Renal Protective Effect of Everolimus in Liver Transplantation: A Prospective Randomized Open-Label Trial.

Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months. METHODS: This was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test. RESULTS: Each arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months. CONCLUSIONS: EVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.

Multispecialty screening, brief intervention, and referral to treatment (SBIRT) training in an academic medical center: Resident training experience across specialties.

BACKGROUND: The Substance Abuse and Mental Health Services Administration (SAMHSA) has recently begun to fund programs that train medical residents on how to utilize an evidence-based validated system known as screening, brief intervention, and referral to treatment (SBIRT) for providing early detection and brief treatment of unhealthy substance use. This paper investigates training outcomes of multispecialty SBIRT training at one such program at Albany Medical Center (AMC), one of the initial SAMHSA grantees. METHODS: Training outcomes were measured across 3 domains of learning: trainee satisfaction, acquired knowledge, and perceived usefulness. The authors explored differences in learning experience by postgraduate year and by specialty. RESULTS: Overall, residents were highly satisfied with the training, and learning outcomes met objectives. Residents' ratings of usefulness did not vary by program year. However, the results indicate that relative to residents in other programs, residents in psychiatry and pediatrics found the training components significantly more useful, whereas emergency medicine residents found training components to have less utility. Residents who found the training relevant to their daily work were more satisfied and more receptive to SBIRT training overall, which may help explain difference scores by program. CONCLUSIONS: Residents were highly satisfied with SBIRT skills training, although ratings of usefulness varied by residency program. Specialization by program and on-site modeling by senior faculty may enhance trainee satisfaction and perceived usefulness.

Residents' experience of screening, brief intervention, and referral to treatment (SBIRT) as a clinical tool following practical application: A mixed-methods study.

BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT), an evidence-based validated system for providing early detection and brief treatment of substance use disorders, has been widely used in the training of medical residents across specialties at a number of sites. This article investigates the effectiveness of SBIRT training during short-term follow-up at Albany Medical Center, one of the initial Substance Abuse and Mental Health Services Administration (SAMHSA) grantees. METHODS: Training outcomes were measured by training satisfaction following opportunities to apply SBIRT skills in clinical work, the rate at which these techniques were applied in clinical work, and the degree to which residents felt that the SBIRT training provided skills that were applicable to their practice. We examined differences in learning experience by postgraduate year and by program, and conducted a qualitative analysis in a convergent parallel mixed-methods design to elucidate barriers encountered by residents upon using SBIRT techniques in clinical practice. RESULTS: Residents remained highly satisfied with the training at 4-month follow-up, with 80.1% reporting that they had used SBIRT skills in their clinical work. Use of SBIRT techniques was high at 6-month follow-up as well, with 85.9% of residents reporting that they regularly screened their patients for substance use, 74.4% reporting that they had applied brief intervention techniques, and 78.2% indicating that SBIRT training had made them overall more effective in helping patients with substance use issues. Differences in application rates and satisfaction were found by specialty. Qualitative analyses indicated that residents encountered patient readiness and specific contextual factors, such as time constraints, externally imposed values, and clinical norms, as barriers to implementation. CONCLUSIONS: Despite encountering obstacles such as time constraints and patient readiness, residents utilized many of the skills they had learned during SBIRT training in clinical practice and reported finding these skills useful in their management of patients with substance use issues.

Cross-functionalities of Bacillus deacetylases involved in bacillithiol biosynthesis and bacillithiol-S-conjugate detoxification pathways.

BshB, a key enzyme in bacillithiol biosynthesis, hydrolyses the acetyl group from N-acetylglucosamine malate to generate glucosamine malate. In Bacillus anthracis, BA1557 has been identified as the N-acetylglucosamine malate deacetylase (BshB); however, a high content of bacillithiol (~70%) was still observed in the B. anthracis ∆BA1557 strain. Genomic analysis led to the proposal that another deacetylase could exhibit cross-functionality in bacillithiol biosynthesis. In the present study, BA1557, its paralogue BA3888 and orthologous Bacillus cereus enzymes BC1534 and BC3461 have been characterized for their deacetylase activity towards N-acetylglucosamine malate, thus providing biochemical evidence for this proposal. In addition, the involvement of deacetylase enzymes is also expected in bacillithiol-detoxifying pathways through formation of S-mercapturic adducts. The kinetic analysis of bacillithiol-S-bimane conjugate favours the involvement of BA3888 as the B. anthracis bacillithiol-S-conjugate amidase (Bca). The high degree of specificity of this group of enzymes for its physiological substrate, along with their similar pH-activity profile and Zn²âº-dependent catalytic acid-base reaction provides further evidence for their cross-functionalities.

Analysis of mutants disrupted in bacillithiol metabolism in Staphylococcus aureus.

Bacillithiol (BSH), an α-anomeric glycoside of l-cysteinyl-d-glucosaminyl-l-malate, is a major low molecular weight thiol found in low GC Gram-positive bacteria, such as Staphylococcus aureus. Like other low molecular weight thiols, BSH is likely involved in protection against a number of stresses. We examined S. aureus transposon mutants disrupted in each of the three genes associated with BSH biosynthesis. These mutants are sensitive to alkylating stress, oxidative stress, and metal stress indicating that BSH and BSH-dependent enzymes are involved in protection of S. aureus. We further demonstrate that BshB, a deacetylase involved in the second step of BSH biosynthesis, also acts as a BSH conjugate amidase and identify S. aureus USA 300 LAC 2626 as a BSH-S-transferase, which is able to conjugate chlorodinitrobenzene, cerulenin, and rifamycin to BSH.

Properties of phosphoenolpyruvate mutase, the first enzyme in the aminoethylphosphonate biosynthetic pathway in Trypanosoma cruzi.

Phosphoenolpyruvate (PEP) mutase catalyzes the conversion of phosphoenolpyruvate to phosphonopyruvate, the initial step in the formation of many naturally occurring phosphonate compounds. The phosphonate compound 2-aminoethylphosphonate is present as a component of complex carbohydrates on the surface membrane of many trypanosomatids including glycosylinositolphospholipids of Trypanosoma cruzi. Using partial sequence information from the T. cruzi genome project we have isolated a full-length gene with significant homology to PEP mutase from the free-living protozoan Tetrahymena pyriformis and the edible mussel Mytilus edulis. Recombinant expression in Escherichia coli confirms that it encodes a functional PEP mutase with a Km apparent of 8 microM for phosphonopyruvate and a kcat of 12 s-1. The native enzyme is a homotetramer with an absolute requirement for divalent metal ions and displays negative cooperativity for Mg2+ (S0.5 0.4 microM; n = 0.46). Immunofluorescence and sub-cellular fractionation indicates that PEP mutase has a dual localization in the cell. Further evidence to support this was obtained by Western analysis of a partial sub-cellular fractionation of T. cruzi cells. Southern and Western analysis suggests that PEP mutase is unique to T. cruzi and is not present in the other medically important parasites, Trypanosoma brucei and Leishmania spp.