Celestial Matrix Model.

We construct a Hermitian random matrix model that provides a stable nonperturbative completion of Cangemi-Jackiw (CJ) gravity, a two-dimensional theory of flat spacetimes. The matrix model reproduces, to all orders in the topological expansion, the Euclidean partition function of CJ gravity with an arbitrary number of boundaries. The nonperturbative completion enables the exact computation of observables in flat space quantum gravity which we use to explicitly characterize the Bondi Hamiltonian spectrum. We discuss the implications of our results for the flat space S-matrix and black holes.

Long-term Efficacy and Safety of Everolimus Versus Mycophenolate in Kidney Transplant Recipients Receiving Tacrolimus.

BACKGROUND: The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking. METHODS: This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101). RESULTS: There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103). CONCLUSIONS: In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.

Is There Sufficient Evidence Justifying Limited Access of Jehovah's Witness Patients to Kidney Transplantation?

BACKGROUND: Jehovah's Witnesses (JWs) refuse blood transfusions due to religious issues. This situation may impact kidney transplantation (KT) outcomes in case of hemorrhagic complications. We evaluated demographic characteristics of this population, hematologic safety, and graft outcomes. METHODS: This was a retrospective, single-center study comparing KT outcomes in JW patients versus a non-JW control group. Hematologic endpoints included clinical indication for blood transfusion (hemoglobin <7 g/dL), decrease of hemoglobin >2 g/dL or hematocrit >5% in the first week after KT, hemorrhagic complications requiring surgery, and de novo prescription of erythropoiesis-stimulating agents. Secondary endpoints included delayed graft function, treated biopsy-proven acute rejection, renal function, mortality, and graft survival at 12 months. RESULTS: From January 1989 to September 2018, we identified 143 JW (10 pediatric) and selected 142 matched control (non-JW) patients. There were no differences in the incidence of clinical indication for transfusion (13.3% versus 11.3%, P = 0.640), but a higher proportion of non-JW patients received transfusions (2.1% versus 9.2%, P = 0.010). There were no differences in the proportion of patients with decreased hemoglobin concentration, in reinterventions due to hemorrhagic complications, in the use of erythropoiesis-stimulating agents at hospital discharge, in the incidence of acute rejection, in renal function, and in mortality or graft survival rate at 12 months. CONCLUSIONS: In summary, this matched control cohort study suggests that, when clinically indicated, blood transfusions can be safely avoided in the majority of JW kidney transplant, who achieve and maintain comparable hemoglobin concentrations during the first year after transplantation compared with non-JW patients.

Low dissolved oxygen levels increase stress in piava (Megaleporinus obtusidens): iono-regulatory, metabolic and oxidative responses.

The aquatic environment presents daily and/or seasonal variations in dissolved oxygen (DO) levels. Piava faces different DO levels in the water due to its distributional characteristics. The goal of this study was to describe the effects of low DO levels on plasma ion, biochemical and oxidative variables in piava juveniles. Fish were exposed to different DO levels, including 1.0, 2.0, 3.0, 4.0 and 5.0 mg L-1 of DO for 96 h, after which blood and tissue samples (liver, kidney, gill and muscle) were collected. The decrease in DO levels decreased plasma Na+, Cl-, K+ and NH3 levels as well as protein and glycogen levels in the liver, kidney and muscle; increased Na+/K+-ATPase activity in the gills and kidney as well as glucose and ammonia levels in the liver, kidney and muscle; and increased lactate levels in the kidney and muscle. Thiobarbituric acid-reacting substances, catalase and non-protein thiol levels decreased in the tissues of piavas exposed to low DO levels. It is concluded that piava can apparently cope with hypoxic conditions; however, low DO levels are a stressor, and the tolerance of piava to hypoxia involves iono-regulatory, metabolic and oxidative adjustments.

Targeted preemptive therapy according to perceived risk of CMV infection after kidney transplantation.

BACKGROUND: The identification of the best strategy to manage cytomegalovirus infection is hampered by uncertainties regarding the risk/benefit ratios of universal prophylaxis versus preemptive therapy, the impact of indirect cytomegalovirus effects and the associated costs. This study investigated the efficacy and safety of targeted preemptive therapy according to perceived risk of cytomegalovirus infection after kidney transplantation. METHODS: 144 adult kidney transplant recipients were enrolled in this 12-month study. None received cytomegalovirus pharmacological prophylaxis. Only high risk patients (positive donor/negative recipient (D+/R-), use of induction therapy with antithymocyte globulin, treatment of rejection) received preemptive therapy based on the result of pp65 antigenemia test. Low-risk patients with symptoms related to cytomegalovirus were screened for pp65 antigenemia and treatment initiated if confirmed cytomegalovirus disease. Blinded cytomegalovirus DNAemia was collected weekly during the first three months. RESULTS: The incidence of cytomegalovirus infection was 34% and cytomegalovirus disease was 17%. The incidence was 25% in D+/R-, 69% in those receiving induction with rabbit antithymocite globulin (r-ATG), 46% in those treated for acute rejection, and 28% in low risk patients. By week 3 DNAemia was observed in 30% of patients who were not treated for cytomegalovirus infection/disease, and values ≥2.169UI/mL showed 61% sensitivity and 85% specificity to detect cytomegalovirus disease (AUC=0.849±0.042, p<0.001). Using multivariate analysis, only anti-thymocyte globulin induction was associated with cytomegalovirus infection/disease whereas only expanded donor criteria and renal function at 30 days were associated with renal function 12 months after transplantation. CONCLUSION: Targeted preemptive therapy in patients with perceived higher risk for cytomegalovirus infection/disease was effective in preventing severe clinical presentation, including tissue invasive and late cytomegalovirus infection. This strategy is associated with direct and indirect cost-savings.

Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation.

BACKGROUND: Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data. METHODS: This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124). RESULTS: There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively. CONCLUSIONS: The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria.

Reviewing 15 years of experience with sirolimus.

Here, we review 15 years of clinical use of sirolimus in our transplant center, in context with the developing immunosuppressive strategies use worldwide. The majority of studies were conducted in de novo kidney transplant recipients, using sirolimus (SRL) in combination with calcineurin inhibitors (CNIs). We also explored steroid (ST) or CNI-sparing therapies, including CNI minimization, elimination, or conversion strategies in combination with mycophenolate (MMF/MPS). Pooled long-term outcomes were comparable with those obtained with CNI and antimetabolite combination. Surprisingly, there are still several areas that need further investigation to improve the risk/benefit profile of SRL in kidney transplantation, including pharmacokinetic/pharmacodynamic drug-to-drug interaction with cyclosporine (CsA) or tacrolimus (TAC), mechanisms of SRL-associated adverse reactions and combinations with other drugs such as belatacept and once-daily TAC, possibly leading to improved long-term adherence. These studies, along with others investigating the benefits of SRL associated lower viral infections and malignancies, are essential as we do not expect the introduction of new immunosuppressive drugs in the near future.

Current minimally invasive practice patterns among postgraduate urologists.

PURPOSE: To determine laparoscopic and robotic surgical practice patterns among current postgraduate urologists. MATERIALS AND METHODS: There were 9,095 electronic surveys sent to practicing urologists with e-mail addresses registered with the American Urological Association. RESULTS: Responses were received from 864 (9.5%) urologists; 84% report that laparoscopic or robotic procedures are performed in their practice. The highest training obtained by the primary laparoscopist was fellowship (31%), residency (23%), or 2- to 3-day courses (22%). Eighty-six percent report performance of laparoscopic nephrectomy in their practice, and 71% consider it the standard of care. Sixty-six percent of practices have access to at least one robotic unit, and 9% plan on purchasing one within a year. Attitudes toward robotics are favorable, with 80% indicating that it will increase in volume and potential procedures. Thirty-one percent state that robot-assisted prostatectomy is standard of care, while 50% believe this procedure looks promising. Respondents think that optimal training in minimally invasive techniques is fellowships (23%), minifellowships (23%), or hands-on courses (23%). Twenty-nine percent think that they were trained adequately in laparoscopy and robotics from residency, and 62% believe residents should be able to perform most laparoscopic procedures on completion of residency. CONCLUSIONS: The practice and availability of laparoscopic and robotic procedures have increased since previous evaluations. Opinions regarding these techniques are favorable and optimistic. As the field of urology continues to see a growing demand for minimally invasive procedures, training of postgraduate urologists and residents remains essential.

Clinical impact of polymorphisms of transport proteins and enzymes involved in the metabolism of immunosuppressive drugs.

Individualization of immunosuppressive therapy after solid organ transplantation is a goal that has been pursued for a long time. Nevertheless, in clinical practice, we are still stratifying patients in subgroups in which risk is assessed using demographic information and population analysis. Then, a combination of immunosuppressive drugs is chosen and doses are individualized to compensate for intra- and interindividual variabilities in drug pharmacokinetics, to obtain similar plasma/blood concentrations that are believed to be therapeutic, again based on data derived from population analysis. One step further in this strategy is to recognize, before initiation of immunotherapy, those patients at higher risk to be either under- or overexposed to currently used immunosuppressive drugs. Several studies have been undertaken to correlate single nucleotide polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in the disposition of immunosuppressive drugs. Overall, the results from these studies have been mixed. The causes of these sometimes conflicting results include methodologic, genetic, or nongenetic factors. The degree of linkage disequilibrium, the measure of nonrandom associations between polymorphisms at different loci, not necessarily on the same chromosome, is perhaps the main genetic factor. The influence of the environment, physiology (such as kidney and liver functions), disease state, use of multidrug regimens, and inherent drug-to-drug interactions are present nongenetic factors. Moreover, it is also important to increase our knowledge of the genetic factors involved in the variabilities observed in drug responses of pharmacodynamics. True individualized therapy, with the ability to improve health outcomes of each transplant recipient, will depend on our knowledge of the genetic factors involved in immunological response and drug pharmacokinetics and pharmacodynamics.

Ion fluxes in silver catfish (Rhamdia quelen) juveniles exposed to different dissolved oxygen levels

Low dissolved oxygen levels in the water (hypoxia) can be provoked by oxygen consumption by fish and other organisms, organic matter decomposition, phytoplankton blooms, and temperature increase. The objective of the present study was to investigate Na+, Cl-, K+, and ammonia fluxes in silver catfish (Rhamdia quelen) exposed to different dissolved oxygen levels. Juveniles (9 ± 1g) maintained at 6.0 mg.L-1 dissolved oxygen were transferred to four 40 L aquaria with different dissolved oxygen levels (in mg.L-1): 6.0, 4.5, 3.5, and 2.5. In another series of experiments, juveniles were acclimated at 6.0 or 2.5 mg.L-1 dissolved oxygen levels, and then placed in two 40 L aquaria with 6.0 mg.L-1 dissolved oxygen. For both series of experiments, 1, 24, 48 or 120 h after transference juveniles were placed in individual chambers of 200 mL (with the same dissolved oxygen levels of their respective aquaria) for 3 h. Water samples were collected for analysis of Na+, Cl-, K+, and ammonia levels. The obtained results allow concluding that exposure to 2.5 mg.L-1 dissolved oxygen levels promotes loss of ions and lower ammonia excretion in silver catfish juveniles, but these losses are rapidly stabilized for Na+ and Cl-. Exposure to less hypoxic levels also changes ion fluxes and ammonia excretion, but there is no clear relationship between both parameters in this species. Therefore, silver catfish osmoregulation seems to be affected when this species is transferred from normoxic to hypoxic waters and vice-versa.

Baixos níveis de oxigênio dissolvido na água (hipóxia) podem ser causados pelo consumo de oxygênio por peixes e outros organismos, decomposição de matéria orgânica, "blooms" de fitoplâncton e aumento de temperatura. O objetivo do presente estudo foi analisar os fluxos de Na+, Cl-, K+ e amônia em jundiás (Rhamdia quelen) expostos a diferentes níveis de oxigênio dissolvido. Juvenis (9 ± 1g) mantidos em 6,0 mg.L-1 oxigênio dissolvido foram transferidos para quatro aquários de 40 L com diferentes níveis de oxigênio dissolvido (em mg.L-1): 6,0; 4,5; 3,5 e 2,5. Em outra série de experimentos, juvenis foram aclimatados a 6,0 ou 2,5 mg.L-1 oxigênio dissolvido e então colocados em dois aquários de 40 L com 6,0 mg.L-1 oxigênio dissolvido. Para ambas séries de experimentos, 1, 24, 48 ou 120 h depois da transferência os juvenis foram colocados em câmaras individuais de 200 mL (com os mesmos níveis de oxigênio dissolvido dos seus respectivos aquários) por 3 h. Amostras de água foram coletadas para análise dos níveis de Na+, Cl-, K+ e amônia. Os resultados obtidos permitem concluir que a exposição a 2,5 mg.L-1 oxigênio dissolvido promove uma perda de íons nos juvenis de jundiá, mas estas perdas são estabilizadas rapidamente no caso de Na+ e Cl-. A exposição a níveis não tão hipóxicos também altera os fluxos iônicos, mas não há nenhuma relação clara entre ambos parâmetros. Portanto, a osmorregulação do jundiá parece ser afetada quando exemplares são transferidos de águas normóxicas to hipóxicas e vice-versa.

Immunotherapy for De Novo renal transplantation: what's in the pipeline?

Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation. Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors. Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy. Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.