Real-World Evaluation of an Automated Algorithm to Detect Patients With Potentially Undiagnosed Hypertension Among Patients With Routine Care in Hawai'i.

BACKGROUND: This real-world evaluation considers an algorithm designed to detect patients with potentially undiagnosed hypertension, receiving routine care, in a large health system in Hawai'i. It quantifies patients identified as potentially undiagnosed with hypertension; summarizes the individual, clinical, and health system factors associated with undiagnosed hypertension; and examines if the COVID-19 pandemic affected detection. METHODS AND RESULTS: We analyzed the electronic health records of patients treated across 6 clinics from 2018 to 2021. We calculated total patients with potentially undiagnosed hypertension and compared patients flagged for undiagnosed hypertension to those with diagnosed hypertension and to the full patient panel across individual characteristics, clinical and health system factors (eg, clinic of care), and timing. Modified Poisson regression was used to calculate crude and adjusted risk ratios. Among the eligible patients (N=13 364), 52.6% had been diagnosed with hypertension, 2.7% were flagged as potentially undiagnosed, and 44.6% had no evidence of hypertension. Factors associated with a higher risk of potentially undiagnosed hypertension included individual characteristics (ages 40-84 compared with 18-39 years), clinical (lack of diabetes diagnosis) and health system factors (clinic site and being a Medicaid versus a Medicare beneficiary), and timing (readings obtained after the COVID-19 Stay-At-Home Order in Hawai'i). CONCLUSIONS: This evaluation provided evidence that a clinical algorithm implemented within a large health system's electronic health records could detect patients in need of follow-up to determine hypertension status, and it identified key individual characteristics, clinical and health system factors, and timing considerations that may contribute to undiagnosed hypertension among patients receiving routine care.

Racial and ethnic disparities in obesity prevalence among children, adolescents, and young adults receiving inpatient care in Hawai'i, 2015-2016.

The number of hospitalizations with an obesity diagnosis have increased among youth in the past two decades, yet remain understudied, particularly among racial/ethnic minority groups. The purpose of this study was to characterize obesity prevalence among children, adolescents, and young adults receiving inpatient care in Hawai'i acute care hospitals during 2015-2016. This study analyzed statewide administrative data from a racially and ethnically diverse population. Participants (N = 7,751) included Hawai'i residents aged 5-29 years receiving inpatient care, excluding those hospitalized due to pregnancy. Recorded height and weight were used to calculate body mass index (BMI) and classify obesity. Primary or secondary diagnoses for obesity were assessed. A multivariable logistic regression model was used to determine characteristics associated with obesity, including race/ethnicity-sex interaction, age group, insurance payer, and county of residence. Based on BMI, 28.4% (2,202/7,751) of patients had obesity. However, an obesity diagnosis was present only in 40.4% (889/2,202) of patients with obesity based on BMI (11.9% of all patients). In the multivariable model, compared to whites, the odds of having obesity were highest among Pacific Islanders [adjusted odds ratio (aOR) = 4.07, 95% CI(3.16-5.23)] and Native Hawaiians [aOR = 2.16, 95% CI(1.75-2.67)] for females, and among Pacific Islanders [aOR = 5.39, 95% CI(4.27-6.81)], Native Hawaiians [aOR = 2.36, 95% CI(1.91-2.91)], and Filipinos [aOR = 2.08, 95% CI(1.64-2.64)] for males. Obesity was also associated with age group, but not insurance payer type or county of residence. These findings support the need for greater attention to obesity in the inpatient setting and equity-focused interventions to reduce obesity among younger hospitalized patients.

Insights in Public Health: Development, Implementation, and Evaluation of the Prevent Diabetes, Hawai'i Campaign.

The Prevent Diabetes, Hawai'i campaign aimed to increase awareness of prediabetes by encouraging adults to take a Diabetes Risk Test and share the results with their doctors or healthcare providers. The campaign was developed based on social marketing principles, and focus groups were used to inform the marketing mix. Television, radio, digital, and print advertisements featured local actor and comedian Frank De Lima, and a website with an online Diabetes Risk Test and resources for patients and providers were promoted in all advertisements. From March 2017 to November 2019, more than 55,000 Hawai'i residents visited the campaign website. Campaign outcomes were assessed through state-added questions to the 2017 Behavioral Risk Factor Surveillance System. Overall, 35.0% of adults said that they remembered seeing or hearing an advertisement featuring Frank De Lima and/or the Prevent Diabetes, Hawai'i message. Five percent of respondents reported taking an online or paper version of the Diabetes Risk Test in the past 12 months, and an additional 19.7% said that they planned to take it. Among those who reported taking the Diabetes Risk Test, 60.2% said they had already spoken to their doctor or other healthcare provider about the test results or risk for type 2 diabetes. The State Department of Health will continue efforts to increase awareness of type 2 diabetes and prediabetes, reach priority populations most at risk, and expand availability of evidence-based lifestyle change programs.

Insights in Public Health: Formative Factors for a Statewide Tobacco Control Advocacy Infrastructure: Insights from Hawai'i.

Hawai'i has comprehensive statewide tobacco control policies and was the first US state to raise the minimum age of sale, purchase, and possession of tobacco products to age 21 ("Tobacco 21") in a policy including not just cigarettes, but also electronic smoking devices and other tobacco products. This insights article provides strategic thinking about tobacco control advocacy planning. Specifically, we identify formative factors critical to building and sustaining our cross-sector, statewide advocacy infrastructure that has been able to address many ongoing challenges of tobacco-use prevention and control over time. This can provide new insights for other large-scale tobacco-control advocacy efforts.

Incidence of hepatocellular carcinoma according to hepatitis B virus genotype in Alaska Native people.

BACKGROUND & AIMS: Most regions of the world have ≤3 co-circulating hepatitis B virus (HBV) genotypes, which limits direct comparisons of hepatocellular carcinoma (HCC) risk among HBV-infected persons by genotype. We evaluated HCC incidence by HBV genotype in a cohort of Alaska Native (AN) persons where five HBV genotypes (A, B, C, D, F) have been identified. METHODS: Our cohort comprised AN persons with chronic HBV infection identified during 1983-2012 who consented to participate in this study. Cohort persons were offered annual hepatitis B e antigen (HBeAg) testing and semi-annual HCC screening. We developed a logistic regression model to compare HCC risk by genotype, adjusting for age, sex, region and HBeAg status. RESULTS: Among the 1235 consenting study participants, 711 (57.6%) were male, 510 (41.3%) were HBeAg positive at cohort entry and 43 (3.5%) developed HCC. The HBV genotype was known for 1142 (92.5%) persons (13.5% A, 3.9% B, 6.7% C, 56.9% D, 19.0% F). The HCC incidence/1000 person-years of follow-up for genotypes A, B, C, D and F was 1.3, 0, 5.5, 0.4 and 4.2 respectively. Compared with persons with HBV genotype B/D infection, the HCC risk was higher for persons with genotypes A [adjusted odds ratio (aOR): 3.9, 95% confidence interval (CI): 1.14-13.74], C (aOR: 16.3, 95% CI: 5.20-51.11) and F (aOR: 13.9, 95% CI: 5.30-36.69). CONCLUSION: HBV genotype is independently associated with HCC risk. AN persons with genotypes A, C and F are at higher risk compared with genotypes B or D.

Insights in Public Health: For the Love of Data! The Hawai'i Health Data Warehouse.

Data form the framework around which important public health decisions are made. Public health data are essential for surveillance and evaluating change. In Hawai'i, public health data come from a multitude of sources and agencies. The Hawai'i Health Data Warehouse (HHDW) was created to pull those data into a single location and to present results in a form that is easy for the public to access and utilize. In the years since its creation, HHDW has built a second consumer-focused web site, Hawai'i Health Matters, and is now introducing new functionality on the original site that allows users to define their own enquiry. The newly adopted Indicator-Based Information System (IBIS) uses a web interface to perform real-time data analysis and display results. This gives users the power to examine health data by a wide range of demographic and socioeconomic dimensions, permitting them to pinpoint the data they need.

Protection against tuberculosis with homologous or heterologous protein/vector vaccine approaches is not dependent on CD8+ T cells.

Considerable effort has been directed to develop Mycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4(+) and CD8(+) T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate tuberculosis vaccine, ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE), which induces potent Th1 CD4 T cells. Ad5-ID93 generates ID93-specific CD8(+) T cell responses and induces protection against M. tuberculosis. When Ad5-ID93 is administered in a prime-boost strategy with ID93/GLA-SE, both CD4(+) and CD8(+) T cells are generated and provide protection against M. tuberculosis. In a MHC class I-deficient mouse model, all groups including the Ad5-ID93 group elicited an Ag-specific CD4(+) T cell response and significantly fewer Ag-specific CD8(+) T cells, but were still protected against M. tuberculosis, suggesting that CD4(+) Th1 T cells could compensate for the loss of CD8(+) T cells. Lastly, the order of the heterologous immunizations was critical. Long-lived vaccine protection was observed only when Ad5-ID93 was given as the boost following an ID93/GLA-SE prime. The homologous ID93/GLA-SE prime/boost regimen also induced long-lived protection. One of the correlates of protection between these two approaches was an increase in the total number of ID93-specific IFN-γ-producing CD4(+) T cells 6 mo following the last immunization. Our findings provide insight into the development of vaccines not only for tuberculosis, but other diseases requiring T cell immunity.

The importance of adjuvant formulation in the development of a tuberculosis vaccine.

An effective protein-based vaccine for tuberculosis will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including alum and the oil-in-water-based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmithKline Biologics), AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved products is AS04, which combines monophosphoryl lipid A, a TLR-4 agonist, with alum. In this study, we compared two adjuvants: a stable oil-in-water emulsion (SE) and a stable oil-in-water emulsion incorporating glucopyranosyl lipid adjuvant, a synthetic TLR-4 agonist (GLA-SE), each together with a recombinant protein, ID93. Both the emulsion SE and GLA-SE adjuvants induce potent cellular responses in combination with ID93 in mice. ID93/SE induced Th2-biased immune responses, whereas ID93/GLA-SE induced multifunctional CD4(+) Th1 cell responses (IFN-γ, TNF-α, and IL-2). The ID93/GLA-SE vaccine candidate induced significant protection in mice and guinea pigs, whereas no protection was observed with ID93/SE, as assessed by reductions in bacterial burden, survival, and pathology. These results highlight the importance of properly formulating subunit vaccines with effective adjuvants for use against tuberculosis.

Transcriptional profiling of TLR-4/7/8-stimulated guinea pig splenocytes and whole blood by bDNA assay.

Toll-like receptor (TLR) agonists are currently being examined as adjuvants for vaccines, with several lead candidates now in licensed products or in late-stage clinical development. Guinea pigs are widely used for preclinical testing of drugs and vaccines; however, evaluation of TLR agonists in this model is hindered by the limited availability of immunological tools and reagents. In this study, we validated the use of a branched-chain DNA (bDNA) assay known as the QuantiGene Plex 2.0 Reagent System for measuring innate cytokine and chemokine mRNA levels following TLR stimulation of guinea pig cells. Gene expression for T-helper-1 (Th1) polarizing cytokines (TNF-α, IL-1ß, IL-12) and chemokines (CXCL1, CCL2) was upregulated following ex vivo stimulation of guinea pig splenocytes and whole blood with TLR-4 or TLR-7/8 agonists. These data confirm the utility of the QuantiGene system both as an alternative to RT-PCR for measuring transcript levels and as a high-throughput screening tool for dissecting the immunological response to TLR stimulation in guinea pigs. Overall, the QuantiGene platform is reliable, reproducible, and sensitive. These agonists have the potential to be used as adjuvant components in vaccines against various pathogens.

Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection.

The characterization of the cross-reactive, or heterologous, neutralizing antibody responses developed during human immunodeficiency virus type 1 (HIV-1) infection and the identification of factors associated with their generation are relevant to the development of an HIV vaccine. We report that in healthy HIV-positive, antiretroviral-naïve subjects, the breadth of plasma heterologous neutralizing antibody responses correlates with the time since infection, plasma viremia levels, and the binding avidity of anti-Env antibodies. Anti-CD4-binding site antibodies are responsible for the exceptionally broad cross-neutralizing antibody responses recorded only in rare plasma samples. However, in most cases examined, antibodies to the variable regions and to the CD4-binding site of Env modestly contributed in defining the overall breadth of these responses. Plasmas with broad cross-neutralizing antibody responses were identified that targeted the gp120 subunit, but their precise epitopes mapped outside the variable regions and the CD4-binding site. Finally, although several plasmas were identified with cross-neutralizing antibody responses that were not directed against gp120, only one plasma with a moderate breadth of heterologous neutralizing antibody responses contained cross-reactive neutralizing antibodies against the 4E10 epitope, which is within the gp41 transmembrane subunit. Overall, our study indicates that more than one pathway leads to the development of broad cross-reactive neutralizing antibodies during HIV infection and that the virus continuously escapes their action.

The first hypervariable region of the gp120 Env glycoprotein defines the neutralizing susceptibility of heterologous human immunodeficiency virus type 1 isolates to neutralizing antibodies elicited by the SF162gp140 immunogen.

Current vaccine efforts to elicit cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus (HIV) focus on the engineering of soluble mimetics of the trimeric HIV Env glycoprotein (commonly termed gp140 immunogens). Such immunogens are thought to be more effective than previously tested monomeric gp120 immunogens at eliciting cross-reactive NAbs. Still, the breadth of neutralizing antibody responses elicited by gp140 immunogens is narrow. Understanding why antibodies elicited by gp140 immunogens fail to neutralize a wide range of heterologous primary HIV isolates is necessary for improving the design of such immunogens. We previously reported that antibodies elicited in macaques by SF162 Env-derived gp140 immunogens fail to neutralize several heterologous "neutralization-resistant" primary HIV type 1 isolates, such as JRFL, ADA, and YU2. Here we show that by replacing the V1 region of Env on these heterologous viruses with that of SF162, we render them highly susceptible to neutralization by the SF162gp140-elicited antibodies. We observed that viral neutralization was mediated not only by vaccine-elicited anti-V1 but also by anti-V3 antibodies and antibodies directed against as yet unidentified Env regions, depending on the heterologous Env background. Our study indicates that common neutralization epitopes are differentially exposed on diverse primary HIV isolates and that the V1 loop contributes to this differential exposure. Therefore, the antibody responses elicited by soluble gp140 immunogens will have to overcome several distinct obstacles in order to neutralize diverse primary HIV isolates.