Fatal Neonatal Influenza A Myocarditis.

A term baby underwent unexpected, fatal resuscitation in the delivery room. The mother suffered from a common cold during her last trimester of pregnancy. All other examinations throughout gestation were normal. Despite immediate, extended and effective resuscitation, heart rate did not exceed 15-20 beats/minute. In the autopsy, fetal myocarditis due to influenza A infection was detected.

The healthcare costs of increased body mass index-evidence from The Trøndelag Health Study.

BACKGROUND: Earlier studies have estimated the impact of increased body mass index (BMI) on healthcare costs. Various methods have been used to avoid potential biases and inconsistencies. Each of these methods measure different local effects and have different strengths and weaknesses. METHODS: In the current study we estimate the impact of increased BMI on healthcare costs using nine common methods from the literature: multivariable regression analyses (ordinary least squares, generalized linear models, and two-part models), and instrumental variable models (using previously measured BMI, offspring BMI, and three different weighted genetic risk scores as instruments for BMI). We stratified by sex, investigated the implications of confounder adjustment, and modelled both linear and non-linear associations. RESULTS: There was a positive effect of increased BMI in both males and females in each approach. The cost of elevated BMI was higher in models that, to a greater extent, account for endogenous relations. CONCLUSION: The study provides solid evidence that there is an association between BMI and healthcare costs, and demonstrates the importance of triangulation.

Vitamin D Levels and SARS-CoV-2 Infection among Medically Underserved Populations in the Minority and Rural Coronavirus Insights Study.

BACKGROUND: Extant literature presents contradictory findings on the role of vitamin D on SARS-CoV-2 infection. Our study included an examination of the relationship between vitamin D levels and SARS-CoV-2 infection among the Minority and Rural Coronavirus Insights Study (MRCIS) cohort, a diverse population of medically underserved persons presenting at five Federally qualified health centers in the United States. METHODS: We conducted a descriptive analysis to explore the relationship between vitamin D levels and SARS-CoV-2 infection among medically underserved participants. A combined molecular and serologic assessment was used to determine the prevalence of SARS-CoV-2 infection. Vitamin D was examined as both a categorical (vitamin D status: deficient, insufficient, optimal) and continuous (vitamin D level) variable. Chi-squared testing, polynomial regression models, and logistic regression models were used to assess the relationship between vitamin D and SARS-CoV-2 infection. RESULTS: The overall SARS-CoV-2 infection rate among participants was 25.9%. Most participants were either vitamin D deficient (46.5%) or insufficient (29.7%), and 23.8% had an optimal level. Vitamin D status was significantly associated with key SARS-CoV-2 infection risk factors. As mean vitamin D levels increased, the proportion of participants with SARS-CoV-2 infection decreased. For every 10 ng/mL increase in vitamin D levels the odds of SARS-CoV-2 infection decreased by 12% when adjusting for race/ethnicity and age (main effect model). Participants who identified as Hispanic/Latino or Black non-Hispanic had approximately two times increased odds of SARS-CoV-2 infection when adjusting for age and vitamin D levels compared to white non-Hispanics. However, when additional factors were added to the main effect model, the relationship between vitamin D levels and SARS-CoV-2 infection did not remain significant. CONCLUSION: Vitamin D levels were associated with an increased risk of SARS-CoV-2 infection. Hispanic/Latino and Black, non-Hispanic compared to White, non-Hispanic participants were at increased odds for infection, after adjusting for race/ethnicity and age.

The Minority and Rural Coronavirus Insights Study: Design and Baseline Characteristics of a Minority Cohort.

The Minority and Rural Coronavirus Insights Study (MRCIS) is an ongoing prospective cohort study examining health disparities associated with SARS-CoV-2 infection among medically underserved populations. This report describes procedures implemented to establish the MRCIS cohort and examines the factors associated with the molecular and serological assessment of SARS-CoV-2 infection status at participant enrollment. Participants were recruited from 5 geographically dispersed federally qualified health centers between November 2020 and April 2021. At baseline, participants completed a detailed demographic survey and biological samples were collected for testing. SARS-CoV-2 infection status was determined based on the combined molecular and serological test results. Chi-squared and logistic regression analyses were conducted to examine associations between sociodemographic factors, COVID-19 safety measures, existing comorbidities, and SARS-CoV-2 infection status. The final cohort included 3238 participants. The mean age of participants was 50.2 ± 15.8 years. Most participants identified as female (60.0%), heterosexual or straight (93.0%), White (47.6%), and Hispanic or Latino (49.1%). Approximately 26.1% of participants had at least one positive SARS-CoV-2 test result. The main effect model included age, sex, and race/ethnicity. Compared with adults ≥65 years, participants in all other age groups had ∼2 times increased odds of a positive SARS-CoV-2 test result. In addition, racial/ethnic minorities had ∼2 times increased odds of a positive SARS-CoV-2 infection status compared with non-Hispanic Whites. A unique cohort of a traditionally medically underserved minority population was established. Significant racial and ethnic disparities in SARS-CoV-2 infection status at baseline were discovered.

Healthcare costs associated with overweight and obesity at an individual versus a population level - a HUNT study. / Helsetjenestekostnader ved overvekt og fedme på individnivå versus populasjonsnivå ­ en HUNT-studie.

BACKGROUND: The interpretation of research results is affected by how results are presented. We show the importance of presenting the association between body mass index (BMI) and healthcare costs from both the individual perspective and the population perspective. MATERIAL AND METHOD: Using measurements of height and weight from the Nord-Trøndelag Health Study (HUNT Study) linked to register data on specialist healthcare costs and demographics, we estimated the association between BMI and specialist healthcare costs by means of regression analyses. RESULTS: From an individual perspective, the association between BMI and specialist healthcare costs was strongest in people in obesity classes 2 and 3 (BMI ≥ 35 kg/m2). In contrast, from a population perspective, the association was strongest in the case of overweight (BMI ≥ 25 kg/m2) or obesity class 1 (BMI ≥ 30 kg/m2), as there are more people in this BMI range. INTERPRETATION: The study emphasises the importance of including the population perspective in research studies and policy decision-making processes. People with severe obesity have a high individual risk, but their use of health services has less significance for the overall costs of health care since they are fewer people in this group.

Cost-Effectiveness of Vaccination of Older Adults with an MF59®-Adjuvanted Quadrivalent Influenza Vaccine Compared to Standard-Dose and High-Dose Vaccines in Denmark, Norway, and Sweden.

Individuals aged 65 years and above are at increased risk of complications and death from influenza compared with any other age group. Enhanced vaccines, as the MF59®-adjuvanted quadrivalent influenza vaccine (aQIV) and the high-dose quadrivalent influenza vaccine (HD-QIV), provide increased protection for older adults in comparison to the traditional standard-dose quadrivalent influenza vaccines (SD-QIV). This study aimed to assess the cost-effectiveness of aQIV compared to SD-QIV and HD-QIV in Denmark, Norway, and Sweden for adults aged ≥65 years. A static decision tree model was used to evaluate costs and outcomes of different vaccination strategies from healthcare payer and societal perspectives. This model projects that compared to SD-QIV, vaccination with aQIV could prevent a combined total of 18,772 symptomatic influenza infections, 925 hospitalizations, and 161 deaths in one influenza season across the three countries. From a healthcare payer perspective, the incremental costs per quality adjusted life year (QALY) gained with aQIV versus SD-QIV were EUR 10,170/QALY in Denmark, EUR 12,515/QALY in Norway, and EUR 9894/QALY in Sweden. The aQIV was cost saving compared with HD-QIV. This study found that introducing aQIV to the entire population aged ≥65 years may contribute to reducing the disease and economic burden associated with influenza in these countries.

Demographic Determinants and Geographical Variability of COVID-19 Vaccine Hesitancy in Underserved Communities: Cross-sectional Study.

BACKGROUND: COVID-19 hospitalizations and deaths disproportionately affect underserved and minority populations, emphasizing that vaccine hesitancy can be an especially important public health risk factor in these populations. OBJECTIVE: This study aims to characterize COVID-19 vaccine hesitancy in underserved diverse populations. METHODS: The Minority and Rural Coronavirus Insights Study (MRCIS) recruited a convenience sample of adults (age≥18, N=3735) from federally qualified health centers (FQHCs) in California, the Midwest (Illinois/Ohio), Florida, and Louisiana and collected baseline data in November 2020-April 2021. Vaccine hesitancy status was defined as a response of "no" or "undecided" to the question "Would you get a coronavirus vaccine if it was available?" ("yes" categorized as not hesitant). Cross-sectional descriptive analyses and logistic regression models examined vaccine hesitancy prevalence by age, gender, race/ethnicity, and geography. The expected vaccine hesitancy estimates for the general population were calculated for the study counties using published county-level data. Crude associations with demographic characteristics within each region were assessed using the chi-square test. The main effect model included age, gender, race/ethnicity, and geographical region to estimate adjusted odds ratios (ORs) and 95% CIs. Interactions between geography and each demographic characteristic were evaluated in separate models. RESULTS: The strongest vaccine hesitancy variability was by geographic region: California, 27.8% (range 25.0%-30.6%); the Midwest, 31.4% (range 27.3%-35.4%); Louisiana, 59.1% (range 56.1%-62.1%); and Florida, 67.3% (range 64.3%-70.2%). The expected estimates for the general population were lower: 9.7% (California), 15.3% (Midwest), 18.2% (Florida), and 27.0% (Louisiana). The demographic patterns also varied by geography. An inverted U-shaped age pattern was found, with the highest prevalence among ages 25-34 years in Florida (n=88, 80.0%,) and Louisiana (n=54, 79.4%; P<.05). Females were more hesitant than males in the Midwest (n= 110, 36.4% vs n= 48, 23.5%), Florida (n=458, 71.6% vs n=195, 59.3%), and Louisiana (n= 425, 66.5% vs. n=172, 46.5%; P<.05). Racial/ethnic differences were found in California, with the highest prevalence among non-Hispanic Black participants (n=86, 45.5%), and in Florida, with the highest among Hispanic (n=567, 69.3%) participants (P<.05), but not in the Midwest and Louisiana. The main effect model confirmed the U-shaped association with age: strongest association with age 25-34 years (OR 2.29, 95% CI 1.74-3.01). Statistical interactions of gender and race/ethnicity with the region were significant, following the pattern found by the crude analysis. Compared to males in California, the associations with the female gender were strongest in Florida (OR=7.88, 95% CI 5.96-10.41) and Louisiana (OR=6.09, 95% CI 4.55-8.14). Compared to non-Hispanic White participants in California, the strongest associations were found with being Hispanic in Florida (OR=11.18, 95% CI 7.01-17.85) and Black in Louisiana (OR=8.94, 95% CI 5.53-14.47). However, the strongest race/ethnicity variability was observed within California and Florida: the ORs varied 4.6- and 2-fold between racial/ethnic groups in these regions, respectively. CONCLUSIONS: These findings highlight the role of local contextual factors in driving vaccine hesitancy and its demographic patterns.

Body mass index and healthcare costs: using genetic variants from the HUNT study as instrumental variables.

BACKGROUND: Past studies have found associations between obesity and healthcare costs, however, these studies have suffered from bias due to omitted variables, reverse causality, and measurement error. METHODS: We used genetic variants related to body mass index (BMI) as instruments for BMI; thereby exploiting the natural randomization of genetic variants that occurs at conception. We used data on measured height and weight, genetic information, and sociodemographic factors from the Nord-Trøndelag Health Studies (HUNT), and individual-level registry data on healthcare costs, educational level, registration status, and biological relatives. We studied associations between BMI and general practitioner (GP)-, specialist-, and total healthcare costs in the Norwegian setting using instrumental variable (IV) regressions, and compared our findings with effect estimates from ordinary least squares (OLS) regressions. The sensitivity of our findings to underlying IV-assumptions was explored using two-sample Mendelian randomization methods, non-linear analyses, sex-, healthcare provider-, and age-specific analyses, within-family analyses, and outlier removal. We also conducted power calculations to assess the likelihood of detecting an effect given our sample 60,786 individuals. RESULTS: We found that increased BMI resulted in significantly higher GP costs; however, the IV-based effect estimate was smaller than the OLS-based estimate. We found no evidence of an association between BMI and specialist or total healthcare costs. CONCLUSIONS: Elevated BMI leads to higher GP costs, and more studies are needed to understand the causal mechanisms between BMI and specialist costs.

The relationship between body mass index and income: Using genetic variants from HUNT as instrumental variables.

Several studies have estimated effects of body mass index (BMI) on labour market outcomes, and these studies have mixed findings. A significant challenge has been to adequately control for omitted variables, selection, reverse causality, and measurement error. We examine the impact of BMI on income using genetic variants as instrumental variables for BMI. Individual-level pre-tax income from tax records was merged with health survey data containing measured height and weight, and data on genetic variants. The analyses were stratified by sex and a variety of methods were used to explore the sensitivity and validity of the instrumental variable (IV) strategy. For females we found that BMI had a negative effect on the logarithm of income. The effect estimated from the IV models (-0.02) was larger than the effect estimated from naïve ordinary least squares regressions (-0.01). For males, the coefficients for the effect of BMI on income were imprecise, and both positive and negative coefficients were estimated depending on the estimation method. Our results suggest that females are susceptible to reduced income levels following increased BMI.

Body mass index and lifetime healthcare utilization.

BACKGROUND: Overweight and obesity is a major global public health challenge, and understanding the implications for healthcare systems is essential for policy planning. Past studies have typically found positive associations between obesity and healthcare utilization, but these studies have not taken into consideration that obesity is also associated with early mortality. We examined associations between body mass index (BMI, reported as kg/m2) and healthcare utilization with and without taking BMI-specific survival into consideration. METHODS: We used nationally representative data on 33 882 adults collected between 2002 and 2015. We computed BMI- and age-specific primary and secondary care utilization and multiplied the estimated values with gender-, age-, and BMI-specific probabilities of surviving to each age. Then, we summed the average BMI-specific utilization between 18 and 85 years. RESULTS: During a survival-adjusted lifetime, males with normal weight (BMI: 18.5-24.9) had, on average, 167 primary care, and 77 secondary care contacts. In comparison, males with overweight (BMI: 25.0-29.9), category I obesity (BMI: 30.0-34.9), and category II/III obesity (BMI ≥35.0) had 11%, 41%, and 102% more primary care, and 14%, 29%, and 78% more secondary care contacts, respectively. Females with normal weight had, on average, 210 primary care contacts and 91 secondary care contacts. Females with overweight, category I obesity, and category II/III obesity had 20%, 34%, and 81% more primary care contacts, and 26%, 16%, and 16% more secondary care contacts, respectively. CONCLUSION: The positive association between BMI and healthcare utilization was reduced, but not offset, when BMI-specific survival was taken into consideration. Our findings underpin previous research and suggest that interventions to offset the increasing prevalence of overweight, and especially obesity, are warranted.

Evaluating costs and health consequences of sick leave strategies against pandemic and seasonal influenza in Norway using a dynamic model.

OBJECTIVES: To quantify population-level health and economic consequences of sick leave among workers with influenza symptoms. INTERVENTIONS: Compared with current sick leave practice (baseline), we evaluated the health and cost consequences of: (1) increasing the proportion of workers on sick leave from 65% (baseline) to 80% or 90%; (2) shortening the maximum duration from symptom onset to sick leave from 4 days (baseline) to 2 days, 1.5 days, 1 day and 0.5 days; and (3) combinations of 1 and 2. METHODS: A dynamic compartmental influenza model was developed using Norwegian population data and survey data on employee sick leave practices. The sick leave interventions were simulated under 12 different seasonal epidemic and 36 different pandemic influenza scenarios. These scenarios varied in terms of transmissibility, the proportion of symptomatic cases and illness severity (risk of primary care consultations, hospitalisations and deaths). Using probabilistic sensitivity analyses, a net health benefit approach was adopted to assess the cost-effectiveness of the interventions from a societal perspective. RESULTS: Compared with current sick leave practice, sick leave interventions were cost-effective for 31 (65%) of the pandemic scenarios, and 11 (92%) of the seasonal scenarios. Economic benefits from sick leave interventions were greatest for scenarios with low transmissibility, high symptomatic proportions and high illness severity. Overall, the health and economic benefits were greatest for the intervention involving 90% of sick workers taking sick leave within one-half day of symptoms. Depending on the influenza scenario, this intervention resulted in a 44.4%-99.7% reduction in the attack rate. Interventions involving sick leave onset beginning 2 days or later, after the onset of symptoms, resulted in economic losses. CONCLUSIONS: Prompt sick leave onset and a high proportion of sick leave among workers with influenza symptoms may be cost-effective, particularly during influenza epidemics and pandemics with low transmissibility or high morbidity.

Re-evaluation of the cost-effectiveness and effects of childhood rotavirus vaccination in Norway.

BACKGROUND: Rotavirus vaccination was included into the Norwegian childhood immunisation programme in 2014. Before implementation, rotavirus vaccination was found to be cost-effective from a societal perspective, but not from a healthcare perspective. Since introduction, new data on the incidence and economic effects of rotavirus disease have become available. We assessed early epidemiological effects of the rotavirus vaccination programme and re-evaluated its cost-effectiveness in Norway for the years 2015-2019. METHODS: Using a dynamic transmission model, we compared the epidemiological effects of the ongoing two-dose vaccination programme with Rotarix®, and a hypothetical 3-dose programme with RotaTeq® with no vaccination. A baseline cost of € 54 per fully vaccinated child was used. Cost-effectiveness was computed from a healthcare and societal perspective, using a decision analytical model. Data on healthcare use and costs, productivity losses and health utilities were based on published and own estimates. Uncertainty was accounted for in one-way, multi-way, and probabilistic sensitivity analyses. RESULTS: During 2015-2019, 114,658 home care cases, 34,571 primary care cases, 7,381 severe cases, and 2 deaths associated with rotavirus disease were avoided due to vaccination. Under baseline assumptions vaccination was cost-effective from a healthcare perspective with a cost per QALY of € 47,447 for Rotarix® and € 52,709 for RotaTeq®. The break-even price was € 70 for Rotarix® and € 67 for RotaTeq®. Vaccination was cost-saving from the societal perspective, and also from a healthcare perspective for vaccine prices below € 25 and € 22 per vaccinated child for Rotarix® and RotaTeq®, respectively. CONCLUSION: Ongoing childhood rotavirus vaccination in Norway has reduced the rotavirus disease burden substantially, and is cost-effective compared with no vaccination.

Lost workdays and healthcare use before and after hospital visits due to rotavirus and other gastroenteritis among young children in Norway.

BACKGROUND: Cost-effectiveness of rotavirus vaccination is affected by assumptions used in health economic evaluations. To inform such evaluations, we assessed healthcare use before and after hospitalisations due to rotavirus and other acute gastroenteritis (AGE) among children <5years of age in Norway and estimated daycare and work absenteeism. METHODS: We conducted post-discharge interviews with caregivers of 282 children hospitalised with AGE at two hospitals in Norway during April 2014-February 2017. We collected data on healthcare use and absenteeism from daycare and work. We examined healthcare seeking and absenteeism patterns for RV-specific and other gastroenteritis. RESULTS: Caregivers of 485 (37%) of 1 298 hospitalised children were invited to participate, and 282 (58%) completed the questionnaire. Among these, 106 (38%) were rotavirus-positive, 119 (42%) were rotavirus-negative, and for 57 (20%) children no rotavirus testing was performed. Overall, 97% of children had been in contact with a healthcare provider before hospital admission and 28% had contacted a healthcare provider after discharge. Children that attended daycare were absent from daycare for a mean of 6.3days (median 5days). Caregivers of these children reported work absenteeism in 74% of cases. The mean duration of work absenteeism among caregivers was 5.9days (median 5days) both for RV-positive and RV-negative cases. CONCLUSION: In Norway, work absenteeism and healthcare use before and after hospitalisation due to rotavirus and non-rotavirus gastroenteritis are considerable and impose an economic burden on the healthcare system and society.

Influenza in workplaces: transmission, workers' adherence to sick leave advice and European sick leave recommendations.

BACKGROUND: Knowledge about influenza transmission in the workplace and whether staying home from work when experiencing influenza-like illness can reduce the spread of influenza is crucial for the design of efficient public health initiatives. AIM: This review synthesizes current literature on sickness presenteeism and influenza transmission in the workplace and provides an overview of sick leave recommendations in Europe for influenza. METHODS: A search was performed on Medline, Embase, PsychINFO, Cinahl, Web of Science, Scopus and SweMed to identify studies related to workplace contacts, -transmission, -interventions and compliance with recommendations to take sick leave. A web-based survey on national recommendations and policies for sick leave during influenza was issued to 31 European countries. RESULTS: Twenty-two articles (9 surveys; 13 modelling articles) were eligible for this review. Results from social mixing studies suggest that 20-25% of weekly contacts are made in the workplace, while modelling studies suggest that on average 16% (range 9-33%) of influenza transmission occurs in the workplace. The effectiveness of interventions to reduce workplace presenteeism is largely unknown. Finally, estimates from studies reporting expected compliance with sick leave recommendations ranged from 71 to 95%. Overall, 18 countries participated in the survey of which nine (50%) had issued recommendations encouraging sick employees to stay at home during the 2009 A(H1N1) pandemic, while only one country had official recommendations for seasonal influenza. CONCLUSIONS: During the 2009 A(H1N1) pandemic, many European countries recommended ill employees to take sick leave. Further research is warranted to quantify the effect of reduced presenteeism during influenza illness.

Triglyceride-rich lipoprotein modulates endothelial vascular cell adhesion molecule (VCAM)-1 expression via differential regulation of endoplasmic reticulum stress.

Circulating triglyceride-rich lipoproteins (TGRL) from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC), defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα) stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNFα stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNFα-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK) and inositol requiring protein 1α (IRE1α), and downstream effectors including eukaryotic initiation factor-2α (eIF2α), spliced X-box-binding protein 1 (sXBP1) and C/EBP homologous protein (CHOP), directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1), a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2α/CHOP pathway and IRF-1-mediated VCAM-1 expression. We conclude that ER stress and the UPR contribute to the regulation of Vcam-1 transcription as a function of the atherogenic nature of TGRL.

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium.

Dyslipidemia is a primary risk factor for cardiovascular disease, but the specific mechanisms that determine the localization of atherosclerotic plaques in arteries are not well defined. Triglyceride-rich lipoproteins (TGRL) isolated from human plasma after a high-fat meal modulate TNF-α-induced VCAM-1 expression in cultured human aortic endothelial cells (HAECs) via an interferon regulatory factor (IRF)-1-dependent transcriptional mechanism. We examined whether fluid shear stress acts as a mediator of IRF-1-dependent VCAM-1 expression in response to cytokine and dietary lipids. IRF-1 and VCAM-1 were examined by immunofluorescence in TNF-α-stimulated HAEC monolayers exposed to TGRL and a linear gradient of shear stress ranging from 0 to 16 dyn/cm(2) in a microfluidic device. Shear stress alone modulated TNF-α-induced VCAM-1 expression, eliciting a 150% increase at low shear stress (2 dyn/cm(2)) and a 70% decrease at high shear stress (12 dyn/cm(2)) relative to static. These differences correlated with a 60% increase in IRF-1 expression under low shear stress and a 40% decrease under high shear stress. The addition of TGRL along with cytokine activated a fourfold increase in VCAM-1 expression and a twofold increase in IRF-1 expression. The combined effect of shear stress and TGRL on the upregulation of membrane VCAM-1 was abolished by transfection of HAECs with IRF-1-specific small interfering RNA. In a healthy swine model, elevated levels of endothelial IRF-1 were also observed within atherosusceptible regions of the aorta by Western blot analysis and immunohistochemistry, implicating arterial hemodynamics in the regulation of IRF-1 expression. These data demonstrate direct roles for fluid shear stress and postprandial TGRL from human serum in the regulation of IRF-1 expression and downstream inflammatory responses in HAECs.

Prevalence of pulmonary arteriovenous malformations in children versus adults with hereditary hemorrhagic telangiectasia.

It is unclear whether pulmonary arteriovenous malformations (PAVMs) in hereditary hemorrhagic telangiectasia develop later in life or are preformed in childhood. We show that the prevalence of PAVMs in children is similar to that in their parents, providing evidence against de novo PAVM formation in hereditary hemorrhagic telangiectasia.

IRF-1 and miRNA126 modulate VCAM-1 expression in response to a high-fat meal.

RATIONALE: A high-fat diet accompanied by hypertriglyceridemia increases an individual's risk for development of atherosclerosis. An early event in this process is monocyte recruitment through binding to vascular cell adhesion molecule 1 (VCAM-1) upregulated on inflamed arterial endothelium. Diets high in polyunsaturated fatty acids (PUFAs) may provide athero-protection by ameliorating this effect. OBJECTIVE: We investigated the acute regulation of VCAM-1 expression in human aortic endothelial cells (HAEC) in response to triglyceride-rich lipoproteins (TGRL) isolated from subjects after consumption of a high-fat meal. METHODS AND RESULTS: Postprandial TGRL isolated from 38 subjects were categorized as proatherogenic or antiatherogenic according to their capacity to alter the inflammatory response of HAEC. Proatherogenic TGRL increased expression of VCAM-1, intercellular adhesion molecule 1 (ICAM-1), and E-selectin by ≈20% compared with stimulation with tumor necrosis factor-α alone, whereas antiatherogenic TGRL decreased VCAM-1 expression by ≈20% while still upregulating ICAM-1. The relative atherogenicity of TGRL positively correlated with particle density of TG, apolipoprotein (Apo)CIII, ApoE, and cholesterol. Ω3-PUFA mimicked the effect of antiatherogenic TGRL by downregulating VCAM-1 expression. TGRL exerted this differential regulation of VCAM-1 by reciprocally modulating expression and activity of the transcription factor interferon regulatory factor 1 (IRF-1) and expression of microRNA 126 (miR-126). Overexpression or silencing of IRF-1 or miR-126 expression recapitulated the proatherogenic or antiatherogenic regulation of VCAM-1. CONCLUSIONS: In response to a high-fat meal, TGRL bias the inflammatory response of endothelium via transcriptional and posttranscriptional editing of VCAM-1. Subjects with an anti-inflammatory response to a meal produced TGRL that was enriched in nonesterified fatty acids, decreased IRF-1 expression, increased miR-126 activity, and diminished monocyte arrest.