Evidence to support health system prioritization of health behaviors in the COVID-19 era.

BACKGROUND: Since the COVID-19 pandemic health systems have shifted necessarily from chronic to infectious disease treatment, but chronic disease remains critical. One large health system uniquely tracks member health behaviors. This analysis compares data from select months of an ongoing monthly cross-sectional survey before and during the pandemic. METHODS: Responses in April 2019 (pre-pandemic), April 2020 (early pandemic) or April 2021 (later pandemic) were included in the primary analysis (N = 252). Differences in meeting health behavior guidelines were analyzed via logistic regression. RESULTS: A significant decline was seen for physical activity (19% not meeting guidelines pre-pandemic vs. 41% later pandemic) but not fruit/vegetable, alcohol, or sleep from early to later pandemic. Prevalence of women not meeting tobacco guidelines increased from early (5%) to later pandemic (10%) while prevalence in men decreased (10% vs 4% respectively). The percent of people not thinking about the good things that happen to them fluctuated closely with reports of new COVID-19 cases. CONCLUSIONS: Findings show the nuance of changing health behaviors throughout the pandemic. Results should be used by health systems to tailor support based on insights from the pandemic experience.

Structure-activity relationship studies on 2,5,6-trisubstituted benzimidazoles targeting Mtb-FtsZ as antitubercular agents.

Filamenting temperature sensitive protein Z (FtsZ) is an essential bacterial cell division protein and a promising target for the development of new antibacterial therapeutics. As a part of our ongoing SAR studies on 2,5,6-trisubstituted benzimidazoles as antitubercular agents targeting Mtb-FtsZ, a new library of compounds with modifications at the 2 position was designed, synthesized and evaluated for their activity against Mtb-H37Rv. This new library of trisubstituted benzimidazoles exhibited MIC values in the range of 0.004-50 µg mL-1. Compounds 6b, 6c, 20f and 20g showed excellent growth inhibitory activities ranging from 0.004-0.08 µg mL-1. This SAR study has led to the discovery of a remarkably potent compound 20g (MIC 0.0039 µg mL-1; normalized MIC 0.015 µg mL-1). Our 3DQSAR model predicted 20g as the most potent compound in the library.

A strategy to promote population-wide life satisfaction while advancing equity.

OBJECTIVES: To develop a strategy to promote life satisfaction with equity for a diverse insured population. STUDY DESIGN: Cross-sectional survey and claims analysis. METHODS: We conduct an ongoing survey of a stratified random sample of adult plan members. Among other questions, the survey asks about adequacy of physical activity, healthy eating, abstinence from tobacco, limited alcohol consumption, adequate sleep, and whether the respondent takes time to think about the good things that happen to them (hereafter referred to as "healthy thinking"). We assessed the association of demographic characteristics and the 6 behaviors with life satisfaction. RESULTS: We found that although all 6 behaviors were positively associated with life satisfaction, healthy thinking was the behavior associated with the greatest difference in life satisfaction between individuals who did and those who did not practice the behavior. We also found that although members insured through Medicaid or who had a psychosocial diagnosis tended to report significantly lower levels of life satisfaction, two-thirds of the opportunity to improve life satisfaction across the member population was among individuals with neither of these attributes. CONCLUSIONS: The most effective strategy to promote both overall life satisfaction and equity will address social determinants for members with unmet social needs, provide the behavioral and mental health services that benefit members with these needs, and promote healthy lifestyles with an emphasis on healthy thinking for the entire population.

The Predicted Impact of Adopting Health-Promoting Behaviors on Disease Burden in a Commercially Insured Population.

OBJECTIVE: The aim of this study was to better understand, in a commercially insured population, the potential impact of adopting six health-promoting behaviors relative to treating diseases and conditions. METHODS: We combined survey and insurance claims data to compare the potential benefit from adopting behaviors relative with the burden from 27 groups of diseases and conditions. RESULTS: If every member adopted all six behaviors, an 11.6% reduction in disability-adjusted life years (DALYs) might be expected, and a 7.6% reduction in DALYs might be expected if they adopted the one most impactful behavior that they did not currently practice. These amounts are, respectively, greater than the DALYs attributed to all but the two and five most burdensome groups of diseases and conditions in this population. CONCLUSIONS: The potential impact of adopting health-promoting behaviors is large relative to the burden from most medical conditions.

The health and well-being of an ACO population.

OBJECTIVES: To identify opportunities to improve the health and well-being of members of HealthPartners, a health plan based in Minnesota. STUDY DESIGN: Cross-sectional analysis of insurance claims, death records, and survey data. METHODS: We calculated a current health score from insurance claims and death records for all 754,584 members 18 years and older who met inclusion and exclusion criteria for the period January 1, 2015, to December 31, 2015, and/or January 1, 2016, to December 31, 2016. Adjusting responses to represent the member population, we calculated a future health score based on 7 items and a 1-item well-being score from survey data that we collected between July 1, 2015, and December 31, 2016. RESULTS: Forty-four percent of the loss to the current health score among HealthPartners members is attributable to musculoskeletal, psychosocial, and neurologic conditions. Among the 7 components of the future health score, the greatest opportunity for improvement (31% of the total potential) is increasing dietary fruits and vegetables. Although 42% of the members reported high levels of well-being, 14% reported low levels. On average, members with the lowest levels of well-being were insured by a Medicaid product and had low educational achievement. CONCLUSIONS: By applying the summary measures of health and well-being to the HealthPartners member population, we identified opportunities to address conditions that created a high burden on current health, opportunities to improve prospects for future health, and subpopulations who would benefit from interventions that would increase their sense of well-being.

Validating a method to assess disease burden from insurance claims.

OBJECTIVES: To validate a method that estimates disease burden as disability-adjusted life-years (DALYs) from insurance claims and death records for the purpose of identifying the conditions that place the greatest burden of disease on an insured population. STUDY DESIGN: Comparison of the DALYs generated from death records and insurance claims with functional status and health status reported by individuals who were insured with one of HealthPartners' commercial products and completed a health assessment in 2011, 2012, or 2013. METHODS: We calculated values of Spearman's ρ, the rank-order coefficient of correlation, for the correlation of DALYs with self-reported function and self-reported health. We did the same for the number of medical conditions per member and the cost of claims per member. RESULTS: The Spearman's ρ values for the correlation of DALYs with function were -0.241, -0.238, and -0.229 in 2011, 2012, and 2013, respectively (all P <.0001). The respective Spearman's ρ values for the correlation of DALYs with health were -0.197, -0.189, and -0.192 (all P <.0001). These Spearman's ρ values were similar in magnitude to those for the correlation of the number of medical conditions per member with function (-0.212, -0.213, and -0.205) and health (-0.199, -0.196, and -0.198) over the 3 years. The Spearman's ρ values for the correlation of DALYs with function and health were greater than or equal to those for the correlation of cost of claims per member with function (-0.144, -0.193, and -0.186) and greater than those for the cost of claims per member with health (-0.126, -0.150, and -0.151). CONCLUSIONS: Health plans can use DALYs calculated from their own health insurance claims and death records as a valid and inexpensive method to identify the conditions that place the greatest burden of poor function and ill health on their insured populations.

Comparing Population-based Risk-stratification Model Performance Using Demographic, Diagnosis and Medication Data Extracted From Outpatient Electronic Health Records Versus Administrative Claims.

BACKGROUND: There is an increasing demand for electronic health record (EHR)-based risk stratification and predictive modeling tools at the population level. This trend is partly due to increased value-based payment policies and the increasing availability of EHRs at the provider level. Risk stratification models, however, have been traditionally derived from claims or encounter systems. This study evaluates the challenges and opportunities of using EHR data instead of or in addition to administrative claims for risk stratification. METHODS: This study used the structured EHR records and administrative claims of 85,581 patients receiving outpatient care at a large integrated provider system. Common data elements for risk stratification (ie, age, sex, diagnosis, and medication) were extracted from outpatient EHR records and administrative claims. The performance of a validated risk-stratification model was assessed using data extracted from claims alone, EHR alone, and claims and EHR combined. RESULTS: EHR-derived metrics overlapped considerably with administrative claims (eg, number of chronic conditions). The accuracy of the model, when using EHR data alone, was acceptable with an area under the curve of ∼0.81 for hospitalization and ∼0.85 for identifying top 1% utilizers using the concurrent model. However, when using EHR data alone, the predictive model explained a lower amount of variation in utilization-based outcomes compared with administrative claims. DISCUSSION: The results show a promising performance of models predicting cost and hospitalization using outpatient EHR's diagnosis and medication data. More research is needed to evaluate the benefits of other EHR data types (eg, lab values and vital signs) for risk stratification.

Thermal and Photoinduced Copper-Promoted C-Se Bond Formation: Synthesis of 2-Alkyl-1,2-benzisoselenazol-3(2H)-ones and Evaluation against Mycobacterium tuberculosis.

2-Alkyl-1,2-benzisoselenazol-3(2H)-ones, represented by ebselen (1a), are being studied intensively for a range of medicinal applications. We describe both a new thermal and photoinduced copper-mediated cross-coupling between potassium selenocyanate (KSeCN) and N-substituted ortho-halobenzamides to form 2-alkyl-1,2-benzisoselenazol-3(2H)-ones containing a C-Se-N bond. The copper ligand (1,10-phenanthroline) facilitates C-Se bond formation during heating via a mechanism that likely involves atom transfer (AT), whereas, in the absence of ligand, photoinduced activation likely proceeds through a single electron transfer (SET) mechanism. A library of 15 2-alkyl-1,2-benzisoselenazol-3(2H)-ones was prepared. One member of the library was azide-containing derivative 1j that was competent to undergo a strain-promoted azide-alkyne cycloaddition. The library was evaluated for inhibition of Mycobacterium tuberculosis (Mtb) growth and Mtb Antigen 85C (Mtb Ag85C) activity. Compound 1f was most potent with a minimal inhibitory concentration (MIC) of 12.5 µg/mL and an Mtb Ag85C apparent IC50 of 8.8 µM.

Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.

A critical goal of lead compound selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodynamics and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, we predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-containing diphenyl ether with an increased residence time on InhA due to transition-state destabilization rather than ground-state stabilization. In the present work, we evaluate the inhibition of InhA by 14 triazole-based diphenyl ethers and use a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to 3 orders of magnitude. In addition, we identify a novel inhibitor with a residence time on InhA of 220 min, which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.

Concordance Between Life Satisfaction and Six Elements of Well-Being Among Respondents to a Health Assessment Survey, HealthPartners Employees, Minnesota, 2011.

INTRODUCTION: We assessed and tracked perceptions of well-being among employees of member companies of HealthPartners, a nonprofit health care provider and health insurance company in Bloomington, Minnesota. The objective of our study was to determine the concordance between self-reported life satisfaction and a construct of subjective well-being that comprised 6 elements of well-being: emotional and mental health, social and interpersonal status, financial status, career status, physical health, and community support. METHODS: We analyzed responses of 23,268 employees (of 37,982 invitees) from 6 HealthPartners companies who completed a health assessment in 2011. We compared respondents' answers to the question, "How satisfied are you with your life?" with their indicators of well-being where "high life satisfaction" was defined as a rating of 9 or 10 on a scale of 0 (lowest) to 10 (highest) and "high level of well-being" was defined as a rating of 9 or 10 for 5 or 6 of the 6 indicators of well-being. RESULT: We found a correlation between self-reported life satisfaction and the number of well-being elements scored as high (9 or 10) (r = 0.62, P < .001); 73.6% of the respondents were concordant (high on both or high on neither). Although 82.9% of respondents with high overall well-being indicated high life satisfaction, only 34.7% of those indicating high life satisfaction reported high overall well-being. CONCLUSION: The correlation between self-reported life satisfaction and our well-being measure was strong, and members who met our criterion of high overall well-being were likely to report high life satisfaction. However, many respondents who reported high life satisfaction did not meet our criterion for high overall well-being, which suggests that either they adapted to negative life circumstances or that our well-being measure did not identify their sources of life satisfaction.

Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis.

Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log10 CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log10 reduction in the spleen with animals treated with both SB-PT070 and RIF.

New Summary Measures of Population Health and Well-Being for Implementation by Health Plans and Accountable Care Organizations.

Health plans and accountable care organizations measure many indicators of patient health, with standard metrics that track factors such as patient experience and cost. They lack, however, a summary measure of the third leg of the Triple Aim, population health. In response, HealthPartners has developed summary measures that align with the recommendations of the For the Public's Health series of reports from the Institute of Medicine. (The series comprises the following 3 reports: For the Public's Health: Investing in a Healthier Future, For the Public's Health: Revitalizing Law and Policy to Meet New Challenges, and For the Public's Health: The Role of Measurement in Action and Accountability.) The summary measures comprise 3 components: current health, sustainability of health, and well-being. The measure of current health is disability-adjusted life years (DALYs) calculated from health care claims and death records. The sustainability of health measure comprises member reporting of 6 behaviors associated with health plus a clinical preventive services index that indicates adherence to evidence-based preventive care guidelines. Life satisfaction represents the summary measure of subjective well-being. HealthPartners will use the summary measures to identify and address conditions and factors that have the greatest impact on the health and well-being of its patients, members, and community. The method could easily be implemented by other institutions and organizations in the United States, helping to address a persistent need in population health measurement for improvement.

Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis.

Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 µM) and showed an impressive potency (MIC = 0.20-0.44 µM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.

Thiolactomycin-Based Inhibitors of Bacterial ß-Ketoacyl-ACP Synthases with in Vivo Activity.

ß-Ketoacyl-ACP synthases (KAS) are key enzymes involved in the type II bacterial fatty acid biosynthesis (FASII) pathway and are putative targets for antibacterial discovery. Several natural product KAS inhibitors have previously been reported, including thiolactomycin (TLM), which is produced by Nocardia spp. Here we describe the synthesis and characterization of optically pure 5R-thiolactomycin (TLM) analogues that show improved whole cell activity against bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and priority pathogens such as Francisella tularensis and Burkholderia pseudomallei. In addition, we identify TLM analogues with in vivo efficacy against MRSA and Klebsiella pneumoniae in animal models of infection.

Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model.

OBJECTIVES: The increasing number of clinical strains resistant to one or more of the front-line TB drugs complicates the management of this disease. To develop next-generation benzimidazole-based FtsZ inhibitors with improved efficacy, we employed iterative optimization strategies based on whole bacteria potency, bactericidal activity, plasma and metabolic stability and in vivo efficacy studies. METHODS: Candidate benzimidazoles were evaluated for potency against Mycobacterium tuberculosis H37Rv and select clinical strains, toxicity against Vero cells and compound stability in plasma and liver microsomes. The efficacy of lead compounds was assessed in the acute murine M. tuberculosis infection model via intraperitoneal and oral routes. RESULTS: MICs of SB-P17G-A33, SB-P17G-A38 and SB-P17G-A42 for M. tuberculosis H37Rv and select clinical strains were 0.18-0.39 mg/L. SB-P17G-A38 and SB-P17G-A42 delivered at 50 mg/kg twice daily intraperitoneally or orally demonstrated efficacy in reducing the bacterial load by 5.7-6.3 log10 cfu in the lungs and 3.9-5.0 log10 cfu in the spleen. SB-P17G-A33 delivered at 50 mg/kg twice daily intraperitoneally or orally also reduced the bacterial load by 1.7-2.1 log10 cfu in the lungs and 2.5-3.4 log10 cfu in the spleen. CONCLUSIONS: Next-generation benzimidazoles with excellent potency and efficacy against M. tuberculosis have been developed. This is the first report on benzimidazole-based FtsZ inhibitors showing an equivalent level of efficacy to isoniazid in an acute murine M. tuberculosis infection model.

Guide for developing an information technology investment road map for population health management.

Many health systems recovering from a massive investment in electronic health records are now faced with the prospect of maturing into accountable care organizations. This maturation includes the need to cooperate with new partners, involve substantially new data sources, require investment in additional information technology (IT) solutions, and become proficient in managing care from a new perspective. Adding to the confusion, there are hundreds of population health management (PHM) vendors with overlapping product functions. This article proposes an organized approach to investing in PHM IT. The steps include assessing the organization's business and clinical goals, establishing governance, agreeing on business requirements, evaluating the ability of current IT systems to meet those requirements, setting time lines and budgets, rationalizing current and future needs and capabilities, and installing the new systems in the context of a continuously learning organization. This article will help organizations chart their position on the population health readiness spectrum and enhance their chances for a successful transition from volume-based to value-based care.

In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacterium tuberculosis.

Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of Mycobacterium tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro-in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro-in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis.

Rational design of broad spectrum antibacterial activity based on a clinically relevant enoyl-acyl carrier protein (ACP) reductase inhibitor.

Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms.

Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents.

Filamenting temperature-sensitive protein Z (FtsZ), an essential cell division protein, is a promising target for the drug discovery of new-generation antibacterial agents against various bacterial pathogens. As a part of SAR studies on benzimidazoles, we have synthesized a library of 376 novel 2,5,6-trisubstituted benzimidazoles, bearing ether or thioether linkage at the 6-position. In a preliminary HTP screening against Mtb H37Rv, 108 compounds were identified as hits at a cut off concentration of 5 µg/mL. Among those hits, 10 compounds exhibited MIC values in the range of 0.63-12.5 µg/mL. Light scattering assay and TEM analysis with the most potent compound 5a clearly indicate that its molecular target is Mtb-FtsZ. Also, the Kd of 5a with Mtb-FtsZ was determined to be 1.32 µM.

A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis.

Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73 ± 0.24 Log10 CFU and 2.68 ± Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy.