SOHO State of the Art Updates and Next Questions: An Update on Higher Risk Myelodysplastic Syndromes.

Higher-risk myelodysplastic syndromes (HR-MDS) are clonal myeloid neoplasms that cause life-limiting complications from severe cytopenias and leukemic transformation. Efforts to better classify, prognosticate, and assess therapeutic responses in HR-MDS have resulted in publication of new clinical tools in the last several years. Given limited current treatment options and suboptimal outcomes, HR-MDS stands to benefit from the study of investigational agents.Higher-risk myelodysplastic syndromes (HR-MDS) are a heterogenous group of clonal myeloid-lineage malignancies often characterized by high-risk genetic lesions, increased blood transfusion needs, constitutional symptoms, elevated risk of progression to acute myeloid leukemia (AML), and therapeutic need for allogeneic bone marrow transplantation. Use of blast percentage and other morphologic features to define myelodysplastic neoplasm subtypes is rapidly shifting to incorporate genetics, resulting in a subset of former HR-MDS patients now being considered as AML in presence of leukemia-defining genetic alterations. A proliferation of prognostic tools has further focused use of genetic features to drive decision making in clinical management. Recently, criteria to assess response of HR-MDS to therapy were revised to incorporate more clinically meaningful endpoints and better match AML response criteria. Basic science investigations have resulted in improved understanding of the relationship between MDS genetic lesions, bone marrow stromal changes, germline predispositions, and disease phenotype. However, therapeutic advances have been more limited. There has been import of the IDH1 inhibitor ivosidenib, initially approved for AML; the Bcl-2 inhibitor venetoclax and liposomal daunorubicin/cytarabine (CPX-351) are under active investigation as well. Unfortunately, effective treatment of TP53-mutated disease remains elusive, though preliminary evidence suggests improved outcomes with oral decitabine/cedazuridine over parenteral hypomethylating agent monotherapy. Investigational agents with novel mechanisms of action may help expand the repertoire of treatment options for HR-MDS and trials continue to offer a hopeful therapeutic avenue for suitable patients.

Caring for high-need patients.

OBJECTIVE: We aimed to explore the construct of "high need" and identify common need domains among high-need patients, their care professionals, and healthcare organizations; and to describe the interventions that health care systems use to address these needs, including exploring the potential unintended consequences of interventions. METHODS: We conducted a modified Delphi panel informed by an environmental scan. Expert stakeholders included patients, interdisciplinary healthcare practitioners (physicians, social workers, peer navigators), implementation scientists, and policy makers. The environmental scan used a rapid literature review and semi-structured interviews with key informants who provide healthcare for high-need patients. We convened a day-long virtual panel meeting, preceded and followed by online surveys to establish consensus. RESULTS: The environmental scan identified 46 systematic reviews on high-need patients, 19 empirical studies documenting needs, 14 intervention taxonomies, and 9 studies providing construct validity for the concept "high need." Panelists explored the construct and terminology and established that individual patients' needs are unique, but areas of commonality exist across all high-need patients. Panelists agreed on 11 domains describing patient (e.g., social circumstances), 5 care professional (e.g., communication), and 8 organizational (e.g., staffing arrangements) needs. Panelists developed a taxonomy of interventions with 15 categories (e.g., care navigation, care coordination, identification and monitoring) directed at patients, care professionals, or the organization. The project identified potentially unintended consequences of interventions for high-need patients, including high costs incurred for patients, increased time and effort for care professionals, and identification of needs without resources to respond appropriately. CONCLUSIONS: Care for high-need patients requires a thoughtful approach; differentiating need domains provides multiple entry points for interventions directed at patients, care professionals, and organizations. Implementation efforts should consider outlined intended and unintended downstream effects on patients, care professionals, and organizations.

Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification.

Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.

The Times, They Are A-Changing: The Impact of Next-Generation Sequencing on Diagnosis, Classification, and Prognostication of Myeloid Malignancies With Focus on Myelodysplastic Syndrome, AML, and Germline Predisposition.

Myeloid malignancies are a manifestation of clonal expansion of hematopoietic cells driven by somatic genetic alterations that may arise in a potential background of deleterious germline variants. As next-generation sequencing technology has become more accessible, real-world experience has allowed integration of molecular genomic data with morphology, immunophenotype, and conventional cytogenetics to refine our understanding of myeloid malignancies. This has prompted revisions in the classification and the prognostication schema of myeloid malignancies and germline predisposition to hematologic malignancies. This review provides an overview of significant changes in the recently published classifications of AML and myelodysplastic syndrome, emerging prognostic scoring, and the role of germline deleterious variants in predisposing to MDS and AML.

Cross-sectional study examining household factors associated with SARS-CoV-2 seropositivity in low-income children in Los Angeles.

OBJECTIVES: This study aims to quantify the degree to which an underserved, Hispanic population in Los Angeles is impacted by SARS-CoV-2, and determine factors associated with paediatric seropositivity. DESIGN: Cross-sectional. SETTING: AltaMed, a Federally Qualified Health Center in Los Angeles. PARTICIPANTS: A random sample of households who had received healthcare at AltaMed Medical Group was invited to participate. Households with at least one adult and one paediatric participant between 5 and 17 years of age were eligible to participate. Consented participants completed a survey on social determinants of health and were tested for antibodies using Abbott Architect SARS-CoV-2-IgG and SARS-CoV-2-IgM tests. PRIMARY OUTCOME MEASURE: Seropositive status. RESULTS: We analysed 390 adults (mean age in years, 38.98 (SD 12.11)) and 332 paediatric participants (11.26 (SD 3.51)) from 196 households. Estimated seropositivity was 52.11% (95% CI 49.61% to 55.19%) in paediatric participants and 63.58% (95% CI 60.39% to 65.24%) in adults. Seropositivity was 11.47% (95% CI 6.82% to 14.09%) lower in paediatric participants, but high relative to other populations. A household member with type 2 diabetes (OR 2.94 (95% CI 1.68 to 5.14)), receipt of food stamps (OR 1.66 (95% CI 1.08 to 2.56)) and lower head-of-household education (OR 1.73 (95% CI 1.06 to 2.84)) were associated with paediatric seropositivity. CONCLUSIONS: SARS-CoV-2 seropositivity is high in Hispanic children and adolescents in Los Angeles. Food insecure households with low head-of-household education, and at least one household member with type 2 diabetes, had the highest risk. These factors may inform paediatrician COVID-19 mitigation recommendations. TRIAL REGISTRATION NUMBER: NCT04901624.

Chronic myeloid leukemia (CML) evolves from Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) with unexpected frequency.

Myeloproliferative neoplasms (MPN) are chronic clonal disorders characterized by overproduction of myeloid-lineage blood cells and potential risk of evolution to acute myeloid leukemia (AML). Chronic myeloid leukemia (CML) is distinct from other MPNs in that its pathophysiology stems from the BCR-ABL fusion protein of the Philadelphia chromosome (Ph +). Though there are known cases of Ph- and Ph + MPNs coexisting in a single patient, overall prevalence has never been quantified in a prospective cohort. Here, we review our center's MPN registry, which shows 0.6% of Ph- MPN patients later developed CML. This development occurred no less than 10 and up to 36 years after Ph- MPN diagnosis. This rate of chronic transformation exceeds what is expected, as the incidence of CML in the United States is 2 per 100,000 people-years. The probability of this CML case rate in an average-risk population is less than 0.001%, suggesting there are shared risk factors between Ph- and Ph + MPNs. We speculate that these risk factors may include exposures, genetic predispositions, or be inherent to disease biology. Abrupt-onset leukocytosis heralded post-MPN CML in all cases here and suggests this salient clinical feature should trigger hematologists to consider this diagnosis and perform appropriate testing.

Improving Quality and Safety for Patients After Hospital Discharge: Primary Care as the Lead Integrator in Postdischarge Care Transitions.

To understand current and idealized primary care-based care transition workflow processes for hospitalized patients, we conducted 133 interviews with staff at 9 primary care sites; community agency staff (n = 18); recently discharged patients (n = 33); and primary care thought leaders (n = 9). Current postdischarge workflows in primary care vary widely across settings, are often implemented inconsistently, and rarely involve communications with the patient or inpatient team during hospitalization. Based on these findings, we propose 5 principles for primary care practices to facilitate active involvement in postdischarge care, beginning during the hospital admission and extending until after the initial postdischarge primary care visit.

Myelodysplastic syndrome and autoimmune disorders: two sides of the same coin?

Systemic inflammatory and autoimmune diseases and myelodysplastic syndromes have been linked in individual patients and in larger case series for at least 25 years. These associations frequently include thyroid disease, neutrophilic dermatoses, polyarthritis, connective tissue diseases, vasculitis, and autoimmune cytopenias. Studies have found that autoimmune disease (or its therapy) is a risk factor for the development of myelodysplastic syndromes, but such syndromes might also be an instigator of autoimmune disease. Epidemiological studies examining disease risk in myelodysplastic syndromes with and without comorbid autoimmune illness have reached mixed conclusions. The pathophysiology of myelodysplastic syndromes is tightly linked to excessive inflammatory activity in the bone marrow microenvironment, which could promote systemic inflammatory and autoimmune diseases directly or by stimulation of the adaptive immune response. Alternatively, autoimmune diseases could promote clonal evolution and disordered bone marrow growth, promoting the development of myeloid malignancy. Additionally, therapy-related myeloid neoplasms-including myelodysplastic syndromes-have been diagnosed after treatment of autoimmune diseases with immunosuppressant therapies. These associations raise the following question: are myelodysplastic syndromes and systemic inflammatory and autoimmune diseases two sides of the same coin-that is, do they share an underlying disease state that can manifest as a myeloid neoplasm, an autoinflammatory illness, or both? VEXAS syndrome, which was first reported in 2020, is caused by a mutation that affects myeloid-restricted cells and manifests with both myelodysplasia and autoinflammation, and could give insight into this biological possibility. We note that systemic inflammatory and autoimmune diseases are often steroid-dependent; however, studies have also evaluated the roles of other immunomodulating therapies. In this Viewpoint, we critically appraise and review the literature on the epidemiology, pathophysiology, and management of systemic inflammatory and autoimmune diseases that are associated with myelodysplastic syndromes and related diseases.

Community-Based Health Care Navigation's Impact on Access to Primary Care for Low-Income Latinos.

INTRODUCTION: Despite the Affordable Care Act's insurance expansion, low-income Latinos are less likely to have a primary care provider compared with other racial/ethnic and income groups. We examined if community-based health care navigation could improve access to primary care in this population. METHODS: We surveyed adult clients of a community-based navigation program serving predominantly low-income Latinos throughout Los Angeles County in 2019. We used multivariable logistic regression models, adjusting for sociodemographic characteristics, to calculate odds ratios for differences in access to primary care and barriers to care between clients who had experienced approximately 1 year of navigation services (intervention group) and clients who were just introduced to navigation (comparison group). RESULTS: Clients in the intervention group were more likely to report having a primary care clinic than the comparison group (Adjusted Odds Ratio [aOR] 3.0, 95%CI: 1.7, 5.4). The intervention group was also significantly less likely to experience several barriers to care, such as not having insurance, not being able to pay for a visit, and not having transportation. CONCLUSIONS: Community-based navigation has the potential to reduce barriers and improve access to primary care for low-income Latinos. In addition to expanding insurance coverage, policymakers should invest in health care navigation to reduce disparities in primary care.

Impact of a school-level intervention on leisure-time physical activity levels on school grounds in under-resourced school districts.

Even the best school physical education programs fall short of providing enough physical activity (PA) to meet students' PA guidelines thus increasing PA at other times throughout the school day could help students meet recommended PA levels. Unstructured leisure-time periods during the school day represent an opportunity to promote PA, particularly among students in underserved school districts. Between 2014 and 2018, we partnered with 14 elementary and 5 secondary schools in low-income Latino communities to increase students' leisure time moderate to vigorous physical activity (MVPA). Schools received consultation and technical assistance on their wellness policy, and some created wellness committees. Schools selected 1-2 PA/nutrition promotion activities for the academic year. Following the System for Observing Play and Leisure Activity in Youth protocol, we conducted a pre- vs. post- analysis of observations of school time student PA (levels of MVPA, energy expenditure, proportion of areas in which games and sports were prominent) in 4936 pre-intervention play areas and 4404 post-intervention areas before school, during lunch recess, and after school. We utilized linear and logistic regression analyses to test pre/post changes in these dependent variables using school area characteristics, period of observation, and temperature as covariates. Following our intervention, MVPA levels before school, during lunch recess, and after school increased significantly from 19.8% at baseline to 25.6% among elementary girls and from 25.4% to 33.2% among elementary boys. Decomposition of these effects suggested that the benefits were partially mediated by increased adult playground supervision. We did not observe any significant changes in PA levels among secondary school girls or boys. Our school-level intervention aimed at promoting PA was associated with modest but meaningful increases in leisure-time PA among elementary, but not secondary, school students. The effects were attributable in part to increased adult supervision on the playground.

Allocation of scarce resources in a pandemic: rapid systematic review update of strategies for policymakers.

OBJECTIVE: In pandemics like COVID-19, the need for medical resources quickly outpaces available supply. policymakers need strategies to inform decisions about allocating scarce resources. STUDY DESIGN AND SETTING: We updated a systematic review on evidence-based approaches and searched databases through May 2020 for evaluation of strategies for policymakers. RESULTS: The 201 identified studies evaluated reducing demand for healthcare, optimizing existing resources, augmenting resources, and adopting crisis standards of care. Most research exists to reduce demand (n = 149); 39 higher quality studies reported benefits of contact tracing, school closures, travel restrictions, and mass vaccination. Of 28 strategies to augment resources, 6 higher quality studies reported effectiveness of establishing temporary facilities, use of volunteers, and decision support software. Of 23 strategies to optimize existing resources, 12 higher quality studies reported successful scope of work expansions and building on existing interagency agreements. Of 15 COVID-19 studies, 5 higher quality studies reported on combinations of policies and benefits of community-wide mask policies. CONCLUSION: Despite the volume, the evidence base is limited; few strategies were empirically tested in robust study designs. The review provides a comprehensive overview of the effects of strategies to allocate resources and provides critical appraisal to identify the best available evidence.

From the hospital to the streets: Bringing care to the unsheltered homeless in Los Angeles.

Homelessness is a neglected crisis throughout the United States. In Los Angeles (L.A.) County, nearly 59,000 residents are homeless, and the vast majority are unsheltered. An academic institution and L.A county's largest public hospital formed a partnership to launch a Street Medicine (SM) program. SM assists the inpatient team with discharge planning and builds rapport with the patient experiencing homelessness. After discharge, the SM team follows up and brings care to the patient on the streets, often developing a trusting relationship and establishing continuity of primary care. During a 12-month period, SM provided inpatient consults for 206 unsheltered homeless patients.

Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion.

Transduction of primary human natural killer (NK) cells with lentiviral vectors has historically been challenging. We sought to evaluate multiple parameters to optimize lentiviral transduction of human peripheral blood NK cells being expanded to large numbers using a good manufacturing practice (GMP)-compliant protocol that utilizes irradiated lymphoblastoid (LCL) feeder cells. Although prestimulation of NK cells with interleukin (IL)-2 for 2 or more days facilitated transduction with vesicular stomatitis virus glycoprotein (VSVG)-pseudotyped lentivirus, there was a subsequent impairment in the capacity of transduced NK cells to proliferate when stimulated with LCL feeder cells. In contrast, incubation of human NK cells with LCL feeder cells plus IL-2 before transduction in the presence of the TBK1 inhibitor BX795 resulted in efficient lentiviral integration (mean of 23% transgene+ NK cells) and successful subsequent proliferation of the transduced cells. Investigation of multiple internal promoter sequences within the same lentiviral vector revealed differences in percentage and level of transgene expression per NK cell. Bicistronic lentiviral vectors encoding both GFP and proteins suitable for the isolation of transduced cells with magnetic beads led to efficient transgene expression in NK cells. The optimized approaches described herein provide a template for protocols that generate large numbers of fully functional and highly purified lentivirus-transduced NK cells for clinical trials.