Evaluation of a prospective adverse event reporting system in interventional radiology.

AIM: To assess the performance of a prospective adverse event (AE) reporting system. MATERIALS AND METHODS: Four hundred and seventy-one consecutive arterial procedures were performed in 465 patients (median age, 65 years; interquartile range, 54-77; 276 men) over 2 years by four interventional radiologists at a single centre where clinical follow-up was not performed routinely by interventional radiology (IR). AEs were reported prospectively using a radiology information system or in interventional radiologists' electronic records and combined in a departmental listing of adverse events (DLAE). A retrospective medical record review was performed to identify a reference standard list of AEs for this observational cohort study. AEs were graded according to the Society of Interventional Radiology AE classification system. Descriptive statistics were calculated for the performance of the DLAE. A model comparing the rate of reporting of AEs with and without integration of clinical follow-up was tested for significance. RESULTS: Thirty-eight of the 471 (8%) IR procedures had an AE according to the reference standard. The DLAE identified 20/38 (53%) of AEs (K=0.67 [good agreement], 95% confidence interval [CI] agreement=0.53-0.81; p=0.0001; sensitivity 52.6% [95% CI, 36-69%], specificity 100% [95% CI, 99-100%], positive predictive value [PPV] 100%, negative predictive value [NPV] 96 [95% CI, 94.5-97%], accuracy 96% [95% CI, 94-97%]). The performance of the AE reporting system will improve with integration of clinical follow-up (p=0.0015). CONCLUSION: A prospective AE reporting system without clinical integration will not detect all procedure complications.

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

Impact of surgeon laparoscopic training and case volume of laparoscopic surgery on conversion during elective laparoscopic colorectal surgery.

AIM: The study aimed to determine whether laparoscopic volume and type of training influence conversion during elective laparoscopic colorectal surgery. METHOD: An Institutional Review Board-approved prospective database was reviewed for patients who underwent colorectal resection, performed by six colorectal surgeons, for all diagnoses from 2009 to 2014. Surgeons were designated as laparoscopic- or open-trained based on formal laparoscopic colorectal surgery training, and were classified as low laparoscopic volume (LLV) (i.e. had performed < 100 laparoscopic procedures) or high laparoscopic volume (HLV) (i.e. had performed ≥ 100 laparoscopic procedures). Technique was laparoscopic, open or converted (pre-emptive or reactive). Conversion was compared among three groups: LLV, laparoscopic trained (group A); LLV, open trained (group B); and HLV, open trained (group C). RESULTS: In total, 159/567 procedures were open and 408 laparoscopic procedures were attempted. Of the 408 laparoscopic procedures, 73 were converted. Among the 567 patients [mean age: 56 ± 17 years (44% male)], the overall conversion rate was 13% (73/567), including 75% pre-emptive and 25% reactive. Conversion rates for groups A, B and C were 17.9%, 42.6% and 14.3%, respectively. Significantly higher conversion was seen in group B compared with group C (P = 0.01), but not between group A and group C (P = 0.85) or between group B and group A (P = 0.11). Converted patients were older (P < 0.001), with lower rates of proctectomy (P = 0.007), higher rates of anastomosis (P < 0.001) and higher body mass index (BMI) (P < 0.001). After adjusting for patient and surgeon factors, training type was not associated with conversion (P = 0.15). Compared with successful laparoscopy, converted patients had a significantly higher incidence of ileus (P < 0.001), length of stay (P = 0.002), time to flatus (OR = 3.21, P < 0.001) and time to solids (P < 0.001). Converted patients experienced increased morbidity. CONCLUSION: Training is not associated with conversion. Rather, HLV surgeons, regardless of training, convert less frequently than do LLV surgeons.

What is the fate of the cholecystostomy tube following percutaneous cholecystostomy?

INTRODUCTION: Cholecystectomy is the preferred treatment for acute cholecystitis with percutaneous cholecystostomy (PC) considered an alternative therapy in severely debilitated patients. The aim of this study was to evaluate the efficacy and outcomes of PC at a tertiary referral center. METHODS: We retrospectively reviewed all patients that had undergone PC from 2000 to 2014. Data collected included baseline demographics, comorbidities, details of PC placement and management, and post-procedure outcomes. The Charlson comorbidity index (CCI) was calculated for all patients at the time of PC. RESULTS: Four hundred and twenty-four patients underwent PC placement from 2000 to 2014, and a total of 380 patients had long-term data available for review. Within this cohort, 223 (58.7 %) of the patients were male. The mean age at the time of PC placement was 65.3 ± 14.2 years of age, and the mean CCI was 3.2 ± 2.1 for all patients. One hundred and twenty-five (32.9 %) patients went on to have a cholecystectomy following PC placement. Comparison of patients who underwent PC followed by surgical intervention revealed that they were significantly younger (p = 0.0054) and had a lower CCI (p < 0.0001) compared to those who underwent PC alone. CONCLUSIONS: PC placement appears to be a viable, long-term alternative to cholecystectomy for the management of biliary disease in high-risk patients. Old and frail patients benefit the most, and in this cohort PC may be the definitive treatment.

Outcomes of concomitant ventral hernia repair performed during bariatric surgery.

BACKGROUND: Currently there is no consensus on management of ventral hernias encountered during bariatric surgery (BS). This study aims to evaluate the incidence and outcomes of concomitant ventral hernia repair (VHR) during BS at our institution. METHODS: Patients who had concomitant VHR during BS from 2004 to 2015 were identified. Data collected included baseline demographics, comorbidities, perioperative parameters, surgical approach and postoperative outcomes. RESULTS: A total of 159 patients underwent concomitant VHR during the study period at the time of BS. One hundred and one (64 %) patients were female; median age was 53 years (IQR 45.0-60.3) and median BMI was 48.2 kg/m2 (IQR 41.6-54.1). Comorbidities included: hypertension (n = 124, 78 %), type 2 diabetes (n = 103, 65 %), hyperlipidemia (n = 100, 63 %), obstructive sleep apnea (n = 98, 62 %) and reflux disease (n = 54, 34 %). Out of 159 patients, 41 patients (26 %) had a prior VHR. Out of 103 patients, 69 patients (67 %) had a previous abdominal surgery. Of the concomitant VHR, 144 (91 %) were completed laparoscopically, 12 (7 %) patients were converted to open surgery and 3 (2 %) patients underwent primary open procedures. Technique included primary suture closure in 115 (72 %) and mesh repair in 44. Early postoperative complications (<30 days) were reported in 16 (10 %) patients, with superficial wound infection (n = 9), bowel obstruction (n = 2), marginal ulcer (n = 2), DVT (n = 1) and pneumonia (n = 1). Hernia recurrence was reported in 3 patients (2 %) in the early post-op period and in 40 patients (25 %) as a late (>30 days) complication. Surgery for recurrent hernia was performed in 31/42 patients during follow-up. At 12-month follow-up, median BMI and % excess weight loss were 34.2 kg/m2 (IQR 29.5-40.9) and 59.6 % (IQR 44.9-74.8 %), respectively. CONCLUSION: Ventral hernia is a common finding in patients undergoing BS. Both primary suture repair and mesh repair result in acceptable results, both in terms of recurrence and perioperative complications.

Comparing Normothermic Machine Perfusion Preservation With Different Perfusates on Porcine Livers From Donors After Circulatory Death.

The utilization of normothermic machine perfusion (NMP) may be an effective strategy to resuscitate livers from donation after circulatory death (DCD). There is no consensus regarding the efficacy of different perfusates on graft and bile duct viability. The aim of this study was to compare, in an NMP porcine DCD model, the preservation potential of three different perfusates. Twenty porcine livers with 60 min of warm ischemia were separated into four preservation groups: cold storage (CS), NMP with Steen solution (Steen; XVIVO Perfusion Inc., Denver, CO), Steen plus red blood cells (RBCs), or whole blood (WB). All livers were preserved for 10 h and reperfused to simulate transplantation for 24 h. During preservation, the NMP with Steen group presented the highest hepatocellular injury. At reperfusion, the CS group had the lowest bile production and the worst hepatocellular injury compared with all other groups, followed by NMP with Steen; the Steen plus RBC and WB groups presented the best functional and hepatocellular injury outcomes, with WB livers showing lower aspartate aminotransferase release and a trend toward better results for most parameters. Based on our results, a perfusate that contains an oxygen carrier is most effective in a model of NMP porcine DCD livers compared with Steen solution. Specifically, WB-perfused livers showed a trend toward better outcomes compared with Steen plus RBCs.

Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial.

BACKGROUND: Low fibrinogen (Fg) concentrations in trauma haemorrhage are associated with poorer outcomes. Cryoprecipitate is the standard source for Fg administration in the UK and USA and is often given in the later stages of transfusion therapy. It is not known whether early cryoprecipitate therapy improves clinical outcomes. The primary aim of this feasibility study was to determine whether it was possible to administer cryoprecipitate, within 90 min of admission to hospital. Secondary aims were to evaluate laboratory measures of Fg and clinical outcomes including thrombotic events, organ failure, length of hospital stay and mortality. METHODS: This was an unblinded RCT, conducted at two civilian UK major trauma centres of adult trauma patients (age ≥16 yrs), with active bleeding and requiring activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy (STANDARD) (n=22), or to standard haemorrhage therapy plus two early pools of cryoprecipitate (CRYO) (n=21). RESULTS: 85% (95% CI: 69-100%) CRYO participants received cryoprecipitate within 90 min, median time 60 min (IQR: 57-76) compared with 108 min (67-147), CRYO and STANDARD arms respectively (P=0.002). Fg concentrations were higher in the CRYO arm and were maintained above 1.8 g litre(-1) at all time-points during active haemorrhage. All-cause mortality at 28 days was not significantly different (P=0.14). CONCLUSIONS: Early Fg supplementation using cryoprecipitate is feasible in trauma patients. This study supports the need for a definitive RCT to determine the effect of early Fg supplementation on mortality and other clinical outcomes. TRIAL REGISTRY NUMBER: ISRCTN55509212.

What is the role of 'the letter to the editor'?

The letter to the editor plays a dual role in the literature. It serves a corrective critical function but also has the capacity to spread and share knowledge. We sought to identify the role and theme of letters to the editor published in four leading otorhinolaryngology journals, to elicit how well this form of communication is being utilised. All letters to the editor published in; Clinical Otolaryngology, The Laryngoscope, The European Archives of Otorhinolarygnology and The Journal of Laryngology and Otology, for the year 2012, were examined and the individual journal guidelines for submission of letters were noted. Seventeen different countries produced a total of 92 letters for the year 2012. The majority of letters originated from Otolaryngology/Head and Neck departments (78 %). Clinical Otolaryngology contributed to 58 % of total letters, of which 55 % were unrelated to original journal material (n = 29). The Laryngoscope published letters solely in response to original journal material. The Journal of Laryngology and Otology was the only journal to index letters with their corresponding article. More letters agreeing (49 %) than disagreeing (32 %) were published, with the remaining letters either clarifying or ignoring issues raised. Letters to the editor serve two main purposes; post-publication peer review and sharing experiences with fellow readers. Both are equally important in maintaining journals' high standards. Indexing needs to be improved otherwise valuable comment does not endure while the original manuscript's message lives on.

The reporting of research ethics committee approval and informed consent in otolaryngology journals.

OBJECTIVES: Medical research involving human subjects must follow ethical standards as outlined in the Declaration of Helsinki of the World Medical Association. The aim of this study was to assess the frequency of reporting of informed consent and regional ethical committee (REC) approval in all reports of trials published in the major European Otolaryngology journals. DESIGN: Review of all clinical research articles published online in the calendar year 2012. SETTING: Three leading European Otolaryngology journals. PARTICIPANTS: Clinical Otolaryngology, The Journal of Laryngology and Otology and The European Achieves of Oto-Rhino-Laryngology. MAIN OUTCOME MEASURES: Evaluate the incidence of reporting of REC approval and informed consent. RESULTS: Of the 767 articles reviewed, 401 met the inclusion criteria (manuscripts reporting human subjects, human tissue or identifiable personal data research which require ethical approval). 49.9% lacked a statement of REC approval and 42.9% lacked disclosure of informed consent. Articles that did not state REC approval were associated with not stating informed consent (P < 0.05). CONCLUSION: Articles that lack explicit statements of REC approval and informed consent are frequent and continue to be published in major otolaryngology journals.

Autologous inferior dermal sling (autoderm) with concomitant skin-envelope reduction mastectomy: an excellent surgical choice for women with macromastia and clinically significant ptosis.

BACKGROUND: Skin-sparing mastectomy and prosthetic reconstruction can be complicated by poor surgical outcomes in large-breasted, obese women. This article describes a single surgeon's experience comparing conventional skin-sparing mastectomy (SSM) and skin-reduction mastectomy using an autologous vascularized inferior dermal/cutaneous sling (autoderm). METHODS: From July 2007 to May 2012, patients undergoing skin-sparing mastectomy were evaluated for surgical outcomes. After July 2009, the surgeon performed skin-reduction mastectomies with autoderm (SRM-AD) on all patients with macromastia or grade 3-4 ptosis. Remaining patients in this time period (SSM-cont) underwent conventional skin-sparing mastectomies while all previous patients (historical) also underwent skin-sparing mastectomies (SSM-hist). A predictive model was used to compare the large historical patients (who would have had reduction mastectomy if available) with the smaller historical patients to evaluate the effect of the procedure. RESULTS: Body mass index (BMI) and specimen weight were higher in both the SRM group and large historical group. The hazard ratio for having skin-reduction mastectomy was 0.53 (P = 0.51) compared with the historical group. There was a total of 16 complications for the whole study. Smoking was the only significant risk factor. CONCLUSIONS: This study shows that mastectomy with prosthetic reconstruction using a skin-reduction technique with autoderm can be done safely with a low complication rate and improved cosmetic outcomes in the traditionally "at-risk" group of women with high BMI and large ptotic breasts.

Clinical and biomarker profile of trauma-induced secondary cardiac injury.

BACKGROUND: Secondary cardiac injury has been demonstrated in critical illness and is associated with worse outcomes. The aim of this study was to establish the existence of trauma-induced secondary cardiac injury, and investigate its impact on outcomes in injured patients. METHODS: Injured adult patients eligible for enrolment in the Activation of Coagulation and Inflammation in Trauma 2 study, and admitted to the intensive care unit between January 2008 and January 2010, were selected retrospectively for the study. Markers of cardiac injury (brain natriuretic peptide (BNP), heart-type fatty acid binding protein (H-FABP) and troponin I) were measured on admission, and after 24 and 72 h in blood samples from injured patients. Individual records were reviewed for adverse cardiac events and death. RESULTS: During the study period, 135 patients were enrolled (106 male, 78·5 per cent) with a median age of 40 (range 16-89) years. Eighteen patients (13·3 per cent) had an adverse cardiac event during admission and these events were not associated with direct thoracic injury. The in-hospital mortality rate was higher among the adverse cardiac event cohort: 44 per cent (8 of 18) versus 17·1 per cent (20 of 117) (P = 0·008). Raised levels of H-FABP and BNP at 0, 24 and 72 h, and troponin I at 24 and 72 h, were associated with increased adverse cardiac events. BNP levels were higher in non-survivors on admission (median 550 versus 403 fmol/ml; P = 0·022), after 24 h (794 versus 567 fmol/ml; P = 0·033) and after 72 h (1043 versus 753 fmol/ml; P = 0·036), as were admission troponin I levels. CONCLUSION: Clinical and cardiac biomarker characteristics support the existence of trauma-induced secondary cardiac injury, which is associated with death, and unrelated to direct thoracic injury.

Radiologists are increasingly recommending follow-up of chest radiographs: a 10-year review.

PURPOSE: To assess for changes in trends of GP chest radiograph reporting over a 10-year period and to assess if there has been a change in recommendations for follow-up. METHODS: Retrospective study of an Irish tertiary referral center. The total number of GP-referred chest x-rays performed per year from 2007 to 2017 are recorded. One-hundred male/100 female GP-referred chest x-rays are chosen at random from NIMIS data for each of 2007, 2010, 2013, and 2017. Reports are analyzed with regard to abnormal findings, recommendation for follow-up, and yield of follow-up imaging. RESULTS: There were 4917 GP CXRs performed in 2007, 4856 in 2010, 5561 in 2013, and 6492 in 2017. Follow-up was recommended in 17 studies(8.5%) in 2007, 19 studies(9.5%) in 2010, 22 studies(11%) in 2013, and 27 studies(13.5%) in 2017. Indications for follow-up recommendation were largely to ensure resolution of infection (52%) or for nodule surveillance (43%). There has been a notable increase in lung nodule follow-up, with suggested follow-ups increasing from 6 in 2007, to 7 in 2010, 9 in 2013, and 14 in 2017, an increase of 58%. CONCLUSION: Along with the increase in the quantity of GP-referred chest radiographs over the past 10 years, suggestions for follow-up have increased, particularly for nodule surveillance. Reasons for this increase may include lack of availability of CT to GPs for lung cancer screening, insensitivity of plain radiographs to early cancer detection, and possible fear of litigation for missing lesions, making radiologists more cautious.

Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial.

PURPOSE: Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). METHODS: This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). RESULTS: Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76-1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54-1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84-5.34). CONCLUSION: There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.

Combining in silico and in vitro models to inform cell seeding strategies in tissue engineering.

The seeding density of therapeutic cells in engineered tissue impacts both cell survival and vascularization. Excessively high seeded cell densities can result in increased death and thus waste of valuable cells, whereas lower seeded cell densities may not provide sufficient support for the tissue in vivo, reducing efficacy. Additionally, the production of growth factors by therapeutic cells in low oxygen environments offers a way of generating growth factor gradients, which are important for vascularization, but hypoxia can also induce unwanted levels of cell death. This is a complex problem that lends itself to a combination of computational modelling and experimentation. Here, we present a spatio-temporal mathematical model parametrized using in vitro data capable of simulating the interactions between a therapeutic cell population, oxygen concentrations and vascular endothelial growth factor (VEGF) concentrations in engineered tissues. Simulations of collagen nerve repair constructs suggest that specific seeded cell densities and non-uniform spatial distributions of seeded cells could enhance cell survival and the generation of VEGF gradients. These predictions can now be tested using targeted experiments.

Diagnostic accuracy of SUVmax in predicting malignancy of supraclavicular lymph nodes from primary oesophageal cancer.

PURPOSE: To determine the diagnostic accuracy and optimum cut-off value of SUVmax on PET to predict malignancy of supraclavicular lymph nodes (SCLNs) in patients with oesophageal carcinoma. MATERIAL AND METHODS: All diagnosed cases of oesophageal cancer were retrospectively reviewed (2010-2016). Patients that had a confirmed diagnosis of oesophageal cancer with avid SCLNs on staging PET were included in the study. 33 SCLNs that subsequently underwent ultrasound guided biopsy for staging were analysed. The maximum uptake values (SUVmax) of the SCLNs and primary tumours were measured. A receiver operating characteristic (ROC) analysis was performed to determine the optimum cut off of SUVmax in predicting malignancy. RESULTS: 24/33 PET-detected SCLNs were malignant. ROC analysis identified the best nodal SUVmax cut-off to be 3.0. The diagnostic accuracy of PET was 76.0 % (sensitivity = 78.9 %, specificity = 66.6 %). For SCLNs with SUVmax > 3.0, PET showed a positive predictor value of 88.2 %; for SCLNs < 3.0, PET showed a negative predictor value of 50 %. The median SUVmax of pathologically negative and positive nodes were 2.8 (range 1.8-6.0) and 5.3 (range 1.9-13.4). The median primary tumour SUVmax was 13.8 (range 3.7-30.0). The SUVmax of metastatic lymph nodes were significant higher than those of benign lesions (p < 0.05). CONCLUSION: Our study revealed an accuracy rate of 76 % for PET detected SCLNs in patients with oesophageal carcinoma. For SCLNs with SUVmax > 3.0, PET had a high PPV (88 %), which can minimize the need for further diagnostic tests.

The value of multimodality imaging in the investigation of a PSA recurrence after radical prostatectomy in the Irish hospital setting.

INTRODUCTION: The diagnostic evaluation of a PSA recurrence after RP in the Irish hospital setting involves multimodality imaging with MRI, CT, and bone scanning, despite the low diagnostic yield from imaging at low PSA levels. We aim to investigate the value of multimodality imaging in PC patients after RP with a PSA recurrence. METHODS: Forty-eight patients with a PSA recurrence after RP who underwent multimodality imaging were evaluated. Demographic data, postoperative PSA levels, and imaging studies performed at those levels were evaluated. RESULTS: Eight (21%) MRIs, 6 (33%) CTs, and 4 (9%) bone scans had PCa-specific findings. Three (12%) patients had a positive MRI with a PSA <1.0 ng/ml, while 5 (56%) were positive at PSA ≥1.1 ng/ml (p = 0.05). Zero patient had a positive CT TAP at a PSA level <1.0 ng/ml, while 5 (56%) were positive at levels ≥1.1 ng/ml (p = 0.03). Zero patient had a positive bone at PSA levels <1.0 ng/ml, while 4 (27%) were positive at levels ≥1.1 ng/ml (p = 0.01). CONCLUSION: The diagnostic yield from multimodality imaging, and isotope bone scanning in particular, in PSA levels <1.0 ng/ml, is low. There is a statistically significant increase in the frequency of positive findings on CT and bone scanning at PSA levels ≥1.1 ng/ml. MRI alone is of investigative value at PSA <1.0 ng/ml. The indication for CT, MRI, or isotope bone scanning should be carefully correlated with the clinical question and how it will affect further management.

An allogeneic 'off the shelf' therapeutic strategy for peripheral nerve tissue engineering using clinical grade human neural stem cells.

Artificial tissues constructed from therapeutic cells offer a promising approach for improving the treatment of severe peripheral nerve injuries. In this study the effectiveness of using CTX0E03, a conditionally immortalised human neural stem cell line, as a source of allogeneic cells for constructing living artificial nerve repair tissue was tested. CTX0E03 cells were differentiated then combined with collagen to form engineered neural tissue (EngNT-CTX), stable aligned sheets of cellular hydrogel. EngNT-CTX sheets were delivered within collagen tubes to repair a 12 mm sciatic nerve injury model in athymic nude rats. Autologous nerve grafts (autografts) and empty tubes were used for comparison. After 8 weeks functional repair was assessed using electrophysiology. Further, detailed histological and electron microscopic analysis of the repaired nerves was performed. Results indicated that EngNT-CTX supported growth of neurites and vasculature through the injury site and facilitated reinnervation of the target muscle. These findings indicate for the first time that a clinically validated allogeneic neural stem cell line can be used to construct EngNT. This provides a potential 'off the shelf' tissue engineering solution for the treatment of nerve injury, overcoming the limitations associated with nerve autografts or the reliance on autologous cells for populating repair constructs.