Efficacy of a new fixed-dose combination injectable (0.2 mg/kg doramectin + 6.0 mg/kg levamisole hydrochloride) in Australian cattle against artificial infections of gastrointestinal nematodes.

We describe a new fixed-dose combination injectable (FDCI) formulated with doramectin and levamisole hydrochloride (HCl) to target broad and overlapping spectra of gastrointestinal nematodes (GINs) through two distinct modes of action. Here, we demonstrate the superior efficacy of the FDCI against mixed populations of cattle GINs in two dose confirmation studies conducted in Australia using artificially induced adult (Study 1) and immature (Study 2) GIN infections. Artificial infections consisted of Cooperia spp., Haemonchus placei, Ostertagia ostertagi, and Trichostrongylus axei. In both studies, cattle were inoculated with third-stage larvae and infections were confirmed by fecal egg count (FEC). Treatment groups in both studies were as follows: (1) negative control (saline, 0.9% sodium chloride), (2) positive control injectable endectocide (Study 1-0.2 mg/kg ivermectin; Study 2-0.2 mg/kg doramectin), (3) positive control injectable anthelmintic (7.5 mg/kg levamisole HCl), and (4) FDCI (0.2 mg/kg doramectin + 6.0 mg/kg levamisole HCl). Cattle were treated either 28 days (Study 1) or 6 days (Study 2) post-infection. On Days 14-16 (Study 1) or Days 20-21 (Study 2) post-treatment, cattle were euthanized and necropsied for the recovery, identification, and enumeration of worms. Treatment efficacy was calculated as reduction in worm burdens of treated cattle compared to saline-treated cattle, and treatments were considered effective if the geometric mean worm burden in the treatment group was reduced by ≥ 95% compared to the negative control group. In both studies, saline-treated cattle remained positive for GIN infections for the study duration. Ivermectin was less than 95% effective against Cooperia spp. (80.2%) and H. placei (24.8%) in Study 1, and levamisole HCl was less than 95% effective against Ostertagia spp. (47.1%) in Study 2. In contrast, the novel FDCI was 100% effective in treating adult and immature life stages of all cattle GINs included in the artificial infections, with no worms recovered at necropsy from doramectin + levamisole HCl-treated cattle. These data show a single administration of the FDCI provides broad-spectrum treatment of economically important cattle GINs.

Efficacy of a fixed-dose combination injectable (0.2 mg/kg doramectin + 6.0 mg/kg levamisole hydrochloride) in Australian cattle against naturally acquired gastrointestinal nematode infections.

Australian producers have long used macrocyclic lactones (MLs) to successfully control cattle gastrointestinal nematodes (GINs) and consequently improve production parameters. However, the trajectory of ML resistance development in cattle GINs is following that of small ruminant nematode populations, highlighting a need for novel treatment options to provide efficacy in the current environment and interrupt the long-term establishment of ML-resistant GIN populations in Australian cattle. Here, we describe three field studies conducted in Australia to evaluate the efficacy of a single administration of a novel fixed-dose combination injectable (FDCI) endectocide against naturally acquired infections of cattle GINs. The FDCI is administered subcutaneously to deliver 0.2 mg/kg doramectin and 6 mg/kg levamisole hydrochloride (HCl). Study sites consisted of three farms in New South Wales (n = 2) and Victoria (n = 1). At each site, cattle were randomly allocated into one of three treatment groups: (1) untreated control (saline), (2) FDCI (0.2 mg/kg doramectin, 6 mg/kg levamisole HCl) or (3) positive control (0.2 mg/kg ivermectin). All treatments were administered on Day 0. Fecal samples were collected prior to treatment on Days -1 (Study 3) or 0 (Studies 1 and 2) and again on Day 14 (post-treatment) to evaluate efficacy via fecal egg count (FEC) and for coproculture. Adequacy of infection was confirmed at all three study sites, with Day 14 geometric mean (GM) FECs for saline-treated cattle ranging from 32.5 eggs per gram (EPG) to 623.7 EPG. FECs for FDCI-treated cattle were significantly reduced compared to saline-treated cattle (p ≤ 0.0001) on Day 14, with GM-based efficacy ≥ 99.7% at all three study sites. In contrast, ivermectin was 97.4% effective against cattle GINs in Study 1 but was only 47.2% and 39.8% effective at study site 2 and 3, respectively. Genus-specific efficacies suggest the presence of ivermectin-resistant Cooperia spp. (Study 1), Haemonchus spp. (Study 2) and Ostertagia spp. (Study 3) populations in the naturally infected cattle used in these studies. The post-treatment FEC and genus-specific efficacy estimations indicate the doramectin + levamisole HCl FDCI was highly efficacious against cattle GINs even in the face of ivermectin LOE at study sites 2 and 3. The efficacy of the new FDCI against both ML-susceptible and ML-resistant economically important cattle GINs in Australia affirms it is a valuable treatment option for producers operating in an environment of ML loss of efficacy.

Efficacy of a fixed-dose combination injectable (0.2 mg/kg doramectin + 6.0 mg/kg levamisole hydrochloride) in New Zealand cattle against naturally acquired gastrointestinal nematode populations with demonstrated resistance to doramectin.

Intensive farming practices and heavy reliance on anthelmintics have contributed significantly to the problem of macrocyclic lactone (ML) resistance in New Zealand. Farmers now have few options for effectively controlling cattle gastrointestinal nematodes (GINs) and regularly experience sub-optimal efficacy against economically important species. We present a novel fixed-dose combination injectable (FDCI) that simultaneously delivers 0.2 mg/kg doramectin and 6 mg/kg levamisole hydrochloride (HCl) to target a broad spectrum of cattle GINs in a single dose, providing an additional solution to endoparasite control in an environment of anthelmintic resistance. A dose confirmation study was conducted using naturally acquired infections of GINs in beef cattle in New Zealand. Cattle with GIN infections confirmed by fecal egg count (FEC) were randomly allocated (n = 12 per group) to the control (saline-treated), FDCI-treated or doramectin-treated group. On Day 0, cattle were weighed and administered a single subcutaneous injection of saline or endectocide. Rectal fecal samples were collected from each animal on Day 7 for individual duplicate fecal egg count (FEC) analysis, and coprocultures were conducted on pooled fecal samples within each treatment group. All animals were euthanized and necropsied for worm recovery on Days 14 through 16. Treatment efficacy was calculated based on reduction in FECs and worm burdens. All enrolled cattle were positive for GINs based on Day -5 FECs, with geometric mean (GM) FECs ranging from 337 to 521 eggs per gram (EPG). All saline-treated cattle remained positive for GIN infections for the study duration (Day 7 GM FEC = 427 EPG). Necropsy and worm recoveries revealed the presence of doramectin-resistant Cooperia oncophora, C. surnabada and Trichostrongylus longispicularis, as evidenced by ≤ 72.3 % efficacy of doramectin against these species. The new FDCI was ≥ 99.8 % effective against all GIN species, including ML-resistant C. oncophora, C. surnabada and T. longispicularis, providing broad-spectrum efficacy and eliminating economically important cattle GINs, including ML-resistant populations.

Toward Precision Medicine: Circadian Rhythm of Blood Pressure and Chronotherapy for Hypertension - 2021 NHLBI Workshop Report.

Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.

Cross-Neutralization of Vanguard C4 Vaccine Against Australian Isolates of Canine Parvovirus Variants CPV-2a, CPV-2b, and CPV-2c.

Canine parvovirus type 2 (CPV-2) remains one of the most significant viral pathogens in dogs in Australia and worldwide despite the availability of safe and effective CPV vaccines. At least three different variants of CPV-2 have emerged and spread all around the world, namely CPV-2a, CPV-2b, and CPV-2c. The ability of the current vaccines containing either original CPV-2 type or CPV-2b variant to cross protect the heterologous variants has been well demonstrated in laboratory studies, despite some concerns regarding the vaccine efficacy against the emerging variants. Vanguard®, a series of multivalent vaccines, has been in the market for a considerable period of time and demonstrated to provide efficacy against all three types of CPV variants CPV-2a, CPV-2b, and CPV-2c. The purpose of this study was to evaluate the ability of the recently registered Vanguard C4 vaccine to induce cross-neutralizing antibodies against the Australian isolates of CPV-2a, CPV-2b, and CPV-2c variants. Blood samples collected from dogs vaccinated with Vanguard C4 were analyzed by virus neutralizing assays developed for each of three CPV variants. The results of the study demonstrated that Vanguard vaccine induced cross-neutralizing antibodies against the Australian isolates of CPV-2a, CPV-2b, and CPV-2c, thus offering cross protection against all three Australian CPV variants.

Impaired B Cell Apoptosis Results in Autoimmunity That Is Alleviated by Ablation of Btk.

While apoptosis plays a role in B-cell self-tolerance, its significance in preventing autoimmunity remains unclear. Here, we report that dysregulated B cell apoptosis leads to delayed onset autoimmune phenotype in mice. Our longitudinal studies revealed that mice with B cell-specific deletion of pro-apoptotic Bim (BBimfl/fl ) have an expanded B cell compartment with a notable increase in transitional, antibody secreting and recently described double negative (DN) B cells. They develop greater hypergammaglobulinemia than mice lacking Bim in all cells and accumulate several autoantibodies characteristic of Systemic Lupus Erythematosus (SLE) and related Sjögren's Syndrome (SS) including anti-nuclear, anti-Ro/SSA and anti-La/SSB at a level comparable to NODH2h4 autoimmune mouse model. Furthermore, lymphocytes infiltrated the tissues including submandibular glands and formed follicle-like structures populated with B cells, plasma cells and T follicular helper cells indicative of ongoing immune reaction. This autoimmunity was ameliorated upon deletion of Bruton's tyrosine kinase (Btk) gene, which encodes a key B cell signaling protein. These studies suggest that Bim-mediated apoptosis suppresses and B cell tyrosine kinase signaling promotes B cell-mediated autoimmunity.

The ARIC (Atherosclerosis Risk In Communities) Study: JACC Focus Seminar 3/8.

ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research to improve health.

Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop.

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.

Report of the National Heart, Lung, and Blood Institute Working Group on Hypertension: Barriers to Translation.

The National Heart, Lung, and Blood Institute convened a multidisciplinary working group of hypertension researchers on December 6 to 7, 2018, in Bethesda, MD, to share current scientific knowledge in hypertension and to identify barriers to translation of basic into clinical science/trials and implementation of clinical science into clinical care of patients with hypertension. The goals of the working group were (1) to provide an overview of recent discoveries that may be ready for testing in preclinical and clinical studies; (2) to identify gaps in knowledge that impede translation; (3) to highlight the most promising scientific areas in which to pursue translation; (4) to identify key challenges and barriers for moving basic science discoveries into translation, clinical studies, and trials; and (5) to identify roadblocks for effective dissemination and implementation of basic and clinical science in real-world settings. The working group addressed issues that were responsive to many of the objectives of the National Heart, Lung, and Blood Institute Strategic Vision. The working group identified major barriers and opportunities for translating research to improved control of hypertension. This review summarizes the discussion and recommendations of the working group.

Association of Influenza-like Illness Activity With Hospitalizations for Heart Failure: The Atherosclerosis Risk in Communities Study.

Importance: Influenza is associated with an increased risk of cardiovascular events, but to our knowledge, few studies have explored the temporal association between influenza activity and hospitalizations, especially those caused by heart failure (HF). Objective: To explore the temporal association between influenza activity and hospitalizations due to HF and myocardial infarction (MI). We hypothesized that increased influenza activity would be associated with an increase in hospitalizations for HF and MI among adults in the community. Design, Setting, and Participants: As part of the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) study, a population-based study with hospitalizations sampled from 4 US communities, data were collected from 451 588 adults aged 35 to 84 years residing in the ARIC communities from annual cross-sectional stratified random samples of hospitalizations during October 2010 to September 2014. Exposures: Monthly influenza activity, defined as the percentage of patient visits to sentinel clinicians for influenza-like illness by state, as reported by the Centers for Disease Control and Prevention Surveillance Network. Main Outcomes and Measures: The monthly frequency of MI hospitalizations (n = 3541) and HF hospitalizations (n = 4321), collected through community surveillance and adjudicated as part of the ARIC Study. Results: Between October 2010 and September 2014, 2042 (47.3%) and 1599 (45.1%) of the sampled patients who were hospitalized for HF and MI, respectively, were women and 2391 (53.3%) and 2013 (57.4%) were white, respectively. A 5% monthly absolute increase in influenza activity was associated with a 24% increase in HF hospitalization rates, standardized to the total population in each community, within the same month after adjusting for region, season, race/ethnicity, sex, age, and number of MI/HF hospitalizations from the month before (incidence rate ratio, 1.24; 95% CI, 1.11-1.38; P < .001), while overall influenza activity was not significantly associated with MI hospitalizations (incidence rate ratio, 1.02; 95% CI, 0.90-1.17; P = .72). Influenza activity in the months before hospitalization was not associated with either outcome. Our model suggests that in a month with high influenza activity, approximately 19% of HF hospitalizations (95% CI, 10%-28%) could be attributable to influenza. Conclusions and Relevance: Influenza activity was temporally associated with an increase in HF hospitalizations across 4 influenza seasons. These data suggest that influenza may contribute to the risk of HF hospitalization in the general population.

Temporal trends in validated ischaemic stroke hospitalizations in the USA.

BACKGROUND: Accurate assessment of the burden of stroke, a major cause of disability and death, is crucial. We aimed to estimate rates of validated ischaemic stroke hospitalizations in the USA during 1998-2011. METHODS: We used the Atherosclerosis Risk in Communities (ARIC) study cohort's adjudicated stroke data for participants aged ≥55 years, to construct validation models for each International Classification of Diseases (ICD)-code group and patient covariates. These models were applied to the Nationwide Inpatient Sample (NIS) data to estimate the probability of validated ischaemic stroke for each eligible hospitalization. Rates and trends in NIS using ICD codes vs estimates of validated ischaemic stroke were compared. RESULTS: After applying validation models, the estimated annual average rate of validated ischaemic stroke hospitalizations in the USA during 1998-2011 was 3.37 [95% confidence interval (CI): 3.31, 3.43) per 1000 person-years. Validated rates declined during 1998-2011 from 4.7/1000 to 2.9/1000; however, the decline was limited to 1998-2007, with no further decline subsequently through 2011. Validation models showed that the false-positive (∼23% of strokes) and false-negative rates of ICD-9-CM codes in primary position for ischaemic stroke approximately cancel. Therefore, estimates of ischaemic stroke hospitalizations did not substantially change after applying validation models. CONCLUSIONS: Overall, ischaemic stroke hospitalization rates in the USA have declined during 1998-2007, but no further decline was observed from 2007 to 2011. Validated ischaemic stroke hospitalizations estimates were similar to published estimates of hospitalizations with ischaemic stroke ICD codes in primary position. Validation of national discharge data using prospective chart review data is important to estimate the accuracy of reported burden of stroke.

Association of usual 24-h sodium excretion with measures of adiposity among adults in the United States: NHANES, 2014.

Background: Both excessive sodium intake and obesity are risk factors for hypertension and cardiovascular disease. The association between sodium intake and obesity is unclear, with few studies assessing sodium intake using 24-h urine collection. Objectives: Our objective was to assess the association between usual 24-h sodium excretion and measures of adiposity among US adults. Methods: Cross-sectional data were analyzed from a sample of 730 nonpregnant participants aged 20-69 y who provided up to 2 complete 24-h urine specimens in the NHANES 2014 and had data on overweight or obesity [body mass index (kg/m2) ≥25] and central adiposity [waist circumference (WC): >88 cm for women, >102 cm for men]. Measurement error models were used to estimate usual sodium excretion, and multiple linear and logistic regression models were used to assess its associations with measures of adiposity, adjusting for sociodemographic, health, and dietary variables [i.e., energy intake or sugar-sweetened beverage (SSB) intake]. All analyses accounted for the complex survey sample design. Results: Unadjusted mean ± SE usual sodium excretion was 3727 ± 43.5 mg/d and 3145 ± 55.0 mg/d among participants with and without overweight/obesity and 3653 ± 58.1 mg/d and 3443 ± 35.3 mg/d among participants with or without central adiposity, respectively. A 1000-mg/d higher sodium excretion was significantly associated with 3.8-units higher BMI (95% CI: 2.8, 4.8) and a 9.2-cm greater WC (95% CI: 6.9, 11.5 cm) adjusted for covariates. Compared with participants in the lowest quartile of sodium excretion, the adjusted prevalence ratios in the highest quartile were 1.93 (95% CI: 1.69, 2.20) for overweight/obesity and 2.07 (95% CI: 1.74, 2.46) for central adiposity. The associations also were significant when adjusting for SSBs, instead of energy, in models. Conclusions: Higher usual sodium excretion is associated with overweight/obesity and central adiposity among US adults.

Central Arterial Stiffness Is Associated With Structural Brain Damage and Poorer Cognitive Performance: The ARIC Study.

Background Central arterial stiffening and increased pulsatility, with consequent cerebral hypoperfusion, may result in structural brain damage and cognitive impairment. Methods and Results We analyzed a cross-sectional sample of ARIC - NCS (Atherosclerosis Risk in Communities-Neurocognitive Study) participants (aged 67-90 years, 60% women) with measures of cognition (n=3703) and brain magnetic resonance imaging (n=1255). Central arterial hemodynamics were assessed as carotid-femoral pulse wave velocity and pressure pulsatility (central pulse pressure). We derived factor scores for cognitive domains. Brain magnetic resonance imaging using 3-Tesla scanners quantified lacunar infarcts; cerebral microbleeds; and volumes of white matter hyperintensities, total brain, and the Alzheimer disease signature region. We used logistic regression, adjusted for demographics, apolipoprotein E ɛ4, heart rate, mean arterial pressure, and select cardiovascular risk factors, to estimate the odds of lacunar infarcts or cerebral microbleeds. Linear regression, additionally adjusted for intracranial volume, estimated the difference in log-transformed volumes of white matter hyperintensities , total brain, and the Alzheimer disease signature region. We estimated the mean difference in cognitive factor scores across quartiles of carotid-femoral pulse wave velocity or central pulse pressure using linear regression. Compared with participants in the lowest carotid-femoral pulse wave velocity quartile, participants in the highest quartile of carotid-femoral pulse wave velocity had a greater burden of white matter hyperintensities ( P=0.007 for trend), smaller total brain volumes (-18.30 cm3; 95% CI , -27.54 to -9.07 cm3), and smaller Alzheimer disease signature region volumes (-1.48 cm3; 95% CI , -2.27 to -0.68 cm3). These participants also had lower scores in executive function/processing speed (ß=-0.04 z score; 95% CI , -0.07 to -0.01 z score) and general cognition (ß=-0.09 z score; 95% CI , -0.15 to -0.03 z score). Similar results were observed for central pulse pressure . Conclusions Central arterial hemodynamics were associated with structural brain damage and poorer cognitive performance among older adults.

Benefit-Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE®) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph-) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph- R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

Validity of predictive equations for 24-h urinary potassium excretion based on timing of spot urine collection among adults: the MESA and CARDIA Urinary Sodium Study and NHANES Urinary Sodium Calibration Study.

Background: 24-h urine collections are the suggested method to measure daily urinary potassium excretion (uK) but are costly and burdensome to implement. Objective: This study tested how well existing equations with the use of spot urine samples can estimate 24-h uK and if accuracy varies by timing of spot urine collection, age, race, or sex. Design: This cross-sectional study used data from 407 participants aged 18-39 y from the Washington, DC area in 2011 and 554 participants aged 45-79 y from Chicago in 2013. Spot urine samples were collected in individual containers for 24 h, and 1 for each timed period (morning, afternoon, evening, and overnight) was selected. For each selected timed spot urine, 24-h uK was predicted through the use of published equations. Difference (bias) between predicted and measured 24-h uK was calculated for each timed period and within age, race, and sex subgroups. Individual-level differences were assessed through the use of Bland-Altman plots and correlation tests. Results: For all equations, regardless of the timing of spot urine, mean bias was usually significantly different than 0. No one prediction equation was unbiased across all sex, race, and age subgroups. With the use of the Kawasaki and Tanaka equations, 24-h uK was overestimated at low levels and underestimated at high levels, whereas observed differential bias with the Mage equation was in the opposite direction. Depending on prediction equation and timing of urine sample, 61-75% of individual 24-h uKs were misclassified among 500-mg incremental categories from <1500 to ≥3000 mg. Correlations between predicted and measured 24-h uK were poor to moderate (0.19-0.71). Conclusion: Because predicted 24-h uK accuracy varies by timing of spot urine collection, published prediction equations, and within age-race-sex subgroups, study results making use of predicted 24-h uK in association with health outcomes should be interpreted with caution. It is possible that a more accurate prediction equation can be developed leading to different results.

Socioeconomic status and access to care and the incidence of a heart failure diagnosis in the inpatient and outpatient settings.

PURPOSE: Despite well-documented associations of socioeconomic status with incident heart failure (HF) hospitalization, little information exists on the relationship of socioeconomic status with HF diagnosed in the outpatient (OP) setting. METHODS: We used Poisson models to examine the association of area-level indicators of educational attainment, poverty, living situation, and density of primary care physicians with incident HF diagnosed in the inpatient (IP) and OP settings among a cohort of Medicare beneficiaries (n = 109,756; 2001-2013). RESULTS: The age-standardized rate of HF incidence was 35.8 (95% confidence interval [CI], 35.1-36.5) and 13.9 (95% CI, 13.5-14.4) cases per 1000 person-years in IP and OP settings, respectively. The incidence rate differences (IRDs) per 1000 person-years in both settings suggested greater incidence of HF in high- compared to low-poverty areas (IP IRD = 4.47 [95% CI, 3.29-5.65], OP IRD = 1.41 [95% CI, 0.61-2.22]) and in low- compared to high-education areas (IP IRD = 3.73 [95% CI, 2.63-4.82], OP IRD = 1.72 [95% CI, 0.97-2.47]). CONCLUSIONS: Our results highlight the role of area-level social determinants of health in the incidence of HF in both the IP and OP settings. These findings may have implications for HF prevention policies.

Estimated 24-Hour Urinary Sodium and Potassium Excretion in US Adults.

Importance: In 2010, the Institute of Medicine (now the National Academy of Medicine) recommended collecting 24-hour urine to estimate US sodium intake because previous studies indicated 90% of sodium consumed was excreted in urine. Objective: To estimate mean population sodium intake and describe urinary potassium excretion among US adults. Design, Setting, and Participants: In a nationally representative cross-sectional survey of the US noninstitutionalized population, 827 of 1103 (75%) randomly selected, nonpregnant participants aged 20 to 69 years in the examination component of the National Health and Nutrition Examination Survey (NHANES) collected at least one 24-hour urine specimen in 2014. The overall survey response rate for the 24-hour urine collection was approximately 50% (75% [24-hour urine component response rate] × 66% [examination component response rate]). Exposures: 24-hour collection of urine. Main Outcomes and Measures: Mean 24-hour urinary sodium and potassium excretion. Weighted national estimates of demographic and health characteristics and mean electrolyte excretion accounting for the complex survey design, selection probabilities, and nonresponse. Results: The study sample (n = 827) represented a population of whom 48.8% were men; 63.7% were non-Hispanic white, 15.8% Hispanic, 11.9% non-Hispanic black, and 5.6% non-Hispanic Asian; 43.5% had hypertension (according to 2017 hypertension guidelines); and 10.0% reported a diagnosis of diabetes. Overall mean 24-hour urinary sodium excretion was 3608 mg (95% CI, 3414-3803). The overall median was 3320 mg (interquartile range, 2308-4524). In secondary analyses by sex, mean sodium excretion was 4205 mg (95% CI, 3959-4452) in men (n = 421) and 3039 mg (95% CI, 2844-3234) in women (n = 406). By age group, mean sodium excretion was 3699 mg (95% CI, 3449-3949) in adults aged 20 to 44 years (n = 432) and 3507 mg (95% CI, 3266-3748) in adults aged 45 to 69 years (n = 395). Overall mean 24-hour urinary potassium excretion was 2155 mg (95% CI, 2030-2280); by sex, 2399 mg (95% CI, 2253-2545) in men and 1922 mg (95% CI, 1757-2086) in women; and by age, 1986 mg (95% CI, 1878-2094) in adults aged 20 to 44 years and 2343 mg (95% CI, 2151-2534) in adults aged 45 to 69 years. Conclusions and Relevance: In cross-sectional data from a 2014 sample of US adults, estimated mean sodium intake was 3608 mg per day. The findings provide a benchmark for future studies.

Association Between Urinary Sodium and Potassium Excretion and Blood Pressure Among Adults in the United States: National Health and Nutrition Examination Survey, 2014.

BACKGROUND: Higher levels of sodium and lower levels of potassium intake are associated with higher blood pressure. However, the shape and magnitude of these associations can vary by study participant characteristics or intake assessment method. Twenty-four-hour urinary excretion of sodium and potassium are unaffected by recall errors and represent all sources of intake, and were collected for the first time in a nationally representative US survey. Our objective was to assess the associations of blood pressure and hypertension with 24-hour urinary excretion of sodium and potassium among US adults. METHODS: Cross-sectional data were obtained from 766 participants age 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 National Health and Nutrition Examination Survey, a nationally representative survey of the US noninstitutionalized population. Usual 24-hour urinary electrolyte excretion (sodium, potassium, and their ratio) was estimated from ≤2 collections on nonconsecutive days, adjusting for day-to-day variability in excretion. Outcomes included systolic and diastolic blood pressure from the average of 3 measures and hypertension status, based on average blood pressure ≥140/90 and antihypertensive medication use. RESULTS: After multivariable adjustment, each 1000-mg difference in usual 24-hour sodium excretion was directly associated with systolic (4.58 mm Hg; 95% confidence interval [CI], 2.64-6.51) and diastolic (2.25 mm Hg; 95% CI, 0.83-3.67) blood pressures. Each 1000-mg difference in potassium excretion was inversely associated with systolic blood pressure (-3.72 mm Hg; 95% CI, -6.01 to -1.42). Each 0.5 U difference in sodium-to-potassium ratio was directly associated with systolic blood pressure (1.72 mm Hg; 95% CI, 0.76-2.68). Hypertension was linearly associated with progressively higher sodium and lower potassium excretion; in comparison with the lowest quartile of excretion, the adjusted odds of hypertension for the highest quartile was 4.22 (95% CI, 1.36-13.15) for sodium, and 0.38 (95% CI, 0.17-0.87) for potassium (P<0.01 for trends). CONCLUSIONS: These cross-sectional results show a strong dose-response association between urinary sodium excretion and blood pressure, and an inverse association between urinary potassium excretion and blood pressure, in a nationally representative sample of US adults.

The Validity of Predictive Equations to Estimate 24-Hour Sodium Excretion: The MESA and CARDIA Urinary Sodium Study.

We examined the population distribution of urinary sodium concentrations and the validity of existing equations predicting 24-hour sodium excretion from a single spot urine sample among older adults with and without hypertension. In 2013, 24-hour urine collections were obtained from 554 participants in the Multi-Ethnic Study of Atherosclerosis and the Coronary Artery Risk Development in Young Adults study, who were aged 45-79 years and of whom 56% were female, 58% were African American, and 54% had hypertension, in Chicago, Illinois. One-third provided a second 24-hour collection. Four timed (overnight, morning, afternoon, and evening) spot urine specimens and the 24-hour collection were analyzed for sodium and creatinine concentrations. Mean 24-hour sodium excretion was 3,926 (standard deviation (SD), 1,623) mg for white men, 2,480 (SD, 1,079) mg for white women, 3,454 (SD, 1,651) mg for African-American men, and 3,397 (SD, 1,641) mg for African-American women, and did not differ significantly by hypertensive status. Mean bias (difference) in predicting 24-hour sodium excretion from the timed spot urine specimens ranged from -182 (95% confidence interval: -285, -79) to 1,090 (95% confidence interval: 966, 1,213) mg/day overall. Although the Tanaka equation using the evening specimen produced the least bias overall, no single equation worked well across subgroups of sex and race/ethnicity. A single spot urine sample is not a valid indicator of individual sodium intake. New equations are needed to accurately estimate 24-hour sodium excretion for older adults.

Association of Central Arterial Stiffness and Pressure Pulsatility with Mild Cognitive Impairment and Dementia: The Atherosclerosis Risk in Communities Study-Neurocognitive Study (ARIC-NCS).

BACKGROUND: The association of central arterial stiffness and pressure pulsatility with mild cognitive impairment (MCI) and dementia is not well characterized in the population-based setting. OBJECTIVE: The aim of this study was to quantify the cross-sectional association of arterial stiffness and pressure pulsatility with MCI and dementia among 4,461 older white and black adults from the population-based Atherosclerosis Risk in Communities Study-Neurocognitive Study. METHODS: We used race-stratified multinomial logistic regression to evaluate associations of percentile cut points of carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure, and pulse pressure amplification with MCI and dementia versus no cognitive impairment. RESULTS: Among whites, those with carotid-femoral pulse wave velocity or central systolic blood pressure ≥75th percentile had a higher prevalence of MCI compared to participants <75th percentile (conditional odds ratio (OR); 95% confidence interval (CI): 1.27 (1.02, 1.56) and 1.28 (1.04, 1.57), respectively) and those with central pulse pressure ≥75th percentile had a higher prevalence of MCI (OR 1.27 (95% CI: 1.03, 1.58)) and dementia (OR 1.76 (95% CI: 1.06, 2.92) compared to participants <75th percentile. Also among whites, those with pulse pressure amplification ≤25th percentile had a higher prevalence of dementia compared to participants >25th percentile (OR 1.65; (95% CI: 1.01, 2.70). Weaker associations were seen among black participants. CONCLUSION: Higher arterial stiffness and pulsatility were associated with MCI and dementia in white participants. Longitudinal characterization of the observed associations is warranted to assess whether arterial stiffness and pressure pulsatility predict MCI and dementia among older adults.