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Simulation, if appropriately integrated into surgical training, may provide a time efficient, cost effective and safe method of training. The use of simulation in urology training is supported by a growing evidence base for its use, leading many authors to call for it to be integrated into the curriculum. There is growing evidence for the utilisation of part task (technical skills) simulators to shorten the learning curve in an environment that does not compromise patient safety. There is also evidence that non-technical skills affect patient outcomes in the operating room and that high fidelity team based simulation training can improve non-technical skills and surgical team performance. This evidence has strengthened the argument of surgical educators who feel that simulation should be formally incorporated into the urology training curriculum to develop both technical and non-technical skills with the aim of optimising performance and patient safety., (Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Background Aims: Immunotherapy with allodepleted donor T cells improves immunity after T cell-depleted hematopoietic stem cell transplantation. We developed a methodology for selective depletion of alloreactive T cells after activation with host antigen-presenting cells by targeting T cells up-regulating CD25 and CD71. Combined depletion of these cells yields a pool of allodepleted donor T cells with antiviral properties with minimal capacity to cause graft-versus-host disease., Methods: Mature dendritic cells were irradiated and used to stimulate donor peripheral blood mononuclear cells for 4 days. The co-culture was stained with anti-CD71-biotin followed by CliniMACS CD25 and Anti-Biotin Reagents (Miltenyi Biotec GmbH; Bergisch Gladbach, Germany) before depletion on the CliniMACS Plus (Miltenyi Biotec GmbH). Residual alloreactivity was tested by flow cytometry, a secondary mixed lymphocyte reaction and limiting dilution analysis, and specific anti-viral immunity with pentamer staining. The large-scale protocol was tested under current good manufacturing practice conditions in five donor-recipient pairs of human leukocyte antigen-matched volunteer donors., Results: We developed a closed-system methodology using cell differentiation bags for cell culture and the COBE2991 Cell Processor (CaridianBCT, Lakewood, CO, USA). We also validated an anti-CD71-biotin generated for ex vivo clinical use. In five large-scale runs, the depleted fraction demonstrated excellent viability (99.9%), minimal residual expression of CD3/CD25 and CD3/CD71 (<0.2%) and passed tests for Mycoplasma, endotoxin, bacterial and fungal sterility. In secondary mixed lymphocyte reaction assays, the median response to host after allodepletion was 0%, whereas responses to third-party peripheral blood mononuclear cells were preserved (median, 105%; range 37%-350%). Limiting dilution analysis assays also demonstrated a reduction in response to host (median, -1.11 log) with preservation of third-party responses, and testing with human leukocyte antigen-restricted pentamers showed that populations of Epstein-Barr virus-specific and cytomegalovirus-specific CD8(+) T cells were retained after depletion., Conclusions: We optimized a protocol for the combined immunomagnetic depletion of alloreactive CD25/CD71 T cells under current good manufacturing practice conditions and tested the efficacy in five donor-recipient pairs., (Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to examine the prevalence of all substance use disorders (SUD) and cannabis-specific SUDs reported in two first-episode epidemiological studies, conducted in the same catchment area, 5 years apart., Methods: The prevalence of schizophrenia in Nottingham and Aetiology and Ethnicity of Schizophrenia and Other Psychoses studies included all people with a first-episode of psychosis between 1992 and 1994 and 1997 and 1999, respectively. Those individuals with a comorbid diagnosis of a SUD (ICD-10 harmful use or dependence) were identified., Results: An upward (but not statistically significant) trend in all SUDs was found for the first-episode study population as a whole, between the two cohorts (11.9-18.2%). When analysed by age, a significant increase in cannabis-specific SUDs was observed for all first-episode cases aged 16-29 between cohorts (3.2-10.6%). When analysed by age and gender, a significant increase in all SUDs was apparent for female first-episode patients aged 16-29 between cohorts (6.1-24.2%), this same increase was not seen in male patients., Conclusions: Illegal drug misuse is common in patients with a first-episode of psychosis. However, most concerning is that when both age and gender are considered, females with a first-episode of psychosis aged 16-29 show a highly significant rise in the prevalence of all SUDs over the 1990s. More recent drug use data from England and Wales shows that the prevalence of drug use in the 21st century is declining; further epidemiological studies are required to determine whether this is also the case in young female first-episode psychosis populations.

Objective: To evaluate the face, content and construct validity, and to identify whether participants improved with practice, for the Procedicus MIST Nephrectomy simulator (Mentice, Gothenburg, Sweden), which incorporates force feedback and can record numerous performance measures (metrics) during the simulation, and which is the first virtual reality simulator for laparoscopic nephrectomy., Subjects and Methods: Eight expert urological laparoscopic surgeons, 10 novices and 10 trainee urologists completed at least one simulated retroperitoneal radical nephrectomy. They completed a structured questionnaire to assess face and content validity; the performance of experts and novices were then compared to evaluate construct validity., Results: Face validity was established by the experts who all felt the simulator was a good training tool. Content validity was established by the experts who rated all aspects of the simulator as above average for realism. When performance metrics were analysed, experts completed the simulated nephrectomy significantly faster than novices, with fewer errors, less simulated haemorrhage and less tool travel, which established construct validity. After practice, both novices and trainees were able to perform the simulation faster, with fewer errors, less blood loss and less tool travel., Conclusions: This study has established the face, content and construct validity for the Procedicus MIST Nephrectomy. The simulator can distinguish experts from novices and it has potential as a laparoscopic training tool for urology.

Immunotherapy with allodepleted donor T cells (ADTs) improves immunity after T cell-depleted stem cell transplantation, but infection/relapse remain problematic. To refine this approach, we characterized the expression of surface markers/cytokines on proliferating alloreactive T cells (ATs). CD25 was expressed on 83% of carboxyfluorescein diacetate succinimidyl ester(dim) ATs, confirming this as an excellent target for allodepletion. Seventy percent of CD25(-) ATs expressed CD71 (transferrin receptor), identifying this as a novel marker to target ATs persisting after CD25 depletion. Comparison of residual alloreactivity after combined CD25/71 versus CD25 immunomagnetic depletion showed enhanced depletion of alloreactivity to host with CD25/71 depletion in both secondary (2 degrees) mixed lymphocyte reactions (P < .01) and interferon-gamma enzyme-linked immunospot assays (P < .05) with no effect on third-party responses. In pentamer/interferon-gamma enzyme-linked immunospot assays, antiviral responses to cytomegalovirus, Epstein-Barr virus, and adenovirus were preserved after CD25/71 allodepletion. CD25/71 ADTs can be redirected to recognize leukemic targets through lentiviral transfer of a chimeric anti-CD19zeta T-cell receptor. Finally, we have established conditions for clinically applicable CD25/71 allodepletion under European Union Good Manufacturing Practice conditions, resulting in highly effective, reproducible, and selective depletion of ATs (median residual alloreactivity to host in 2 degrees mixed lymphocyte reaction of 0.39% vs third-party response of 62%, n = 5). This strategy enables further clinical studies of adoptive immunotherapy with larger doses of ADTs to enhance immune reconstitution after T cell-depleted stem cell transplantation.

Epstein-Barr virus (EBV)-driven posttransplantation lymphoproliferative disease (PTLD) is a serious complication of immunosuppression after either stem cell transplantation (SCT) or solid organ transplantation (SOT). Adoptive transfer of EBV-specific cytotoxic T lymphocytes (EBV-CTLs) is an effective prophylaxis and treatment for PTLD after SCT, but not for PTLD after SOT when pharmacologic immunosuppression cannot be discontinued. We report the generation of calcineurin (CN) mutants that render EBV-CTL resistant to the immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA): mutant CNa12 confers resistance to CsA but not FK506, and mutant CNa22 confers resistance to FK506 but not CsA, whereas mutant CNb30 renders CTLs resistant to both calcineurin inhibitors. Untransduced EBV-CTLs do not proliferate in the presence of FK506/CsA. However, EBV-CTLs transduced with a retroviral vector coding for these mutants retain the ability to both proliferate and secrete normal levels of interferon-gamma in the presence therapeutic levels of FK506 (CNa12), CsA (CNa22), or both (CNb30). The cytotoxicity and phenotype of EBV-CTL lines were unaffected by expression of these mutant CNs. This approach should allow effective immunotherapy with EBV-CTLs in the SOT setting without risking the graft by reduction in immunosuppression, and represents a generic approach to improving immunotherapy in the face of immunosuppression.

Cervical ribs are an important cause of neurovascular compression at the thoracic outlet. Previous studies have shown the prevalence of cervical ribs to be between 0.05 and 3%, depending on the sex and race of the population studied. We examined 1,352 chest radiographs to determine the prevalence of cervical ribs in a London population of mixed sex and ethnicity. Our study found that the overall prevalence of cervical ribs was 0.74% with a higher rate in females compared with males (1.09 and 0.42%, respectively). Of the 10 individuals with a cervical rib, five were on the left, three were on the right and two were bilateral. The presence of elongated C7 transverse processes (transverse apophysomegaly) was also noted. We found a total of 30 elongated transverse processes with an overall prevalence of 2.21%. They were also more common in females (3.43%) than males (1.13%)., ((c) 2009 Wiley-Liss, Inc.)

Cytomegalovirus (CMV), adenovirus (Ad), and Epstein-Barr virus (EBV) are a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Adoptive immunotherapy with donor-derived cytotoxic T cells (CTLs) directed against EBV or CMV prevents the clinical manifestations of these viruses. We have designed a protocol for the simultaneous generation of polyclonal CTL specific for CMV, Ad, and EBV, which could be used to restore immunity to multiple viruses after SCT. EBV-transformed lymphoblastoid cell lines (LCLs), transduced with an adenoviral vector carrying a transgene for the immunodominant CMV antigen pp65 (Ad5f35-pp65GFP), were used to stimulate peripheral blood mononuclear cells in 6 normal donors. We detected the simultaneous presence of CD8 CTL recognizing peptide epitopes from all 3 viruses by pentamer staining. Enzyme-linked immunospot assays demonstrated a median 29-fold (8 to 248), 47-fold (2 to 137), or 18-fold (5 to 29) increase in cells secreting interferon-gamma in response to CMV, adenoviral, or EBV antigens, respectively, compared with unmanipulated peripheral blood mononuclear cell, with concomitant loss of alloreactivity. The CTL lines showed cytotoxicity against autologous LCL alone and increased cytotoxicity to autologous LCLs pulsed with CMV pp65 peptides or infected with Ad. In summary, we have developed a protocol for the generation of CTL with trivirus specificity, enabling adoptive transfer of CTL recognizing multiple viruses to restore cellular immunity after SCT.

Minor physical anomalies (MPAs) occur more frequently in a range of developmental disorders. They are also more frequent in schizophrenia supporting a neurodevelopmental aetiology of the illness. Contemporary MPA scales are yet to be validated for the effects of age. It is hypothesised that the effects of ageing may be confounding when these scales are applied to an elderly population. The distribution of MPAs in a normal elderly population was compared with younger subjects. Fifty subjects over the age of 60, and 50 subjects below the age of 60, with no known major mental illness, were evaluated. MPAs were assessed using a modified Lane scale [Psychol. Med. 27 (1997) 1155]. Elderly subjects showed an excess of absent trichions due to alopecia (p=0.004) short and broad palates (p=0.01) and greater ear protrusion (p=0.004) relative to young subjects. The differences reported are probably due to hair loss, edentulousness and growth of the auriculocephalic angle with age. These findings question the validity of studies of MPAs in schizophrenia that do not control for age.