Defining quality assessment in vascular surgery training: an expert Delphi process.

INTRODUCTION: A robust and reproducible way of assessing training should optimise and standardise vascular surgical training. This study describes the methodology supporting the Vascular Surgery Specialty Advisory Committee regional quality assurance reports for vascular surgery training programmes in the UK. METHODS: A Delphi consensus exercise was performed to establish the domains of training that most appropriately assess the quality of a vascular surgery training programme. A total of 54 stakeholders were invited to participate, including trainees, training programme directors and members of the vascular speciality advisory committee (SAC), vascular society executive and education committees. RESULTS: A total of 39 stakeholders successfully completed the three-stage Delphi process over 15 weeks. The domains identified as most appropriate to assess the quality of a vascular training programme were: Joint Committee on Surgical Training (JCST) survey results, clinical experience, regional education programmes, radiology support, timetable, regional support for trainees, trainer support for trainees, opportunities for professional development, trainee-rated quality of consultant teaching and training, and trainee recommendation of the post. CONCLUSIONS: This study describes a method to identify and prioritise domains that are appropriate to assess the quality of a vascular training programme. The domains that were identified as appropriate to assess quality are transferable internationally and the Delphi methodology could be used by other training schemes to 'fine-tune' their own domains to review and optimise the quality of their own training programmes.

Diaphragmatic crural augmentation utilising cross-linked porcine dermal collagen biologic mesh (Permacol) in the repair of large and complex para-oesophageal herniation: a retrospective cohort study.

OBJECTIVE: To evaluate the safety, efficacy and durability of selective integration of porcine dermal collagen (Permacol) biologic mesh for crural re-construction in large or complex para-oesophageal hernia surgery. BACKGROUND: Surgical repair of para-oesophageal herniation has been associated with high rates of failure. The utilisation of prosthetic mesh is controversial with complications including erosion and fistulation. Long-term outcomes for biologic mesh crural augmentation are unclear. METHODS: A retrospective analysis of patients who underwent a biologic mesh (Permacol) augmented cruroplasty in the repair of large and/or complex para-oesophageal hernia was performed utilising the prospectively maintained oesophago-gastric database at the Royal Devon and Exeter Hospital between October 2004 and January 2013. This technique was selectively used for patients where the lateral extent of the diaphragmatic-crural defect prevented the fashioning of a sound, tension-free repair with sutures alone, or previous surgery had failed. Successful outcome was defined by resolution of symptoms and structural integrity of the repair. RESULTS: Fifty one procedures were performed on 49 patients (15 male), median age 75 (range 25-91). Post-operative morbidity included 2 (3.9%) oesophageal injuries managed conservatively, and 2 (3.9%) patients who suffered early repair breakdown requiring immediate surgical re-intervention. Four patients (8%) required endoscopic dilatation due to dysphagia, one (2%) in the early post-operative phase. The median follow-up was 36 months (range 6-105). All patients reported initial symptomatic resolution. Two patients (4%) were demonstrated to have breakdown of their repair during the follow-up period, both of whom underwent revision mesh-augmented surgery and are re-incorporated in this series. Late-onset dysphagia in two (4%) patients may be mesh-related, but no other complications were observed and a Kaplan-Meier analysis of this series predicts a symptom-free rate of approximately 94% at 5 years. CONCLUSIONS: The selective integration of biologic mesh to augment the crural repair in para-oesophageal hernia with extensive diaphragmatic defects appears to be safe, effective and infers the potential of long-term satisfactory outcomes.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight­week randomized, double-blind, placebo-controlled, parallel-group phase III trial.

OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. METHODS: This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. RESULTS: ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). CONCLUSION: Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

The Contribution of DOPA to Substrate-Peptide Adhesion and Internal Cohesion of Mussel-Inspired Synthetic Peptide Films.

Mussels use a variety of 3, 4-dihydroxyphenyl-l-alanine (DOPA) rich proteins specifically tailored to adhering to wet surfaces. Synthetic polypeptide analogues of adhesive mussel foot proteins (specifically mfp-3) are used to study the role of DOPA in adhesion. The mussel-inspired peptide is a random copolymer of DOPA and N(5) -(2-hydroxyethyl)-l-glutamine synthesized with DOPA concentrations of 0-27 mol% and molecular weights of 5.9-7.1 kDa. Thin films (3-5 nm thick) of the mussel-inspired peptide are used in the surface forces apparatus (SFA) to measure the force-distance profiles and adhesion and cohesion energies of the films in an acetate buffer. The adhesion energies of the mussel-inspired peptide films to mica and TiO(2) surfaces increase with DOPA concentration. The adhesion energy to mica is 0.09 µJ m(-2) mol(DOPA) (-1) and does not depend on contact time or load. The adhesion energy to TiO(2) is 0.29 µJ m(-2) mol(DOPA) (-1) for short contact times and increases to 0.51 µJ m(-2) mol(DOPA) (-1) for contact times >60 min in a way suggestive of a phase transition within the film. Oxidation of DOPA to the quinone form, either by addition of periodate or by increasing the pH, increases the thickness and reduces the cohesion of the films. Adding thiol containing polymers between the oxidized films recovers some of the cohesion strength. Comparison of the mussel-inspired peptide films to previous studies on mfp-3 thin films show that the strong adhesion and cohesion in mfp-3 films can be attributed to DOPA groups favorably oriented within or at the interface of these films.

Protocols for high efficiency, stage-specific retroviral transduction of murine fetal thymocytes and thymic epithelial cells.

Viral vectors have the potential to provide a fast and economic alternative to transgenic methods for manipulating gene expression in studies of immune system development and function. Although protocols exist for the infection of hematopoietic precursors and peripheral T cells in vitro, critical stages of T cell differentiation are strictly dependent upon a three-dimensional thymic architecture and their analysis poses unique technical challenges. Whole fetal thymic lobes have been used as targets for retroviral and adenoviral infection, both in situ and in vitro, but this approach does not allow for discrimination between lymphoid and stromal components. Isolated thymocytes have been infected by co-culture with viral producer cells, but under these conditions they rapidly lose their developmental potential. To overcome these problems we have combined a number of efficient techniques for retroviral production, concentration, and infection that allow us to rapidly achieve significant transduction rates of purified populations of double-negative (DN) and double-positive (DP) thymocytes, single-positive (SP) T lymphocytes, as well as fetal thymic MHC II(+) epithelial cells without the need for co-culture with viral producer cells. Reaggregate thymic organ culture (RTOC) techniques were used to assess the development and function of transduced cells in defined cellular environments. As a demonstration of the utility of these methods, CD80 (B7.1) was transduced into thymic epithelial cells and shown to allow them to mediate negative selection of DP thymocytes, and to act as antigen-presenting cells (APC) to mature T cells. The ability to genetically manipulate primary cells of a specified type and differentiation stage provides a powerful complement to RTOC techniques for the study of T cell development.

IFN-alpha super-induction of HLA class I expression by a variant thymoma cell line involves nuclear translocation of Rel complexes.

Variant thymoma lines have been described which exhibit a substantially increased level of HLA class I induction by IFN-alpha, but not by IFN-gamma, and an unchanged response of other IFN-alpha-stimulated genes (Burrone et al., EMBO J. 1985. 4: 2855-2860). We report that their amplified response correlates with the nuclear translocation of Rel transcription factors upon prolonged treatment with IFN-alpha. The variant cells contain an IkappaBalpha subset with a significantly shortened half-life, and a constitutively active form of IkappaBalpha efficiently blocks HLA class I induction. Therefore, in addition to STAT-mediated induction, prolonged exposure to IFN-alpha can affect transcription involving Rel factors, which are implicated in the regulation of numerous immune response and viral genes.

Suppression of tumorigenicity in Ras-transformed fibroblasts by alpha 2(I) collagen.

Transformed fibroblasts exhibit reduced adhesion to substrata, a characteristic attributable in part to reduced expression/increased degradation of extracellular matrix (EM) proteins such as type I collagen. To directly assess the role of EM proteins in cellular transformation, a vKRas-transformed mouse fibroblast cell line was transfected with an alpha 2(I) collagen expression construct. Stable transfectants displaying a partial restoration of type I collagen expression showed a flatter morphology with increased adherence to the substratum. These clones also exhibited a reduced ability to clone in soft agar, slower growth kinetics, and suppression of tumorigenicity in nude mice. Restoration of type I collagen is correlated with down-regulation of ras oncogene-responsive NVL3 VL30 gene expression. These results suggest that in addition to suppressing tumorigenicity by promoting cellular adhesion and cytoskeletal organization, EM proteins such as type I collagen may also act to subvert oncoprotein signaling pathways associated with the malignant phenotype.

Regulation of cell differentiation in C2C12 myoblasts by the Id3 helix-loop-helix protein.

To investigate the biological functions of the helix-loop-helix Id3 protein, we have examined the effects of ectopic modulation of Id3 expression on in vitro induced differentiation of mouse C2C12 myoblast cells. Transient and stable C2C12 transfectants expressing either inducible or constitutive levels of exogenous Id3 were impaired in their ability to differentiate in response to removal of mitogenic serum growth factors. Stable Id3 transfectants displayed an enhanced proliferative capacity associated with a delay in exit from the cell cycle in response to differentiation induction. Antisense blockade of Id3 potentiated differentiation and exit from S phase of the cell cycle. These observations suggest that Id3 functions as a negative regulator of differentiation by integrating mitogenic growth factor signaling into the gene regulatory program maintaining cell cycle progression.

[The subjective experience in catatonia: systematic study of 24 catatonic patients]. / Subjektives Erleben in der Katatonie: Systematische Untersuchung bei 24 katatonen Patienten.

Catatonic patients are often not able to communicate their subjective experiences behind their "fassade of immobility." Therefore was retrospectively (3 weeks later) investigated subjective experiences in 24 catatonic patients with a self-assessment-scale especially for catatonia developed by us. Our results showed that catatonic patients subjectively experience less their altered movements but rather cognitive, i.e. ambivalence, or affective, i.e. intense emotions which couldn't be controlled, alterations. According to our results we were able to distinguish an emotive (intense anxiety) from a non-emotive, i.e. cognitive (predominating ambivalence), subtype in catatonia with regard to subjective experience.

Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study.

A prospective study was designed to evaluate the outcome of patients with localized resectable neuroblastoma without regional lymph node involvement when no therapy beyond surgical resection was administered. One hundred one patients observed for 3 to 60 months had a 2-year disease-free survival of 89% (SE = 5%). Of the nine patients experiencing relapse, only three have died. There were no apparent distinguishing characteristics of the nine failures. Due to the favorable prognosis of the subset of neuroblastoma patients, prognostic factor analysis had very limited power and lacked clinical importance. Complete gross removal of the localized tumors is adequate therapy to ensure the survival of the majority of these patients.

Papillary adenocarcinoma of rete testis. Autopsy findings, histochemistry, immunohistochemistry, ultrastructure, and clinical correlations.

Adenocarcinoma of the rete testis is a rare neoplasm that usually occurs in men after the age of 60 and carries a variable prognosis. We report an occurrence of this tumor in a 91-year-old man who had been treated for 2 years for an hydrocele. At the time of diagnosis, metastases were not evident; and the patient was treated with local radiotherapy. The diagnosis of papillary adenocarcinoma of the rete testis was made on the basis of: (a) a transition from normal rete testis to atypical and neoplastic rete epithelium; (b) exclusion of primary germinal and nongerminal testicular tumors and spread from distant sources; and (c) electron-microscopic findings, histochemical and immunological studies, and autopsy findings supporting the diagnosis. This is the first reported case of adenocarcinoma of the rete testis that includes documentation of the tumor's metastatic pattern.

Severe cardiopathy in branching enzyme deficiency.

A 7 1/2-year-old girl had exercise intolerance and exertional dyspnea. Four months later, congestive heart failure developed, with recurrent chylous pleural effusions, and she died at age 8 1/2 years. Endomyocardial biopsy tissue showed abundant PAS-positive, diastase-resistant cytoplasmic deposits. Similar inclusions were seen in muscle, skin, and liver specimens. Postmortem studies showed that the abnormal polysaccharide was especially abundant in heart and muscle, but was also present in all other tissues, including the central nervous system. Glycogen isolated from heart, muscle, and spinal cord showed a shift of the iodine spectrum toward higher than normal wavelengths. Branching enzyme activity was lacking in the muscle biopsy specimen and in all postmortem tissues; glycogenolytic enzymes had normal activities. These studies show that cardiomyopathy can be the first symptom of generalized branching enzyme deficiency and that the degree of accumulation of the abnormal polysaccharide may vary in different tissues.

The influence of repeated carotid plaque hemorrhages on the production of cerebrovascular symptoms.

Single carotid intraplaque hemorrhage has been related to the occurrence of cerebrovascular ischemic symptoms. We were unable to reproduce these findings; therefore, our patient population was reinvestigated to ascertain the importance of repeated plaque hemorrhages and their possible relationship to the production of neurologic symptoms. Eighty-five consecutive patients underwent 95 carotid endarterectomies. Plaques were separated into three groups: those from patients with lateralizing symptoms, nonlateralizing symptoms, and no symptoms. All the plaques were inspected microscopically for evidence of hemorrhage, specifically, repeated hemorrhages. Repeated hemorrhages were found in 29 of 44 plaques (66%) in the lateralizing symptom group, 6 of 19 (32%) in the nonlateralizing symptom group, and 12 of 32 (37%) in the no symptom group. We conclude that repeated rather than single intraplaque hemorrhage is the critical factor related to the production of specific cerebrovascular ischemic symptoms.

Chemical cholecystitis associated with hepatic arterial chemotherapy delivered by a permanently implanted pump.

The introduction of chemotherapeutic agents directly into the proper hepatic artery via an indwelling catheter results in perfusion of the gallbladder, because the cystic artery is usually a branch of the right hepatic artery. Five gallbladders, removed two to 16 months after insertion of permanently implanted Infusaid model 400 pumps, were examined. All of the gallbladders had significant arteritis, with narrowing or occlusion of lumina or necrosis of vessel walls. Fibrosis of the gallbladder wall was also a constant finding. Nuclear atypia of mucosal epithelium and connective tissue was common. Varying degrees of acute and chronic inflammation were present. These abnormalities may have a radiomimetic and direct irritant pathogenesis.

Intraplaque hemorrhage: its significance in cerebrovascular disease.

Recently, carotid plaque factors, specifically intraplaque hemorrhage, have been studied with respect to the production of cerebrovascular symptoms. Ninety-five carotid endarterectomies were performed and the plaques that were removed were examined for intraplaque hemorrhage. Patients were separated into three groups: those with specific neurologic symptoms, those with nonlateralizing symptoms, and those who were asymptomatic. In the group of patients who presented with specific neurologic symptoms, correlation was made between the age of the intraplaque hemorrhage and the timing of symptoms. The vast majority of patients with specific neurologic symptoms exhibited carotid plaque hemorrhage, but patients with nonlateralizing symptoms and those who were asymptomatic also demonstrated an unexpectedly high percentage of intraplaque hemorrhage. Moreover, our results show a poor relationship between the timing of symptoms and the age of the intraplaque hemorrhage. These data do not refute the concept that intraplaque hemorrhage may play a role in the production of cerebrovascular symptoms, but they do refute the notion that the mere presence of hemorrhage causes specific neurologic symptoms and they also refute the previous report that demonstrates a good correlation between the timing of symptoms and the age of the intraplaque hemorrhage.