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The data presented here are related and supplementary data to the research article “Implantation and long-term assessment of the stability and biocompatibility of a novel 98 channel suprachoroidal visual prosthesis in sheep” [1] . In Eggenberger et al., nine sheep of the Suffolk (N=2) and Dorper (N=7) breeds were implanted in the left eye with an electrically inactive, suprachoroidal retinal stimulator (Bionic Eye) for durations of up to 100 days. The surgical safety, implant stability and device biocompatibility were assessed. Intraocular pressure measurements, indirect and infrared ophthalmoscopy and optical coherence tomography were performed at fixed time points to evaluate the clinical effects of the surgery and device implantation. Post-mortem eye tissue collection and histology was performed to measure the effects of the intervention at the cellular level. The data, including a comprehensive collection of fundus, infrared, optical coherence tomography and histology images can be used as a reference for comparison with other research, for example, active retinal stimulators. Furthermore, these data can be used to evaluate the suitability of the sheep model, in particular Dorper sheep, for future research.

Background: Staff training in infection prevention and control (IPC) across hospital settings has a crucial role in reducing the incidence of healthcare associated infections (HAIs). However the application of dynamic visualisation approaches in this context is under-developed, with very few in-depth evaluation studies of related processes and impacts.\ud \ud Methods: A prototype training tablet app for hospital staff, using interactive visuals was developed and evaluated. To demonstrate different pathogen behaviour, dynamic visualisations of norovirus, C. difficile, and MRSA were developed in relation to location, survival and transmission within a virtual hospital ward model using evidence-based microbiological and staff behavioural data. A three-stage evaluation process was designed, involving a mixed sample of UK National Health Service staff (doctors, nurses and domestic staff, n = 150).\ud \ud Results: Participants reported improved awareness and understanding of the pathogens responsible for HAI, the types of information relevant for different staff cohorts, those aspects of the visualisations which worked well and those which were prone to cause misunderstandings, and suggestions for further development and improvement. The tool appeared to offer staff a new perspective on pathogens, being able to ‘see’ them contextualised in the virtual ward, making them seem more real.\ud \ud Conclusions: Results showed the benefits of a detailed co-development process and a more contextualised understanding of the potential for visual apps to be used in IPC training.

The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5+ malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5+-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T ‘on-target, off-tissue’ toxicity are required to enable a clinical impact of this approach in solid malignancies. Electronic supplementary material The online version of this article (doi:10.1007/s00262-017-2034-7) contains supplementary material, which is available to authorized users.

Background The ideal intravenous fluid for kidney transplantation has not been defined, despite the common use of normal saline during the peri-operative period. The high chloride content of normal saline is associated with an increased risk of hyperchloraemic metabolic acidosis, which may in turn increase the risk of hyperkalaemia and delayed graft function. Balanced electrolyte solutions have a lower chloride content which may decrease this risk and avoid the need for dialysis due to hyperkalaemia in the immediate post-transplant period. Randomised controlled trials (RCTs) addressing this issue have used biochemical outcomes to compare fluids and have been underpowered to address patient-centred outcomes such as delayed graft function. Objectives To examine the effect of lower-chloride solutions versus normal saline on delayed graft function, hyperkalaemia and acid-base status in kidney transplant recipients. Search methods We searched the Cochrane Kidney and Transplant's Specialised Register to 26 November 2015 through contact with the Information Specialist using search terms relevant to this review. Selection criteria RCTs of kidney transplant recipients that compared peri-operative intravenous lower-chloride solutions to normal saline were included. Data collection and analysis Two independent investigators assessed studies for eligibility and risk of bias. Data from individual studies were extracted using standardised forms and pooled according to a published protocol. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Main results Six studies (477 participants) were included in the review. All participants were adult kidney transplant recipients and 70% of participants underwent live-donor kidney transplantation. The overall risk of bias was low for selection bias and unclear for remaining domains. There was no difference in the risk of delayed graft function (3 studies, 298 participants: RR 1.03, 95% CI 0.62 to 1.70) or hyperkalaemia (2 studies, 199 participants: RR 0.48, 95% CI 0.04 to 6.10) for participants who received balanced electrolyte solutions compared to normal saline. Intraoperative balanced electrolyte solutions compared to normal saline were associated with higher blood pH (3 studies, 193 participants: MD 0.07, 95% CI 0.05 to 0.09), higher serum bicarbonate (3 studies, 215 participants: MD 3.02 mEq/L, 95% CI 2.00 to 4.05) and lower serum chloride (3 studies, 215 participants: MD -9.93 mmol/L, 95% CI -19.96 to 0.11). There were four cases of graft loss in the normal saline group and one in the balanced electrolyte solution group, and four cases of acute rejection in the normal saline group compared to two cases in the balanced electrolyte solution group. Authors' conclusions Balanced electrolyte solutions are associated with less hyperchloraemic metabolic acidosis compared to normal saline, however it remains uncertain whether lower-chloride solutions lead to improved graft outcomes compared to normal saline.

Training in infection prevention and control (IPC) measures is crucial to minimise the incidence of healthcare-associated infections (HAIs), a growing cause of patient illness and death in hospital. This paper describes a participative approach to developing a prototype tablet-based digital training tool using dynamic visualisation-led techniques to raise awareness and understanding of IPC and HAIs for hospital-based staff. An evidence-based and iterative visualisation prototyping process was used to engage staff and invite contributions from across a number of roles within the NHS, a typically hierarchical sector. Findings suggest the visualisation-led approach was helpful in articulating the behaviours of pathogens and staff and their interactions within the complex setting and service ecology of the NHS and in making IPC training materials clearer and more engaging.

Background: International guidelines recommend that all patients undergoing hip fracture surgery receive specific thromboprophylaxis. The purpose of the present study was to examine current thromboprophylaxis practice patterns in patients undergoing hip fracture surgery at Royal Perth Hospital. Methods: A total of 129 consecutive patients admitted to Royal Perth Hospital between 4 February and 21 July 2002 for surgical repair of a fractured neck of femur, was studied. The primary outcome was the frequency, type, and duration of thromboprophylaxis use during hospitalization. Results: Mean patient age was 79.4 ± 13.4 years and 69.8% (90/129) were female. Seventy-four patients (57.8%; 95% confidence interval (CI): 48.8−66.8%) received specific thromboprophylaxis during hospitalization, including 50 patients (39.1%; 95%CI: 30.6−48.1%) who received pharmacological prophylaxis only, three (2.3%; 95%CI: 0.5−6.7%) who received mechanical prophylaxis only, and 21 (16.4%; 95%CI: 10.5−24.0%) who received both mechanical and pharmacological prophylaxis. Of those receiving pharmacological prophylaxis, 35 (49.3%; 95%CI: 37.2−61.4%) received low-molecular-weight heparin, 26 (36.6%; 95%CI: 25.5−48.9%) received low-dose unfractionated heparin, eight (11.3%; 95%CI: 5.0−21.0%) received warfarin, 35 (49.3%; 95%CI: 37.2−61.8%) received aspirin or clopidogrel, and 27 (38.0%; 95% CI: 26.8−50.3%) received combined anticoagulant and antiplatelet prophylaxis. The median duration of mechanical prophylaxis was 8 days (range: 6−12 days) and that of pharmacological prophylaxis was 12 days (range: 6−26 days). When the 32 patients already taking aspirin or warfarin at the time of admission were excluded, only 45 (46.9%; 95%CI: 36.6−57.3%) of the remaining 96 patients received specific thromboprophylaxis. Conclusion: Specific thromboprophylaxis remains under-utilized in patients undergoing surgery for hip fracture at Royal Perth Hospital. These data should prompt the implementation of effective strategies to improve thromboprophylaxis practice patterns in high-risk orthopaedic patients.

Cell proliferation in the developing renal tubules of Drosophila is strikingly patterned, occurring in two phases to generate a consistent number of tubule cells. The later phase of cell division is promoted by EGF receptor signalling from a specialised subset of tubule cells, the tip cells, which express the protease Rhomboid and are thus able to secrete the EGF ligand, Spitz. We show that the response to EGF signalling, and in consequence cell division, is patterned by the specification of a second cell type in the tubules. These cells are primed to respond to EGF signalling by the transcription of two pathway effectors, PointedP2, which is phosphorylated on pathway activation, and Seven up. While expression of pointedP2 is induced by Wingless signalling, seven up is initiated in a subset of the PointedP2 cells through the activity of the proneural genes. We demonstrate that both signalling and responsive cells are set aside in each tubule primordium from a proneural gene-expressing cluster of cells, in a two-step process. First, a proneural cluster develops within the domain of Wingless-activated, pointedP2-expressing cells to initiate the co-expression of seven up. Second, lateral inhibition, mediated by the neurogenic genes, acts within this cluster of cells to segregate the tip cell precursor, in which proneural gene expression strengthens to initiate rhomboid expression. As a consequence, when the precursor cell divides, both daughters secrete Spitz and become signalling cells. Establishing domains of cells competent to transduce the EGF signal and divide ensures a rapid and reliable response to mitogenic signalling in the tubules and also imposes a limit on the extent of cell division, thus preventing tubule hyperplasia.

We explored the imaging of bombesin receptors and evaluated the clinical use of [(99m)Tc]Demobesin 4 ([(99m)Tc]DB4) in prostate cancer patients.[(99m)Tc]DB4 was prepared according to Good Manufacturing Practice. Patients with prostate cancer underwent serial planar and SPECT imaging up to 3 h after administration. Blood and urine samples were taken to assess pharmacokinetics.[(99m)Tc]DB4 is safe and clears rapidly from the bloodstream via the kidneys resulting in low background activity. The tracer binds strongly to the gastrin-releasing peptide receptor (GRPR) in vivo as indicated by the high uptake in the pancreas seen in all patients. In patients who had undergone hormone therapy, [(99m)Tc]DB4 did not efficiently image metastatic prostate cancer. In contrast, in newly diagnosed patients local disease was visualised.The GRPR is an unsuitable target for imaging refractory prostate cancer but may be useful in untreated disease. [(99m)Tc]DB4 is a promising radiopharmaceutical which merits further exploration in this specific group of patients.

Convenient syntheses of the ferrocene-based fulvalene-bridged heterobimetallic complexes [( η -C 5 H 5 )Fe( μ - η : η -C 5 H 4 C n R m )M(CO) 2 ( η -C 3 H 5 )] (M  Mo or W; C n R m  1-indenyl, C 5 Me 4 or C 5 H 2 Me 2 ) are described.

The vital task of vectorial solute transport is often energised by a plasma membrane, proton-motive V-ATPase. However, its proposed partner, an apical alkali-metal/proton exchanger, has remained elusive. Here, both FlyAtlas microarray data and in situ analyses demonstrate that the bacterial kefB and kefC (members of the CPA2 family) homologues in Drosophila, CG10806 and CG31052, respectively, are both co-expressed with V-ATPase genes in transporting epithelia. Immunocytochemistry localises endogenous CG10806 and CG31052 to the apical plasma membrane of the Malpighian (renal) tubule. YFP-tagged CG10806 and CG31052 both localise to the plasma membrane of Drosophila S2 cells, and when driven in principal cells of the Malpighian tubule, they localise specifically to the apical plasma membrane. V-ATPase-energised fluid secretion is affected by overexpression of CG10806, but not CG31052; in the former case, overexpression causes higher basal rates, but lower stimulated rates, of fluid secretion compared with parental controls. Overexpression also impacts levels of secreted Na+ and K+. Both genes rescue exchanger-deficient (nha1 nhx1) yeast, but act differently; CG10806 is driven predominantly to the plasma membrane and confers protection against excess K+, whereas CG31052 is expressed predominantly on the vacuolar membrane and protects against excess Na+. Thus, both CG10806 and CG31052 are functionally members of the CPA2 gene family, colocalise to the same apical membrane as the plasma membrane V-ATPase and show distinct ion specificities, as expected for the Wieczorek exchanger.

Purpose 5-Fluorouracil (5-FU) + mitomycin C (MMC)–based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. Methods and Materials Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m 2 ) on Day 1 and capecitabine on each RT treatment day in two divided doses (825 mg/m 2 b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. Results Thirty-one patients entered the trial. The median age was 61 years (range 45–86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. Conclusions Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.

2534 Background: Phase I oncology trials are crucial in cancer drug development and have evolved over the years. We examined the trends in trial characteristics, dose-limiting toxicities (DLTs) and...

2583 Background: The clinical utility of agents that target EGFR and VEGFR signaling in Non-Small Cell Lung Cancer (NSCLC) is limited by resistance due to emergent alternative growth stimulatory pa...

International guidelines recommend that all patients undergoing hip fracture surgery receive specific thromboprophylaxis. The purpose of the present study was to examine current thromboprophylaxis practice patterns in patients undergoing hip fracture surgery at Royal Perth Hospital.A total of 129 consecutive patients admitted to Royal Perth Hospital between 4 February and 21 July 2002 for surgical repair of a fractured neck of femur, was studied. The primary outcome was the frequency, type, and duration of thromboprophylaxis use during hospitalization.Mean patient age was 79.4 +/- 13.4 years and 69.8% (90/129) were female. Seventy-four patients (57.8%; 95% confidence interval (CI): 48.8-66.8%) received specific thromboprophylaxis during hospitalization, including 50 patients (39.1%; 95%CI: 30.6-48.1%) who received pharmacological prophylaxis only, three (2.3%; 95%CI: 0.5-6.7%) who received mechanical prophylaxis only, and 21 (16.4%; 95%CI: 10.5-24.0%) who received both mechanical and pharmacological prophylaxis. Of those receiving pharmacological prophylaxis, 35 (49.3%; 95%CI: 37.2-61.4%) received low-molecular-weight heparin, 26 (36.6%; 95%CI: 25.5-48.9%) received low-dose unfractionated heparin, eight (11.3%; 95%CI: 5.0-21.0%) received warfarin, 35 (49.3%; 95%CI: 37.2-61.8%) received aspirin or clopidogrel, and 27 (38.0%; 95% CI: 26.8-50.3%) received combined anticoagulant and antiplatelet prophylaxis. The median duration of mechanical prophylaxis was 8 days (range: 6-12 days) and that of pharmacological prophylaxis was 12 days (range: 6-26 days). When the 32 patients already taking aspirin or warfarin at the time of admission were excluded, only 45 (46.9%; 95%CI: 36.6-57.3%) of the remaining 96 patients received specific thromboprophylaxis.Specific thromboprophylaxis remains under-utilized in patients undergoing surgery for hip fracture at Royal Perth Hospital. These data should prompt the implementation of effective strategies to improve thromboprophylaxis practice patterns in high-risk orthopaedic patients.

Using the renal tubules ofDrosophilaas an example, we explore how cell specification leads to the morphogenetic movements that underlie the generation of tissue architecture. Taking two stages of development, we show first that the tubule cells are allocated by signalling between the endodermal and ectodermal compartments of the posterior gut. Activation of the Wnt pathway patterns the ectodermal anlage, resulting in the expression of tubule genes in a subset of cells and their eversion from the hindgut to form the tubule primordia. We argue that early gene expression directs these morphogenetic movements but not the complete programme of tubule differentiation. In the second example we show that the allocation of the mitogenic tip cell lineage in each tubule is required not only for the normal pattern of cell division but also for the stereotyped three–dimensional arrangement of the mature tubules. Analysis of mutants in which the tip cell lineage is misspecified reveals that both daughters of the tip cell progenitor are required for the tubules to navigate through the body cavity, so that the distal tips locate in their characteristic positions. We show that the regulator of Rac, Myoblast city, is essential for this second morphogenetic process.

A unique cell, the tip mother cell, arises in the primordium of each Drosophila Malpighian tubule by lateral inhibition within a cluster of achaete-expressing cells. This cell maintains achaete expression and divides to produce daughters of equivalent potential, of which only one, the tip cell, adopts the primary fate and continues to express achaete, while in the other, the sibling cell, achaete expression is lost (M. Hoch et al., 1994, Development 120, 3439–3450). In this paper we chart the mechanisms by which achaete expression is differentially maintained in the tip cell lineage to stabilise cell fate. First, wingless is required to maintain the expression of achaete in the tubule primordium so that wingless mutants lack tip cells. Conversely, increasing wingless expression results in the persistence of achaete expression in the cell cluster. Second, Notch signalling is restricted by the asymmetric segregation of Numb, as the tip mother cell divides, so that achaete expression is maintained only in the tip cell. In embryos mutant for Notch tip cells segregate at the expense of sibling cells, whereas in numb neither daughter cell adopts the tip cell fate resulting in tubules with two sibling cells. Conversely, when numb is overexpressed two tip cells segregate and tubules have no sibling cells. Analysis of cell proliferation in the developing tubules of embryos lacking Wingless after the critical period for tip cell allocation reveals an additional requirement for wingless for the promotion of cell division. In contrast, alteration in the expression of numb has no effect on the final tubule cell number.

Reaction of Li[C5H4Fe(C5H5)] with 2,3,4,5-tetramethylcyclopent-2-enone followed by acid work-up afforded the ferrocenyl-substituted cyclopentadiene [Fe(C5H5)(C5H4C5Me 4H)] 1. Lithiation of 1 with LiBun in hexane gave Li[C5Me4C5H4Fe(C5H 5)]. Reactions of this salt or the previously described lithium 3,4-dimethylcyclppentadienide or indenide homologues, Li[C5H2Me2C5H4Fe(C 5H5)] or Li[C9H6C5H4Fe(C5H 5)], with the allyl complexes [MoBr(MeCN)2(CO)2(η-C3H5)] or [WCl(MeCN)2(CO)2-(η-C3H5)] led to the corresponding fulvalene (and related)-bridged, Fe-Mo or Fe-W heterobimetallic derivatives [(C5H5)Fe(C5H4C5Me 4)Mo(CO)2(η-C3H5)] 2, [(C5H5)Fe(C5H4C5H 2Me2)M(CO)2(η-C3H5)] (M = Mo 3 or W 4) and [(C5H5)Fe(C5H4C9H 6)M(CO)2(η-C3H5)] (M = Mo 5 or W 6). The crystal structure of 5 has been determined. Reaction of the cinnamyl complex [MoBr(MeCN)2(CO)2(η-C3H4Ph)] with Li[C5H2Me2-C5H4Fe(C 5H5)] or Li[C9H6C5H4Fe(C5H 5)] yielded [(C5H5)Fe(C5H4C5H 2Me2)Mo(CO)2(H-C3H4Ph)] 7 or [(C5H5)Fe(C5H4C9H 6)Mo(CO)2(η-C3H4Ph)] 8 respectively, both of which exist as a mixture of isomers. Treatment of 7 with [Cr(CO)6] in Bun2O-tetrahydrofuran gave the Fe-Mo-Cr heterotrimetallic complex [(C5H5)Fe(CH4C5H2Me 2)(OC)2Mo(μ-η3:η6-C 3H4Ph)Cr(CO)3] 9. The new monometallic analogue [Mo(CO)2-(η-C3H5)(η-CMe5)] 10 has also been prepared. Cyclic voltammetric studies of some of the new heterobimetallic complexes and of 10, [Mo(CO)2(η-C3H5)(η -C5H5)] and [Mo(CO)2(η-C3H5)(η-C9H 7)] are described.

Background— Randomized trials and meta-analyses have reached conflicting conclusions about the role of thrombolytic therapy for the treatment of acute pulmonary embolism. Methods and Results— We performed a meta-analysis of all randomized trials comparing thrombolytic therapy with heparin in patients with acute pulmonary embolism. Eleven trials, involving 748 patients, were included. Compared with heparin, thrombolytic therapy was associated with a nonsignificant reduction in recurrent pulmonary embolism or death (6.7% versus 9.6%; OR 0.67, 95% CI 0.40 to 1.12, P for heterogeneity=0.48), a nonsignificant increase in major bleeding (9.1% versus 6.1%; OR 1.42, 95% CI 0.81 to 2.46), and a significant increase in nonmajor bleeding (22.7% versus 10.0%; OR 2.63, 95% CI 1.53 to 4.54; number needed to harm=8). Thrombolytic therapy compared with heparin was associated with a significant reduction in recurrent pulmonary embolism or death in trials that also enrolled patients with major (hemodynamically unstable) pulmonary embolism (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treat=10) but not in trials that excluded these patients (5.3% versus 4.8%; OR 1.07, 95% CI 0.50 to 2.30), with significant heterogeneity between these 2 groups of trials ( P =0.10). Conclusions— Currently available data provide no evidence for a benefit of thrombolytic therapy compared with heparin for the initial treatment of unselected patients with acute pulmonary embolism. A benefit is suggested in those at highest risk of recurrence or death. The number of patients enrolled in randomized trials to date is modest, and further evaluation of the efficacy and safety of thrombolytic therapy for the treatment of high-risk patients with acute pulmonary embolism appears warranted.