The Association of Surgeons in Training (ASiT) Consensus Statement on Major Trauma Training in the UK.

INTRODUCTION: Since the establishment of the Major Trauma Networks in 2012, it is estimated that an extra 1,600 lives have been saved across England. Although the delivery of trauma care has improved significantly, the provision of trauma training has not and remains fragmented. The Association of Surgeons in Training (ASiT), an independent organisation run by trainees, is dedicated to excellence in surgical training within the United Kingdom (UK) and Republic of Ireland (ROI). The aim of this study was to develop a consensus statement representing the views of the ASiT on the future of trauma surgery training. METHODS: A modified nominal group technique was used in five stages: 1, scoping exercise; 2, virtual consultation; 3, nominal group consensus meeting; 4, virtual feedback from stakeholders; and 5, virtual confirmation by the ASiT Council. The design and reporting of the consensus followed best practice methodology for consensus research. RESULTS: Overall, 62 participants gave 90 statements across stages 1-3. Eleven key themes were identified, all of which met the consensus of the ASiT Council. The key findings were widespread support for increased exposure to trauma for medical students and early surgical trainees as well as an increased use of simulation methods and improved focus on non-technical skills within trauma surgery. CONCLUSIONS: This study sets out the position of the ASiT on the future of trauma surgery training and how training in major trauma surgery in the UK and ROI could be improved.

'Factors influencing future career choices of Queen's University Belfast Medical students.'

INTRODUCTION: Decisions made by medical students on future career choice have demonstrated concordance with subsequent postgraduate career path. This study aimed to understand the factors that impact undergraduate career decision making. METHODS: An anonymous voluntary survey consisting of binominal, Likert and free text responses was distributed to all medical students registered at Queen's University Belfast (QUB). Data was collected over 6 weeks in April-May 2021. The primary outcome was future career aspirations. The secondary outcomes were the impact of mentorship on career choice, the likelihood of students completing their medical degree and practicing medicine upon graduation. Local ethical approval was obtained. RESULTS: 202 responses were received (response rate 15%). 67% (n = 135) were female. One third of respondents remained undecided about their future career choice. Surgery was both the most popular definite career choice (16.3%) of respondents, butalsothespecialtymarkedmostoftenas'Least preferred Specialty' (33%). Factors positively influencing career choice were academic interest and flexibility in working hours. Negative predictors of career choice were lack of interest in the area, perceived workload, and duration of training schemes. 71% (n=144) of respondents reported that a subspecialty mentor would positively influence their career choice and two-thirds of respondents reported that financial factors would influence their career decision. 11% (n= 22) of respondents were unsure or undecided if they would continue medicine as a career upon graduation. CONCLUSION: Uncertainty over future career intention remains common with surgery the least popular speciality. Mentorship, integrating flexibility in training and enhancing academic interest should be considered by educational stakeholders as mechanisms to generating undergraduate interest in a subspecialty. Furthermore, the reported rate of students intention to leave their medical degree prior to graduation by this cohort is concerning, warranting further investigation.

The quantitative impact of COVID-19 on surgical training in the United Kingdom.

BACKGROUND: COVID-19 has had a global impact on all aspects of healthcare including surgical training. This study aimed to quantify the impact of COVID-19 on operative case numbers recorded by surgeons in training, and annual review of competency progression (ARCP) outcomes in the UK. METHODS: Anonymized operative logbook numbers were collated from electronic logbook and ARCP outcome data from the Intercollegiate Surgical Curriculum Programme database for trainees in the 10 surgical specialty training specialties.Operative logbook numbers and awarded ARCP outcomes were compared between predefined dates. Effect sizes are reported as incident rate ratios (IRR) with 95 per cent confidence intervals. RESULTS: Some 5599 surgical trainees in 2019, and 5310 in surgical specialty training in 2020 were included. The IRR was reduced across all specialties as a result of the COVID-19 pandemic (0.62; 95 per cent c.i. 0.60 to 0.64). Elective surgery (0.53; 95 per cent c.i. 0.50 to 0.56) was affected more than emergency surgery (0.85; 95 per cent c.i. 0.84 to 0.87). Regional variation indicating reduced operative activity was demonstrated across all specialties. More than 1 in 8 trainees in the final year of training have had their training extended and more than a quarter of trainees entering their final year of training are behind their expected training trajectory. CONCLUSION: The COVID-19 pandemic has had a major effect on surgical training in the UK. Urgent, coordinated action is required to minimize the impacts from the reduction in training in 2020.

Adapting an emergency general surgery service in response to the COVID-19 pandemic.

INTRODUCTION: In response to the COVID-19 pandemic, our emergency general surgery (EGS) service underwent significant restructuring, including establishing an enhanced ambulatory service and undertaking nonoperative management of selected pathologies. The aim of this study was to compare the activity of our EGS service before and after these changes. METHODS: Patients referred by the emergency department were identified prospectively over a 4-week period beginning from the date our EGS service was reconfigured (COVID) and compared with patients identified retrospectively from the same period the previous year (Pre-COVID), and followed up for 30 days. Data were extracted from handover documents and electronic care records. The primary outcomes were the rate of admission, ambulation and discharge. RESULTS: There were 281 and 283 patients during the Pre-COVID and COVID periods respectively. Admission rate decreased from 78.7% to 41.7%, while there were increased rates of ambulation from 7.1% to 17.3% and discharge from 6% to 22.6% (all p<0.001). For inpatients, mean duration of admission decreased (6.9 to 4.8 days), and there were fewer operative or endoscopic interventions (78 to 40). There were increased ambulatory investigations (11 to 39) and telephone reviews (0 to 39), while early computed tomography scan was increasingly used to facilitate discharge (5% vs 34.7%). There were no differences in 30-day readmission or mortality. CONCLUSIONS: Restructuring of our EGS service in response to COVID-19 facilitated an increased use of ambulatory services and imaging, achieving a decrease of 952 inpatient bed days in this critical period, while maintaining patient safety.

Predicting the safety of medicines in pregnancy: A workshop report.

The framework for developmental toxicity testing has remained largely unchanged for over 50 years and although it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience. Advances in omics, in silico approaches and alternative assays are providing opportunities to enhance our understanding of embryo-fetal development and the prediction of potential risks associated with the use of medicines in pregnancy. A workshop organised by the Medicines and Healthcare products Regulatory Agency (MHRA), "Predicting the Safety of Medicines in Pregnancy - a New Era?", was attended by delegates representing regulatory authorities, academia, industry, patients, funding bodies and software developers to consider how to improve the quality of and access to nonclinical developmental toxicity data and how to use this data to better predict the safety of medicines in human pregnancy. The workshop delegates concluded that based on comparative data to date alternative methodologies are currently no more predictive than conventional methods and not qualified for use in regulatory submissions. To advance the development and qualification of alternative methodologies, there is a requirement for better coordinated multidisciplinary cross-sector interactions coupled with data sharing. Furthermore, a better understanding of human developmental biology and the incorporation of this knowledge into the development of alternative methodologies is essential to enhance the prediction of adverse outcomes for human development. The output of the workshop was a series of recommendations aimed at supporting multidisciplinary efforts to develop and validate these alternative methodologies.

Innovation in surgical practice: The Association of Surgeons in Training conference - Belfast 2019.

The Association of Surgeons in Training (ASiT) advocates for and represents surgical trainees throughout the United Kingdom and the Republic of Ireland. It promotes excellence in surgical training for the benefit of both surgeons and patients. Originally founded in 1976, ASiT is independent of the National Health Service (NHS), Surgical Royal Colleges, and Specialty Associations. The 2019 Annual Conference in Belfast hosted a record number of delegates (n = 855) over the 3-day educational weekend. The conference theme, "Innovation in Surgical Practice" focused on the latest educational and technological innovation to enhance trainee's knowledge and experience of surgical innovation to ultimately enhance patient care. A record number of technical and non-technical pre-conference courses (n = 13) covering a diverse range of topics was offered. A new feature, a 24-h Hackathon, was successfully delivered in parallel to the Conference. This opportunity generated productive, cross speciality collaboration, to address and solve current problems in healthcare. Over 1000 abstract submissions were received and there were over 30 poster and oral prizes on offer for winning submissions. The ASiT conference and the Association continues to grow annually and we look forward to welcoming delegates to Birmingham from the 6-8th March 2020 to enjoy another action packed weekend focused on "Optimising Performance".

Simulation in surgical training: Prospective cohort study of access, attitudes and experiences of surgical trainees in the UK and Ireland.

BACKGROUND: Surgical training is evolving, and simulation is becoming more important as a way to expedite the early learning curve and augment surgical techniques. With novel technology, and innovation, major changes are possible in how surgeons are trained. The integration of these concepts into the surgical curriculum may drive up educational standards and enhance patient safety. This survey sought to determine surgical trainees views on the current place of simulation in surgical training and explore their vision for the future. MATERIAL AND METHODS: This is a prospective, questionnaire-based cross-sectional study by *** and the ***, England. Surgical trainees were surveyed about their experiences of simulation during their training through an electronic questionnaire distributed in the UK and Republic of Ireland through mailing lists of RCS and ***. Quantitative and qualitative research methodology was used. RESULTS: Of 462 surveys submitted, a total of 323 were fully completed and included in the analysis. Core Surgical Trainees represented 28.4% of respondents. The vast majority of respondents (98.9%) considered that simulation training was important, however 55.0% felt it was delivered inadequately. 86.2% wanted greater access to simulation training: Less than half of respondents had access to simulation training at their current place of work or had simulation incorporated into their formal teaching programme (42.4% and 41.6% respectively). CONCLUSION: This study highlights the importance of simulation to trainees. Delivery and accessibility of simulation training varies widely. We highlight areas for improvement and best practice. In a culture of accountability, where patient safety is our highest priority, a "see one, do one, teach one" approach to training is no longer appropriate; instead we must utilise available simulation tools to augment learning.

Applying dynamic data collection to improve dry electrode system performance for a P300-based brain-computer interface.

OBJECTIVE: Dry electrodes have an advantage over gel-based 'wet' electrodes by providing quicker set-up time for electroencephalography recording; however, the potentially poorer contact can result in noisier recordings. We examine the impact that this may have on brain-computer interface communication and potential approaches for mitigation. APPROACH: We present a performance comparison of wet and dry electrodes for use with the P300 speller system in both healthy participants and participants with communication disabilities (ALS and PLS), and investigate the potential for a data-driven dynamic data collection algorithm to compensate for the lower signal-to-noise ratio (SNR) in dry systems. MAIN RESULTS: Performance results from sixteen healthy participants obtained in the standard static data collection environment demonstrate a substantial loss in accuracy with the dry system. Using a dynamic stopping algorithm, performance may have been improved by collecting more data in the dry system for ten healthy participants and eight participants with communication disabilities; however, the algorithm did not fully compensate for the lower SNR of the dry system. An analysis of the wet and dry system recordings revealed that delta and theta frequency band power (0.1-4 Hz and 4-8 Hz, respectively) are consistently higher in dry system recordings across participants, indicating that transient and drift artifacts may be an issue for dry systems. SIGNIFICANCE: Using dry electrodes is desirable for reduced set-up time; however, this study demonstrates that online performance is significantly poorer than for wet electrodes for users with and without disabilities. We test a new application of dynamic stopping algorithms to compensate for poorer SNR. Dynamic stopping improved dry system performance; however, further signal processing efforts are likely necessary for full mitigation.

Respirable dust concentrations in equine stables. Part 2: the benefits of soaking hay and optimising the environment in a neighbouring stable.

The effect of soaking hay to minimise equine breathing zone respirable dust concentration (RDC) is unknown, as is the duration of soaking required. Additionally, the influence of the bedding and forage used in one stable on the mean and maximum RDC in a neighbouring stable within a common airspace is unknown. Consequently, in the management of equine environmental respiratory disease uncertainty remains about the necessity for optimising conditions in neighbouring stables. Investigations using a real-time continuous particle monitor revealed that when feeding hay, horses' mean breathing zone RDC was significantly reduced if the hay was immersed or soaked for a prolonged time, prior to feeding. There was no advantage in soaking for an extended time period. Implementing management changes in one stable (changing from straw bedding and hay feeding to wood shavings bedding and haylage feeding) significantly reduced mean and maximum background RDC in a neighbouring stable within a common airspace.

Respirable dust concentrations in equine stables. Part 1: validation of equipment and effect of various management systems.

Traditional methods of measuring airborne dust concentrations (ADC) in animal housing have included the collection of dust onto pre-weighed filters permitting the calculation of mean, not maximum, ADC. However real-time continuous particle monitors are advantageous in identifying short duration elevations in ADC which may be detrimental to equine respiratory health in the face of a relatively low mean ADC. These monitors have not previously been used to measure ADC in equine stables. Comparisons of a filter-based sampler and a real-time continuous particle monitor revealed no significant difference (P=0.079) and good agreement (>or=95% of the points fell within two standard deviations of the mean of the differences and the mean of the differences approximated zero) between the devices, with respect to mean respirable dust concentration (RDC) measurements. Investigations of the influence of various equine management systems on RDC revealed that both mean and maximum breathing zone RDC were significantly reduced (P<0.05) in equine stables by changing the environment from hay feed and straw bedding, to haylage feed and wood shavings bedding (reduction in mean - 0.0867mg/m(3) to 0.0260mg/m(3); reduction in maximum - 4.0758mg/m(3) to 0.2182mg/m(3), respectively).

Inhibition of matrix metalloproteinases and tumour necrosis factor alpha converting enzyme as adjuvant therapy in pneumococcal meningitis.

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.

Expression of specific matrix metalloproteinases in inflammatory myopathies.

The family of matrix metalloproteinases (MMPs) comprises endopeptidases that are capable of degrading all extracellular matrix components. Given these actions, it is conceivable that MMPs may play a pathogenic role in inflammatory myopathies. These immune-mediated disorders are characterized by the invasion of mononuclear phagocytes and T lymphocytes and the loss of muscle fibres. We examined whether specific MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases; TIMPs) are expressed in muscle during acute inflammatory attacks by studying muscle biopsies obtained from patients diagnosed as having polymyositis, dermatomyositis, sporadic inclusion body myositis and, for comparison, from cases of various muscular dystrophies. Quantitative polymerase chain reaction analysis revealed significantly elevated mRNA expression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) in polymyositis and dermatomyositis and to a lesser extent in inclusion body myositis, whereas the level of expression of TIMPs remained unchanged in comparison with controls. Increased mRNA levels were associated with enhanced enzyme expression, as determined by immunoblotting, gelatin zymography and in situ zymography. Immunohistochemically, MMP-1 could be localized around the sarcolemma of diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed to be expressed primarily by invading T lymphocytes. Raised levels of MMPs could not be detected in the sera of affected patients, emphasizing the crucial action of MMPs in the inflamed muscle. Our results imply a pathogenic role for specific MMPs in the genesis of inflammatory myopathies, and open new strategies for therapeutic intervention.

Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor.

Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 A, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureus protected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents.

The matrix metalloproteinase inhibitor BB-1101 prevents experimental autoimmune uveoretinitis (EAU).

EAU is characterized by breakdown of the blood-retinal barrier and extravasation of leucocytes into retinal tissue leading to destruction of photoreceptor cells. Matrix metalloproteinases (MMP) have been implicated in trafficking of cells into tissues, but their role in inflammatory eye disease is unclear. A synthetic MMP inhibitor, BB-1101, was administered subcutaneously, from either day 0 or day 7, to Lewis rats challenged with bovine S-antigen to induce EAU. When given up to day 14, BB-1101 reduced the incidence of disease and delayed the day of onset of clinical disease. When administered from day 7 until day 21, EAU was completely abrogated. A quantitative polymerase chain reaction (PCR) assay showed an increase of both matrilysin (MMP-7), neutrophil collagenase (MMP-8) and macrophage metalloproteinase (MMP-12) in retinas from EAU animals compared with naive controls. These enzymes are produced by activated leucocytes and act on components of the basement membrane. These results therefore implicate these MMP as integral to the development of pathology in EAU.

Differential expression of matrix metalloproteinases in bacterial meningitis.

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined. We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats. In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals. Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity. The mRNA expression pattern of six other MMPs was investigated. Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated. In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged. As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption. Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings. Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system.

Effective treatment of models of multiple sclerosis by matrix metalloproteinase inhibitors.

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.

Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS.

In an experimentally-induced DTH model of MS, we examined mRNA and protein expression of a range of MMPs and of TNFalpha to establish the contribution that individual MMPs might make to the pathogenesis. In control rat brain, mRNA for all of the MMPs examined was detectable. However, by immunohistochemistry, only MMP-2 could be detected. In the DTH lesions, significant increases in the level of mRNA expression were observed for MMP-7, MMP-8, MMP-12, and TNFalpha. Where expression of MMP mRNA was increased, there was a corresponding increase in protein expression detected by immunohistochemistry. To determine whether the upregulated MMPs could invoke destructive events in the CNS, highly purified activated MMP-7, MMP-8, and MMP-9 were stereotaxically injected into the brain parenchyma. All provoked recruitment of leukocytes and BBB breakdown. In addition, MMPs 7 and 9 induced loss of myelin staining. In conclusion, specific MMPs are upregulated in DTH lesions; for the most part, measurement of mRNA was a predictor of increased protein expression. From our injections of MMPs, it is clear that the upregulated MMPs in the DTH lesions could participate in the disruption of the BBB, leukocyte recruitment, and tissue damage.