Inattentional deafness to auditory alarms: Inter-individual differences, electrophysiological signature and single trial classification.

Inattentional deafness can have deleterious consequences in complex real-life situations (e.g. healthcare, aviation) leading to miss critical auditory signals. Such failure of auditory attention is thought to rely on top-down biasing mechanisms at the central executive level. A complementary approach to account for this phenomenon is to consider the existence of visual dominance over hearing that could be implemented via direct visual-to-auditory pathways. To investigate this phenomenon, thirteen aircraft pilots, equipped with a 32-channel EEG system, faced a low and high workload scenarii along with an auditory oddball task in a motion flight simulator. Prior to the flying task, the pilots were screened to assess their working memory span and visual dominance susceptibility. The behavioral results disclosed that the volunteers missed 57.7% of the auditory alarms in the difficult condition. Among all evaluated capabilities, only the visual dominance index was predictive of the miss rate in the difficult scenario. These findings provide behavioral evidences that other early cross-modal competitive process than top down modulation process could account for inattentional deafness. The electrophysiological analyses showed that the miss over the hit alarms led to a significant amplitude reduction of early perceptual (N100) and late attentional (P3a and P3b) event-related potentials components. Eventually, we implemented an EEG-based processing pipeline to perform single-trial classification of inattentional deafness. The results indicate that this processing chain could be used in an ecological setting as it led to 72.2% mean accuracy to discriminate missed from hit auditory alarms.

Resistant Cytomegalovirus Infection After Renal Transplantation: Literature Review.

BACKGROUND: Resistant cytomegalovirus (R-CMV) is an emerging problem in the renal transplantation population. The most frequent CMVs are high-resistance mutations (UL97 gene). METHODS: We describe our experience in management of R-CMV after renal transplant at our center (2012-2016). RESULTS: We encountered 3 cases of R-CMV infection after renal transplant (all primary infections). All 3 patients received induction therapy with corticosteroids, tacrolimus, and mycophenolate mofetil. The first patient (basiliximab induction, preemptive CMV) developed CMV replication on day +53, which responded poorly both to standard-dose valganciclovir (vGCV) and high-dose ganciclovir (GCV) (creatinine clearance [CrCl] >70 mL/min; vGCV 900 mg twice daily for 50 days and GCV 7.5 mg/kg twice daily for 8 days). Hematologic toxicity occurred. The R-CMV test was positive and foscarnet (FOS) was initiated (90 mg/kg twice daily for 21 days). The second patient presented CMV infection (day +30, thymoglobulin induction, CMV prophylaxis), which was not controlled with the high dose (CrCl 23 mL/min; GCV 3.5 mg/kg twice daily and vGCV 900 mg twice daily), resulting in severe neutropenia. R-CMV was detected and FOS initiated (FOS 50 mg/kg twice daily for 7 days and 50 mg/kg every 2 days for 13 days). The third patient's infection occurred on day +22 (basiliximab induction, preemptive CMV). Standard-dose vGCV was uneffective (CrCl >70 mL/min, vGCV 900 mg twice daily) and it did not respond to the high dose (GCV 7.5 mg/kg twice daily and vGCV 2700 mg/d). Moderate hematologic toxicity occurred. R-CMV was diagnosed and FOS treatment begun (FOS 70 mg/kg per day for 2 weeks). CONCLUSIONS: Resistant CMV infection may be severe due to viral infection and side effects of high-dose antiviral treatment. We presented 3 cases requiring the use of FOS in the absence of response or toxic effects from the usual treatment, with an optimal sustained response (temporary in case 2) and without serious side effects.

EFFECTIVENESS AND OUTCOMES OF CURRENT PRACTICE IN TREATING VITAMIN D DEFICIENCY IN PATIENTS LISTED FOR LIVER TRANSPLANTATION.

OBJECTIVE: Vitamin D deficiency is prevalent in cirrhotic patients awaiting liver transplantation (LT). Optimal vitamin D management for these patients remains undefined. We sought to determine the effectiveness of our practice in addressing vitamin D deficiency in LT patients. METHODS: This retrospective study included 127 patients who received a first LT between July 2010 and July 2011. Outcomes measured included readmission rates, fractures, and functional status post-LT. 25-Hydroxyvitamin D (25-OH D) deficiency was stratified as: mild (20-30 ng/mL), moderate (15-19.9 ng/mL), and severe (<15 ng/mL). We estimated the amount of vitamin D supplementation required for each patient. RESULTS: At LT evaluation, 107 patients (84%) had vitamin D deficiency, and 74% remained vitamin D deficient at LT. Only 62% received vitamin D supplementation pre-LT. Moderate and severe deficiencies were less common at LT and rare 4 months post-LT. There was an association between improvement in vitamin D deficiency category at LT and increased vitamin D (>400,000 IU total) supplementation (P = .004). We found no association between vitamin D deficiency at LT and functional status, fractures, or readmissions post-LT. Patients receiving induction immunosuppressant therapy with basiliximab had a significantly greater degree of worsening in bone mineral density (BMD) post-LT. CONCLUSION: Moderate-to-severe vitamin D deficiency was very prevalent in a cohort of patients undergoing evaluation for LT. Deficiency was improved with increased vitamin D replacement therapy. Vitamin D deficiency at LT was not associated with worse bone or functional outcomes post-LT. The influence of basiliximab on bone health post-LT requires further evaluation.

Impact of enterococcal colonization and infection in solid organ transplantation recipients from the Swiss transplant cohort study.

BACKGROUND: The burden of enterococcal infections has increased over the last decades with vancomycin-resistant enterococci (VRE) being a major health problem. Solid organ transplantation is considered as a risk factor. However, little is known about the relevance of enterococci in solid organ transplantation recipients in areas with a low VRE prevalence. METHODS: We examined the epidemiology of enterococcal events in patients followed in the Swiss Transplant Cohort Study between May 2008 and September 2011 and analyzed risk factors for infection, aminopenicillin resistance, treatment, and outcome. RESULTS: Of the 1234 patients, 255 (20.7%) suffered from 392 enterococcal events (185 [47.2%] infections, 205 [52.3%] colonizations, and 2 events with missing clinical information). Only 2 isolates were VRE. The highest infection rates were found early after liver transplantation (0.24/person-year) consisting in 58.6% of Enterococcus faecium. The highest colonization rates were documented in lung transplant recipients (0.33/person-year), with 46.5% E. faecium. Age, prophylaxis with a betalactam antibiotic, and liver transplantation were significantly associated with infection. Previous antibiotic treatment, intensive care unit stay, and lung transplantation were associated with aminopenicillin resistance. Only 4/205 (2%) colonization events led to an infection. Adequate treatment did not affect microbiological clearance rates. Overall mortality was 8%; no deaths were attributable to enterococcal events. CONCLUSIONS: Enterococcal colonizations and infections are frequent in transplant recipients. Progression from colonization to infection is rare. Therefore, antibiotic treatment should be used restrictively in colonization. No increased mortality because of enterococcal infection was noted.

Biological therapy in acute severe ulcerative colitis: Indian experience.

Biologicals have a well established role as rescue therapy in management of steroid refractory cases of Ulcerative colitis and Crohn's disease. However, high cost and potential risk of infections like tuberculosis limits their use in developing countries. As there is paucity of data on the use of various biological agents from developing countries like India, we are reporting the limited Indian experience with the available agents. Infliximab has been used as a rescue therapy for severe refractory Ulcerative colitis while other agents have been used as a part of multicentre clinical trials.

Improving the efficacy of Photoimmunotherapy (PIT) using a cocktail of antibody conjugates in a multiple antigen tumor model.

Tumors are characterized by a high degree of diversity and heterogeneity in receptor expression. Monoclonal antibodies (mAbs) are an established therapeutic method of targeting cell surface receptors. However, high affinity antibodies targeting highly expressed receptors are often prevented from distributing evenly throughout the tumor due to the "binding site barrier" whereby antibody is trapped peripherally before it can reach deeper into the tumor that leads inhomogeneous micro-distribution. When employing armed antibodies it is important that the toxin (in this case, phototoxin) be distributed evenly to more effectively treat the cancer. By adding an additional antibody conjugate, targeting a secondary, unsaturated receptor with lower expression, a more uniform distribution of the phototoxin can be achieved. In this study, panitumumab (Pan) and basiliximab (Bas) were conjugated with the phthalocyanine dye, IRDye700DX (IR700). Upon exposure to near infrared light, these armed antibodies produce rapid cell death only when bound to their respective receptors, a treatment termed photo-immunotherapy (PIT). ATAC4 cells which demonstrate high expression of human epidermal growth factor receptor (EGFR) and low expression of interleukin-2 receptor-alpha (CD25) were treated by PIT using a cocktail of Pan-IR700 and Bas-IR700. An in vivo study showed that the cocktail Pan-Bas-IR700 resulted in significantly reduced tumor growth and prolonged survival in ATAC4 tumor-bearing mice compared with either Pan-IR700 or Bas-IR700 alone. In conclusion, a cocktail injection of two different antibody-IR700 conjugates created a more homogeneous microdistribution of antibody-conjugates resulting in enhanced therapeutic effects after PIT, compared to the use of either antibody-IR700 conjugate.

The cost-effectiveness of basiliximab induction in "old-to-old" kidney transplant programs: Bayesian estimation, simulation, and uncertainty analysis.

INTRODUCTION: Markov models are employed in economic analyses to evaluate all possible expectations in a dilemna. The introduction of a new clinical protocol (Basiliximab induction with calcineurin-sparing protocols) for a group of kidney transplant recipients receiving organs from marginal donors was validated with a Markov simulation model, demonstrating the usefulness of combining simulation with Bayesian estimation methods for analysis of cost-effectiveness data collected alongside a clinical trial. We sought to determine whether calcineurin-sparing protocols using anti-interleukin-2/antibody induction (Simulect) would show a beneficial effect on initial kidney function and reduce transplantation costs upon admission, clinical incidences, graft function, and complications during the first month after transplant. PATIENTS AND METHODS: A Markov Chain Monte Carlo (MCMC) was used to estimate a system of generalized linear models relating costs and outcomes to a kidney transplant process affected by treatment under alternative therapies. The Markov simulation model was established following three chains: a calcineurin-free regimen with Basiliximab induction (chain A); a calcineurin-sparing protocol with Basiliximab induction (chain B); and a conventional immunosuppressive regimen (chain C). The MCMC draws were used as parameters in simulations that yielded inferences about the relative cost-effectiveness of the novel therapy under a variety of scenarios. After designing the Markov chain and cohorts, 31 patients from the "old-to-old" program were assigned; eight to chain A; eight to chain B; and 15 to chain C. A year after transplantation a cost-benefit study was performed guided by the three branches of the Markov model. RESULTS: The Markov model showed a benefit of induction therapies in elderly patients. A cost-benefit model showed that after a year, there was a clear benefit from calcineurin-free plus Basiliximab induction therapies, with a slight benefit from calcineurin-sparing protocols. CONCLUSIONS: Markov models are extremely useful when introducing new clinical therapies. The approach allows flexibility in assessing treatment using various premises and quantifies the global effect of parametric uncertainty on a decision maker's confidence to adopt one therapy over another. In our transplant program, a cost-effective analysis of outcomes in old patients using the Markov model showed a clear benefit of calcineurin-sparing protocols with Basixilimab induction.

Induction immunosuppression in kidney transplant recipients older than 60 years of age : safety and efficacy of ATGAM, OKT3 and Simulect.

BACKGROUND: The choice of induction immunosuppression for kidney transplantation in elderly recipients is dictated by the consideration of the risk of infection as well as efficacy in the prevention of acute rejection, thus allowing a reduction in subsequent maintenance immunosuppression and its attendant long-term adverse effects. OBJECTIVE: To compare the efficacy and safety of the antibody induction immunosuppression strategies in elderly recipients of kidney transplants. PATIENTS AND METHODS: We present retrospective data analysis on 183 kidney transplant recipients > or = 60 years of age at Hahnemann University Hospital (Philadelphia, PA, USA) over a 12-year period. We compared four consecutive cohorts of kidney transplant recipients receiving lymphocyte immune globulin, equine antithymocyte globulin (ATGAM) [n = 29]; muromonab CD3 (OKT3) [n = 45]; basiliximab (Simulect) with corticosteroid maintenance [n = 40]; and Simulect without corticosteroid maintenance (n = 69). RESULTS: Delayed graft function (DGF) was observed in 48% of patients receiving ATGAM, 35.6% in the OKT3 group and 35% in the Simulect group with corticosteroid maintenance and 36.2% in the Simulect group without corticosteroid maintenance. The rejection rate within the first 3 months was 31% in the ATGAM and OKT3 groups, 17.5% in the Simulect group with corticosteroid maintenance and 14.5% in the Simulect group without corticosteroid maintenance. These differences for DGF and acute rejection were statistically significant between patients receiving ATGAM and OKT3, ATGAM or OKT3 and both groups of Simulect (all p < 0.05). Patients receiving Simulect were free of adverse effects typically encountered by patients receiving polyclonal and monoclonal antibodies for induction. Patients receiving Simulect had much shorter hospital stays and benefited from significant reduction of costs compared with other groups. CONCLUSION: Our data indicate that kidney transplant recipients > or = 60 years of age benefit from induction therapy with Simulect followed by corticosteroid-free maintenance immunosuppression.

Basiliximab (Simulect) for the treatment of steroid-resistant rejection in pediatric liver transpland recipients: a preliminary experience.

BACKGROUND: The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients. METHODS: This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil. RESULTS: The median time from transplant to SRR was 30 days (range, 8 days-23 months). Five children received two doses of basiliximab (10 mg, 3-7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5-32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease. CONCLUSION: Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.