Search

Ellen Childs,1,* Christy D Remein,2,* Robina M Bhasin,3 Angelique C Harris,4 Alyssa Day,4 Lisa M Sullivan,5 David L Coleman,4 Emelia J Benjamin4,6 1Division of Health and Environment, Abt Associates, Rockville, MD, USA; 2Institute of Spirituality and Health, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA; 3Penn Foster Education Group, Boston, MA, USA; 4Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 5Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; 6Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Christy D RemeinInstitute of Spirituality and Health, George Washington University School of Medicine and Health Sciences, 2600 Virginia Avenue, NW – Room 342, Washington, Washington, 20037, USATel +12029943549Email cdremein@email.gwu.eduPurpose: Drawing on the decade of experience of Boston University Medical Campus’ Faculty Development Office, this paper reports strategies used to launch and continually improve faculty development programming within an academic health sciences campus.Patients and Methods: The authors explain the steps that Boston University Medical Campus took to institute their set of faculty development programs, including an overview of resources on how to periodically conduct needs assessments, engage key institutional stakeholders, design and evaluate an array of programming to meet the needs of a diverse faculty, and institute real-time program modifications.Results: In a step-by-step guide, and by highlighting vital lessons learned, the authors describe a process by which biomedical educators can create and sustain a robust faculty development office within their own institutions.Conclusion: This paper identifies steps to launch and improve faculty development program. Faculty development programs should be expanded to support faculty in academic medical centers.Keywords: faculty development, career development, mentoring, medical education

BACKGROUND: Group medical clinics (GMCs) are widely used in the management of diabetes and hypertension, but data on their effectiveness are limited. OBJECTIVE: To test the effectiveness of GMCs in the management of comorbid diabetes and hypertension. DESIGN: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00286741) SETTING: 2 Veterans Affairs Medical Centers in North Carolina and Virginia. PATIENTS: 239 patients with poorly controlled diabetes (hemoglobin A(1c) [HbA(1c)] level > or =7.5%) and hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg). INTERVENTION: Patients were randomly assigned within each center to either attend a GMC or receive usual care. Clinics comprised 7 to 8 patients and a care team that consisted of a primary care general internist, a pharmacist, and a nurse or other certified diabetes educator. Each session included structured group interactions moderated by the educator. The pharmacist and physician adjusted medication to manage each patient's HbA(1c) level and blood pressure. MEASUREMENTS: Hemoglobin A(1c) level and systolic blood pressure, measured by blinded research personnel at baseline, study midpoint (median, 6.8 months), and study completion (median follow-up, 12.8 months). Linear mixed models, adjusted for clustering within GMCs, were used to compare HbA(1c) levels and systolic blood pressure between the intervention and control groups. RESULTS: Mean baseline systolic blood pressure and HbA(1c) level were 152.9 mm Hg (SD, 14.2) and 9.2% (SD, 1.4), respectively. At the end of the study, mean systolic blood pressure improved by 13.7 mm Hg in the GMC group and 6.4 mm Hg in the usual care group (P = 0.011 by linear mixed model), whereas mean HbA(1c) level improved by 0.8% in the GMC group and 0.5% in the usual care group (P = 0.159). LIMITATION: Measurements of effectiveness may have been limited by concomitant improvements in the usual care group that were due to co-intervention. CONCLUSION: Group medical clinics are a potent strategy for improving blood pressure but not HbA(1c) level in diabetic patients. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs Health Services Research and Development Service. [ABSTRACT FROM AUTHOR]

Free-breeding dogs have occupied the Galápagos Islands at least since the 1830s; however, it was not until the 1900s that dog populations grew substantially, endangering wildlife and spreading disease. 1 , 2 , 3 , 4 In 1981, efforts to control the population size of free-roaming dogs began. 1 Yet, there exist large free-roaming dog populations on the islands of Isabela and Santa Cruz whose ancestry has never been assessed on a genome-wide scale. We thus performed a complete genomic analysis of the current Galápagos dog population, as well as historical Galápagos dogs sampled between 1969 and 2003, testing for population structure, admixture, and shared ancestry. Our dataset included samples from 187 modern and six historical Galápagos dogs, together with whole-genome sequences from over 2,000 modern purebred and village dogs. Our results indicate that modern Galápagos dogs are recently admixed with purebred dogs but show no evidence of a population bottleneck related to the culling. Additionally, identity-by-descent analyses reveal evidence of shared shepherd-dog ancestry in the historical dogs. Overall, our results demonstrate that the 1980s culling of dogs was ineffective in controlling population size and did little to reduce genetic diversity, instead producing a stable and expanding population with genomic signatures of modern purebred dogs. The insights from this study can be used to improve population control strategies for the Galápagos Islands and other endangered endemic communities., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Revision total hip arthroplasty (rTHA) and revision total knee arthroplasty (rTKA) require considerable surgical proficiency, but are frequently delegated to the least experienced surgeons. This study examined the influence of surgeon experience on revision outcomes., Methods: Prospective data on confirmed aseptic rTHAs (n = 122) and rTKAs (n = 195) performed by 4 fellowship-trained surgeons in the same practice were retrospectively analyzed. Surgeons were grouped based on years in practice (inexperienced [IE] first 2 years, early experience [EE] 4 to 6 years, and senior experience [SE] 15 to 17 years). Procedure duration, estimated blood loss (EBL), and reoperation rates were compared, controlling for potential covariates., Results: Procedure durations varied based on surgeon experience for 3 of 4 rTHA diagnoses (P ≤ 0.001). Relative to the SE surgeon, procedure duration was 80.0 (95% confidence interval 61.7 to 98.4, P < 0.001) minutes longer for IE surgeons and 30.9 (95% confidence interval 17.5 to 44.3, P < 0.001) minutes longer for the EE surgeon. Procedure durations also varied based on surgeon experience for 3 of 4 rTKA diagnoses (P < 0.001), with the longest durations for IE surgeons. Procedure durations varied based on the interaction of surgeon experience, patient age, and body mass index. The EBL did not differ in rTHA based on surgeon experience (P = 0.978), but did differ for rTKA (P = 0.004). There were 25% of rTHAs performed by IE surgeons compared to 15.5% for the EE surgeon and 3.6% for the SE surgeon that underwent reoperation within a year of the index procedure (P = 0.064), with significantly more reoperations for the same indication among IE and EE surgeons (P = 0.046)., Conclusions: Complex procedures completed by less experienced surgeons may result in longer procedures, higher EBL, and more early reoperations. Study findings implicate a learning curve for revision arthroplasty that continues for several years, warranting consideration of existing patient allocation and referral patterns., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Current literature lacks details on the impact of pediatric chronic graft-versus-host disease (cGVHD) on long-term survivorship after allogeneic hematopoietic cell transplantation (HCT). Nonetheless, cGVHD remains a leading cause of post-transplant morbidity and mortality in children and adolescents, which is particularly relevant given the longer life-expectancy after HCT (measured in decades) compared to older adults. To address this knowledge gap, leaders of the Pediatric Transplant and Cellular Therapy Consortium convened a multidisciplinary taskforce of experts in pediatric cGVHD and HCT late effects known as RESILIENT after Chronic GVHD (Research and Education towards Solutions for Late effects to Innovate, Excel, and Nurture after cGVHD). Our goals were to define: (1) the current state of understanding about how cGVHD impacts long-term survivorship in children transplanted <18 yr of age; (2) practical aspects of care to help clinicians managing long-term pediatric cGVHD survivors; and (3) develop a research framework for the next decade to further our knowledge. Four working groups were formed, each tasked with addressing a unique theme: (1) cGVHD natural history (phases of cGVHD) and its impact on clinicians' ability to taper and durably discontinue systemic therapy; (2) organ dysfunction and immune reconstitution in relation to survivorship; (3) how cGVHD and its treatment impact growth, metabolism, and development in children; and (4) psychosocial health and patient reported outcomes. The 4 groups met before the 2024 BMT Tandem Meeting in San Antonio, Texas, and then convened a larger in-person RESILIENT conference held on February 20, 2024, at the Tandem meeting to put forth recommendations from their respective working groups and garner feedback. These recommendations are now presented in a series of 4 manuscripts. This current manuscript focuses on the first theme and discusses the phases of cGVHD, challenges in differentiating clinically active from quiescent cGVHD in clinical practice, and the resultant difficulties in determining when and if to taper systemic therapy. To overcome these challenges, we propose revised categorization of long-term cGVHD outcomes and practical recommendations for clinicians and researchers around the long-term follow-up for these patients, including determining when and if to taper systemic therapy, along with the integration of non-immunosuppressive supportive care interventions., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: Approximately 25% of patients with essential thrombocythemia (ET) present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 × 109/L. ExT patients may have an increased bleeding risk associated with acquired von Willebrand syndrome. We retrospectively analyzed the risk of bleeding and thrombosis in ExT vs non-ExT patients with ET at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2014 to 2022 to inform treatment decisions. We abstracted the first major bleed, clinically relevant nonmajor bleed (CRNMB), and thrombotic events from medical records. We identified 128 ExT patients (28%) and 323 non-ExT patients (72%). Cumulative incidence of bleeding was not different in ExT vs non-ExT patients (21% vs 13% [P = .28] for major bleed; 16% vs 15% [P = .50] for CRNMB). Very low and low thrombotic risk ExT patients were more likely to be cytoreduced than very low- and low-risk non-ExT patients (69% vs 50% [P = .060] for very low risk; 83% vs 53% [P = .0059] for low risk). However, we found no differences in bleeding between ExT and non-ExT patients when restricting the risk of bleed from diagnosis to cytoreduction start date (28% vs 19% [P = .29] for major bleed; 24% vs 22% [P = .75] for CRNMB). Cumulative incidence of thrombosis was also not different between ExT and non-ExT patients (28% vs 25%; P = .98). This suggests that cytoreduction may not be necessary to reduce bleeding risk based only on a platelet count of 1 million. We identified novel risk factors for bleeding in patients with ET including diabetes mellitus and the DNMT3A mutation., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Graft-versus-host disease (GVHD) is a complication following allogeneic hematopoietic cell transplant that frequently causes multiorgan affection and decrease in quality of life. Global assessment and care of these patients require a multidisciplinary approach, but access to focused clinics is limited given their scarcity and location in major cities, as well as mobility and transportation challenges that frequently affect these patients. Thus, we established a multispecialty GVHD telehealth (TH) clinic and hypothesized that a virtual platform will expand access to clinical care in children and adults. The clinic team members included BMT specialist, nursing, dermatologist, dentist, nutritionist, physiatrist, research personnel, and others as needed. We evaluated all GVHD-related visits (in-person and TH) conducted in a single center from 01/2022 to 12/2022. Ninety-three patients received a total of 308 visits, and one-third were via TH. Approximately half of the in-person group had at least 1 TH visit, and 10 patients were seen exclusively via TH. Most patients had advanced chronic GVHD. More male patients were seen in GVHD clinic, but female patients had increased in clinic visits via TH (41% TH versus 32% in-person). One-third of clinic visits were from patients of racial and ethnic minorities. While only 6% (n = 12/217) of in-person visits were for patients living >100 miles from the center, 34% (n = 31/91) of TH visits were from far distances including out-of-state. At baseline, the most common patient-reported symptoms in a subset of patients included fatigue, disturbed sleep, and distress. Fifteen patients completed a follow-up symptom survey and reported significantly reduced distress regarding their GVHD (P = .02), although other symptoms remained stable. A multidisciplinary TH clinic provided care for adult and pediatric patients with GVHD. We demonstrated preliminary feasibility of building a robust TH platform with a collaborative multispecialty approach that allowed access and continuity of medical care. Gender inequalities were reduced, and distance to our center represented a lesser barrier to attending specialized care via TH. Additionally, patients reported a significant reduction in distress. Our findings support the ongoing development of a virtual platform to improve access to specialized GVHD care., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: While the Liaison Committee on Medical Education emphasizes the teaching of cultural competence in medical education, the concept of cultural humility, focusing on self-reflection and lifelong learning, has been proposed as a more effective approach. Although there have been numerous discussions on both topics, understanding how faculty in clinical settings help students develop cultural humility skills remains limited., Objective: Our multimethod study utilized a survey and semi-structured interviews to identify strategies that faculty at one institution use to help students develop cultural humility skills., Methods: We administered a 10-question survey to assess faculty demographics, teaching characteristics, and familiarity with cultural humility. Participants most familiar with cultural humility were invited for semi-structured interviews. Survey data were analyzed with descriptive statistics, and interview data were thematically analyzed to identify key teaching strategies., Results: In our study of 49 medical faculty members, the majority of participants were female (61%) and predominantly White (67%), covering a wide range of specialties and years of teaching. Of the participants, 74% expressed being at least somewhat familiar with cultural humility, and 10 consented to interviews. Strategies for cultural humility education included one-on-one instruction, feedback, and reflections. Thematic analysis underscored fostering learner curiosity about cultures, early patient exposure, and incorporating diverse learning perspectives as essential in developing students' cultural humility skills., Conclusion: Cultural humility is an important attribute for healthcare professionals that can enhance patient-centered care. Through focused interviews with faculty in our study and subsequent thematic analysis, our results suggest the need for longitudinal and multimodal educational strategies to cultivate cultural humility among medical students. By understanding current teaching methods, educators can design and assess more effective curricula to prepare future doctors for a culturally diverse patient population., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Aims: Transition of paediatric patients is challenging. This study aimed to assess the transition pathway for patients who underwent an ACE procedure as a child and to understand ongoing support requirements., Methods: A retrospective review was conducted of all patients on the Pelvic Floor Clinical Specialist Nurse's (PFCNS) database from a tertiary adult hospital. Patients receiving their ACE as an adult or patients who did not attend any outpatient appointments (OPAs) were excluded. Data was gathered on complications, additional procedures and outcomes., Results: Sixty-three patients met the inclusion criteria. The median age at referral to an appropriate team was 18 years but the median age of referral to the PFCNS was 23 years. Only 7(11 %) were referred to the PFCNS by Paediatric Services. Patients experienced a variety of problems including change in equipment (n = 38, 60 %), change in washout regime (n = 28, 44 %), ACE leakage (n = 15, 24 %), stenosis (n = 15, 24 %) and ineffective washouts (n = 11, 17 %). Of those where data was available, there was a median of 7 PFCNS and 2.5 Colorectal Consultant (CC) OPAs per patient. Surgical intervention was common including procedures to the ACE (n = 8, 13 %), excision of ACE (n = 5, 7.9 %) manual evacuation (n = 5, 7.9 %) and formation of a stoma (n = 1%). 35 (56 %) were still using their ACE with a median time since transition of 11 years., Conclusion: Patients with an ACE need considerable ongoing support yet few are appropriately transitioned. There needs to be a clear transition pathway for these patients to the PFCNS and if appropriate a CC., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Opioid use disorder (OUD) is a neuropsychological disease that has a devastating impact on public health. Substantial individual differences in vulnerability exist, the neurobiological substrates of which remain unclear. To address this question, we investigated genome-wide gene transcription (RNA-seq) and chromatin accessibility (ATAC-seq) in the medial prefrontal cortex (mPFC) of male and female rats exhibiting differential vulnerability in behavioral paradigms modeling different phases of OUD: Withdrawal-Induced Anhedonia (WIA), Demand, and Reinstatement. Ingenuity Pathway Analysis (IPA) of RNA-seq revealed greater changes in canonical pathways in Resilient (vs. Saline) rats in comparison to Vulnerable (vs. Saline) rats across 3 paradigms, suggesting brain adaptations that might contribute to resilience to OUD across its trajectory. Analyses of gene networks and upstream regulators implicated processes involved in oligodendrocyte maturation and myelination in WIA, neuroinflammation in Demand, and metabolism in Reinstatement. Motif analysis of ATAC-seq showed changes in chromatin accessibility to a small set of transcription factor (TF) binding sites as a function either of opioid exposure (i.e., morphine versus saline) generally or of individual vulnerability specifically. Some of these were shared across the 3 paradigms and others were unique to each. In conclusion, we have identified changes in biological pathways, TFs, and their binding motifs that vary with paradigm and OUD vulnerability. These findings point to the involvement of distinct transcriptional and epigenetic mechanisms in response to opioid exposure, vulnerability to OUD, and different stages of the disorder.

Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Harris and Gewirtz.)

Introduction: Literature demonstrates the detrimental impact of discrimination and microaggressions at personal and institutional levels in the health care workplace. Residents in our program requested curricula to help with addressing manifestations of bias. In response, we designed and implemented an adaptable and reproducible 4-hour virtual simulation session aimed at helping residents identify and constructively respond to microaggressions., Methods: This curriculum, influenced by a preceding needs assessment, was delivered to 68 senior internal medicine residents. It began with a didactic overview to establish foundational knowledge of bias. This was followed by a workshop focused on strategies to address microaggressions. The session culminated with skills practice in a virtual simulation activity where learners addressed microaggressions as bystanders in realistic case scenarios employing simulated participants. We administered pre- and postevaluation individual key-linked surveys assessing learner confidence in responding to microaggressions., Results: A total of 68 residents participated in the curriculum over two academic years, 27 of whom provided complete data for analysis. Overall, there was a statistically significant increase in learner confidence identifying microaggressions. As both a bystander and target/recipient of microaggressions, there were statistically significant increases in learner confidence addressing gender-based microaggressions, race-based microaggressions, and microaggressions reflecting other types of bias. Furthermore, there were statistically significant increases in learner confidence addressing microaggressions in low-acuity contexts, high-acuity contexts, across interprofessional disciplines, with a supervisor, and with a supervisee., Discussion: Our virtual experiential curriculum on responding to microaggressions can help increase learner confidence in addressing microaggressions., (© 2024 Govindraj et al.)

Introduction: Sex differences in vulnerability to opioid use disorder (OUD) have been reported in some clinical and preclinical studies, but findings are mixed and further research is needed in this area. The goal of this study was to compare elasticity of demand (reinforcement efficacy) in an i.v. morphine self-administration (SA) model in male and female rats using a translationally relevant behavioral economics approach. Rate of acquisition and predictors of individual differences in demand (e.g., cumulative morphine infusions during acquisition) were also evaluated in both sexes., Materials Methods and Results: Acquisition of morphine SA (0.4 mg/kg/infusion) under a fixed ratio (FR) 1 schedule of reinforcement was slower and infusions earned were lower in females than in males ( n  = 30-31/sex), but infusions earned did not differ between sexes during the FR 2 and FR 3 phases of acquisition. Increases in the FR response requirement across sessions during demand testing (FR 1-FR 96) resulted in a progressive reduction in morphine infusions in both sexes. Morphine consumption was well-described by an exponential demand function in both sexes and was associated with considerable individual vulnerability. There were no sex differences in elasticity of demand (rate of decline in morphine consumption with increasing price) or intensity of demand (consumption at zero price). A higher number of infusions earned during the FR 2 and FR 3 phases of acquisition and greater maximum response rates during demand testing were associated with lower demand elasticity (i.e., greater reinforcing efficacy) in both males and females, whereas other relationships were sex-specific (e.g., higher intensity of demand was associated with lower elasticity of demand in males but not in females)., Conclusion: Our findings indicate similar elasticity of demand and predictors of individual differences in demand for morphine in male and female rats, although sex differences were observed in initial rate of acquisition and in some correlations between morphine SA measures. These data are consistent with findings of similar OUD vulnerability in males and females in some human and animal studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Harris, Muelken, Liu, Smethells, LeSage and Gewirtz.)

Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12-22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background Aims: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism., Methods: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment., Results: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted., Conclusions: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (AGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of AGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 AGVHD, only AGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 AGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified AGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between AGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant AGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131)., (Copyright © 2024. Published by Elsevier Inc.)

Background Aims: Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT., Methods: Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses., Results: In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods., Conclusions: Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method., Competing Interests: Declaration of competing interest KJC: research support: Novartis, Celgene, Cellectis, Atara Bio; consultant: Novartis, Atara Bio. SEP: support for the conduct of clinical trials: AlloVir, Jasper Therapeutics, Atara Biotherapeutics; consultation (last 24 months) CellEvolve, ADMA, Regeneron; intellectual property related to the use of third-party VSTs licensed to Atara Biotherapeutics with all rights assigned to Memorial Sloan Kettering Cancer Center. RJO: royalties following licensure of EBV-specific T-cell bank by Atara Biotherapeutics, research support and consultant fees from Atara Biotherapeutics. JJB: consulting Sobi, Bluebird Bio, Avrobio, BlueRock, SmartImmune, Sanofi, Omeros, Advanced Clinical (DMC Chair). All other authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)