CycLing and EducATion (CLEAT): protocol for a single centre randomised controlled trial of a cycling and education intervention versus standard physiotherapy care for the treatment of hip osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disorder for which there is no known cure. Non-surgical management for people with mild-to-moderate hip OA focuses mainly on alleviating pain and maximising function via the National Institute for Health and Care Excellence (NICE) recommended combination of education and advice, exercise, and, where appropriate, weight loss. The CHAIN (Cycling against Hip pAIN) intervention is a group cycling and education intervention conceived as a way of implementing the NICE guidance. METHODS: CycLing and EducATion (CLEAT) is a pragmatic, two parallel arm, randomised controlled trial comparing CHAIN with standard physiotherapy care for the treatment of mild-to-moderate hip OA. We will recruit 256 participants referred to the local NHS physiotherapy department over a 24-month recruitment period. Participants diagnosed with hip OA according to NICE guidance and meeting the criteria for GP exercise referral will be eligible to participate. Primary outcome is the difference in Hip Disability and Osteoarthritis Outcome Score (HOOS) function, daily living subscale between those receiving CHAIN and standard physiotherapy care. Secondary outcomes include performance-based functional measures (40 m walking, 30s chair stand and stair climb tests), ability for patient to self-care (patient activation measure) and self-reported health-related resource use including primary and secondary care contacts. The primary economic endpoint is the number of quality adjusted life years (QALYs) at 24 weeks follow-up. The study is funded by the National Institute for Health Research, Research for Patient Benefit PB-PG-0816-20033. DISCUSSION: The literature identifies a lack of high-quality trials which inform on the content and design of education and exercise in the treatment of patients with hip OA and explore cost-effectiveness. CLEAT is a pragmatic trial which seeks to build further evidence of the clinical benefits of the CHAIN intervention compared to standard physiotherapy care within a randomised, controlled trial setting, and examine its cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN19778222. Protocol v4.1, 24th October 2022.

Genome-wide characterization of the routes to pluripotency.

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and -independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org.

Editorial Commentary: I Am Not a Number! I Am a Resident! Can the Assessment of Surgical Skill Be Reduced to a Score?

Competency-based surgical training requires assessment tools, and these should be both valid and reliable. Global rating scales are one such method, with several developed and investigated for use in arthroscopic skills assessment. These global rating scales have shown acceptable reliability and construct validity, most commonly demonstrated using simulated arthroscopic tasks. However, questions remain regarding their readiness for use in the operating room and for the assessment of complex tasks.

A Single-Centre Feasibility Randomised Controlled Trial Comparing the Incidence of Asymptomatic and Symptomatic Deep Vein Thrombosis Between a Neuromuscular Electrostimulation Device and Thromboembolism Deterrent Stockings in Post-Operative Patients Recovering From Elective Total Hip Replacement Surgery.

BACKGROUND: Total hip replacement is recognised as a major risk factor for deep vein thrombosis (DVT). The aim of this study was to investigate the feasibility of using a novel neuromuscular electrical stimulation device (NMES) for DVT prevention in patients recovering from elective hip replacement surgery. METHODS: Twenty-eight patients undergoing total hip replacement were randomised to receive postoperative treatment with either the NMES device or compression stockings continually from post-surgery until discharge (day 4). The primary outcome measure was the presence of symptomatic or asymptomatic DVT at 48 hours post-surgery and on the day of discharge from hip replacement surgery, as assessed by Duplex ultrasound. Secondary outcomes included hemodynamic responses to the devices, lower limb oedema, sit-to-stand and timed-up-and-go (TUG) scores, and hip range of motion. RESULTS: In the compression stockings group, two cases of asymptomatic DVT were identified by Duplex ultrasound at 48 hours post-surgery. No cases were found in the NMES group. Patients in the NMES group demonstrated a general trend of a decrease in leg volume from post-surgery to discharge, whereas leg volume largely remained static for the compression stockings group. In addition, positive hemodynamic effects were found in favour of the NMES group in the non-operated leg. The change in TUG scores also favoured the NMES group (NMES: 150 ± 152%, compression stockings: 363 ± 257% (p=0.03)), whereas no differences in sit-to-stand scores or hip range of motion were observed. CONCLUSIONS: This study supports the feasibility of NMES as an alternative mechanical prophylaxis worn in the postoperative phase until discharge and provides important findings for clinicians considering novel mechanical prophylaxis options.

Consensus statement for perioperative care in total hip replacement and total knee replacement surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations.

Background and purpose - There is a large volume of heterogeneous studies across all Enhanced Recovery After Surgery (ERAS®) components within total hip and total knee replacement surgery. This multidisciplinary consensus review summarizes the literature, and proposes recommendations for the perioperative care of patients undergoing total hip replacement and total knee replacement with an ERAS program.Methods - Studies were selected with particular attention being paid to meta-analyses, randomized controlled trials, and large prospective cohort studies that evaluated the efficacy of individual items of the perioperative treatment pathway to expedite the achievement of discharge criteria. A consensus recommendation was reached by the group after critical appraisal of the literature.Results - This consensus statement includes 17 topic areas. Best practice includes optimizing preoperative patient education, anesthetic technique, and transfusion strategy, in combination with an opioid-sparing multimodal analgesic approach and early mobilization. There is insufficient evidence to recommend that one surgical technique (type of approach, use of a minimally invasive technique, prosthesis choice, or use of computer-assisted surgery) over another will independently effect achievement of discharge criteria.Interpretation - Based on the evidence available for each element of perioperative care pathways, the ERAS® Society presents a comprehensive consensus review, for the perioperative care of patients undergoing total hip replacement and total knee replacement surgery within an ERAS® program. This unified protocol should now be further evaluated in order to refine the protocol and verify the strength of these recommendations.

Prolonged operative time increases risk of blood loss and transfusion requirements in revision hip surgery.

INTRODUCTION: Revision hip surgery is well documented to have a high association with substantial blood loss and the associated need for a blood transfusion. This exposes the patient to increased risk of transfusion reaction and blood borne infection. There are many strategies to minimize allogeneic transfusion rates in revision surgery such as pre-operative autologous donation, peri-operative tranexamic acid, thrombin sealants, normovolaemic haemodilution, intra-operative blood salvage and the use of post-operative autologous drains. PATIENTS AND METHODS: We prospectively looked at 177 consecutive cases performed at one centre by a single surgical and anaesthetic team to identify which patient and operative factors were most significant in minimizing the requirement for an allogeneic blood transfusion. RESULTS: Our results identified the duration of surgery as being the only significant variable affecting the level of blood loss. We noted a 3% increase in the probability of massive blood loss (> 2000 mls) for every minute of increased surgical time in our series. CONCLUSIONS: We conclude that measures to minimize the duration of surgery would be beneficial in reducing blood loss and the risks of requiring blood transfusions in revision hip surgery.

Validation of the Hip Arthroscopy Module of the VirtaMed Virtual Reality Arthroscopy Trainer.

OBJECTIVE: To assess the face, content and construct validity of a virtual reality hip arthroscopy simulator (Arthros™, VirtaMed AG, Schlieren, Switzerland). DESIGN: Participants were divided into Expert and Novice groups depending on whether or not they had assisted with or performed more than 50 hip arthroscopy procedures. Participants were given a standardized introduction and shown a video on how to use the simulator. To familiarise themselves with the equipment, they were then given a 5-minute diagnostic task to complete. Participants then performed a therapeutic task. On completion, the simulator produced a summary of performance metrics for the following domains: Operation Time, Safety, Economy, Detailed Visualization and Overall Score. Participants completed a 7-point Likert-scale questionnaire to assess the face and content validity of the simulator. SETTING: University lab or exhibition stand at an orthopaedic conference. PARTICIPANTS: Clinicians from a hospital orthopaedic department and attendees at a UK orthopaedic conference with varying levels of experience in hip arthroscopy surgery. RESULTS: Twenty-two participants were recruited. Six were classified as Expert and 16 as Novice. Statistically significant differences were found between the Expert and Novice groups for Overall Score (p=0.001), Safety (p=0.002) and Economy (p=0.033), but not Detailed Visualization (p=0.097). Questionnaire responses were positive for all items related to face and content validity. CONCLUSION: This study suggests that training on the ArthroS™ VR hip arthroscopy simulator has construct, face and content validity. It expands the evidence base for VR simulator training and is the first study to evaluate this hip arthroscopy module.

Validation of the Anterior Cruciate Ligament (ACL) Module of the VirtaMed Virtual Reality Arthroscopy Trainer.

OBJECTIVE: To assess the newly developed anterior cruciate ligament (ACL) module of a VR arthroscopy trainer for content, construct and face validity. DESIGN: Participants were divided into expert and novice groups based on their experience with ACL arthroscopy. Participants were given a standardized introduction, shown a video on how to use the simulator, and performed a 5-minute partial meniscectomy task, to familiarise them with the equipment. Participants then undertook an ACL reconstruction task. On completion, the simulator produced a summary of performance metrics for the following domains: Operation Time, ACL Reconstruction, Safety, Economy, Detailed Visualization and Total Score. A 7-point Likert scale questionnaire was used to assess the face and content validity of the simulator. PARTICIPANTS: Twenty one participants from a hospital orthopaedic department were recruited. Five were classified as expert, 16 as novice. RESULTS: An independent Mann-Whitney U test showed no significant differences between experts and novices for any of the domains. Questionnaire responses regarding hand-eye coordination, camera navigation training, diagnostic training, tunnel preparation and overall training capacity were scored as either 'good' or 'excellent' by more than 70% of the participants. All responses regarding the 'graft insertion task' scored low. CONCLUSION: The current iteration of the VR knee ArthroS™ simulator (VirtaMed AG, Zurich, Switzerland) is promising, but requires further development of the ACL procedure, in particular the graft insertion task, before it can be considered as part of training curricula.

Can the introduction of Enhanced Recovery After Surgery (ERAS) reduce the variation in length of stay after total ankle replacement surgery?

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been successfully adopted across a range of procedures. This study explores whether there is scope to improve length of stay (LOS) for total ankle replacement surgery (TAR) in the UK by implementing ERAS pathways. METHODS: Hospital Episode Statistics (HES) data (April 2015/March 2016) on LOS for TAR were analysed. A literature search was then carried out to examine whether there were any publications on outpatient TAR and/or the use of ERAS protocols. RESULTS: Mean observed LOS was 3.3days (range 0-17.3) days. Case mix-adjusted expected LOS range was 2.0-5.7 days. It is likely that the wide observed LOS range is due to differences in local processes and pathways. Two papers were found by the literature search. CONCLUSIONS: TAR should aim to be outpatient surgery as the literature, and data demonstrating scope for improvement in LOS, suggest this should be possible.

A dynamic intron retention program in the mammalian megakaryocyte and erythrocyte lineages.

Intron retention (IR) is a form of alternative splicing that can impact mRNA levels through nonsense-mediated decay or by nuclear mRNA detention. A complex, dynamic IR pattern has been described in maturing mammalian granulocytes, but it is unknown whether IR occurs broadly in other hematopoietic lineages. We globally assessed IR in primary maturing mammalian erythroid and megakaryocyte (MK) lineages as well as their common progenitor cells (MEPs). Both lineages exhibit an extensive differential IR program involving hundreds of introns and genes with an overwhelming loss of IR in erythroid cells and MKs compared to MEPs. Moreover, complex IR patterns were seen throughout murine erythroid maturation. Similarly complex patterns were observed in human erythroid differentiation, but not involving the murine orthologous introns or genes. Despite the common origin of erythroid cells and MKs, and overlapping gene expression patterns, the MK IR program is entirely distinct from that of the erythroid lineage with regards to introns, genes, and affected gene ontologies. Importantly, our results suggest that IR serves to broadly regulate mRNA levels. These findings highlight the importance of this understudied form of alternative splicing in gene regulation and provide a useful resource for studies on gene expression in the MK and erythroid lineages.

RBM3 regulates temperature sensitive miR-142-5p and miR-143 (thermomiRs), which target immune genes and control fever.

Fever is commonly used to diagnose disease and is consistently associated with increased mortality in critically ill patients. However, the molecular controls of elevated body temperature are poorly understood. We discovered that the expression of RNA-binding motif protein 3 (RBM3), known to respond to cold stress and to modulate microRNA (miRNA) expression, was reduced in 30 patients with fever, and in THP-1-derived macrophages maintained at a fever-like temperature (40 °C). Notably, RBM3 expression is reduced during fever whether or not infection is demonstrable. Reduced RBM3 expression resulted in increased expression of RBM3-targeted temperature-sensitive miRNAs, we termed thermomiRs. ThermomiRs such as miR-142-5p and miR-143 in turn target endogenous pyrogens including IL-6, IL6ST, TLR2, PGE2 and TNF to complete a negative feedback mechanism, which may be crucial to prevent pathological hyperthermia. Using normal PBMCs that were exogenously exposed to fever-like temperature (40 °C), we further demonstrate the trend by which decreased levels of RBM3 were associated with increased levels of miR-142-5p and miR-143 and vice versa over a 24 h time course. Collectively, our results indicate the existence of a negative feedback loop that regulates fever via reduced RBM3 levels and increased expression of miR-142-5p and miR-143.

Simulation-Based Training Platforms for Arthroscopy: A Randomized Comparison of Virtual Reality Learning to Benchtop Learning.

PURPOSE: To determine whether a virtual reality (VR) arthroscopy simulator or benchtop (BT) arthroscopy simulator showed superiority as a training tool. METHODS: Arthroscopic novices were randomized to a training program on a BT or a VR knee arthroscopy simulator. The VR simulator provided user performance feedback. Individuals performed a diagnostic arthroscopy on both simulators before and after the training program. Performance was assessed using wireless objective motion analysis and a global rating scale. RESULTS: The groups (8 in the VR group, 9 in the BT group) were well matched at baseline across all parameters (P > .05). Training on each simulator resulted in significant performance improvements across all parameters (P < .05). BT training conferred a significant improvement in all parameters when trainees were reassessed on the VR simulator (P < .05). In contrast, VR training did not confer improvement in performance when trainees were reassessed on the BT simulator (P > .05). BT-trained subjects outperformed VR-trained subjects in all parameters during final assessments on the BT simulator (P < .05). There was no difference in objective performance between VR-trained and BT-trained subjects on final VR simulator wireless objective motion analysis assessment (P > .05). CONCLUSIONS: Both simulators delivered improvements in arthroscopic skills. BT training led to skills that readily transferred to the VR simulator. Skills acquired after VR training did not transfer as readily to the BT simulator. Despite trainees receiving automated metric feedback from the VR simulator, the results suggest a greater gain in psychomotor skills for BT training. Further work is required to determine if this finding persists in the operating room. CLINICAL RELEVANCE: This study suggests that there are differences in skills acquired on different simulators and skills learnt on some simulators may be more transferable. Further work in identifying user feedback metrics that enhance learning is also required.

Can Surgical Trainees Achieve Arthroscopic Competence at the End of Training Programs? A Cross-sectional Study Highlighting the Impact of Working Time Directives.

PURPOSE: To provide training guidance on procedure numbers by assessing how the number of previously performed arthroscopic procedures relate to both competent and expert performance in simulated arthroscopic shoulder tasks. METHODS: A cross-sectional study that assessed simulated shoulder arthroscopic performance was undertaken. A total of 45 participants of varying experience performed 2 validated tasks: a simple diagnostic task and a more complex Bankart labral repair task. All participants provided logbook numbers for previously performed arthroscopies. Performance was assessed with the Global Rating Scale and motion analysis. Receiver operating characteristic curve analyses were conducted to identify optimum cut points for task proficiency at both "competent" and "expert" levels. RESULTS: Increasing surgical experience resulted in significantly better performance for both tasks as assessed by Global Rating Scale or motion analysis (P < .0001). Receiver operating characteristic curve analyses demonstrated 52 previous arthroscopies were needed to perform to a competent level at the diagnostic task and 248 to be competent at the complex task. To perform at an expert level, 290 and 476 previous arthroscopies, respectively, were needed. CONCLUSIONS: This study provides quantified guidance for arthroscopic training and highlights the positive relationship between arthroscopic case load and arthroscopic competency. We have estimated that the number of arthroscopies required to achieve competency in a basic arthroscopic task exceed those recommended in some countries. These estimates provide useful guidance to those responsible for training program. CLINICAL RELEVANCE: The numbers to achieve competent arthroscopic performance in the assessed simulated tasks exceed what is recommended and what is possible during surgical training programs in some countries.

Newly acquired arthroscopic skills: Are they transferable during simulator training of other joints?

PURPOSE: This randomized study investigates whether novices learning simulation-based arthroscopic skills in one anatomical joint environment can immediately transfer their learnt skills to another joint. METHODS: Medical students were randomized to a simulated diagnostic knee or shoulder arthroscopic task on benchtop training models. After nine task repetitions over 3 weeks on one model, each participant undertook the simulation task of the other anatomical joint. Performance was objectively measured using a validated electromagnetic motion analysis system and a validated global rating scale (GRS). RESULTS: Eighteen students participated; eight started the knee task and ten the shoulder task. All participants demonstrated a learning curve in all parameters during task repetition (time taken, hand path length, number of hand movements and GRS scores; p < 0.001) with learning effects >1 SD from initial performance (range 1.1-2.2 SD). When the groups swapped models, there was no immediate evidence of skill transfer, with a significant drop in performance between the final training episode and the transfer task (all parameters p < 0.003). In particular, the transfer task performance was no better than the first episode performance on that model by these novices. CONCLUSION: This study showed basic arthroscopic skills did not immediately transfer to an unfamiliar anatomical environment within a simulated setting. These findings have important clinical implications with regard to surgical training as they potentially challenge the assumption that arthroscopic skills acquired in one joint are universally transferrable to other joints. Future orthopaedic simulation training should aim to deliver exposure to a greater variety of arthroscopic procedures and joint environments. This would allow trainees to become familiar with the different arthroscopic setting before undertaking real surgery and consequently improve patient safety. LEVEL OF EVIDENCE: Therapeutic, Level II.

miREval 2.0: a web tool for simple microRNA prediction in genome sequences.

RESULT: We have developed miREval 2.0, an online tool that can simultaneously search up to 100 sequences for novel microRNAs (miRNAs) in multiple organisms. miREval 2.0 uses multiple published in silico approaches to detect miRNAs in sequences of interest. This tool can be used to discover miRNAs from DNA sequences or to validate candidates from sequencing data. AVAILABILITY: http://mimirna.centenary.org.au/mireval/.

Older patients have the most to gain from orthopaedic enhanced recovery programmes.

BACKGROUND: Between August 2007 and May 2009, 2128 consecutive patients underwent either primary hip or knee joint replacement surgery at our institute on an enhanced recovery pathway. We aimed to investigate the potential benefits of this pathway in patients over the age of 85 years. METHODS: Data extracted from Hospital Episode Statistics were analysed. This data are prospectively collected and independently collated. RESULTS: In all patients median length of stay was reduced when compared with both our own data before the introduction of the pathway (6 to 4 days) and national averages over the same time period for both hip and knee replacements (5 to 4 days). Difference in length of stay was most pronounced in the group of patients aged 85 years and over (9 to 5 days for total hip replacement and 8 to 5 days for total knee replacement). Nearly all patients were discharged directly home (97.4%). Readmission rates were over 45% lower in patients aged 85 and over when compared with national averages (5.2 vs. 9.4%). CONCLUSIONS: This is the first series in the literature to assess the role of enhanced recovery pathways in the very elderly. This study not only shows that successful fast track rehabilitation can be achieved in the very elderly population undergoing elective joint replacement surgery, but that it is this cohort of vulnerable patients who have the most to gain from such multidisciplinary recovery programmes.

Validating a global rating scale to monitor individual resident learning curves during arthroscopic knee meniscal repair.

PURPOSE: To determine whether a global rating scale (GRS) with construct validity can also be used to assess the learning curve of individual orthopaedic trainees during simulated arthroscopic knee meniscal repair. METHODS: An established arthroscopic GRS was used to evaluate the technical skill of 19 orthopaedic residents performing a standardized arthroscopic meniscal repair in a bioskills laboratory. The residents had diagnostic knee arthroscopy experience but no experience with arthroscopic meniscal repair. Residents were videotaped performing an arthroscopic meniscal repair on 12 separate occasions. Their performance was assessed by use of the GRS and motion analysis objectively measuring the time taken to complete tasks, path length of the subject's hands, and number of hand movements. One author assessed all 228 videos, whereas 2 other authors rated 34 randomly selected videos, testing the interobserver reliability of the GRS. The validity of the GRS was tested against the motion analysis. RESULTS: Objective assessment with motion analysis defined the surgeon's learning curve, showing significant improvement by each subject over 12 episodes (P < .0001). The GRS also showed a similar learning curve with significant improvements in performance (P < .0001). The median GRS score improved from 15 of 34 (interquartile range, 14 to 17) at baseline to 22 of 34 (interquartile range, 19 to 23) in the final period. There was a moderate correlation (P < .0001, Spearman test) between the GRS and motion analysis parameters (r = -0.58 for time, r = -0.58 for path length, and r = -0.51 for hand movements). The inter-rater reliability among 3 trained assessors using the GRS was excellent (Cronbach α = 0.88). CONCLUSIONS: When compared with motion analysis, an established arthroscopic GRS, with construct validity, also offers a moderately feasible method to monitor the learning curve of individual residents during simulated knee meniscal repair. CLINICAL RELEVANCE: An arthroscopic GRS can be used for monitoring skill improvement during knee meniscal repair and has the potential for use as a training and assessment tool in the real operating room.

Healthy Eating for Elective Major Orthopedic Surgery: Quality, Quantity, and Timing.

Improvements to enhanced recovery pathways in orthopedic surgery are reducing the time that patients spend in the hospital, giving an increasingly vital role to prehabilitation and/or rehabilitation after surgery. Nutritional support is an important tenant of perioperative medicine, with the aim to integrate the patient's diet with food components that are needed in greater amounts to support surgical fitness. Regardless of the time available between the time of contemplation of surgery and the day of admission, a patient who eats healthy is reasonably more suitable for surgery than a patient who does not meet the daily requirements for energy and nutrients. Moreover, a successful education for healthy food choices is one possible way to sustain the exercise therapy, improve recovery, and thus contribute to the patient's long-term health. The expected benefits presuppose that the patient follows a healthy diet, but it is unclear which advice is needed to improve dietary choices. We present the principles of healthy eating for patients undergoing major orthopedic surgery to lay the foundations of rational and valuable perioperative nutritional support programs. We discuss the concepts of nutritional use of food, requirements, portion size, dietary target, food variety, time variables of feeding, and the practical indications on what the last meal to be consumed six hours before the induction of anesthesia may be together with what is meant by clear fluids to be consumed until two hours before. Surgery may act as a vital "touch point" for some patients with the health service and is therefore a valuable opportunity for members of the perioperative team to promote optimal lifestyle choices, such as the notion and importance of healthy eating not just for surgery but also for long-term health benefit.