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Background While many interventions to reduce hospital admissions and emergency department (ED) visits for patients with cardiovascular disease have been developed, identifying ambulatory cardiac patients at high risk for admission can be challenging. Hypothesis A computational model based on readily accessible clinical data can identify patients at risk for admission. Methods Electronic health record (EHR) data from a tertiary referral center were used to generate decision tree and logistic regression models. International Classification of Disease (ICD) codes, labs, admissions, medications, vital signs, and socioenvironmental variables were used to model risk for ED presentation or hospital admission within 90 days following a cardiology clinic visit. Model training and testing were performed with a 70:30 data split. The final model was then prospectively validated. Results A total of 9326 patients and 46 465 clinic visits were analyzed. A decision tree model using 75 patient characteristics achieved an area under the curve (AUC) of 0.75 and a logistic regression model achieved an AUC of 0.73. A simplified 9‐feature model based on logistic regression odds ratios achieved an AUC of 0.72. A further simplified numerical score assigning 1 or 2 points to each variable achieved an AUC of 0.66, specificity of 0.75, and sensitivity of 0.58. Prospectively, this final model maintained its predictive performance (AUC 0.63–0.60). Conclusion Nine patient characteristics from routine EHR data can be used to inform a highly specific model for hospital admission or ED presentation in cardiac patients. This model can be simplified to a risk score that is easily calculated and retains predictive performance.

Background The transvaginal natural orifice specimen extraction (NOSE) approach for right-side colon surgery has been proven to exhibit favorable short-term outcomes. However, thus far, no study has reported the advantages of transrectal NOSE for right-side colon surgery. The aim of this study was to compare the technical feasibility, safety, and short-term outcomes of minimally invasive right hemicolectomy using the transrectal NOSE method and those of conventional mini-laparotomy specimen extraction. Methods A study was conducted on consecutive patients who had minimally invasive right hemicolectomy either for malignancy or benign disease at Chang Gung Memorial Hospital, Linkou, Taiwan, between January 2017 and December 2018. The patients were divided into two groups: conventional surgery with specimen extraction using mini-laparotomy and NOSE surgery. Surgical outcomes, including complications, postoperative short-term recovery, and pain intensity, were analyzed. Results We enrolled 297 patients (151 males, mean age 64.9 ± 12.8 years) who had minimally invasive right hemicolectomy. Of these 297 patients, 272 patients had conventional surgery with specimen extraction through mini-laparotomy and 25 patients had NOSE surgery (23 transrectal, 2 transvaginal). The diagnosis of colon disease did not differ significantly between the conventional and NOSE groups. Postoperative morbidity and mortality rates were comparable. The postoperative hospital stay was significantly (p = 0.004) shorter in the NOSE group (median 5 days, range 3–17 days) than in the conventional group (median 7 days, range 3–45 days). Postoperative pain was significantly (p = 0.026 on postoperative day 1 and p = 0.002 on postoperative day 2) greater in the conventional group than in the NOSE group. Conclusions NOSE was associated with acceptable short-term surgical outcomes that were comparable to those of conventional surgery. NOSE results in less postoperative wound pain and a shorter hospital stay than conventional surgery. Larger studies are needed

Background The pathogenesis of vascular stiffening and hypertension is marked by non‐compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho‐associated coiled‐coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known. Methods and Results Hemizygous Rock mice ( Rock1 +/− and Rock2 +/− ) were used to determine the role of ROCK1 and ROCK2 in age‐related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild‐type mice compared with that of Rock1 +/− and Rock2 +/− mice. As a model for age‐related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L‐N ω ‐nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12‐week‐old male Rock1 +/− and Rock2 +/− mice. Similar to advancing age, angiotensin II/L‐N ω ‐nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in Rock2 +/− , and to a lesser extent, Rock1 +/− mice. The reduction of aortic stiffening in Rock2 +/− mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor‐β1 or angiotensin II was greatly attenuated in Rock2 −/− mouse embryonic fibroblasts. Conclusions These findings indicate that ROCK1 and ROCK2 mediate both age‐related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age‐related vascular stiffening.

Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1(+/−) and Ccm3(+/−) mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1(+/−) and Ccm3(+/−) transgenic mice were treated for three (Ccm3(+/−)) or four months (Ccm1(+/−)), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3(+/−)Trp53(−/−) lesions. Ccm1(+/−)Msh2(−/−) (n=68) and Ccm3(+/−)Trp53(−/−) (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.

BACKGROUND The purpose of this study was to examine the longitudinal association between rising violent crime and elevated blood pressure (BP). METHODS We analyzed 217,816 BP measurements from 17,783 adults during a temporal surge in violent crime in Chicago (2014–2016). Serial observations were abstracted from the electronic health record at an academic medical center and paired to the City of Chicago Police Data Portal. The violent crime rate (VCR) was calculated as the number of violent crimes per 1,000 population per year for each census tract. Longitudinal multilevel regression models were implemented to assess elevated BP (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg) as a function of the VCR, adjusting for patient characteristics, neighborhood characteristics, and time effects. Secondary dependent measures included elevated heart rate, obesity, missed outpatient appointments, all-cause hospital admissions, and cardiovascular hospital admissions. RESULTS At baseline, the median VCR was 41.3 (interquartile range: 15.2–66.8), with a maximum rise in VCR of 59.1 over the 3-year surge period. A 20-unit rise in the VCR was associated with 3% higher adjusted odds of having elevated BP (95% confidence interval [CI]: 1.01–1.06), 8% higher adjusted odds of missing an outpatient appointment (95% CI: 1.03–1.13), and 6% higher adjusted odds of having a cardiovascular-related hospital admission (95% CI: 1.01–1.12); associations were not significant for elevated heart rate and obesity. CONCLUSION Rising violent crime was associated with increased BP during a temporal crime surge.

Background and Purpose— Previously, murine models Krit1 +/− Msh2 −/ − and Ccm2 +/ − Trp53 −/ − showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods— The murine models, Pdcd10 +/ − Trp53 −/ − and Pdcd10 +/ − Msh2 −/ − , were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results— The Pdcd10 +/ − Trp53 −/ − /Msh2 −/ − models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P =0.027) by fasudil, and to 0.0047 ( P =0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions— These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.

Charles Darwin viewed eyes as the epitome of evolution by natural selection, describing them as organs of extreme perfection and complication. The visual system is therefore fertile ground for teaching fundamental concepts in optics and biology, subjects with scant representation during the rise and spread of immersive technologies in K-12 education. The visual system is an ideal topic for three-dimensional (3D) virtual reality learning environments (VRLEs), and here we describe a 3D VRLE that simulates the vision of a tarsier, a nocturnal primate that lives in southeast Asia. Tarsiers are an enduring source of fascination for having enormous eyes, both in absolute size and in proportion to the size of the animal. Our motivation for developing a tarsier-inspired VRLE, or Tarsier Goggles, is to demonstrate the optical and selective advantages of hyperenlarged eyes for nocturnal visual predation. In addition to greater visual sensitivity, users also experience reductions in visual acuity and color vision. On a philosophical level, we can never know the visual world of another organism, but advances in 3D VRLEs allow us to try in the service of experiential learning and educational outreach.

Statins, 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, have been used for decades for the prevention of coronary artery disease and stroke. They act primarily by lowering serum cholesterol through the inhibition of cholesterol synthesis in the liver, which results in the upregulation of low-density lipoprotein receptors in the liver. This results in the removal of low-density lipoproteincholesterol. Studies have suggested that statins may demonstrate additional effects that are independent of their effects on low-density lipoprotein-cholesterol. These have been termed “pleiotropic” effects. Pleiotropic effects may be due to the inhibition of isoprenoid intermediates by statins. Isoprenoid inhibition has effects on the small guanosine triphosphate binding proteins Rac and Rho which in turn effects nicotinamide adenine dinucleotide phosphate oxidases. Therefore, there are changes in endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypetrophy development. Recently, statins have been compared to the ezetimibe and the recently published outcomes data on the proprotein convertase subtilisin kexin type 9 inhibitors has allowed for a reexamination of statin pleiotropy. As a result of these diverse effects, it has been suggested that statins also have anti-arrhythmic effects. This review focuses on the mechanisms of statin pleiotropy and discusses evidence from the statin clinical trials as well as examining the possible anti-arrhythmic effects atrial fibrillation and ventricular tachyarrhythmias.

Over the past four decades, no class of drugs has had more impact on cardiovascular health than the 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors or statins. Developed as potent lipid-lowering agents, statins were later shown to reduce morbidity and mortality of patients who are at risk for cardiovascular disease. However, retrospective analyses of some of these clinical trials have uncovered some aspects of their clinical benefits that may be additional to their lipid-lowering effects. Such ‘pleiotropic’ effects of statins garnered intense interest and debate over its contribution to cardiovascular risk reduction. This review will provide a brief background of statin pleiotropy, assess the available clinical evidence for and against their non-lipid-lowering benefits, and propose future research directions in this field.

Significance: Label-free quantitative phase imaging is a promising technique for the automatic detection of abnormal red blood cells (RBCs) in real time. Although deep-learning techniques can accurately detect abnormal RBCs from quantitative phase images efficiently, their applications in diagnostic testing are limited by the lack of transparency. More interpretable results such as morphological and biochemical characteristics of individual RBCs are highly desirable. Aim: An end-to-end deep-learning model was developed to efficiently discriminate thalassemic RBCs (tRBCs) from healthy RBCs (hRBCs) in quantitative phase images and segment RBCs for single-cell characterization. Approach: Two-dimensional quantitative phase images of hRBCs and tRBCs were acquired using digital holographic microscopy. A mask region-based convolutional neural network (Mask R-CNN) model was trained to discriminate tRBCs and segment individual RBCs. Characterization of tRBCs was achieved utilizing SHapley Additive exPlanation analysis and canonical correlation analysis on automatically segmented RBC phase images. Results: The implemented model achieved 97.8% accuracy in detecting tRBCs. Phase-shift statistics showed the highest influence on the correct classification of tRBCs. Associations between the phase-shift features and three-dimensional morphological features were revealed. Conclusions: The implemented Mask R-CNN model accurately identified tRBCs and segmented RBCs to provide single-RBC characterization, which has the potential to aid clinical decision-making.

Background and introduction The difference in cardiovascular disease risk between age-matched women and men narrows as transition through menopause in observational studies. Estrogen exerts complex physiological effects via its non-nuclear and nuclear actions. Experimental studies have shown that endothelial estrogen receptors mediate vasoprotection via endothelial nitric oxide production, reendothelialization, and atherosclerosis. Prior studies in vitro addressed estrogen's effects on endothelial cells and vascular smooth muscle cells, leading to vasoprotection. However, the in vivo evidences are lacking for beneficial effects of endothelium non-nuclear ERα signaling on vascular remodelling in response to injury. Purpose This study aims to clarify the impact of endothelial ERα non-nuclear signaling in the vasoprotection, using a novel mouse model lacking tissue-specific ERα non-nuclear signaling. Methods We identified the amino acids of ERα which were responsible for its binding to p85α subunit of phosphatidylinositol 3-kinase in vitro. We generated a novel mouse model in which non-nuclear signaling of ERα was ablated in endothelial cells by crossing Tie2-Cre transgenic mice with floxed ERα mutants (RR259/260AA) in which p85α and ERα interaction was disrupted. Results In endothelial cells isolated from ERαKI/KITie2 cre/+ animals, E2 failed to induce phosphorylation of Akt, confirming the absence of ERα non-nuclear signaling. Baseline characteristics at 8 to 12 weeks of age were undistinguishable between the genotypes, including body weight, systolic blood pressure, uterine weight and echocardiographic fractional shortening. We then assessed how vascular remodelling process was impacted in a carotid artery wire injury model. Histological analyses with Elastica van Gieson staining two weeks after injury revealed that estrogen dependent suppression of remodelling response (intima to medial ratio) was abolished in ERαki/kiTie2cre/+mice (P=0.0004). Masson's Trichrome staining showed that in the presence of E2 fibrosis was significantly higher in ERαki/kiTie2cre/+ mice than ERαki/kiTie2cre/− mice (P=0.0015). Conclusions We generated a novel mouse model for tissue-specific ablation of ERα non-nuclear signaling by interfering ERα-PI3K interaction. Our results demonstrate that the pivotal role for ERα non-nuclear signaling of endothelial cells in carotid arterial protection following injury with its minimal impact on baseline cardiovascular phenotype. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Japan Heart Foundation Research Grant, SENSHIN Medical Research Foundation

Background: Myocardial ischemia occurs during myocardial infarction results in the stabilization of Hypoxia-inducible factors (HIFs). Hif2α expresses profoundly in vascular endothelial cells (EC), and its embryonic deletion increases vessel permeability. It has been shown that HIF2a is protective from renal and pulmonary injury. However, the direct role of ecHIF2α in ischemia heart disease is unknown. We hypothesized that ecHIF2a expression in response to myocardial infarction (MI) protects cardiac barrier dysfunction and against heart failure. Methods and Results: We generated the Inducible endothelial-specific knockout mice (ecHIF2a -/- ) by crossing Hif2a flox/flox mice with Cre ERT2 mice under the VE-cadherin promoter. Followed with MI, ecHIF2a -/- mice displayed worsened cardiac function determined by echocardiography, and they had increased mortality as compared to the controls. In vitro, we used primary mouse cardiac microvascular endothelial cells (mCMVEC) from ecHIF2a -/- mouse hearts. We found that under hypoxia condition or 1mM Dimethyloxalylglycine treatment, the deficiency of HIF2a in the mCMVEC increased endothelial permeability determined by trans-endothelial electrical resistance. The knocking down of HIF2a in HUVECs induced by a HIF2a siRNA led to impaired tube formation accessed by the significant reduction in total node counts, junctions, meshes, and full tube length compared to control-siRNA treated cells. HIF2α deletion and hypoxia both reduced endothelial cell migration, and interestingly, the retarded HIF2α-/- ECs migration seems to be independent of hypoxia. Moreover, apoptosis assay showed that ecHIF2a -/- ECs increased cell early apoptotic stage compared to WT in hypoxic conditions, but not in normoxia indicating the critical role of HIF2α in ECs survival during cardiac ischemia. Finally, several increased markers of inflammation, such as ICAM-1 and VCAM-1, are associated with HIF2a deletion. Conclusion: These data revealed an essential role of HIF2α in protecting cardiac remodeling in response to MI, which might through promoting endothelial cell migration, barrier function, as well as vascularization. Thus, HIF2α is a potential therapeutic target in the treatment of ischemic heart disease.

Introduction: Impaired endothelial function leads to the progression of heart failure after Ischemia-reperfusion (IR). Kinin activation of bradykinin receptor 1 (B1R), a G protein-coupled receptor that has been found to induce capillary leakage, may serve as a critical mediator in cardiac microvascular barrier dysfunction. However, the underlying mechanisms are not clear. We found that B1R inhibition abolished IR-induced endothelial matrix metalloprotease (MMP3) expression and improved endothelial barrier formation. Thus, we hypothesized that B1R antagonist protects against cardiac IR injury through an MMP3 pathway. Methods and Results: MMP3-/- mice and their littermate controls (WT) were subjected to either cardiac IR or sham control. The baseline characteristics of these mice showed minimal phenotypes. Cardiac function was determined at 3, 7 and 24 days post-IR by echocardiography. The MMP3-/- mice displayed improved cardiac function compared to the control mice, as determined by fractional shortening (26% ± 1.1 MMP3-/- vs. 21% ± 0.9 WT, p Conclusions: MMP3 is a critical regulator of cardiac microvascular barrier function, and B1R/MMP3 could potentially serve as a novel therapeutic target for heart failure in response to IR injury.

BACKGROUND: Low-socioeconomic, urban, minority patients with heart failure (HF) often have unique barriers to care. Community health workers (CHWs) are specially trained laypeople who serve as liaisons between underserved communities and the health system. It is not known whether CHWs improve outcomes in low-socioeconomic, urban, minority patients with HF. HYPOTHESIS: CHWs reduce rehospitalizations, emergency department (ED) visits, and healthcare costs for low-socioeconomic urban patients with HF. METHODS: Patients admitted with acute decompensated HF were assigned to receive weekly visits by CHW after discharge. Patients were propensity score matched with controls who received usual care. HF-related rehospitalizations, ED visits, and inpatient costs were compared for 12 months following index admission versus the same period before. RESULTS: Twenty-eight patients who received weekly visits from a CHW for 12 months after discharge were matched with 28 control patients who did not receive CHWs. Patients who received a CHW had a 75% decrease in HF-related ED visits (0.71 vs. 0.18 visits per patient, P < 0.001), an 89% decrease in HF-related readmissions (0.64 vs. 0.07 admissions per patient, P < 0.005), and a significant decrease in inpatient cost for HF-related visits. In controls receiving usual care, there was no significant change in hospitalizations, ED visits, or costs. CONCLUSIONS: In conclusion, CHWs are associated with reduced rehospitalizations, ED visits, and inpatient costs in low-socioeconomic, urban, minority patients with HF. CHWs may be a cost-effective method to reduce health care utilization and improve outcomes for this population.

Background More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. Objective To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. Methods The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. Expected outcomes The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. Discussion With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Objectives Cognitive dysfunction and dementia are common following ischemic stroke. Endothelial nitric oxide synthase (eNOS) has been found to play an important role in neurologic function and cognition. The purpose of the present study was to assess the specific role of eNOS in cognitive performance after stroke. Design Male wild-type and mice lacking eNOS (eNOS) underwent middle cerebral artery occlusion or sham-surgery. Primary outcomes were repeated measures of neurologic score, limb asymmetry, sensory/motor function, and spatial memory/learning assessed at intervals up to 28 days postsurgery. Group differences in brain microglia activation and infiltration and levels of interferon-gamma were examined. Results There was no genotype × surgery interaction effect on the pattern of change in neurologic score, limb asymmetry, or sensory motor function across the 28 days postsurgery. In the Morris water maze, eNOS-/- middle cerebral artery occlusion mice displayed learning and memory deficits not evident in wild-type middle cerebral artery occlusion mice. Poorer spatial memory and learning in eNOS-/- middle cerebral artery occlusion mice was associated with a reduction in the number of activated microglia in the striatum on the lesion side and decreased brain tissue levels of interferon-gamma. Conclusions This study's data support a role for eNOS in cognitive performance after stroke. This finding may lead to the development of novel interventions to treat poststroke cognitive deficits.

Traditional informatics in comparative genomics work only with static representations of biomolecules (i.e., sequence and structure), thereby ignoring the molecular dynamics (MD) of proteins that define function in the cell. A comparative approach applied to MD would connect this very short timescale process, defined in femtoseconds, to one of the longest in the universe: molecular evolution measured in millions of years. Here, we leverage advances in graphics-processing-unit-accelerated MD simulation software to develop a comparative method of MD analysis and visualization that can be applied to any two homologous Protein Data Bank structures. Our open-source pipeline, DROIDS (Detecting Relative Outlier Impacts in Dynamic Simulations), works in conjunction with existing molecular modeling software to convert any Linux gaming personal computer into a “comparative computational microscope” for observing the biophysical effects of mutations and other chemical changes in proteins. DROIDS implements structural alignment and Benjamini-Hochberg-corrected Kolmogorov-Smirnov statistics to compare nanosecond-scale atom bond fluctuations on the protein backbone, color mapping the significant differences identified in protein MD with single-amino-acid resolution. DROIDS is simple to use, incorporating graphical user interface control for Amber16 MD simulations, cpptraj analysis, and the final statistical and visual representations in R graphics and UCSF Chimera. We demonstrate that DROIDS can be utilized to visually investigate molecular evolution and disease-related functional changes in MD due to genetic mutation and epigenetic modification. DROIDS can also be used to potentially investigate binding interactions of pharmaceuticals, toxins, or other biomolecules in a functional evolutionary context as well.

Undoped GaSb is p-type with the residual acceptor concentration of about 1e17 cm−3 due to the gallium vacancies and gallium in antimony site. Counter-doping of GaSb with low level of Te can reduce the net carrier concentration resulting in higher optical transparency in a broad IR spectral range. In this work, the carrier concentration, mobility and sheet resistance of n-type and p-type Te-doped GaSb substrates were measured using Hall method at 300 K and 77 K. The Hall carrier concentration data at 300 K were correlated with the absorption coefficients of GaSb in the IR spectral range. An empirical relationship between these values was established. Based on this correlation, we discuss application of FTIR spectroscopy for non-destructive optical screening of the substrates that allows construction of the carrier concentration distribution map across GaSb wafers. Investigations of the electronic properties of the low-doped p-type and n-type GaSb substrates upon cooling down to 77 K indicate the reduction of the hole carrier concentration background for both GaSb types. This is evident from the decrease in the Hall-measured carrier concentration for p-type GaSb. For n-type GaSb, an increase in the carrier concentration is observed due to the reduction of the hole carrier concentration background.

Background and Purpose— We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease. Methods— Two heterozygous murine models, Ccm1 +/− Msh2 − /− and Ccm2 +/− Trp53 −/− , were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity. Results— Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1 +/− Msh2 −/− mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1 +/− Msh2 −/− mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of Ccm1 +/− Msh2 −/− mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1 +/− Msh2 −/− mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2 +/− Trp53 −/− mice alone, and Fasudil benefit seemed limited to males. Conclusions— ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.

Background: Estrogen plays a significant role in cardiovascular benefits. As one of its beneficial pathways, ERα non-nuclear signaling is known to be protective for the vascular system, but its role for cardiac remodeling is unknown thus far. We previously reported cGMP pathways are one of the critical therapeutic targets for heart failure and ERα non-nuclear signaling played a pivotal role in cardioprotection and was indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition. However, it is still remaining undetermined which cells are playing the key role in cardioprotective effects via ERα non-nuclear signaling. Methods: We generated genetically modified mouse lacking ERα in cardiomyocytes (ERα f/f /αMHC Cre/+ ) or endothelial cells (ERα f/f /Tie2 Cre/+ ) and assessed the effects of chronic pressure-overload (TAC) and the efficacy of PDE5 inhibitor (PDE5i) sildenafil after TAC. In addition, for the first time we generated endothelial cell specific genet-modified mouse lacking interactions between p85α and ERα which are critical for non-nuclear signaling (ERα KI/KI /Tie2 Cre/+ ). Cardiac functions were assessed for evaluating the effects of endothelial ERα non-nuclear singlaing to failing hearts. Results: Under physiological E2 status, PDE5i’s anti-remodeling effects after TAC were abrogated in ERα f/f /Tie2 Cre/+ (FS(%) ± SEM with vs without PDE5i 28.16 ± 3.43 vs 31.87 ± 2.30) but not in ERα f/f /αMHC Cre/+ (FS(%) ± SEM with PDE5i vs without PDE5i 54.57 ± 3.418 vs 43.3 ± 1.21) consistent with hemodynamic analysis. Assessment with ERα KI/KI /Tie2 Cre/+ showed decreased cardiac functions even with physiological E2. Hemodynamic analysis also supported the cardioprotective effects of ERα non-nuclear signaling in endothelial cells. Conclusion: ERα non-nuclear reaction in endothelial cells plays an important role in cardio-protective mechanism, and endothelial estrogen signals are indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition. Our results clarified one of the cardioprotective signals of estrogen and highlighted the new strategy for heart failure treatment.

OBJECTIVE Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA). METHODS Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA. RESULTS After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 ± 0.25 to 0.69 ± 0.25 (P

Background: Dual antiplatelet therapy (aspirin plus clopidogrel/ticagrelor - DAPT) is a mainstay treatment for NSTEMI. However, studies suggest that early administration of clopidogrel may not confer significant benefit over later administration. As the time to peak plasma concentration is much shorter for ticagrelor (1-2 hours) vs. clopidogrel (8-12 hours), we hypothesized that earlier administration of ticagrelor may confer survival benefit over later administration. Methods: Patients treated for NSTEMI at our center using DAPT, January 2012 through May 2017, between 18 and 90 years old, were retrospectively identified. Patients who left the hospital against medical advice, were discharged to hospice, or were already treated with DAPT or an anticoagulant at the time of presentation were excluded. Patients who received ticagrelor ≤ 2 hours from arrival were matched with similar patients who received ticagrelor > 2 hours from arrival using 30 clinical and demographic variables. Patients who received clopidogrel were matched similarly. We then compared survival for 500 days using a log rank test. Results: 349 patients met the inclusion criteria. Of these, 18 received ticagrelor within 2 hours and 41 received clopidogrel within 2 hours. These were matched with 18 and 41 control patients, respectively, who received ticagrelor/clopidogrel > 2 hours from arrival. As shown in Figure 1a, patients who received ticagrelor ≤ 2 hours from arrival had significantly lower 500-day mortality than patients who received ticagrelor > 2 hours from arrival (0.0% vs. 27.7%; p=0.017). There was no difference in mortality between the early and late clopidogrel groups (Figure 1b). Conclusion: In the ticagrelor era, early administration of DAPT with ticagrelor (within 2 hours of arrival) may be associated with improved mortality in patients with NSTEMI, an effect not seen with clopidogrel. Larger studies investigating the impact of door to DAPT time in patients with NSTEMI are needed.

Background: Nonsurgical bleeding is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations. We hypothesized that deregulation of an angiogenic factor, angiopoietin-2 (Ang-2), in patients with LVADs leads to increased angiogenesis and higher nonsurgical bleeding. Methods: Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure, LVAD, or orthotopic heart transplantation. Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation from serum from each patient with or without Ang-2–blocking antibody. Ang-2 gene expression was measured by reverse transcription–polymerase chain reaction in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker vorapaxar. Results: Compared with patients with heart failure or those with orthotopic heart transplantation, serum levels and endothelial expression of Ang-2 were higher in LVAD patients ( P =0.001 and P P P =0.003), which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells ( P P =0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more nonsurgical bleeding events compared with patients with Ang-2 levels below the mean ( P =0.003). Conclusions: Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher nonsurgical bleeding events. Ang-2 therefore may contribute to arteriovenous malformation formation and subsequent bleeding in LVAD patients.

Hypertensive cardiac remodeling is characterized by left ventricular hypertrophy and interstitial fibrosis, which can lead to heart failure with preserved ejection fraction. The Rho-associated coiled-coil containing kinases (ROCKs) are members of the serine/threonine protein kinase family, which mediates the downstream effects of the small GTP-binding protein RhoA. There are 2 isoforms: ROCK1 and ROCK2. They have different functions in different types of cells and tissues. There is growing evidence that ROCKs contribute to the development of cardiovascular diseases, including cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling. Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling. Indeed, clinical studies with fasudil have suggested that ROCKs could be potential novel therapeutic targets for cardiovascular diseases. In this review, we summarize the current understanding of the roles of ROCKs in the development of cardiac fibrosis and hypertrophy and discuss their therapeutic potential for deleterious cardiac remodeling. (Circ J 2016; 80: 1491-1498).

To investigate the superiority of free-breathing coronary computed tomography angiography (CCTA) with 16-cm wide-detector CT for challenging patients who cannot hold their breath.A total of 76 patients (62% with either heart rate75 beats/min or arrhythmia) who were unable to breath-hold underwent both free-breathing CCTA and invasive coronary angiography (ICA) were included. Two reviewers evaluated coronary arteries on a per-segment, per-vessel, and per-patient basis for image quality using a four-point scale and stenosis degree. CCTA results were compared with ICA to calculate the diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).Out of 1,368 segments, 228 (16.7%) were1.5 mm in diameter and were excluded. Thirty-two (2.3%) with calcification and 26 (1.9%) with motion artefacts were considered positive at CT. One thousand and eighty-two segments (79.1%) were evaluated both on CCTA and ICA, and 128 (11.8%) segments had ≥50% stenosis on ICA. The diagnostic accuracy, sensitivity, specificity, PPV, and NPV of CCTA were 90.8%, 88.3%, 91.1%, 57.1%, and 98.3% on a per-segment basis; 93.4%, 90.6%, 94.2%, 80.5% and 97.4% on a per-vessel basis; and 92.1%, 100%, 85%, 85.7% and 100% on a per-patient basis. For patients with high heart rates or arrhythmia, 81% (versus 79.1%) segments were evaluable, and the accuracy, sensitivity, specificity, PPV, and NPV were statistically the same as the entire study population.Free-breathing CCTA using 16-cm wide-detector CT has high accuracy compared to ICA for detecting coronary artery stenosis for challenging patients.

Background: Recent studies suggest that regulator of G-protein signaling 5 (RGS5), a negative modulator of the G-protein coupled receptors (GPCR) signaling pathways, may be an important modulator of glutamate receptor activation and calcium overload in endothelial cells after ischemic stroke. While glutamate may cause neuronal damage, it is unknown how glutamate affects blood-brain barrier (BBB) permeability. Methods: To investigate the effects of RGS5 on stroke severity, wild type (WT) and RGS5 -/- mice were subjected to 30 minutes of middle cerebral artery occlusion (MCAO). Cerebral infarct volume was evaluated by TTC and Nissl staining, while neurological deficit was assessed using a 5-point motor grading scale and adhesive tape removal test. BBB permeability was analyzed by measuring brain edema with the wet/dry method and by injecting 40kDA FITC-Dextran into the femoral vein. The role of RGS5 in regulating ischemia/glutamate-induced Rho/ROCK signaling in human brain microvasculare cells (HBMEC) was investigated using lentiviral transduction of RGS5 shRNA. To mimic brain ischemic conditions in vitro , we used a model consisting of 3-hour oxygen-glucose deprivation (OGD) with L-glutamate. RhoA/ROCK activity was determined by the phosphorylation MYPT1. In vitro permeability was assessed by Transwell permeability assays. Formation of actin stress fibers was observed with Phalloidin staining. Redistribution of important tight junction (TJ) proteins was analyzed by immunostaining. Results: Following MCAO, RGS5 -/- mice exhibited larger cerebral infarct volume and greater neurological deficits compared to controls. Brain water content and FITC-Dextran leakage were higher in the ipsilateral hemisphere of RGS5 -/- mice compared to controls. Furthermore, the Transwell permeability assay demonstrated increased permeability of FITC-Dextran in RGS5-deficient HBMEC, higher Rho/ROCK activation, greater actin-stress fiber formation, and redistribution of TJ proteins. Conclusion: These findings indicate that RGS5 plays an important role in actin cytoskeleton remodeling and BBB permeability following focal cerebral ischemia, in part, through the upregulation of RhoA/ROCK pathway.

BACKGROUND Rho-associated kinases (ROCK1 and ROCK2) are important regulators of the actin cytoskeleton and endothelial nitric oxide synthase (eNOS). Because the phosphorylation of eukaryotic elongation factor-1A1 (eEF1A1) by ROCK2 is critical for eNOS expression, we hypothesized that this molecular pathway may play a critical role in neuroprotection following focal cerebral ischemia.Methods and Results:Adult male wild-type (WT) and mutant ROCK2 and eNOS-/-mice were subjected to middle cerebral artery occlusion (MCAO), and cerebral infarct size, neurological deficit and absolute cerebral blood flow were measured. In addition, aortic endothelium-dependent response to acetylcholine, NG-nitro-L-arginine methyl ester (L-NAME) and sodium nitroprusside were assessed ex vivo. Endothelial cells from mouse brain or heart were used to measure eNOS and eEF1A activity, as well as NO production and eNOS mRNA half-life. In global hemizygous ROCK2+/-and endothelial-specific EC-ROCK2-/-mice, eNOS mRNA stability and eNOS expression were increased, which correlated with enhanced endothelium-dependent relaxation and neuroprotection following focal cerebral ischemia. Indeed, when ROCK2+/-mice were place on an eNOS-/-background, the neuroprotective effects observed in ROCK2+/-mice were abolished. CONCLUSIONS These findings indicate that the phosphorylation of eEF1A1 by ROCK2 is physiologically important for eNOS expression and NO-mediated neuroprotection, and suggest that targeting endothelial ROCK2 and eEF1A may have therapeutic benefits in ischemic stroke and cardiovascular disease.

Rho-associated kinases play an important role in a variety of cellular functions. Although Rho-associated kinase activity has been shown to be an independent predictor for future cardiovascular events in a general population, there is no information on Rho-associated kinase activity in patients with acute coronary syndrome. We evaluated leukocyte Rho-associated kinase activity by Western blot analysis in 73 patients with acute coronary syndrome and 73 age- and gender-matched control subjects. Rho-associated kinase activity within 2 hours of acute coronary syndrome onset was higher in patients with acute coronary syndrome than in the control subjects (0.95±0.55 versus 0.69±0.31; P P =0.03 and P =0.03, respectively) and then gradually decreased to 0.83±0.52 after 7 days, 0.78±0.42 after 14 days, and 0.72±0.30 after 6 months ( P =0.22, P =0.29, and P =0.12, respectively). During a median follow-up period of 50.8 months, 31 first major cardiovascular events (death from cardiovascular causes, myocardial infarction, ischemic stroke, and coronary revascularization) occurred. After adjustment for age, sex, cardiovascular risk factors, and concomitant treatment with statins, increased Rho-associated kinase activity was associated with increasing risk of first major cardiovascular events (hazard ratio, 4.56; 95% confidence interval, 1.98–11.34; P

The epidemiology of candidaemia varies between hospitals and geographic regions. Although there are many studies from Asia, a large-scale cross-sectional study across Asia has not been performed. We conducted a 12-month, laboratory-based surveillance of candidaemia at 25 hospitals from China, Hong Kong, India, Singapore, Taiwan and Thailand. The incidence and species distribution of candidaemia were determined. There were 1601 episodes of candidaemia among 1.2 million discharges. The overall incidence was 1.22 episodes per 1000 discharges and varied among the hospitals (range 0.16–4.53 per 1000 discharges) and countries (range 0.25–2.93 per 1000 discharges). The number of Candida blood isolates and the total number of fungal isolates were highly correlated among the six countries ( R ² = 0.87) and 25 hospitals ( R ² = 0.77). There was a moderate correlation between incidence of candidaemia and the intensive care unit (ICU)/total bed ratio ( R ² = 0.47), although ICUs contributed to only 23% of candidaemia cases. Of 1910 blood isolates evaluated, Candida albican s was most frequently isolated (41.3%), followed by Candida tropicalis (25.4%), Candida glabrata (13.9%) and Candida parapsilosis (12.1%). The proportion of C. tropicalis among blood isolates was higher in haemato-oncology wards than others wards (33.7% versus 24.5%, p 0.0058) and was more likely to be isolated from tropical countries than other Asian countries (46.2% versus 18.9%, p 0.04). In conclusion, the ICU settings contribute, at least in part, to the incidence variation among hospitals. The species distribution is different from Western countries. Both geographic and healthcare factors contribute to the variation of species distribution.

The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases (ROCKs) in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma (APA), 23 patients with idiopathic hyperaldosteronism (IHA), and 40 age-, sex-, and blood pressure–matched patients with essential hypertension (EHT). FMD was significantly lower in the APA group than in the IHA and EHT groups (3.2±2.0% versus 4.6±2.3% and 4.4±2.2%; P P r =−0.31; P r =−0.35; P r =−0.34; P r =−0.24; P =0.04), plasma aldosterone concentration ( r =0.33; P r =0.46; P

The RhoA/Rho-associated kinase (ROCK) pathway has a key physiological role in the pathogenesis of atherosclerosis. Increased ROCK activity is associated with cardiovascular diseases. Endogenous nitric oxide (NO) has an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in patients with angina pectoris. This is a prospective, open-label, randomized, controlled study. A total of 30 patients with angina pectoris were randomly assigned to receive 40 mg day−1 of isosorbide mononitrate (n = 15, 12 men and 3 women, mean age of 63 ± 12 years, isosorbide mononitrate group) or conventional treatment (n = 15, 13 men and 2 women, mean age of 64 ± 13 years, control group) for 12 weeks. ROCK activity in peripheral leukocytes was measured by western blot analysis. ROCK activities at 4 and 12 weeks after treatment were decreased in the isosorbide mononitrate group (0.82 ± 0.33 at 0 week, 0.62 ± 0.20 at 4 weeks, 0.61 ± 0.19 at 12 weeks, n = 15 in each group, P < 0.05, respectively) but not altered in the control group. ROCK1 and ROCK2 expression levels were similar in all treatment periods in the two groups. These findings suggest that the administration of exogenous NO can inhibit ROCK activity, indicating that the usage of exogenous NO could have a protective effect in patients with angina pectoris.

Stroke is a major cause of disability and the fifth leading cause of death. Currently, the only approved acute medical treatment of ischemic stroke is tissue plasminogen activator (tPA), but its effectiveness is greatly predicated upon early administration of the drug. There is, therefore, an urgent need to find new therapeutic options for acute stroke. Areas covered: In this review, we summarize the role of Rho-associated coiled-coil containing kinase (ROCK) and its potential as a therapeutic target in stroke pathophysiology. ROCK is a major regulator of cell contractility, motility, and proliferation. Many of these ROCK-mediated processes in endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, glia, neurons, leukocytes, and platelets are important in stroke pathophysiology, and the inhibition of such processes could improve stroke outcome. Expert commentary: ROCK is a potential therapeutic target for cardiovascular disease and ROCK inhibitors have already been approved for human use in Japan and China for the treatment of acute stroke. Further studies are needed to determine the role of ROCK isoforms in the pathophysiology of cerebral ischemia and whether there are further therapeutic benefits with selective ROCK inhibitors.

Although left ventricular (LV) diastolic dysfunction is often associated with hypertension, little is known regarding its underlying pathophysiological mechanism. Here, we show that the actin cytoskeletal regulator, Rho-associated coiled-coil containing kinase-2 (ROCK2), is a critical mediator of LV diastolic dysfunction. In response to angiotensin II (Ang II), mutant mice with fibroblast-specific deletion of ROCK2 (ROCK2Postn-/-) developed less LV wall thickness and fibrosis, along with improved isovolumetric relaxation. This corresponded with decreased connective tissue growth factor (CTGF) and fibroblast growth factor-2 (FGF2) expression in the hearts of ROCK2Postn-/- mice. Indeed, knockdown of ROCK2 in cardiac fibroblasts leads to decreased expression of CTGF and secretion of FGF2, and cardiomyocytes incubated with conditioned media from ROCK2-knockdown cardiac fibroblasts exhibited less hypertrophic response. In contrast, mutant mice with elevated fibroblast ROCK activity exhibited enhanced Ang II-stimulated cardiac hypertrophy and fibrosis. Clinically, higher leukocyte ROCK2 activity was observed in patients with diastolic dysfunction compared with age- and sex-matched controls, and correlated with higher grades of diastolic dysfunction by echocardiography. These findings indicate that fibroblast ROCK2 is necessary to cause cardiac hypertrophy and fibrosis through the induction CTGF and FGF2, and they suggest that targeting ROCK2 may have therapeutic benefits in patients with LV diastolic dysfunction.

Background Non-surgical bleeding (NSB) due to angiodysplasia is common in left ventricular assist device (LVAD) patients. Thrombin-induced angiopoietin-2 (Ang-2) expression in LVAD patients leads to altered angiogenesis and is associated with lower angiopoietin-1 (Ang-1) and increased NSB. However, the mechanism for decreased Ang-1, made by pericytes, is unknown and the origin of thrombin in LVAD patients is unclear. We hypothesized that high tumor necrosis factor-α (TNF-α) levels in LVAD patients induce pericyte apoptosis, tissue factor (TF) expression and vascular instability. Methods We incubated cultured pericytes with serum from patients with heart failure (HF), LVAD or orthotopic heart transplantation (OHT), with or without TNF-α blockade. We performed several measurements: Ang-1 expression was assessed by reverse transcript-polymerase chain reaction (RT-PCR) and pericyte death fluorescently; TF expression was assessed by RT-PCR in cultured endothelial cells incubated with patient plasma with or without TNF-α blockade; and TF expression was assessed in endothelial biopsy samples from these patients by immunofluorescence. We incubated cultured endothelial cells on Matrigel with patient serum with or without TNF-α blockade and determined tube formation by microscopy. Results Serum from LVAD patients had higher levels of TNF-α, suppressed Ang-1 expression in pericytes, and induced pericyte death, and there was accelerated endothelial tube formation compared with serum from patients without LVADs. TF was higher in both plasma and endothelial cells from LVAD patients, and plasma from LVAD patients induced more endothelial TF expression. All of these effects were reversed or reduced with TNF-α blockade. High levels of TNF-α were associated with increased risk of NSB. Conclusions Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis and expression of TF and Ang-1.

Aim: To correlate cerebral cavernous malformations (CCMs) disease aggressiveness with peripheral blood biomarkers hypothesized mechanistically. Patients & methods: A prospective case–control study enrolled 43 CCM patients, where 25-(OH) vitamin D, HDL and non-HDL cholesterol, CRP plasma levels and leukocyte ROCK activity were correlated with parameters of disease aggressiveness reflecting chronic and acute domains. Results: Patients with one or more features of chronically aggressive disease (early age at symptom onset, two or more symptomatic bleeds, high lesion burden) had significantly lower 25-(OH) vitamin D and non-HDL cholesterol levels in comparison to patients without these features. Conclusion: Validation of these biomarkers and their potential treatment modulation may influence the clinical care of patients with CCM disease.

In recent years, piezoelectric fans and their feasibility of cooling electronic devices have been widely studied. Nonetheless, there is few study about using piezoelectric fans to generate radial air flow. In this study, a radial multiple fan system (RMFS) was developed for the thermal management of high power LEDs. This system used one piezoelectric actuator and the magnetic repulsive force to activate up to 20 passive fans, which featured low power consumption and a large cooling area. The RMFS was embedded in a circular heat sink in order to evaluate its thermal performance. To find the optimal design of the RMFS, some geometry parameters were investigated. Besides, the performance of different designs was compared with commercially available axial fan. The results showed that design E had the better thermal performance because of its relatively large frequency and amplitude. The thermal resistance and the percentage improvement under 15 W heat flux were 0.84 K/W and 41.9 %, respectively. Moreover, a dimensionless number for the RMFS (M RMFS ) was defined to assess the enhancement of the convective heat transfer coefficient. In design E, M RMFS was 2.1 when the power consumption of the RMFS was only 0.2 W.

In this study, a multiple fans system with a piezoelectric actuator (MFPA) was integrated with a vapor chamber. The integrated system was embedded in a micro-computer for its thermal management. The MFPA utilized magnetic repulsive force to transfer power from the piezoelectric actuator to the adjacent passive fans. Models with different fan length, fan pitch and the number of the fans were developed. The thermal performance, vibrational amplitude, and power consumption of different models were investigated. The experiment results showed that the thermal resistance of all the models decreased when the input power increased. Besides, the model with shorter carbon fiber plate length, larger fan pitch and larger fan number had the lower thermal resistance. The model with five fans, 11 mm fan pitch, 40 mm carbon fiber plate and 10 mm Mylar plate had the lowest thermal resistance at 3.14 °C/W under the 12 W input power, while the thermal resistance of natural convection was 4.88 °C/W. The power consumption of the model was merely 0.05 W.

Social determinants of health (SDOH) critically impact healthcare access and outcomes. However, few studies have examined spatial relationships between SDOH and disease prevalence at neighborhood scales. In this study, we merged electronic health record (EHR) data from a major Chicago hospital

Hypertension and diabetes are common among poor urban dwellers. We hypothesized that blood pressure and glucose are higher for patients living farther from the pharmacy they typically use. Medical records of adult South Side dwellers who received care at the University of Chicago's outpatient

Despite improvements in treatments for heart failure in the last 30 years, significant barriers exist for underserved populations including access to care, nonadherence to prescribed treatments, and lack of support for self-management. Community health workers (CHW) are specially trained lay-people

Background Recent evidence suggests that Rho-kinase (ROCK) plays an important role in the pathogenesis of atherosclerosis and a marker of atherosclerotic burden. Polyvascular disease with concomitant peripheral arterial disease (PAD) and coronary artery disease (CAD) is common and associated with a worse prognosis. The aim of this study was to evaluate ROCK activity as a marker of polyvascular disease. Hypothesis Methods We retrospectively analyzed patients undergoing coronary angiography at our institution between February 2009 and May 2009. Patients with only CAD (n = 40) defined by coronary artery stenosis of ≥50% by angiography, only PAD (n = 40) defined by an ankle brachial index (ABI)