Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation.

Introduction: It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR5-ion) develop cardiovascular dysfunction by 12 months post-radiation. Methods: To investigate the biological basis of this dysfunction, here we performed a quantitative mass spectrometry-based proteomics analysis of heart tissue (proteome and phosphoproteome) and plasma (proteome only) from these mice at 8 months post-radiation. Results: Differentially expressed proteins (DEPs) for irradiated versus sham irradiated samples (fold-change ≥1.2 and an adjusted p-value of ≤0.05) were identified for each proteomics data set. For the heart proteome, there were 87 significant DEPs (11 upregulated and 76 downregulated); for the heart phosphoproteome, there were 60 significant differentially phosphorylated peptides (17 upregulated and 43 downregulated); and for the plasma proteome, there was only one upregulated protein. A Gene Set Enrichment Analysis (GSEA) technique that assesses canonical pathways from BIOCARTA, KEGG, PID, REACTOME, and WikiPathways revealed significant perturbation in pathways in each data set. For the heart proteome, 166 pathways were significantly altered (36 upregulated and 130 downregulated); for the plasma proteome, there were 73 pathways significantly altered (25 upregulated and 48 downregulated); and for the phosphoproteome, there were 223 pathways significantly affected at 0.1 adjusted p-value cutoff. Pathways related to inflammation were the most highly perturbed in the heart and plasma. In line with sustained inflammation, neutrophil extracellular traps (NETs) were demonstrated to be increased in GCR5-ion irradiated hearts at 12-month post irradiation. NETs play a fundamental role in combating bacterial pathogens, modulating inflammatory responses, inflicting damage on healthy tissues, and escalating vascular thrombosis. Discussion: These findings suggest that a single exposure to GCR5-ion results in long-lasting changes in the proteome and that these proteomic changes can potentiate acute and chronic health issues for astronauts, such as what we have previously described with late cardiac dysfunction in these mice.

Analysis of Protein Cysteine Acylation Using a Modified Suspension Trap (Acyl-Trap).

Protein cysteine thiols undergo reversible S-acylation via a thioester linkage in vivo. S-palmitoylation, modification by C16:0 fatty acid, is a common S-acylation that mediates protein-membrane and protein-protein interactions critical to an array of biological processes, from homeostatic lung surfactant function to cellular transformation. The most widely used S-acylation assays, including acyl-biotin exchange (ABE) and acyl resin-assisted capture (Acyl-RAC), utilize blocking of free Cys thiols, hydroxylamine-dependent cleavage of the thioester and subsequent labeling of nascent thiol. ABE and Acyl-RAC have enabled both the proteome-wide identification of S-palmitoylation sites and basic biochemical studies. Yet, these assays generally utilize hundreds of micrograms to milligrams of input material and require numerous reagent removal and washing steps, making them laborious and ill-suited for high throughput and low input applications. To overcome this, we devised "Acyl-Trap", a suspension trap-based assay that utilizes a thiol-reactive quartz to enable buffer exchange and hydroxylamine-mediated S-acyl enrichment from 20-50 micrograms of input protein. The method is compatible with protein-level detection of Sacylated proteins as well as S-acyl site-based identification and quantification using on-quartz isobaric (tandem mass tag) labeling and LC-MS/MS. Also described are conditions for long-term hydroxylamine storage, which further expedites the assay and minimizes waste. More generally, Acyl-Trap serves as a proof-of-concept for PTM-tailored suspension traps suitable for both traditional intact protein detection and chemoproteomic workflows.

The positive impact of conservation action.

Governments recently adopted new global targets to halt and reverse the loss of biodiversity. It is therefore crucial to understand the outcomes of conservation actions. We conducted a global meta-analysis of 186 studies (including 665 trials) that measured biodiversity over time and compared outcomes under conservation action with a suitable counterfactual of no action. We find that in two-thirds of cases, conservation either improved the state of biodiversity or at least slowed declines. Specifically, we find that interventions targeted at species and ecosystems, such as invasive species control, habitat loss reduction and restoration, protected areas, and sustainable management, are highly effective and have large effect sizes. This provides the strongest evidence to date that conservation actions are successful but require transformational scaling up to meet global targets.

Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, damage to multiple organ systems, and, as a result, shortened life expectancy. Sickle cell disease nephropathy (SCDN) and pulmonary hypertension (pHTN) are common and frequently co-occurring complications of SCD; both are associated with markedly accelerated mortality. To identify candidate circulating biomarkers of SCDN and pHTN, we used mass spectrometry to quantify the relative abundance of >1000 proteins in plasma samples from 189 adults with SCD from the Outcome Modifying Genes in SCD (OMG-SCD) cohort (ProteomeXchange identifier PXD048716). Forty-four proteins were differentially abundant in SCDN, most significantly cystatin-C and collagen α-1(XVIII) chain (COIA1), and 55 proteins were dysregulated in patients with SCDN and pHTN, most significantly insulin-like growth factor-binding protein 6 (IBP6). Network analysis identified a module of 133 coregulated proteins significantly associated with SCDN, that was enriched for extracellular matrix proteins, insulin-like growth factor binding proteins, cell adhesion proteins, EGF-like calcium binding proteins, and several cadherin family members. Collectively, these data provide a comprehensive understanding of plasma protein changes in SCDN and pHTN which validate numerous studies of chronic kidney disease and suggest shared profiles of protein disruption in kidney dysfunction and pHTN among SCD patients.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

ABSTRACT: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.

A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.

Indices of Narrative Language Associated with Disability.

Narratives skills are associated with long-term academic and social benefits. While students with disabilities often struggle to produce complete and complex narratives, it remains unclear which aspects of narrative language are most indicative of disability. In this study, we examined the association between a variety of narrative contents and form indices and disability. Methodology involved drawing 50 K-3 students with Individual Education Programs (IEP) and reported language concerns from a large diverse sample (n = 1074). Fifty typically developing (TD) students were matched to the former group using propensity score matching based on their age, gender, grade, mother's education, and ethnicity. Narrative retells and generated language samples were collected and scored for Narrative Discourse and Sentence Complexity using a narrative scoring rubric. In addition, the number of different words (NDW), subordination index (SI), and percentage of grammatical errors (%GE) were calculated using computer software. Results of the Mixed effect model revealed that only Narrative Discourse had a significant effect on disability, with no significant effect revealed for Sentence Complexity, %GE, SI, and NDW. Additionally, Narrative Discourse emerged as the sole significant predictor of disability. At each grade, there were performance gaps between groups in the Narrative Discourse, Language Complexity, and SI. Findings suggest that difficulty in Narrative Discourse is the most consistent predictor of disability.

Impact of Discourse Type and Elicitation Task on Language Sampling Outcomes.

PURPOSE: Language sampling is a critical component of language assessments. However, there are many ways to elicit language samples that likely impact the results. The purpose of this study was to examine how different discourse types and elicitation tasks affect various language sampling outcomes. METHOD: A diverse group of K-3 students (N = 1,037) contributed eight spoken language samples in four elicitation conditions: (a) expository generation, (b) expository retell, (c) narrative generation, and (d) narrative retell. Samples were audio-recorded, transcribed, and coded for number of total words, number of different words, mean length of utterance in words (MLUW), and number of clauses per communication unit (i.e., Subordination Index [SI]). RESULTS: Narrative retell and expository generation conditions yielded the largest samples with the greatest lexical diversity when compared to narrative generation and expository retell. MLUW was higher in expository conditions, but mean SI was higher in narrative conditions. For both measures of syntax, narrative retell and expository generation yielded the highest mean scores. For each outcome, there were expected increases corresponding to grades; however, the differences faded between second and third grade. CONCLUSION: As a component of language assessments, clinicians' selection of language sampling procedures will impact the sample length, lexical diversity, utterance length, and syntactical complexity of the samples. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24185649.

Weyl nodal ring states and Landau quantization with very large magnetoresistance in square-net magnet EuGa4.

Magnetic topological semimetals allow for an effective control of the topological electronic states by tuning the spin configuration. Among them, Weyl nodal line semimetals are thought to have the greatest tunability, yet they are the least studied experimentally due to the scarcity of material candidates. Here, using a combination of angle-resolved photoemission spectroscopy and quantum oscillation measurements, together with density functional theory calculations, we identify the square-net compound EuGa4 as a magnetic Weyl nodal ring semimetal, in which the line nodes form closed rings near the Fermi level. The Weyl nodal ring states show distinct Landau quantization with clear spin splitting upon application of a magnetic field. At 2 K in a field of 14 T, the transverse magnetoresistance of EuGa4 exceeds 200,000%, which is more than two orders of magnitude larger than that of other known magnetic topological semimetals. Our theoretical model suggests that the non-saturating magnetoresistance up to 40 T arises as a consequence of the nodal ring state.

Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait.

BACKGROUND: Sickle cell trait affects approximately 8% of Black individuals in the United States, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests that sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including kidney failure. The mechanisms underlying these associations remain poorly understood. We used proteomic profiling to gain insight into the pathobiology of sickle cell trait. METHODS: We measured proteomics ( N =1285 proteins assayed by Olink Explore) using baseline plasma samples from 592 Black participants with sickle cell trait and 1:1 age-matched Black participants without sickle cell trait from the prospective Women's Health Initiative cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait. RESULTS: In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in Black participants from two independent cohorts (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are known biomarkers of kidney function or injury ( e.g. , hepatitis A virus cellular receptor 1 [HAVCR1]/kidney injury molecule-1 [KIM-1], uromodulin [UMOD], ephrins), related to red cell physiology or hemolysis (erythropoietin [EPO], heme oxygenase 1 [HMOX1], and α -hemoglobin stabilizing protein) and/or inflammation (fractalkine, C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 [MCP-1], and urokinase plasminogen activator surface receptor [PLAUR]). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during Women's Health Initiative follow-up (odds ratio, 1.32; 95% confidence interval, 1.10 to 1.58). CONCLUSIONS: We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.

Barriers and facilitators associated with implementing interventions to support oral anticancer agent adherence in academic and community cancer center settings.

PURPOSE: The goal of this study is to determine barriers and facilitators to the implementation of medication adherence interventions to support cancer patients taking novel, targeted oral anticancer agents (OAAs). METHODS: We conducted qualitative interviews using a semi-structured guide from the Consolidated Framework for Implementation Research (CFIR). We used purposive sampling to identify clinicians (physicians, pharmacists, nurse practitioners, nurses) and administrators (leadership from medicine, pharmacy, and nursing) who delivered care and/or oversee care delivery for patients with chronic leukemia prescribed an OAA. RESULTS: A total of 19 individuals participated in an interview (12 clinicians and 7 administrators), with 10 primarily employed by an academic cancer center; 5 employed by the community cancer center; and 4 employed by the integrated health-system specialty pharmacy. Barriers identified included low awareness of adherence interventions, difficulty in adherence measurement, complexity of designing and implementing a structured adherence intervention, and competing priorities. Facilitators identified included support of hospital administrators, value for pharmacists, and willingness to embrace change. Participants also made recommendations moving forward including standardizing workflow, designating champions, iterating implementation strategies, and improving communication between clinicians and with patients. CONCLUSION: Individual and system level factors were identified as determinants of implementation effectiveness of medication adherence interventions. A multidisciplinary advisory panel will be assembled to design comprehensive and actionable strategies to refine and implement a structured intervention to improve medication adherence in cancer patients.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Speech-language disorder severity, academic success, and socioemotional functioning among multilingual and English children in the United States: The National Survey of Children's Health.

Research points to negative associations between educational success, socioemotional functioning, and the severity of symptoms in some speech-language disorders (SLDs). Nonetheless, the majority of studies examining SLDs in children have focused on monolinguals. More research is needed to determine whether the scant findings among multilinguals are robust. The present study used parent report data from the U.S. National Survey of Children's Health (2018 to 2020) to gain a better understanding of the impacts of SLD severity on indicators of academic success and socioemotional functioning among multilingual (n = 255) and English monolingual (n = 5,952) children with SLDs. Tests of between-group differences indicated that multilingual children evidenced more severe SLDs, had lower school engagement, and had lower reports of flourishing than English monolingual children with SLDs. Further, a greater proportion of multilingual children with SLDs missed more school days than English monolinguals. However, multilinguals were less likely to bully others or have been bullied than monolinguals. While the previous between-group differences were statistically significant, they were small (vs ≤ 0.08). Increased SLD severity predicted an increased number of repeated school grades, increased absenteeism, and decreased school engagement, when age and socioeconomic status were controlled. Increased SLD severity also predicted greater difficulty making and keeping friends and decreased flourishing. The effect of SLD severity on being bullied was statistically significant for the monolinguals but not multilinguals. There was a statistically significant interaction for SLD severity and sex for school engagement and difficulty making and keeping friends for monolinguals but not multilinguals. The interactions indicated that school engagement decreased more for females than for males while difficulties making and keeping friends increased more for males than females as one's SLD severity increased. While some findings were specific to monolinguals, tests of measurement invariance indicated that the same general pattern of relations among the variables were evident across the groups of multilinguals and monolinguals. These final findings can inform the interpretation of the results from both the current and future studies, while the overall findings can inform the development of intervention programs, thereby improving the long-term academic and socioemotional outcomes of children with SLDs.

Octreotide may improve pharyngocutaneous fistula healing through downregulation of cystatins: A pilot study.

Background: Pharyngocutaneous fistula (PCF) and salivary leaks are well known complications of head and neck surgery. The medical management of PCF has included the use of octreotide without a well-defined understanding of its therapeutic mechanism. We hypothesized that octreotide induces alterations in the saliva proteome and that these alterations may provide insight into the mechanism of action underlying improved PCF healing. We undertook an exploratory pilot study in healthy controls that involved collecting saliva before and after a subcutaneous injection of octreotide and performing proteomic analysis to determine the effects of octreotide. Methods: Four healthy adult participants provided saliva samples before and after subcutaneous injection of octreotide. A mass-spectrometry based workflow optimized for the quantitative proteomic analysis of biofluids was then employed to analyze changes in salivary protein abundance after octreotide administration. Results: There were 3076 human, 332 Streptococcus mitis, 102 G. haemolyans, and 42 Granulicatella adiacens protein groups quantified in saliva samples. A paired statistical analysis was performed using the generalized linear model (glm) function in edgeR. There were and ~300 proteins that had a p < .05 between the pre- and post-octreotide groups ~50 proteins with an FDR-corrected p < .05 between pre- and post-groups. These results were visualized using a volcano plot after filtering on proteins quantified by 2 more or unique precursors. Both human and bacterial proteins were among the proteins altered by octreotide treatment. Notably, four isoforms of the human cystatins, belonging to a family of cysteine proteases, that had significantly lower abundance after treatment. Conclusion: This pilot study demonstrated octreotide-induced downregulation of cystatins. By downregulation of cystatins in the saliva, there is decreased inhibition of cysteine proteases such as Cathepsin S. This results in increased cysteine protease activity that has been linked to enhanced angiogenic response, cell proliferation and migration that have resulted in improved wound healing. These insights provide first steps at furthering our understanding of octreotide's effects on saliva and reports of improved PCF healing.

The urinary proteome infers dysregulation of mitochondrial, lysosomal, and protein reabsorption processes in chronic kidney disease of unknown etiology (CKDu).

Chronic kidney disease (CKD) of uncertain etiology (CKDu) is a global health concern affecting tropical farming communities. CKDu is not associated with typical risk factors (e.g., diabetes) and strongly correlates with environmental drivers. To gain potential insights into disease etiology and diagnosis, here we report the first urinary proteome comparing patients with CKDu and non-CKDu controls from Sri Lanka. We found 944 differentially abundant proteins. In silico analyses identified 636 proteins of likely kidney and urogenital origin. As expected, renal tubular injury in patients with CKDu was evinced by increases in albumin, cystatin C, and ß2-microglobulin. However, several proteins typically elevated under CKD, including osteopontin and α-N-acetylglucosaminidase, were decreased in patients with CKDu. Furthermore, urinary excretion of aquaporins found higher in CKD was lower in CKDu. Comparisons with previous CKD urinary proteome datasets revealed a unique proteome for CKDu. Notably, the CKDu urinary proteome was relatively similar to that of patients with mitochondrial diseases. Furthermore, we report a decrease in endocytic receptor proteins responsible for protein reabsorption (megalin and cubilin) that correlated with an increase in abundance of 15 of their cognate ligands. Functional pathway analyses identified kidney-specific differentially abundant proteins in patients with CKDu denoted significant changes in the complement cascade and coagulation systems, cell death, lysosomal function, and metabolic pathways. Overall, our findings provide potential early detection markers to diagnose and distinguish CKDu and warrant further analyses on the role of lysosomal, mitochondrial, and protein reabsorption processes and their link to the complement system and lipid metabolism in CKDu onset and progression.NEW & NOTEWORTHY CKDu is a global health concern debilitating a number of tropical rural farming communities. In the absence of typical risk factors like diabetes and hypertension and the lack of molecular markers, it is crucial to identify potential early disease markers. Here, we detail the first urinary proteome profile to distinguish CKDu from CKD. Our data and in silico pathway analyses infer the roles of mitochondrial, lysosomal, and protein reabsorption processes in disease onset and progression.

Review of the National Quality Forum's Measure Endorsement Process.

ABSTRACT: The National Quality Forum (NQF) evaluates healthcare performance measures for endorsement based on a broad set of criteria. We extracted data from NQF technical reports released between spring 2018 and spring 2019. Measures were commonly stewarded by federal agencies (44.29%), evaluated for maintenance (67.14%), classified as outcome (42.14%) or process (39.29%) measures, and used a statistical model for risk adjustment (48.57%). For 80% of the measures reviewed, a patient advocate was present on the reviewing committee. Validity was evaluated using face validity (65.00%) or score-level empirical validity (67.14%), and reliability was frequently evaluated using score-level testing (71.43%). Although 91.56% of all reviewed measures were endorsed, most standing committee members voted moderate rather than high support on key assessment criteria like measure validity, measure reliability, feasibility of use, and whether the measure addresses a key performance gap. Results show that although the Consensus Development Process includes multidisciplinary stakeholder input and thorough evaluations of measures, continued work to identify and describe appropriate and robust methods for reliability and validity testing is needed. Further work is needed to study the extent to which stakeholder input is truly representative of diverse viewpoints and improve processes for considering social factors when risk adjusting.

Outpatient initiation of venetoclax in patients with acute myeloid leukemia.

INTRODUCTION: Venetoclax is a treatment option in patients with acute myeloid leukemia (AML) in both the front-line and relapsed/refractory settings. Initiation of therapy has been previously restricted to the inpatient setting at some institutions due to a risk of tumor lysis syndrome (TLS) and limitations in medication access efficiency given the high cost of therapy. METHODS: We assessed the safety of initiating venetoclax in the outpatient setting through a single-arm, retrospective study of adult AML patients between April 1, 2019 and June 30, 2020. RESULTS: Eighty-two patients started venetoclax during this time, with 47 (57%) patients initiated in the outpatient setting. Fifty-five percent of patients received venetoclax as first-line treatment for AML (n = 45) and 45% of patients received venetoclax for relapsed/refractory AML (n = 37). Successful initiation, defined as no hospitalizations secondary to TLS within seven days of therapy initiation, occurred in 98% of patients. The rate of TLS was 2.1% (n = 1) following venetoclax initiation. TLS symptoms were managed during hospitalization, requiring only one day of missed AML therapy. Median turnaround time for medication access was three days. Hospitalizations within seven days occurred in 17% of patients (n = 8), with the majority due to febrile neutropenia. CONCLUSIONS: The results of our study provide further evidence for the safety and feasibility of initiating venetoclax in the outpatient setting with a pharmacist-led interdisciplinary protocol.

Time spent at home among older adults with acute myeloid leukemia receiving azacitidine- or venetoclax-based regimens.

Time at home is a critically important outcome to adults with acute myeloid leukemia (AML) when selecting treatment; however, no study to date has adequately described the amount of time older adults spend at home following initiation of chemotherapy. We queried records from a multi-institution health system to identify adults aged ≥60 years newly diagnosed with AML who were treated with azacitidine or venetoclax and evaluated the proportion of days at home (PDH) following diagnosis. Days were considered "at home" if patients were not admitted or seen in the emergency department or oncology/infusion clinic. Assessed covariates included demographics and disease risk. Associations between PDH and baseline characteristics were evaluated via linear regression, adjusted for log length of follow-up. From 2015-2020, 113 older adults were identified. Most received azacitidine plus venetoclax (51.3%) followed by azacitidine monotherapy (38.9%). The mean PDH for all patients was 0.58 (95% confidence interval: 0.54-0.63, median 0.63). PDH increased among survivors over time. PDH did not differ between therapy groups (adjusted mean, azacitidine plus venetoclax: 0.68; azacitidine monotherapy: 0.66; P=0.64) or between disease risk categories (P=0.34). Compared to patients receiving azacitidine monotherapy, patients receiving azacitidine plus venetoclax had longer clinic visits (median minutes: 127.9 vs. 112.9, P<0.001) and infusion visits (median minutes: 194.3 vs. 132.5, P<0.001). The burden of care for older adults with AML treated with "less intense" chemotherapy is high. The addition of venetoclax to azacitidine did not translate into increased time at home. Future prospective studies should evaluate patient-centered outcomes, including time at home, to inform shared decision-making and drug development.