Consultation and involvement in the Library of Birmingham

This paper outlines the role of consultation in the development of a new city centre library. The initial section focuses on the planning behind Birmingham City Council’s project to replace its existing Central Library with a new Library of Birmingham on the other side of the city centre. The paper then goes on to discuss the role of public consultation in the early stages of this project, outlining the purposes, constraints, methods used, early findings and the longer-term ideas, questions and potential

Feasibility of recruitment to an oral dysplasia trial in the United Kingdom

Background: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up-regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX-inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK. Methods: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies. Results: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre. Conclusion: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non-steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555

Randomized Phase 2b Trial of Tofacitinib (CP‐690,550) in De Novo Kidney Transplant Patients: Efficacy, Renal Function and Safety at 1 Year

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93568/1/j.1600-6143.2012.04127.x.pd

Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with Thymoglobulin or Campath

BACKGROUND: Multiple drug immunosuppression has allowed the near elimination of rejection, but without commensurate improvements in longterm graft survival and at the cost of quality of life. We have suggested that transplantation outcomes can be improved by modifying the timing and dosage of immunosuppression to facilitate natural mechanisms of alloengraftment and acquired tolerance. STUDY DESIGN: Two therapeutic principles were applied for kidney transplantation: pretransplant recipient conditioning with antilymphoid antibody preparations (Thymoglobulin [Sangstat] or Campath [ILEX Pharmaceuticals]), and minimal posttransplant immunosuppression with tacrolimus monotherapy including "spaced weaning" of maintenance doses when possible. The results in Thymoglobulin- (n = 101) and Campath-pretreated renal transplantation recipients (n = 90) were compared with those in 152 conventionally immunosuppressed recipients in the immediately preceding era. RESULTS: Spaced weaning was attempted in more than 90% of the kidney transplant recipients after pretreatment with both lymphoid-depleting agents, and is currently in effect in two-thirds of the survivors. Although there was a much higher rate of acute rejection in the Thymoglobulin-pretreated recipients than in either the Campath-pretreated or historic control recipients, patient and graft survival in both lymphoid depletion groups is at least equivalent to that of historic control patients. In the Thymoglobulin-conditioned patients for whom followups are now 24 to 40 months, chronic allograft nephropathy (CAN) progressed at the same rate as in historic control patients. Selected patients on weaning developed donor-specific nonreactivity. CONCLUSIONS: After lymphoid depletion, kidney transplantation can be readily accomplished under minimal immunosuppression with less dependence on late maintenance immunosuppression and a better quality of life. Campath was the more effective agent for pretreatment. Guidelines for spaced weaning need additional refinement. © 2005 by the American College of Surgeons

Tectonic evolution of the Southern Ocean between Antarctica, South America and Africa over the past 84Ma

An improved method has been developed for carrying out 2-plate reconstructions, in which fracture zone locations are fitted to synthetic flowlines and magnetic anomaly picks are rotated and fitted to great circles representing other, not necessarily conjugate, anomaly isochrons. This enables the determination of finite rotation poles for regions with sparse data coverage, or where much of one or both plates has been subducted. Misfits and partial derivatives are calculated for each type of data, and combined in a single iterative inversion, allowing the direct calculation of confidence intervals. This method is then extended to a 3-plate reconstruction, taking closure into consideration. The South American - African - Antarctic plate system is then studied. Fracture zone locations are identified from a gravity map constructed from GEOSAT altimeter data, and magnetic anomalies are identified from ship profiles. Two-plate reconstructions are carried out for each plate pair, giving good fits to the observed data, and then all three datasets are combined in a 3-plate reconstruction. Comparison of the results reveals a discontinuity in spreading in the Weddell Sea, believed to be related to pseudo-asymmetric spreading caused by ridge re-organisation in the Paleocene and early Eocene. A revised 3-plate inversion, taking this discontinuity into account, produces an internally consistent set of poles, indicating a closed 3-plate system since anomaly 34 (83Ma), with no evidence for a Malvinas Plate extending into the Weddell Sea in the Late Cretaceous. Disruption to the system from anomaly 32 (71Ma) until anomaly 24 (52Ma), appears to be related to the collision of Africa with Eurasia. A study of the past motion, configuration and stability of the Bouvet Triple junction suggests that for the majority of the past 50Ma it has been in a RFF configuration, in theory considerably less stable than RRR, the other possible configuration

Antilymphoid antibody preconditioning and tacrolimus monotherapy for pediatric kidney transplantation

Objective: Heavy post-transplant immunosuppression may contribute to long-term immunosuppression dependence by subverting tolerogenic mechanisms; thus, we sought to determine if this undesirable consequence could be mitigated by pretransplant lymphoid depletion and minimalistic post-transplant monotherapy. Study design: Lymphoid depletion in 17 unselected pediatric recipients of live (n = 14) or deceased donor kidneys (n = 3) was accomplished with antithymocyte globulin (ATG) (n = 8) or alemtuzumab (n = 9). Tacrolimus was begun post-transplantation with subsequent lengthening of intervals between doses (spaced weaning). Maintenance immunosuppression, morbidity, graft function, and patient/graft survival were collated. Results: Steroids were added temporarily to treat rejection in two patients (both ATG subgroup) or to treat hemolytic anemia in two others. After 16 to 31 months (mean 22), patient and graft survival was 100% and 94%, respectively. The only graft loss was in a nonweaned noncompliant recipient. In the other 16, serum creatinine was 0.85 ± 0.35 mg/dL and creatinine clearance was 90.8 ± 22.1 mL/1.73 m2. All 16 patients are on monotherapy (15 tacrolimus, one sirolimus), and 14 receive every other day or 3 times per week doses. There were no wound or other infections. Two patients developed insulin-dependent diabetes. Conclusion: The strategy of lymphoid depletion and minimum post-transplant immunosuppression appears safe and effective for pediatric kidney recipients. © 2006 Elsevier Inc. All rights reserved

The regulation of miRNAs by reconstituted high-density lipoproteins in diabetes-impaired angiogenesis

Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. We recently found that reconstituted high-density lipoproteins (rHDL) rescue diabetes-impaired angiogenesis. microRNAs (miRNAs) regulate angiogenesis and are transported within HDL to sites of injury/repair. The role of miRNAs in the rescue of diabetes-impaired angiogenesis by rHDL is unknown. Using a miRNA array, we found that rHDL inhibits hsa-miR-181c-5p expression in vitro and using a hsa-miR-181c-5p mimic and antimiR identify a novel anti-angiogenic role for miR-181c-5p. miRNA expression was tracked over time post-hindlimb ischaemic induction in diabetic mice. Early post-ischaemia when angiogenesis is important, rHDL suppressed hindlimb mmu-miR-181c-5p. mmu-miR-181c-5p was not detected in the plasma or within HDL, suggesting rHDL specifically targets mmu-miR-181c-5p at the ischaemic site. Three known angiogenic miRNAs (mmu-miR-223-3p, mmu-miR-27b-3p, mmu-miR-92a-3p) were elevated in the HDL fraction of diabetic rHDL-infused mice early post-ischaemia. This was accompanied by a decrease in plasma levels. Only mmu-miR-223-3p levels were elevated in the hindlimb 3 days post-ischaemia, indicating that rHDL regulates mmu-miR-223-3p in a time-dependent and site-specific manner. The early regulation of miRNAs, particularly miR-181c-5p, may underpin the rescue of diabetes-impaired angiogenesis by rHDL and has implications for the treatment of diabetes-related vascular complications

Effect of pathologic tumor response and nodal status on survival in the medical research council adjuvant gastric infusional chemotherapy trial

Purpose: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial established perioperative epirubicin, cisplatin, and fluorouracil chemotherapy as a standard of care for patients with resectable esophagogastric cancer. However, identification of patients at risk for relapse remains challenging. We evaluated whether pathologic response and lymph node status after neoadjuvant chemotherapy are prognostic in patients treated in the MAGIC trial. Materials and Methods: Pathologic regression was assessed in resection specimens by two independent pathologists using the Mandard tumor regression grading system (TRG). Differences in overall survival (OS) according to TRG were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards method established the relationships among TRG, clinical-pathologic variables, and OS. Results: Three hundred thirty resection specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months. On univariate analysis, high TRG and lymph node metastases were negatively related to survival (Mandard TRG 3, 4, or 5: hazard ratio [HR], 1.94; 95% CI, 1.11 to 3.39; P = .0209; lymph node metastases: HR, 3.63; 95% CI, 1.88 to 7.0; P < .001). On multivariate analysis, only lymph node status was independently predictive of OS (HR, 3.36; 95% CI, 1.70 to 6.63; P < .001). Conclusion: Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in the MAGIC trial. Prospective evaluation of whether omitting postoperative chemotherapy and/or switching to a noncross-resistant regimen in patients with lymph node-positive disease whose tumor did not respond to preoperative epirubicin, cisplatin, and fluorouracil may be appropriate