Normothermic liver perfusion derived extracellular vesicles have concentration-dependent immunoregulatory properties.

Extracellular vesicles (EVs) are major contributors to immunological responses following solid organ transplantation. Donor derived EVs are best known for their role in transplant rejection through transferring donor major histocompatibility complex proteins to recipient antigen presenting cells, a phenomenon known as ?cross-decoration'. In contrast, donor liver-derived EVs are associated with organ tolerance in small animal models. Therefore, the cellular source of EVs and their cargo could influence their downstream immunological effects. To investigate the immunological effects of EVs released by the liver in a physiological and transplant-relevant model, we isolated EVs being produced during normothermic ex vivo liver perfusion (NEVLP), a novel method of liver storage prior to transplantation. We found EVs were produced by the liver during NEVLP, and these EVs contained multiple anti-inflammatory miRNA species. In terms of function, liver-derived EVs were able to cross-decorate allogeneic cells and suppress the immune response in allogeneic mixed lymphocyte reactions in a concentration-dependent fashion. In terms of cytokine response, the addition of 1 × 109 EVs to the mixed lymphocyte reactions significantly decreased the production of the inflammatory cytokines TNF-α, IL-10 and IFN-γ. In conclusion, we determined physiologically produced liver-derived EVs are immunologically regulatory, which has implications for their role and potential modification in solid organ transplantation.

The Immunological Effect of Oxygen Carriers on Normothermic Ex Vivo Liver Perfusion.

Introduction: Normothermic ex vivo liver perfusion (NEVLP) is an organ preservation method that allows liver graft functional assessment prior to transplantation. One key component of normothermic perfusion solution is an oxygen carrier to provide oxygen to the liver to sustain metabolic activities. Oxygen carriers such as red blood cells (RBCs) or hemoglobin-based oxygen carriers have an unknown effect on the liver-resident immune cells during NEVLP. In this study, we assessed the effects of different oxygen carriers on the phenotype and function of liver-resident immune cells. Methods: Adult Lewis rat livers underwent NEVLP using three different oxygen carriers: human packed RBCs (pRBCs), rat pRBCs, or Oxyglobin (a synthetic hemoglobin-based oxygen carrier). Hourly perfusate samples were collected for downstream analysis, and livers were digested to isolate immune cells. The concentration of common cytokines was measured in the perfusate, and the immune cells underwent phenotypic characterization with flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The stimulatory function of the liver-resident immune cells was assessed using mixed lymphocyte reactions. Results: There were no differences in liver function, liver damage, or histology between the three oxygen carriers. qRT-PCR revealed that the gene expression of nuclear factor κ light chain enhancer of activated B cells (NF-kB), Interleukin (IL-1ß), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 7 (CCL7), and CD14 was significantly upregulated in the human pRBC group compared with that in the naive, whereas the rat pRBC and Oxyglobin groups were not different from that of naive. Flow cytometry demonstrated that the cell surface expression of the immune co-stimulatory protein, CD86, was significantly higher on liver-resident macrophages and plasmacytoid dendritic cells perfused with human pRBC compared to Oxyglobin. Mixed lymphocyte reactions revealed increased allogeneic T-cell proliferation in the human and rat pRBC groups compared to that in the Oxyglobin group. Conclusions: Liver-resident immune cells are important mediators of rejection after transplantation. In this study, we show that the oxygen carrier used in NEVLP solutions can affect the phenotype of these liver-resident immune cells. The synthetic hemoglobin-based oxygen carrier, Oxyglobin, showed the least amount of liver-resident immune cell activation and the least amount of allogeneic proliferation when compared to human or rat pRBCs. To mitigate liver-resident immune cell activation during NEVLP (and subsequent transplantation), Oxyglobin may be an optimal oxygen carrier.

Single-cell RNA sequencing distinguishes dendritic cell subsets in the rat, allowing advanced characterization of the effects of FMS-like tyrosine kinase 3 ligand.

Tissue-resident dendritic cells (DCs) are essential for immunological homeostasis and hold promise for a variety of therapeutic interventions. The rare nature of tissue-resident DCs and their suboptimal description in the lab rat model has limited their characterization. To address this limitation, FMS-like tyrosine kinase 3 ligand (FLT3L) has been utilized to expand these population in vitro and in vivo for investigative or therapeutic purposes. However, conflicting reports have suggested that FLT3L can either promote immune tolerance or enhance immunogenicity, necessitating clarification of the effects of FLT3L on DC phenotype and functionality. We first paired single-cell RNA sequencing with multicolour spectral flow cytometry to provide an updated strategy for the identification of tissue-resident classical and plasmacytoid DCs in the rat model. We then administered FLT3L to Lewis rats in vivo to investigate its effect on tissue-resident DC enumeration and phenotype in the liver, spleen, and mesenteric lymph nodes. We found that FLT3L expands classical DCs (cDCs) 1 and 2 in a dose-dependent manner and that cDC1 and cDC2 in secondary lymphoid organs had altered MHC I, MHC II, CD40, CD80, CD86, and PD-L1 cell-surface expression levels following FLT3L administration. These changes were accompanied by an increase in gene expression levels of toll-like receptors 2, 4, 7, and 9 as well as inflammatory cytokines IL-6 and TNF-α. In conclusion, FLT3L administration in vivo increases cDC enumeration in the liver, spleen, and mesenteric lymph nodes accompanied by a tissue-restricted alteration in expression of antigen presentation machinery and inflammatory mediators.

How did the Affordable Care Act Medicaid Expansion Affect Coverage and Access to Care for Low-Income Parents Who Were Eligible for Medicaid Before the Law Was Passed?

We use the National Health Interview Survey from 2010 to 2017 and a difference-in-differences approach to assess the impact of the Affordable Care Cct (ACA) Medicaid expansion on coverage and access to care for a subset of low-income parents who were already eligible for Medicaid when the ACA was passed. Any gains in coverage would typically be expected to improve access to and affordability of care, but there were concerns that by increasing the total population with coverage and thereby straining provider capacity, that the ACA would reduce access to care for individuals who were already eligible for Medicaid prior to the passage of the law. We found that the expansion reduced uninsurance among previously eligible parents by 12.6 percentage points, or a 40 percent decline from their 2012-2013 uninsurance rate. Moreover, these effects grew stronger over time with a 55 percent decline in uninsurance 2 to 3 years following expansion. Though we identified very few statistically significant impacts of the expansion on affordability of care, descriptive estimates show substantial declines in unmet needs due to cost and problems paying family medical bills. Descriptively, we find no significant increases in provider access problems for previously eligible parents, and very limited evidence that the Medicaid expansion was associated with more constrained provider capacity. Though sample size constraints were likely a factor in our ability to identify impacts on access and affordability measures, our overall findings suggest that the ACA Medicaid expansion positively affected our sample of low-income parents who met pre-ACA Medicaid eligibility criteria.

Post-ACA, More Than One-Third Of Women With Prenatal Medicaid Remained Uninsured Before Or After Pregnancy.

Medicaid has a long history of serving pregnant women, but many women are not eligible for Medicaid before pregnancy or after sixty days postpartum. We used data for new mothers with Medicaid-covered prenatal care in 2015-18 from forty-three states participating in the Pregnancy Risk Assessment Monitoring System (PRAMS) to describe patterns of perinatal uninsurance and health outcomes of women experiencing uninsurance. We found that 26.8 percent of new mothers with Medicaid-covered prenatal care were uninsured before pregnancy, 21.9 percent became uninsured two to six months postpartum, and 34.5 percent were uninsured in either period, with higher perinatal uninsurance rates in nonexpansion states and for Hispanic women who completed the PRAMS survey in Spanish. Together, our findings indicate that despite recent coverage gains, further policy change is needed to help women maintain health insurance coverage before and after pregnancy and to allow them to address ongoing health issues including obesity and depression.

Stabilizing and Strengthening the Affordable Care Act: Opportunities for a New Administration.

For the past decade, the Affordable Care Act (ACA) has successfully reduced uninsurance and improved access to and affordability of health care services for millions of Americans. But the law was weakened when the Trump administration shortened the open enrollment period in the federal Marketplace, reduced outreach and enrollment funding, and revised the public charge rule, among other actions. The Biden administration will have the chance to reverse some of these changes and further strengthen the law to improve health care access and affordability. In this article, the author explores options for expanding access to affordable coverage and care for those who do not qualify for Medicaid or marketplace financial assistance and further discusses opportunities for increasing enrollment among those who are already eligible. The author also examines opportunities for expanding access to specific services, including reproductive health care, among those with insurance. Any attempts to modify or build on the ACA will likely be complicated by the ongoing coronavirus pandemic as well as slim Democratic majorities in the House and Senate, but regulatory solutions will likely be easier to achieve than those that require changes to federal law or state policy.

ACA Medicaid Expansion and Insurance Coverage Among New Mothers Living in Poverty.

BACKGROUND: Medicaid plays a critical role during the perinatal period, but pregnancy-related Medicaid eligibility only extends for 60 days post partum. In 2014, the Affordable Care Act's (ACA's) Medicaid expansions increased adult Medicaid eligibility to 138% of the federal poverty level in participating states, allowing eligible new mothers to remain covered after pregnancy-related coverage expires. We investigate the impact of ACA Medicaid expansions on insurance coverage among new mothers living in poverty. METHODS: We define new mothers living in poverty as women ages 19 to 44 with incomes below the federal poverty level who report giving birth in the past 12 months. We use 2010-2017 American Community Survey data and a difference-in-differences approach using parental Medicaid-eligibility thresholds to estimate the effect of ACA Medicaid expansions on insurance coverage among poor new mothers. RESULTS: A 100-percentage-point increase in parental Medicaid-eligibility is associated with an 8.8-percentage-point decrease (P < .001) in uninsurance, a 13.2-percentage-point increase (P < .001) in Medicaid coverage, and a 4.4-percentage-point decrease in private or other coverage (P = .001) among poor new mothers. The average increase in Medicaid eligibility is associated with a 28% decrease in uninsurance, a 13% increase in Medicaid coverage, and an 18% decline in private or other insurance among poor new mothers in expansion states. However, in 2017, there were ∼142 000 remaining uninsured, poor new mothers. CONCLUSIONS: ACA Medicaid expansions are associated with increased Medicaid coverage and reduced uninsurance among poor new mothers. Opportunities remain for expansion and nonexpansion states to increase insurance coverage among new mothers living in poverty.

Ten Years Later: Reflections on Critics' Worst-Case Scenarios for the Affordable Care Act.

The primary goals of the Affordable Care Act (ACA) were to increase the availability and affordability of health insurance coverage and thereby improve access to needed health care services. Numerous studies have overwhelmingly confirmed that the law has reduced uninsurance and improved affordability of coverage and care for millions of Americans. Not everyone believed that the ACA would lead to positive outcomes, however. Critics raised numerous concerns in the years leading up to the law's passage and full implementation, including about its consequences for national health spending, labor supply, employer health insurance markets, provider capacity, and overall population health. This article considers five frequently heard worst-case scenarios related to the ACA and provides research evidence that these fears did not come to pass.

The Relationship Between Insurance Coverage and Use of Prescription Contraception by Race and Ethnicity: Lessons From the Affordable Care Act.

BACKGROUND: We describe contraception use by race and ethnicity before and after the Affordable Care Act (ACA) and assess the relationship between insurance coverage and prescription contraception use in both periods. STUDY DESIGN: Using data for women ages 15 to 45 at risk of unintended pregnancy from the 2006-2010 and 2015-2017 National Surveys of Family Growth, we examined changes in patterns of contraception use over time by race and ethnicity. We also examined changes in insurance coverage over the same period and considered how the relationship between insurance coverage and prescription contraception use has changed over time within each racial and ethnic group using both descriptive and multivariate regression methods. RESULTS: Before the ACA, Black and Hispanic women were less likely than White women to use prescription contraception by 13.2 and 9.9 percentage points, respectively. After the ACA Medicaid and Marketplace coverage expansions, all groups experienced a decrease in uninsurance, but only Black women experienced a significant increase in prescription contraception use. As a result, the post-ACA Black-White difference in prescription contraception use narrowed to 3.9 percentage points, and the Hispanic-White gap remained unchanged. CONCLUSIONS: Our results suggest that, despite significant declines in uninsurance under the ACA, there was no increase in use of prescription contraception for White or Hispanic women. Moreover, the decrease in uninsurance among Black women did not fully explain the large increase in use of prescription contraception for this population.

Off-Marketplace Enrollment Remains An Important Part Of Health Insurance Under The ACA.

The introduction of Marketplaces under the Affordable Care Act greatly expanded individual-market health insurance coverage in 2014, but millions of adults continued to purchase individual coverage outside of the Marketplaces. They were more likely to be male, be white, have higher incomes, and be in excellent or very good health, compared to Marketplace enrollees.

Medicaid Expansion Increased Coverage, Improved Affordability, And Reduced Psychological Distress For Low-Income Parents.

Despite receiving less attention than their childless counterparts, low-income parents also experienced significant expansions of Medicaid eligibility under the Affordable Care Act (ACA). We used data for the period 2010-15 from the National Health Interview Survey to examine the impacts of the ACA's Medicaid expansion on coverage, access and use, affordability, and health status for low-income parents. We found that eligibility expansions increased coverage, reduced problems paying medical bills, and reduced severe psychological distress. We found only limited evidence of increased use of care among parents in states with the smallest expansions, and no significant effects of the expansions on general health status or problems affording prescription drugs or mental health care. Together, our results suggest that the improvements in mental health status may be driven by reduced stress associated with improved financial security from insurance coverage. We also found large missed opportunities for low-income parents in states that did not expand Medicaid: If these states had expanded Medicaid, uninsurance rates for low-income parents would have fallen by an additional 28 percent.

Marketplaces Helped Drive Coverage Gains In 2015; Affordability Problems Remained.

Health insurance coverage through the Marketplaces increased in 2015, with more nonelderly adult enrollees insured all year and fewer reporting health care affordability problems than in 2014. In 2015 more Marketplace enrollees in Medicaid nonexpansion states reported trouble paying family medical bills, compared to those in expansion states (23 percent versus 15 percent).

Medicaid Expansions from 1997 to 2009 Increased Coverage and Improved Access and Mental Health Outcomes for Low-Income Parents.

OBJECTIVE: To assess the effects of past Medicaid eligibility expansions to parents on coverage, access to care, out-of-pocket (OOP) spending, and mental health outcomes, and consider implications for the Affordable Care Act (ACA) Medicaid expansion. DATA SOURCES: Person-level data from the National Health Interview Survey (1998-2010) is used to measure insurance coverage and related outcomes for low-income parents. Using state identifiers available at the National Center for Health Statistics Research Data Center, we attach state Medicaid eligibility thresholds for parents collected from a variety of sources to NHIS observations. STUDY DESIGN: We use changes in the Medicaid eligibility threshold for parents within states over time to identify the effects of changes in eligibility on low-income parents. PRINCIPAL FINDINGS: We find that expanding Medicaid eligibility increases insurance coverage, reduces unmet needs due to cost and OOP spending, and improves mental health status among low-income parents. Moreover, our findings suggest that uninsured populations in states not currently participating in the ACA Medicaid expansion would experience even larger improvements in coverage and related outcomes than those in participating states if they chose to expand eligibility. CONCLUSIONS: The ACA Medicaid expansion has the potential to improve a wide variety of coverage, access, financial, and health outcomes for uninsured parents in states that choose to expand coverage.

Insurance Coverage and Access to Care Under the Affordable Care Act.

This brief details changes in insurance coverage and access to care under the Affordable Care Act. About 20 million individuals gained coverage under the law and access to care improved. Despite these gains, more than 27 million individuals are still uninsured, and many others face barriers in accessing care. As a result of the 2016 elections, the future of the ACA is uncertain. As the next Administration and policymakers debate further health system reforms, they should consider the scope of the ACA's effects on their constituents.

California's Early Coverage Expansion under the Affordable Care Act: A County-Level Analysis.

OBJECTIVE: To assess the coverage effects of California's 2011 Low-Income Health Program (LIHP), enacted as an "early expansion" under the Affordable Care Act (ACA), and to demonstrate the feasibility of using Census data to measure county-level coverage changes. DATA SOURCES/STUDY SETTING: 2008-2012 American Community Survey (ACS). The sample contained California adults ages 19-64 years (n = 237,876) and children 0-18 years (n = 113,159) with incomes below 200 percent of the federal poverty level. STUDY DESIGN: Differences-in-differences analysis comparing public coverage, private insurance, and the uninsured rate in counties that expanded the LIHP in 2011 versus California counties not expanding during this time. Additional analyses tested for heterogeneous impacts of the LIHP and spillover effects on children. PRINCIPAL FINDINGS: Compared to nonexpansion counties, public coverage for adults increased by 1.8 percentage points (p = .02) in expanding counties, while the uninsured rate declined by 2.1 percentage points (p = .01). There was no significant change in private coverage. Public coverage gains were largest for Latinos and those with limited English proficiency. The expansion produced a positive spillover effect on children's Medicaid enrollment. CONCLUSIONS: California's 2011 expansion produced significant increases in public coverage for low-income individuals, particularly Latinos. Substate coverage analyses with the ACS can add valuable detail to future assessments of the ACA.

Primary Care Providers Ordered Fewer Preventive Services For Women With Medicaid Than For Women With Private Coverage.

As the number of beneficiaries in the Medicaid program grows under the Affordable Care Act, with over half of the states opting to expand Medicaid eligibility, it is important to understand more about the care provided to Medicaid patients. Using visit-level data for 2006-10 from the National Ambulatory Medical Care Survey, we examined the provision of recommended preventive services to women with Medicaid and those with private insurance at visits to primary care providers in private office-based practices. We found that after patient and provider characteristics were controlled for, Medicaid-insured visits were less likely than privately insured visits to include several preventive services, including clinical breast exams and Pap tests. The differences in provision of services by payer were generally driven by the differences in care at visits classified as preventive and at visits to obstetrician-gynecologists. Further investigation is required to determine what may be driving the differences in content of care across payers and their implications for quality of care.

Access to Private Coverage for Children Enrolled in CHIP.

OBJECTIVE: To provide updated information on the potential substitution of public for private coverage among low-income children by examining the type of coverage held by children before they enrolled in Children's Health Insurance Program (CHIP) and exploring the extent to which children covered by CHIP had access to private coverage while they were enrolled. METHODS: We conducted a major household telephone survey in 2012 of enrollees and disenrollees in CHIP in 10 states. We used the survey responses and Medicaid/CHIP administrative data to estimate the coverage distribution of all new enrollees in the 12 months before CHIP enrollment and to identify children who may have had access to employer coverage through one of their parents while enrolled in CHIP. RESULTS: About 13% of new enrollees had any private coverage in the 12 months before enrolling in CHIP, and most were found to have lost that coverage as a result of parental job loss. About 40% of CHIP enrollees had a parent with an employer-sponsored insurance (ESI) policy, but only half reported that the policy could cover the child. Approximately 30% of new enrollees had public coverage during the year before but were uninsured just before enrolling. CONCLUSIONS: Access to private coverage among CHIP enrollees is relatively limited. Furthermore, even when there is potential access to ESI, affordability is a serious concern for parents, making it possible that many children with access to ESI would remain uninsured in the absence of CHIP.

Associations between practice-reported medical homeness and health care utilization among publicly insured children.

BACKGROUND: The patient-centered medical home (PCMH) is widely promoted as a model to improve the quality of primary care and lead to more efficient use of health care services. Few studies have examined the relationship between PCMH implementation at the practice level and health care utilization by children. Existing studies show mixed results. METHODS: Using practice-reported PCMH assessments and Medicaid claims from child-serving practices in 3 states participating in the Children's Health Insurance Program Reauthorization Act of 2009 Quality Demonstration Grant Program, this study estimates the association between medical homeness (tertiles) and receipt of well-child care and nonurgent, preventable, or avoidable emergency department (ED) use. Multilevel logistic regression models are estimated on data from 32 practices in Illinois (IL) completing the National Committee for Quality Assurance's (NCQA) medical home self-assessment and 32 practices in North Carolina (NC) and South Carolina (SC) completing the Medical Home Index (MHI) or Medical Home Index-Revised Short Form (MHI-RSF). RESULTS: Medical homeness was not associated with receipt of age-appropriate well-child visits in either sample. Associations between nonurgent, preventable, or avoidable ED visits and medical homeness varied. No association was seen among practices in NC and SC that completed the MHI/MHI-RSF. Children in practices in IL with the highest tertile NCQA self-assessment scores were less likely to have a nonurgent, preventable, or avoidable ED visit than children in practices with low (odds ratio 0.65; 95% confidence interval 0.47-0.92; P < .05) and marginally less likely to have such a visit compared with children in practices with medium tertile scores (odds ratio 0.72, 95% confidence interval 0.52-1.01; P = .06). CONCLUSIONS: Higher levels of medical homeness may be associated with lower nonurgent, preventable, or avoidable ED use by publicly insured children. Robust longitudinal studies using multiple measures of medical homeness are needed to confirm this observation.