How I Treat: Differentiation Therapy in Acute Myeloid Leukemia.

An increasing number of acute myeloid leukemia (AML) therapeutics have been developed, not as cytotoxic therapies, but rather as targeted agents able to restore the aberrant and leukemogenic "block" in normal differentiation. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are classic examples of differentiating agents for treatment of acute promyelocytic leukemia (APL); newer therapies functioning through differentiation include isocitrate dehydrogenase (IDH) 1 and 2 inhibitors, FMS-like tyrosine kinase 3 (FLT3) inhibitors, and menin inhibitors. The terminal differentiation of leukemic blasts via differentiating agent therapy can lead to a constellation of signs and symptoms, originally referred to as "retinoic acid syndrome" and now termed "differentiation syndrome" (DS), characterized predominantly by systemic inflammatory response system (SIRS)-like features of dyspnea, pulmonary infiltrates, pleural and pericardial effusions, unexplained fevers, hypotension, edema, and renal insufficiency. DS in patients with newly diagnosed APL is generally straightforward to identify, however DS in patients with multiply relapsed AML can be more challenging to diagnose, due to non-specific signs and symptoms which can be mistakenly attributed to infectious etiologies or the underlying refractory leukemia itself. Prompt consideration of DS, rapid initiation of systemic corticosteroids, and early cytoreduction in the setting of concomitant hyperleukocytosis, are essential for optimal management.

Quantifying Protein Acetylation in Diabetic Nephropathy from Formalin-Fixed Paraffin-Embedded Tissue.

PURPOSE: Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of chronic kidney disease and end-stage renal disease. One potential mechanism underlying cellular dysfunction contributing to kidney disease is aberrant protein post-translational modifications. Lysine acetylation is associated with cellular metabolic flux and is thought to be altered in patients with diabetes and dysfunctional renal metabolism. EXPERIMENTAL DESIGN: A novel extraction and LC-MS/MS approach was adapted to quantify sites of lysine acetylation from formalin-fixed paraffin-embedded (FFPE) kidney tissue and from patients with DKD and non-diabetic donors (n = 5 and n = 7, respectively). RESULTS: Analysis of FFPE tissues identified 840 total proteins, with 225 of those significantly changing in patients with DKD. Acetylomic analysis quantified 289 acetylated peptides, with 69 of those significantly changing. Pathways impacted in DKD patients revealed numerous metabolic pathways, specifically mitochondrial function, oxidative phosphorylation, and sirtuin signaling. Differential protein acetylation in DKD patients impacted sirtuin signaling, valine, leucine, and isoleucine degradation, lactate metabolism, oxidative phosphorylation, and ketogenesis. CONCLUSIONS AND CLINICAL RELEVANCE: A quantitative acetylomics platform was developed for protein biomarker discovery in formalin-fixed and paraffin-embedded biopsies of kidney transplant patients suffering from DKD.

Adverse childhood experiences (ACEs), resilience, and outcomes in older adulthood: A scoping review.

BACKGROUND: Previous research has demonstrated a dose-response relationship between exposure to adverse childhood experiences (ACEs) and adverse outcomes in adulthood. Despite widely known associations, previous reviews have primarily focused on outcomes in younger and middle-aged adults exposed to ACEs to the exclusion of older adults and do not consider the potential role of resilience for understanding outcomes in older adulthood. OBJECTIVE: The present scoping review aimed to examine the extent and nature of existing literature on the influence of ACEs and resilience on the cognitive, physical, mental, and social health outcomes among older adults. METHODS: We conducted a search of five electronic databases (CINAHL, MEDLINE, PsycINFO, AgeLine, Scopus) using the following keywords: adversity, resilience, aging, and older adults. We limited our inclusion criteria to works published in English or French after 1998 as Felitti et al. published the first study describing ACEs in this year. RESULTS: Of the 4926 studies screened, 27 studies met the inclusion criteria. Overall, results from the included studies indicated that exposure to adversity during childhood was associated with worse outcomes in older adulthood. Additionally, we found that resilience and resiliency-related factors (e.g., problem-focused coping strategies) mitigated or reduced harms associated with ACEs to improve outcomes in older adulthood. CONCLUSIONS: Exposure to ACEs is associated with reduced functioning in later adulthood. Findings from this review indicate a need for further exploration into the role of ACEs, and the potential effects of resilience, on health outcomes in older adults to develop better individual- and population-level interventions for this group.

Primary Infection Site as a Predictor of Sepsis Development in Emergency Department Patients.

BACKGROUND: Sepsis is a life-threatening condition but predicting its development and progression remains a challenge. OBJECTIVE: This study aimed to assess the impact of infection site on sepsis development among emergency department (ED) patients. METHODS: Data were collected from a single-center ED between January 2016 and December 2019. Patient encounters with documented infections, as defined by the Systematized Nomenclature of Medicine-Clinical Terms for upper respiratory tract (URI), lower respiratory tract (LRI), urinary tract (UTI), or skin or soft-tissue infections were included. Primary outcome was the development of sepsis or septic shock, as defined by Sepsis-1/2 criteria. Secondary outcomes included hospital disposition and length of stay, blood and urine culture positivity, antibiotic administration, vasopressor use, in-hospital mortality, and 30-day mortality. Analysis of variance and various different logistic regression approaches were used for analysis with URI used as the reference variable. RESULTS: LRI was most associated with sepsis (relative risk ratio [RRR] 5.63; 95% CI 5.07-6.24) and septic shock (RRR 21.2; 95% CI 17.99-24.98) development, as well as hospital admission rates (odds ratio [OR] 8.23; 95% CI 7.41-9.14), intensive care unit admission (OR 4.27; 95% CI 3.84-4.74), in-hospital mortality (OR 6.93; 95% CI 5.60-8.57), and 30-day mortality (OR 7.34; 95% CI 5.86-9.19). UTIs were also associated with sepsis and septic shock development, but to a lesser degree than LRI. CONCLUSIONS: Primary infection sites including LRI and UTI were significantly associated with sepsis development, hospitalization, length of stay, and mortality among patients presenting with infections in the ED.

Remote assessment and management of patients with dizziness: development, validation, and feasibility of a gamified vestibular rehabilitation therapy platform.

Introduction: Dizziness is a growing public health concern with as many as 95 million adults in Europe and the United States experiencing vestibular hypofunction, which is associated with reduced quality of life, poorer health, and falls. Vestibular rehabilitation therapy (VRT) is effective in reducing symptoms and improving balance; however, limited access to qualified clinicians and poor patient adherence impedes optimal delivery. The goal of this study was to develop and evaluate the feasibility of a remote therapeutic monitoring VRT Platform application (APP) for the assessment and treatment of vestibular dysfunction. Methods: User-centered iterative design process was used to gather and integrate the needs of users (clinicians and patients) into the design at each stage of development. Commonly used vestibular patient-reported outcome measures (PROs) were integrated into the APP and adults with chronic dizziness were enrolled to evaluate validity and reliability of the APP compared to standard clinical measures (CLIN). Gaze stabilization exercises were gamified to provide an engaging experience and an off-the-shelf sensor captured eye and head movement to provide feedback on accuracy of performance. A prospective, pilot study design with pre-and post-treatment assessment assessed feasibility of the APP compared to standard VRT (CLIN). Results: Participants with dizziness wanted a summary rehabilitation report shared with their clinicians, felt that an app could help with accountability, and believed that a gaming format might help with exercise adherence. Clinicians felt that the app should include features to record and track eye and head movement, monitor symptoms, score accuracy of task performance, and measure adherence. Validity and reliability of the digital PROs (APP) were compared to scores from CLIN across two sessions and found to have good validity, good to excellent test-retest reliability, and excellent usability (≥88%ile). The pilot study demonstrated feasibility for use of the APP compared to CLIN for treatment of vestibular hypofunction. The mean standard system usability score of the APP was 82.5 indicating excellent usability. Discussion: Both adult patients with chronic dizziness and VRT clinicians were receptive to the use of technology for VRT. The HiM-V APP is a feasible alternative to clinical management of adults with chronic peripheral vestibular hypofunction.

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.

The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes.

BACKGROUND: An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis. METHODS: In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes. RESULTS: We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths. CONCLUSIONS: In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).

Germline Predisposition in Hematologic Malignancies: Testing, Management, and Implications.

Although numerous barriers for clinical germline cancer predisposition testing exist, the increasing recognition of deleterious germline DNA variants contributing to myeloid malignancy risk is yielding steady improvements in referrals for testing and testing availability. Many germline predisposition alleles are common in populations, and the increasing number of recognized disorders makes inherited myeloid malignancy risk an entity worthy of consideration for all patients regardless of age at diagnosis. Germline testing is facilitated by obtaining DNA from cultured skin fibroblasts or hair bulbs, and cascade testing is easily performed via buccal swab, saliva, or blood. Increasingly as diagnostic criteria and clinical management guidelines include germline myeloid malignancy predisposition, insurance companies recognize the value of testing and provide coverage. Once an individual is recognized to have a deleterious germline variant that confers risk for myeloid malignancies, a personalized cancer surveillance plan can be developed that incorporates screening for other cancer risk outside of the hematopoietic system and/or other organ pathology. The future may also include monitoring the development of clonal hematopoiesis, which is common for many of these cancer risk disorders and/or inclusion of strategies to delay or prevent progression to overt myeloid malignancy. As research continues to identify new myeloid predisposition disorders, we may soon recommend testing for these conditions for all patients diagnosed with a myeloid predisposition condition.

BRAF mutation in myeloid neoplasm: incidences and clinical outcomes.

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

Estimating the size and scope of the academic emergency physician workforce.

BACKGROUND: Academic emergency medicine (EM) is foundational to the EM specialty through the development of new knowledge and clinical training of resident physicians. Despite recent increased attention to the future of the EM workforce, no evaluations have specifically characterized the U.S. academic EM workforce. We sought to estimate the national proportion of emergency physicians (EPs) identified as academic and the proportion of emergency department (ED) visits that take place at academic sites. METHODS: We performed a cross-sectional analysis of EPs and EDs using data from the American Hospital Association, the Centers for Medicare & Medicaid Services, and Doximity's Residency Navigator. EPs were identified as "academic" if they were affiliated with at least one facility determined to be academic, defined as EDs officially designated by the Accreditation Council for Graduate Medical Education (ACGME) as clinical training sites at accredited EM residency programs. Our primary outcomes were to estimate the national proportion of EPs identified as academic and the proportion of ED visits performed at academic sites. RESULTS: Our analytic sample included 26,937 EPs practicing clinically across 4920 EDs and providing care during 130,471,386 ED visits. Among EPs, 11,720 (43.5%) were identified as academic, and among EDs, 635 (12.9%) were identified as academic sites, including 585 adult/general sites, 45 pediatric-specific sites, and 10 sites affiliated with the Department of Veterans Affairs. In 2021, academic EDs provided care for 42,794,106 ED visits or 32.8% of all ED visits nationally. CONCLUSIONS: Approximately four in 10 EPs practice in at least one clinical training site affiliated with an ACGME-accredited EM residency program, and approximately one in three ED visits nationally occur in these academic EDs. We encourage further work using alternative definitions of an academic EPs and EDs, along with longitudinal research to identify trends in the workforce's composition.

Outcomes and genetic dynamics of acute myeloid leukemia at first relapse.

Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.

Hospital admissions among patients with Comorbid Substance Use disorders: a secondary analysis of predictors from the NavSTAR Trial.

BACKGROUND: Individuals with substance use disorders (SUDs) frequently use acute hospital services. The Navigation Services to Avoid Rehospitalization (NavSTAR) trial found that a patient navigation intervention for hospitalized patients with comorbid SUDs reduced subsequent inpatient admissions compared to treatment-as-usual (TAU). METHODS: This secondary analysis extends previous findings from the NavSTAR trial by examining whether selected patient characteristics independently predicted hospital service utilization and moderated the effect of the NavSTAR intervention. Participants were 400 medical/surgical hospital patients with comorbid SUDs. We analyzed 30- and 90-day inpatient readmissions (one or more readmissions) and cumulative incidence of inpatient admissions through 12 months using multivariable logistic and negative binomial regression, respectively. RESULTS: Consistent with primary findings and controlling for patient factors, NavSTAR participants were less likely than TAU participants to be readmitted within 30 (P = 0.001) and 90 (P = 0.03) days and had fewer total readmissions over 12 months (P = 0.008). Hospitalization in the previous year (P < 0.001) was associated with cumulative readmissions over 12 months, whereas Medicaid insurance (P = 0.03) and index diagnoses of infection (P = 0.001) and injuries, poisonings, or procedural complications (P = 0.004) were associated with fewer readmissions. None of the selected covariates moderated the effect of the NavSTAR intervention. CONCLUSIONS: Previous findings showed that patient navigation could reduce repeat hospital admissions among patients with comorbid SUDs. Several patient factors were independently associated with readmission. Future research should investigate risk factors for hospital readmission among patients with comorbid SUDs to optimize interventions. TRIAL REGISTRATION: NIH ClinicalTrials.gov NCT02599818, Registered November 9, 2015 https://classic. CLINICALTRIALS: gov/ct2/show/NCT02599818 .

Molecular responses in decitabine- and decitabine/venetoclax-treated patients with acute myeloid leukemia and myelodysplastic syndromes.

Not available.

Evaluation, analysis, and reporting of medication adherence for clinical trials of anticoagulants in children: guidance from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis.

In response to growing recognition that nonadherence prevents children, adolescents, and young adults from achieving the therapeutic benefits of anticoagulant medication, the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis convened a working party on medication adherence. The primary aim of this article was to synthesize recommendations from the larger adherence science literature to provide guidance regarding the classification, collection, and interpretation of anticoagulation adherence data. The secondary aim of this article was to evaluate the degree to which trials published from 2013 to 2023 adhered to these guidance recommendations. As less than half of all trials reported on adherence and none included all recommended elements, the proposed International Society on Thrombosis and Haemostasis Scientific and Standardization Committee guidance has the potential to enhance the rigor and reproducibility of pediatric anticoagulant research.

Characteristics and outcomes of acute myeloid leukaemia patients with baseline CD7 expression.

Targeted therapy development for acute myeloid leukaemia (AML) requires an understanding of specific expression profiles. We collected flow cytometry data on 901 AML patients and recorded aberrant CD7 expression on leukaemic blasts. 263 (29.2%) had blasts positive for CD7. CD7+ AML was more likely to be adverse risk (64.6% vs. 55.6%, p = 0.0074) and less likely to be favourable risk (15.2% vs. 24.1%, p = 0.0074) by European LeukemiaNet 2022 criteria. Overall survival was inferior (11.9 [95% CI, 9.7-15.9] vs. 19.0 months [95% CI, 16.1-23.0], p = 0.0174). At relapse, 30.4% lost and 19.0% gained CD7, suggesting moderate instability over time.

Somatic gene mutation patterns and burden influence outcomes with enasidenib in relapsed/refractory IDH2-mutated AML.

Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this large R/R AML patient cohort, targeted next-generation sequencing at baseline (screening) revealed distinct co-mutation patterns and mutational burden between subgroups bearing different IDH2 variants: variant IDH2-R140 was associated with greater mutational burden and was enriched predominantly with poor-risk mutations, including FLT3, RUNX1, and NRAS, while variant IDH2-R172 was associated with lower mutational burden and was preferentially co-mutated with DNMT3A. In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.