The measure of impact: Proposal of quality metrics for solid organ transplant pharmacy practice.

As healthcare continues its transition toward value-based care, it is increasingly important for transplant pharmacists to demonstrate their impact on patient care, health-related outcomes, and healthcare costs. Evidence-based quality and performance metrics are recognized as crucial tools for measuring the value of service. Yet, there is a lack of well-developed and agreed-upon specific metrics for many clinical pharmacy specialties, including solid organ transplantation. To address this need, a panel of transplant pharmacy specialists conducted a detailed literature review and engaged in several panel discussions to identify quality metrics to be considered for assessing the value of clinical pharmacy services provided to solid organ transplant recipients and living donors. The proposed metrics are based on the Donabedian model and are categorized to coincide with the typical phases of transplant care. The measures focus on key issues that arise in transplant recipients related to medication therapy, including adverse drug events, nonadherence, and clinical outcomes attributable to medication therapy management. This article proposes a comprehensive set of measures, any number of which transplant pharmacists can adopt and measure over time to objectively gauge the value of services they are providing to transplant recipients, the transplant center, and the overall healthcare system.

Relational closeness- not parasociality- determines the intensity of grief responses to celebrity death.

This study interrogates the common assumption that parasocial grief, or grief for celebrities, is always less intense than grief for people in social relationships. An online 2 (Parasocial or Social) × 2 (Close or Distant) experiment with participants recruited on MTurk (N = 271) examined differences in people's anticipated grief responses after imagining the hypothetical death of either a celebrity or a person in their social network, who they considered to be either close or a more distant acquaintance. The results revealed that closeness, but unexpectedly not parasociality, affected people's imagined grief. Specifically, for both close others (i.e., parasocial and social friends) and mere acquaintances (i.e., parasocial and social connections who are less familiar), higher levels of closeness were associated with more intense grief. It did not matter whether participants reported on the death of a celebrity or not. These findings provide evidence that parasocial grief is comparable to grief for deaths in social relationships.

Normative Influence of the Stars: The Relative Indirect Effects of Celebrity Exemplars on Vaping Norm Perceptions Through Liking, Parasocial Relationship Strength, and Wishful Identification.

Although the influence of celebrities on public health-related attitudes and behaviors is well established, the specific role that celebrity examples play in shaping health-related social norm perceptions is not well understood. To examine the effect of celebrities on social norm perceptions, young adults were randomly assigned to read news articles about vaping that either featured one of four film stars using a vape pen or did not contain any celebrity exemplar. The presence or absence of a celebrity exemplar did not affect readers' perceptions of vaping social norms. However, three types of audience involvement with the celebrities - liking, parasocial relationship strength, and wishful identification, were examined as mediators of the relative effects of the different celebrities on vaping norm perceptions. The results suggest that celebrities who people like more and those who they wishfully identify with less can wield a greater influence on social norms. PSR strength did not mediate indirect effects of celebrity on social norm perceptions. These findings indicate that celebrities can shape public perceptions of social norms through some types of involvement.

Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.

PURPOSE: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. EXPERIMENTAL DESIGN: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. RESULTS: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. CONCLUSIONS: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials. See related commentary by Kato et al., p. 4527.

Single-cell molecular profiling using ex vivo functional readouts fuels precision oncology in glioblastoma.

BACKGROUND: Functional profiling of freshly isolated glioblastoma (GBM) cells is being evaluated as a next-generation method for precision oncology. While promising, its success largely depends on the method to evaluate treatment activity which requires sufficient resolution and specificity. METHODS: Here, we describe the 'precision oncology by single-cell profiling using ex vivo readouts of functionality' (PROSPERO) assay to evaluate the intrinsic susceptibility of high-grade brain tumor cells to respond to therapy. Different from other assays, PROSPERO extends beyond life/death screening by rapidly evaluating acute molecular drug responses at single-cell resolution. RESULTS: The PROSPERO assay was developed by correlating short-term single-cell molecular signatures using mass cytometry by time-of-flight (CyTOF) to long-term cytotoxicity readouts in representative patient-derived glioblastoma cell cultures (n = 14) that were exposed to radiotherapy and the small-molecule p53/MDM2 inhibitor AMG232. The predictive model was subsequently projected to evaluate drug activity in freshly resected GBM samples from patients (n = 34). Here, PROSPERO revealed an overall limited capacity of tumor cells to respond to therapy, as reflected by the inability to induce key molecular markers upon ex vivo treatment exposure, while retaining proliferative capacity, insights that were validated in patient-derived xenograft (PDX) models. This approach also allowed the investigation of cellular plasticity, which in PDCLs highlighted therapy-induced proneural-to-mesenchymal (PMT) transitions, while in patients' samples this was more heterogeneous. CONCLUSION: PROSPERO provides a precise way to evaluate therapy efficacy by measuring molecular drug responses using specific biomarker changes in freshly resected brain tumor samples, in addition to providing key functional insights in cellular behavior, which may ultimately complement standard, clinical biomarker evaluations.

The expanded role of the transplant pharmacist: A 10-year follow-up.

The role of the transplant pharmacist is recognized by transplant programs, governmental groups, and professional organizations as an essential part of the transplant multidisciplinary team. This role has evolved drastically over the last decade with the advent of major advances in the science of transplantation and the growth of the field, which necessitate expanded pharmacy services to meet the needs of patients. Data now exist within all realms of the phases of care for a transplant recipient regarding the utility and benefit of a solid organ transplant (SOT) pharmacist. Furthermore, governing bodies now have the opportunity to use Board Certification in Solid Organ Transplant Pharmacotherapy as a mechanism to identify and recognize specialty knowledge and expertise within the field of SOT pharmacotherapy. The purpose of this paper is to provide an overarching review of the current and future state of SOT pharmacy while also identifying major changes to the profession, forthcoming challenges, and expected areas of growth.

ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma.

PURPOSE: Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.

The cascade of care in testing and treatment of latent tuberculosis infection in liver transplant candidates.

BACKGROUND: Testing and treatment for latent tuberculosis infection (LTBI) can mitigate risk of active tuberculosis (TB) post-liver transplant (LT). Testing and treatment completion rates have been reported low in this population. Our study aims to quantify the proportion of LT candidates who completed LTBI care cascade in our center. METHODS: A retrospective chart review was conducted on LT candidates from 2012 to 2021. Primary outcome was the proportion of patients who completed each cascade stage. Secondary outcome was an analysis of factors associated with positive and indeterminate LTBI testing. RESULTS: Of the 273 LT candidates, 265 (97.1%) were referred to transplant infectious disease (TID), 264 (96.7%) had orders for interferon-gamma release assay (IGRA), 262 (96%) underwent TID evaluation, and 259 (94.9%) completed IGRA. Twenty had LTBI, and 18 were treatment naïve and recommended for treatment. Of the 18, 15 (83.3%) agreed to therapy, 14 (77.8%) initiated treatment, and 12 (66.7%) completed treatment. No posttransplant TB reactivation occurred. Patients born in Asia, previous incarceration, past military service, and granuloma findings on chest imaging were likely to have positive IGRA (p < .05). Older age and travel to TB-endemic countries were likely to have indeterminate IGRA (p < .05). Indeterminate IGRAs were more common in QuantiFERON (QTF)-Gold Plus TB (15.3%) versus QTF-Gold TB (9.3%, p < .001). CONCLUSIONS: High rates of LTBI testing and treatment initiation and completion can be attributed to a standardized process that includes TID evaluation. Future studies in larger cohort are needed to better understand factors that can optimize the completion rates of LTBI treatment in LT candidates.

Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors.

The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.

Overall Infectious Complications Related to Belatacept Conversion in Comparison to Tacrolimus in Kidney Transplant Recipients.

Introduction: Belatacept has demonstrated effectiveness for preventing rejection in kidney transplant and has a favorable side effect profile. Studies assessing long-term infectious complications with belatacept compared to tacrolimus are limited. Project Aims: The purpose of this program evaluation was to determine the proportion of patients who developed an infection when converted to belatacept compared to those on tacrolimus. Design: In this retrospective evaluation, kidney transplant recipients receiving belatacept were matched 1:1 to those receiving tacrolimus, based on transplant date, age, induction immunosuppression, and cytomegalovirus risk. Data collection was initiated in tacrolimus patients on the date of belatacept conversion in the belatacept-matched patients. Data were extracted until study conclusion, death, or discontinuation of belatacept. Patients were stratified into 3 groups based on time of conversion posttransplant, which included early, late, and very late conversion. The primary outcome was the proportion of patients with an infection in belatacept compared to tacrolimus. Outcome data were calculated using chi-square, Fisher's exact test, student's t-test or Mann-Whitney U test where appropriate. Results: A total of 328 matched patients were included in the analysis. More patients on belatacept developed an infection compared to tacrolimus (42.7% vs 29.9%, P = 0.02), which was primarily driven by pneumonia (6.1% vs 0.5%; P = 0.01). Higher incidences of infections were identified in those converted within 6 months from transplant. Conclusions: Belatacept was associated with a higher proportion of patients with infections compared to tacrolimus, particularly in those converted within 6 months from time of transplant.

Evaluating Potentially Inappropriate Medications in Older Kidney Transplant Recipients.

OBJECTIVES: Beers Criteria and the Screening Tool of Older Persons' Prescriptions (STOPP) Criteria/Screening Tool to Alert to Right Treatment Criteria are used to assess potentially inappropriate prescribing and medications, which could pose a harm to those of older age. The purpose of this study was to assess and compare the use of Beers and STOPP Criteria in older kidney transplant recipients. METHODS: This was a dual-center, retrospective chart review from May 1, 2014, to March 1, 2018, including kidney transplant recipients 65 years and older. Those who underwent a dual transplant or had incomplete medical records were excluded. Outcomes included number of potentially inappropriate medications (PIMs) comparing Beers and STOPP Criteria on transplant admission, number of PIMs on admission compared with discharge, and readmissions within 3 months related to these medications. RESULTS: A total of 121 recipients were evaluated. On admission, 60 medications were listed on the STOPP Criteria compared with 106 medications on the Beers Criteria. When comparing PIMs on admission to discharge, there was a 38% decrease in the number of medications on discharge using the STOPP Criteria, whereas there was a 9% increase using the Beers Criteria. CONCLUSIONS: Older recipients were more likely to be on a medication listed in the Beers Criteria on admission and have a new medication listed in the Beers Criteria upon discharge compared with the STOPP Criteria.

Evaluating clinical effectiveness of SARS-CoV-2 vaccine in solid organ transplant recipients: A propensity score matched analysis.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at disproportionate risk for severe Coronavirus Disease 2019 (COVID-19). Vaccination is a key preventative strategy but is associated with decreased humoral responses among SOTR. Whether dampened immune responses correlate with reduced clinical effectiveness is unclear. Our study was designed to evaluate the clinical effectiveness of SARS-CoV-2 vaccination in the early vaccine era. METHODS: We conducted a retrospective cohort study comparing SARS-CoV-2 infection rates between SOTRs who received two doses of mRNA or one dose of Ad26.Cov2.S vaccine and those not fully vaccinated (partially vaccinated and unvaccinated). To evaluate clinical effectiveness of vaccine, cause-specific Cox regression model and modified Poisson regression model were built using the propensity score-matched cohort. Additionally, the clinical outcomes of COVID-19 of fully vaccinated and not fully vaccinated SOTR were compared. RESULTS: Of 2705 SOTRs, 1668 were included in our final matched analysis, which showed a 73% reduction of SARS-CoV-2 infection and 76% reduction of all-cause-mortality among fully vaccinated patients. Thirty-nine SOTRs developed SARS-CoV-2 infection, including nine fully vaccinated and 30 not fully vaccinated. Among fully vaccinated patients, 22% had severe/critical COVID-19 and 0% mortality versus not fully vaccinated SOTRs, of whom 37% had severe/critical COVID-19 and 6.67% COVID-19-related mortality. CONCLUSION: In SOTRs, completion of primary vaccine series in the early vaccine era was associated with a significant reduction of COVID-19 and was protective against severe/critical disease and death. Further studies are needed to evaluate the clinical effectiveness of current vaccine recommendations for SOTR against emerging new variants.

Pharmacist-Managed Diabetes Programs: Improving Treatment Adherence and Patient Outcomes.

The health and economic burden of diabetes mellitus across the United States and the world is such that effective care is crucial to improving outcomes, including macro and microvascular complications, and lowering health care costs. Pharmacists are well placed within communities to provide the critical care necessary for patients with diabetes and have a unique skillset that has demonstrated clear benefits in clinical and non-clinical outcomes. Here, we will provide a narrative review of the literature including the role of the pharmacist in different care models, outcomes associated with pharmacist care, and future directions and opportunities for pharmacist-managed diabetes.

Real-world experience with available, outpatient COVID-19 therapies in solid organ transplant recipients during the omicron surge.

The SARS-CoV-2 pandemic continues to place a substantial burden on healthcare systems. Outpatient therapies for mild-to-moderate disease have reduced hospitalizations and deaths in clinical trials, but the real-world effectiveness of monoclonal antibodies and oral antiviral agents in solid organ transplant recipients (SOTR) with coronavirus disease-2019 (COVID-19) is largely uncharacterized. We conducted a single-center, retrospective review of 122 SOTR diagnosed with COVID-19 in the outpatient setting during the Omicron surge to address this knowledge gap. The mean age was 54 years, 57% were males, and 67% were kidney transplant recipients. The mean time from transplant to COVID-19 diagnosis was 75 months. Forty-nine (40%) received molnupiravir, 24 (20%) received sotrovimab, and 1 (0.8%) received nirmatrelvir/ritonavir. No outpatient therapy was administered in 48 (39%). All 122 SOTR had >30 days follow-up. Rates of hospitalization within 30 days of initiating therapy for molnupiravir, nirmatrelvir/ritonavir, and sotrovimab were 16% (8/49), 0% (0/1), and 8% (2/24), respectively, compared to 27% (13/48) in patients without outpatient therapy. There were no deaths in those who received any therapy versus 3 (6%) deaths in patients without outpatient therapy (p = .002). Overall, our experience suggests a role for monoclonal antibodies and oral antiviral agents in reducing COVID-19-related morbidity and mortality in SOTR.

Genetic and Epidemiologic Analyses of an Outbreak of Pneumocystis jirovecii Pneumonia Among Kidney Transplant Recipients in the United States.

BACKGROUND: Pneumocystis jirovecii is an opportunistic fungus that causes Pneumocystis pneumonia (PCP) in immunocompromised hosts. Over an 11-month period, we observed a rise in cases of PCP among kidney-transplant recipients (KTR), prompting an outbreak investigation. METHODS: Clinical and epidemiologic data were collected for KTR diagnosed with PCP between July 2019 and May 2020. Pneumocystis strain typing was performed using restriction fragment length polymorphism analyses and multilocus sequence typing in combination with next-generation sequencing. A transmission map was drawn, and a case-control analysis was performed to determine risk factors associated with PCP. RESULTS: Nineteen cases of PCP in KTR were diagnosed at a median of 79 months post-transplantation; 8 received monthly belatacept infusions. Baseline characteristics were similar for KTR on belatacept versus other regimens; the number of clinic visits was numerically higher for the belatacept group during the study period (median 7.5 vs 3). Molecular typing of respiratory specimens from 9 patients revealed coinfection with up to 7 P. jirovecii strains per patient. A transmission map suggested multiple clusters of interhuman transmission. In a case-control univariate analysis, belatacept, lower absolute lymphocyte count, non-White race, and more transplant clinic visits were associated with an increased risk of PCP. In multivariate and prediction power estimate analyses, frequent clinic visits was the strongest risk factor for PCP. CONCLUSIONS: Increased clinic exposure appeared to facilitate multiple clusters of nosocomial PCP transmission among KTR. Belatacept was a risk factor for PCP, possibly by increasing clinic exposure through the need for frequent visits for monthly infusions.

Impact of Low-Dose Fluconazole on Tacrolimus Dosing in Renal Transplant.

BACKGROUND: The interaction between azole antifungal therapy and immunosuppressant tacrolimus (TAC) is a barrier to use. OBJECTIVE: This study quantified the drug interaction between low-dose fluconazole (LDF) and TAC to determine the appropriate TAC dose adjustment when used concurrently in renal transplant recipients. METHODS: We conducted a single-center retrospective chart review of renal transplant patients >18 years who received LDF or nystatin (NYS), and TAC. The primary outcome was the difference in tacrolimus total daily dose (TAC TDD) for LDF versus NYS groups. Secondary outcomes included days with supratherapeutic, therapeutic and subtherapeutic tacrolimus levels, time to therapeutic level, incidence of adverse drug reactions and graft rejection. RESULTS: We evaluated 94 patients and included 81. Low-dose fluconazole received a greater TAC TDD prior to post-operative day (POD) 10 (10.5 ± 4.7 mg vs. 7.1 ± 4.5 mg, p < 0.001), but a decreased TAC TDD POD 10 - 30 (8.6 ± 2.2 mg vs. 9.8 ± 0.8 mg, p < 0.001) and following LDF discontinuation (6.9 ± 0.1 mg vs. 9.0 ± 0.4 mg, p < 0.001). Low-dose fluconazole had more patient-days with supratherapeutic (17.9 ± 7.0 vs. 13.9 ± 8.5; p = 0.02) but fewer with subtherapeutic (6.7 ± 5.7 vs. 12.9 ± 7.2; p < 0.01) TAC levels. There was no difference in patient-days with therapeutic TAC levels (15.9 ± 5.8 vs. 14.4 ± 6.6, p = 0.28), meanwhile LDF required less patient-days to therapeutic TAC level (7.1 ± 2.7 vs. 11.5 ± 7.7; p < 0.01). There was no difference in adverse drug reactions between groups and no incidence of graft rejection. CONCLUSION: A 20% reduction in TAC TDD is warranted in renal transplant patients when used concomitantly with LDF to achieve therapeutic levels.

Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.