B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

BACKGROUND: Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. METHODS: We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. FINDINGS: Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). INTERPRETATION: Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. FUNDING: Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).

Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN): Protocol for a Cross-Sectional Study.

BACKGROUND: The unequal distribution of academic and professional outcomes between different minority groups is a pervasive issue in many fields, including surgery. The implications of differential attainment remain significant, not only for the individuals affected but also for the wider health care system. An inclusive health care system is crucial in meeting the needs of an increasingly diverse patient population, thereby leading to better outcomes. One barrier to diversifying the workforce is the differential attainment in educational outcomes between Black and Minority Ethnic (BME) and White medical students and doctors in the United Kingdom. BME trainees are known to have lower performance rates in medical examinations, including undergraduate and postgraduate exams, Annual Review of Competence Progression, as well as training and consultant job applications. Studies have shown that BME candidates have a higher likelihood of failing both parts of the Membership of the Royal Colleges of Surgeons exams and are 10% less likely to be considered suitable for core surgical training. Several contributing factors have been identified; however, there has been limited evidence investigating surgical training experiences and their relationship to differential attainment. To understand the nature of differential attainment in surgery and to develop effective strategies to address it, it is essential to examine the underlying causes and contributing factors. The Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN) study aims to describe and compare the factors and outcomes of attainment between different ethnicities of doctors and medical students. OBJECTIVE: The primary aim will be to compare the effect of experiences and perceptions of surgical education of students and doctors of different ethnicities. METHODS: This protocol describes a nationwide cross-sectional study of medical students and nonconsultant grade doctors in the United Kingdom. Participants will complete a web-based questionnaire collecting data on experiences and perceptions of surgical placements as well as self-reported academic attainment data. A comprehensive data collection strategy will be used to collect a representative sample of the population. A set of surrogate markers relevant to surgical training will be used to establish a primary outcome to determine variations in attainment. Regression analyses will be used to identify potential causes for the variation in attainment. RESULTS: Data collected between February 2022 and September 2022 yielded 1603 respondents. Data analysis is yet to be competed. The protocol was approved by the University College London Research Ethics Committee on September 16, 2021 (ethics approval reference 19071/004). The findings will be disseminated through peer-reviewed publications and conference presentations. CONCLUSIONS: Drawing upon the conclusions of this study, we aim to make recommendations on educational policy reforms. Additionally, the creation of a large, comprehensive data set can be used for further research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40545.

Neuronal melatonin type 1 receptor overexpression promotes M2 microglia polarization in cerebral ischemia/reperfusion-induced injury.

Microglial activation is readily detected following cerebral ischemia/reperfusion-induced injury. Activated microglia polarize into either classic pro-inflammatory M1 or protective M2 microglia following ischemia/reperfusion-induced injury. Melatonin is protective immediately after ischemia/reperfusion-induced brain injury. However, the ability of melatonin to affect longer-term recovery from ischemic/reperfusion-induced injury as well as its ability to modulate microglia/macrophage polarization are unknown. The goal of this study is to understand the impact of melatonin on mice 14 days after injury, as well as to understand how melatonin affects microglial polarization of neuronal MT1 activation following cerebral ischemia/reperfusion. We utilized NSEMT1-GFP transgenic mice which overexpress MT1 (melatonin type 1 receptor) in neurons. Melatonin-treated or vehicle treated wild type and NSEMT1-GFP mice underwent middle cerebral artery occlusion (MCAO)/reperfusion and followed for 14 days. Neuronal MT1 overexpression significantly reduced infarct volumes, improved motor function, and ameliorated weight loss. Additionally, melatonin treatment reduced infarct volume in NSEMT1-GFP mice as compared to untreated wild type, melatonin treated wild type, and untreated NSEMT1-GFP mice. Melatonin improved neurological function and prevented weight loss in NSEMT1-GFP mice compared with melatonin treated wild type mice. Finally, melatonin treatment in combination with MT1 overexpression reduced the numbers of Iba1+/CD16+ M1 microglia and increased the numbers of Iba1+/ CD206+ M2 microglia after ischemic injury. In conclusion, neuronal MT1 mediates melatonin-induced long-term recovery after cerebral ischemia, at least in part, by shifting microglial polarization toward the neuroprotective M2 phenotype.

Virtual classroom proficiency-based progression for robotic surgery training (VROBOT): a randomised, prospective, cross-over, effectiveness study.

Robotic surgery training has lacked evidence-based standardisation. We aimed to determine the effectiveness of adjunctive interactive virtual classroom training (VCT) in concordance with the self-directed Fundamentals of Robotic Surgery (FRS) curriculum. The virtual classroom is comprised of a studio with multiple audio-visual inputs to which participants can connect remotely via the BARCO weConnect platform. Eleven novice surgical trainees were randomly allocated to two training groups (A and B). In week 1, both groups completed a robotic skills induction. In week 2, Group A received training with the FRS curriculum and adjunctive VCT; Group B only received access to the FRS curriculum. In week 3, the groups received the alternate intervention. The primary outcome was measured using the validated robotic-objective structured assessment of technical skills (R-OSAT) at the end of week 2 (time-point 1) and 3 (time-point 2). All participants completed the training curriculum and were included in the final analyses. At time-point 1, Group A achieved a statistically significant greater mean proficiency score compared to Group B (44.80 vs 35.33 points, p = 0.006). At time-point 2, there was no significant difference in mean proficiency score in Group A from time-point 1. In contrast, Group B, who received further adjunctive VCT showed significant improvement in mean proficiency by 9.67 points from time-point 1 (95% CI 5.18-14.15, p = 0.003). VCT is an effective, accessible training adjunct to self-directed robotic skills training. With the steep learning curve in robotic surgery training, VCT offers interactive, expert-led learning and can increase training effectiveness and accessibility.

Retained intravascular catheter fragment at removal of implantable vascular access device: Incidence, risk factors, and outcomes.

BACKGROUND: Retained intravascular catheter fragments (RICF) are a rare complication of implantable vascular access device (IVAD) removal for which there is limited understanding of aetiology. There is a varied approach to management among the currently published literature. AIMS: The aim of this study was to establish incidence, risk factors, and outcomes for RICF after attempted removal of IVADs. METHODS: A single institution retrospective review was undertaken of individuals ≤ 25 years undergoing removal of IVADs from October 2014 to June 2019. Risk factors for RICF were explored using univariable logistic and Cox regression analysis. RESULTS: Six cases of RICF were identified among 654 line removal episodes (0.92% (95% CI 0.37-2%)) in patients aged 6-17 years (median 11, IQR 6-15 years). The main risk factor for RICF at removal was found to be line duration (OR 3.5/year, 95% CI 2.1-5.84, p < 0.0001). No RICFs occurred in lines indwelling for < 3 years. Five children with RICF ≤ 16 years were discussed with a paediatric cardiothoracic centre, and all were left in situ with 4 remaining asymptomatic. One had the fragment tip extruded through a wound, which required trimming. The other (17 years of age) developed an infected sinus for which partial removal with open excision followed by full removal with endovascular snare retrieval was performed by the adult vascular surgeons. CONCLUSION: IVADs in-situ for longer than a three-year period are at greatest risk of RICF upon removal. Management with transfixion of line fragments to surrounding muscle seems prudent while invasive attempts at retrieval appear unwarranted.

Virtual Interactive Surgical Skills Classroom: A Parallel-group, Non-inferiority, Adjudicator-blinded, Randomised Controlled Trial (VIRTUAL).

OBJECTIVE: This study evaluated the efficacy of virtual classroom training (VCT) in comparison to face-to-face training (FFT) and non-interactive computer-based learning (CBL) for basic surgical skills training. DESIGN: This was a parallel-group, non-inferiority, prospective randomised controlled trial with three intervention groups conducted in 2021. There were three intervention groups with allocation ratio 1:1:1. Outcome adjudicators were blinded to intervention assignment. Interventions consisted of 90-minute training sessions. VCT was delivered via the BARCO weConnect platform, FFT was provided in-person by expert instructors and CBL was carried out by participants independently. The primary outcome was post-intervention Objective Structured Assessment of Technical Skills score, adjudicated by two experts and adjusted for baseline proficiency. The assessed task was to place three interrupted sutures with hand-tied knots. SETTING: This multicentre study recruited from five medical schools in London. PARTICIPANTS: Inclusion criteria were medical student status and access to a personal computer and smartphone. One hundred fifty-nine eligible individuals applied online. Seventy-two participants were randomly selected and stratified by subjective and objective suturing experience prior to permuted block randomization. RESULTS: Twenty-four participants were allocated to each intervention, all were analysed per-protocol. The sample was 65.3% female with mean age 21.3 (SD 2.1). VCT was non-inferior to FFT (adjusted difference 0.44, 95% CI: -0.54 to 1.75, delta 0.675), VCT was superior to CBL (adjusted difference 1.69, 95% CI: 0.41-2.96) and FFT was superior to CBL (adjusted difference 1.25, 95% CI: 0.20-2.29). The costs per-attendee associated with VCT, FFT and CBL were £22.15, £39.69 and £16.33 respectively. Instructor hours used per student for VCT and FFT were 0.25 and 0.75, respectively. CONCLUSIONS: VCT provides greater accessibility and resource efficiency compared to FFT, with similar educational benefit. VCT has the potential to improve global availability and accessibility of surgical skills training.

Virtual Interactive Surgical Skills Classroom: Protocol for a Parallel-Group, Noninferiority, Adjudicator-Blinded, Randomized Controlled Trial (VIRTUAL).

BACKGROUND: Traditional face-to-face training (FFT) for basic surgical skills is inaccessible and resource-intensive. Noninteractive computer-based learning is more economical but less educationally beneficial. Virtual classroom training (VCT) is a novel method that permits distanced interactive expert instruction. VCT may optimize resources and increase accessibility. OBJECTIVE: We aim to investigate whether VCT is superior to computer-based learning and noninferior to FFT in improving proficiency in basic surgical skills. METHODS: This is a protocol for a parallel-group, noninferiority, randomized controlled trial. A sample of 72 undergraduates will be recruited from 5 medical schools in London. Participants will be stratified by subjective and objective suturing experience level and allocated to 3 intervention groups at a 1:1:1 ratio. VCT will be delivered using the BARCO weConnect software, and FFT will be provided by expert instructors. Optimal student-to-teacher ratios of 12:1 for VCT and 4:1 for FFT will be maintained. The assessed task will be interrupted suturing with hand-tied knots. RESULTS: The primary outcome will be the postintervention Objective Structured Assessment of Technical Skills score, adjudicated by 2 experts blinded to the study and adjusted for baseline proficiency. The noninferiority margin (δ) will be defined using historical data. CONCLUSIONS: This study will serve as a comprehensive appraisal of the suitability of virtual basic surgical skills classroom training as an alternative to FFT. Our findings will assist the development and implementation of further resource-efficient, accessible, virtual basic surgical skills training programs during the COVID-19 pandemic and in the future. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN12448098; https://www.isrctn.com/ISRCTN12448098. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/28671.

The Segond fracture occurs at the site of lowest sub-entheseal trabecular bone volume fraction on the tibial plateau.

In a series of human cadaveric experiments, Dr. Paul Segond first described the avulsion injury occurring at the anterolateral tibial plateau that later took his name. The fracture is thought to arise as a consequence of excessive tibia internal rotation which often also elicits damage to other connective tissue of the knee. The exact mechanism behind the avulsion is, however, unclear. A number of ligamentous structures have been proposed in separate studies to insert into the Segond fragment. Suggestions include the iliotibial band (ITB), biceps femoris and the controversial 'anterolateral ligament' (ALL). Despite increasing knowledge of tibial plateau bony microarchitecture in both healthy and disease states, no studies have yet, to our knowledge, considered the role of tibial sub-entheseal bone structure in pathogenesis of the Segond fracture. The goal of this study was thus to elucidate the differences in trabecular properties at regions across the tibial plateau in order to provide an explanation for the susceptibility of the anterolateral region to avulsion injury. Twenty human tibial plateaus from cadaveric donors were dissected and imaged using a Nikon-XTH225-µCT scanner with <80 µm isotropic voxel size. Scans were reconstructed using MicroView 3D Image Viewer and Analysis Tool. Subsequent virtual biopsy at ten anatomically defined regions of interest (ROI) generated estimates of bone volume fraction ('bone volume divided by total volume' (BV/TV)). The overall mean BV/TV value across all 20 tibiae and all 10 ROIs was 0.271. Univariate repeated-measurements ANOVA demonstrated that BV/TV values differed between ROIs. BV/TV values at the Segond site (Sα, Sß or Sγ) were lower than all other ROIs at 0.195, 0.192 and 0.193, respectively. This suggests that, notwithstanding inter- and intra-specimen variation, the Segond site tends to have a lower trabecular bone volume fraction than entheseal sites elsewhere on the tibia. Since BV/TV correlates with tensile and torsional strength, the lower BV/TV at the Segond site could equate to a region of local weakness in certain individuals which predisposes them to an avulsion injury following the application of force from excessive internal rotation. The low BV/TV recorded at the Segond site also challenges the idea that the fracture occurs due to pull from a discrete 'anterolateral ligament', as the tension exerted focally would be expected to elicit a hypertrophic response in line with Frost's Mechanostat hypothesis. Our data would instead agree with the aforementioned reports of the fibrous band at the Segond site being part of a broader insertion of an 'anterolateral complex'.