Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation.

BACKGROUND: Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). METHODS: This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. RESULTS: From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS: Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.

"They Have Shown Me It Is Possible to Thrive within STEM": Incorporating Learning Assistants in General Chemistry Enhances Student Belonging and Confidence.

Students often experience social and psychological barriers to success in General Chemistry, which is a key gateway to many students' science pathways. Learning assistants (LAs) have the potential to reduce these barriers and to strengthen students' sense of belonging in General Chemistry and STEM more broadly. Here, we used a 17-item Likert scale to determine whether incorporating LAs into General Chemistry I and II enhances students' sense of belonging in these courses. The incorporation of LAs into General Chemistry I had a significant positive effect and a medium to large effect size for students in all student groups examined: women and men; students in both racially and ethnically underrepresented and well-represented groups; first- and continuing-generation students. In General Chemistry II, similar results were observed for women and men; students in well-represented racial and ethnic groups; continuing-generation students. Further, we asked students to reflect on the impact that working with LAs had on their sense of belonging in STEM and confidence in talking about science. Sixty percent of students indicated that working with LAs had a positive impact on their STEM belonging, with five themes describing LA impacts: reducing isolation, serving as inspirational role models, providing mentoring, increasing opportunities for engagement and confidence building, and serving as accessible and approachable sources of support. Sixty-one percent of students also indicated that working with LAs increased their confidence in talking about science, with three themes emerging: fostering an environment with a lower risk of negative judgment, providing increased opportunities for feedback, and supporting students as they practiced their growing skills. Together, these results indicate that LAs can be an important means to reduce social and psychological barriers for students in gateway science courses, increasing their sense that they belong to the class and STEM more broadly.

"It made me feel like a bigger part of the STEM community": Incorporation of Learning Assistants Enhances Students' Sense of Belonging in a Large Introductory Biology Course.

Large introductory science courses are a particularly important and challenging target for creating inclusive learning environments. In this study, we examined the impact of incorporating learning assistants (LAs) on the learning environment in an introductory biology course taught with two different structures: an in-person lecture with intermittent active-learning components and an online setting taught with a flipped instructional approach. Using a survey that measured sense of belonging in a single class, we found that students in sections with LAs reported greater sense of belonging than students in sections without LAs in both class structures. Further, student focus groups revealed that LAs promoted learning and engagement in the class by answering questions and providing clarity; allowing more use of active- and interactive-learning structures; and serving as accessible, approachable, and immediate sources of help. Student responses also indicated that LAs promoted a sense of belonging in science, technology, engineering, and mathematics (STEM) by decreasing feelings of isolation, serving as inspirational role models, clarifying progression through the STEM educational system, and helping students become more engaged and confident in their STEM-related knowledge and skills. These findings indicate that LAs can support multiple elements of inclusive STEM learning environments.

An evaluation of the safety and preliminary efficacy of peri- and post-operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients.

BACKGROUND: Orthotopic liver transplantation (OLT) is the only treatment option for various end-stage liver diseases. Ischemia and reperfusion (I/R) injury is one of the unavoidable complications/conditions in OLT. In 2019, a total of 8896 livers were transplanted of which >94% organs were procured from deceased donors. An increase in the use of extended criteria donor (ECD) livers for transplantation further unraveled the role of hepatic I/R injury on short-term and long-term graft outcomes. Despite promising outcomes with the use of antioxidants, free radical scavengers, and vasodilators; I/R-mediated liver injury persists and significantly influences the overall clinical outcomes. Treprostinil, a synthetic prostacyclin I2  (PGI2 ) analog, due to its vasodilatory property, antiplatelet activity, and its ability to downregulate pro-inflammatory cytokines can potentially minimize I/R injury. AIM: We investigated the safety and preliminary efficacy of continuous intravenous infusion of treprostinil in liver transplant recipients in a prospective, single-center, non-randomized, interventional study. MATERIAL AND METHODS: This was a dose escalation (3 + 3 design) phase 1/2 study. Deceased donor liver transplant recipients received 5 ng/kg/min for two days, or 2.5, 5, and 7.5 ng/min/kg for 5 days as a continuous infusion. Multiple blood samples were collected for biochemical parameter assessment and for measuring treprostinil levels. Indocyanine green plasma disappearance rate was used as a measure of hepatic functional capacity. RESULTS: Subjects tolerated continuous infusion of treprostinil up to 5 ng/kg/min for 120 h with no occurrence of primary graft non-function (PNF), minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival, and improved hepatobiliary excretory function comparable to normal healthy adults. DISCUSSION: Treprostinil can be administered to liver transplant patients safely during the perioperative period. CONCLUSION: Based on this phase 1/2 study, further efficacy studies of treprostinil in preventing I/R injury of liver should be conducted to potentially increase the number of livers available for transplantation.

Effects of Cross-Training on Medical Teams' Teamwork and Collaboration: Use of Simulation.

Previous research in the US Navy demonstrated that cross-training enhances teamwork and interpersonal collaboration. Limited data exists on cross-training effectiveness in medical education. This research aimed to assess whether cross-training would have similar effects on medical teams. A multidisciplinary pair of resident participants-consisting of one physician and one pharmacist-was randomly assigned to cross-training or current training condition. The training experience involved one video-based content module (training a pharmacist's task of pharmacokinetic dosing and a physician's task of intubation) and one simulation-based practice scenario (collaborative treatment of an unstable critically ill simulated patient). Interprofessional pairs randomized to cross-training condition participated in both the content module and practice scenario in the alternative professional role whereas pairs randomized to current training condition participated in their own professional role. Pairs also participated in pre- and post- training assessment scenarios in their own professional role. Teamwork and interprofessionalism were measured immediately following assessment scenarios. Knowledge assessments were conducted at the start and end of the scenario sequence. Multidisciplinary pairs experiencing cross-training showed a significant improvement in teamwork (increased by 6.11% vs. 3.24%, p < 0.05). All participants demonstrated significant improvement in knowledge scores (increase of 14% cross-training, p < 0.05, and increase of 13.9% control, p < 0.05). Our project suggests that cross-training can improve teamwork in interprofessional medical teams.

Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers.

BACKGROUND/PURPOSE: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH. METHODS: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. FINDINGS/RESULTS: Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation. IMPLICATIONS/CONCLUSIONS: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder-alcohol use disorder.

Low vitamin D exposure is associated with higher risk of infection in renal transplant recipients.

BACKGROUND: Vitamin D is a steroid hormone with multiple vital roles within the immune system. Various studies evaluated the influence of vitamin D on infections postrenal transplantation and found contrasting results. This study aimed to assess the relationship between vitamin D status and the incidence of infection in renal transplant recipients. METHODS: This is a retrospective cohort study of adult renal transplant recipients at the University of Pittsburgh Medical Center between 2005 and 2012. Patients were grouped as vitamin D sufficient (≥30 ng/mL) or deficient (<30 ng/mL) based on total serum 25-hydroxyvitamin D concentrations. The association between vitamin D levels collected at any point post-transplantation and incidence of infection within ±90 days of the vitamin D levels were assessed using logistic and Poisson's regression models. RESULTS: Vitamin D sufficiency at any point post-transplantation was significantly associated with a 66% lower odds (OR: 0.34; 95% CI: 0.22-0.52; P<.001) and 43% lower rate of infections (incident rate ratio (IRR): 0.57; 95% CI: 0.46-0.71; P<.001) within ±90 days of the vitamin D level. Baseline vitamin D level was also associated with lower incidence and risk for infections within the first year post-transplantation. CONCLUSION: Adequate levels of vitamin D in kidney transplant recipients are associated with lower infection risk in the first year and at any time post-transplantation.

Adverse Drug Reactions: Type A (Intrinsic) or Type B (Idiosyncratic).

Hepatotoxic adverse drug reactions are associated with significant morbidity and mortality and are the leading cause of postmarketing regulatory action in the United States. They are classified as Type A (intrinsic) or Type B (idiosyncratic). Type A are predictable, dose-related toxicities, often identified in preclinical or clinical trials, and usually occur in overdose settings or with pre-existing hepatic impairment. Type B are not clearly related to increasing dose and are associated with drug-specific and patient-specific characteristics and environmental risks. Rare Type B reactions are often identified postmarketing. Identification and management, including electronic resources, has evolved.

Drug Class Combination-Associated Acute Kidney Injury.

OBJECTIVE: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI). DATA SOURCES: A search of MEDLINE and Embase databases was completed using the following terms: "risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication)." STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria were the following: English language, full-text availability, and at least 1 drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.. DATA SYNTHESIS: Out of 2139 total citations, 151 were assessed for full-text review, with 121 citations (6%) meeting inclusion criteria, producing76 unique drug class combinations. Overall, 56 combinations (73.7%) were considered very low quality; 12 (15.8%) were considered low quality. There were 8 (10.5%) of moderate quality, and no combination was considered high quality. 58 (76%) combinations that had a single citation,with a mean of 1.6 citations per drug class combination. The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics was reported in 10 citations, the largest number of citations. CONCLUSIONS: Our study demonstrates a lack of well-designed studies addressing drug class combination-associated AKI. The combination of NSAIDs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest level of evidence. Despite limitations, the information included in this review may result in additional scrutiny about combining certain individual nephrotoxic drugs.

Incidence and Management of Rash in Telaprevir-Treated Patients.

BACKGROUND: Telaprevir-induced rash is a common, therapy-limiting adverse drug event (ADE) for patients with hepatitis c virus (HCV) infection. Given the similarity between telaprevir and simeprevir, real-world management of rash during treatment with an NS3/4A protease inhibitor and its implications are important. OBJECTIVE: The objectives of this study were to determine the incidence of rash in telaprevir-treated patients, its management, and the impact on sustained virological response and to identify any risk factors for rash development. METHOD: This was a retrospective study of adult patients who were treated with telaprevir in a hepatology clinic from July 1, 2011, to August 31, 2012. Pertinent information on demographics, past medical history, medications, laboratory data, outcomes of rash, other ADEs related to treatment, and physician grading of rash were collected. RESULT: Of 159 patients included, 44% (70/159) developed rash, and 4% (7/159) discontinued therapy because of rash. Median number of days until rash did not differ between patients who continued and discontinued therapy (25 vs 45, respectively; P = 0.88). Patients who developed rash were more likely to have lower actual body weight (ABW) or body mass index (BMI; P ≤ 0.01). No significant difference in rash development when drug-allergy history was considered was found. Most patients who continued telaprevir were prescribed topical corticosteroids (93.7%) and cetirizine (41.3%). Patients who discontinued therapy were more likely to be evaluated by dermatology (P = 0.002), prescribed oral corticosteroids (P = 0.02), hydroxyzine (P = 0.001), and topical triamcinolone (P = 0.01). CONCLUSION: ABW and BMI appear to be related to rash development. This finding may have implications in the treatment of HCV with simeprevir, given its similarity to telaprevir.