Circulating extracellular vesicles from patients with acute chest syndrome disrupt adherens junctions between endothelial cells.

BACKGROUND: Small cell-derived extracellular vesicles (EVs) can affect endothelial function. We previously found that patients with sickle cell disease (SCD) have greater numbers of circulating EVs than subjects without the disease, and the EVs differentially disrupt endothelial integrity in vitro. Because endothelial disruption is a critical component of acute chest syndrome (ACS), we hypothesized that EVs isolated during ACS would induce greater endothelial damage than those isolated at baseline. METHODS: Nine pediatric subjects had plasma isolated at baseline and during ACS from which EVs were isolated. Cultured microvascular endothelial cells were treated with EVs and then studied by immunofluorescence microscopy to localize VE-cadherin and F-actin. RESULTS: The EVs had a diameter of 95 nm. They contained CD63 and flotillin-1, which were increased in SCD patients (5-13-fold compared to control) and further increased between baseline and ACS (24-57%). The EVs contained hemoglobin, glycophorin A, and ferritin. Treatment with baseline EVs caused modest separation of endothelial cells, while ACS EVs caused substantial disruptions of the endothelial cell monolayers. EVs from subjects with ACS also caused a 50% decrease in protein levels of VE-cadherin. CONCLUSIONS: These results suggest that circulating EVs can modulate endothelial integrity contributing to the development of ACS in SCD patients by altering cadherin-containing intercellular junctions. IMPACT: Sickle cell disease patients have circulating extracellular vesicles (EVs) that modulate endothelial integrity by altering cadherin-containing intercellular junctions. Disruption is more severe by EVs obtained during acute chest syndrome (ACS). These results expand our knowledge of the pathophysiology of acute chest syndrome and the vasculopathies of sickle cell disease.

Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease.

BACKGROUND: Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions. METHODS: This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated. RESULTS: Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals. CONCLUSION: aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD.

Health Care Spending Effectiveness: Estimates Suggest That Spending Improved US Health From 1996 To 2016.

Health care spending effectiveness is the ratio of an increase in spending per case of illness or injury to an increase in disability-adjusted life-years (DALYs) averted per case. We report US spending-effectiveness ratios, using comprehensive estimates of health care spending from the Disease Expenditure Project and DALYs from the Global Burden of Disease Study 2017. We decomposed changes over time to estimate spending per case and DALYs averted per case, controlling for changes in population size, age-sex structure, and incidence or prevalence of cases. Across all causes of health care spending and disease burden, median spending was US$114,339 per DALY averted between 1996 and 2016. Twelve of thirty-four causes with the highest spending or highest burden had median spending that was less than $100,000 per DALY averted. Using decomposition results, we calculated an outcome-adjusted health care price index by assigning a dollar value to DALYs averted per case. When we used $100,000 as the dollar value per DALY averted, prices increased by 4 percent more than the broader economy; when we used $150,000 per DALY averted, relative prices fell by 13 percent, meaning that much of the growth in health care spending over time has purchased health improvements.

Cost-effectiveness of rotavirus vaccination in children under five years of age in 195 countries: A meta-regression analysis.

BACKGROUND: Rotavirus caused an estimated 151,714 deaths from diarrhea among children under 5 in 2019. To reduce mortality, countries are considering adding rotavirus vaccination to their routine immunization program. Cost-effectiveness analyses (CEAs) to inform these decisions are not available in every setting, and where they are, results are sensitive to modeling assumptions, especially about vaccine efficacy. We used advances in meta-regression methods and estimates of vaccine efficacy by location to estimate incremental cost-effectiveness ratios (ICERs) for rotavirus vaccination in 195 countries. METHODS: Beginning with Tufts University CEA and Global Health CEA registries we used 515 ICERs from 68 articles published through 2017, extracted 938 additional one-way sensitivity analyses, and excluded 33 ICERs for a sample of 1,418. We used a five-stage, mixed-effects, Bayesian metaregression framework to predict ICERs, and logistic regression model to predict the probability that the vaccine was cost-saving. For both models, covariates were vaccine characteristics including efficacy, study methods, and country-specific rotavirus disability-adjusted life-years (DALYs) and gross domestic product (GDP) per capita. All results are reported in 2017 United States dollars. RESULTS: Vaccine efficacy, vaccine cost, GDP per capita and rotavirus DALYs were important drivers of variability in ICERs. Globally, the median ICER was $2,289 (95% uncertainty interval (UI): $147-$38,993) and ranged from $85 per DALY averted (95% UI: $13-$302) in Central African Republic to $70,599 per DALY averted (95% UI: $11,030-$263,858) in the United States. Among countries eligible for support from Gavi, The Vaccine Alliance, the mean ICER was $255 per DALY averted (95% UI: $39-$918), and among countries eligible for the PAHO revolving fund, the mean ICER was $2,464 per DALY averted (95% UI: $382-$3,118). CONCLUSION: Our findings incorporate recent evidence that vaccine efficacy differs across locations, and support expansion of rotavirus vaccination programs, particularly in countries eligible for support from Gavi, The Vaccine Alliance.

Variation in Health Care Access and Quality Among US States and High-Income Countries With Universal Health Insurance Coverage.

Importance: Based on mortality estimates for 32 causes of death that are amenable to health care, the US health care system did not perform as well as other high-income countries, scoring 88.7 out of 100 on the 2016 age-standardized Healthcare Access and Quality (HAQ) index. Objective: To compare US age-specific HAQ scores with those of high-income countries with universal health insurance coverage and compare scores among US states with varying insurance coverage. Design, Setting, and Participants: This cross-sectional study used 2016 Global Burden of Diseases, Injuries, and Risk Factor study results for cause-specific mortality with adjustments for behavioral and environmental risks to estimate the age-specific HAQ indices. The US national age-specific HAQ scores were compared with high-income peers (Canada, western Europe, high-income Asia Pacific countries, and Australasia) in 1990, 2000, 2010, and 2016, and the 2016 scores among US states were also analyzed. The Public Use Microdata Sample of the American Community Survey was used to estimate insurance coverage and the median income per person by age and state. Age-specific HAQ scores for each state in 2010 and 2016 were regressed based on models with age fixed effects and age interaction with insurance coverage, median income, and year. Data were analyzed from April to July 2018 and July to September 2020. Main Outcomes and Measures: The age-specific HAQ indices were the outcome measures. Results: In 1990, US age-specific HAQ scores were similar to peers but increased less from 1990 to 2016 than peer locations for ages 15 years or older. For example, for ages 50 to 54 years, US scores increased from 77.1 to 82.1 while high-income Asia Pacific scores increased from 71.6 to 88.2. In 2016, several states had scores comparable with peers, with large differences in performance across states. For ages 15 years or older, the age-specific HAQ scores were 85 or greater for all ages in 3 states (Connecticut, Massachusetts, and Minnesota) and 75 or less for at least 1 age category in 6 states. In regression analysis estimates with state-fixed effects, insurance coverage coefficients for ages 20 to 24 years were 0.059 (99% CI, 0.006-0.111); 45 to 49 years, 0.088 (99% CI, 0.009-0.167); and 50 to 54 years, 0.101 (99% CI, 0.013-0.189). A 10% increase in insurance coverage was associated with point increases in HAQ scores among the ages of 20 to 24 years (0.59 [99% CI, 0.06-1.11]), 45 to 49 years (0.88 [99% CI, 0.09-1.67]), and 50 to 54 years (1.01 [99% CI, 0.13-1.89]). Conclusions and Relevance: In this cross-sectional study, the US age-specific HAQ scores for ages 15 to 64 years were low relative to high-income peer locations with universal health insurance coverage. Among US states, insurance coverage was associated with higher HAQ scores for some ages. Further research with causal models and additional explanations is warranted.

Cost-effectiveness of HPV vaccination in 195 countries: A meta-regression analysis.

Cost-effectiveness analysis (CEA) is a well-known, but resource intensive, method for comparing the costs and health outcomes of health interventions. To build on available evidence, researchers are developing methods to transfer CEA across settings; previous methods do not use all available results nor quantify differences across settings. We conducted a meta-regression analysis of published CEAs of human papillomavirus (HPV) vaccination to quantify the effects of factors at the country, intervention, and method-level, and predict incremental cost-effectiveness ratios (ICERs) for HPV vaccination in 195 countries. We used 613 ICERs reported in 75 studies from the Tufts University's Cost-Effectiveness Analysis (CEA) Registry and the Global Health CEA Registry, and extracted an additional 1,215 one-way sensitivity analyses. A five-stage, mixed-effects meta-regression framework was used to predict country-specific ICERs. The probability that HPV vaccination is cost-saving in each country was predicted using a logistic regression model. Covariates for both models included methods and intervention characteristics, and each country's cervical cancer burden and gross domestic product per capita. ICERs are positively related to vaccine cost, and negatively related to cervical cancer burden. The mean predicted ICER for HPV vaccination is 2017 US$4,217 per DALY averted (95% uncertainty interval (UI): US$773-13,448) globally, and below US$800 per DALY averted in 64 countries. Predicted ICERs are lowest in Sub-Saharan Africa and South Asia, with a population-weighted mean ICER across 46 countries of US$706 per DALY averted (95% UI: $130-2,245), and across five countries of US$489 per DALY averted (95% UI: $90-1,557), respectively. Meta-regression analyses can be conducted on CEA, where one-way sensitivity analyses are used to quantify the effects of factors at the intervention and method-level. Building on all published results, our predictions support introducing and expanding HPV vaccination, especially in countries that are eligible for subsidized vaccines from GAVI, the Vaccine Alliance, and Pan American Health Organization.