N-cadherin directs the collective Schwann cell migration required for nerve regeneration through Slit2/3-mediated contact inhibition of locomotion.

Collective cell migration is fundamental for the development of organisms and in the adult for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective SC migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased SC collective migration and increased clustering of SCs within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.

The IMPROVE trial: study protocol for a pragmatic cluster randomised controlled trial to assess the effectiveness of using lay health workers to improve uptake and completion of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) is a programme of exercise and education and the most effective treatment for the symptoms and disability associated with chronic obstructive pulmonary disease. However, the benefits of PR are limited by poor uptake and completion. This trial will determine whether using trained volunteer lay health workers, called "PR buddies," improves uptake and completion of PR and is cost-effective. This trial protocol outlines the methods for evaluating effectiveness, cost-effectiveness, and acceptability. METHODS: The IMPROVE trial is a pragmatic, open, cluster randomised controlled trial planned in 38 PR services across England and Wales. PR services will be randomised to either intervention arm-offering support from PR buddies to patients with chronic obstructive pulmonary disease-or to usual care as the control arm. PR staff in trial sites randomised to the intervention arm will receive training in recruiting and training PR buddies. They will deliver training to volunteers, recruited from among people who have recently completed PR in their service. The 3-day PR-buddy training programme covers communication skills, confidentiality, boundaries of the PR-buddy role and behaviour change techniques to help patients overcome obstacles to attending PR. An internal pilot will test the implementation of the trial in eight sites (four intervention sites and four in control arm). The primary outcome of the trial is the uptake and completion of PR. A process evaluation will investigate the acceptability of the intervention to patients, PR staff and the volunteer PR buddies, and intervention fidelity. We will also conduct a cost-effectiveness analysis. DISCUSSION: Improving outcomes for chronic obstructive pulmonary disease and access to PR are priorities for the UK National Health Service (NHS) in its long-term plan. The trial hypothesis is that volunteer PR buddies, who are recruited and trained by local PR teams, are an effective and cost-effective way to improve the uptake and completion rates of PR. The trial is pragmatic, since it will test whether the intervention can be incorporated into NHS PR services. Information obtained in this trial may be used to influence policy on the use of PR buddies in PR and other similar services in the NHS. TRIAL REGISTRATION: ISRCTN12658458. Registered on 23/01/2023.

Absolute cardiovascular risk assessment by Australian early-career general practitioners: a cross-sectional study.

OBJECTIVE: To determine the prevalence and associations of general practice registrars' performing absolute cardio-vascular risk (ACVR) assessment (ACVRa). DESIGN: A cross-sectional study employing data (2017-2018) from the Registrar Clinical Encounters in Training project, an ongoing inception cohort study of Australian GP registrars. The outcome measure was whether an ACVRa was performed. Analyses employed univariable and multivariable regression. Analysis was conducted for all patient problems/diagnoses, then for an 'at-risk' population (specific problems/diagnoses for which ACVRa is indicated). SETTING: Three GP regional training organisations (RTOs) across three Australian states. PARTICIPANTS: GP registrars training within participating RTOs. RESULTS: 1003 registrars (response rate 96.8%) recorded details of 69 105 problems either with Aboriginal and/or Torres Strait patients aged 35 years and older or with non-Indigenous patients aged 45 years and older. Of these problems/diagnoses, 1721 (2.5% (95% CI 2.4% to 2.6%)) involved an ACVRa. An ACVRa was 'plausibly indicated' in 10 384 problems/diagnoses. Of these, 1228 (11.8% (95% CI 11.2% to 12.4%)) involved ACVRa. For 'all problems/diagnoses', on multivariable analysis female gender was associated with reduced odds of ACVRa (OR 0.61 (95% CI 0.54 to 0.68)). There was some evidence for Aboriginal and/or Torres Strait Islander people being more likely to receive ACVRa (OR 1.40 (95% CI 0.94 to 2.08), p=0.10). There were associations with variables related to continuity of care, with reduced odds of ACVRa: if the patient was new to the registrar (OR 0.65 (95% CI 0.57 to 0.75)), new to the practice (OR 0.24 (95% CI 0.15 to 0.38)) or the problem was new (OR 0.68 (95% CI 0.59 to 0.78)); and increased odds if personal follow-up was organised (OR 1.43 (95% CI 1.24 to 1.66)). For 'ACVRa indicated' problems/diagnoses, findings were similar to those for 'all problems/diagnoses'. Association with Aboriginal and/or Torres Strait Islander status, however, was significant at p<0.05 (OR 1.60 (95% CI 1.04 to 2.46)) and association with female gender was attenuated (OR 0.88 (95% CI 0.77 to 1.01)). CONCLUSION: Continuity of care is associated with registrars assessing ACVR, reinforcing the importance of care continuity in general practice. Registrars' assessment of an individual patient's ACVR is targeted to patients with individual risk factors, but this may entail ACVRa underutilisation in female patients and younger age groups.

Development and results of a patient-reported treatment experience questionnaire on a 1.5 T MR-Linac.

INTRODUCTION: With the implementation of new radiotherapy technology, it is imperative that patient experience is investigated alongside efficacy and outcomes. This paper presents the development of a specifically designed validated questionnaire and a first report of international multi-institutional preliminary patient experience of MRI-guided adaptive radiotherapy (MRgART) on the 1.5 T MR-Linac (MRL). METHODS: A patient experience questionnaire was developed and validated before being distributed to the Elekta MRL Consortium, to gather first patient-reported experience from participating centres worldwide. The final version of the questionnaire contains 18 questions covering a range of themes and was scored on a Likert scale of 0-3. Responses were post-processed so that a score of 0 represents a negative response and 3 represents the most favourable response. These results were analysed for patient-reported experience of treatment on the MRL. Results were also analysed for internal consistency of the questionnaire using Chronbach's Alpha and the questionnaire contents were validated for relevance using content validity indexes (CVI). RESULTS: 170 responses were received from five centres, representing patients with a wide range of tumour treatment sites from four different countries. MRgART was well tolerated with an 84% favourable response across all questions and respondents. When analysed by theme, all reported the highest percentage of results in the favourable categories (2 and 3). Internal consistency in the questionnaire was high (Cronbach's α = 0.8) and the item-level CVI for each question was 0.78 or above and the Scale-level CVI was 0.93, representing relevant content. CONCLUSION: The developed questionnaire has been validated as relevant and appropriate for use in reporting experience of patients undergoing treatment on the MRL. The overall patient-reported experience and satisfaction from multiple centres within the Elekta MRL Consortium was consistently high. These results can reinforce user confidence in continuing to expand and develop MRL use in adaptive radiotherapy.

Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition.

Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increases expression of postsynaptic GABAA receptor ß2/3-subunits and neuroligin 3, enhancing synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered E/I balance and circuit dysfunction in CYFIP1-associated neurological disorders.