Balancing innovation and affordability in anti-obesity medications: the role of an alternative weight-maintenance program.

Despite remarkable clinical advances in highly effective anti-obesity medications, their high price and potential budget impact pose a major challenge in balancing equitable access and affordability. While most attention has been focused on the amount of weight loss achieved, less consideration has been paid to interventions to sustain weight loss after an individual stops losing weight. Using a policy simulation model, we quantified the impact of a weight-maintenance program following the weight-loss plateau from the initial full-dose glucagon-like peptide 1 (GLP-1) receptor agonists or incretin mimetic use. We measured long-term health care savings and the loss of some health benefits (eg, maintenance of weight loss, improvements in cardiometabolic risk factors, and reductions in diabetes and cardiovascular events). Our model suggested that, compared with continuous long-term full-dose GLP-1 receptor agonists or incretin mimetic drugs, the alternative weight-maintenance program would generate slightly fewer clinical benefits while generating substantial savings in lifetime health care spending. Using less expensive and potentially less effective alternative weight-maintenance programs may provide additional headroom to expand access to anti-obesity medications during the active weight-loss phase without increasing total health care spending.

Donor matters: Donor selection impact on hematopoietic stem cell transplantation outcomes in Hispanic patients with B-cell acute lymphocytic leukemia: Insights from a myeloablative HSCT study.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a pivotal treatment for high-risk acute lymphocytic leukemia (ALL), although limited by suitable human leukocyte antigen (HLA)-matched sibling donors (MSD). This study evaluates the impact of donor selection on outcomes in post-HSCT Hispanic B-cell ALL patients. METHODOLOGY: This single-center retrospective study evaluates outcomes in 88 adult Hispanic B-cell ALL patients who underwent haploidentical, MSD, or MUD myeloablative HSCT between 2013 and 2023. RESULTS: Compared to Haploidentical transplants, MSD exhibited worse cumulative incidence of relapse (CIR) (HR = 3.39; P = 0.014) and disease-free survival (DFS) (HR = 2.44; P = 0.048) whereas MUD outcomes did not differ. This effect persisted even when controlling for pre-HSCT stage and Minimal residual disease (MRD) status. In addition, Ph-like was a significant predictor of worse DFS (HR = 3.60; P=0.014) and CIR (HR = 2.97; P=0.035) on multivariate analysis. Older donor age correlated with worse GVHD-free, relapse-free survival (GRFS) in haploidentical transplants (HR = 1.05; P=0.036). CONCLUSION: Our data highlights improved outcomes with younger, haploidentical donors among Hispanic B-cell ALL patients undergoing myeloablative HSCT. This underscores the importance of donor selection in optimizing outcomes for ALL patients.

Impact of Berberine or Berberine Combination Products on Lipoprotein, Triglyceride and Biological Safety Marker Concentrations in Patients with Hyperlipidemia: A Systematic Review and Meta-Analysis.

Monoclonal antibody Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors reduce total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL), and triglycerides (TG). We assessed the ability of berberine, a natural PCSK9 inhibitor, to reduce lipid concentrations either alone or combined with other nutraceuticals. We searched PubMed, Scopus and EMBASE from inception to September 30th, 2022 for randomized controlled trials (RCTs) assessing 8-18 wk of berberine therapy on. A total of 41 RCTs with 4,838 patients met our inclusion criteria. Berberine containing products significantly reduced TC (MD -17.42 mg/dL [95%CI: -22.91 to -11.93]), LDL (MD -14.98 mg/dL [95%CI: -20.67 to -9.28]), and TG (MD -18.67 mg/dL [95%CI: -25.82 to -11.51]) while raising HDL (MD 1.97 mg/dL [95%CI: 1.16 to 2.78]) versus control (I2 > 72% for all analyses). Products with berberine alone had less robust effects on TC (MD -12.08 mg/dL [95%CI: -21.79 to -2.37]), LDL (MD -9.26 mg/dL [95%CI: -20.31 to 1.78]), and HDL (MD 1.38 mg/dL [95%CI: -1.27 to 4.03]) but TG effects were similar (MD -17.40 mg/dL [95%CI: -32.57 to -2.23]). Berberine along with red yeast rice reduced TC (MD -19.62 mg/dL [95%CI: -28.56 to -10.68]) and LDL (MD -18.79 mg/dL [95%CI: -28.03 to -9.54]) as did combination therapy with Silybum maranium for TC (MD -31.81 mg/dL [95%CI: -59.88 to -3.73]) and LDL (MD -30.82 mg/dL [95%CI: -56.48 to -5.16]). Berberine, alone or with other nutraceuticals, can provide a modest positive impact on lipid concentrations.

Concordance of Next-Generation Sequencing and Multiparametric Flow Cytometry Methods for Detecting Measurable Residual Disease in Adult Acute Lymphoblastic Leukemia: Optimizing Prediction of Clinical Outcomes From a Single-Center Study.

INTRODUCTION: Detection of measurable residual disease (MRD) in adults with acute lymphoblastic leukemia (ALL) is a vital biomarker in risk prediction and treatment selection. Next-generation sequencing (NGS) offers greater sensitivity relative to multiparametric flow cytometry (MFC) and may be a better predictive tool for identifying ALL patients at risk of relapse. PATIENTS AND METHODS: This single-center retrospective study compares MRD detection by NGS versus MFC in 52 adult B- and T-ALL patients treated at our institution between 2018 and 2023. Pretreatment bone marrow samples were used for assay calibration, while post-treatment MRD assessment was completed up to 4.5 months after the first complete remission (CR1) using an MRD cutoff of 10-6 for distinguishing relapse risk. RESULTS: The 2-year cumulative incidence of relapse (CIR) among patients who were MRD positive using MFC and NGS was 39.5% and 46.2%, respectively. Unlike MFC, post-CR1 MRD positivity with NGS significantly predicted CIR (HR = 9.47, P = .028). In patients who were MRD negative by MFC, low levels of MRD detected by NGS distinguished patients at high risk of relapse (HR 10.3, P = .026, 2-year CIR 51.6%). CONCLUSION: Our data suggests that assessment of post-CR1 MRD using a highly sensitive NGS assay can identify ALL patients undergoing frontline therapy at increased risk of relapse and guide the use of adjuvant therapy.

Safety and Efficacy of Intramuscular Tixagevimab-Cilgavimab in Prevention of COVID-19 in Patients Who Are Immunocompromised.

INTRODUCTION: Patients who are immunocompromised face an increased chance of severe COVID-19 infection compared with patients who are immunocompetent. However, vaccine efficacy for COVID-19 appears to be lower in patients who are immunocompromised. Tixagevimab-cilgavimab are monoclonal antibodies designed to enhance immune defense against COVID-19. Nevertheless, the safety and efficacy of tixagevimab-cilgavimab specifically in patients who are immunocompromised remains unknown. METHODS: The authors conducted a retrospective case study of patients who were immunocompromised and received tixagevimab-cilgavimab between January 3, 2022 to July 31, 2022 at Kaiser Permanente Southern California. All patients were monitored for 180 days following tixagevimab-cilgavimab administration. Patients who were immunocompromised included those with solid tumors, hematologic malignancies, primary immunodeficiencies, recipients of solid organ or hematopoietic stem cell transplants, and patients undergoing treatment with immunosuppressive medications (eg, chemotherapy, high-dose corticosteroids, tumor necrosis factor blockers, and certain biologic agents). RESULTS: A total of 2352 patients who were immunocompromised were included in the study. Among them, 101 patients (4.3%) tested positive for COVID-19, and 13 patients (0.6%) required COVID-19-related hospital admissions. Notably, no deaths were reported within 180 days following tixagevimab-cilgavimab administration. Additionally, 4 patients (0.17%) sought same-day medical care after receiving tixagevimab-cilgavimab. Within 30 days, there were 39 non-COVID-19-related hospital admissions (1.7%) and within 7 days, 11 hospital admissions (0.5%) occurred after tixagevimab-cilgavimab administration. DISCUSSION: Tixagevimab-cilgavimab demonstrated a low incidence of COVID-19 and COVID-19-related hospital admissions in patients who were immunocompromised, with no reported mortality. Furthermore, there were no significant adverse effects associated with the use of these monoclonal antibodies. CONCLUSION: Tixagevimab-cilgavimab exhibited a low incidence of COVID-19 and adverse effects in patients who were immunocompromised.

Into the Unknown: Characterizing Fellow Uncertainty During the Transition to Unsupervised Practice.

Background: Helping fellows confront and manage uncertainty in the course of diagnosis and treatment of patients has been a growing focus of medical education. How these same fellows confront uncertainty as they make a transition in their professional development is less commonly a focus of training programs. Better understanding of how fellows experience these transitions will allow fellows, training programs, and hiring institutions to navigate transitions more easily. Objective: This study aimed to explore how fellows in the United States experience uncertainty during the transition to unsupervised practice. Methods: Using constructivist grounded theory, we invited participants to engage in semi-structured interviews exploring experiences with uncertainty as they navigate the transition to unsupervised practice. Between September 2020 and March 2021, we interviewed 18 physicians in their final year of fellowship training from 2 large academic institutions. Participants were recruited from adult and pediatric subspecialties. Data analysis was conducted using an inductive coding approach. Results: Experiences with uncertainty during the transition process were individualized and dynamic. Primary sources of uncertainty identified included clinical competence, employment prospects, and career vision. Participants discussed multiple strategies for mitigating uncertainty, including structured graduated autonomy, leveraging professional networks locally and non-locally, and utilizing established program and institutional supports. Conclusions: Fellows' experiences with uncertainty during their transitions to unsupervised practice are individualized, contextual, and dynamic with several shared overarching themes.

Primary Palliative Care for Pediatric Residents: A Curricular Framework and Pilot.

PROBLEM: Palliative care (PC) is high-value, holistic care for a child and their family across the entire arc of an illness. All physicians should be competent in symptom management and providing goal-concordant care that acknowledges the quality of life; however, there is insufficient education in pediatric residency to develop competence in basic or ..úPrimary..Ñ PC. APPROACH: We completed a needs assessment and developed a longitudinal, comprehensive, and integrated primary PC curriculum for pediatric residents with the goal of developing foundational primary PC skills regardless of eventual career trajectory. After 1 year of implementation, we assessed resident comfort with primary PC skills via a retrospective pre-post survey. OUTCOMES: We found a statistically significant (P.ß<.ß.05) increase in residents... comfort with pain management, delivering serious news, and discussing goals of care. An increase in comfort with the management of other symptoms was not statistically significant. NEXT STEPS: After 1 year of implementation, residents describe an increase in comfort with primary PC skills. The next steps include more rigorous evaluation and expansion to include more education in medical ethics. While the educational need is universal, resident needs are constantly evolving and each institution should tailor this curriculum to fit their specific trainee needs and institutional expertise.

Incidence, Risk Factors, and Outcomes of COVID-19 Infection in a Large Cohort of Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients (SOTr) are at increased risk for severe disease from coronavirus disease 2019 (COVID-19) compared with non-SOTr. METHODS: We performed a retrospective cohort study between March 1, 2020, and March, 30, 2021, in an integrated healthcare system with 4.3 million members aged ≥18 y including 5126 SOTr. Comparisons in COVID-19 mortality, hospitalization, and incidence were made between SOTr and non-SOTr, and between different SOTr organs. Multivariate analysis was performed to identify risk factors for COVID-19 mortality and hospitalization. RESULTS: There were 600 SOTr (kidney, liver, heart, and lung) with COVID-19. Per person-year incidence of COVID-19 among SOTr was 10.0% versus 7.6% among non-SOTr (P < 0.0001). Compared with uninfected SOTr, infected SOTr were older (57.1 ± 14.0 versus 45.7 ± 17.9 y, P < 0.001), predominantly Hispanic/Latino (58.8% versus 38.6%, P < 0.0001), hypertensive (77.0% versus 23.8%; P < 0.0001), and diabetic (49.6% versus 13.0%; P = 0.0009). Compared with non-SOTr, infected SOTr had higher hospitalization (39.5% versus 6.0%; P < 0.0001), intensive care unit admission (29.1% versus 15.5%; P < 0.0001), and mortality (14.7% versus 1.8%; P < 0.0001) from COVID-19. Older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.05-1.10), male gender (HR, 1.79; 95% CI, 1.11-2.86), and higher body mass index (HR, 1.04; 95% CI, 1.00-1.09; P = 0.047) were associated with increased mortality from COVID-19, whereas race, diabetes, and number/type of immunosuppressive medications were not. Among the different SOTr, COVID-19 mortality risk was lowest in liver recipients (HR, 0.34; 95% CI, 0.16-0.73) and highest in lung recipients (HR, 1.74; 95% CI, 0.68-4.42). CONCLUSIONS: SOTr have higher rates of hospitalization and mortality from COVID-19 compared with the general population. Among the SOTr, the incidence and outcomes were distinct among different transplantation types.

Review of Urate-Lowering Therapeutics: From the Past to the Future.

We reviewed all currently available ULT, as well as any medications in development using following databases: United States Food and Drug Administration (FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Medical Devices Agency (PMDA), and ClinicalTrials.gov. We identified a total of 36 drugs, including 10 approved drugs, 17 in clinical testing phases, and 9 in preclinical developmental phases. The 26 drugs currently undergoing testing and development include 5 xanthine oxidase inhibitors, 14 uricosurics, 6 recombinant uricases, and one with multiple urate-lowering mechanisms of action. Herein, we reviewed the benefit and risk of each drug summarizing currently available drugs. New trials of uricosuric agents are underway to develop the new indication. New drugs are going on to improve the potency of recombinant uricase and to develop the new route administration of such as oral formulation. This review will provide valuable information on the properties, indications, and limitations of ULTs.

Introduction of an Electronic Clinical Decision Support Tool to Inform Prescribing for Pediatric Diarrhea in Bangladesh and Mali: Do Provider Expectations Predict Experiences?

Nonindicated antibiotics for childhood diarrhea is a major contributor to global antimicrobial resistance. Electronic clinical decision support tools (eCDSTs) may reduce unnecessary antibiotics. This study examined how providers' expectations of an eCDST to predict diarrhea etiology compared with their experiences using the tool. Providers were enrolled from public hospitals in Bangladesh (n = 15) and Mali (n = 15), and surveys were completed at baseline and after using the eCDST. Baseline surveys assessed expectations (utility, ease of use, and threat to autonomy), and post surveys assessed experiences in the same domains. Providers' experiences with ease of use exceeded their baseline expectations, and providers reported less experienced threat to autonomy after use, compared with baseline expectations. Providers' expectations of threat to autonomy significantly predicted their experienced threat to autonomy. Findings suggest that an eCDST to inform antimicrobial prescribing for diarrhea is feasible and acceptable, but training should promote local ownership for sustainability.

Efficacy of Xanthine Oxidase Inhibitors in Lowering Serum Uric Acid in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Objective: Current guidelines for gout recommend a treat-to-target approach with serum uric acid (SUA). However, there is little evidence for the dose-dependent effects of urate-lowering therapy (ULT). Herein, we analyzed the reported SUA-lowering effect and SUA target achievement differences for various doses of xanthine oxidase inhibitors. Methods: Approved ULT drugs were selected from the FDA Drug Database. We included prospective randomized controlled trials of ULT drugs from ClinicalTrials.gov, articles published in the journal "Drugs", and Embase, a literature database. A meta-analysis was performed to determine the ability of different ULT drugs and doses to lower and maintain a target SUA < 6 mg/dL. Results: We identified 35 trials including 8172 patients with a baseline SUA of 8.92 mg/dL. The allopurinol, febuxostat, and topiroxostat showed dose-proportional SUA-lowering responses. Compared with allopurinol 300 mg daily, febuxostat 80 mg daily and 120 mg daily more effectively maintained SUA < 6 mg/dL. Conclusion: Allopurinol, febuxostat, and topiroxostat showed dose-proportional ability to lower and achieve a target SUA < 6 mg/dL. Significance and Innovations. We showed dose-dependent SUA lowering effects of allopurinol, febuxostat, and topiroxostat. Febuxostat is effective at ULT compared to allopurinol and could be potentially offered as an alternative agent when patients (1) have CKD, (2) have the human leukocyte antigen HLA-B*5801 allele, and (3) become refractory to allopurinol. Gradual allopurinol dose increase with a lower starting dose is needed in CKD.

GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity.

Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 103). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.

Acral lentiginous melanoma-Population, treatment, and survival using the NCDB from 2004 to 2015.

Acral lentiginous melanoma (ALM) is a rare histological subtype of cutaneous malignant melanoma that typically presents on the palms and soles. To characterize the demographic and treatment characteristics of ALM, we used the National Cancer Database (NCDB) to describe a large multi-institutional cohort of ALM patients, consisting of 4,796 ALM patients from 2004 to 2015. ALM was more likely to be diagnosed at a later stage overall compared with non-ALM cutaneous melanomas, and more likely to be thicker, ulcerated, lymph node positive, and have lymphovascular invasion and positive margins. When stratified by stage, ALM had worse survival compared with non-ALM patients, most notably in stage III patients with 5-year survival of 47.5% versus 56.7%, respectively (p < .001). In ALM patients, older age, male sex, higher comorbidity burden, increased tumor thickness and ulceration, positive lymph nodes, and positive metastasis were independently associated with lower 5-year survival. Multimodality therapy, defined as surgery in addition to systemic therapy and/or radiation therapy, was associated with higher survival in stage III patients but not in other stages. These results call for further investigation into possible treatment intensification in the ALM population in the future.

Acute pulmonary pressure change after transition to sacubitril/valsartan in patients with heart failure reduced ejection fraction.

AIMS: Sacubitril/valsartan combines renin-angiotensin-aldosterone system inhibition with amplification of natriuretic peptides. In addition to well-described effects, natriuretic peptides exert direct effects on pulmonary vasculature. The effect of sacubitril/valsartan on pulmonary artery pressure (PAP) has not been fully defined. METHODS AND RESULTS: This was a retrospective case-series of PAP changes following transition from angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to sacubitril/valsartan in patients with heart failure reduced ejection fraction and a previously implanted CardioMEMS™ sensor. Pre-sacubitril/valsartan and post-sacubitril/valsartan PAPs were compared for each patient by examining averaged consecutive daily pressure readings from 1 to 5 days before and after sacubitril/valsartan exposure. PAP changes were also compared between patients based on elevated trans-pulmonary gradients (trans-pulmonary gradient ≥ 12 mmHg) at time of CardioMEMS™ sensor implantation. The cohort included 18 patients, 72% male, mean age 60.1 ± 13.6 years. There was a significant decrease in PAPs associated with transition from ACEI/ARB to sacubitril/valsartan. The median (interquartile range) pre-treatment and post-treatment change in mean, systolic and diastolic PAPs were -3.6 (-9.8, -0.7) mmHg (P < 0.001), -6.5 (-15.0, -2.0) mmHg (P = 0.001), and -2.5 (-5.7, -0.7) (P = 0.001), respectively. The decrease in PAPs was independent of trans-pulmonary gradient (F(1,16) = 0.49, P = 0.49). CONCLUSIONS: In this retrospective case series, transition from ACEI/ARB to sacubitril/valsartan was associated with an early and significant decrease in PAPs.

Family Meetings in the Intensive Care Unit During the Coronavirus Disease 2019 Pandemic.

PURPOSE: Visitor restrictions during the COVID-19 pandemic limit in-person family meetings for hospitalized patients. We aimed to evaluate the quantity of family meetings by telephone, video and in-person during the COVID-19 pandemic by manual chart review. Secondary outcomes included rate of change in patient goals of care between video and in-person meetings, the timing of family meetings, and variability in meetings by race and ethnicity. METHODS: A retrospective cohort study evaluated patients admitted to the intensive care unit at an urban academic hospital between March and June 2020. Patients lacking decision-making capacity and receiving a referral for a video meeting were included in this study. RESULTS: Most patients meeting inclusion criteria (N = 61/481, 13%) had COVID-19 pneumonia (n = 57/61, 93%). A total of 650 documented family meetings occurred. Few occurred in-person (n = 70/650, 11%) or discussed goals of care (n = 233/650, 36%). For meetings discussing goals of care, changes in patient goals of care occurred more often for in-person meetings rather than by video (36% vs. 11%, p = 0.0006). The average time to the first goals of care family meeting was 11.4 days from admission. More documented telephone meetings per admission were observed for White (10.5, SD 9.5) and Black/African-American (7.1, SD 6.6) patients compared to Hispanic or Latino patients (4.9, SD 4.9) (p = 0.02). CONCLUSIONS: During this period of strict visitor restrictions, few family meetings occurred in-person. Statistically significant fewer changes in patient goals of care occurred following video meetings compared to in-person meetings, providing support limiting in-person meetings may affect patient care.

Development of Subspecialty-Specific Reporting Milestones for Hospice and Palliative Medicine Fellowship Training in the U.S.

Continuing the transition to competency-based education, Hospice and Palliative Medicine (HPM) fellowship programs began using context-free reporting milestones (RMs) for internal medicine subspecialties in 2014 but quickly recognized that they did not reflect the nuanced practice of the field. This article describes the development of 20 subspecialty-specific RMs through consensus group process and vetting by HPM educators. A workgroup of content experts used an iterative consensus building process between December 2017 and February 2019 to draft new RMs and create a supplemental guide that outlines the intent of each RM, examples of each developmental trajectory, assessment methods, and resources to guide educators. Program directors, program coordinators, and designated institutional officers were contacted directly to solicit feedback. Most respondents agreed or strongly agreed that each RM represented a realistic progression of knowledge, skills, and behaviors, and that the set of milestones adequately discriminated between meaningful levels of competency. Similarly, respondents felt that the supplemental guide was a useful resource. The result is a set of carefully developed and broadly vetted RMs that represent a progression of development for HPM physicians during one year of clinical fellowship training.

Hearing loss and speech understanding in noise in Aboriginal and Torres Strait Islander children from locations varying in remoteness and socio-educational advantage.

OBJECTIVE: Otitis media resulting in conductive hearing loss is a major health issue for Aboriginal and Torres Strait Islander children, which can also lead to the child developing spatial processing disorder (SPD). This study examined the prevalence of hearing loss and deficits in speech understanding in noise, including SPD, in Aboriginal and Torres Strait Islander children from schools varying in remoteness and socio-educational advantage. METHOD: 288 Aboriginal and Torres Strait Islander children aged 4-14 years from three schools varying in remoteness and socio-educational advantage completed audiological assessment and the Listening in Spatialized Noise - Sentences test to assess for hearing loss and SPD. Children also completed Sound Scouts, a self-administered tablet-based hearing test which screens for these deficits. The prevalence of hearing issues was compared to what is expected from a typical population. RESULTS: The proportion of children with hearing problems was related to the school's socio-educational advantage, with higher proportions in schools with a lower socio-educational advantage. Proportions of children with speech-in-noise deficits (including SPD) was related to the remoteness of the school, with higher proportions in schools that were more remote. CONCLUSIONS: The prevalence of hearing loss and SPD is much higher in Aboriginal and Torres Strait Islander children than described for non-Aboriginal populations, and is related to the socio-educational advantage or remoteness of the school. Resources are needed to reduce the incidence of hearing loss and health disparity in Aboriginal communities, especially those in remote areas with lower socio-educational advantages.

Integration of Pediatric Palliative Care Into Cardiac Intensive Care: A Champion-Based Model.

Integration of pediatric palliative care (PPC) into management of children with serious illness and their families is endorsed as the standard of care. Despite this, timely referral to and integration of PPC into the traditionally cure-oriented cardiac ICU (CICU) remains variable. Despite dramatic declines in mortality in pediatric cardiac disease, key challenges confront the CICU community. Given increasing comorbidities, technological dependence, lengthy recurrent hospitalizations, and interventions risking significant morbidity, many patients in the CICU would benefit from PPC involvement across the illness trajectory. Current PPC delivery models have inherent disadvantages, insufficiently address the unique aspects of the CICU setting, place significant burden on subspecialty PPC teams, and fail to use CICU clinician skill sets. We therefore propose a novel conceptual framework for PPC-CICU integration based on literature review and expert interdisciplinary, multi-institutional consensus-building. This model uses interdisciplinary CICU-based champions who receive additional PPC training through courses and subspecialty rotations. PPC champions strengthen CICU PPC provision by (1) leading PPC-specific educational training of CICU staff; (2) liaising between CICU and PPC, improving use of support staff and encouraging earlier subspecialty PPC involvement in complex patients' management; and (3) developing and implementing quality improvement initiatives and CICU-specific PPC protocols. Our PPC-CICU integration model is designed for adaptability within institutional, cultural, financial, and logistic constraints, with potential applications in other pediatric settings, including ICUs. Although the PPC champion framework offers several unique advantages, barriers to implementation are anticipated and additional research is needed to investigate the model's feasibility, acceptability, and efficacy.

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence.

PURPOSE: Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape. EXPERIMENTAL DESIGN: Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 chimeric antigen receptor (CAR) as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality. RESULTS: We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, and improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFNγ production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response. CONCLUSIONS: We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.See related commentary by Guedan and Delgado, p. 5188.

Development of Curricular Milestones for Hospice and Palliative Medicine Fellowship Training in the U.S.

CONTEXT: A physician workgroup of the American Academy of Hospice and Palliative Medicine sought to define curricular milestones (CMs) for hospice and palliative medicine (HPM) Fellowship Programs. The developed list of CMs would serve as components upon which to organize curriculum and standardize what to teach during training. These would complement entrustable professional activities previously developed by this group and new specialty-specific reporting milestones (RMs) for HPM developed through the Accreditation Council for Graduate Medical Education. OBJECTIVES: The objective of this study was to develop and vet CMs for HPM fellowships in the U.S. METHODS: A draft of CMs was developed through an iterative consensus group process with repeated cycles of drafting, analyzing, and revising by a broadly representative expert workgroup who then gained input from HPM educators at a national meeting workshop. The CM draft was subsequently revised and then vetted through a national survey to 203 fellowship educators. Respondents were asked to "keep," "revise," or "exclude" each proposed CM with space for comments. An agreement of 75% among respondents was set as the criteria a priori for keeping a CM. Eighty-four of the 203 potential respondents participated in the survey. All items met the minimum agreement level of 75% or greater recommending keeping the CM. Greater than 85% of the respondents agreed to keep 19 of the 22 CMs with no revisions. Comments for revisions on other CMs were primarily related to changes in language and formatting, not conceptual underpinnings. CONCLUSION: A group consensus method strengthened by inclusion of a national survey to HPM fellowship educators resulted in a CM document that is both carefully developed and broadly vetted. Along with entrustable professional activities and new specialty-specific RMs, these CMs offer educators and trainees tools to create more comprehensive curricula and behaviorally based assessment tools for HPM fellowships and their stakeholders.