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.

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.

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.

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.

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 during experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.

Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barré syndrome.

Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis. The present study investigated the expression of 92-kd gelatinase (MMP-9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune experimental neuritis (EAN), an experimental model of the Guillain-Barré syndrome (GBS). Quantitative polymerase chain reaction analysis revealed an up-regulation of MMP-9 mRNA with peak levels concurrent with maximal disease severity. Increased mRNA expression was associated with enhanced enzyme activity, as detected by gelatin zymography. Immunohistochemically, MMP-9 could be localized primarily around blood vessels within the epineurium and endoneurium in diseased but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of matrilysin (MMP-7) were found to be up-regulated at the peak of the disorder, remaining at high levels throughout the clinical recovery phase of the disease. To apply these findings to human disease, sural nerve biopsies from GBS patients were examined. By using immunohistochemistry, positive immunoreactivity against MMP-9 and MMP-7 was noted and corroborated by demonstrating augmented mRNA expression in comparison with noninflammatory neuropathies. Furthermore, increased MMP-9 activity was detected by zymography. These findings indicate that 92-kd gelatinase and matrilysin are selectively up-regulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the peripheral nervous system.

Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumour necrosis factor-alpha inhibitor.

Matrix metalloproteinases (MMPs) are a large family of Zn2+ endopeptidases that are expressed in inflammatory conditions and are capable of degrading connective tissue macromolecules. MMP-like enzymes are also involved in the processing of a variety of cell surface molecules including the pro-inflammatory cytokine TNF-alpha. MMPs and TNF-alpha have both been implicated in the pathology associated with neuro-inflammatory diseases (NIDs), particularly multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). We have shown that BB-1101, a broad spectrum hydroxamic acid-based combined inhibitor of MMP activity and TNF processing, reduces the clinical signs and weight loss in an acute EAE model in Lewis rats. However, little is known about which MMPs are involved in the neuroinflammatory process. In order to determine the optimum inhibitory profile for an MMP inhibitor in the treatment of NID, we investigated the profile of MMP expression and activity during EAE. The development of disease symptoms was associated with a 3-fold increase in MMP activity in the cerebrospinal fluid (CSF), which could be inhibited by treatment with BB-1101, and an increase in 92 kDa gelatinase activity detected by gelatin substrate zymography. Quantitative PCR analysis of normal and EAE spinal cord revealed the expression of at least seven MMPs. Of these, matrilysin showed the most significant change, being elevated over 500 fold with onset of clinical symptoms and peaking at maximum disease severity. Of the other six MMPs detected, 92 kDa gelatinase showed a modest 5 fold increase which peaked at the onset of clinical signs and then declined during the most severe phase of the disease. Matrilysin was localised by immunohistochemistry to the invading macrophages within the inflammatory lesions of the spinal cord. Matrilysin's potent broad spectrum proteolytic activity and its localisation to inflammatory lesions in the CNS suggest this enzyme could be particularly involved in the pathological processes associated with neuro-inflammatory disease.

Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview.

The matrix metalloproteinases (MMPs) are a family of at least 14 zinc-dependent enzymes which are known to degrade the protein components of extracellular matrix. In addition, MMPs and related enzymes can also process a number of cell surface cytokines, receptors, and other soluble proteins. In particular we have shown that the release of the pro-inflammatory cytokine, tumor necrosis factor-alpha, from its membrane-bound precursor is an MMP-dependent process. MMPs are expressed by the inflammatory cells which are associated with CNS lesions in animal models of multiple sclerosis (MS) and in tissue from patients with the disease. MMP expression will contribute to the tissue destruction and inflammation in MS. Drugs which inhibit MMP activity are effective in animal models of MS and may prove to be useful therapies in the clinic.

Quantitation of matrix metalloproteinases in cultured rat astrocytes using the polymerase chain reaction with a multi-competitor cDNA standard.

Matrix metalloproteinases (MMPs) are a family of Zn2+ endopeptidases that are expressed in many inflammatory conditions and that contribute to connective tissue breakdown and the release of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha). There is emerging evidence that MMPs have a role in inflammatory disorders of the central nervous system (CNS) such as multiple sclerosis. However, little is known about the expression of MMPs by inflamed tissue within the CNS or by the glia, neurones, and leucocytes which participate in the inflammatory response. To address this issue we have developed a polymerase chain reaction (PCR)-based method for the quantitation of rat MMP mRNA levels, which we have applied to astrocyte cultures with and without inflammatory stimulation. The technique relies on a competition reaction in which a synthetic standard cDNA is co-amplified with the target cDNA in the same PCR reaction. Standard multi-competitor cDNAs, containing priming sites for nine MMPs, and two housekeeping genes were constructed. We have shown that MMP activity is increased over three-fold in neonatal rat astrocyte cultures following stimulation with lipopolysaccharide (LPS). At the mRNA level, MT-MMP-1, 72 kDa gelatinase, and stromelysin-3 were constitutively expressed and unaffected by LPS treatment, whereas 92 kDa gelatinase, and stromelysin-1 were strongly induced (1,000-fold). Stromelysin-2, rat collagenase, and macrophage metalloelastase were modestly upregulated by LPS treatment. Matrilysin was not expressed. This technique is suitable for quantifying MMP expression in the cells which contribute to inflammation in the CNS and could also be applied directly to tissue samples from animal models of disease.

Matrix metalloproteinases and processing of pro-TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is released from a cell membrane-anchored precursor by proteolytic cleavage. We have shown that broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs) prevent the processing of the TNF precursor but do not inhibit the release of other cytokines. Purified MMPs, stromelysin, matrilysin, collagenase, and the gelatinases can all cleave a recombinant pro-TNF substrate to yield mature TNF. MMP inhibitors prevent the rise in blood levels of TNF after endotoxin administration in rats and are effective in animal models of inflammatory disease such as adjuvant arthritis. Drugs that inhibit MMP action and TNF release show great promise for the treatment of autoimmune inflammatory diseases.

Expression and characterisation of a very-late antigen-4 (alpha 4 beta 1) integrin-binding fragment of vascular cell-adhesion molecule-1.

We have used an Escherichia coli expression system to produce forms of vascular cell-adhesion molecule-1 (VCAM-1) containing the first two and three supposed immunoglobulin-like domains. A form consisting of the first two domains of VCAM-1 is shown to promote very-late antigen-4-dependent spreading of a melanoma cell line comparable to that found for the equivalent region in the full seven-domain form. Preliminary structural analysis by CD and NMR is consistent with an immunoglobulin fold which is predicted from sequence comparison studies.

Macrophage-inflammatory protein protects multipotent hematopoietic cells from the cytotoxic effects of hydroxyurea in vivo.

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) has been assessed for its potential in vivo to protect hematopoietic progenitor cells from the cytotoxic effects of a cycle-specific drug--in this case hydroxyurea (HU). Two doses of HU, 7 hours apart, were administered to mice to induce spleen colony-forming unit (CFU-S) cycling and then to kill them during DNA-synthesis. MIP-1 alpha, in a variety of dose and time combinations, was injected before the second dose of HU in an attempt to prevent recruitment or maintain CFU-S quiescence, and thus protect them from the second dose of HU. Without MIP-1 alpha, recovery of the CFU-S population was complete in 7 days. In a dose-dependent manner, MIP-1 alpha either reduced the initial kill and accelerated recovery, or completely protected the CFU-S population. We conclude that MIP-1 alpha does protect multipotent progenitor cells in vivo and that these observations provide a base from which to build practical clinical applications.