Evaluation of Tacrolimus Concentrations and Clinical Outcomes Between Extended and Immediate Release Formulations in Kidney Transplant.

Objectives: Tacrolimus remains the mainstay of immunosuppression in kidney transplantation. Understanding the relationship between therapeutic tacrolimus levels and outcomes of acute rejection, patient/graft survival, and tolerability are important. The relationship between time to therapeutic tacrolimus levels and outcomes has not been well established, specifically with the use of extended release tacrolimus formulation (LCP-Tac). This study investigated time to therapeutic tacrolimus levels of 2 tacrolimus formulations, LCP-Tac and immediate release tacrolimus (IR-Tac), as a predictor of clinical outcomes. Methods: This was a single-center, retrospective, cohort study of kidney transplant recipients at Duke Hospital between 2013-2021. The primary objective evaluated the difference in time to therapeutic tacrolimus levels with LCP-Tac vs IR-Tac regimens. Secondary endpoints included time within therapeutic range during the first 3 months post-transplant, incidence of biopsy-proven rejection, development of de novo donor specific antibodies, and patient and allograft survival at 12 months post-transplant. Results: 128 patients were included (63 in LCP-Tac group and 65 in IR-Tac group). The time to therapeutic tacrolimus level was similar between formulations (7.2 days with LCP-Tac compared to 6.7 days with IR-Tac, P = .63). The time within therapeutic range during the first 3 months post-transplant, via modified Rosendaal, was similar with LCP-Tac and IR-Tac (56.1% vs 64.8%, respectively). Rates of biopsy-proven acute rejection at 12 months were similar (7/63 (11.1%) compared to 4/65 (6.2%)). There was no difference in patient/graft survival between groups. Conclusions: The time to therapeutic tacrolimus levels did not differ based on tacrolimus formulation and was not correlated with clinical outcomes.

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder.

BACKGROUND: Buprenorphine-naloxone is a medication shown to improve outcomes for individuals seeking treatment for opioid use disorder (OUD); however, outcomes are limited by low medication adherence rates. This is especially true during the early stages of treatment. METHODS: The present study proposes to utilize a sequential multiple assignment randomized trial design to compare two psychological interventions targeting buprenorphine-naloxone adherence: (1) contingency management (CM) and (2) brief motivational interviewing plus substance-free activities session plus mindfulness (BSM). Participants will be N = 280 adults who present to a university-based addictions clinic seeking treatment for OUD. Participants will be randomized to condition to receive 4 sessions of their assigned intervention (CM or BSM). Participants who are adherent, defined as attending physician appointments and having buprenorphine present in urine toxicology, will enter maintenance intervention for an additional 6 months. Those who are not adherent will be re-randomized to receive either the other intervention or both interventions. Follow-up will occur at 8 months post-randomization. CONCLUSIONS: This novel design will examine the benefit of sequential treatment decisions following non-adherence. The primary outcome of this study is buprenorphine-naloxone medication adherence, as assessed by physician visit attendance and presence of buprenorphine in urine. Results will elicit the relative efficacy of CM and BSM compared to one another and whether keeping the initial treatment approach when adding the alternative approach for initially non-adherent individuals is beneficial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04080180.

Impact of Tacrolimus Trough Variability on Acute Rejection Following Lung Transplantation.

BACKGROUND: Acute rejection is a risk factor for the development of chronic lung allograft dysfunction, the leading cause of morbidity and mortality in lung transplant recipients. Calcineurin inhibitors are the cornerstone of immunosuppression regimens after lung transplantation. METHODS: We retrospectively evaluated the association of tacrolimus level variability with total acute rejection score at 12 months post-transplant. Secondary outcomes included the development of chronic lung allograft dysfunction and antibody-mediated rejection at 24months post-transplant. There were 229 lung transplant recipients included. RESULTS: The mean (standard deviation) total rejection score of the cohort was 1.6 (1.7). Patients with high tacrolimus variability at 0 to 3, 3 to 6, and 6 to 12 months on average scored 0.18 (mean 1.6 vs 1.5; 95% CI): -0.3 to 0.66, P =.46), 0.14 (mean 1.7 vs 1.5; 95% CI: -0.32 to 0.6, P = .55), and 0.12 (mean 1.6 vs 1.5; 95% CI: -0.34 to 0.58, P = .62) point higher in 12-month total acute rejection scores, respectively; however, these differences were not statistically significant. The incidences of chronic lung allograft dysfunction and antibody-mediated rejection were numerically greater in the high variability group throughout certain periods; however, this was not consistent throughout all study timeframes and statistical significance was not evaluated. CONCLUSIONS: High tacrolimus variability was not associated with increased 12-month total acute rejection score. Further studies are needed to assess long-term outcomes with tacrolimus level variability.

A Systematic Review of Multilevel Influenced Risk-Taking in Helicopter and Small Airplane Normal Operations.

The violation of aviation rules, particularly meteorological flight rules, can have fatal outcomes. Violation can sometimes be explained by intentional risk-taking, alternatively it can be the manifestation of a strategy to enhance performance and influence outcomes, such as saving time or fulfilling customer expectations. The aim of this study was to determine the types of risk-taking behavior within extant empirical research and identify multilevel antecedents related to risk-taking in the context of aviation operations, via a systematic literature review. 4,742 records were identified, which after screening resulted in the detailed consideration of 10 studies, three qualitative and seven quantitative studies, which met the eligibility criteria. Only published works were included in the review, thus the results may have been subject to publication bias, however, the types of risk taking within the research were consistent with that observed in Australian and New Zealand accident reports. The predominate risk-taking behavior was that of continuing Visual Flight Rules (VFR) flight into deteriorating conditions / Instrument Meteorological Conditions (IMC). Multilevel influences could be categorized under two overarching themes, being "continuation influence" and "acceptance of risk / normalization of deviance." One or both themes was consistently observed across the finding in all studies, although precaution should be given to the relative frequency of the reported associations. This review indicates the value of considering the social and organizational influences on risk-taking, and suggests avenues for future research, in particular exploring the influences through a Self-Determination Theory (SDT) lens.

Early versus delayed initiation of cytomegalovirus prophylaxis after liver transplant.

OBJECTIVES: Delaying cytomegalovirus (CMV) prophylaxis after liver transplantation may limit medication side effects and reduce inpatient drug costs. The primary objective of this study was to determine the incidence of CMV DNAemia in liver transplant recipients who initiated prophylaxis immediately after transplant (early prophylaxis) and those who initiated prophylaxis on postoperative day 7 or at discharge, whichever came first (delayed prophylaxis). STUDY DESIGN: This was a retrospective, single-center study of adult liver transplant recipients between February 2017 and February 2019. Patients who were at low risk for CMV (D-/R-), received dual organs, had a history of invasive CMV disease, or received prophylaxis with an agent other than ganciclovir/valganciclovir were excluded. Chart review of patient profiles was completed 9 months following the transplant, and the primary end point was the first positive CMV PCR within that timeframe. Cumulative incidence of CMV DNAemia was estimated by adjusting for competing events for early and delayed prophylaxis groups. The subdistribution hazard model was utilized to examine the effect of the timing of prophylaxis on CMV DNAemia while accounting for CMV serostatus. Secondary end points included peak quantifiable viral load, time to detection, and incidence of tissue-invasive disease. RESULTS: A total of 119 patients (60 early prophylaxis and 59 delayed prophylaxis) were included, and baseline demographics were similar except for sex. Twenty patients in the early group and 17 in the delayed group developed CMV DNAemia within 9 months of transplant with a cumulative incidence of 31.7% (95% confidence interval (CI) 20%, 44%) and 28.8% (95% CI 18%, 41%), respectively. After controlling for CMV serostatus, the relative incidence of DNAemia was similar between prophylaxis groups (subdistribution hazard ratio: 1.01, 95% CI 0.53, 1.90). CONCLUSIONS: No significant difference in CMV DNAemia within 9 months of liver transplant was observed between patients who received early and delayed prophylaxis. Future studies are warranted to conclude that delaying prophylaxis can be considered a safe alternative to initiating prophylaxis immediately after transplant.

Assessment of the prevalence of burnout and well-being in solid organ transplant pharmacists.

BACKGROUND: Solid organ transplant (SOT) pharmacist burnout and well-being has not been described. METHODS: A survey of SOT pharmacists was distributed to transplant pharmacy organization listservs. Burnout was assessed with the full 22 item Maslach Burnout Inventory Human Services Survey for Medical Personnel (MBI-HSS-MP) and well-being was assessed with the Mayo Well-Being Index (WBI). Logistic multivariate regression was constructed to identify risk factors for a composite burnout assessment. RESULTS: In total, 230 responses were included (estimated response rate 36.2%). Survey participants were predominantly Caucasian (80.4%), female (79.1%), married/partnered (67.4%), and were within the first 5 years of practice (32.2%) as clinical pharmacist/specialists (87%). According to the MBI-HSS-MP, 63% met criteria for burnout. Comparing the groups with or without burnout, low quality of life (40.4% vs. 9.5%; P<.001), extreme fatigue (52.1% vs. 19%; P<.001), and likelihood of leaving the job for reasons other than retirement (38.5% vs. 10.7%; P<.001) were more common. The incidence of SOT pharmacists with WBI scores ≥ 5 (decreased well-being) was 26.5%. Among clinical pharmacists, risk factors for burnout included > 10 h per week of clinical duties outside of transplant (OR 2.669, P = .021) and extreme fatigue (OR 3.473, P<.001). CONCLUSIONS: Pharmacist burnout in SOT practice was similar to that reported in various pharmacy specialties (53-61%), which impacts clinical workforce retention and personal well-being.

Effects of Sofosbuvir-Based Hepatitis C Treatment Regimens on Calcineurin Inhibitor Dosing in Liver and Kidney Transplant Recipients.

OBJECTIVES: Available data have suggested that directacting antivirals for hepatitis C virus may decrease calcineurin inhibitor concentrations. In this study, our aim was to determine the effects of hepatitis C directacting antivirals on calcineurin inhibitor doses and trough levels. MATERIALS AND METHODS: This retrospective, singlecenter study included 52 abdominal transplant recipients treated with sofosbuvir-based regimens between 2014 and 2017. The primary outcome was percent change in calcineurin inhibitor troughs and total daily doses between the week before treatment with direct-acting antivirals, days 21 to 35 oftreatment, and days 21 to 35 aftertreatment. Secondary outcomes included sustained virologic response and biopsyproven acute rejection rates. RESULTS: The median percent difference in calcineurin inhibitor troughs from pretreatment to during treatment was -20.5% (interquartile range, -36.2% to 13.1%) and from pretreatment to posttreatment was -13.5% (interquartile range, -33.7% to 10.7%). Corresponding percent changes in calcineurin inhibitor doses were 0% (interquartile range, 0%-0%) and 0% (interquartile range, -10.5% to 33.3%), respectively. Patients on tacrolimus experienced statistically significant changes in troughs but not doses. During treatment, 65% of patients required no dose change, 23% underwent a dose increase, and 12% had a dose decrease. The sustained virologic response rate was 98%, and the biopsy-proven acute rejection rate was 0%. CONCLUSIONS: Hepatitis C direct-acting antiviraltherapy may decrease calcineurin inhibitor levels, but this was not associated with clinically different dosing requirements or rejection rates.

Harnessing 64Cu/67Cu for a theranostic approach to pretargeted radioimmunotherapy.

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

Delayed vs initial cytomegalovirus prophylaxis after kidney transplantation.

It is recommended to start cytomegalovirus (CMV) prophylaxis within 10 days of solid organ transplant, if indicated. Our center underwent a cost-savings initiative to delay CMV prophylaxis initiation from postoperative day zero to postoperative day 7 or upon discharge, hypothesizing this would not affect clinical outcomes but could impact costs. The purpose of this retrospective study was to determine the effects of early vs delayed (<72 vs >72 hours after transplant) CMV prophylaxis in kidney and kidney/pancreas transplant recipients transplanted between June 2014 and January 2017. The primary endpoint was incidence of CMV infection within 1 year. Secondary endpoints included CMV disease, CMV testing, and valganciclovir cost during index hospitalization. A total of 173 patients (114 early, 59 delayed) were included. CMV infection occurred in 61% vs 54% in the early vs delayed group (P = .5). Excluding low-level DNAemia (QNAT < 200 IU/mL), infection occurred in 30% vs 22% in the early vs late group (P = .4). The median days to starting prophylaxis were 0 and 6 in the early and delayed group (P < .05), which led to a median cost savings of $497.00 per patient during index hospitalization (P < .05). Delaying prophylaxis initiation did not impact CMV outcomes in this cohort and decreased costs.

Effects of Ideal Versus Total Body Weight Dosage of Rabbit Antithymocyte Globulin on Outcomes of Kidney Transplant Patients With High Immunologic Risk.

OBJECTIVES: The optimal dose of rabbit antithymocyte globulin induction therapy in kidney transplant recipients with high immunologic risk lacks consensus. The purpose of this study was to evaluate the effect of using ideal body weight rather than total body weight for the weight-based dose calculations in this patient population. MATERIALS AND METHODS: Data were retrospectively collected on 89 adult patients who received rabbit antithymocyte globulin induction therapy for high immunologic risk kidney transplant. Hospital protocol changed from the use of cumulative rabbit antithymocyte globulin doses of 7.5 mg/kg total body weight to 7.5 mg/kg ideal body weight in 2009. Patients were separated into 2 cohorts based on the amount of rabbit antithymocyte globulin (in mg/kg total body weight) received. Rate of biopsy-proven acute rejection, patient survival, and allograft function were evaluated at 90 days and 1 year after transplant. Cost of induction therapy was also evaluated. RESULTS: Baseline demographics were predominantly similar between the 2 cohorts. No significant difference in maintenance immunosuppression was identified. Rates of biopsy-proven acute rejection at 90 days and 1 year were similar between ideal and total body weight cohorts (4.2% vs 0% at 90 days, P = .5; 8.7% vs 0% at 1 year, P = .13). Patient survival and allograft function were also similar. Median cost of rabbit antithymocyte globulin induction therapy per patient was lower in the ideal body weight cohort, but this difference was not statistically significant ($17 542 vs $19 934; P = .3). CONCLUSIONS: Our results suggest that use of ideal body weight for dose calculations of rabbit antithymocyte globulin induction therapy in high immunologic risk kidney transplant recipients at 7.5 mg/kg results in low rates of acute rejection with a safety profile similar to that shown with a total body weight dosage. Use of ideal body weight for lower cumulative doses may still need further evaluation in this patient population.

High Affinity Binders to EphA2 Isolated from Abdurin Scaffold Libraries; Characterization, Binding and Tumor Targeting.

Abdurins are a novel antibody-like scaffold derived from the engineering of a single isolated CH2 domain of human IgG. Previous studies established the prolonged serum half-life of Abdurins, the result of a retained FcRn binding motif. Here we present data on the construction of large, diverse, phage-display and cell-free DNA display libraries and the isolation of high affinity binders to the cancer target, membrane-bound ephrin receptor tyrosine kinase class A2 (EphA2). Antigen binding regions were created by designing combinatorial libraries into the structural loops and Abdurins were selected using phage display methods. Initial binders were reformatted into new maturation libraries and low nanomolar binders were isolated using cell-free DNA display, CIS display. Further characterization confirmed binding of the Abdurins to both human and murine EphA2 proteins and exclusively to cell lines that expressed EphA2, followed by rapid internalization. Two different EphA2 binders were labeled with 64Cu, using a bifunctional MeCOSar chelator, and administered to mice bearing tumors from transplanted human prostate cancer cells, followed by PET/CT imaging. The anti-EphA2 Abdurins localized in the tumors as early as 4 hours after injection and continued to accumulate up to 48 hours when the imaging was completed. These data demonstrate the ability to isolate high affinity binders from the engineered Abdurin scaffold, which retain a long serum half-life, and specifically target tumors in a xenograft model.

Sarcoidosis manifesting as a pseudotumorous renal mass.

A 53 year-old African American woman with a three-year history of pulmonary sarcoidosis had a follow-up computed tomographic scan to evaluate the status of her disease and response to treatment. On the scan, an abnormal, hypodense mass on the left renal superior pole, which was not present on previous scans, was incidentally discovered. The initial concern was of carcinoma, despite her lack of any urinary symptoms. She underwent further evaluation with magnetic resonance, and the enhancement pattern and the shape of the mass were more suggestive of lymphoma or infarction than a carcinoma. A review of literature revealed sparse case reports demonstrating sarcoidosis presenting as infiltrative granulomatous masses resembling tumors with nonspecific imaging qualities. This diagnosis was entertained and then proven by biopsy. Pseudotumorous renal sarcoid should be in the differential of renal masses, especially in patients with a history of sarcoidosis, as it alters clinical management.

Subcritical hydrothermal liquefaction of cattle manure to bio-oil: Effects of conversion parameters on bio-oil yield and characterization of bio-oil.

In this study, cattle manure was converted to bio-oil by subcritical hydrothermal liquefaction in the presence of NaOH. The effects of conversion temperature, process gas, initial conversion pressure, residence time and mass ratio of cattle manure to water on the bio-oil yield were studied. The bio-oil was characterized in terms of elemental composition, higher heating value, ultraviolet-visible (UV/Vis) spectroscopy, Fourier transform infrared spectroscopy (FTIR), gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Results showed that the bio-oil yield depended on the conversion temperature and the process gas. Higher initial conversion pressure, longer residence time and larger mass ratio of cattle manure to water, however, had negative impacts on the bio-oil yield. The higher heating value of bio-oil was 35.53MJ/kg on average. The major non-polar components of bio-oil were toluene, ethyl benzene and xylene, which are components of crude oil, gasoline and diesel.

Simulating the continuous curvilinear capsulorhexis procedure during cataract surgery on the EYESI system.

This paper describes a technique for simulating the capsulorhexis procedure during cataract surgery on the EYESI system. The continuous curvilinear capsulorhexis technique can be a difficult procedure for beginning ophthalmology surgeons. In the initial phase of tearing the tissue, the tear vector is tangential to the circumference of the tear circle. However, without the proper re-grasping of the flap of torn tissue close to the tear point, the tear vector angle quickly runs downhill possibly causing severe damage to the tissue. Novice surgeons tend to try to complete the capsulorhexis without the time consuming re-grasping of the tissue flap. Other factors such as anterior bowing of the lens diaphragm, patient age, and shallow anterior chambers add to the problematic nature of the procedure. The tissue area is modeled as a curvilinear mesh of nodes and springs. Deformation is accomplished via a physically based particle model utilizing a heuristic algorithm to constrain the deformation calculations to the locality of the tear area to speed up computations. The training software alerts the user of any potential tear problems before they occur thus instructing the novice surgeon. The EYESI hardware system (from VRMagic GmbH) provides the user with stereoscopic images thus providing 3D viewing. Our capsulorhexis simulator software models a number of tear problems and anomalies to provide a useful training environment without the dangers of using live patients.

Using an approximation to the euclidean skeleton for efficient collision detection and tissue deformations in surgical simulators.

This paper describes a technique for efficient collision detection and deformation of abdominal organs in surgical simulation using an approximation of the Euclidean skeleton. Many researchers have developed surgical simulators, but one of the most difficult underlying problems is that of organ-instrument collision detection followed by the deformation of the tissue caused by the instrument. Much of the difficulty is due to the vast number of polygons in high resolution complex organ models. A high resolution gall bladder model for instance can number in the tens of thousands of polygons. Our methodology utilizes the reduction power of the skeleton to reduce computations. First, we recursively compute approximations to the Euclidean skeleton to generate a set of skeletal points for the organ. Then we pre-compute for each vertex in each polygon the associated skeleton point (minimal distance discs). A spring is then connected from each vertex to its associated skeleton point to be used in the deformation algorithm. The data structure for the organ thus stores for each skeletal point its maximum and minimum distances and the list of associated vertices. A heuristic algorithm using the skeleton structure of the instrument and the skeleton of the organ is used to determine instrument collisions with the organ.