Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity

Opioid Overdoses Among High-Risk Medicaid Members: Healthcare Cost, Service Utilization, and Risk Factor Analysis

Research Objective: Identify risk factors associated with opioid overdoses among three high-risk populations of Medicaid members related to cost and service utilization. Study Design: Repeated cross-sectional study using five years of Massachusetts Medicaid (MassHealth) claims and state agency data. Population Studied: MassHealth members aged 11-64 years considered to be high-risk (homeless, unstably housed, and/or criminal justice-involved) and in need of support services, especially those with extensive behavioral health (BH) needs. These three populations were identified as being particularly vulnerable to non-fatal and/or fatal opioid overdoses. Principal Findings: MassHealth members who were both justice-involved and unstably housed were at much higher risk of an opioid overdose than the MassHealth population overall, especially those with a substance use disorder (SUD) or a serious mental illness (SMI). Experiencing both homelessness and justice involvement substantially compounded members’ non-fatal overdose risk, regardless of BH diagnosis. Co-occurring SUD/SMI was a key driver of high overdose prevalence, particularly among the justice-involved. Compared to MassHealth members in general, those with justice involvement and unstable housing had costs that were 50-65% higher; members who experienced homelessness had triple the costs. Healthcare service use both before and after an overdose was relatively low, including the timeframe between multiple non-fatal overdoses. In multivariate analyses, all three high-risk factors (i.e., populations) were significantly related to an increased opioid overdose risk after controlling for additional risk factors (BH diagnoses, chronic medical conditions, and demographic characteristics). Males and whites were more likely to have an opioid overdose; those with diabetes or hypertension were less likely. These results were similar when assessing various opioid overdose outcomes (non-fatal and/or fatal). Conclusions: These findings helped inform MassHealth’s understanding of its members’ experiences regarding medical and BH services, especially among high-risk populations with an opioid overdose. The identification of risk factors most predictive of a subsequent overdose may help address the needs of these high-risk groups. For most of the populations studied, prevalence of co-occurring BH diagnoses was much higher than MassHealth members in general and appeared to impact opioid overdose rates. Most members received services for 1-2 months in both the pre- and post-overdose periods; service use was relatively low in the year following a non-fatal overdose, suggesting retention was also low. Multivariate analyses consistently showed that gender and race were significantly associated with increased overdose risk. Implications for Policy or Practice: Understanding opioid overdose risk factors and identifying service utilization gaps and missed opportunities are important. As payment reforms evolve under the umbrella of accountable care organizations, BH community partnership models are key for collaborating with healthcare and social service providers, and community resources for care management, care coordination, and referrals to support services. Our study initially developed an in-depth descriptive analysis of individuals with SUD, SMI, or both identified as being at high risk for an opioid overdose. Understanding service trajectory and outcomes through additional analyses was critical for planning and prioritizing appropriate services. As payors are actively making decisions about effective systems of care, they are particularly interested in understanding the need for community-based and residential services, particularly for those with housing instability and/or criminal justice involvement

A classification model of homelessness using integrated administrative data: Implications for targeting interventions to improve the housing status, health and well-being of a highly vulnerable population

Homelessness is poorly captured in most administrative data sets making it difficult to understand how, when, and where this population can be better served. This study sought to develop and validate a classification model of homelessness. Our sample included 5,050,639 individuals aged 11 years and older who were included in a linked dataset of administrative records from multiple state-maintained databases in Massachusetts for the period from 2011-2015. We used logistic regression to develop a classification model with 94 predictors and subsequently tested its performance. The model had high specificity (95.4%), moderate sensitivity (77.8%) for predicting known cases of homelessness, and excellent classification properties (area under the receiver operating curve 0.94; balanced accuracy 86.4%). To demonstrate the potential opportunity that exists for using such a modeling approach to target interventions to mitigate the risk of an adverse health outcome, we also estimated the association between model predicted homeless status and fatal opioid overdoses, finding that model predicted homeless status was associated with a nearly 23-fold increase in the risk of fatal opioid overdose. This study provides a novel approach for identifying homelessness using integrated administrative data. The strong performance of our model underscores the potential value of linking data from multiple service systems to improve the identification of housing instability and to assist government in developing programs that seek to improve health and other outcomes for homeless individuals

Cytokine production pattern of T lymphocytes in neonatal arterial ischemic stroke during the first month of life

BACKGROUND: The perinatal period carries the highest risk for stroke in childhood; however, the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available. A new pathophysiological model describes the development of neonatal arterial ischemic stroke (NAIS) as the combined result of prenatal inflammation and hypoxic-ischemic insult. Neuroinflammation and a systemic inflammatory response are also important features of NAIS. Identifying key players of the inflammatory system is in the limelight of current research. CASE PRESENTATION: We present four NAIS cases, in whom detailed analysis of intracellular and plasma cytokine levels are available from the first month of life. All neonates were admitted with the initial diagnosis of hypoxic ischemic encephalopathy (HIE); however, early MRI examination revealed NAIS. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Peripheral blood mononuclear cells were assessed with flow cytometry and plasma cytokine levels were measured. Pooled data from the cohort of four NAIS patients were compared to infants with HIE. At 6 and 72 h of age, the prevalence of IL10+ CD8+ lymphocytes remained lower in NAIS. At 6 h, CD8+ lymphocytes in NAIS produced more IL-17. At 72 h, CD8+ cells produced more IL-6 in severe HIE than in NAIS, but IL-6 production remained elevated in CD8 cells at 1 month in NAIS, while it decreased in HIE. At 1 week, the prevalence of TGF-beta + lymphocytes prone to enter the CNS was elevated in NAIS. On the other hand, by 1 month of age, the prevalence of TGF-beta + CD4+ lymphocytes decreased in NAIS compared to HIE. At 72 h, we found elevated plasma levels of IL-5, MCP-1, and IL-17 in NAIS. By 1 month, plasma levels of IL-4, IL-12, and IL-17 decreased in NAIS but remained elevated in HIE. CONCLUSIONS: Differences in the cytokine network are present between NAIS and HIE. CD8 lymphocytes appear to shift towards the pro-inflammatory direction in NAIS. The inflammatory response appears to be more pronounced at 72 h in NAIS but decreases faster, reaching lower plasma levels of inflammatory markers at 1 month

Overdose risk for veterans receiving opioids from multiple sources

OBJECTIVES: The aim of this study was to evaluate whether veterans in Massachusetts receiving opioids and/or benzodiazepines from both Veterans Health Administration (VHA) and non-VHA pharmacies are at higher risk of adverse events compared with those receiving opioids at VHA pharmacies only. STUDY DESIGN: A cohort study of veterans who filled a prescription for any Schedule II through V substance at a Massachusetts VHA pharmacy. Prescriptions were recorded in the Massachusetts Department of Public Health Chapter 55 data set. METHODS: The study sample included 16,866 veterans residing in Massachusetts, of whom 9238 (54.8%) received controlled substances from VHA pharmacies only and 7628 (45.2%) had filled prescriptions at both VHA and non-VHA pharmacies ( dual care users ) between October 1, 2013, and December 31, 2015. Our primary outcomes were nonfatal opioid overdose, fatal opioid overdose, and all-cause mortality. RESULTS: Compared with VHA-only users, more dual care users resided in rural areas (12.6% vs 10.6%), received high-dose opioid therapy (26.3% vs 7.3%), had concurrent prescriptions of opioids and benzodiazepines (34.8% vs 8.2%), and had opioid use disorder (6.8% vs 1.6%) (P \u3c .0001 for all). In adjusted models, dual care users had higher odds of nonfatal opioid overdose (odds ratio [OR], 1.29; 95% CI, 0.98-1.71) and all-cause mortality (OR, 1.66; 95% CI, 1.43-1.93) compared with VHA-only users. Dual care use was not associated with fatal opioid overdoses. CONCLUSIONS: Among veterans in Massachusetts, receipt of opioids from multiple sources was associated with worse outcomes, specifically nonfatal opioid overdose and mortality. Better information sharing between VHA and non-VHA pharmacies and prescribers has the potential to improve patient safety

Massachusetts Prevalence of Opioid Use Disorder Estimation Revisited: Comparing a Bayesian Approach to Standard Capture–Recapture Methods

Background: The National Survey on Drug Use and Health (NSDUH) estimated the prevalence of opioid use disorder (OUD) among the civilian, noninstitutionalized people aged 12 years or older in Massachusetts as 1.2% between 2015 and 2017. Accurate estimation of the prevalence of OUD is critical to the success of treatment and resource planning. Various indirect estimation approaches have been used but are subject to data availability and infrastructure-related issues. Methods: We used 2015 data from the Massachusetts Public Health Data Warehouse (PHD) to compare the results of two approaches to estimating OUD prevalence in the Massachusetts population. First, we used a seven-dataset capture–recapture analysis under log–linear model parameterization, controlling for the source dependence and effects of age, sex, and county through stratification. Second, we applied a benchmark-multiplier method in a Bayesian framework by linking health care claims data to death certificate data assuming an extrapolation of death rates from observed untreated OUD to unobserved OUD. Results: Our estimates for OUD prevalence among Massachusetts residents (aged 18–64 years) were 4.62% (95% CI = 4.59%, 4.64%) in the capture–recapture approach and 4.29% (95% CrI = 3.49%, 5.32%) in the Bayesian model. Both estimates were approximately four times higher than NSDUH estimates. Conclusion: The synthesis of our findings suggests that the disease surveillance system misses a large portion of the population with OUD. Our study also suggests that concurrent use of multiple methods improves the justification and facilitates the triangulation and interpretation of the resulting estimates. Trial registration: ClinicalTrials.gov Identifier: NCT04111939

Cytomegalovirus serostatus affects autoreactive NK cells and outcomes of IL2-based immunotherapy in acute myeloid leukemia

Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML