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Background: The DAWN antivirals trial was a multicentric, randomised placebo-controlled trial evaluating antiviral medication for COVID-19 in general practice. The trial was prematurely terminated because of insufficient recruitment. Aim: To explore which factors contributed to the premature termination. Design & setting: General practice in Belgium. Method: Patients were randomised to camostat or placebo (patients and physicians blinded) between June 2021 and July 2022; a third arm evaluating molnupiravir (open label) was opened in March 2022. The outcome assessor was blinded for all comparisons except for the patient reported outcomes in case of molnupiravir. The authors analysed available trial data and evaluated trial context, implementation, and mechanisms of impact based on semi-structured interviews with trial stakeholders. Results: The trial recruited 44 participants; 19 were allocated to camostat (median age 55 years), 8 to molnupiravir (median age 60 years), and 17 to placebo (median age 56 years). There were no serious adverse events in either group. Most difficulties were related to the pandemic context: disruption to routine clinical services; multiple changes to the service model for COVID-19 patients; overwhelmed clinical staff; delays of trial medication; and staff shortages in the sponsor and clinical team. In addition, regulatory approval processes were lengthy and led to additional study procedures. It was felt that the trial started too late, when vaccinations had already begun. Conclusion: The DAWN antivirals trial was stopped prematurely. Although many barriers were related to the pandemic itself, hurdles such as a small and inexperienced sponsor and clinical teams, delays in regulatory processes, and research capacity in routine settings could be overcome by established research infrastructure and standardisation of processes.

Introduction Although sexual health has been holistically defined to include sexual satisfaction, it has been largely absent in health services and sexual and reproductive health and rights programmes in many parts of the world. We propose sexual satisfaction as a useful indicator, as one of the proxy measures for sexual health and well-being and as a component of well-being in general.Methods The Sialon II project is a multicentre biological and behavioural cross-sectional community-based survey implemented across 13 European cities during 2013–2014 among men who have sex with men. Sexual satisfaction was explored using one single item: ‘How satisfied are you with your sex life?’ A multivariable multilevel logistic random-intercept model was estimated to identify factors associated with reporting positive sexual satisfaction versus negative sexual satisfaction.Results Age, the number of partners and self-reported HIV status were not significantly associated with sexual satisfaction in the multivariate model. Participants reporting an insertive role or reported both an insertive and receptive role during the last anal intercourse were more likely to be sexually satisfied, compared with a receptive role. Participants reporting anal intercourse with a condom were more likely to be satisfied than those declaring no anal intercourse in the last 6 months, but no significant association was found compared with anal intercourse without condom. Knowledge of HIV-serostatus concordance with the last sexual partner was positively correlated with sexual satisfaction. Having had sexual intercourse with non-steady partners only in the last 6 months was negatively correlated. The more positive participants perceived their work/school, parents and friends/acquaintances’ attitudes towards gay or bisexual persons, the higher the odds they were satisfied with their sexual life.Conclusion Using a single item on sexual satisfaction in a bio-behavioural study, our analysis has shown that it is associated with individual, interpersonal and social/structural factors and has proven its usefulness as a sexual health indicator among men who have sex with men.

Abstract Background A previous individual participant data meta-analysis (IPD-MA) of antibiotics for adults with clinically diagnosed acute rhinosinusitis (ARS) showed a marginal overall effect of antibiotics, but was unable to identify patients that are most likely to benefit from antibiotics when applying conventional (i.e. univariable or one-variable-at-a-time) subgroup analysis. We updated the systematic review and investigated whether multivariable prediction of patient-level prognosis and antibiotic treatment effect may lead to more tailored treatment assignment in adults presenting to primary care with ARS. Methods An IPD-MA of nine double-blind placebo-controlled trials of antibiotic treatment (n=2539) was conducted, with the probability of being cured at 8–15 days as the primary outcome. A logistic mixed effects model was developed to predict the probability of being cured based on demographic characteristics, signs and symptoms, and antibiotic treatment assignment. Predictive performance was quantified based on internal-external cross-validation in terms of calibration and discrimination performance, overall model fit, and the accuracy of individual predictions. Results Results indicate that the prognosis with respect to risk of cure could not be reliably predicted (c-statistic 0.58 and Brier score 0.24). Similarly, patient-level treatment effect predictions did not reliably distinguish between those that did and did not benefit from antibiotics (c-for-benefit 0.50). Conclusions In conclusion, multivariable prediction based on patient demographics and common signs and symptoms did not reliably predict the patient-level probability of cure and antibiotic effect in this IPD-MA. Therefore, these characteristics cannot be expected to reliably distinguish those that do and do not benefit from antibiotics in adults presenting to primary care with ARS.

AbstractBackground Nursing home residents (NHR) and staff have been disproportionally affected by the COVID-19 pandemic and were therefore prioritised in the COVID-19 vaccination strategy. However, frail older adults, like NHR, are known to have decreased antibody responses upon vaccination targeting other viral antigens.Objectives As real-world data on vaccine responsiveness, we assessed the prevalence of SARS-CoV-2 antibodies among Belgian NHR and staff during the primary COVID-19 vaccination campaign.Methods In total, we tested 1629 NHR and 1356 staff across 69 Belgian NHs for the presence of SARS-CoV-2 IgM/IgG antibodies using rapid tests. We collected socio-demographic and COVID-19-related medical data through questionnaires. Sampling occurred between 1 February and 24 March 2021, in a randomly sampled population that received none, one or two BNT162b2 vaccine doses.Results We found that during the primary vaccination campaign with 59% of the study population fully vaccinated, 74% had SARS-CoV-2 antibodies. Among fully vaccinated individuals only, fewer residents tested positive for SARS-CoV-2 antibodies (77%) than staff (98%), suggesting an impaired vaccine-induced antibody response in the elderly, with lowest seroprevalences observed among infection naïve residents. COVID-19 vaccination status and previous SARS-CoV-2 infection were predictors for SARS-CoV-2 seropositivity. Alternatively, age ≥ 80 years old, the presence of comorbidities and high care dependency predicted SARS-CoV-2 seronegativity in NHR.Conclusion These findings highlight the need for further monitoring of SARS-CoV-2 immunity upon vaccination in the elderly population, as their impaired humoral responses could imply insufficient protection against COVID-19.Trial registration This study was retrospectively registered on ClinicalTrials.gov (NCT04738695).

Background Long-term use of antidepressant drugs (AD), much longer than recommended by guidelines, in nursing homes (NH) is common. NH home residents may have a relatively higher risk of adverse events. Moreover, in an NH setting nursing staff and relatives are intensively involved in the decision-making process. In many countries, General Practitioners’ (GPs) provide care for residents in NHs. Little is known about GPs’ perspectives on discontinuation of long-term AD in NH residents.Objectives To explore GPs’ views of discontinuing long-term AD in NH residents.Methods An exploratory qualitative study, with semi-structured interviews, was conducted with a purposive sample of 20 Belgian GPs. Interviews, conducted over six months in 2019, were analysed by thematic analysis.Results Twenty interviews were conducted until data saturation. The first theme, ‘reluctance to rock the boat: not worth taking the risk’, describes that GPs perceive discontinuation as an unpredictable risk without clear benefits. GPs’ main concern was the risk of destabilising the fragile balance in an older patient. Second, ‘it takes at least three to tango’, captures the unspoken alliance between GPs, nursing staff and relatives and suggests that agreement of at least these three partners is required. The third, ‘Opening the door: triggers to discontinue’, points to severe health problems and dementia as strong facilitators for discontinuation.Conclusion Discontinuation of long-term AD in NHs is a complex process for GPs. More evidence and attention to the role nursing staff and relatives play are needed to better guide the discontinuation of AD in older NH patients.

BackgroundThe COVID-19 pandemic brought global disruption to health, society and economy, including to the conduct of clinical research. In the European Union (EU), the legal and ethical framework for research is complex and divergent. Many challenges exist in relation to the interplay of the various applicable rules, particularly with respect to compliance with the General Data Protection Regulation (GDPR). This study aimed to gain insights into the experience of key clinical research stakeholders [investigators, ethics committees (ECs), and data protection officers (DPOs)/legal experts working with clinical research sponsors] across the EU and the UK on the main challenges related to data protection in clinical research before and during the pandemic.Materials and methodsThe study consisted of an online survey and follow-up semi-structured interviews. Data collection occurred between April and December 2021. Survey data was analyzed descriptively, and the interviews underwent a framework analysis.Results and conclusionIn total, 191 respondents filled in the survey, of whom fourteen participated in the follow-up interviews. Out of the targeted 28 countries (EU and UK), 25 were represented in the survey. The majority of stakeholders were based in Western Europe. This study empirically elucidated numerous key legal and ethical issues related to GDPR compliance in the context of (cross-border) clinical research. It showed that the lack of legal harmonization remains the biggest challenge in the field, and that it is present not only at the level of the interplay of key EU legislative acts and national implementation of the GDPR, but also when it comes to interpretation at local, regional and institutional levels. Moreover, the role of ECs in data protection was further explored and possible ways forward for its normative delineation were discussed. According to the participants, the pandemic did not bring additional legal challenges. Although practical challenges (for instance, mainly related to the provision of information to patients) were high due to the globally enacted crisis measures, the key problematic issues on (cross-border) health research, interpretations of the legal texts and compliance strategies remained largely the same.

BackgroundOwing to the infectious nature of COVID-19, alternative solutions, such as electronic informed consent (eIC), needed to be implemented to inform research participants about study-related information and to obtain their consent. This study aimed to investigate stakeholders’ experiences with alternative consenting methods as well as their views on any regulatory or legal guidelines for eIC implementation in clinical research. Results may serve as the cornerstone to rethink the informed consent process in clinical research.Materials and methodsThis study consisted of an online survey among three stakeholder groups across European Union (EU) Member States and the United Kingdom. The stakeholder groups included (i) investigators, (ii) data protection officers (DPOs) or legal experts working in the pharmaceutical industry, academia, and academic biobanks, and (iii) ethics committee (EC) members. Data collection occurred between April and December 2021. The data collected were analyzed using descriptive and inferential statistics.ResultsThe online survey was completed by 191 respondents, of whom 52% were investigators. Respondents were active in 24 out of the 27 EU Member States and the United Kingdom. The majority of each stakeholder group considered validated electronic methods moderately or extremely useful to re-consent previously enrolled research participants upon study amendments or to obtain consent from COVID-19 patients. Nevertheless, this exploratory survey identified that only 13% of DPOs/legal experts, 26% of investigators, and 41% of EC members had experience with eIC. In addition, results suggest that the legal acceptance of eIC across EU Member States and the United Kingdom is variable and that a definition of eIC, issued by national law or policy, is rarely available. The results also showed that the COVID-19 pandemic brought additional challenges to inform participants and to obtain their consent; for example, related to travel restrictions.ConclusionA number of alternative consenting methods were recommended, for example by the European Medicines Agency, to ensure clinical study continuation during the COVID-19 pandemic. Although stakeholders support the use of eIC in clinical research, it seems that the experience with eIC is low. To harmonize eIC practices as much as possible, further investments in multi-stakeholder, multi-national guidance are needed.

BackgroundRapid technological advancements are reshaping the conduct of clinical research. Electronic informed consent (eIC) is one of these novel advancements, allowing to interactively convey research-related information to participants and obtain their consent. The COVID-19 pandemic highlighted the importance of establishing a digital, long-distance relationship between research participants and researchers. However, the regulatory landscape in the European Union (EU) is diverse, posing a legal challenge to implement eIC in clinical research. Therefore, this study takes the necessary steps forward by providing an overview of the current regulatory framework in the EU, relevant to eIC.MethodsWe reviewed and analyzed the key EU regulations, such as the EU General Data Protection Regulation (GDPR) and the Clinical Trials Regulation (CTR). We investigated the legality of eIC in several EU Member States, Switzerland, and the United Kingdom. To this end, we contacted the medicines agencies of various countries to clarify the national requirements related to the implementation and use of eIC in clinical research. Our research was complemented by comparing the legal acceptance of eIC between the EU and the United States.ResultsIn the EU, a distinction must be made between eIC for participation in clinical research and eIC for processing the participants’ personal data, complying respectively with requirements laid down by the CTR and the GDPR. On a national level, countries were classified into three groups: (1) countries accepting and regulating the use of eIC, (2) countries accepting the use of eIC without explicitly regulating it, and (3) countries not accepting the use of eIC. As a result, the regulation of eIC through laws and guidelines shows a large variety among EU Member States, while in the United States, it is harmonized through the Code of Federal Regulations.ConclusionVarious requirements must be considered when implementing eIC in clinical research. Nevertheless, requirements across the EU Member States may differ significantly, whereas, in the United States, efforts have already been made to achieve a harmonized approach.

Background: The implementation of primary care for mental health is often insufficient, which leaves its mark on staff. A team-based approach of mental healthcare prevents poor staff morale. A community health centre (CHC), therefore, set up a project promoting interprofessional collaboration with a mental health team (MHT). Objectives: This study aimed to understand how an MHT would influence staff morale in a primary care setting, aiming to formulate some recommendations for future projects. Methods: In 2017, interviews and a focus group discussion were conducted among the staff of a CHC. Using a qualitative approach, we aimed to unravel contextual factors and mechanisms that determine the effect of an MHT on staff morale. Results: The project relieved the burden of the patient encounters and staff members felt more valuable to patients. Underlying mechanisms were recognition, altered attitudes towards patients and role clarity. Facilitating factors were intercultural care mediators and a positive team atmosphere, whereas inhibiting factors were inefficient time management and communicative issues. Conclusion: Our study elucidated mechanisms and the contextual factors by which an MHT in general practice improves staff morale. KEY MESSAGES An MHT improves staff morale in a CHC, through nurturing recognition, through altering staff members' attitudes and through ensuring role clarity. Pitfalls are inefficient time management and poor communication. Policymakers should stimulate interprofessional collaboration in primary mental health.

Abstract Background Inappropriate laboratory test ordering poses an important burden for healthcare. Clinical decision support systems (CDSS) have been cited as promising tools to improve laboratory test ordering behavior. The objectives of this study were to evaluate the effects of an intervention that integrated a clinical decision support service into a computerized physician order entry (CPOE) on the appropriateness and volume of laboratory test ordering, and on diagnostic error in primary care. Methods This study was a pragmatic, cluster randomized, open-label, controlled clinical trial. Setting Two hundred eighty general practitioners (GPs) from 72 primary care practices in Belgium. Patients Patients aged ≥ 18 years with a laboratory test order for at least one of 17 indications: cardiovascular disease management, hypertension, check-up, chronic kidney disease (CKD), thyroid disease, type 2 diabetes mellitus, fatigue, anemia, liver disease, gout, suspicion of acute coronary syndrome (ACS), suspicion of lung embolism, rheumatoid arthritis, sexually transmitted infections (STI), acute diarrhea, chronic diarrhea, and follow-up of medication. Interventions The CDSS was integrated into a computerized physician order entry (CPOE) in the form of evidence-based order sets that suggested appropriate tests based on the indication provided by the general physician. Measurements The primary outcome of the ELMO study was the proportion of appropriate tests over the total number of ordered tests and inappropriately not-requested tests. Secondary outcomes of the ELMO study included diagnostic error, test volume, and cascade activities. Results CDSS increased the proportion of appropriate tests by 0.21 (95% CI 0.16–0.26, p < 0.0001) for all tests included in the study. GPs in the CDSS arm ordered 7 (7.15 (95% CI 3.37–10.93, p = 0.0002)) tests fewer per panel. CDSS did not increase diagnostic error. The absolute difference in proportions was a decrease of 0.66% (95% CI 1.4% decrease–0.05% increase) in possible diagnostic error. Conclusions A CDSS in the form of order sets, integrated within the CPOE improved appropriateness and decreased volume of laboratory test ordering without increasing diagnostic error. Trial registration ClinicalTrials.gov Identifier: NCT02950142 , registered on October 25, 2016

In the context of host-pathogen interactions, gram-negative bacterial virulence factors, such as effectors, may be transferred from bacterial to eukaryotic host cytoplasm by multicomponent Type III protein secretion systems (T3SSs). Central to Salmonella enterica serovar Typhimurium (S. Typhimurium) pathogenesis is the secretion of over 40 effectors by two T3SSs encoded within pathogenicity islands SPI-1 and SPI-2. These effectors manipulate miscellaneous host cellular processes, such as cytoskeleton organization and immune signaling pathways, thereby permitting host colonization and bacterial dissemination. Recent research on effector biology provided mechanistic insights for some effectors. However, for many effectors, clearly defined roles and host target repertoires—further clarifying effector interconnectivity and virulence networks—are yet to be uncovered. Here we demonstrate the utility of the recently described viral-like particle trapping technology Virotrap as an effective approach to catalog S. Typhimurium effector-host protein complexes (EH-PCs). Mass spectrometry-based Virotrap analysis of the novel E3 ubiquitin ligase SspH2 previously shown to be implicated in modulating actin dynamics and immune signaling, exposed known host interactors PFN1 and−2 besides several putative novel, interconnected host targets. Network analysis revealed an actin (-binding) cluster among the significantly enriched hits for SspH2, consistent with the known localization of the S-palmitoylated effector with actin cytoskeleton components in the host. We show that Virotrap complements the current state-of-the-art toolkit to study protein complexes and represents a valuable means to screen for effector host targets in a high-throughput manner, thereby bridging the knowledge gap between effector-host interplay and pathogenesis.

Abstract Background Laboratory testing is an important clinical act with a valuable role in screening, diagnosis, management and monitoring of diseases or therapies. However, inappropriate laboratory test ordering is frequent, burdening health care spending and negatively influencing quality of care. Inappropriate tests may also result in false-positive results and potentially cause excessive downstream activities. Clinical decision support systems (CDSSs) have shown promising results to influence the test-ordering behaviour of physicians and to improve appropriateness. Order sets, a form of CDSS where a limited set of evidence-based tests are proposed for a series of indications, integrated in a computerised physician order entry (CPOE) have been shown to be effective in reducing the volume of ordered laboratory tests but convincing evidence that they influence appropriateness is lacking. The aim of this study is to evaluate the effect of order sets on the quality and quantity of laboratory test orders by physicians. We also aim to evaluate the effect of order sets on diagnostic error and explore the effect on downstream or cascade activities. Methods We will conduct a cluster randomised controlled trial in Belgian primary care practices. The study is powered to measure two outcomes. We will primarily measure the influence of our CDSS on the appropriateness of laboratory test ordering. Additionally, we will also measure the influence on diagnostic error. We will also explore the effects of our intervention on cascade activities due to altered results of inappropriate tests. Discussion We have designed a study that should be able to demonstrate whether the CDSS aimed at diagnostic testing is not only able to influence appropriateness but also safe with respect to diagnostic error. These findings will influence a lager, nationwide implementation of this CDSS. Trial registration ClinicalTrials.gov, NCT02950142 .

Background/Aims: A large proportion of men with normal sperm results as analyzed using conventional techniques have fragmented DNA in their spermatozoa. We performed a prospective study to examine the incidence of DNA fragmentation in sperm in cases of couples with previously unexplained infertility and treated with intra-uterine insemination. We evaluated whether there was any predictive value of DNA fragmentation for pregnancy outcome in such couples.Methods: The percentage of DNA fragmentation and all classical variables to evaluate sperm before and after sperm treatment were determined. We studied the probable association between these results and pregnancy outcome in terms of clinical and ongoing pregnancy rate per started first cycle. We also assessed the optimal threshold level to diagnose DNA fragmentation in our center.Results: When using threshold levels of 20%, 25%, and 30%, the occurrence of DNA fragmentation was 42.9%, 33.3%, and 28.6%, respectively. Receiver operating characteristic (ROC) analysis of all cases revealed an area under the curve (AUC) of 80% to predict the clinical pregnancy rate per cycle from testing the sperm motility (a+b) before treatment. We failed to generate an ROC curve to estimate pregnancy outcome from the amount of DNA fragmentation before treatment. However, when selecting only those men with a pre-treatment DNA fragmentation of at least 20%, the pre-treatment result was statistically different between couples who achieved a clinical pregnancy and those who did not.Conclusion: DNA fragmentation is often diagnosed in couples with unexplained infertility. Each center should evaluate the type of test it uses to detect DNA fragmentation in sperm and determine its own threshold values.

Abstract Background Self-management support is seen as a cornerstone of good diabetes care and many countries are currently engaged in initiatives to integrate self-management support in primary care. Concerning the organisation of these programs, evidence is growing that engagement of health care professionals, in particular of GPs, is critical for successful application. This paper reports on a study exploring why a substantial number of GPs was (initially) reluctant to refer patients to a self-management education program in Belgium. Methods Qualitative analysis of semi-structured face-to-face interviews with a purposive sample of 20 GPs who were not regular users of the service. The Greenhalgh diffusion of innovation framework was used as background and organising framework. Results Several barriers, linked to different components of the Greenhalgh model, emerged from the interview data. One of the most striking ones was the limited readiness for innovation among GPs. Feelings of fear of further fragmentation of diabetes care and frustration and insecurity regarding their own role in diabetes care prevented them from engaging in the innovation process. GPs needed time to be reassured that the program respects their role and has an added value to usual care. Once GPs considered referring patients, it was not clear enough which of their patients would benefit from the program. Some GPs expressed the need for training in motivational skills, so that they could better motivate their patients to participate. A practical but often mentioned barrier was the distance to the centre where the program was delivered. Further, uncertainty about continuity interfered with the uptake of the offer. Conclusions The study results contribute to a better understanding of the reasons why GPs hesitate to refer patients to a self-management education program. First of all, the role of GPs and other health care providers in diabetes care needs to be clarified before introducing new functions. Feelings of security and a basic trust of providers in the health system are a prerequisite for participation in care innovation. Moreover, some important lessons regarding the implementation of an education program in primary care have been learned from the study.

Abstract Background Clinical guidelines are intended to improve healthcare. However, even if guidelines are excellent, their implementation is not assured. In subfertility care, the European Society of Human Reproduction and Embryology (ESHRE) guidelines have been inventoried, and their methodological quality has been assessed. To improve the impact of the ESHRE guidelines and to improve European subfertility care, it is important to optimise the implementability of guidelines. We therefore investigated the implementation barriers of the ESHRE guideline with the best methodological quality and evaluated the used instrument for usability and feasibility. Methods We reviewed the ESHRE guideline for the diagnosis and treatment of endometriosis to assess its implementability. We used an electronic version of the guideline implementability appraisal (eGLIA) instrument. This eGLIA tool consists of 31 questions grouped into 10 dimensions. Seven items address the guideline as a whole, and 24 items assess the individual recommendations in the guideline. The eGLIA instrument identifies factors that influence the implementability of the guideline recommendations. These factors can be divided into facilitators that promote implementation and barriers that oppose implementation. A panel of 10 experts from three European countries appraised all 36 recommendations of the guideline. They discussed discrepancies in a teleconference and completed a questionnaire to evaluate the ease of use and overall utility of the eGLIA instrument. Results Two of the 36 guideline recommendations were straightforward to implement. Five recommendations were considered simply statements because they contained no actions. The remaining 29 recommendations were implementable with some adjustments. We found facilitators of the guideline implementability in the quality of decidability, presentation and formatting, apparent validity, and novelty or innovation of the recommendations. Vaguely defined actions, lack of facilities, immeasurable outcomes, and inflexibility within the recommendations formed barriers to implementation. The eGLIA instrument was generally useful and easy to use. However, assessment with the eGLIA instrument is very time-consuming. Conclusions The ESHRE guideline for the diagnosis and treatment of endometriosis could be improved to facilitate its implementation in daily practice. The eGLIA instrument is a helpful tool for identifying obstacles to implementation of a guideline. However, we recommend a concise version of this instrument.