Using Cost-Effectiveness Analysis to Address Health Equity Concerns

This articles serves as a guide to using cost-effectiveness analysis (CEA) to address health equity concerns. We first introduce the "equity impact plane," a tool for considering trade-offs between improving total health—the objective underpinning conventional CEA—and equity objectives, such as reducing social inequality in health or prioritizing the severely ill. Improving total health may clash with reducing social inequality in health, for example, when effective delivery of services to disadvantaged communities requires additional costs. Who gains and who loses from a cost-increasing health program depends on differences among people in terms of health risks, uptake, quality, adherence, capacity to benefit, and—crucially—who bears the opportunity costs of diverting scarce resources from other uses. We describe two main ways of using CEA to address health equity concerns: 1) equity impact analysis, which quantifies the distribution of costs and effects by equity-relevant variables, such as socioeconomic status, location, ethnicity, sex, and severity of illness; and 2) equity trade-off analysis, which quantifies trade-offs between improving total health and other equity objectives. One way to analyze equity trade-offs is to count the cost of fairer but less cost-effective options in terms of health forgone. Another method is to explore how much concern for equity is required to choose fairer but less cost-effective options using equity weights or parameters. We hope this article will help the health technology assessment community navigate the practical options now available for conducting equity-informative CEA that gives policymakers a better understanding of equity impacts and trade-offs.     

SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats (n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein–cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.     

Genotoxicity and cytotoxicity of selected pyrrolizidine alkaloids, a possible alkenal metabolite of the alkaloids, and related alkenals

Recently our laboratory isolated trans-4-OH-2-hexenal from the hepatic microsomal metabolism of the macrocyclic pyrrolizidine alkaloid (PA) senecionine and demonstrated in vivo that hepatic necrosis occurred following injection into the hepatic portal vein. To demonstrate similarities in the toxic effects of these compounds, as well as additional macrocyclic PAs and alkenals, genotoxicity and cytotoxicity were examined in primary cultures of rat hepatocytes. A positive cytotoxic response was exhibited by senecionine, retrorsine, seneciphylline, 19-OH-senecionine, trans-4-OH-2-hexenal, trans-4-OH-2-nonenal, and nonenal as measured by the release of LDH. A weaker response was elicited by hexenal. Dosages used of each of these compounds ranged from 30 to 600 nmol/10(6) cells, with each compound exhibiting a linear dose response within this range. All eight compounds exhibited a positive, dose-related genotoxic response as measured by autoradiographic detection of unscheduled DNA synthesis. These results would predict a carcinogenic role for both the PAs and the alkenals. This would suggest similarities in the mechanisms of action of the PAs and alkenals, lending support to the proposed role of trans-4-OH-2-hexenal as an important toxic metabolite of the PAs.     

Rheumatoid factor in acute bacterial endocarditis

Sera from 55 parenteral drug abusers with endocarditis due to Staphylococcus aureus were assayed for the presence and titer of rheumatoid factor. Thirteen (24%) of the 55 patients with endocarditis had sera positive for rheumatoid factor at one point or another in their courses; only 2 (7%) of 30 noninfected drug users were found to be positive. It appeared that more severe cases, as evidenced by duration of fever after initiation of antibiotic therapy, were more likely to develop rheumatoid factor.     

Regulating a novel drug: An evaluation of changes in use of Salvia divinorum in the first year of Florida's ban

BackgroundA plant with dissociative and psychoactive properties began to attract the attention of the media and United States policymakers following a well-publicized suicide in 2006 and reports that the plant served as a ‘legal high’ and substitute for cannabis. As a result, Salvia divinorum and its active ingredient, salvinorin A, were classified as Schedule I substances by the Florida Legislature on July 1, 2008. As of yet, no research has explored the efficacy of this policy or similar policies in other jurisdictions.MethodsThree self-report studies collected from young adults both prior to and following the policy's implementation are employed to investigate the potential relationship between the policy and usage rates. In addition, law enforcement personnel from the state's most populated areas were interviewed to determine the extent to which they were encountering salvia in their work.ResultsIt was indicated that less than two-thirds of those surveyed were aware of the drug's legal status. Lifetime prevalence of salvia use was largely unchanged. However, the rates of self-reported past year and past month use in Florida were significantly lower following the scheduling. Though use of Salvia divinorum appears to have decreased, perceptions of peer use increased markedly. Law enforcement officers and laboratories reported rarely, if ever, dealing with cases of salvia possession.ConclusionsData suggests the classification of Salvia divinorum as a Schedule I drug was followed by a substantial reduction in recreational use. We caution that other factors may have influenced use, that the efficacy of scheduling novel substances is likely to vary by drug type, that such a reduction in reported use may only exist transiently until a sophisticated illicit market develops to replace the legitimate one, and that a state's success in regulating salvia may be related to their regulation of and enforcement of other drug prohibitions.     

Challenges and opportunities for the implementation of the Three Rs in Canadian vaccine quality control

A case-study approach was used to identify opportunities and challenges to the implementation of the Three Rs in vaccine testing in Canada. Data was obtained through interviews with 16 Canadian stakeholders involved in the production, testing and evaluation of vaccines. Participants identified inconsistent regulatory testing requirements, the lack of biological functionality of some in vitro methods, the benchmarking of in vitro against in vivo assays, and high caution towards method changes as major challenges to implementation. Opportunities to implementation were identified as the desire for and steps taken towards harmonization of test methods between countries, collaborations on new method development, the poor performance of traditional animal methods, the domino effect of one regulatory authority accepting a method after another, and stakeholder concerns for the ethical care and use of animals used in vaccine testing. These results suggest that industry and the Canadian government are open to implementing the Three Rs in vaccine quality control, but methods adopted must be reliable and biologically relevant. Improving the harmonization of regulatory requirements will assist in furthering the implementation of alternative methods.     

Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway

To assess the relationship between venous thrombosis and plasma glucosylceramide (GlcCer) or phosphatidylethanolamine (PE), plasma levels of GlcCer and PE were determined for 70 venous thrombosis patients referred for evaluation and 70 healthy blood donors. The mean GlcCer level, but not the PE level, was lower in patients versus controls (4.9 vs 6.5 microg/mL [P =.0007] and 66 vs 71 microg/mL [P =.48], respectively). As a measure of relative risk, the odds ratio for deep vein thrombosis in subjects with GlcCer levels below the 10th percentile of controls was 5.7 (95% CI, 2.3-14). To assess the influence of glycolipids on anticoagulant response to activated protein C (APC):protein S in modified prothrombin time assays, the effects of depleting endogenous plasma GlcCer by glucocerebrosidase treatment or of adding exogenous purified GlcCer or other neutral glycolipids to plasma were tested. Glucocerebrosidase treatment reduced plasma sensitivity to APC:protein S in parallel with GlcCer reduction. Exogenously added GlcCer and the homologous Glc-containing globotriaosylceramide (Gb3Cer), but not galactosylceramide, dose-dependently prolonged clotting times of normal plasma in the presence, but not absence, of APC:protein S, which suggests that GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. These results suggest that the neutral glycolipids GlcCer and Gb3Cer may directly contribute to the anticoagulant activity of the protein C pathway and that deficiency of plasma GlcCer may be a risk factor for venous thrombosis. (Blood. 2001;97:1907-1914)     

Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells

Mediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo.     

A needs assessment study of what health care consumers seek from social media and social networking

Given that prevention is crucial to long healthy life and restraining escalating health care costs, this study examines social media and networking (SM&N) needs among health consumers regarding preventive health. Results showed the most important SM&N needs included: education about health issues, connecting to a support group, knowing the implications of health condition, opportunities and understanding of preventive health care, and tracking physical activity. Among demographic groups women, younger aged groups, and African Americans considered SM&N needs to be more important. Homemakers indicated greatest need for information about health issues and facilitating interaction with others. Full-time employees placed greater importance on managing their own health.