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Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47–77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37–7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56–5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

BACKGROUND: Integrated cardiothoracic surgery residencies began 2006 to address workforce shortages in cardiothoracic surgery. As more attention has been given to racial and gender disparities, our goal was to examine trends in diversity among integrated cardiothoracic residents. METHODS: All US accredited integrated cardiothoracic programs that had accepted residents through 2020 were included. A resident list was collected through online websites and direct institutional contact. Gender, race, and year of entry were recorded. Linear regression models were used to evaluate racial and gender trends over time. RESULTS: From 2006 through 2020, 321 residents were accepted into integrated cardiothoracic training programs. Men comprised 72% (232/321) of the cohort. The racial distribution was 66.4% White (213/321), 26.2% Asian (84/321), 5.3% Hispanic (17/321), and 2.2% African American (7/321). Over the study period the time slope for Whites was −2.95 (P < .01), indicating an approximately 3% decrease each year. The time slope for Asians was 1.60 (P < .01), whereas the time slope did not change significantly for African Americans (0.10, P = .94) or Hispanics (0.13, P = .91). Adjusting for the number of integrated programs each year as a covariate did not change trends for any race. The time slope did not change significantly over the time period for men (−0.25, P = .71). CONCLUSIONS: Gender and racial diversity have not improved over time in integrated cardiothoracic residencies. Institutions should strive to recruit medical students from underrepresented backgrounds and increase their focus on gender diversity.

Background. \ud HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized and difficult to match but not much is known about its long-term graft and patient survival.\ud \ud Methods. \ud One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.\ud \ud Results. \ud The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P = 0.001; and microbead assay/flow cytometry crossmatch, P = 0.837), although those with a low CDC titer (

Clinical datasets are commonly limited in size, thus restraining applications of Machine Learning (ML) techniques for predictive modelling in clinical research and organ transplantation. We explored the potential of Decision Tree (DT) and Random Forest (RF) classification models, in the context of small dataset of 80 samples, for outcome prediction in high-risk kidney transplantation. The DT and RF models identified the key risk factors associated with acute rejection: the levels of the donor specific IgG antibodies, the levels of IgG4 subclass and the number of human leucocyte antigen mismatches between the donor and recipient. Furthermore, the DT model determined dangerous levels of donor-specific IgG subclass antibodies, thus demonstrating the potential of discovering new properties in the data when traditional statistical tools are unable to capture them. The DT and RF classifiers developed in this work predicted early transplant rejection with accuracy of 85%, thus offering an accurate decision support tool for doctors tasked with predicting outcomes of kidney transplantation in advance of the clinical intervention.

Introduction\ud As part of the BSc (Hons) Diagnostic Radiography programme students learn and undertake research relevant to their development as first post radiographers (dose optimisation and image quality) within the Research-Informed Teaching experience (RiTe). Due to the COVID-19 pandemic, the delivery of RiTe to our year 2 students was moved to an online format using Microsoft Teams and Blackboard Collaborate and focused on a key area of current practice - COVID-19 and chest X-ray imaging. Within RiTe students are placed into collaborative enquiry-based learning (CEBL) groups to share tasks, but to also support and learn from one another.\ud \ud Methods\ud An online survey was used to explore the year 2 student cohort task value and self-efficacy of this online version of RiTe.\ud \ud Results\ud A 73% (32/44) response rate was achieved. Students found the online version of RiTe to be a positive learning and development experience. There was strong agreement that they not only found it relevant to their area of practice (task-value), but also strongly agreed that they understood and could master the skills taught (self-efficacy).\ud \ud Conclusion\ud This online version of RiTe was effectively structured to help scaffold student learning and development of research data analysis skills despite the lack of face-to-face teaching. The students also valued the topic area (COVID-19 and chest X-ray imaging). A blended learning approach with RiTe will be used next year with a combination of collaborative online teaching and physical data collection and analysis in the university-based X-ray imaging laboratory. Further evaluation and data collection will also be undertaken.\ud \ud Implications for practice\ud University-based empirical work in groups to learn about research can be replaced by an online mechanism whilst still maintaining task-value and acceptable self-efficacy.

Introduction\ud \ud With the introduction of digital radiography, the feedback between image quality and over-exposure has been partly lost which in some cases has led to a steady increase in dose. Over the years the introduction of exposure index (EI) has been used to resolve this phenomenon referred to as ‘dose creep’. Even though EI is often vendor specific it is always a related of the radiation exposure to the detector. Due to the nature of this relationship EI can also be used as a patient dose indicator, however this is not widely investigated in literature.\ud \ud Methods\ud \ud A total of 420 dose-area-product (DAP) and EI measurements were taken whilst varying kVp, mAs and body habitus on two different anthropomorphic phantoms (pelvis and chest). Using linear regression, the correlation between EI and DAP were examined. Additionally, two separate region of interest (ROI) placements/per phantom where examined in order to research any effect on EI.\ud \ud Results\ud \ud When dividing the data into subsets, a strong correlation between EI and DAP was shown with all R-squared values > 0.987. Comparison between the ROI placements showed a significant difference between EIs for both placements.\ud \ud Conclusion\ud \ud This research shows a clear relationship between EI and radiation dose which is dependent on a wide variety of factors such as ROI placement, body habitus. In addition, pathology and manufacturer specific EI’s are likely to be of influence as well.\ud \ud Implications for practice\ud \ud The combination of DAP and EI might be used as a patient dose indicator. However, the influencing factors as mentioned in the conclusion should be considered and examined before implementation.

Author(s): Toyoda, Izumi; Vernau, William; Sturges, Beverly K; Vernau, Karen M; Rossmeisl, John; Zimmerman, Kurt; Crowe, Chelsea M; Woolard, Kevin; Giuffrida, Michelle; Higgins, Robert J; Dickinson, Peter J | Abstract: BackgroundHistiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic.ObjectiveTo characterize the clinicopathological inflammatory features, breed predisposition, and survival in dogs with CNS HS.AnimalsOne hundred two dogs with HS, 62 dogs with meningioma.MethodsRetrospective case series. Records were reviewed for results of cerebrospinal fluid (CSF) analysis, CBC, treatment, and outcome data.ResultsPredisposition for CNS HS was seen in Bernese Mountain Dogs, Golden Retrievers, Rottweilers, Corgis, and Shetland Sheepdogs (P ≤ .001). Corgis and Shetland Sheepdogs had predominantly primary tumors; Rottweilers had exclusively disseminated tumors. Marked CSF inflammation was characteristic of primary rather than disseminated HS, and neoplastic cells were detected in CSF of 52% of affected dogs. Increased neutrophil to lymphocyte ratios were seen in all groups relative to controls (P l.008) but not among tumor subtypes. Definitive versus palliative treatment resulted in improved survival times (P l .001), but overall prognosis was poor.Conclusions and clinical importanceClinicopathological differences between primary and disseminated HS suggest that tumor biological behavior and origin may be different. Corgis and Shetland Sheepdogs are predisposed to primary CNS HS, characterized by inflammatory CSF. High total nucleated cell count and the presence of neoplastic cells support the use of CSF analysis as a valuable diagnostic test. Prognosis for CNS HS is poor, but further evaluation of inflammatory mechanisms may provide novel therapeutic opportunities.

Introduction: Smart glasses can be adapted to display radiographic images to allow clinician’s gaze not to be directionally fixed or predetermined by computer monitor location. This study presents an analysis of eye lens dose during interventional fluoroscopy guided procedures, comparing fixed monitor positions against the use of smart glasses.\ud \ud Methods: Using a head phantom (simulating the clinician), thermoluminescent dosimeters and lead shielded glasses, the dose to the eye was measured for different head ‘rotations and tilts’ for: gaze directed towards the main scattering source (patient / primary beam) to represent potential gaze direction if smart glasses are used; gaze directed to a range of potential computer monitor positions. An anthropomorphic pelvis phantom was utilised to simulate the patient. Accumulated dose rates (µGy.sˉ¹) from five 10-second exposures at 75 kV 25.2 mAs were recorded. \ud \ud Results: An average DAP reading of 758.84 cGy.cm2 was measured during each 10 second exposure. Whilst wearing lead shielded glasses a 6.10 – fold reduction in dose rate to the lens is possible (p\ud \ud Conclusion: If the clinician’s gaze is directed towards the main scattering source a potential exists for reducing eye lens dose compared with fixed location computer monitors. Introduction of lead lined smart glasses into interventional radiology may lead to improvements in patient care, reducing the need for the clinician to look away from the patient to observe a radiographic image.

Background Qualitative studies suggest that substance use is central to the identities and cultures of many gay and bisexual men (gbMSM) – and a salient factor in how they manage HIV risk. To quantitatively assess this, we examined patterns of substance use and associations with awareness, interest, and uptake of key prevention strategies. Methods Canadian gbMSM were recruited online and asked to report their frequency of substance use. Latent class analysis identified patterns in use. Demographic-adjusted multivariable multinomial logistic regression models, stratified by HIV-status, assessed associations with key prevention strategies (TasP awareness, PrEP interest, HIV-testing). Results Among 669 HIV-positive and 7,184 HIV-negative men, six substance use classes were characterized: ‘limited’ (46.0%; i.e., infrequent/low use of most drugs), ‘conventional’ (25.9%; i.e., alcohol, marijuana, and tobacco), ‘club’ (9.5%; i.e., alcohol, cocaine, and psychedelics), ‘sex’ (11.4%; i.e., alcohol, crystal meth, GHB, poppers, and erectile dysfunction drugs), ‘prescription’ (12.1%; i.e., alcohol and prescription drugs), and ‘assorted’ (4.5%; i.e., most drugs) use. Limited use was selected as the referent class in all analyses. Other HIV-positive men were no more likely to have detectable viral-loads, nor were they less likely to know about the preventative benefits of TasP. HIV-negative men in the prescription (aOR:1.37,95%CI:1.15–1.63) and sex (aOR:1.58,95%CI:1.21–2.06) drug use classes were more likely to know about TasP. HIV-negative men in the prescription (aOR:1.6, 95%CI:1.34–1.91), conventional (aOR:1.30,95%CI:1.16–1.45), club (aOR:1.44,95%CI:1.15–1.81), sex (aOR:3.94,95%CI:2.92–5.33), and assorted (aOR:3.06,95%CI:1.64–5.72) use classes were more likely to report interest in taking PrEP. Membership in these classes was associated with higher odds of HIV-testing. Conclusion Among HIV-positive men, we observed high levels of viral-load undetectability and TasP awareness, independent of substance use. Among HIV-negative men, multiple patterns of substance use traditionally associated with heightened risk for acquiring HIV were associated with awareness, interest, and uptake of HIV risk management strategies, contravening stereotypes that link substance use to risk-indifferent attitudes. Disclosure No significant relationships.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

One-day Workshop delivered to academics and clinical tutors as part of the International student conference in health sciences "Health in our Hands" held at Tartu Healthcare College, Estonia.

Antibodies against donor HLA determine access to solid organ transplantation and in many cases the outcome of transplantation, but graft failure is not an inevitable consequence of their presence. Much research has been performed with two main aims – which antibodies represent the highest risk factor prior to transplantation, and second to understand how donor specific HLA antibodies behave after transplantation, with a long-term aim of being able to manipulate their production. HLA antibody incompatible kidney transplantation is the best model for examining antibody responses and this review looks at methods for interrogating the antibodies using ‘traditional’ snapshot techniques such as cytoxicity testing, and newer dissection techniques such as antibody subclass, complement binding and activity and affinity. Integral to the understanding of the large datasets generated is sophisticated mathematical analysis using techniques such as decision tree analysis and unsupervised machine learning. This review examines key aspects of this work, performed by us and others.

Background Travelers’ diarrhea (TD) is a leading threat to military readiness. Most trials of rifaximin chemoprophylaxis involve civilians or short-duration travel, whereas military travelers are exposed for longer periods at austere locations and are often physically taxed. We sought to assess efficacy of two regimens among military personnel deployed overseas. Methods This was a multi-site, double-blind, placebo-controlled trial of deployed military, randomized to placebo, rifaximin 550 mg daily, or rifaximin 550 mg twice-daily, for up to 42 days (1:1:1; 6 randomizations/block). Diaries were reviewed with subjects on return. Primary endpoint was time to first unformed stool (TFUS) in a TD episode. Other endpoints were assessed by intention to treat (ITT) and subgroups included incidence of any loose stool, meeting criteria for TD, safety, efficacy, adherence and impact to activity endpoints. Results 343 subjects were included in the ITT population. All UK travelers deployed to a single-site in Kenya; US travelers mostly deployed to various Asia-Pacific locations. Of 73 (21.2%) subjects reporting diarrhea, 42 (57.5%) met TD criteria. Among rifaximin-treated subjects, 15.9% (n=17) reported diarrhea in the twice-daily arm, 20.7% (n=25) in the daily arm, vs. 27.0% (n=31) of placebo recipients; p=.04 and 0.26 respectively. TD was reported by 10.3% (n=11) and 10.7% (n=13) in the daily and twice-daily arms, vs. 15.7% (n=18) among placebo recipients; p=0.24 vs. 0.26 respectively. Among UK personnel, a twice-daily regimen vs. placebo resulted in significantly fewer TD episodes (1.6% vs. 11.9%; p=0.03). Adverse events were similar between groups. Table 1: Demographics, endpoints, and adverse events (Comparisons are across placebo vs. each dosing regimen. Intent-to-treat [ITT] population defined as subjects enrolled into the study, randomized, travelled and had follow-up. p-values calculated from chi-square or Fisher’s exact test [categorical variables] and Wilcoxon-Mann-Whitney test [continuous variables]. Analyses performed on SAS v9.4. BID: twice-daily) Conclusion This is the first trial comparing two high-dose regimens of rifaximin prophylaxis in deployed personnel. Unlike prior reports, neither regimen was associated with an overall significant decrease in TD, potentially due to low overall TD incidence. However, the twice-daily regimen was associated with a numerically lower incidence of diarrheal stool, and in the UK subject group, there was a significant decrease of both TD and diarrheal stool. The impact of variability in regional TD risk, pathogen distribution and adherence in austere deployment environments on efficacy will be reviewed. Disclosures All Authors: No reported disclosures

Choroid plexus tumors (CPTs) occur spontaneously in humans and dogs providing an opportunity for comparative cross species analysis of common tumor mechanisms. Large scale chromosomal copy number alterations are the hallmark of human CPTs and identification of driver genes within these regions is problematic. Copy number alterations in 12 spontaneous dog CPTs were defined using an Illumina 170 K single nucleotide polymorphism array and were characterized by highly recurrent whole chromosomal losses in up to 100% of cases with few chromosome wide gains. Loss of canine chromosomes 2, 5, 8, and 20 were seen in 90%-100% of cases and included regions syntenic to loci within commonly reported whole chromosome losses in human choroid plexus tumors. These regions included previously defined tumor suppressor clusters on chromosome 3p and 17p as well as genes associated with chromosomal instability such as TP53 and VHL. This karyotypic signature is similar to a previously defined hypodiploid subgroup of human choroid plexus carcinomas. The nonrandom, highly recurrent alterations in dog CPTs suggest specific selection pressures and oncogenic mechanisms are present. More extensive analysis of this spontaneous tumor model is warranted and may provide key insights into driver mechanisms common to both species.

HLA specific antibodies vary in their pathogenicity and this is likely to be the net effect of constant chain usage, quantity, specificity, and affinity. Here we have measured the affinity of human monoclonal antibodies for a range of HLA proteins. Purified antibodies and ligands allowed dynamic interactions to be measured directly by surface plasmon resonance. Physiochemical differences between pairs of ligands were quantified using electrostatic mismatch and hydrophobic mismatch scores. \ud \ud All antibodies were characterized by fast on-rates and slow off rates but with a wide range of association rates (kon, 3.63-24.25 × 10(5) per mol per second) and dissociation rates (koff, 0.99-10.93 × 10(-3) per second). Dissociation constants (KD) ranged from 5.9 × 10(-10) M to 3.0 × 10(-8) M. SN320G6 has approximately a twenty-fold greater affinity for HLA A2 compared with SN607D8, but has a similar affinity for HLA-A2 and B57. In contrast, SN607D8 has greater than a twofold greater affinity for HLA-A2 compared with A68. Similarly, WK1D12 has about a threefold greater affinity for HLA-B27 compared with B7. The higher affinity interactions correlate with the specificity of stimulating antigen. This is the first study to directly measure the binding kinetics and affinity constants for human alloantibodies against HLA.

The 3rd International Transplant Conference took place on 31st October and 1st November 2014 at the University of Warwick, Coventry, UK. Key focal points of the meeting were the exploration of the molecular basis of antibody–antigen interactions and their relation to clinical practice and to share experiences and knowledge regarding strategies to transplant the ‘high-risk’ patient. In addition, lively debate sessions were hosted where controversial clinical and immunological themes were discussed by leading experts in the field.

Falls in the serum levels of donor specific HLA antibodies (DSA) after kidney transplantation are of great clinical interest, as they are associated with resolution of rejection and good long term outcomes in patients at high risk of graft loss. A data-driven model in the form of third order differential equation has been developed to describe the dynamics of the falls in DSA after renal transplantation. The model characterises the post transplant DSA behaviour for two groups of renal transplant recipients: those who experienced acute antibody mediated rejection (AMR) in the first days after operation and those who did not. A variational Bayesian inference method was employed to find the form of the model, infer the system parameters and extract the information of the recognisable patterns and the common features in DSA post transplant dynamics. Three models of different order have been investigated, and the third order linear model with four parameters outperformed the models of lower orders. The inferred deterministic parameters were found to be significantly different between the two groups of people with and without AMR. The eigenvalues for each DSA time series have been calculated and compared between the groups. A higher frequency of oscillation and a faster dissipation rate of antibodies have been found in the AMR group, which demonstrate a potential for intelligent laboratory interrogation of the underlying immunological mechanisms, which at present are entirely opaque.

BACKGROUND Patients with advanced chronic kidney disease (CKD) experience complex functional and structural changes of the cardiopulmonary and musculoskeletal system. This results in reduced exercise tolerance, quality of life and ultimately premature death. We investigated the relationship between subjective measures of health related quality of life and objective, standardised functional measures for cardiovascular and pulmonary health. METHODS Between April 2010 and January 2013, 143 CKD stage-5 or CKD5d patients (age 46.0±1.1y, 62.2% male), were recruited prospectively. A control group of 83 healthy individuals treated for essential hypertension (HTN; age 53.2±0.9y, 48.22% male) were recruited at random. All patients completed the SF-36 health survey questionnaire, echocardiography, vascular tonometry and cardiopulmonary exercise testing. RESULTS Patients with CKD had significantly lower SF-36 scores than the HTN group; for physical component score (PCS; 45.0 vs 53.9, p

Background. ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. Methods. The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. Results. For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. Conclusions. Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

The dynamics of donor specific human leukocyte antigen (HLA) antibodies during early stage after transplantation are of great clinical interest as they are considered to be associated with short and long term outcomes (graft function and rejection). However, the limited number of such detailed donor-specific antibody (DSA) time series currently available and their diverse patterns have made the task of modelling difficult. Focusing on one typical dynamic pattern with rapid falls and stable settling levels, a novel data-driven model in the form of a third order differential equation has been developed to describe such post-transplant dynamics in DSAs for the first time. A variational Bayesian inference method has been applied to select a model and learn its parameters for 39 time series from two groups of graft recipients, i.e. patients with and without acute antibody-mediated rejection (AMR) episodes. Linear and nonlinear dynamic models of different order were attempted to fit the time series, and the third order linear model provided the best description of the common features in both groups. Both deterministic and stochastic parameters are found to be significantly different in the AMR and no-AMR groups. Eigenvalues have been calculated for each fitting, and phase portraits have been plotted to show the trajectories of the system states for both groups. The results from our previous study with fewer cases have been further confirmed: the time series in the AMR group have significantly higher frequency of oscillations and faster dissipation rates, which may potentially lead to better laboratory measurement strategy and a better chance of understanding the underlying immunological mechanisms.

Introduction: This small scale qualitative research study investigated the perceptions by both academic tutors and clinical placement educators of integrating the research-informed teaching experience (RiTe) within an undergraduate radiography curriculum to support the learning and practice of image quality and dose optimization.\ud \ud \ud Method: A purposeful sampling approach was used to recruit participants and two asynchronous online focus groups (OFG) were used for data collection. An inductive thematic approach was taken to analyse both sets of OFG data.\ud \ud \ud Results and discussion: Five academic tutors and four clinical placement educators participated in the research. Three overarching themes common to both sets of OFG data were identified. Findings confirmed that both OFGs felt that the RiTe supported student learning of image quality and dose optimization as well as the development of research skills. However, the clinical placement educators did identify that students may find it difficult to transfer and apply this knowledge into practice (theory-practice gap).\ud \ud \ud Conclusion: Results from both OFGs suppor tRiT ewith regard tot he teaching and practice of image quality and dose optimization.However, greater involvement by clinical placement educators may help to overcome issues with the translation of RiTe by students into the clinical environment (theory-practice gap) and support its continued development within the curriculum. It was also identified that RiTe could be developed for qualified staff for continued professional development.

Reports of primary nervous system tumors in wild raccoons are extremely rare. Olfactory tumors were diagnosed postmortem in 9 free-ranging raccoons from 4 contiguous counties in California and 1 raccoon from Oregon within a 26-month period between 2010 and 2012. We describe the geographic and temporal features of these 10 cases, including the laboratory diagnostic investigations and the neuropathologic, immunohistochemical, and ultrastructural characteristics of these tumors in the affected animals. All 9 raccoons from California were found within a localized geographic region of the San Francisco Bay Area (within a 44.13-km radius). The tight temporal and geographic clustering and consistent anatomic location in the olfactory system of tumor types not previously described in raccoons (malignant peripheral nerve sheath tumors and undifferentiated sarcomas) strongly suggest either a common cause or a precipitating factor leading to induction or potentiation of neuro-oncogenesis and so prompted an extensive diagnostic investigation to explore possible oncogenic infectious and/or toxic causes. By a consensus polymerase chain reaction strategy, a novel, recently reported polyomavirus called raccoon polyomavirus was identified in all 10 tumors but not in the normal brain tissue from the affected animals, suggesting that the virus might play a role in neuro-oncogenesis. In addition, expression of the viral protein T antigen was detected in all tumors containing the viral sequences. We discuss the potential role of raccoon polyomavirus as an oncogenic virus.

Donation after circulatory determination of death (DCDD) has the potential to increase the number of organs available for transplantation. Because consent and management of potential donors must occur before death, DCDD raises unique ethical and policy issues.To develop an ethics and health policy statement on adult and pediatric DCDD relevant to critical care and transplantation stakeholders.A multidisciplinary panel of stakeholders was convened to develop an ethics and health policy statement. The panel consisted of representatives from the American Thoracic Society, Society of Critical Care Medicine, International Society for Heart and Lung Transplantation, Association of Organ Procurement Organizations, and the United Network of Organ Sharing. The panel reviewed the literature, discussed important ethics and health policy considerations, and developed a guiding framework for decision making by stakeholders.A framework to guide ethics and health policy statement was established, which addressed the consent process, pre- and post mortem interventions, the determination of death, provisions of end-of-life care, and pediatric DCDD.The information presented in this Statement is based on the current evidence, experience, and clinical rationale. New clinical research and the development and dissemination of new technologies will eventually necessitate an update of this Statement.

Primary and secondary nervous system involvement occurs in 4% and 5%–12%, respectively, of all canine non-Hodgkin lymphomas. The recent new classification of canine malignant lymphomas, based on the human World Health Organization classification, has been endorsed with international acceptance. This histological and immunocytochemical classification provides a unique opportunity to study the histologic anatomic distribution patterns in the central and peripheral nervous system of these defined lymphoma subtypes. In this study, we studied a cohort of 37 dogs with lymphoma, which at necropsy had either primary (n = 1, 2.7%) or secondary (n = 36; 97.3%) neural involvement. These T- (n = 16; 43.2%) or B-cell (n = 21; 56.8%) lymphomas were further classified into 12 lymphoma subtypes, with predominant subtypes including peripheral T-cell lymphoma (PTCL) or diffuse large B-cell lymphoma (DLBCL), respectively. This systematic study identified 6 different anatomically based histologically defined patterns of lymphoma infiltration in the nervous system of dogs. Different and distinct combinations of anatomical patterns correlated with specific lymphoma subtypes. Lymphoma infiltration within the meningeal, perivascular, and periventricular compartments were characteristic of DLBCL, whereas peripheral nerve involvement was a frequent feature of PTCL. Similarly cell counts above 64 cells/μL in cerebrospinal samples correlated best with marked meningeal and periventricular lymphoma infiltration histologically. Prospective studies are needed in order to confirm the hypothesis that these combinations of histological neuroanatomic patterns reflect targeting of receptors specific for the lymphoma subtypes at these various sites.

During the last 20 years, waiting lists for renal transplantation (RT) have grown significantly older. However, elderly patients (ie ≥65 years of age) are still more rarely referred or accepted to waiting lists and, if enlisted, have less chances of actually receiving a kidney allograft, than younger counterparts. In this review, we looked at evidence for the benefits and risks of RT in the elderly trying to answer the following questions: Should RT be advocated for elderly patients? What should be the criteria to accept elderly patients on the waiting list for RT? What strategies might be used to increase the rate of RT in waitlisted elderly candidates? For selected elderly patients, RT was shown to be superior to dialysis in terms of patient survival. Virtually all guidelines recommend that patients should not be deemed ineligible for RT based on age alone, although a short life expectancy generally might preclude RT. Concerning the assessment of comorbidities in the elderly, special attention should be paid to cardiac evaluation and screening for malignancy. Comorbidity scores and frailty assessment scales might help the decision making on eligibility. Psychosocial issues should also be evaluated. To overcome the scarcity of organ donors, elderly RT candidates should be encouraged to consider expanded criteria donors and living donors, as alternatives to deceased standard criteria donors. It has been demonstrated that expanded criteria donor RT in patients 60 years or older is associated with higher survival rates than remaining on dialysis, whereas living donor RT is superior to all other options. This position paper was written on behalf of the Descartes Working Group and ERBP, which are both official bodies of the ERA-EDTA. Both Descartes and ERBP are financially supported by ERA-EDTA. Ionuţ Nistor is a fellow of ERBP, amember of the Methods Support Team of ERBP, and supported by a grant of the ERA-EDTA.

Spontaneous gliomas in dogs occur at a frequency similar to that in humans and may provide a translational model for therapeutic development and comparative biological investigations. Copy number alterations in 38 canine gliomas, including diffuse astrocytomas, glioblastomas, oligodendrogliomas, and mixed oligoastrocytomas, were defined using an Illumina 170K single nucleotide polymorphism array. Highly recurrent alterations were seen in up to 85% of some tumor types, most notably involving chromosomes 13, 22, and 38, and gliomas clustered into 2 major groups consisting of high-grade IV astrocytomas, or oligodendrogliomas and other tumors. Tumor types were characterized by specific broad and focal chromosomal events including focal loss of the INK4A/B locus in glioblastoma and loss of the RB1 gene and amplification of the PDGFRA gene in oligodendrogliomas. Genes associated with the 3 critical pathways in human high-grade gliomas (TP53, RB1, and RTK/RAS/PI3K) were frequently associated with canine aberrations. Analysis of oligodendrogliomas revealed regions of chromosomal losses syntenic to human 1p involving tumor suppressor genes, such as CDKN2C, as well as genes associated with apoptosis, autophagy, and response to chemotherapy and radiation. Analysis of high frequency chromosomal aberrations with respect to human orthologues may provide insight into both novel and common pathways in gliomagenesis and response to therapy.

Background Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established. Hypothesis NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA. Animals 88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination. Procedures Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses. Results Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls. Conclusions and Clinical Importance NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.

Adenovirus-associated enteritis was diagnosed by histopathology of small intestine in a 2-year-old alpaca ( Vicugna pacos). Electron microscopy confirmed intracytoplasmic and intranuclear adenoviral particles within enterocytes. Nucleic acid was extracted from paraffin-embedded tissue sections, and a pan-adenovirus nested polymerase chain reaction (PCR) assay was employed to target a partial sequence of the polymerase gene. The PCR product (321 bp) was cloned and sequenced. Comparison of the nucleotide sequence against the National Center for Biotechnology Information (NCBI) nucleotide database demonstrated 68% identity with the isolates Canine adenovirus 1 and Bovine adenovirus 3. Comparison of the predicted amino acid sequence against the NCBI database demonstrated 75% identity with Bovine adenovirus 3. Phylogenetic analysis supported the relatively close relationship of this isolate to Bovine adenovirus 3, but the alpaca isolate was sufficiently distant to be considered a potentially novel adenovirus for this species.

Anti-human leukocyte antigen (HLA) antibodies are recognized as an important problem in organ transplant recipients. This is because antibodies formed against a graft months or years after implantations are the major cause of late allograft failure, and also because protocols allow the transplantation of some grafts across pre-formed HLA antibodies. Advances in our understanding of anti-HLA antibody- mediated rejection (AMR) have occurred because of a better understanding of the histological findings during AMR; more sensitive and specific methods to measure anti-HLA antibodies; and through clinical investigation of patients transplanted across an HLA barrier. Despite advances in therapy and investigation, AMR remains a major problem and treatment protocols often fail to treat it successfully. This review aims to describe the issues in each of these areas and to suggest how clinicians may be able to improve the management of patients with anti-HLA antibodies.

Antibody incompatible transplantation (AiT) is on the rise. This is because of advances in detection of donor specific antibodies, even at very low levels. In spite of this there is an increased risk of acute antibody mediated rejection. There are multiple protocols to prevent and treat antibody mediated rejection. Though they are reasonably successful in reversing acute rejection, graft loss still occurs due to ongoing chronic antibody mediated rejection.