The molecular basis of atherosclerosis is not fully understood and mice studies have shown that Ephrins and EPH receptors play a role in the atherosclerotic process. We set out to assess the role for monocytic EPHB2 and its Ephrin ligands in human atherosclerosis and show a role for EPHB2 in monocyte functions independently of its EphrinB ligands. Immunohistochemical staining of human aortic sections at different stages of atherosclerosis showed that EPHB2 and its ligand EphrinB are expressed in atherosclerotic plaques and that expression proportionally increases with plaque severity. Functionally, stimulation with EPHB2 did not affect endothelial barrier function, nor did stimulation with EphrinB1 or EphrinB2 affect monocyte‐endothelial interactions. In contrast, reduced expression of EPHB2 in monocytes resulted in decreased monocyte adhesion to endothelial cells and a decrease in monocyte transmigration, mediated by an altered morphology and a decreased ability to phosphorylate FAK. Our results suggest that EPHB2 expression in monocytes results in monocyte accumulation by virtue of an increase of transendothelial migration, which can subsequently contribute to atherosclerotic plaque progression.

ObjectivesUrinary tract infections (UTIs) are the most prevalent cause for women to consult a general practitioner (GP) and are commonly treated with (broad-spectrum) empirical antibiotics, even though 50% of UTIs are self-limiting. In this study, we aim to explore women’s attitudes and experiences regarding UTIs, in order to determine patients’ willingness to accept delayed antibiotic prescriptions.DesignAn internet-based cross-sectional surveySettingWe recruited participants during 2 weeks of March and April in 2020 through several social media platforms.ParticipantsWe obtained 1476 responses, of which 975 were eligible for analysis.ResultsWe asked women about their knowledge, attitudes and practice regarding UTI-related symptoms. Participants ranked ‘confirmation of diagnosis’ (43.8%) as the most important reason to consult a GP with urinary symptoms, followed by ‘pain relief’ (32%), and ‘antibiotic prescription’ (14.3%). For treatment, 71% of participants reported that their GP prescribed immediate antibiotics, while only 3% received a delayed antibiotic prescription and 1% was advised pain medication. Furthermore, 50% of respondents were aware of the possible self-limiting course of UTIs and 70% would be willing to accept delayed antibiotic treatment, even if a certain diagnosis of UTI was established. Willingness to delay was lower in experienced patients compared to inexperienced patients.ConclusionsWomen are quite receptive to delayed antibiotics as an alternative to immediate antibiotics for UTIs or urinary symptoms. GPs should consider discussing delayed antibiotic treatment more often with women presenting with urinary symptoms.

Urinary tract infections (UTIs) are the most common reason for women to consult a general practitioner (GP). While UTIs are self-limiting in half of cases, most women are prescribed antibiotics, often in discordance with established guidelines. Researchers have employed different interventions to improve GPs’ prescribing behavior, especially for respiratory infections, but it is uncertain whether these are effective for UTI care. Therefore, we performed a systematic review, including (cluster) randomized clinical trials investigating the effect of interventions targeted at GPs to improve antibiotic prescriptions for UTI. From September to December 2021 we searched the Medline, Web of Science, and CENTRAL databases, ultimately including ten studies describing eleven trials. We determined the effect of the interventions on the decision to prescribe and on the choice of antibiotic. Results showed that most studies employed multifaceted interventions, most frequently including audit & feedback and/or educational meetings. Seven out of nine trials that recorded first-choice prescriptions saw an increased proportion of first-choice antibiotics in the intervention groups compared to control groups. The employed interventions also caused a decreased proportion of at least one broad-spectrum antibiotic in five out of six studies that measured broad-spectrum antibiotic prescriptions. However, the total number of antibiotic prescriptions for UTIs increased in four out of eight studies. Therefore, while effective at influencing GPs’ prescribing behavior, future interventions should also focus on improving the decision to prescribe at all.

Objective: Besides hyperlipidemia, inflammation is an important determinant in the initiation and the progression of atherosclerosis. As Neuroimmune Guidance Cues (NGCs) are emerging as regulators of atherosclerosis, we set out to investigate the expression and function of inflammation-regulated NGCs.Methods and results: NGC expression in human monocytes and endothelial cells was assessed using a publicly available RNA dataset. Next, the mRNA levels of expressed NGCs were analyzed in primary human monocytes and endothelial cells after stimulation with IL1β or TNFα. Upon stimulation a total of 14 and 19 NGCs in monocytes and endothelial cells, respectively, were differentially expressed. Since plexin A4 (PLXNA4) was strongly downregulated in endothelial cells under inflammatory conditions, the role of PLXNA4 in endothelial function was investigated. Knockdown of PLXNA4 in endothelial cells markedly impaired the integrity of the monolayer leading to more elongated cells with an inflammatory phenotype. In addition, these cells showed an increase in actin stress fibers and decreased cell-cell junctions. Functional assays revealed decreased barrier function and capillary network formation of the endothelial cells, while vascular leakage and trans-endothelial migration of monocytes was increased.Conclusion: The current study demonstrates that pro-inflammatory conditions result in differential expression of NGCs in endothelial cells and monocytes, both culprit cell types in atherosclerosis. Specifically, endothelial PLXNA4 is reduced upon inflammation, while PLXNA4 maintains endothelial barrier function thereby preventing vascular leakage of fluids as well as cells. Taken together, PLXNA4 may well have a causal role in atherogenesis that deserves further investigation.

While there are many alternatives to antibiotics for the symptomatic treatment of urinary tract infections (UTIs), their application in practice is limited. Among other things, general practitioners (GPs) often feel pressure from patients to prescribe antibiotics. To gain a better understanding of why this happens and where this pressure originates from, we investigated experiences, expectations, motivations, and perspectives of patients with UTIs in general practice. During this qualitative study we performed 14 semi-structured online interviews among female UTI patients in general practice. Interviews were based on a topic list derived from sensitising concepts. All the interviews were recorded, transcribed, and analysed using a constant comparative technique. Three main categories emerged from the data; (1) experienced versus unexperienced patients with UTI, (2) patient’s lack of knowledge, and (3) patients feeling understood. Inexperienced patients consult a general practitioner for both diagnosis and symptom relief, while experienced patients seem to consult specifically to obtain antibiotics. In addition, patients have a lack of knowledge with regard to the diagnosis, treatment, self-care, and cause of UTIs. Finally, patients’ satisfaction is increased by involving them more in the process of decision making, so they feel understood and taken seriously. Patients’ expectations in UTI management in general practice often arise during their first experience(s) and play a major role in subsequent episodes. In conclusion, preventing misconceptions is especially important in the inexperienced patient group, as this may prevent future overtreatment of UTIs. In addition, involving patients in the decision making process will lead to greater understanding of the GP’s treatment choices.