A2/A2B to B kidney transplantation outcomes: A single center 7-year experience.

INTRODUCTION: Data on long-term outcomes following A2/A2B to B kidney transplants since the 2014 kidney allocation system (KAS) changes are few. The primary aim of this study is to report our 7-year experience with A2/A2B to B kidney transplants and to compare post-transplant outcomes of A2/A2B to a concurrent group of B to B kidney transplants. Additionally, the study evaluates the impact of pre-transplant anti-A1 titers on survival outcomes in A2/A2B transplants. METHODS: This retrospective, single-center analysis included all adults who received A2/A2B to B deceased donor kidney transplants from December 2014 to June 2021 compared to B to B recipients. The effects of pre-transplant IgM/IgG titers, stratified as ≤1:8 and ≥1:16, on death-censored, rejection-free, and overall graft survival were tested. RESULTS: Fifty-three A2/A2B and 114 B to B adults were included with a median follow-up time of 32 months. Overall graft survival, patient survival, and rejection-free graft survival did not differ between the two groups. There were no differences between the groups' overall kidney function values (p > .80) or their temporal trajectories (time by group interaction p > .11). Unadjusted death-censored graft survival was lower in A2/A2B to B compared to B recipients (p = .03), but the effect was not significant (p = .195) after adjusting for any readmissions (p = .96), rejection episodes (p < .001) or BK infection (p = .76). We did not detect an effect of pre-transplant titer group on death-censored (p = .59), rejection-free (p = .61), or overall graft survival (p = .26) CONCLUSIONS: A2/A2B to B kidney transplants have comparable overall patient and graft survival, rejection-free graft survival, and longitudinal renal function compared to B to B transplants at our center. Allograft survival outcomes were not significantly different between patients with low and high pre-transplant anti-A1 IgM/IgG titers.

Kidney Transplantation Anastomotic Time Is Jointly Associated With Resident and Attending Experience.

INTRODUCTION: Few studies evaluate the interplay of attending and resident learning curves in surgical education. Anastomotic time is known to be correlated with transplant outcomes in kidney transplantation. We aimed to evaluate the correlation between the combination of resident and attending experience and anastomotic time in kidney transplantation. METHODS: We conducted a single-center retrospective cohort study of deceased donor kidney transplants from 2006 to 2019. To analyze the effect of attending and resident experience, dyads were classified as six combinations of early versus later practice attending and resident postgraduate year (PGY-2, PGY-3, and PGY-4/5). Attendings with less than 3 y of postfellowship practice were considered early practice. Linear mixed effects models tested the effects of attending experience, resident PGY, recipient body mass index, and technical operative characteristics (number of donor arteries, operative side) on anastomosis time. RESULTS: The final linear mixed effects model included 1306 transplants. Compared to later practice attendings with PGY-4/5 residents as reference, early practice attendings paired with PGY-2 or PGY-3 residents had longer anastomotic times (P ≤ 0.005) when adjusted for recipient body mass index, number of donor arteries, and transplant side. When PGY-4/5 residents were paired with early practice attendings, no difference in anastomotic time was demonstrated. When paired with later practice attendings, PGY-2 residents had longer anastomotic times (P < 0.001) while PGY-3 anastomotic times did not differ from PGY-4/5. CONCLUSIONS: This study demonstrates the correlation between trainee and attending experience jointly and anastomotic time, suggesting that pairing residents and attendings by experience may improve surgical training and potentially patient-related outcomes.

A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC. METHODS: The 516-003 trial (NCT03606174) is an open-label, multicohort phase 2 study evaluating sitravatinib plus nivolumab in patients with advanced/metastatic UC enrolled in eight cohorts depending on prior treatment with CPI, platinum-based chemotherapy (PBC), or antibody-drug conjugate (ADC). Overall, 244 patients were enrolled and treated with sitravatinib plus nivolumab (median follow-up 14.1-38.2 mo). Sitravatinib (free-base capsules 120 mg once daily [QD] or malate capsule 100 mg QD) plus nivolumab (240 mg every 2 wk/480 mg every 4 wk intravenously). KEY FINDINGS AND LIMITATIONS: The primary endpoint was objective response rate (ORR; RECIST v1.1). The secondary endpoints included progression-free survival (PFS) and safety. The Predictive probability design and confidence interval methods were used. Among patients previously treated with PBC, ORR, and median PFS were 32.1% and 3.9 mo in CPI-naïve patients (n = 53), 14.9% and 3.9 mo in CPI-refractory patients (n = 67), and 5.4% and 3.7 mo in CPI- and ADC-refractory patients (n = 56), respectively. Across all cohorts, grade 3 treatment-related adverse events (TRAEs) occurred in 51.2% patients and grade 4 in 3.3%, with one treatment-related death (cardiac failure). Immune-related adverse events occurred in 50.4% patients. TRAEs led to sitravatinib/nivolumab discontinuation in 6.1% patients. CONCLUSIONS AND CLINICAL IMPLICATIONS: Sitravatinib plus nivolumab demonstrated a manageable safety profile but did not result in clinically meaningful ORRs in patients with advanced/metastatic UC in the eight cohorts studied. PATIENT SUMMARY: In this study, the combination of two anticancer drugs, sitravatinib and nivolumab, resulted in manageable side effects but no meaningful responses in patients with bladder cancer.

Twelve-month kidney and liver outcomes of kidney transplantation from Hepatitis C Viremic deceased donors to aviremic recipients.

INTRODUCTION: Utilization of hepatitis C viremic (HCV+) deceased donor kidneys (DDKT) for aviremic recipients increases opportunities for transplantation with excellent short-term outcomes. Our primary aim was to understand longer-term outcomes, specifically assessing kidney and liver function in the first year posttransplant. METHODS: This was a retrospective single-center study of adult DDKT recipients of HCV+ kidneys (cases) matched 1:1 to recipients of HCV- kidneys (comparators). Between-group outcomes were analyzed using comparisons of means and proportions, survival analysis methods, and multivariable mixed effects models. RESULTS: Sixty-five cases and 65 comparators had statistically comparable demographic and clinical characteristics. There were no between-group differences in serum creatinine or estimated glomerular filtration rate at month 12 (p = .662) or in their trajectories over months 1-12 (p > .292). Within the first 60 days, rates of liver function values >3 times upper limit of normal among cases were comparable to comparators for aspartate aminotransferase (AST) (14% vs. 6%, p = .242) and higher for alanine transaminase (ALT) (23% vs. 6%, p = .011). AST declined during the first 8 weeks (p = .005) and stabilized for both groups (p = .406) during the following 10 months. ALT declined during the first 8 weeks (p < .001), continued to decline over months 3-12 (p = .016), and the trajectory was unrelated to antiviral therapy initiation among cases. CONCLUSIONS: Aviremic recipients of HCV+ kidneys had comparable kidney outcomes to matched recipients of HCV- kidneys. Despite more HCV+ recipients having an elevation in ALT within the first 60 days, ALT values normalized with no identified liver complications attributed to HCV.

The Kidney Transplant: Maintaining Excellent Outcomes While Increasing Skills Acquisition.

OBJECTIVE/BACKGROUND: Kidney transplantation is a complex operation that incorporates multiple fundamental surgical techniques and is an excellent opportunity for surgical skill development during residency training. We hypothesized that increasing resident competency, measured as anastomosis time, could be demonstrated while maintaining high-quality surgical outcomes during the learning process. METHODS: We performed a retrospective cohort study of surgical resident involvement in kidney transplantation and recorded the anastomosis time. The study population comprised adult, single organ kidney transplants (n = 2052) at a large academic transplant center between 2006 and 2019. Descriptive statistics included frequencies, medians, and means. A mixed model of anastomosis time on number of procedures was fitted. Poisson models were fitted with outcomes of the number of patients with delayed graft function and number of patients that underwent reoperation postoperatively, with the exposure being number of kidney transplants performed by resident. RESULTS: Results from the mixed model suggest that as the number of times a resident performs the surgery increases, the time to conduct the operation decreases with statistical significance. The Poisson regression demonstrated no significant relationship between the operative volume of a resident and postoperative complications. CONCLUSION: This study demonstrated statistical evidence that with an increase in the number of renal transplantations performed by a surgical resident, anastomosis time decreased. It also demonstrated no significant relationship between number of kidney transplants performed by a resident and postoperative complications, suggesting that patient outcomes for this operation are not adversely affected by resident involvement.

Analytics of self-regulated learning scaffolding: effects on learning processes.

Self-regulated learning (SRL) is the ability to regulate cognitive, metacognitive, motivational, and emotional states while learning and is posited to be a strong predictor of academic success. It is therefore important to provide learners with effective instructions to promote more meaningful and effective SRL processes. One way to implement SRL instructions is through providing real-time SRL scaffolding while learners engage with a task. However, previous studies have tended to focus on fixed scaffolding rather than adaptive scaffolding that is tailored to student actions. Studies that have investigated adaptive scaffolding have not adequately distinguished between the effects of adaptive and fixed scaffolding compared to a control condition. Moreover, previous studies have tended to investigate the effects of scaffolding at the task level rather than shorter time segments-obscuring the impact of individual scaffolds on SRL processes. To address these gaps, we (a) collected trace data about student activities while working on a multi-source writing task and (b) analyzed these data using a cutting-edge learning analytic technique- ordered network analysis (ONA)-to model, visualize, and explain how learners' SRL processes changed in relation to the scaffolds. At the task level, our results suggest that learners who received adaptive scaffolding have significantly different patterns of SRL processes compared to the fixed scaffolding and control conditions. While not significantly different, our results at the task segment level suggest that adaptive scaffolding is associated with earlier engagement in SRL processes. At both the task level and task segment level, those who received adaptive scaffolding, compared to the other conditions, exhibited more task-guided learning processes such as referring to task instructions and rubrics in relation to their reading and writing. This study not only deepens our understanding of the effects of scaffolding at different levels of analysis but also demonstrates the use of a contemporary learning analytic technique for evaluating the effects of different kinds of scaffolding on learners' SRL processes.

Incisional Hernia Development after Live Donor Nephrectomy: Impact of Surgical Technique.

BACKGROUND: Characteristics of incisional hernia (IH) formation after live donor nephrectomy (LDN) are not well-defined. The goal of this study was to describe the incidence of IH within 3 years after LDN and identify risk factors contributing to their formation. METHODS: We performed a single-center, retrospective review of all LDN between February 2013 and October 2018. Patients with and without IH were compared based on donor and operative variables. Data were analyzed using chi-square tests with column proportions. Multivariable logistic regression with backward elimination was used to evaluate the likelihood of IH on the basis of potential risk factors. RESULTS: Three hundred one individuals underwent live donor nephrectomy. Twenty-eight patients (9.3%) developed an IH, with a median time to development of 7 months (range: 2-24 months). Obesity (body mass index ≥30), periumbilical hand port, and vertical infraumbilical hand port were associated with increased risk of IH development on univariate analysis. On multivariate analysis, obesity and periumbilical hand port location were persistent risk factors for IH. CONCLUSIONS: The incidence of IH after LDN is prevalent and associated with obesity and operative technique. Placing the hand port infraumbilical with a transverse fascial incision may reduce the risk of IH after LDN.

High Rates of Anxiety Among Adolescents in a Partial Hospitalization Program.

Background: Anxiety disorders are garnering increasing attention for their contribution to high-risk issues and functional impairment. Adolescents are typically admitted to partial hospitalization programs (PHPs) due to high-risk presentations. However, the frequency of anxiety disorders in PHPs is not well-established, in part because anxiety can be overlooked in acute settings due to limited lengths of stay and focus on stabilization. Objective: This study aims to evaluate the frequency and severity of anxiety disorders among a sample of adolescent PHP patients to assess the need for anxiety-specific assessment and interventions in higher acuity settings. Methods: Participants were 158 youths ages 13 to 19 years old (M = 15.49 years, SD = 1.50) who were admitted to an adolescent PHP and their caregivers. Clinician-reported diagnostic information was collected from the youth's electronic medical record, and self- and caregiver-rated severity of anxiety was collected using the Screen for Child Anxiety Related Emotions Disorders (SCARED-C/P). Frequency of anxiety and related disorder diagnoses and self- and caregiver-reported severity were assessed using descriptive statistical methods. Results: 75% of participants were diagnosed with an anxiety disorder (n = 118). On average, participants with anxiety disorders had elevated SCARED-C scores. Youths with depressive disorders had elevated SCARED-C scores even when they did not carry anxiety disorder diagnoses. Caregiver ratings of the youth's anxiety symptoms on the SCARED-P were elevated when youths had anxiety disorders. Conclusions: These findings suggest that anxiety is common in an adolescent PHP setting and support investing in evidence-based assessment and treatment of anxiety in high-acuity settings.

A feasibility study for a unified, multimodal analysis of online information foraging in health-related topics.

Background: Digital health literacy (DHL) is the ability to find, understand, and appraise online health-related information, as well as apply it to health behavior. It has become a core competence for navigating online information and health service environments. DHL involves solving ill-structured problems, where the problem and its solution are not clearcut and may have no single answer, such as in the process of sensemaking. We employ and expand on information foraging theory to address how experts and novices in information retrieval perform a search task. Our overarching aim is to pinpoint best practices and pitfalls in understanding and appraising health-related information online to develop a digital intervention to increase DHL and critical thinking. Methods: In this feasibility study, we recruited a total of twenty participants for our expert and novice subsamples. We collected sociodemographic data with a self-developed survey, video data through an observation protocol of a 10-minute search task, as well as audio-video data via a retrospective think-aloud. The three, multimodal data streams were transcribed and aligned. Codes were developed inductively in several iterations, then applied deductively to the entire dataset. Tabularized, coded and segmented qualitative data were used to create various quantitative models, which demonstrate viability for the qualitative and statistical comparison of our two subsamples. Results: Data were visualized with Epistemic Network Analysis to analyze code co-occurrences in the three aligned data streams, and with Qualitative/Unified Exploration of State Transitions to examine the order in which participants in our two subsamples encountered online content. Conclusions: This paper describes our methods and planned analyses elaborated with mock figures. Quantifying qualitative data, aligning data streams, and representing all information in a tabularized dataset allows us to group data according to various participant attributes and employ data visualization techniques to pinpoint patterns therein.

Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial.

BACKGROUND: CheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib. METHODS: CheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0-1. Cohort A1 included patients with postchemotherapy mCRPC (1-2 prior taxane-based regimens) and ≤2 prior novel hormonal therapies (eg, abiraterone, enzalutamide, apalutamide); cohort A2 included patients with chemotherapy-naïve mCRPC and prior novel hormonal therapy. Patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day (nivolumab dosing ≤2 years). Coprimary endpoints were objective response rate (ORR) per Prostate Cancer Clinical Trials Working Group 3 and prostate-specific antigen response rate (PSA50-RR; ≥50% PSA reduction) in all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. RESULTS: Outcomes (95% CI) among all-treated, HRD-positive, and BRCA1/2-positive populations for cohort A1 were confirmed ORR: 10.3% (3.9-21.2) (n=58), 17.2% (5.8-35.8) (n=29), and 33.3% (7.5-70.1) (n=9); confirmed PSA50-RR: 11.9% (5.9-20.8) (n=84), 18.2% (8.2-32.7) (n=44), and 41.7% (15.2-72.3) (n=12); median rPFS: 4.9 (3.7-5.7) (n=88), 5.8 (3.7-8.4) (n=45), and 5.6 (2.8-15.7) (n=12) months; and median OS: 13.9 (10.4-15.8) (n=88), 15.4 (11.4-18.2) (n=45), and 15.2 (3.0-not estimable) (n=12) months. For cohort A2 they were confirmed ORR: 15.4% (5.9-30.5) (n=39), 25.0% (8.7-49.1) (n=20), and 33.3% (7.5-70.1) (n=9); confirmed PSA50-RR: 27.3% (17.0-39.6) (n=66), 41.9 (24.5-60.9) (n=31), and 84.6% (54.6-98.1) (n=13); median rPFS: 8.1 (5.6-10.9) (n=71), 10.9 (6.7-12.0) (n=34), and 10.9 (5.6-12.0) (n=15) months; and median OS: 20.2 (14.1-22.8) (n=71), 22.7 (14.1-not estimable) (n=34), and 20.2 (11.1-not estimable) (n=15) months. In cohorts A1 and A2, respectively, the most common any-grade and grade 3-4 treatment-related adverse events (TRAEs) were nausea (40.9% and 40.8%) and anemia (20.5% and 14.1%). Discontinuation rates due to TRAEs were 27.3% and 23.9%, respectively. CONCLUSIONS: Nivolumab plus rucaparib is active in patients with HRD-positive postchemotherapy or chemotherapy-naïve mCRPC, particularly those harboring BRCA1/2 mutations. Safety was as expected, with no new signals identified. Whether the addition of nivolumab incrementally improves outcomes versus rucaparib alone cannot be determined from this trial. TRIAL REGISTRATION NUMBER: NCT03338790.

Team Cognition in Handoffs: Relating System Factors, Team Cognition Functions and Outcomes in Two Handoff Processes.

OBJECTIVE: This study investigates how team cognition occurs in care transitions from operating room (OR) to intensive care unit (ICU). We then seek to understand how the sociotechnical system and team cognition are related. BACKGROUND: Effective handoffs are critical to ensuring patient safety and have been the subject of many improvement efforts. However, the types of team-level cognitive processing during handoffs have not been explored, nor is it clear how the sociotechnical system shapes team cognition. METHOD: We conducted this study in an academic, Level 1 trauma center in the Midwestern United States. Twenty-eight physicians (surgery, anesthesia, pediatric critical care) and nurses (OR, ICU) participated in semi-structured interviews. We performed qualitative content analysis and epistemic network analysis to understand the relationships between system factors, team cognition in handoffs and outcomes. RESULTS: Participants described three team cognition functions in handoffs-(1) information exchange, (2) assessment, and (3) planning and decision making; information exchange was mentioned most. Work system factors influenced team cognition. Inter-professional handoffs facilitated information exchange but included large teams with diverse backgrounds communicating, which can be inefficient. Intra-professional handoffs decreased team size and role diversity, which may simplify communication but increase information loss. Participants in inter-professional handoffs reflected on outcomes significantly more in relation to system factors and team cognition (p < 0.001), while participants in intra-professional handoffs discussed handoffs as a task. CONCLUSION: Handoffs include team cognition, which was influenced by work system design. Opportunities for handoff improvement include a flexibly standardized process and supportive tools/technologies. We recommend incorporating perspectives of the patient and family in future work.

Quantifying the qualitative: exploring epistemic network analysis as a method to study work system interactions.

Studying interactions faces methodological challenges and existing methods, such as configural diagramming, have limitations. This work demonstrates Epistemic Network Analysis (ENA) as an analytical method to construct configural diagrams. We demonstrated ENA as an analytical tool by applying this method to study dementia caregiver work systems. We conducted 20 semi-structured interviews with caregivers to collect caregiving experiences. Guided by the Patient Work System model, we conducted a directed content analysis to identify work system components and used ENA to study interactions between components. By using ENA to create configural diagrams, we identified five frequently occurring interactions, compared work system configurations of caregivers providing care at home and away from home. Although we were underpowered to determine statistically significant differences, we identified visual and qualitative differences. Our results demonstrate the capability of ENA as an analytical method for studying work system interactions through configural diagramming. Practitioner summary: A new methodology, Epistemic Network Analysis (ENA), was presented to better support the study of work system interactions through configural diagramming. ENA was applied to qualitative data to demonstrate the capabilities of this method to construct configural diagrams of the work system. This study successfully demonstrated that ENA can visually represent and describe work system configurations.

Nivolumab plus docetaxel in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer: results from the phase II CheckMate 9KD trial.

BACKGROUND: Docetaxel has immunostimulatory effects that may promote an immunoresponsive prostate tumour microenvironment, providing a rationale for combination with nivolumab (programmed death-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). METHODS: In the non-randomised, multicohort, global phase II CheckMate 9KD trial, 84 patients with chemotherapy-naive mCRPC, ongoing androgen deprivation therapy and ≤2 prior novel hormonal therapies (NHTs) received nivolumab 360 mg and docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice daily (≤10 cycles) and then nivolumab 480 mg every 4 weeks (≤2 years). The co-primary end-points were objective response rate (ORR) and prostate-specific antigen response rate (PSA50-RR; ≥50% decrease from baseline). RESULTS: The confirmed ORR (95% confidence interval [CI]) was 40.0% (25.7-55.7), and the confirmed PSA50-RR (95% CI) was 46.9% (35.7-58.3). The median (95% CI) radiographic progression-free survival (rPFS) and overall survival (OS) were 9.0 (8.0-11.6) and 18.2 (14.6-20.7) months, respectively. In subpopulations with versus without prior NHT, the ORR was 38.7% versus 42.9%, the PSA50-RR was 39.6% versus 60.7%, the median rPFS was 8.5 versus 12.0 months and the median OS was 16.2 months versus not reached. Homologous recombination deficiency status or tumour mutational burden did not appear to impact efficacy. The most common any-grade and grade 3-4 treatment-related adverse events were fatigue (39.3%) and neutropenia (16.7%), respectively. Three treatment-related deaths occurred (1 pneumonitis related to nivolumab; 2 pneumonias related to docetaxel). CONCLUSIONS: Nivolumab plus docetaxel has clinical activity in patients with chemotherapy-naïve mCRPC. Safety was consistent with the individual components. These results support further investigation in the ongoing phase III CheckMate 7DX trial. CLINICALTRIALS. GOV REGISTRATION: NCT03338790.

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

Kidney Transplantation From Hepatitis C Viremic Deceased Donors to Aviremic Recipients in a Real-world Setting.

Transplantation of hepatitis C viremic (HCV+) deceased donor kidney transplants (DDKT) into aviremic (HCV-) recipients is a strategy to increase organ utilization. However, there are concerns around inferior recipient outcomes due to delayed initiation of direct-acting antiviral (DAA) therapy and sustained HCV replication when implemented outside of a research setting. METHODS: This was a retrospective single-center matched cohort study of DDKT recipients of HCV+ donors (cases) who were matched 1:1 to recipients of HCV- donors (comparators) by age, gender, race, presence of diabetes, kidney donor profile index, and calculated panel-reactive antibody. Data were analyzed using summary statistics, t-tests, and chi-square tests for between-group comparisons, and linear mixed-effects models for longitudinal data. RESULTS: Each group consisted of 50 recipients with no significant differences in baseline characteristics. The 6-mo longitudinal trajectory of serum creatinine and estimated glomerular filtration rate did not differ between groups. All recipients had similar rates of acute rejection and readmissions (all P > 0.05). One case lost the allograft 151 d posttransplant because of acute rejection, and 1 comparator died on postoperative day 7 from cardiac arrest. HCV+ recipients initiated DAA on average 29 ± 11 d posttransplant. Ninety-eight percent achieved sustained virologic response at 4 and 12 wks with the first course of therapy; 1 patient had persistent HCV infection and was cured with a second course of DAA. CONCLUSIONS: Aviremic recipients of HCV+ DDKT with delayed DAA initiation posttransplant had similar short-term outcomes compared with matched recipient comparators of HCV- donors.

Association between ezetimibe usage and hepatitis C RNA levels in uninfected kidney transplant recipients who received hepatitis C infected kidneys.

Kidney transplantation (KT) from hepatitis C virus infected (HCV+) donors to HCV negative recipients achieve excellent graft function but have relatively higher rates of post-KT co-infections presumably due to prolonged HCV viremia in transmission-and-treat approach. Ezetimibe acts as an antagonist of Niemann-Pick C1-Like 1 receptor required for HCV entry and theoretically can reduce HCV viremia. However, no data is available to examine the role of ezetimibe as a bridge therapy between KT surgery and direct acting antiviral (DAA) initiation. A retrospective cohort study including 70 HCV+ to HCV negative KT recipients from Methodist University Hospital and Vanderbilt University Medical Center was performed to determine the association between ezetimibe usage and HCV viremia. Twenty patients received ezetimibe daily while 50 patients did not. Primary outcome of study was mean HCV RNA level at 1-2 weeks post-KT and before initiation of DAA. Median (IQR) viral load (VL) in log copies/ml was one log lower in ezetimibe group versus non-ezetimibe group (4.1 [3.7-5.3] vs. 5.1 [4.4-5.5], P = .01), and highest VL was also lower in ezetimibe group (4.2 [3.7-5.4] vs. 5.4 [4.7-5.9], P = .006). We concluded that ezetimibe bridge therapy might be associated with reduction in HCV VL while waiting for DAA initiation in HCV+ to HCV negative KT recipients.

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study.

PURPOSE: Atezolizumab [anti-programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC. PATIENTS AND METHODS: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. RESULTS: All 35 evaluable patients [median age, 68 years (range, 45-83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9-not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. CONCLUSIONS: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

Diagnostic Activities and Diagnostic Practices in Medical Education and Teacher Education: An Interdisciplinary Comparison.

In this article, we investigate diagnostic activities and diagnostic practices in medical education and teacher education. Previous studies have tended to focus on comparing knowledge between disciplines, but such an approach is complicated due to the content specificity of knowledge. We compared 142 learners from medical education and 122 learners from teacher education who were asked to (a) diagnose eight simulated cases from their respective discipline in a simulation-based learning environment and (b) write a justificatory report for each simulated case. We coded all justificatory reports regarding four diagnostic activities: generating hypotheses, generating evidence, evaluating evidence, and drawing conclusions. Moreover, using the method of Epistemic Network Analysis, we operationalized diagnostic practices as the relative frequencies of co-occurring diagnostic activities. We found significant differences between learners from medical education and teacher education with respect to both their diagnostic activities and diagnostic practices. Learners from medical education put relatively more emphasis on generating hypotheses and drawing conclusions, therefore applying a more hypothesis-driven approach. By contrast, learners in teacher education had a stronger focus on generating and evaluating evidence, indicating a more data-driven approach. The results may be explained by different epistemic ideals and standards taught in higher education. Further research on the issue of epistemic ideals and standards in diagnosing is needed. Moreover, we recommend that educators think beyond individuals' knowledge and implement measures to systematically teach and increase the awareness of disciplinary standards.

Exploring patient willingness to accept hepatitis C-infected kidneys for transplantation.

BACKGROUND: As organs infected with Hepatitis C virus (HCV) provide an opportunity to expand the donor pool, the primary aim of this study is to explore patient willingness to accept a kidney from HCV-infected donors compared to other high-risk donors. METHODS: An anonymous, electronic survey was sent to all active kidney transplant waitlist patients at a single large volume transplant center. Patients were asked to respond to three hypothetical organ offers from the following: 1) HCV-infected donor 2) Donor with active intravenous drug use and 3) Donor with longstanding diabetes and hypertension. RESULTS: The survey was sent to 435 patients of which 125 responded (29% response rate). While 86 out of 125 patients (69%) were willing to accept an HCV-infected kidney, only a minority of respondents were willing to accept a kidney from other high-risk donors. In contrast to other studies, by multivariable logistic regression, age and race were not associated with willingness to accept an HCV-infected kidney. CONCLUSIONS: In this exploratory study, utilization of kidneys from HCV-infected donors to expand the donor pool appears to be an acceptable option to patients.