effectiveness of blended care for discontinuing long-term BZRA use in general practice. Methods: A pragmatic cluster randomized controlled superiority trial compared blended care to usual care through urine toxicology screening. In the intervention, care by the general practitioner (GP) was complemented by an interactive e-learning program, based on cognitive behavioral therapy for insomnia. Adults using BZRA daily for minimally 6 months were eligible. Participants were clustered at the level of the GP surgery for allocation (1:1). Effectiveness was measured as the proportion of patients who had discontinued at one-year follow-up. Data analysis followed intention-to-treat principles. Results: In total, 916 patients in 86 clusters, represented by 99 GPs, were randomized. Primary outcome data was obtained from 727 patients (79%). At one-year follow-up, 82 patients (18%) in blended care, compared to 91 patients (20%) in usual care, had discontinued. There was no statistically significant effect for the intervention (OR: 0.924; 95% CI: 0.60; 1.43). No adverse events were reported to the research team. Conclusions: The findings did not support the superiority of blended care over usual care. Both strategies showed clinical effectiveness, with an average of 19% of patients having discontinued at one-year follow-up. Further research is important to study the effect of structurally implementing digital interventions in general practice., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based on anecdotal evidence and expert opinions, due to a lack of solid data and prospective studies. As many questions remain unanswered, cardiac monitoring, in patients receiving ICIs, is not always implemented by oncologists. Hence, an urgent need to investigate the possible short- and long-term CV effects of ICIs, as ICI approval is continuing to expand to the (neo)adjuvant setting. Methods: We have initiated a prospective, multicenter study, i.e. the CAVACI trial, in which a minimum of 276 patients with a solid tumor, eligible for ICI treatment, will be enrolled. The study consists of routine investigations of blood parameters (troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, in particular) and a thorough CV follow-up (electrocardiograms, transthoracic echocardiograms, and coronary calcium scoring) at fixed time points for a total period of two years. The primary endpoint is the cumulative incidence of troponin elevation in the first three months of ICI treatment, compared to baseline levels. Furthermore, secondary endpoints include incidence above the upper limit of normal of both troponin and NT-proBNP levels, evolution in troponin and NT-proBNP levels, the incidence of CV abnormalities/major adverse cardiac events, evaluation of associations between patient characteristics/biochemical parameters and CV events, transthoracic echocardiography parameters, electrocardiography parameters, and progression of coronary atherosclerosis. Recruitment of patients started in January 2022. Enrolment is ongoing in AZ Maria Middelares, Antwerp University Hospital, AZ Sint-Vincentius Deinze, and AZ Sint-Elisabeth Zottegem. Trial registration: ClinicalTria, SCOPUS: ar.j, info:eu-repo/semantics/published

Man-at-the-end (MATE) attackers have full control over the system on which the attacked software runs, and try to break the confidentiality or integrity of assets embedded in the software. Both companies and malware authors want to prevent such attacks. This has driven an arms race between attackers and defenders, resulting in a plethora of different protection and analysis methods. However, it remains difficult to measure the strength of protections because MATE attackers can reach their goals in many different ways and a universally accepted evaluation methodology does not exist. This survey systematically reviews the evaluation methodologies of papers on obfuscation, a major class of protections against MATE attacks. For 571 papers, we collected 113 aspects of their evaluation methodologies, ranging from sample set types and sizes, over sample treatment, to performed measurements. We provide detailed insights into how the academic state of the art evaluates both the protections and analyses thereon. In summary, there is a clear need for better evaluation methodologies. We identify nine challenges for software protection evaluations, which represent threats to the validity, reproducibility, and interpretation of research results in the context of MATE attacks and formulate a number of concrete recommendations for improving the evaluations reported in future research papers.

In this chapter, we present a corpus study of the French rendition of English concatenated nouns, such as climate change, comparing two modes of interlingual mediation at the European Parliament, namely simultaneous interpreting and written translation. Using parallel corpus data extracted from the European Parliament Translation and Interpreting Corpus, we examine how frequently English concatenated nouns are rendered with semantically equivalent items in the two mediation modes, and which factors stimulate the use of these equivalent (vs non-equivalent) renditions. Alongside the complexity and lexicalization of English concatenated nouns, we consider several frequency-related variables inspired by Halverson’s (2017) cognitive linguistic model of translation, the gravitational pull hypothesis. The model posits three cognitive sources of translation effects: gravitational pull (source salience), connectivity (cross-linguistic link strength) and magnetism (target salience). The results show that there are far fewer semantically equivalent renditions in interpreting than in translation. In addition, the regression analysis provides strong evidence that connectivity and magnetism play a crucial role in the selection of semantically equivalent vs non-equivalent renditions in interpretations and translations, alongside the length of source concatenated nouns, with stronger effects in interpreting. By contrast, source-language variables related to gravitational pull and lexicalization do not seem to influence renditions in French. The study brings to the fore key commonalities between translation and interpreting and shows that the three cognitive sources in Halverson’s gravitational pull model can be successfully disentangled in a multifactorial research design.

Aims Patients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality. Methods and results We used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existing heart disease and in-hospital mortality. A total of 16 511 patients with COVID-19 were included (21.1% aged 66-75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male, and often had other comorbid conditions when compared with those without. Mortality was higher in patients with cardiac disease (29.7%; n= 1545 vs. 15.9%; n= 1797). However, following multivariable adjustment, this difference was not significant [adjusted risk ratio (aRR) 1.08, 95% confidence interval (CI) 1.02-1.15; P = 0.12 (corrected for multiple testing)]. Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure (aRR 1.19, 95% CI 1.10-1.30; P <0.018) particularly for severe (New York Heart Association class III/IV) heart failure (aRR 1.41, 95% CI 1.20-1.64; P < 0.018). None of the other heart disease subtypes, including ischaemic heart disease, remained significant after multivariable adjustment. Serious cardiac complications were diagnosed in <1% of patients. Conclusion Considerable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare during hospitalization. [GRAPHICS] .

357 p., ill., SCIENTIFIC REPORT 23 -- 1 INTRODUCTION 23 -- 1.1 OVARIAN CANCER 24 -- 1.1.1 Background 24 -- 1.1.2 Epidemiology of ovarian cancer in Belgium 24 -- 1.2 DISPERSION OF CARE FOR OVARIAN CANCER IN BELGIUM 25 -- 1.3 MEASURING QUALITY 26 -- 2 OBJECTIVES AND SCOPE 27 -- 2.1 AIM OF THE STUDY 27 -- 2.2 SCOPE 27 -- 2.3 TARGET AUDIENCE 27 -- 3 METHODOLOGY 28 -- 3.1 STEP 1: IDENTIFICATION OF THE TARGET POPULATION: DATA SELECTION AND LINKAGE OF DATABASES 28 -- 3.1.1 Selection of the study population in the Belgian Cancer Registry database 28 -- 3.1.2 Linkage with health insurance data 30 -- 3.1.3 Vital status 31 -- 3.1.4 Pathology reports 31 -- 3.1.5 Data unavailable for assessment of quality indicators 31 -- 3.2 STEP 2: IDENTIFICATION AND SELECTION OF POSSIBLE QUALITY INDICATORS 31 -- 3.2.1 Identification of possible quality indicators 31 -- 3.2.2 Selection process and results 31 -- 3.2.3 Measurability of selected quality indicators 32 -- 3.2.4 Final selection of quality indicators to be fully elaborated 32 -- 3.3 STEP 3: OPERATIONALIZATION OF INDICATORS 34 -- 3.3.1 Technical fiches 35 -- 3.3.2 Defining diagnostic and therapeutic procedures 35 -- 3.3.3 Defining the treatment scheme of the patient 41 -- 3.3.4 Case-mix adjustment 41 -- 3.3.5 Statistical analysis 44 -- 3.4 STEP 4: ASSIGNMENT OF EACH PATIENT TO ONE CENTRE 47 -- 3.5 STEP 5: VALIDATION OF DIAGNOSTIC AND THERAPEUTIC DATA 50 -- 3.5.1 Introduction and methodology 50 -- 3.5.2 Results of the validation of the algorithm to assign each patient to one centre of first diagnosis and one centre of main treatment 51 -- 3.5.3 Validation of the patient and tumour characteristics and of diagnostic and therapeutic procedures 52 -- 3.5.4 Validation of the quality indicator results 56 -- 3.5.5 Conclusion 56 -- 4 CHARACTERISTICS OF THE STUDY COHORT 56 -- 4.1 BASELINE DEMOGRAPHICS AND TUMOUR CHARACTERISTICS 57 -- 4.2 MAIN DIAGNOSTIC PROCEDURES 57 -- 4.3 MAIN THERAPEUTIC PROCEDURES 58 -- 4.3.1 Surgical procedures 58 -- 4.3.2 Chemotherapy

29 p., ill., Le Centre fédéral d’Expertise des Soins de santé (KCE) publie un ensemble de 15 indicateurs de qualité pour la prise en charge du cancer de l’ovaire. Cette démarche s’inscrit dans un processus continu d’amélioration de la qualité des soins en oncologie en Belgique et a déjà été appliquée avec fruit pour d’autres types de cancers. Les résultats des 15 indicateurs ont été calculés au niveau national, et tous les hôpitaux recevront ensuite un rapport d'évaluation individuel envoyé par la Fondation Registre du Cancer. Cela leur permettra d'identifier leurs points forts et leurs points faibles et d'améliorer leurs pratiques si nécessaire. Dans une seconde partie, l’étude a démontré que les chances de survie sont nettement plus élevées dans les hôpitaux qui traitent un grand nombre de patientes chaque année. Le KCE plaide donc pour une concentration de la prise en charge du cancer de l’ovaire dans un nombre limité de centres de référence. La reconnaissance de ces centres de référence ne doit cependant pas se baser sur le seul nombre de patientes traitées., PRÉFACE 1 -- MESSAGES CLÉS 2 -- 1. CONTEXTE ET OBJECTIFS 6 -- 1.1. LE SYSTÈME BELGE D’AMÉLIORATION DE LA QUALITÉ DES SOINS EN ONCOLOGIE 6 -- 1.2. LE CANCER DE L’OVAIRE 7 -- 1.3. OBJECTIFS DE CETTE ÉTUDE 7 -- 2. DONNÉES ET MÉTHODES 8 -- 2.1. IDENTIFICATION ET SÉLECTION DES INDICATEURS DE QUALITÉ 8 -- 2.2. POPULATION CIBLE DE CETTE ÉTUDE 8 -- 2.2.1. Sources de données 8 -- 2.2.2. Plus de 5 000 patientes incluses entre 2014 et 2018 9 -- 2.2.3. Traitements administrés 10 -- 2.2.4. Autres caractéristiques prises en compte 10 -- 2.2.5. Assignation de chaque patiente à un hôpital 10 -- 2.3. ÉTUDE DE VALIDATION 10 -- 3. RÉSULTATS DES INDICATEURS DE QUALITÉ 11 -- 3.1. DIAGNOSTIC ET STADIFICATION 13 -- 3.2. CHIMIOTHÉRAPIE 14 -- 3.3. COMPLICATIONS, MORTALITÉ ET SURVIE 15 -- 4. IMPACT DU VOLUME HOSPITALIER SUR LES RÉSULTATS 16 -- 4.1. GRANDE DISPERSION DES SOINS EN BELGIQUE 16 -- 4.2. RELATION ENTRE LE VOLUME HOSPITALIER DE PRISE EN CHARGE THÉRAPEUTIQUE ET LA SURVIE EN BELGIQUE 17 -- 4.3. RELATION ENTRE LE VOLUME CHIRURGICAL HOSPITALIER ET LA SURVIE EN BELGIQUE 18 -- 4.4. REVUE DE LITTÉRATURE INTERNATIONALE 18 -- 5. CONCLUSION 19 -- RECOMMANDATIONS 22 -- RÉFÉRENCES 26

29 p., ill., Het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) publiceert een set van 15 kwaliteitsindicatoren voor de behandeling van eierstokkanker. Dit maakt deel uit van een continu proces om de kwaliteit van de kankerzorg in België te verbeteren en is reeds met succes toegepast bij andere types kanker. De 15 indicatoren werden berekend voor alle ziekenhuizen, die een individueel feedbackrapport van de Stichting Kankerregister zullen ontvangen, zodat zij hun sterke en zwakke punten kunnen identificeren en waar nodig de zorg verbeteren. In een tweede deel toont de studie aan dat de kans van patiënten op overleven duidelijk hoger is in ziekenhuizen die elk jaar een groot aantal patiënten behandelen. Het KCE pleit er dan ook voor de behandeling van eierstokkanker in een beperkt aantal referentiecentra te concentreren. Bij de erkenning van deze referentiecentra mag het aantal behandelde patiënten zeker niet het enige criterium zijn., VOORWOORD 1 --  KERN-BOODSCHAPPEN 2 -- 1. CONTEXT EN DOELSTELLINGEN 7 -- 1.1. HET BELGISCH SYSTEEM TER VERBETERING VAN DE KWALITEIT VAN ZORG IN DE -- ONCOLOGIE 7 -- 1.2. EIERSTOKKANKER 8 -- 1.3. DOELSTELLINGEN VAN DEZE STUDIE 8 -- 2. GEGEVENS EN METHODEN 9 -- 2.1. IDENTIFICATIE EN SELECTIE VAN DE KWALITEITSINDICATOREN 9 -- 2.2. DOELPOPULATIE VAN DE STUDIE 9 -- 2.2.1. Gegevensbronnen 9 -- 2.2.2. Meer dan 5.000 patiënten in de studie opgenomen tussen 2014 en 2018 10 -- 2.2.3. Toegepaste behandelingen 11 -- 2.2.4. Andere kenmerken die in aanmerking werden genomen in de analyses 11 -- 2.2.5. Toewijzing van elke patiënte aan een ziekenhuis 11 -- 2.3. VALIDATIESTUDIE 12 -- 3. RESULTATEN VAN DE KWALITEITSINDICATOREN 12 -- 3.1. DIAGNOSE EN STADIËRING 14 -- 3.2. CHEMOTHERAPIE 16 -- 3.3. COMPLICATIES, STERFTE EN OVERLEVING 17 -- 4. INVLOED VAN HET ZIEKENHUISVOLUME OP DE RESULTATEN 18 -- 4.1. GROTE VERSNIPPERING VAN DE ZORG 18 -- 4.2. VERBAND TUSSEN HET ZIEKENHUISVOLUME VAN BEHANDELING EN DE OVERLEVING IN BELGIË 19 -- 4.3. VERBAND TUSSEN HET CHIRURGISCH VOLUME VAN HET ZIEKENHUIS EN DE OVERLEVING IN BELGIË 19 -- 4.4. LITERATUURSTUDIE 20 -- 5. CONCLUSIE 21 -- AANBEVELINGEN 24 -- REFERENTIES 28

37 p., ill., KEY MESSAGES 1 -- SHORT REPORT 3 -- 1. BACKGROUND 6 -- 1.1. QUALITY IMPROVEMENT INITIATIVES IN ONCOLOGY 6 -- 1.2. EPIDEMIOLOGY OF OVARIAN CANCER 6 -- 1.3. SCOPE 6 -- 1.4. AIM OF THE STUDY 7 -- 2. DATA AND METHODS 7 -- 2.1. IDENTIFICATION AND SELECTION OF QUALITY INDICATORS 7 -- 2.2. DATA SELECTION AND LINKAGE OF DATABASES 7 -- 2.3. DEFINITION OF SURGERY BASED ON PATHOLOGY REPORTS 8 -- 2.4. CASE-MIX ADJUSTMENT 8 -- 2.5. STATISTICAL ANALYSES 8 -- 2.6. ASSIGNMENT OF PATIENTS TO A CENTRE 9 -- 2.7. VALIDATION STUDY AND SUBSEQUENT DATA CHECKS 9 -- 3. QUALITY OF CARE FOR PATIENTS WITH EPITHELIAL OVARIAN CANCER 10 -- 3.1. BASELINE DEMOGRAPHICS AND TUMOUR CHARACTERISTICS 10 -- 3.2. MAIN THERAPEUTIC PROCEDURES 11 -- 3.3. RESULTS FOR 15 QUALITY INDICATORS 12 -- 3.3.1. Diagnosis and staging 14 -- 3.3.2. Treatment 16 -- 3.3.3. Safety of care – 30-day complicated recovery and mortality after surgery 18 -- 3.3.4. Survival after the diagnosis of epithelial ovarian cancer 19 -- 3.4. ASSOCIATION BETWEEN HOSPITAL VOLUME AND OUTCOMES 21 -- 3.4.1. Dispersion of care 21 -- 3.4.2. Hospital main treatment volume 22 -- 3.4.3. Hospital surgical volume 23 -- 3.4.4. Discussion 24 -- 4. STRENGTHS AND LIMITATIONS 25 -- 5. CONCLUSIONS AND PERSPECTIVES FOR THE FUTURE 27 -- RECOMMENDATIONS 30 -- REFERENCES 33

BACKGROUND: There is little evidence about the relation between aetiology, illness severity and clinical course of respiratory tract infections (RTI) in primary care. Understanding these associations would aid to develop effective management strategies for these infections.AIM: To investigate whether the clinical presentation and illness course differ between RTI in whom a viral pathogen was detected and those in whom a potential bacterial pathogen was found.DESIGN AND SETTING: Post hoc analysis of data from a pragmatic randomised trial on the effects of oseltamivir in patients with influenza-like illness (ILI) in primary care (n=3266) in 15 European countries.METHODS: Patient characteristics, signs and symptoms were registered at baseline. Naso-pharyngeal (adults) or nasal and pharyngeal (children) swabs were taken for PCR analysis. Patients were followed up until 28 days after inclusion. Regression models and Kaplan-Meier curves were used to analyse the relation between aetiology, clinical presentation at baseline and course of disease including complications.RESULTS: Except for a less prominent congested nose (OR 0.55, CI 0.35 - 0.86) and acute cough (OR 0.52, CI 0.27 - 0.65) in ILI patients in whom a possible bacterial pathogen was isolated, there were no clear clinical differences in presentations between those with a possible bacterial aetiology than in those with a viral one. Also the course of disease and complications were not related to aetiology.CONCLUSION: Given the currently available microbiological tests and antimicrobial treatments, and outside pandemics like COVID-19, microbiological testing in primary care patients with ILI seems to have limited value.

BACKGROUND: Clinical findings do not accurately predict laboratory diagnosis of influenza. Early identification of influenza is considered useful for proper management decisions in primary care.OBJECTIVE: We evaluated the diagnostic value of the presence and the severity of symptoms for the diagnosis of laboratory-confirmed influenza infection among adults presenting with influenza-like illness (ILI) in primary care.METHODS: Secondary analysis of patients with ILI who participated in a clinical trial from 2015 to 2018 in 15 European countries. Patients rated signs and symptoms as absent, minor, moderate, or major problem. A nasopharyngeal swab was taken for microbiological identification of influenza and other microorganisms. Models were generated considering (i) the presence of individual symptoms and (ii) the severity rating of symptoms.RESULTS: A total of 2,639 patients aged 18 or older were included in the analysis. The mean age was 41.8 ± 14.7 years, and 1,099 were men (42.1%). Influenza was microbiologically confirmed in 1,337 patients (51.1%). The area under the curve (AUC) of the model for the presence of any of seven symptoms for detecting influenza was 0.66 (95% confidence interval [CI]: 0.65-0.68), whereas the AUC of the symptom severity model, which included eight variables-cough, fever, muscle aches, sweating and/or chills, moderate to severe overall disease, age, abdominal pain, and sore throat-was 0.70 (95% CI: 0.69-0.72).CONCLUSION: Clinical prediction of microbiologically confirmed influenza in adults with ILI is slightly more accurate when based on patient reported symptom severity than when based on the presence or absence of symptoms.

Background: Several changes have led to general practitioners (GPs) working in a more differentiated setting today and being supported by other health professions. As practice changes, primary care specific continuing medical education (CME) may also need to adapt. By comparing different primary care specific CME approaches for GPs across Europe, we aim at identifying challenges and opportunities for future development. Methods: Narrative review assessing, analysing and comparing CME programs for general practitioners across different north-western European countries (UK, Norway, the Netherlands, Belgium (Flanders), Germany, Switzerland, and France). Templates containing detailed items across seven dimensions of country-specific CME were developed and used. These dimensions are role of primary care within the health system, legal regulations regarding CME, published aims of CME, actual content of CME, operationalisation, funding and sponsorship, and evaluation. Results: General practice specific CME in the countries under consideration are presented and comparatively analysed based on the dimensions defined in advance. This shows that each of the countries examined has different strengths and weaknesses. A clear pioneer cannot be identified. Nevertheless, numerous impulses for optimising future GP training systems can be derived from the examples presented. Conclusions: Independent of country specific CME programs several fields of potential action were identified: the development of curriculum objectives for GPs, the promotion of innovative teaching and learning formats, the use of synergies in specialist GP training and CME, the creation of accessible yet comprehensive learning platforms, the establishment of clear rules for sponsorship, the development of new financing models, the promotion of fair competition between CME providers, and scientifically based evaluation. Keywords: Continuing medical education; Curriculum; General practice; Narrative review; Program

This report documents the program and the outcomes of Dagstuhl Seminar 19331 ``Software Protection Decision Support and Evaluation Methodologies''. The seminar is situated in the domain of software protection against so-called man-at-the-end attacks, in which attackers have white-box access to the software that embeds valuable assets with security requirements such as confidentiality and integrity. The attackers try to compromise those by reverse-engineering the software and by tampering with it. Within this domain, the seminar focused mainly on three aspects: 1) how to evaluate newly proposed protections and attackers thereon; 2) how to create an appropriate benchmark suite to be used in such evaluations; 3) how to build decision support to aid users of protection tool with the selection of appropriate protections. The major outcomes are a structure for a white-paper on software protection evaluation methodologies, with some concrete input collected on the basis of four case studies explored during the seminar, and a plan for creating a software protection benchmark suite.

Background: Currently, many initiatives are devoted to optimizing informed consent for participation in clinical research. Due to the digital transformation in health care, a shift toward electronic informed consent (eIC) has been fostered. However, empirical evidence on how to implement eIC in clinical research involving neonates is lacking. Methods: Semi-structured interviews were conducted with 31 health care professionals active in Belgium or the Netherlands.

Man-At-The-End (MATE) attackers are almighty adversaries. Protecting programs' integrity is amongst the challenging problems in the context of MATE attackers. This thesis proposes new defenses and combinations (compositions) of protections to improve security and applicability. We conduct performance and security evaluations using a data set of real-world programs to evaluate our protections. Finally, we propose metrics to estimate the resilience of protections against state-of-the-art attacks., Man-at-the-End (MATE)-Angreifer sind mächtige Gegner. Der Schutz der Programmintegrität stellt hier eine große Herausforderung dar. Diese Arbeit soll mit Hilfe neuer Abwehrmechanismen und Kombinationen diverser Schutzmaßnahmen Wege aufzeigen, die Sicherheit und Anwendbarkeit zu verbessern. Um diese zu evaluieren, führen wir Leistungs- und Sicherheitsanalysen anhand von Programmdaten aus der realen Welt durch. Anschließend wird die Resilienz der Schutzmaßnahmen gegen gängige Angriffe gemessen.

The restoration of Nardus grasslands is often hampered by high bioavailability of soil phosphorus and disturbed soil communities. In order to better understand these bottlenecks, we studied Nardus grassland species grown together in communities with fast-growing species in 50-liter pots along a gradient of bioavailable phosphorus with or without inoculated soil biota. These mesocosms allowed the plants to freely interact, including competition for light and nutrients. We investigated changes in the plant community composition along the phosphorus gradient using Threshold Indicator Taxa Analysis (TITAN). We found a negative threshold of 11.5 mg POlsen kg−1 with six significant indicator plant species. Above the threshold, a small increase in phosphorus resulted in a disproportionally large drop in biomass for the indicator species, including four typical Nardus grassland species. The decline in these ‘oligotrophic indicator species’ was also linked to increasing plant community biomass, so we suggest the oligotrophic indicator species to be outcompeted for light by fast-growing plant species. We did not find an effect of the soil biota treatment on the biomass of the oligotrophic indicator species, but did observe a positive effect of inoculation with soil biota on the total biomass of the plant community. Interestingly, the threshold for the plant communities in the mesocosm experiment was comparable to the upper bioavailable phosphorus concentrations in remnant Nardus grasslands in northern Belgium. For the restoration of Nardus grasslands, such phosphorus-poor soil conditions appear to be essential, because the plant species that typically occur in these grasslands are able to handle nutrient limitation, but not light limitation.

L’hypercholestérolémie familiale est une maladie génétique fréquente mais souvent sous-diagnostiquée. Elle est pourtant facile à prendre en charge à condition de la dépister suffisamment précocement et de la traiter de manière appropriée. Nous présentons quelques outils pour la diagnostiquer. Chez un premier patient d'une famille encore inexplorée (patient-index), on utilisera le score DLCN (Dutch Lipid Clinic Network), suivi selon le cas d'une analyse génétique. Une fois le diagnostic confirmé chez ce patient, il sera facile de suspecter la maladie chez d'autres membres du 1er degré à partir d'une table de référence que nous présentons dans cet article. Cette table donne les seuils de concentrations de cholestérol LDL (selon l'âge et le sexe) à partir desquels il faut suspecter l’existence d’une hypercholestérolémie familiale chez un parent au 1er degré. Nous joignons également à cet article un modèle de lettre qui peut être adressé aux membres de cette famille pour éveiller leur attention sur l’existence de cette maladie et faciliter le travail de leur médecin généraliste. Familial hypercholesterolemia is a common, yet often underdiagnosed, genetic disease. Nevertheless, this condition is easily manageable provided that the disease is detected early enough and appropriately treated. Our article presents some diagnostic tools for this condition. In a first patient of an as yet unexplored family, referred to as the index patient, we propose to use the DLCN (Dutch Lipid Clinic Network) score, which should be followed by genetic analysis, depending on the case. Once the diagnosis has been confirmed in this index patient, the disease can easily be identified in other firstdegree relatives based on a reference table that has presented in this article. This table provides the threshold values of LDL cholesterol concentrations, according to age and gender, at which the existence of familial hypercholesterolemia in a first-degree relative should be suspected. To this artic

This doctoral thesis focuses on sexual self-esteem in women, which has been studied mainly in populations affected by specific problems (bulimia, etc.). Based on the analysis of the factors influencing female sexual self-esteem, the objective of this thesis is to propose a better understanding of the cognitive, bodily and societal factors involved in its genesis and maintenance. This thesis shows the importance of the subjective view that women have of their bodies and the impact of this view on their sexual self-esteem. It also highlights the impact of the mass media on the construction of body image. Through three researches, we studied the impact of physical satisfaction on women's sexual self-esteem as well as the elements on which it is based. Our different results have shown that « the relationship to the sexualized body » may be central to the conceptualization of women's sexual self-esteem. We constructed a new aggregate called the « Sexualized Body Perception » and then calculated its moderating and/or mediating effects on women's sexual self-esteem. Finally, we proceeded to the validation of this Sexualized Body Perception., (PSYE - Sciences psychologiques et de l'éducation) -- UCL, 2021

BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

Background: Currently, many initiatives are devoted to optimizing informed consent for participation in clinical research. Due to the digital transformation in health care, a shift toward electronic informed consent (eIC) has been fostered. However, empirical evidence on how to implement eIC in clinical research involving neonates is lacking. Methods: Semi-structured interviews were conducted with 31 health care professionals active in Belgium or the Netherlands. All health care professionals had experience in conducting clinical research involving neonates. Interviews were audio-recorded, transcribed and analyzed using the framework method. Results: Interviewees generally supported the use of eIC in clinical research involving neonates. For example, eIC could enable parents to receive study feedback via the eIC system. Requirements were expressed for parental involvement to decide on which feedback would be appropriate to return. Moreover, experts specialized in presenting information and designing electronic systems should be involved. Broad consensus among health care professionals indicates that the face-to-face-interaction between parents and the research team is vital to establish a relationship of trust. Therefore, it is necessary that the use of eIC runs alongside personal interactions with the parents. Concerns were raised about the accessibility of eIC to parents. For this reason, it was suggested that parents should always be given the possibility to read and sign a paper-based informed consent form or to use eIC. Conclusions: Health care professionals' views indicate that the use of eIC in clinical research with neonates may offer various opportunities. Further development and implementation will require a multi-stakeholder approach.

Although family physicians (FPs) are community-oriented primary care generalists and should be the entry point for the population’s interaction with the health system, they are underrepresented in research on the climate change, migration, and health(care) nexus (hereafter referred to as the nexus). Similarly, FPs can provide valuable insights into building capacity through integrating health-determining sectors for climate-resilient and migration-inclusive health systems, especially in Sub-Saharan Africa (SSA). Here, we explore FPs’ perceptions on the nexus in SSA and on intersectoral capacity building. Three focus groups conducted during the 2019 WONCA-Africa conference in Uganda were transcribed verbatim and analyzed using an inductive thematic approach. Participants’ perceived interactions related to (1) migration and climate change, (2) migration for better health and healthcare, (3) health impacts of climate change and the role of healthcare, and (4) health impacts of migration and the role of healthcare were studied. We coined these complex and reinforcing interactions as continuous feedback loops intertwined with socio-economic, institutional, and demographic context. Participants identified five intersectoral capacity-building opportunities on micro, meso, macro, and supra (international) levels: multi-dimensional and multi-layered governance structures; improving FP training and primary healthcare working conditions; health advocacy in primary healthcare; collaboration between the health sector and civil society; and more responsibilities for high-income countries. This exploratory study presents a unique and novel perspective on the nexus in SSA which contributes to interdisciplinary research agendas and FP policy responses on national, regional, and global levels., SCOPUS: ar.j, info:eu-repo/semantics/published

Back ground: Systematic reviews have concluded that hrHPV DNA testing using target-amplification tests is as accurate on vaginal self-samples as on clinician-taken specimens for the detection of cervical precancer. However, insufficient evidence is available for specific HPV assay/self-sample device combinations. Objectives: The VALHUDES protocol is designed as a diagnostic test accuracy study that aims to compare the clinical sensitivity and specificity of particular hrHPV assay(s) on vaginal self-samples and first-void-urine, collected in agreement with standardized protocols, with hrHPV testing on matched clinician-taken samples. Study design: Five hundred enrolled women referred to a colposcopy clinic are invited to collect a first-void urine sample and one or more vaginal self-samples with particular devices before collection of a cervical sample by a clinician. Sample sets are subsequently analysed in a laboratory accredited for HPV testing. Disease verification for all enrolled patients is provided by colposcopy combined with histological assessment of biopsies. Results: A first VALHUDES study has started in Belgium in December 2017 with enrolment from four colposcopy centres. The following assays are foreseen to be evaluated: RealTime High Risk HPV assay (Abbott), cobas-4800 and -6800 (Roche), Onclarity (BD), Xpert HPV (Cepheid) and Anyplex II HPV HR (Seegene). Conclusion: Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self-sample device combinations that can be translated to a primary screening setting

Aims Oral anticoagulants (OACs) are crucial for treating atrial fibrillation (AF) patients at high thromboembolic risk. However, in AF patients at intermediate thromboembolic risk with a single non-sex-related stroke risk factor (CHA 2 DS

BACKGROUND: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and sho

INTRODUCTION This study examines the effectiveness of integrating mindfulness-based techniques within therapy for women suffering to achieve orgasm. Although widely applied in psychotherapy, this approach has only recently been introduced in the treatment of female sexual dysfunction. AIM To compare the effectiveness of a video-based self-administered treatment, rooted within the cognitive behavioral treatment (CBT) framework, with a video-based self-administered mindfulness treatment applying cognitive behavioral sexual therapy (mindfulness-based cognitive therapy), the latter of which was specifically created to increase women's ability to achieve orgasm. METHODS A convenience sample of 65 women suffering from difficulties to achieve orgasm, aged 18 to 58 years (mean = 32.66, standard deviation = 9.48), were randomly allocated using a randomization procedure to either a mindfulness-based cognitive therapy (N = 35) or CBT (N = 30) group. Each participant completed questionnaires before and after the start of treatment and 2 months after its completion. MAIN OUTCOME MEASURE We applied repeated-measure general linear models to compare the 2 groups (ie, between participant factor) on each dependent variable across time (ie, the within-participant factor). Compare mean analyses for paired samples were only conducted when the interaction effect between condition and time was significant (ie, P <.05). RESULTS Statistical analyses show that women in both groups presented increased sexual functioning ( P = .001) and decreased sexual distress ( P < .001), as well as improved desire, arousal, orgasm, and sexual satisfaction ( P < .05) after their respective treatments. Contrary to our hypothesis, significant reductions in sexual pain were only observed in CBT participants. Clinical Implications To the best of our knowledge, this is the first study to apply a randomized allocation procedure to evaluate the effectiveness of a video-based mindfulness intervention for women stru

Debuggers are a popular reverse engineering and tampering tool. Self-debugging is an effective technique for applications to defend themselves against hostile debuggers. In penetration tests on state-of-the-art self-debugging, we observed several opportunities through which it could be attacked, however. We therefore improved upon the existing technique, making it more resilient by introducing reciprocal debugging and making the transfers of control between protected application and self-debugger more stealthy. This paper presents the improved self-debugging design, and details our research efforts into realizing reciprocal debugging. In our evaluation we show that the improved design is significantly harder for attackers to defeat., Comment: 10 pages, 2 figures

Software protection aims at safeguarding assets embedded in software by preventing and delaying reverse engineering and tampering attacks. This paper presents an architecture and supporting tool flow to renew parts of native applications dynamically. Renewed and diversified code and data belonging to either the original application or to linked-in protections are delivered from a secure server to a client on demand. This results in frequent changes to the software components when they are under attack, thus making attacks harder. By supporting various forms of diversification and renewability, novel protection combinations become available, and existing combinations become stronger. The prototype implementation is evaluated on a number of industrial use cases., Comment: 30 pages

To counter software reverse engineering or tampering, software obfuscation tools can be used. However, such tools to a large degree hard-code how the obfuscations are deployed. They hence lack resilience and stealth in the face of many attacks. To counter this problem, we propose the novel concept of flexible obfuscators, which implement protections in terms of data structures and APIs already present in the application to be protected. The protections are hence tailored to the application in which they are deployed, making them less learnable and less distinguishable. In our research, we concretized the flexible protection concept for opaque predicates. We designed an interface to enable the reuse of existing data structures and APIs in injected opaque predicates, we analyzed their resilience and stealth, we implemented a proof-of-concept flexible obfuscator, and we evaluated it on a number of real-world use cases. This paper presents an in-depth motivation for our work, the design of the interface, an in-depth security analysis, and a feasibility report based on our experimental evaluation. The findings are that flexible opaque predicates indeed provide strong resilience and improved stealth, but also that their deployment is costly, and that they should hence be used sparsely to protect only the most security-sensitive code fragments that do not dominate performance. Flexible obfuscation therefor delivers an expensive but also more durable new weapon in the ever ongoing software protection arms race., Comment: Submitted to ACM Transactions on Privacy and Security

The last years have seen an increase of Man-at-the-End (MATE) attacks against software applications, both in number and severity. However, MATE software protections are dominated by fuzzy concepts and techniques, with security-through-obscurity omnipresent in the field. This paper presents a rationale for adopting and standardizing the protection of software as a risk management process according to the NIST SP800-39 approach. We examine the relevant aspects of formalizing and automating the activities in this process in the context of MATE software protection. We highlight the open issues that the research community still has to address. We discuss the benefits that such an approach can bring to all stakeholders. In addition, we present a Proof of Concept (PoC) of a decision support system that automates many activities in the risk analysis methodology towards the protection of software applications. Despite still being a prototype, the PoC validation with industry experts indicated that several aspects of the proposed risk management process can already be formalized and automated with our existing toolbox, and that it can actually assist decision making in industrially relevant settings

General Matrix Multiplication or GEMM kernels take centre place in high performance computing and machine learning. Recent NVIDIA GPUs include GEMM accelerators, such as NVIDIA's Tensor Cores. Their exploitation is hampered by the two-language problem: it requires either low-level programming which implies low programmer productivity or using libraries that only offer a limited set of components. Because rephrasing algorithms in terms of established components often introduces overhead, the libraries' lack of flexibility limits the freedom to explore new algorithms. Researchers using GEMMs can hence not enjoy programming productivity, high performance, and research flexibility at once. In this paper we solve this problem. We present three sets of abstractions and interfaces to program GEMMs within the scientific Julia programming language. The interfaces and abstractions are co-designed for researchers' needs and Julia's features to achieve sufficient separation of concerns and flexibility to easily extend basic GEMMs in many different ways without paying a performance price. Comparing our GEMMs to state-of-the-art libraries cuBLAS and CUTLASS, we demonstrate that our performance is in the same ballpark of the libraries, and in some cases even exceeds it, without having to write a single line of code in CUDA C++ or assembly, and without facing flexibility limitations., Comment: This paper was submitted to IEEE TPDS

Background: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. Methodology: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. Results: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. Conclusion: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Informed consent is one of the key elements in biomedical research. The introduction of electronic informed consent can be a way to overcome many challenges related to paper-based informed consent; however, its novel opportunities remain largely unfulfilled due to several barriers. Objective: We aimed to provide an overview of the ethical, legal, regulatory, and user interface perspectives of multiple stakeholder groups in order to assist responsible implementation of electronic informed consent in biomedical research. Methods: We conducted a systematic literature search using Web of Science (Core collection), PubMed, EMBASE, ACM Digital Library, and PsycARTICLES. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were used for reporting this work. We included empirical full-text studies focusing on the concept of electronic informed consent in biomedical research covering the ethical, legal, regulatory, and user interface domains. Studies written in English and published from January 2010 onward were selected. We explored perspectives of different stakeholder groups, in particular researchers, research participants, health authorities, and ethics committees. We critically appraised literature included in the systematic review using the Newcastle-Ottawa scale for cohort and cross-sectional studies, Critical Appraisal Skills Programme for qualitative studies, Mixed Methods Appraisal Tool for mixed methods studies, and Jadad tool for randomized controlled trials. Results: A total of 40 studies met our inclusion criteria. Overall, the studies were heterogeneous in the type of study design, population, intervention, research context, and the tools used. Most of the studies' populations were research participants (ie, patients and healthy volunteers). The majority of studies addressed barriers to achieving adequate understanding when using electronic informed consent. Concerns shared by multiple stakeholder groups were rela

Introduction Problematic benzodiazepine use is a global health issue. Although the adverse side effects of long-term use of benzodiazepines are well known, it remains difficult to implement interventions for discontinuation in primary care. Considering the success of blended care for the treatment of sleeping disorders and the support of substance use disorders, evidence suggests that a blended care approach, combining face-to-face consultations with the general practitioner with web-based self-learning by the patient, is beneficial for the discontinuation of chronic benzodiazepine use for primary insomnia in general practice. Therefore, the aim of this study is to evaluate the effectiveness of such an approach for the discontinuation of benzodiazepine and zolpidem, zopiclone and zaleplon drugs ((z-)BZD) use in the long term and evaluate the implementation process. Methods and analysis This study is a multicentre, pragmatic, cluster randomised controlled trial with 1200 patients, included by 120 general practitioners. Allocation to usual or blended care happens at the level of the general practice in a 1:1 ratio using a block randomisation system stratified per language. The study population consists of adult primary care patients who have been using (z-)BZD for primary insomnia on a daily basis for at least 6 months. Primary outcome measure is the proportion of patients that discontinued (z-)BZD at 12 months assessed by toxicological screening for (z-)BZD in urine. Secondary outcomes include discontinuation of (z-)BZD at 6 months, quality of life and the number of defined daily doses of (z-)BZD prescribed. Data will be collected using a study-specific online platform and analysed using the intention-to-treat approach. The process of implementing blended care will be evaluated in a nested study. Ethics and dissemination This trial was approved by the Ethics Committee for Research of UZ/KU Leuven (ref. S61194). Study results will be disseminated via open-access, peer, SCOPUS: ar.j, info:eu-repo/semantics/published

Recent years have seen an increase of extracellular vesicle (EV) research geared towards biological understanding, diagnostics and therapy. However, EV data interpretation remains challenging owing to complexity of biofluids and technical variation introduced during sample preparation and analysis. To understand and mitigate these limitations, we generated trackable recombinant EV (rEV) as a biological reference material. Employing complementary characterization methods, we demonstrate that rEV are stable and bear physical and biochemical traits characteristic of sample EV. Furthermore, rEV can be quantified using fluorescence-, RNA- and protein-based technologies available in routine laboratories. Spiking rEV in biofluids allows recovery efficiencies of commonly implemented EV separation methods to be identified, intra-method and inter-user variability induced by sample handling to be defined, and to normalize and improve sensitivity of EV enumerations. We anticipate that rEV will aid EV-based sample preparation and analysis, data normalization, method development and instrument calibration in various research and biomedical applications