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Objectives: To assess whether older adults with a cognitive impairment were more likely to report challenges interacting with medical providers, or to avoid needed medical care. Methods: Data for this exploratory, cross-sectional analysis were from older adults ( N = 493) ages 60–82 participating in the “LitCog” cohort study. Multivariable generalized linear models compared cognitive impairment (none, mild, moderate, severe) with validated measures of healthcare engagement. Results: A moderate cognitive impairment was associated with delays in medical care due to embarrassment (RR 5.34.95% CI 1.30–22.0) and discomfort asking the doctor questions (RR 4.07, 95% CI 1.00–16.5). Conclusions: Intermediate cognitive deficits, such as with mild cognitive impairment (MCI) or mild dementias, may impact meaningful engagement with healthcare systems, potentially affecting timely detection and appropriate management of cognitive concerns and other chronic medical conditions. More research is needed to understand mechanisms underlying this relationship.

The U.S. public health response to coronavirus disease 2019 (COVID-19) has been widely criticized as having downplayed the potential implications COVID-19 could have on one's personal health. Despite the unprecedented threat of COVID-19, many individuals still believed that it was not at all likely that they would become infected. We sought to investigate trends in adults' perceived susceptibility to COVID-19 over the first year of the pandemic, whether distinct trajectories emerged, and if these trajectories differed by participant socio-demographic characteristics.This was a longitudinal cohort study with 5 time points of data collection (March 13, 2020-March 3, 2021). Subjects included 627 adults living with ≥1 chronic conditions, who completed a baseline interview and at least one follow-up interview. In addition to collecting relevant socio-demographic characteristics, participants' perceived susceptibility to COVID-19 across time was assessed and classified into distinct trajectories.Nearly two-thirds (62.2%) of participants perceived themselves to be highly susceptible to COVID-19 from the onset of the pandemic ("early responders") and sustained this over a year, a third (29.0%) eventually perceived themselves to be highly susceptible ("late responders"), and 8.8% maintained a low likelihood of susceptibility throughout the pandemic ("non-responders"). In multivariable analyses, compared to White participants, Latinx participants were significantly more likely to be non-responders and report low likelihood of perceived susceptibility (Risk Ratio [RR]: 3.46; 95% confidence interval: 1.19, 10.1), as were Black participants (RR: 5.49; 95% confidence interval: 2.19, 13.8).A year into the COVID-19 pandemic, 1 out of 11 participants persistently did not think they might be susceptible and potentially infected. Future studies are needed to understand reasons why certain individuals, particularly those of racial/ethnic minorities, did not perceive themselves at risk for infection.

Despite increased focus on opioid prescribing, little is known about the influence of prescription opioid medication information given to patients in the emergency department (ED). The study objective was to evaluate the effect of an Electronic Medication Complete Communication (EMCThis was a three-arm prospective, randomized controlled pragmatic trial with randomization occurring at the physician level. Consecutive discharged patients at an urban academic ED (88,000 visits) with new hydrocodone-acetaminophen prescriptions received one of three care pathways: 1) usual care, 2) EMCAmong the 652 enrolled, 343 completed follow-up (57% women; mean ± SD age = 42 ± 14.0 years). Demonstrated safe opioid use occurred more often in the EMCThe study found that the EMC

Striatin is a protein regulator of vesicular trafficking in neurons that also binds caveolin-1 and Ca 2+ -calmodulin and could activate endothelial nitric oxide synthase. We have shown that striatin colocalizes with the mineralocorticoid receptor and that mineralocorticoid receptor activation increases striatin levels in vascular cells. To test whether striatin is a regulator of vascular function, wild-type and heterozygous striatin-deficient mice (Strn +/− ) were randomized in crossover intervention to restricted (0.03%) and liberal sodium (1.6%) diets for 7 days on each diet, and blood pressure and aortic vascular function were measured. Compared with wild-type, sodium restriction significantly reduced blood pressure in Strn +/− . On liberal salt intake, phenylephrine and high KCl caused a greater vascular contraction in Strn +/− than wild-type, and endothelium removal, nitric oxide synthase inhibitor L-NAME, and guanylate cyclase inhibitor ODQ enhanced phenylephrine contraction to a smaller extent in Strn +/− than wild-type. On liberal salt, acetylcholine relaxation was less in Strn +/− than in wild-type, and endothelium removal, L-NAME, and ODQ blocked acetylcholine relaxation, suggesting changes in endothelial NO-cGMP. On liberal salt, endothelial nitric oxide synthase mRNA expression and the ratio of endothelial nitric oxide synthase activator pAkt/total Akt were decreased in Strn +/− versus wild-type. Vascular relaxation to NO donor sodium nitroprusside was not different among groups. Thus, striatin deficiency is associated with salt sensitivity of blood pressure, enhanced vasoconstriction, and decreased vascular relaxation, suggesting a critical role for striatin, through modulation of endothelial NO-cGMP, in regulation of vascular function and BP during changes in sodium intake.

Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL. Vascular relaxation to the NO donor sodium nitroprusside was increased with L-NAME + AngII in WT mice but not in cav-1(-/-) mice. Plasma aldosterone levels increased and cardiac MR expression decreased in L-NAME + AngII treated WT and cav-1(-/-) mice and did not change with EPL. Thus, during L-NAME + AngII induced hypertension, MR blockade increases contraction and alters vascular relaxation via NO-cGMP, and these changes are absent in cav-1 deficiency states. The data suggest a cooperative role of MR and cav-1 in regulating vascular contraction and NO-cGMP-mediated relaxation during low NO-high AngII-dependent cardiovascular injury.

Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav-1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1(-/-) mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1(-/-) mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1(-/-)WT and did not change with metformin. Phenylephrine (Phe)- and KCl-induced aortic contraction was in cav-1(-/-)WT; endothelium removal, the nitric-oxide synthase (NOS) blocker L-NAME (N(ω)-nitro-L-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1(-/-)WT, abolished by endothelium removal, L-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1(-/-) than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1(-/-)WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1(-/-). Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1(-/-) mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states.

Normal pregnancy is associated with adaptive hemodynamic, hormonal, and vascular changes, and estrogen (E2) may promote vasodilation during pregnancy; however, the specific E2 receptor (ER) subtype, post-ER signaling mechanism, and vascular bed involved are unclear. We tested whether pregnancy-associated vascular adaptations involve changes in the expression/distribution/activity of distinct ER subtypes in a blood vessel-specific manner. Blood pressure (BP) and plasma E2 were measured in virgin and pregnant ( day 19) rats, and the thoracic aorta, carotid artery, mesenteric artery, and renal artery were isolated for measurements of ERα, ERβ, and G protein-coupled receptor 30 [G protein-coupled ER (GPER)] expression and tissue distribution in parallel with relaxation responses to E2 (all ERs) and the specific ER agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)-tris-phenol (PPT; ERα), diarylpropionitrile (DPN; ERβ), and G1 (GPER). BP was slightly lower and plasma E2 was higher in pregnant versus virgin rats. Western blots revealed increased ERα and ERβ in the aorta and mesenteric artery and GPER in the aorta of pregnant versus virgin rats. Immunohistochemistry revealed that the increases in ERs were mainly in the intima and media. In phenylephrine-precontracted vessels, E2 and PPT caused relaxation that was greater in the aorta and mesenteric artery but similar in the carotid and renal artery of pregnant versus virgin rats. DPN- and G1-induced relaxation was greater in the mesenteric and renal artery than in the aorta and carotid artery, and aortic relaxation to G1 was greater in pregnant versus virgin rats. The nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester with or without the cyclooxygenase inhibitor indomethacin with or without the EDHF blocker tetraethylammonium or endothelium removal reduced E2, PPT, and G1-induced relaxation in the aorta of pregnant rats, suggesting an endothelium-dependent mechanism, but did not affect E2-, PPT-, DPN-, or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. E2, PPT, DPN, and G1 caused relaxation of Ca2+ entry-dependent KCl contraction, and the effect of PPT was greater in the mesenteric artery of pregnant versus virgin rats. Thus, during pregnancy, an increase in ERα expression in endothelial and vascular smooth muscle layers of the aorta and mesenteric artery is associated with increased ERα-mediated relaxation via endothelium-derived vasodilators and inhibition of Ca2+ entry into vascular smooth muscle, supporting a role of aortic and mesenteric arterial ERα in pregnancy-associated vasodilation. GPER may contribute to aortic relaxation while enhanced ERβ expression could mediate other genomic vascular effects during pregnancy.

Pregnancy (Preg) is associated with hormonal and vascular changes, and estrogen (E2) may promote systemic vasodilation during Preg; however, the specific E2 receptor (ER), post-ER signaling mechanisms and vascular bed involved are unclear. To test if Preg is associated with distinct expression/activity of ERs in different blood vessels, BP and plasma E2 were measured in virgin and day-19 Preg rats, and the aorta, carotid, mesenteric and renal artery were isolated for measurement of ERα, ERβ and GPR30 expression, and the responses to E2 and specific ER agonists PPT (ERα), DPN (ERβ) and G1 (GPR30). BP was in Preg (89±6) < virgin (98±4mmHg), and plasma E2 was in Preg (120.5±5.8) > virgin (94.3±7.5pg/ml). Western blots revealed increased ERα and ERβ in aorta and mesenteric artery and GPR30 in aorta of Preg vs virgin. Immunohistochemistry revealed that the increases in ERs were mainly in intima and media. E2 and PPT caused greater relaxation of aorta of Preg (52.8±5.5, 49.3±11.4) than virgin (30.0±3.9, 19.3±3.8%) and of mesenteric artery of Preg (77.9±4.7, 75.4±4.5) than virgin (57.4±5.9, 46.5±9.5%), but similar relaxation in carotid and renal artery of Preg vs virgin. DPN and G1 caused greater relaxation in mesenteric and renal artery (15 to 30%) than aorta and carotid artery ( virgin (5.3±6.7%). The NOS inhibitor L-NAME ± EDHF blocker tetraethylammonium or endothelium removal reduced PPT relaxation in aorta, suggesting an endothelium-dependent mechanism, but did not affect E2, PPT, DPN or G1-induced relaxation in other vessels, suggesting endothelium-independent mechanisms. PPT caused relaxation of Ca 2+ entry-dependent KCl contraction of mesenteric artery that was in Preg (69.7±5.5) > virgin rats (52.9±8.11%). Thus, during pregnancy, an increased ERα expression in endothelial and smooth muscle layers of aorta and mesenteric artery is associated with increased ERα-mediated relaxation via endothelium-derived vasodilators and direct inhibition of Ca 2+ entry pathways, supporting a role of aortic and mesenteric arterial ERα in pregnancy-associated systemic vasodilation. GPR30 may contribute to aortic dilation while the enhanced ERβ may mediate other genomic vascular effects during pregnancy.

Caveolin-1 (cav-1) is a transmembrane protein identified in plasma membrane caveolae, and a potential modulator of renal and vascular function and insulin sensitivity. We have shown that cav-1 gene variants are associated with insulin resistance (IR) in hypertensive humans, and that cav-1 deficiency in mice leads to increased blood pressure (BP) and IR. To test whether these changes in the cav-1 KO involve renal or vascular abnormalities, we treated WT and cav-1 KO mice for 14 days with placebo, the renin inhibitor aliskiren (50 mg/kg/day), or the Ca 2+ channel blocker amlodipine (6 mg/kg/day) and assessed BP, fasting blood glucose, HOMA-IR, plasma aldosterone (ALDO), and vascular function. Cav-1 KO mice, as compared with WT, showed increased BP (131±7 vs. 110±2 mm Hg), blood glucose (112±4 vs. 83±4 mg/dl), HOMA-IR (1.9±1.1 vs. 1.1±0.4), lower plasma ALDO (97±10 vs. 131±42 ng/dl), and altered vascular reactivity--reduced Phe-induced vasoconstriction (0.6±0.2 vs. 1.1±0.2g), enhanced acetylcholine (ACh)-induced relaxation (65±11 vs 23±7%), and enhanced relaxation in response to exogenous NO. Endothelium removal, NOS inhibition, or guanylate cyclase inhibition abolished ACh-induced relaxation, suggesting changes in endothelium-dependent NO-cGMP pathway in cav-1 KO mice. In cav-1 KO mice aliskiren significantly reduced BP to 113±4 mm Hg, ALDO levels by 40%, and HOMA-IR to 0.9±0.1, but had no significant effects on blood glucose, Phe-induced vasoconstriction, ACh- or exogenous NO-induced vasorelaxation. In contrast, amlodipine reduced BP to 117±4 mmHg (this effect did not reach significance), had no effect on ALDO levels, and showed a trend for increased IR. Importantly, amlodipine enhanced the sensitivity to Phe in both WT and cav-1 KO, and reduced the ACh-induced relaxation in cav-1 KO mice to 47±11%. Thus aliskiren treatment in cav-1 KO mice reduced BP possibly through suppression of RAAS and improved insulin sensitivity, but did not affect vascular function. In contrast, amlodipine treatment showed small changes in BP and IR but had adverse effects on vascular reactivity in cav-1 KO mice, raising the concern that it could have similar adverse effects on vascular function in hypertensive individuals that carry the cav-1 minor allele gene variants.

Striatin is a scaffolding protein that plays a role in vesicular trafficking in neurons. Striatin binds to regulatory proteins such as caveolin-1, Ca2+-calmodulin, Gαi and phosphatase 2A, thereby activating transduction molecules such as eNOS and mitogen-activated protein kinase. We have shown that striatin colocalizes with the minerlacorticoid receptor (MR), and that MR activation increases striatin levels in vascular cells in vivo and in vitro. To test the hypothesis that striatin is a critical regulator of vascular function, WT mice and heterozygous striatin-deficient mice lacking one allele for striatin (Strn-HET) were randomized in a crossover intervention to liberal salt (HS, 1.6% NaCl) and low salt (LS, 0.03% NaCl) diets for 7 days on each diet. Blood pressure (BP) and plasma aldosterone (ALDO) levels were measured and the aorta was excised to assess vascular function. Δ Systolic BP (BP on HS - BP on LS) was in Strn-HET > WT (16.5±3.5 vs 3.7±6.1 mmHg). Plasma ALDO levels were higher during LS diet, but were similar in WT and Strn-HET mice (152.6±23.9 vs 131.5±47.6 ng/dL on LS; 72.9±7.7 vs 70.9±8.3 ng/dL on HS). Phenylephrine (Phe) caused vascular contraction that was in Strn-HET (max 0.31±0.07g) > WT (0.23±0.07g). Also, high KCl (96 mM)-induced contraction was in Strn-HET (0.44±0.06g) > WT mice (0.33±0.05g) on HS diet, suggesting that the enhanced vascular contraction is not limited to a particular receptor. Endothelium removal, NOS inhibitor L-NAME and guanylate cyclase inhibitor ODQ enhanced contraction and increased sensitivity to Phe in WT mice and to a greater extent in Strn-HET mice on HS but not LS diet. On HS, acetylcholine (ACh) relaxation was in Strn-HET (max 33.16±4.47%) < WT (50.94±10.88%). ACh relaxation was blocked by endothelium removal, L-NAME and ODQ, supporting a role of the NO-cGMP pathway. Vascular relaxation to the exogenous NO donor sodium nitroprusside was not different between groups. Thus striatin deficiency during HS diet is associated with salt sensitivity of BP, enhanced vasoconstriction and decreased vascular relaxation. The results suggest a critical role for striatin, possibly through modulation of endothelium-dependent NO-cGMP pathway, in regulation of vascular function and BP during changes in dietary sodium intake.