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Arnaud Steyaert,1,2 Romain Bischoff,3 Jean-Marc Feron,4 Anne Berquin2,5 1Department of Anesthesiology, Cliniques universitaires Saint-Luc, Brussels, Belgium; 2Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium; 3General Practice Medecine Internship, Université Catholique de Louvain, Brussels, Belgium; 4Centre Académique de médecine générale, Université Catholique de Louvain, Brussels, Belgium; 5Department of Physical and Rehabilitation Medicine, Cliniques universitaires Saint-Luc, Brussels, BelgiumCorrespondence: Anne Berquin, Department of Physical and Rehabilitation Medicine, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, Brussels, 1200, Belgium, Email anne.berquin@uclouvain.beBackground: Chronic pain prevalence is very high in the general population, much higher than can be managed by chronic pain centers. Therefore, most pain patients are cared for by first-line professionals. However, general practitioners often feel ill at ease with these patients, and only a few studies assess the burden of chronic pain in general practice. To better estimate the resources needed to support these professionals, a good knowledge of (sub)acute and chronic pain prevalence and prognosis in general practices is needed.Methods: We report cross-sectional data from a larger longitudinal study performed in French-speaking general practices in Belgium in November 2018. Fifth-year medical students performing a one-month internship collected data for every third patient they saw each day: demographic information, pain characteristics, lifestyle, general health perception and the short Örebro Musculoskeletal Pain Screening Questionnaire in the French language.Results: 3882 patients (participation rate 66%) accepted to take part in the study. 22 and 50% of these suffered from (sub)acute and chronic pain, respectively. Pain was more often the motive of the consultation for (sub)acute than for chronic pain patients. Pain intensity and functional impact were moderate, irrespective of pain duration. 70% of (sub)acute and 31% of chronic pain patients were at low risk of chronicity.Conclusion: In our sample, chronic pain patients constituted 33– 50% of patient contacts in general practice, indicating the high importance of providing adequate support to general practitioners and other first-line professionals, ie, by reinforcing collaboration with chronic pain centers.Keywords: Acute pain, chronic pain, general practice

Autism is increasingly viewed as an expression of neurodiversity deserving accommodation, rather than merely as a disorder in need of remediation or even prevention. This reconceptualization has inspired calls to broaden the ethical debate on early autism care beyond matters of efficient screenings and effective interventions. We conducted 14 in-depth interviews with 26 parents of infants at an increased likelihood for autism (siblings, preterms and children with persistent feeding difficulties) to understand which benefits and risks these parents see for the implementation of a systematic, early autism detection program in our region. With this study, we aim to contribute empirically to the ethical debate on good and just early autism care in the age of neurodiversity. Data were analyzed according to the QUAGOL-methodology. Three main themes emerged from our analysis. In their evaluation of early autism detection, parents discussed how a diagnosis helps gain a different perspective fostering understanding and recognition for both child and parent. Second, a diagnosis supports parents in adjusting their parenting practices, to justify this deviation from "normal" parenting and to strive for such adjusted environments beyond the nuclear family. Third, an autism diagnosis induces ambiguities parents need to navigate, involving questions on whether and when to mobilize the diagnostic label and which language to use to talk about autism. We discuss the complex position of parents of a (potentially) autistic child in terms of moving back and forth across the ab/normal binary and describe implications for the ethical debate on early autism detection.

The μ-opioid receptor (μOR), a prototypical G protein-coupled receptor (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to the severe side effects of current opioid drugs, there is considerable interest in developing novel modulators of μOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, represent alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the μOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded μOR ligand and uncover the molecular basis for μOR antagonism by determining the cryo-EM structure of the NbE-μOR complex. NbE displays a unique ligand binding mode and achieves μOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a β-hairpin loop formed by NbE that deeply protrudes into the μOR, we design linear and cyclic peptide analogs that recapitulate NbEs antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes lower molecular weight μOR ligands that can serve as a basis for therapeutic developments.

Despite much effort, antibody therapies for Alzheimers disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

Rhodopsin is a prototypical G protein-coupled receptor (GPCR) critical for vertebrate vision. Research on GPCR signaling states has been facilitated using llama-derived nanobodies (Nbs), some of which bind to the intracellular surface to allosterically modulate the receptor. Extracellularly binding allosteric nanobodies have also been investigated, but the structural basis for their activity has not been resolved to date. Here, we report a library of Nbs that bind to the extracellular surface of rhodopsin and allosterically modulate the thermodynamics of its activation process. Crystal structures of Nb2 in complex with native rhodopsin reveal a mechanism of allosteric modulation involving extracellular loop 2 and native glycans. Nb2 binding suppresses Schiff base deprotonation and hydrolysis and prevents intracellular outward movement of helices five and six - a universal activation event for GPCRs. Nb2 also mitigates protein misfolding in a disease-associated mutant rhodopsin. Our data show the power of nanobodies to modulate the photoactivation of rhodopsin and potentially serve as therapeutic agents for disease-associated rhodopsin misfolding.

Background: The goal of this systematic review was to provide an overview of self-report measures of stress in populations on the autism spectrum. In addition, information regarding psychometric properties was discussed as well. Methods: Four databases were systematically searched following the PRISMA guidelines and using strict eligibility criteria. Risk of bias assessment was performed using the COSMIN checklist. Results: Eight questionnaires were previously used in populations on the autism spectrum, reported over 31 studies. Discussion: Future research should focus more on examining psychometric properties of these self-report measures in this population as current evidence is scarce. In addition, it is important to consider which concept of stress one aims to measure as not all questionnaires cover the same aspects of stress.

Ultrasound imaging is a dynamic imaging technique that uses high-frequency sound waves to capture live images of the structures beneath the skin. In addition to its growing use in diagnosis and interventions, ultrasound imaging has the potential to reinforce concepts in the undergraduate medical curriculum. However, research assessing the impact of ultrasound on anatomy learning and student cognition is scarce. The purpose of this study was to compare the impact of ultrasound-based instruction versus narrated videos on students' understanding of anatomical relationships, as well as the role of intrinsic motivation, self-efficacy beliefs, and students' attitudes in this process. A booster course on anterior leg and wrist anatomy was offered to second-year medical students. A randomized controlled trial with a cross-over design allocated students to either an ultrasound-based teaching condition (cohort A) or a narrated anatomy video condition (cohort B). Next, participants were crossed to the alternative intervention. At the start of the study (T0), baseline anatomy knowledge, intrinsic motivation, self-efficacy beliefs, and spatial ability were measured. After the first intervention (T1) and at the end of the study (T2), both cohorts were administered an anatomy test, an intrinsic motivation scale, and a self-efficacy scale. In addition, each student was asked to fill out a perception survey after the ultrasound intervention. Finally, building on the cross-over design, the most optimal sequence of interventions was examined. A total of 181 students participated (cohort A: n = 82, cohort B: n = 99). Both cohorts performed comparably on the baseline anatomy knowledge test, spatial ability test, intrinsic motivation, and self-efficacy scale. At T1, cohort B outperformed cohort A on the anatomy test (p = 0.019), although only a small effect size could be detected (Cohen's d = 0.34). Intrinsic motivation and self-efficacy of both cohorts were similar at T1. At T2, the anatomy test, intrinsic motivation, and self-efficacy scale did not reflect an effect after studying either sequence of the interventions. Students reported favorably about the ultrasound experience, but also mentioned a steep learning curve. Medical students found the hands-on ultrasound sessions to be valuable, increasing their interest in musculoskeletal anatomy and ultrasound imaging. However, the addition of ultrasound did not result in superior spatial anatomy understanding compared to watching anatomy videos. In addition, ultrasound teaching did not have a major effect on student cognition. Ultrasound-based teaching of musculoskeletal anatomy is regarded as difficult to learn, and therefore it is hypothesized that too high levels of cognitive load might explain the presented results.