The factors that influence attitudes toward organ donation for transplantation among UK university students of Indian and Pakistani descent.

BACKGROUND: The shortage of organs donated for transplantation is particularly severe among ethnic minorities. Previous work has often studied ethnic minorities in broad groups, failing to differentiate by age or country of education. We investigated the younger generation of UK-educated ethnically Indian and Pakistani students to determine their attitudes toward organ donation. METHODS: We conducted nine focus groups and eight semi-structured interviews. Participants were divided by ethnicity, gender, and medical/non-medical background. Interview transcripts were analyzed by thematic analysis. RESULTS: Six key factors influencing attitudes toward organ donation were found: religion, awareness of the importance of donation, impact of medical education, culture-specific factors, treatment of donors and their organs, and influence of family. The attitude of Islam to donation was highly relevant to Pakistani participants, more than other factors; for Indians, all six factors were similarly relevant. We found that medical education specifically had an important effect on shaping attitudes toward donation. Cultural changes suggested the younger generation may differ from their elders as they adopt British culture. Awareness of donation was universally low. CONCLUSIONS: Indian and Pakistani students are hesitant to donate organs because of multiple factors, which if addressed in a culturally relevant manner could substantially improve donation rates.

Mice with defective Fas ligand are protected from crescentic glomerulonephritis.

Fas ligand is a well-known inducer of apoptosis in cells expressing its receptor Fas; it also prevents autoimmunity by inducing apoptosis of activated T cells. However, Fas ligand also mediates non-apoptotic functions involving inflammatory cell migration and cytokine responses. We sought here to study the role of Fas ligand in nephrotoxic nephritis, a model of crescentic glomerulonephritis, using generalized lymphoproliferative disorder (GLD) mice on a C57BL/6 background, which have defective Fas ligand and display only mild autoimmunity. These mice were significantly protected from glomerular crescent formation, glomerular thrombosis, renal impairment, and albuminuria 15 days after the induction of glomerulonephritis in comparison with wild-type mice. There were a reduced number of apoptotic cells in the glomeruli of nephritic GLD mice but no defect in their antibody responses or splenocyte proliferation at 15 days following the induction of glomerulonephritis. Bone marrow transplantation from wild-type mice restored disease susceptibility to GLD mice; however, wild-type mice were not protected when transplanted with bone marrow from GLD mice. Mesangial cells express Fas ligand in vitro, and these cells isolated from GLD mice produced lower amounts of monocyte chemoattractive protein-1 following interleukin-1 stimulation compared with cells from wild-type mice. Thus, Fas ligand-defective mice are protected from nephrotoxic nephritis, a disease in which both circulating and intrinsic renal cells appear to have a role.

Live kidney donation: attitudes towards donor approach, motives and factors promoting donation.

BACKGROUND: There are many views regarding the initiation of the process for live donor kidney transplantation (LDKT), the motives of the donor and the appropriate ways to promote LDKT. METHODS: Health care professionals and patients were recruited in a tertiary renal and transplant centre and completed an anonymous questionnaire. They were then divided into focus groups and a structured interview was performed in order to discover the rationale behind the answers in the questionnaire. RESULTS: Four hundred and sixty-four participants completed the questionnaire. There were 168 health care professionals and 296 patients. Most of the participants (26.9%) suggested that the first approach to a potential donor should be made by the potential recipient. Participants believed that the most important motives for a kidney donor are relief as a result of the recipient's improved health after the transplant (82.5%) and altruism (80.4%). About 89.2% of participants believed that proper long-term medical follow-up of the donor is the most important factor for LDKT promotion. Fifty-five participants discussed the rationale of their answers in the focus group interview. CONCLUSIONS: In our study, participants preferred an initial approach of the donor by the recipient. The relief as a result of the recipient's improved health was suggested as a very strong motive for donation. Proper donor follow-up was considered to be paramount for the further development of LDKT.

Analysis of the peripheral T-cell repertoire in kidney transplant patients.

The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression. Despite selecting the patients according to stringent criteria, the patients displayed heterogeneous T-cell repertoire usage, ranging from unbiased to highly selected TCR repertoires; a skewed TCR repertoire correlating with an increase in the CD8(+) /CD4(+) T-cell ratio. T-cell repertoire patterns were compared in patients with clinically opposing outcomes i.e. stable drug-free operationally tolerant recipients and patients with the "suspicious" form of humoral chronic rejection and were found significantly different, from polyclonal to highly selected TCR repertoires, respectively. Moreover, a selected TCR repertoire was found to positively correlate with the Banff score grade. Collectively, these data suggest that TCR repertoire categorization might be included in the calculation of a composite score for the follow-up of patients after kidney transplantation.

Neutrophils express CD52 and exhibit complement-mediated lysis in the presence of alemtuzumab.

Neutropenia is a recognized adverse event in patients treated with the humanized anti-CD52 monoclonal antibody alemtuzumab. However, as it is widely believed that neutrophils do not express CD52, the etiology of alemtuzumab-associated neutropenia is unclear. We have found that neutrophils express both mRNA coding for CD52 and the protein itself on the cell surface. We confirmed cell-surface expression using 3 different anti-CD52 antibodies, and note that neutrophils express lower levels of CD52 than lymphocytes and eosinophils. Further, incubation of alemtuzumab with neutrophils results in dose-dependent, complement-mediated lysis in the presence of both heterologous and autologous complement. These data offer an explanation for the etiology of alemtuzumab-associated neutropenia. In a climate of increased use of alemtuzumab in leukemia and other disease states, as well as in transplantation, these data highlight the need for increased vigilance of emerging neutropenia in patients treated with alemtuzumab.

Attitudes toward live donor kidney transplantation and its commercialization.

Development of live donor kidney transplantation (LDKT) programs has intensified debate regarding acceptability of certain donor categories and potential commercialization. Concerning these issues, we surveyed the views of medical and nursing staff caring for patients with renal failure and renal transplant recipients and donors. Participants were recruited from a tertiary transplant unit and invited to complete an anonymous questionnaire. Four hundred and sixty-four participants completed the questionnaire (42% response). One hundred and sixty-eight (36.2%) were health care professionals and 296 (63.8%) patients; 85.6% of participants were willing to donate to their children, 80.2% to siblings, 80.8% to parents, 72% to a non-blood-related relative or friend, and 15.3% to a stranger. If participants had hypothetical renal failure, they were prepared to accept a kidney from a parent (79.5%), sibling (78.7%), child (56.3%), a non-blood-related relative or friend (79.3%), or stranger (54.1%). Regarding commercialization, responders' attitudes were that the donor should not accept financial reward (29.1%), be compensated for expenses only (60.6%), or should receive a direct financial reward (10.1%). For non-directed donation, 23.5%, 55.6%, and 20.7% were not in support of reward, compensation only, and financial reward, respectively. While live kidney donation was accepted by the majority of individuals surveyed, only the minority approved of commercialization.

Medical Students Raising Concerns.

ABSTRACT: After a number of high-profile incidents and national reports, it has become clear that all health professionals and all medical students must be able to raise concerns about a colleague's behavior if this behavior puts patients, colleagues, or themselves at risk.Detailed evidence from medical students about their confidence to raise concerns is limited, together with examples of barriers, which impair their ability to do so. We describe a questionnaire survey of medical students in a single-center, examining self-reported confidence about raising concerns in a number of possible scenarios. Thematic analysis was applied to comments about barriers identified.Although 80% of respondents felt confident to report a patient safety issue, students were less confident around issues of probity, attitude, and conduct. This needs to be addressed to create clear mechanisms to raise concerns, as well as support for students during the process.

Ethical issues in live donor kidney transplant: views of medical and nursing staff.

OBJECTIVES: The ongoing development of live donor kidney transplant has generated many ethical dilemmas. It is important to be aware of the attitudes of transplant professionals involved in this practice. MATERIALS AND METHODS: An anonymous and confidential questionnaire was sent to 236 members of the medical and nursing staff of the West London Renal and Transplant Centre, to assess their views on the ethics of the current practice of live donor kidney transplant. RESULTS: Of the 236 questionnaires, 108 (45.8%) were returned. Respondents considered live donor kidney transplant ethically acceptable between blood relatives (100%), nonblood relatives and friends (92.6%), and strangers (47.2%). Most respondents were willing to donate a kidney to a blood relative (92.6%) or a nonblood relative or friend (81.5%), and 12.0% were willing to donate to a stranger. Considering themselves as potential recipients if they had end-stage renal disease, most would accept a kidney from a blood relative (91.7%) or nonblood relative or friend (85.2%),while 44.5% would accept a kidney from a stranger. The highest number of respondents (43.5%) believed that the recipient should approach the potential donor. About one-third believed there should be no financial reward, not even compensation for expenses, for donors; 8% favored direct financial rewards for donors known to recipients, and 18% favored rewards for donors not known to recipients. Slightly more than half were in favor of accepting donors with mild to moderate medical problems. CONCLUSIONS: Live related and unrelated kidney donation are considered ethically acceptable procedures, and nondirected donation is gaining support among transplant professionals. A substantial minority favored direct financial rewards for donors, especially in the case of nondirected donation.

Retrospective tissue typing of the kidney donor from recipient urine.

Given that it is possible to extract DNA from the urine of kidney transplant donors and recipients we studied whether the donor HLA type can be determined from recipient urine. This would be useful especially when there is limited information on donors or when the transplant was performed long ago when tissue typing was less precise. We extracted and purified DNA from fresh urine and used the standard HLA class I and class II PCR-SSP assays comparing the findings to those obtained from peripheral blood of donor and recipient HLA types. Using the urine of 31 renal transplant recipients we assayed for the 140 known mismatches, and all were detected in technically successful assays with only a single false positive. This shows that urine samples of transplant recipients can be used to generate historical HLA typing information of the donor thereby aiding post-transplant immunologic monitoring.

BK virus nephropathy in renal transplant patients in London.

BACKGROUND: BK nephropathy (BKN) is an important cause of renal transplant dysfunction, believed to be associated with higher levels of immunosuppression. We assessed the experience of BKN in renal transplant patients in the London region. METHODS: All six London transplant centers participated and case notes of patients with BKN in 2004 to 2005 were reviewed. RESULTS: There were 17 cases of BKN, giving an incidence of 2.1%. Median time to diagnosis was 9 months. Median baseline creatinine rose from 150 to 196 mumol/L. At diagnosis, 16 patients were on tacrolimus, 15 on mycophenolate mofetil, and 10 on triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone. Management of BKN involved reducing immunosuppression; cidofovir was used in two patients and methylprednisolone in five for acute rejection. Median follow-up time was 29.2 months. Creatinine returned to baseline in four patients, remained elevated in 12 and one patient lost his graft. The new median baseline creatinine was 216 mumol/L. Eight patients underwent repeat biopsies of which four became negative for BKV and three subsequently cleared the virus on blood and urine polymerase chain reaction and urine decoy cells. Overall, eight patients cleared the virus. None of age, sex, viral load, or biopsy characteristics (Banff ct score, Drachenberg grade, and number of BKV positive cells) were associated with poorer outcome when patients with increase in creatinine of less than 30% (n=7) or more than 30% (n=10) from baseline were compared. CONCLUSION: The incidence of BKN in this study is comparable with previous studies, with more favorable outcomes. It supports the association of BKN with potent immunosuppression.

A pig allograft model of antibody-mediated rejection.

Allograft rejection caused by antibodies in sensitised individuals remains a real problem in human allotransplantation. There would be value in a simple model of this process to evaluate the mechanisms involved in antibody-mediated damage and the development of accommodation, as well as the impact of potential interventions. We have thus developed a novel large animal model of this process using an allosensitisation system. Two inbred lines of miniature pigs that carry different major histocompatibility antigen haplotypes were used. Pigs of one line were sensitised by the sequential subcutaneous injection of major histocompatibility antigen-mismatched allogeneic peripheral blood mononuclear cells derived from the other inbred line. We demonstrated that this generated high titres of allospecific antibodies. We then transplanted carotid arteries from donors syngeneic to the priming cells into the sensitised animals. After 48 h these vessels showed a profound mononuclear cell inflammatory infiltrate in both intima and media, fibrin deposition, and luminal compromise with thrombus and antibody deposition. The mean endothelial surface affected by this process was 59.2%. No such pathology was seen in any of the controls. This model is technically simple to perform with few post-operative complications. It provides proof-of-principle of a model of antibody-mediated rejection which will be of potential value in elucidating the mechanisms underlying the process and the efficacy of interventions to prevent or treat it.

Range and Consistency of Outcomes Reported in Randomized Trials Conducted in Kidney Transplant Recipients: A Systematic Review.

BACKGROUND: The potential for clinical trials to impact patient care may be limited if the outcomes reported vary by trial and lack direct relevance to patients. Despite the many trials conducted in kidney transplantation, premature death due to cardiovascular disease, infection, and malignancy remains high. We aimed to assess the range and consistency of outcomes reported in trials in kidney transplantation. METHODS: We searched for randomized trials conducted in kidney transplantation. We extracted the outcome measures, classified them into outcome domains, and into categories (clinical, surrogate or patient-reported outcome [PRO]). We assessed the measures used for the top 4 domains. RESULTS: Overall, 397 trials reported 12 047 outcomes measures and time points (median, 19 per trial; interquartile range, 9-42) across 106 different domains, of which 55 (52%) were surrogate, 35 (33%) clinical, and 16 (15%) PRO. The 4 most frequently reported were graft function (322 [81%] trials, 118 outcome measures), acute rejection (234 [59%], 93 measures), graft loss (215 [54%], 48 measures), and mortality (204 [51%], 51 measures). The remaining 102 domains were reported in less than 50% of trials. CONCLUSIONS: Mortality- and graft-related outcome domains were frequently reported and assessed with a multiplicity of measures. Most outcome domains were surrogate outcomes, and the reporting of relevant life-threatening complications and PRO were uncommon. Establishing core outcomes based on the shared priorities of patients/caregivers and health professionals in kidney transplantation may improve the relevance and consistency of outcome reporting in trials to better inform clinical decision making.

Developing Consensus-Based Priority Outcome Domains for Trials in Kidney Transplantation: A Multinational Delphi Survey With Patients, Caregivers, and Health Professionals.

BACKGROUND: Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. METHODS: In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondents' scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically. RESULTS: One thousand eighteen participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, ≥7.5; median, ≥8; proportion, >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin), and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified 5 themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. CONCLUSIONS: Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.

Toward Establishing Core Outcome Domains For Trials in Kidney Transplantation: Report of the Standardized Outcomes in Nephrology-Kidney Transplantation Consensus Workshops.

BACKGROUND: Treatment decisions in kidney transplantation requires patients and clinicians to weigh the benefits and harms of a broad range of medical and surgical interventions, but the heterogeneity and lack of patient-relevant outcomes across trials in transplantation makes these trade-offs uncertain, thus, the need for a core outcome set that reflects stakeholder priorities. METHODS: We convened 2 international Standardized Outcomes in Nephrology-Kidney Transplantation stakeholder consensus workshops in Boston (17 patients/caregivers; 52 health professionals) and Hong Kong (10 patients/caregivers; 45 health professionals). In facilitated breakout groups, participants discussed the development and implementation of core outcome domains for trials in kidney transplantation. RESULTS: Seven themes were identified. Reinforcing the paramount importance of graft outcomes encompassed the prevailing dread of dialysis, distilling the meaning of graft function, and acknowledging the terrifying and ambiguous terminology of rejection. Reflecting critical trade-offs between graft health and medical comorbidities was fundamental. Contextualizing mortality explained discrepancies in the prioritization of death among stakeholders-inevitability of death (patients), preventing premature death (clinicians), and ensuring safety (regulators). Imperative to capture patient-reported outcomes was driven by making explicit patient priorities, fulfilling regulatory requirements, and addressing life participation. Specificity to transplant; feasibility and pragmatism (long-term impacts and responsiveness to interventions); and recognizing gradients of severity within outcome domains were raised as considerations. CONCLUSIONS: Stakeholders support the inclusion of graft health, mortality, cardiovascular disease, infection, cancer, and patient-reported outcomes (ie, life participation) in a core outcomes set. Addressing ambiguous terminology and feasibility is needed in establishing these core outcome domains for trials in kidney transplantation.

Achieving permanent survival of islet xenografts by independent manipulation of direct and indirect T-cell responses.

Recent success in pancreatic islet allotransplantation has raised expectations but has equally highlighted the acute shortage of donor tissue. The use of xenogeneic tissue would help to address this shortage; however, strong cellular immunity limits the application of this approach. T-cell responses to xenogeneic tissues involve recognition of intact species-mismatched major histocompatibility complex (MHC) molecules, the direct pathway, and xenogeneic proteins presented as peptides by responder-type MHC molecules, the indirect pathway. In this study, we exploited the species difference to selectively and sequentially inhibit direct and indirect xenoresponses after transplantation of porcine islets into mice. Selective inhibition of the direct response was achieved using porcine CTLA4-Ig, which binds preferentially to pig versus mouse B7 molecules. Selective inhibition of the indirect response was achieved using murine CTLA4-Ig, which binds preferentially to mouse B7 molecules. Administration of porcine CTLA4-Ig alone caused modest prolongation of islet survival. Injection of murine CTLA4-Ig alone had a minimal effect. However, the injection of the porcine fusion protein early and the murine homolog late after grafting led to permanent survival of the porcine islets, in the absence of any other immunosuppression. These results suggest that a similar approach could have clinical utility in porcine islet xenotransplantation.

Calcific uremic arteriolopathy presenting with small and large bowel involvement.

Calcific uremic arteriolopathy (CUA) is a rare complication of end-stage renal disease in which thrombosis occurs in calcified arteries, leading to infarction and infection of the affected tissues. This brief report describes a fatal case of CUA which presented with intestinal involvement, significantly before the onset of classical skin lesions. It is essential to raise awareness of this rare but clinically relevant form of presentation of CUA. The diagnostic and treatment issues are discussed in this case.

Standardized Outcomes in Nephrology-Transplantation: A Global Initiative to Develop a Core Outcome Set for Trials in Kidney Transplantation.

BACKGROUND: Although advances in treatment have dramatically improved short-term graft survival and acute rejection in kidney transplant recipients, long-term graft outcomes have not substantially improved. Transplant recipients also have a considerably increased risk of cancer, cardiovascular disease, diabetes, and infection, which all contribute to appreciable morbidity and premature mortality. Many trials in kidney transplantation are short-term, frequently use unvalidated surrogate endpoints, outcomes of uncertain relevance to patients and clinicians, and do not consistently measure and report key outcomes like death, graft loss, graft function, and adverse effects of therapy. This diminishes the value of trials in supporting treatment decisions that require individual-level multiple tradeoffs between graft survival and the risk of side effects, adverse events, and mortality. The Standardized Outcomes in Nephrology-Transplantation initiative aims to develop a core outcome set for trials in kidney transplantation that is based on the shared priorities of all stakeholders. METHODS: This will include a systematic review to identify outcomes reported in randomized trials, a Delphi survey with an international multistakeholder panel (patients, caregivers, clinicians, researchers, policy makers, members from industry) to develop a consensus-based prioritized list of outcome domains and a consensus workshop to review and finalize the core outcome set for trials in kidney transplantation. CONCLUSIONS: Developing and implementing a core outcome set to be reported, at a minimum, in all kidney transplantation trials will improve the transparency, quality, and relevance of research; to enable kidney transplant recipients and their clinicians to make better-informed treatment decisions for improved patient outcomes.

Cyclosporine A does not alter ultrasonic indices of renal blood flow: a potential tool for differentiating toxicity from acute rejection?

The narrow therapeutic window of cyclosporine A (CsA) means its use is controlled by pharmacokinetic monitoring. However, pharmacokinetics do not always reflect the functional effects of a drug--its pharmacodynamics, such as vasoconstriction. We developed a technique for measuring renal blood flow and used a pig model to determine whether CsA-induced renal vasoconstriction could be detected, thus offering a tool for pharmacodynamic therapeutic drug monitoring. This has been shown to differentiate acute rejection from acute tubular necrosis. Power Doppler intensitometry was used to assess relative vascular volume, and the renal arteriovenous transit time was determined with an intravenous microbubble bolus. Measurements were taken before and at intervals after an intravenous bolus of CsA (10 mg/kg). There was no correlation between index and CsA concentration. Lack of detectable effect after CsA administration to high concentrations suggests that this technique may be able to differentiate CsA toxicity from acute rejection.

A role for the Fas/Fas ligand apoptotic pathway in regulating myeloid progenitor cell kinetics.

Bone marrow from wild-type mice and mice with mutated Fas (lpr) or mutated Fas ligand (gld) was used to investigate the role of the Fas/FasL system in the regulation of myeloid progenitor cell kinetics.Granulocyte-macrophage colony-forming cells (CFU-GM) were measured by a standard colony assay and the proliferative activity of CFU-GM was measured by replating primary colonies and observing secondary colony formation. Fas expression was restored to lpr mouse bone marrow cells by retrovirus-mediated gene transfer and gld mouse marrow cells were treated with soluble FasL. Wild-type marrow cells were treated with YVAD (a caspase inhibitor) or anti-Fas monoclonal antibodies. There were greater frequencies of myeloid progenitor cells (CFU-GM) in lpr and gld mouse marrow compared to wild-type (WT) marrow (p = 0.0008). The proliferative capacity of CFU-GM was also significantly greater for lpr and gld CFU-GM compared to WT CFU-GM (p = 0.0003 and 0.0001, respectively). Retrovirus-mediated restoration of Fas into lpr marrow, and provision of soluble FasL (sFasL) to gld CFU-GM reduced CFU-GM proliferation to WT levels. Treatment of WT CFU-GM with YVAD or anti-FasL monoclonal antibody increased CFU-GM proliferation to the levels found in lpr and gld CFU-GM. YVAD significantly increased and anti-Fas significantly reduced the proliferative capacity of human CFU-GM (p = 0.015 and 0.04, respectively).Fas, FasL, and caspase activation may play an important role in regulating myeloid progenitor cell kinetics.

A peer outreach initiative to increase the registration of minorities as organ donors.

BACKGROUND: Black, Asian and minority ethnic (BAME) communities are disproportionately affected by inequalities in transplant services in the UK. There are some indications from pilot programmes that appeals for BAME organ donors may be more effectively communicated by employing grassroots, community-networking approaches, but such initiatives have not been adequately described or evaluated. METHODS: Lay individuals from BAME communities were trained as peer outreach workers. They attended a series of public events to promote knowledge of organ donation and transplantation among the public. Information was gathered from 806 evaluation forms completed by event attendees at 34 separate events. From these, 54 follow-up interviews were conducted with event attendees who completed evaluation forms, indicated that they intended to sign up to the NHS Organ Donor Register (ODR) within the next month and consented to follow-up. RESULTS: Peer outreach initiatives of the type evaluated are associated with increased numbers of BAME people registering as organ donors. A total of 8.8% of event attendees signed up to the NHS ODR. The programme was most effective with people who had previously considered becoming organ donors but who did not know how to go about it. It was less effective with people who had not previously considered it, or who were scared about signing up, or who feared family or religious disapproval. CONCLUSIONS: Peer outreach programmes with BAME communities can be an effective way of reducing inequalities by increasing the number of people on the NHS ODR and encouraging people to think about the issue.