Scoping Review of Factors Associated with Stem Cell Mobilization and Collection in Allogeneic Stem Cell Donors.

There is wide interindividual variation in the efficacy of CD34+ cell mobilization and collection in healthy allogenic hematopoietic stem cell donors. Donor characteristics, blood cell counts, and various factors related to mobilization and collection have been associated with blood CD34+ cell count and CD34+ cell yield after granulocyte colony-stimulating factor (G-CSF) mobilization and collection. Given the heterogenous nature of the literature reporting these associations, in this scoping review we clarify the determinants of CD34+ count and yield. Studies published between 2000 and 2023 reporting allogeneic donors undergoing G-CSF mobilization and peripheral blood stem cell (PBSC) collection were evaluated. Eligible studies were those that assessed blood CD34+ cell count or CD34+ cell yield in the first PBSC collection after mobilization with 4 or 5 days of G-CSF treatment. Associations were recorded between these outcomes and donor factors (age, sex, weight, ethnicity), mobilization factors (G-CSF scheduling or dose), collection factors (venous access, processed blood volume [PBV]) or laboratory factors (blood cell counts at baseline or after mobilization). The 52 studies evaluated between 15 and 20,884 donors. Forty-three studies were retrospective, 33 assessed blood CD34+ cell counts, and 39 assessed CD34+ cell yield from PBSCs. Blood CD34+ cell counts consistently predicted CD34+ cell yield. Younger donors usually had higher blood CD34+ cell counts and CD34+ cell yield. Most studies that investigated the effect of donor ancestry found that donors of non-European ancestry had higher blood CD34+ cell counts after mobilization and higher CD34+ cell yields from collection. The poor consensus about the best predictors of blood CD34+ cell count and yield necessitates further prospective studies, particularly of the role of donor ancestry. The current focus on donor sex as a major predictor requires re-evaluation.

Two-year safety outcomes of iPS cell-derived mesenchymal stromal cells in acute steroid-resistant graft-versus-host disease.

The first completed clinical trial of induced pluripotent stem cell (iPS cell)-derived cells was conducted in 15 participants with steroid-resistant acute graft-versus-host disease. After intravenous infusion of mesenchymal stromal cells (CYP-001 derived from a clone of human iPS cells), we reported the safety, tolerability and efficacy within the primary evaluation period at day 100. We now report results at the 2-year follow-up: 9 of 15 (60%) participants survived, which compares favorably with previously reported outcomes in studies of steroid-resistant acute graft-versus-host disease. Causes of death were complications commonly observed in recipients of allogeneic hematopoietic stem cell transplantation, and not considered by the investigators to be related to CYP-001 treatment. There were no serious adverse events, tumors or other safety concerns related to CYP-001. In conclusion, systemic delivery of iPS cell-derived cells was safe and well tolerated over 2 years of follow-up, with sustained outcomes up to 2 years after the first infusion. ClinicalTrials.gov registration: NCT02923375 .

BRD9 regulates normal human hematopoietic stem cell function and lineage differentiation.

Bromodomain containing protein 9 (BRD9), a member of the non-canonical BRG1/BRM-associated factor (ncBAF) chromatin remodeling complex, has been implicated as a synthetic lethal target in AML but its function in normal human hematopoiesis is unknown. In hematopoietic stem and progenitor cells (HSPC) genomic or chemical inhibition of BRD9 led to a proliferative disadvantage and loss of stem cells in vitro. Human HSPCs with reduced BRD9 protein levels produced lower numbers of immature mixed multipotent GEMM colonies in semi-solid media. In lineage-promoting culture conditions, cells with reduced BRD9 levels failed to differentiate into the megakaryocytic lineage and showed delayed differentiation into erythroid cells but enhanced terminal myeloid differentiation. HSPCs with BRD9 knock down (KD) had reduced long-term multilineage engraftment in a xenotransplantation assay. An increased number of downregulated genes in RNAseq analysis after BRD9 KD coupled with a gain in chromatin accessibility at the promoters of several repressive transcription factors (TF) suggest that BRD9 functions in the maintenance of active transcription during HSC differentiation. In particular, the hematopoietic master regulator GATA1 was identified as one of the core TFs regulating the gene networks modulated by BRD9 loss in HSPCs. BRD9 inhibition reduced a GATA1-luciferase reporter signal, further suggesting a role for BRD9 in regulating GATA1 activity. BRD9 is therefore an additional example of epigenetic regulation of human hematopoiesis.

Digital Media and Developing Brains: Concerns and Opportunities.

Purpose of Review: The incorporation of digital technologies and their use in youth's everyday lives has been increasing rapidly over the past several decades with possible impacts on youth development and mental health. This narrative review aimed to consider how the use of digital technologies may be influencing brain development underlying adaptive and maladaptive screen-related behaviors. Recent Findings: To explore and provide direction for further scientific inquiry, an international group of experts considered what is known, important gaps in knowledge, and how a research agenda might be pursued regarding relationships between screen media activity and neurodevelopment from infancy through childhood and adolescence. While an understanding of brain-behavior relationships involving screen media activity has been emerging, significant gaps exist that have important implications for the health of developing youth. Summary: Specific considerations regarding brain-behavior relationships involving screen media activity exist for infancy, toddlerhood, and early childhood; middle childhood; and adolescence. Transdiagnostic frameworks may provide a foundation for guiding future research efforts. Translating knowledge gained into better interventions and policy to promote healthy development is important in a rapidly changing digital technology environment.

Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma.

Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease.

Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.

AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.

Inoculation of Pan02 cells produces tumor nodules in mouse pancreas: Characterization of a novel orthotopic pancreatic ductal adenocarcinoma tumor model for interventional studies.

Preclinical models of cancer are vital for assessing and predicting efficacies and toxicities of novel treatments prior to testing in human subjects. Current pancreatic tumor models exhibit variable growth rates, unpredictable tumor size after implantation in non-native tissues, or require surgical implantation. Surgical implantation in the pancreas may produce not only unpredictable tumor uptake but could also elicit additional inflammatory responses. In searching for a pancreatic carcinoma cell that can be introduced into a mouse via simple injection, we found that Pan02, a murine ductal pancreatic adenocarcinoma derived from a pancreatic lesion of a C57BL/6 mouse, inoculated peritoneally can consistently produce pancreatic tumors. This intraperitoneal, but not intravenous, introduction of Pan02 cells leads to the attachment and growth of Pan02 in the pancreas before spreading to other tissues. Time-course tissue analysis indicates that the Pan02 cells first find, infiltrate, and grow within the pancreas, producing a pancreatic tumor model. This model appears to mimic pancreatic cancer development in humans and is the first reported use of Pan02 cells to produce orthotopic pancreatic and metastatic neoplasms in a mouse model without the need for tumor implantation within matrices or survival surgeries. This orthotopic pancreatic tumor model, with consistent tumor uptake, synchronized tumor development and survival, and predictable outcomes may enable and accelerate the preclinical evaluation of treatment candidates for pancreatic cancer.

Evaluation of the Embrittlement in Reactor Pressure-Vessel Steels Using a Hybrid Nondestructive Electromagnetic Testing and Evaluation Approach.

The nondestructive determination of the neutron-irradiation-induced embrittlement of nuclear reactor pressure-vessel steel is a very important and recent problem. Within the scope of the so-called NOMAD project funded by the Euratom research and training program, novel nondestructive electromagnetic testing and evaluation (NDE) methods were applied to the inspection of irradiated reactor pressure-vessel steel. In this review, the most important results of this project are summarized. Different methods were used and compared with each other. The measurement results were compared with the destructively determined ductile-to-brittle transition temperature (DBTT) values. Three magnetic methods, 3MA (micromagnetic, multiparameter, microstructure and stress analysis), MAT (magnetic adaptive testing), and Barkhausen noise technique (MBN), were found to be the most promising techniques. The results of these methods were in good agreement with each other. A good correlation was found between the magnetic parameters and the DBTT values. The basic idea of the NOMAD project is to use a multi-method/multi-parameter approach and to focus on the synergies that allow us to recognize the side effects, therefore suppressing them at the same time. Different types of machine-learning (ML) algorithms were tested in a competitive manner, and their performances were evaluated. The important outcome of the ML technique is that not only one but several different ML techniques could reach the required precision and reliability, i.e., keeping the DBTT prediction error lower than a ±25 °C threshold, which was previously not possible for any of the NDE methods as single entities. A calibration/training procedure was carried out on the merged outcome of the testing methods with excellent results to predict the transition temperature, yield strength, and mechanical hardness for all investigated materials. Our results, achieved within the NOMAD project, can be useful for the future potential introduction of this (and, in general, any) nondestructive evolution method.

Real-world evidence of heparin and citrate use in extracorporeal photopheresis: A hypothesis-generating data review of device settings and performance.

Extracorporeal photopheresis (ECP) is widely used for the treatment of cutaneous T-cell lymphoma, graft-vs-host disease, and other immune-related conditions. To avoid clotting during treatment, the ECP system used must be effectively primed with an anticoagulant. Heparin is the recommended anticoagulant for the THERAKOS CELLEX System, but acid citrate dextrose-A (ACDA) is often used. We compared system performance between these two anticoagulants for this ECP system. Deidentified data for ECP device performance were obtained at each treatment session, from automatically logged Smart Cards or labels completed by device operators. We compared the effects of ACDA or heparin on overall treatment duration, buffy coat (leukocyte) collection time, photoactivation time and the number of alarms and warnings. The variability in these parameters was also assessed. Data from 23 334 treat sessions were analyzed; ACDA was used in 34.4% and heparin in 65.6%. Overall, the ECP procedure duration, buffy coat collection time and photoactivation time were numerically similar regardless of whether ACDA or heparin was used, and regardless of needle mode. Photoactivation time variability was lower with ACDA compared with heparin in all needle modes. Among treatments that were completed automatically without any operator intervention, total treatment duration and photoactivation time were significantly reduced with ACDA use in both the double- and single-needle modes. The data presented indicate that, in both double- and single-needle modes, the THERAKOS® CELLEX® integrated ECP system performed similarly with ACDA compared to heparin, although ACDA demonstrated potential benefits in reducing variability in photoactivation time.

Persistence of inadequate consent training for interns.

BACKGROUND: Informed consent is a continuous process of communication with the patient and not merely the signing of a form. The Irish Medical Council's Guide to Good Practice and Ethics state that no part of the consent process should be delegated to an intern unless the procedure is a minor with which the intern is very familiar and all relevant information has first been explained to the intern. AIMS: We aimed to evaluate whether practices regarding interns and consent had changed in the past five years. METHODS: An anonymous Google Forms survey was distributed to interns from all intern networks between 24-August and 26-November 2021. RESULTS: Of 854 interns, there were 147(17.2%) survey responses. 129(87.8%) participants had consented for a procedure. 111(86%) responded that they had consented for procedures that they had not witnessed before. 92(71.3%) reported that their medical supervisor did not explain procedures to them prior to obtaining consent. 128(99.2%) of interns were not usually observed by a more senior doctor when obtaining consent. 116(89.9%) were expected to obtain consent from patients on a regular basis, with 78(60.5%) feeling pressured into doing so on at least one occasion. Results were largely unchanged compared to when the same survey was circulated in 2016. CONCLUSIONS: Interns remain routinely involved in the consent process without adequate training or supervision. This is unfair on our most junior doctors and on patients. Steps must be taken to ensure the IMC guidance is adhered to and this deficiency must be highlighted to Senior Clinicians.

Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.

Despite recent advances in the therapy of diffuse large B-cell lymphoma (DLBCL), many patients are still not cured. Therefore, new therapeutic strategies are needed. The anti-apoptotic B-cell lymphoma 2 (BCL2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32;q21) and copy number alterations; however, targeting BCL-2 with the selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a rational combination partner of venetoclax to improve its activity against DLBCL cells. Utilizing a functional assay, dynamic BH3 profiling, we found that the DNA hypomethylating agent decitabine increased mitochondrial apoptotic priming and BCL-2 dependence in DLBCL cells. RNA-sequencing analysis revealed that decitabine suppressed the pro-survival PI3K-AKT pathway and altered the mitochondria membrane composition in DLBCL cell lines. Additionally, it induced a DNA damage response and increased BAX and BAK activities. The combination of decitabine and venetoclax synergistically suppressed proliferation of DLBCL cells both in vitro and in vivo in a DLBCL cell line-derived xenograft mouse model. Our study suggests that decitabine plus venetoclax is a promising combination to explore clinically in DLBCL.

Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.

Patient and Physician Preferences for Acute Myeloid Leukemia Maintenance Treatments Following Hematopoietic Stem Cell Transplantation.

Purpose: This study assessed and compared preferences for treatment attributes of maintenance therapies post-hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and in physicians who treat these patients. Patients and Methods: Patients with AML post HSCT and physicians from the United States, United Kingdom, Canada, and Australia (physicians only) completed a web-based discrete choice experiment (DCE). The DCE used inputs identified via a targeted literature review and qualitative interviews to ascertain relevant treatment attributes and associated levels. Six treatment attributes were selected (chance of 2-year relapse-free survival, quality of life [QoL], risk of serious infections, risk of nausea, chance of achieving transfusion independence, and duration of hospitalization annually), each with three or four levels. The experimental design included 36 choice tasks that presented a pair of hypothetical treatment profiles with varying attribute levels; participants chose a preferred treatment for each choice task. Choice tasks were divided into three blocks of 12 tasks each in the patient survey and 4 blocks of 9 tasks each in the physician survey; survey participants were randomly assigned to one of the blocks. Random parameter logit regression models were used to assess the impact of stated attributes on preferences for maintenance treatment post HSCT. Results: Surveys from 84 patients and 149 physicians were assessed. For patients, QoL was the most important attribute, followed by duration of hospitalization and chance of 2-year relapse-free survival. For physicians, chance of 2-year relapse-free survival was the most important attribute, followed by QoL and risk of serious infections. Conclusion: Differences in how patients and physicians valued post-HSCT maintenance treatment attributes were identified. These differences suggest that patient-centered decision-making may help physicians choose maintenance treatments for patients with AML post HSCT that better meet their treatment needs and improve their treatment satisfaction.

Chimeric Antigen Receptor T Cell Therapy in Acute Myeloid Leukemia: Trials and Tribulations.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy that is often associated with relapse and drug resistance after standard chemotherapy or targeted therapy, particularly in older patients. Hematopoietic stem cell transplants are looked upon as the ultimate salvage option with curative intent. Adoptive cell therapy using chimeric antigen receptors (CAR) has shown promise in B cell malignancies and is now being investigated in AML. Initial clinical trials have been disappointing in AML, and we review current strategies to improve efficacy for CAR approaches. The extensive number of clinical trials targeting different antigens likely reflects the genetic heterogeneity of AML. The limited number of patients reported in multiple early clinical studies makes it difficult to draw conclusions about CAR safety, but it does suggest that the efficacy of this approach in AML lags behind the success observed in B cell malignancies. There is a clear need not only to improve CAR design but also to identify targets in AML that show limited expression in normal myeloid lineage cells.

UK robotic arthroplasty clinical and cost effectiveness randomised controlled trial for hips (RACER-Hip): a study protocol.

INTRODUCTION: The number of robotic-assisted hip replacement procedures has expanded globally with the intended aim of improving outcomes. Intraoperative robotic-arm systems add additional costs to total hip replacement (THR) surgery but may improve surgical precision and could contribute to diminished pain and improved function. Additionally, these systems may reduce the need for expensive revision surgery. Surgery with conventional instruments may be just as successful, quick and affordable. There is timely demand for a robust evaluation of this technology. METHODS AND ANALYSIS: The Robotic Arthroplasty Clinical and cost Effectiveness Randomised controlled trial for Hips (RACER-Hip) is a multicentre (minimum of six UK sites), participant-assessor blinded, randomised controlled trial. 378 participants with hip osteoarthritis requiring THR will be randomised (1:1) to receive robotic-assisted THR, or THR using conventional surgical instruments. The primary outcome is the Forgotten Joint Score at 12 months post-randomisation; a patient-reported outcome measure assessing participants' awareness of their joint when undertaking daily activities. Secondary outcomes will be collected post-operatively (pain, blood loss and opioid usage) and at 3, 6, 12, 24 months, then 5 and 10 years postrandomisation (including function, pain, health-related quality of life, reoperations and satisfaction). Allocation concealment will be accomplished using a computer-based randomisation procedure on the day of surgery. Blinding methods include the use of sham incisions for marker clusters and blinded operation notes. The primary analysis will adhere to the intention-to-treat principle. Results will adhere to Consolidated Standards of Reporting Trials statements. ETHICS AND DISSEMINATION: The trial was approved by an ethics committee (Solihull Research Ethics Committee, 30 June 2021, IRAS: 295831). Participants will provide informed consent before agreeing to participate. Results will be disseminated using peer-reviewed journal publications, presentations at international conferences and through the use of social media. We will develop plans to disseminate to patients and public with our patient partners. TRIAL REGISTRATION NUMBER: ISRCTN13374625.

Programmable multi-kilobase RNA editing using CRISPR-mediated trans-splicing.

Current gene editing approaches in eukaryotic cells are limited to single base edits or small DNA insertions and deletions, and remain encumbered by unintended permanent effects and significant challenges in the delivery of large DNA cargo. Here we describe Splice Editing, a generalizable platform to correct gene transcripts in situ by programmable insertion or replacement of large RNA segments. By combining CRISPR-mediated RNA targeting with endogenous cellular RNA-splicing machinery, Splice Editing enables efficient, precise, and programmable large-scale editing of gene targets without DNA cleavage or mutagenesis. RNA sequencing and measurement of spliced protein products confirm that Splice Editing achieves efficient and specific targeted RNA and protein correction. We show that Splice Editors based on novel miniature RNA-targeting CRISPR-Cas systems discovered and characterized in this work can be packaged for effective delivery to human cells and affect different types of edits across multiple targets and cell lines. By editing thousands of bases simultaneously in a single reversible step, Splice Editing could expand the treatable disease population for monogenic diseases with large allelic diversity without the permanent unintended effects of DNA editing.

Sickle Cell Virtual Support Group Program for Adults: An Implementation Evaluation.

Sickle cell disease (SCD) is associated with medical and psychosocial challenges. SCD in adulthood is characterized by increased morbidity and mortality, vulnerability, inadequate self-management preparation, and limited social support. This study evaluated the implementation of a virtual support group during the COVID-19 pandemic using an intervention parameters framework evaluation. Participants included six adults living with SCD. Content analysis was conducted for each of the six intervention parameters, and satisfaction scores were summarized. Participants positively evaluated all intervention parameters of the virtual support group. Findings confirmed that a community-engaged intervention supports self-management and establishes key social networks for adult participants.

Hip fracture surgery performed by cadaveric simulation-trained versus standard-trained orthopaedic trainees: a preliminary multicentre randomized controlled trial.

Aims: To evaluate if, for orthopaedic trainees, additional cadaveric simulation training or standard training alone yields superior radiological and clinical outcomes in patients undergoing dynamic hip screw (DHS) fixation or hemiarthroplasty for hip fracture. Methods: This was a preliminary, pragmatic, multicentre, parallel group randomized controlled trial in nine secondary and tertiary NHS hospitals in England. Researchers were blinded to group allocation. Overall, 40 trainees in the West Midlands were eligible: 33 agreed to take part and were randomized, five withdrew after randomization, 13 were allocated cadaveric training, and 15 were allocated standard training. The intervention was an additional two-day cadaveric simulation course. The control group received standard on-the-job training. Primary outcome was implant position on the postoperative radiograph: tip-apex distance (mm) (DHS) and leg length discrepancy (mm) (hemiarthroplasty). Secondary clinical outcomes were procedure time, length of hospital stay, acute postoperative complication rate, and 12-month mortality. Procedure-specific secondary outcomes were intraoperative radiation dose (for DHS) and postoperative blood transfusion requirement (hemiarthroplasty). Results: Eight female (29%) and 20 male trainees (71%), mean age 29.4 years, performed 317 DHS operations and 243 hemiarthroplasties during ten months of follow-up. Primary analysis was a random effect model with surgeon-level fixed effects of patient condition, patient age, and surgeon experience, with a random intercept for surgeon. Under the intention-to-treat principle, for hemiarthroplasty there was better implant position in favour of cadaveric training, measured by leg length discrepancy ≤ 10 mm (odds ratio (OR) 4.08 (95% confidence interval (CI) 1.17 to 14.22); p = 0.027). There were significantly fewer postoperative blood transfusions required in patients undergoing hemiarthroplasty by cadaveric-trained compared to standard-trained surgeons (OR 6.00 (95% CI 1.83 to 19.69); p = 0.003). For DHS, there was no significant between-group difference in implant position as measured by tip-apex distance ≤ 25 mm (OR 6.47 (95% CI 0.97 to 43.05); p = 0.053). No between-group differences were observed for any secondary clinical outcomes. Conclusion: Trainees randomized to additional cadaveric training performed hip fracture fixation with better implant positioning and fewer postoperative blood transfusions in hemiarthroplasty. This effect, which was previously unknown, may be a consequence of the intervention. Further study is required.

Ankle fracture internal fixation performed by cadaveric simulation-trained versus standard-trained orthopaedic trainees: a preliminary, multicentre randomized controlled trial.

Aims: Ankle fracture fixation is commonly performed by junior trainees. Simulation training using cadavers may shorten the learning curve and result in a technically superior surgical performance. Methods: We undertook a preliminary, pragmatic, single-blinded, multicentre, randomized controlled trial of cadaveric simulation versus standard training. Primary outcome was fracture reduction on postoperative radiographs. Results: Overall, 139 ankle fractures were fixed by 28 postgraduate year three to five trainee surgeons (mean age 29.4 years; 71% males) during ten months' follow-up. Under the intention-to-treat principle, a technically superior fixation was performed by the cadaveric-trained group compared to the standard-trained group, as measured on the first postoperative radiograph against predefined acceptability thresholds. The cadaveric-trained group used a lower intraoperative dose of radiation than the standard-trained group (mean difference 0.011 Gym2, 95% confidence interval 0.003 to 0.019; p = 0.009). There was no difference in procedure time. Conclusion: Trainees randomized to cadaveric training performed better ankle fracture fixations and irradiated patients less during surgery compared to standard-trained trainees. This effect, which was previously unknown, is likely to be a consequence of the intervention. Further study is required.