IMPORTANCE Because unprofessional behaviors are associated with patient complications, malpractice claims, and well-being concerns, monitoring concerns requiring investigation and individuals identified in multiple reports may provide important opportunities for health care leaders to support all team members. OBJECTIVE To examine the distribution of physicians by specialty who demonstrate unprofessional behaviors measured through safety reports submitted by coworkers. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study was conducted among physicians who practiced at the 193 hospitals in the Coworker Concern Observation Reporting System (CORS), administered by the Vanderbilt Center for Patient and Professional Advocacy. Data were collected from January 2018 to December 2022. EXPOSURE Submitted reports concerning communication, professional responsibility, medical care, and professional integrity. MAIN OUTCOMES AND MEASURES Physicians' total number and categories of CORS reports. The proportion of physicians in each specialty (nonsurgeon nonproceduralists, emergency medicine physicians, nonsurgeon proceduralists, and surgeons) who received at least 1 report and who qualified for intervention were calculated; logistic regression was used to calculate the odds of any CORS report. RESULTS The cohort included 35 120 physicians: 18 288 (52.1%) nonsurgeon nonproceduralists, 1876 (5.3%) emergency medicine physicians, 6743 (19.2%) nonsurgeon proceduralists, and 8213 (23.4%) surgeons. There were 3179 physicians (9.1%) with at least 1 CORS report. Nonsurgeon nonproceduralists had the lowest percentage of physicians with at least 1 report (1032 [5.6%]), followed by emergency medicine (204 [10.9%]), nonsurgeon proceduralists (809 [12.0%]), and surgeons (1134 [13.8%]). Nonsurgeon nonproceduralists were less likely to be named in a CORS report than other specialties (5.6% vs 12.8% for other specialties combined; difference in percentages, -7.1 percentage points; 95% CI, -7.7 to -6.5 percentage points; P < .001). Pediatric-focused nonsurgeon nonproceduralists (2897 physicians) were significantly less likely to be associated with a CORS report than nonpediatric nonsurgeon nonproceduralists (15 391 physicians) (105 [3.6%] vs 927 [6.0%]; difference in percentages, -2.4 percentage points, 95% CI, -3.2 to -1.6 percentage points; P < .001). Pediatric-focused emergency medicine physicians, nonsurgeon proceduralists, and surgeons had no significant differences in reporting compared with nonpediatric-focused physicians. CONCLUSIONS AND RELEVANCE In this cohort study, less than 10% of physicians ever received a coworker report with a concern about unprofessional behavior. Monitoring reports of unprofessional behaviors provides important opportunities for health care organizations to identify and intervene as needed to support team members.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

Purpose Allograft rejection is driven by HLA disparity between donor and recipient despite of the use of various immunosuppression protocols. To better define the risk of allograft failure or complications from overt immunosuppression we applied the epitope-based mismatch approach to quantify the degree of HLA disparity in a in a large multi-center pediatric heart transplant (pHTX) cohort that has been followed for 3-5 years. Methods 274 pHTX recipient/donor pairs were retrospectively HLA genotyped by Next-Generation Sequencing and evaluated for HLA allele (alMM) and eplet mismatch (epMM) loads. HLAMatchmaker version 2.2 was used to determine epMM load at HLA-A/B/C, -DRB1/3/4/5, -DQA1/DQB1 and -DPA1/DPB1. Results Overall, the average total alMM was 13(±2). 76% were ≥5 HLA-A/B/C allele mismatches, 67% were ≥3 HLA-DRB and ≥3 HLA-DQ allele mismatch. The average epMM load was 60 (±17), range 16-112 (Table). 94% of cases had >11 HLA-DR or DQ epMM, a threshold previously shown to be associated with development of HLA donor-specific antibody in renal transplantation. While 159 cases (61.6%) had both DR and DQ epMM >11, only DR epMM or only DQ epMM >11 occurred in 31 (12.0%) and 50 (19.4%) cases, respectively (Figure). Therefore, this cohort can be divided into 3 groups for Class II epMM load: 6% (16) of cases with low, 36% (99) with intermediate and 58% (159) with high load. Conclusion Although this pHTx cohort is highly mismatched, for HLA alleles, there is a large range based on epMM, especially for HLA-DR and -DQ indicating that allele level typing is insufficient for determination of the true degree of mismatching. By correlating these data with clinical parameters, we aim to determine risk stratification based on epMM load in pediatric heart transplantation.

OBJECTIVE: To determine whether faculty who had red flags (unprofessional behavior, delayed response to queries, or delayed submission of required documentation) during pre-employment were more likely to have performance deficiencies than faculty who did not have red flags. METHODS: The study included 187 faculty consecutively hired in a Department of Pediatrics in a large academic health system from 2013 to 2018. Faculty with and without pre-employment red flags were compared to identify the proportion who had subsequent performance deficiencies related to documentation, unprofessional behavior, performance, or premature departure from the faculty. RESULTS: Most of the hired faculty were female (127, 0.68), physicians (136, 0.73), and clinicians or clinician-educators (124, 0.67). Sixteen faculty (0.09) had pre-employment red flags. In the 3 years after hiring, 31 (0.17) of the faculty cohort had at least 1 performance deficiency. Faculty with pre-employment red flags were more than 4 times as likely to experience a performance deficiency during follow-up (0.56 vs 0.13, P<.001). The hazard ratio for performance deficiency comparing faculty with pre-employment red flags to those without was 5.98 (95% confidence interval 2.73-13.1, P<.0001). CONCLUSIONS: Faculty who had pre-employment red flags were significantly more likely to experience subsequent performance deficiencies. Given the substantial investment that individuals and academic medical centers make in recruiting and hiring new faculty, efforts to identify and assist faculty members at risk provide academic departments opportunities to provide the best environment for success for all faculty.

Heart transplantation in children has steadily expanded since the first operation was performed in 1967. It remains the last therapeutic option for patients with end-stage heart failure from congenital heart disease and cardiomyopathy. Patients must undergo a comprehensive evaluation prior to transplant to fully understand the risk and benefits of the procedure. Waitlist mortality currently sits at about 10%, which has decreased dramatically with the advent of the ventricular assist device. Survival has increased as well, with roughly 50% surviving to 15 years posttransplant. While it can significantly prolong one's life, serious complications are common, including graft rejection and multisystem disease secondary to necessary postoperative management and immunosuppression. This chapter provides the reader with an in-depth, state-of-the-art review of pediatric heart transplantation, with focus on management in the intensive care unit.

Background Little is known regarding the full spectrum of illness among children with SARS-CoV-2 infection across ambulatory and inpatient settings. Methods Active surveillance was performed for SARS-CoV-2 by polymerase chain reaction among asymptomatic and symptomatic individuals in a quaternary care academic hospital laboratory in Tennessee from March 12-July 17, 2020. For symptomatic patients ≤18 years of age, we performed phone follow-up and medical record review to obtain sociodemographic and clinical data on days 2, 7, and 30 after diagnosis and on day 30 for asymptomatic patients ≤18 years. Daily and 7-day average test positivity frequencies were calculated for children and adults beginning April 26, 2020. Results SARS-CoV-2 was detected in 531/10327 (5.1%) specimens from patients ≤18 years, including 46/5752 (0.8%) asymptomatic and 485/4575 (10.6%) specimens from 459 unique symptomatic children. Cough (51%), fever (42%), and headache (41%) were the most common symptoms associated with SARS-CoV-2 infection. SARS-CoV-2-related hospitalization was uncommon (18/459 children; 4%); no children with SARS-CoV-2 infection during the study period required intensive care unit admission. Symptom resolution occurred by follow-up day 2 in 192/459 (42%), by day 7 in 332/459 (72%), and by day 30 in 373/396 (94%). The number of cases and percent positivity rose in late June and July in all ages. Conclusions In an integrated healthcare network, most pediatric SARS-CoV-2 infections were mild, brief, and rarely required hospital admission, despite increasing cases as community response measures were relaxed.

PD-L1 expression and tumor mutational burden (TMB) may predict response in patients treated with immunotherapy; however, their prognostic significance in HCC patients treated with surgery remains unclear. We aimed to characterize PD-L1 prevalence and explore the relationship between PD-L1, TMB and overall survival (OS) among patients in Denmark and Korea. This study used archived FFPE tumor and clinical records from 198 patients undergoing surgical treatment, prior to systemic therapy, at either Samsung Medical Center, Aarhus University Hospital or Copenhagen University Hospital. PD-L1 was measured using DAKO’s IHC 22C3 pharmDx assay. PD-L1 positivity was defined as a combined positive score (CPS) ≥1. TMB status, determined via whole exome sequencing, was dichotomized as high/low based on study-specific distributions with the highest quintile classified as TMB-high (H). OS was analyzed using Kaplan-Meier methods and log-rank tests to compare survival curves. OS was calculated from surgery until death for any reason. Median age was 52 in Korea and 65 in Denmark; 76% of the cohort was male and 96% of tissue was collected via resection. Eighty-six percent of patients in Denmark were stage I/II at surgery compared to 23% in Korea. All Denmark patients were Barcelona Clinic Liver Cancer (BCLC) stage 0 or A, compared to Korea where 75% were BCLC C. PD-L1 CPS≥1 prevalence was 36% and 54% in Denmark and Korea, respectively. In Korea, median OS among patients with CPS≥1 was 29 months (m) compared to 46m in CPS<1 (log-rank p=0.01). In Denmark, median OS was similar between PD-L1 subgroups (CPS<1=72m, CPS≥1=79m; p=0.6). TMB-H status was associated with longer OS in Korea (TMB-H=58m, TMB-L=29m; p=0.09) but not Denmark (TMB-H=61m, TMB-L=72m; p=0.7). Our study suggests that PD-L1 CPS<1 and TMB-H-status may be associated with longer survival among HCC patients undergoing surgical treatment in Korea, a trend that was not observed in Denmark. Differences in patient characteristics, etiology, and treatment pathways may explain regional differences in OS and the role of biomarkers in HCC. Further investigations in larger, more diverse patient populations are warranted.

Antibodies to HLA resulting in positive cytotoxicity crossmatch are generally considered a contraindication for cardiac transplantation. However, cardiac transplantations have been performed in children by reducing the Abs and modifying immunosuppression. To identify mechanisms leading to allograft acceptance in the presence of Abs to donor HLA, we analyzed priming events in endothelial cells (EC) by incubating with sera containing low levels of anti-HLA followed by saturating concentration of anti-HLA. Pre-transplant sera were obtained from children with low levels of Abs to HLA who underwent transplantation. EC were selected for donor HLA and exposed to sera for 72 h (priming), followed by saturating concentrations of anti-HLA (challenge). Priming of EC with sera induced the phosphatidylinositol 3-kinase/Akt mediated by the BMP4/WNT pathway and subsequent challenge with panel reactive antibody sera increased survival genes Bcl2 and Heme oxygenase-1, decreased adhesion molecules, induced complement inhibitory proteins and reduced pro-inflammatory cytokines. In contrast, EC which did not express donor HLA showed decreased anti-apoptotic genes. Primed EC, upon challenge with anti-HLA, results in increased survival genes, decreased adhesion molecules, induction of complement inhibitory proteins, and downregulation of pro-inflammatory cytokines which may result in accommodation of pediatric cardiac allografts despite HLA sensitization.

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population. In the absence of preexisting DSAs, patients with ndDSAs had significantly more acute cellular rejection but not antibody-mediated rejection, and there was no impact on graft and patient survival in the first year posttransplantation. Risk factors for ndDSAs included common sensitizing events. Given the early detection of the antibody response, memory responses may be more important in the first year after pediatric heart transplantation and patients with a history of a sensitizing event may be at risk even with a negative pretransplantation antibody screen. The impact on late graft and patient outcomes of first-year ndDSAs is being assessed in an extended cohort of patients.

Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers. At transplantation, subjects were categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI ≥1000 using single antigen beads). Sensitized subjects were further classified as complement‐dependent cytotoxicity crossmatch (CDC‐crossmatch) positive or negative and as donor‐specific antibodies (DSA) positive or negative. Immunosuppression was standardized. CDC‐crossmatch–positive subjects also received perioperative antibody removal, maintenance corticosteroids, and intravenous immunoglobulin. The primary endpoint was the 1 year incidence rate of a composite of death, retransplantation, or rejection with hemodynamic compromise. 317 subjects were screened, 290 enrolled and 240 transplanted (51 with pretransplant DSA, 11 with positive CDC‐crossmatch). The incidence rates of the primary endpoint did not differ statistically between groups; nonsensitized 6.7% (CI: 2.7%, 13.3%), sensitized crossmatch positive 18.2% (CI: 2.3%, 51.8%), sensitized crossmatch negative 10.7% (CI: 5.7%, 18.0%), P = .2354. The primary endpoint also did not differ by DSA status. Freedom from antibody‐mediated and cellular rejection was lower in the crossmatch positive group and/or in the presence of DSA. Follow‐up will determine if acceptable outcomes can be achieved long‐term.

BACKGROUND:BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies. METHODS:We performed a prospective, single-center, randomized, open label pilot trial to evaluate the impact of mycophenolate mofetil (MMF) withdrawal with conversion to the mTORi everolimus versus a 50% reduction of the MMF dose for the treatment of BKV infection after kidney transplantation. Patients maintained on tacrolimus, MMF, and corticosteroids that developed BK viremia or BK viruria ≥1 × 106 copies/mL were eligible. The primary endpoint was a >50% reduction of BK viruria or clearance of viremia at 3 months postrandomization. RESULTS:Forty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively (P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively (P = .47). CONCLUSION:Conversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance.