Prevalence and Survival of Prolonged Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: An Analysis of the Extracorporeal Life Support Organization Registry.

OBJECTIVES: To examine trends in utilization and outcomes among patients with the acute respiratory distress syndrome (ARDS) requiring prolonged venovenous extracorporeal membrane oxygenation (VV ECMO) support. DESIGN: Retrospective observational cohort study. SETTING: Adult patients in the Extracorporeal Life Support Organization registry. PATIENTS: Thirteen thousand six hundred eighty-one patients that required ECMO for the support of ARDS between January 2012 and December 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mortality while supported with VV ECMO and survival to hospital discharge based on ECMO duration were examined utilizing multivariable logistic regression. Among the 13,681 patients supported with VV ECMO, 4,040 (29.5%) were supported for greater than or equal to 21 days and 975 (7.1%) for greater than or equal to 50 days. Patients supported with prolonged VV ECMO were less likely to be discharged alive from the hospital compared with those with short duration of support (46.5% vs. 59.7%; p < 0.001). However, among patients supported with VV ECMO greater than or equal to 21 days, duration of extracorporeal life support was not significantly associated with mortality (odds ratio [OR], 0.99; 95% CI, 0.98-1.01; p = 0.87 and adjusted OR, 0.99; 95% CI, 0.97-1.02; p = 0.48). Even in those supported with VV ECMO for at least 120 days (n = 113), 52 (46.0%) of these patients were ultimately discharged alive from the hospital. CONCLUSIONS: Prolonged VV ECMO support of ARDS has increased and accounts for a substantial portion of cases. Among patients that survive for greater than or equal to 21 days while receiving VV ECMO support, duration is not predictive of survival to hospital discharge and clinical recovery may occur even after very prolonged VV ECMO support.

A proposed device based on MoSe2-ZnO heterojunctions on rGO for enhanced ethanol gas sensing performances at room temperature.

In this research, we report an enhanced sensing response ethanol gas sensing device based on a ternary nanocomposite of molybdenum diselenide-zinc oxide heterojunctions decorated rGO (MoSe2/ZnO/rGO) at room temperature. The sensing performance of the ternary nanocomposite sensing device has been analysed for various concentrations of ethanol gas (1-500 ppm). The gas-sensing results have revealed that for 500 ppm ethanol gas concentration, the sensing device has exhibited an enhanced response value(Rg/Ra)of 50.2. Significantly, the sensing device has displayed a quick response and recovery time of 6.2 and 12.9 s respectively. In addition to this, the sensing device has shown a great prospect for long-term detection of ethanol gas (45 days). The sensing device has demonstrated the ability to detect ethanol at remarkably low concentrations of 1 ppm. The enhanced sensing performance of the ternary nanocomposite sensing device has highlighted the effective synergistic effect between MoSe2nanosheets, ZnO nanorods, and rGO nanosheets. This has been attributed to the formation of two heterojunctions in the ternary nanocomposite sensor: a p-n heterojunction between MoSe2and ZnO and a p-p heterojunction between MoSe2and rGO. The analysis of the results has suggested that the proposed MoSe2/ZnO/rGO nanocomposite sensing device could be considered a promising candidate for the real-time detection of ethanol gas.

Fabrication of rGO-decorated hBNNS hybrid nanocomposite via organic-inorganic interfacial chemistry for enhanced electrocatalytic detection of carcinoembryonic antigen.

Organic-inorganic hybrid nanocomposites (OIHN), with tailored surface chemistry, offer ultra-sensitive architecture capable of detecting ultra-low concentrations of target analytes with precision. In the present work, a novel nano-biosensor was fabricated, acquainting dynamic synergy of reduced graphene oxide (rGO) decorated hexagonal boron nitride nanosheets (hBNNS) for detection of carcinoembryonic antigen (CEA). Extensive spectroscopic and microscopic analyses confirmed the successful hydrothermal synthesis of cross-linked rGO-hBNNS nanocomposite. Uniform micro-electrodes of rGO-hBNNS onto pre-hydrolyzed ITO were obtained via electrophoretic deposition (EPD) technique at low DC potential (15 V). Optimization of antibody incubation time, pH of supporting electrolyte, and immunoelectrode preparation was thoroughly investigated to enhance nano-biosensing efficacy. rGO-modified hBNNS demonstrated 29% boost in electrochemical performance over bare hBNNS, signifying remarkable electro-catalytic activity of nano-biosensor. The presence of multifunctional groups on the interface facilitated stable crosslinking chemistry, increased immobilization density, and enabled site-specific anchoring of Anti-CEA, resulting in improved binding affinity. The nano-biosensor demonstrated a remarkably low limit of detection of 5.47 pg/mL (R2 = 0.99963), indicating exceptional sensitivity and accuracy in detecting CEA concentrations from 0 to 50 ng/mL. The clinical evaluation confirmed its exceptional shelf life, minimal cross-reactivity, and robust recovery rates in human serum samples, thereby unraveling the potential for early, highly sensitive, and reliable CEA detection.

A novel configuration for providing continuous renal replacement therapy via the ECMO circuit in VV ECMO without alarm adjustment.

BACKGROUND: It is common for patients on venovenous extracorporeal membrane oxygenation (VV ECMO) to require continuous renal replacement therapy (CRRT). This can be done using separate vascular access for the CRRT circuit, by placing the CRRT hemofilter within the ECMO circuit, or through a separate CRRT circuit connected to the ECMO circuit. When a CRRT circuit is connected to the ECMO circuit, the inflow and outflow CRRT limbs can both be placed pre-ECMO pump or the CRRT circuit can span the ECMO pump, with the CRRT inflow post-ECMO pump and the outflow pre-ECMO pump. Both configurations require the CRRT alarms to be inactivated due to high positive pressure experienced post-pump and low negative pressure pre-pump. We describe a novel technique that does not require separate venous access and still allows the CRRT alarms to be activated. TECHNIQUE: The CRRT inflow line is connected to the post-oxygenator de-airing port. The CRRT outflow line is connected to the pre-pump side of the ECMO circuit. Pigtails allow for these connections and act as resistors negating the large range of pressures generated by the ECMO centrifugal pump. RESULTS: We implemented this configuration in 11 patients with 100% success rate allowing for alarms to be maintained in all patients. The median number of interruptions per 100 CRRT days was 11.7. The median CRRT filter lifespan was 2.2 days, and the average blood flow was maintained at 311 mL/min. CONCLUSIONS: This configuration allows for efficient use of CRRT in ECMO patients while maintaining the safety alarms on the CRRT machine.

Flow-Sizing Critical Care Resources.

OBJECTIVES: To describe the factors affecting critical care capacity and how critical care organizations (CCOs) within academic centers in the U.S. flow-size critical care resources under normal operations, strain, and surge conditions. DATA SOURCES: PubMed, federal agency and American Hospital Association reports, and previous CCO survey results were reviewed. STUDY SELECTION: Studies and reports of critical care bed capacity and utilization within CCOs and in the United States were selected. DATA EXTRACTION: The Academic Leaders in the Critical Care Medicine Task Force established regular conference calls to reach a consensus on the approach of CCOs to "flow-sizing" critical care services. DATA SYNTHESIS: The approach of CCOs to "flow-sizing" critical care is outlined. The vertical (relation to institutional resources, e.g., space allocation, equipment, personnel redistribution) and horizontal (interdepartmental, e.g., emergency department, operating room, inpatient floors) integration of critical care delivery (ICUs, rapid response) for healthcare organizations and the methods by which CCOs flow-size critical care during normal operations, strain, and surge conditions are described. The advantages, barriers, and recommendations for the rapid and efficient scaling of critical care operations via a CCO structure are explained. Comprehensive guidance and resources for the development of "flow-sizing" capability by a CCO within a healthcare organization are provided. CONCLUSIONS: We identified and summarized the fundamental principles affecting critical care capacity. The taskforce highlighted the advantages of the CCO governance model to achieve rapid and cost-effective "flow-sizing" of critical care services and provide recommendations and resources to facilitate this capability. The relevance of a comprehensive approach to "flow-sizing" has become particularly relevant in the wake of the latest COVID-19 pandemic. In light of the growing risks of another extreme epidemic, planning for adequate capacity to confront the next critical care crisis is urgent.

Graphene oxide-Mn3O4nanocomposites for advanced electrochemical biosensor for fumonisin B1 detection.

Occurrence of mycotoxins in food samples threat to its safety issue due to the presence of high toxicity and carcinogenic behavior, thus requiring highly sensitive and selective detection. Herein, the trimanganese tetraoxide (Mn3O4) nanoparticles in combination with graphene oxide (GO) nanocomposite were used to enhance the electrochemical performance for fabrication of electrochemical biosensor for fumonisin B1 (FB1) detection. The various characterization tools were used to validate the fabrication of GOMn3O4nanocomposites. To fabricate the electrochemical biosensor on an indium tin oxide (ITO) coated glass substrate, a thin film of GOMn3O4nanocomposite was prepared using electrophoretic deposition technique, and antibodies (ab-FB1) were immobilized onto the electrode for selective FB1 detection. The differential pulse voltammetry technique was used to observe the sensing performance. The non-binding sites of the ab-FB1 on the immunoelectrode were blocked with bovine serum albumin (BSA). The biosensor electrode was fabricated as BSA/ab-FB1/GOMn3O4/ITO for the detection of FB1. The sensitivity of the biosensor was obtained as 10.08µA ml ng-1cm-2in the detection range of 1 pg ml-1to 800 ng ml-1with a limit of detection of 0.195 pg ml-1. In addition, the recovery of BSA/ab-FB1/GOMn3O4/ITO immunoelectrodes was also performed on sweet corn samples and is calculated to be 98.91%.

Rapid Development and Deployment of an Intensivist-Led Venovenous Extracorporeal Membrane Oxygenation Cannulation Program.

OBJECTIVES: To determine the safety and efficacy of a rapidly deployed intensivist-led venovenous extracorporeal membrane oxygenation cannulation program in a preexisting extracorporeal membrane oxygenation program. DESIGN: A retrospective observational before-and-after study of 40 patients undergoing percutaneous cannulation for venovenous extracorporeal membrane oxygenation in an established cannulation program by cardiothoracic surgeons versus a rapidly deployed medical intensivist cannulation program. SETTING: An adult ICU in a tertiary academic medical center in Camden, NJ. PATIENTS: Critically ill adult subjects with severe respiratory failure undergoing percutaneous cannulation for venovenous extracorporeal membrane oxygenation. INTERVENTIONS: Percutaneous cannulation for venovenous extracorporeal membrane oxygenation performed by cardiothoracic surgeons compared with cannulations performed by medical intensivists. MEASUREMENTS AND MAIN RESULTS: Venovenous extracorporeal membrane oxygenation cannulation site attempts were retrospectively reviewed. Subject demographics, specialty of physician performing cannulation, type of support, cannulation configuration, cannula size, imaging guidance, success rate, and complications were recorded and summarized. Twenty-two cannulations were performed by three cardiothoracic surgeons in 11 subjects between September 2019 and February 2020. The cannulation program rapidly transitioned to an intensivist-led and performed program in March 2020. Fifty-seven cannulations were performed by eight intensivists in 29 subjects between March 2020 and December 2020. Mean body mass index for subjects did not differ between groups (33.86 vs 35.89; p = 0.775). There was no difference in days on mechanical ventilation prior to cannulation, configuration, cannula size, or discharge condition. There was no difference in success rate of cannulation on first attempt per cannulation site (95.5 vs 96.7; p = 0.483) or major complication rate per cannulation site (4.5 vs 3.5; p = 1). CONCLUSIONS: There is no difference between success and complication rates of percutaneous venovenous extracorporeal membrane oxygenation canulation when performed by cardiothoracic surgeons versus medical intensivist in an already established extracorporeal membrane oxygenation program. A rapidly deployed cannulation program by intensivists for venovenous extracorporeal membrane oxygenation can be performed with high success and low complication rates.

Predicting Nonalcoholic Fatty Liver Disease through a Panel of Plasma Biomarkers and MicroRNAs in Female West Virginia Population.

(1) Background: Nonalcoholic fatty liver disease (NAFLD) is primarily characterized by the presence of fatty liver, hepatic inflammation and fibrogenesis eventually leading to nonalcoholic steatohepatitis (NASH) or cirrhosis. Obesity and diabetes are common risk factors associated with the development and progression of NAFLD, with one of the highest prevalence of these diseased conditions in the West Virginia population. Currently, the diagnosis of NAFLD is limited to radiologic studies and biopsies, which are not cost-effective and highly invasive. Hence, this study aimed to develop a panel and assess the progressive levels of circulatory biomarkers and miRNA expression in patients at risk for progression to NASH to allow early intervention strategies. (2) Methods: In total, 62 female patients were enrolled and blood samples were collected after 8-10 h of fasting. Computed tomography was performed on abdomen/pelvis following IV contrast administration. The patients were divided into the following groups: Healthy subjects with normal BMI and normal fasting blood glucose (Control, n = 20), Obese with high BMI and normal fasting blood glucose (Obese, n = 20) and Obese with high fasting blood glucose (Obese + DM, n = 22). Based on findings from CT, another subset was created from Obese + DM group with patients who showed signs of fatty liver infiltration (Obese + DM(FI), n = 10). ELISA was performed for measurement of plasma biomarkers and RT-PCR was performed for circulating miRNA expression. (3) Results: Our results show significantly increased levels of plasma IL-6, Leptin and FABP-1, while significantly decreased level of adiponectin in Obese, Obese + DM and Obese + DM(FI) group, as compared to healthy controls. The level of CK-18 was significantly increased in Obese + DM(FI) group as compared to control. Subsequently, the expression of miR-122, miR-34a, miR-375, miR-16 and miR-21 was significantly increased in Obese + DM and Obese + DM(FI) group as compared to healthy control. Our results also show distinct correlation of IL-6, FABP-1 and adiponectin levels with the expression of miRNAs in relation to the extent of NAFLD progression. (4) Conclusion: Our results support the clinical application of these biomarkers and miRNAs in monitoring the progression of NAFLD, suggesting a more advanced diagnostic potential of this panel than conventional methods. This panel may provide an appropriate method for early prognosis and management of NAFLD and subsequent adverse hepatic pathophysiology, potentially reducing the disease burden on the West Virginia population.

Beneficial Role of HO-1-SIRT1 Axis in Attenuating Angiotensin II-Induced Adipocyte Dysfunction.

BACKGROUND: Angiotensin II (Ang II), released by the renin-angiotensin-aldosterone system (RAAS), contributes to the modulatory role of the RAAS in adipose tissue dysfunction. Investigators have shown that inhibition of AngII improved adipose tissue function and insulin resistance in mice with metabolic syndrome. Heme Oxygenase-1 (HO-1), a potent antioxidant, has been demonstrated to improve oxidative stress and adipocyte phenotype. Molecular effects of high oxidative stress include suppression of sirtuin-1 (SIRT1), which is amenable to redox manipulations. The mechanisms involved, however, in these metabolic effects of the RAAS remain incompletely understood. HYPOTHESIS: We hypothesize that AngII-induced oxidative stress has the potential to suppress adipocyte SIRT1 via down regulation of HO-1. This effect of AngII will, in turn, upregulate mineralocorticoid receptor (MR). The induction of HO-1 will rescue SIRT1, hence improving oxidative stress and adipocyte phenotype. METHODS AND RESULTS: We examined the effect of AngII on lipid accumulation, oxidative stress, and inflammatory cytokines in mouse pre-adipocytes in the presence and absence of cobalt protoporphyrin (CoPP), HO-1 inducer, tin mesoporphyrin (SnMP), and HO-1 inhibitor. Our results show that treatment of mouse pre-adipocytes with AngII increased lipid accumulation, superoxide levels, inflammatory cytokine levels, interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), and adiponectin levels. This effect was attenuated by HO-1 induction, which was further reversed by SnMP, suggesting HO-1 mediated improvement in adipocyte phenotype. AngII-treated pre-adipocytes also showed upregulated levels of MR and suppressed SIRT1 that was rescued by HO-1. Subsequent treatment with CoPP and SIRT1 siRNA in mouse pre-adipocytes increased lipid accumulation and fatty acid synthase (FAS) levels, suggesting that beneficial effects of HO-1 are mediated via SIRT1. CONCLUSION: Our study demonstrates for the first time that HO-1 has the ability to restore cellular redox, rescue SIRT1, and prevent AngII-induced impaired effects on adipocytes and the systemic metabolic profile.

Ablation of soluble epoxide hydrolase reprogram white fat to beige-like fat through an increase in mitochondrial integrity, HO-1-adiponectin in vitro and in vivo.

We have shown that epoxyeicosatrienoic acids (EETs), specifically 11,12- and 14,15-EETs, reduce adipogenesis in human mesenchymal stem cells and mouse preadipocytes (3T-3L1). In this study, we explore the effects of soluble epoxide hydrolase (sEH) deletion on various aspects of adipocyte-function, including programing for white vs. beige-like fat, and mitochondrial and thermogenic gene-expressions. We further hypothesize that EETs and heme-oxygenase 1 (HO-1) form a synergistic, functional module whose effects on adipocyte and vascular function is greater than the effects of sEH deletion alone. In in vitro studies, we examined the effect of sEH inhibitors on MSC-derived adipocytes. MSC-derived adipocytes exposed to AUDA, an inhibitor of sEH, exhibit an increased number of small and healthy adipocytes, an effect reproduced by siRNA for sEH. in vivo studies indicate that sEH deletion results in a significant decrease in adipocyte size, inflammatory adipokines NOV, TNFα, while increasing adiponectin (p < 0.05). These findings are associated with a decrease in body weight (p < 0.05), and visceral fat (p < 0.05). Importantly, sEH deletion was associated with a significant increase in Mfn1, COX 1, UCP1 and adiponectin (p < 0.03). sEH deletion was manifested by a significant increase in EETs isomers 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET and an increased EETs/DHETEs ratio. Notably, activation of HO-1 gene expression further increased the levels of EETs, suggesting that the antioxidant HO-1 system protects EETs from degradation by ROS. These results are novel in that sEH deletion, while increasing EET levels, resulted in reprograming of white fat to express mitochondrial and thermogenic genes, a phenotype characteristic of beige-fat. Thus, EETs agonist(s) and sEH inhibitors may have therapeutic potential in the treatment of metabolic syndrome and obesity.

Existence of a Strong Correlation of Biomarkers and miRNA in Females with Metabolic Syndrome and Obesity in a Population of West Virginia.

Objectives: Metabolic syndrome causes complications like cardiovascular disease and type 2 diabetes mellitus (T2DM). As metabolic syndrome develops, altered levels of cytokines and microRNAs (miRNA) are measurable in the circulation. We aimed to construct a panel detecting abnormal levels of cytokines and miRNAs in patients at risk for metabolic syndrome. Methods: Participants included 54 patients from a Family Medicine Clinic at Marshall University School of Medicine, in groups of: Control, Obese, and Metabolic Syndrome (MetS). Results: Serum levels of leptin, adiponectin, leptin: adiponectin ratio, IL-6, six miRNAs (320a, 197-3p, 23-3p, 221-3p, 27a-3p, and 130a-3p), were measured. Among the three groups, leptin, and leptin: adiponectin ratio, and IL-6 levels were highest in MetS, and levels in Obese were greater than Control (p>0.05). Adiponectin levels were lower in Obese compared to Control, but lowest in MetS (p<0.05). MiRNAs levels were lowest in MetS, and levels in Obese were lower than Control (p>0.05). Conclusion: Our results support the clinical application of biomarkers in diagnosing early stage MetS, which will enable attenuation of disease progression before onset of irreversible complications. Since West Virginians are high-risk for developing MetS, our biomarker panel could reduce the disease burden on our population.

Dexamethasone promotes hypertension by allele-specific regulation of the human angiotensinogen gene.

The human angiotensinogen (hAGT) gene has polymorphisms in its 2.5-kb promoter that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, and -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C, and -1178G/A). Hap -6A/-217A is associated with human hypertension, whereas Hap -6G/-217G reduces cardiovascular risk. Hap -6A/-217A has increased promoter activity with enhanced transcription factor binding, including to the glucocorticoid receptor (GR). Glucocorticoid therapy frequently causes hypertension, the mechanisms for which are incompletely understood. We have engineered double transgenic (TG) mice containing the human renin gene with either Hap of the hAGT gene and examined the physiological significance of glucocorticoid-mediated allele-specific regulation of the hAGT gene. We have also studied the consequential effects on the renin angiotensin system and blood pressure. TG mice with Hap -6A and -6G were treated with and without a low dose of a GR agonist, dexamethasone (2.5 µg/ml), for 72 h. We found greater chromatin-GR binding with increased GR agonist-induced hAGT expression in liver and renal tissues of Hap -6A mice. Additionally, dexamethasone treatment increased circulating hAGT and angiotensin II levels in Hap -6A mice, as compared with -6G mice. Importantly, GR agonist significantly increased blood pressure and redox markers in TG mice with Hap-6A of the hAGT gene. Taken together, our results show, for the first time, that glucocorticoids affect hAGT expression in a haplotype-dependent fashion with SNPs in Hap -6A favoring agonist-induced GR binding. This leads to increased expression of the hAGT, up-regulation of the renin angiotensin system, and increased blood pressure and oxidative stress in Hap -6A mice.

Pulmonary artery size as a predictor of outcomes in idiopathic pulmonary fibrosis.

UNLABELLED: IPF patients have heightened propensity for pulmonary hypertension, which portends a worse outcome. Presence of pulmonary hypertension may be reflected in an enlarged pulmonary artery. We investigated pulmonary artery size measured on high-resolution computed tomography (HRCT) as an outcome predictor in IPF.We retrospectively reviewed all IPF patients evaluated at a tertiary-care centre between 2008 and 2013. Pulmonary artery and ascending aorta diameters were measured from chest HRCT with pulmonary artery:ascending aorta diameter (PA:A) ratio calculations. Outcome analysis defined by either death or lung transplant based on pulmonary artery size and PA:A ratio over 60 months was performed. Independent effects of different variables on overall outcomes were evaluated using the Cox proportional hazards model.98 IPF patients with available HRCT scans had a mean pulmonary artery diameter and PA:A ratio of 32.8 mm and 0.94, respectively. Patients with a PA:A ratio >1 had higher risk of death or transplant compared with a PA:A ratio ≤1 (p<0.001). A PA:A ratio >1 was also an independent predictor of outcomes in unadjusted and adjusted outcomes analyses (hazard ratio 3.99, p<0.001 and hazard ratio 3.35, p=0.002, respectively).A PA:A ratio >1 is associated with worse outcomes in patients with IPF. HRCT PA: A ratio measurement may assist in risk stratification and prognostication of IPF patients.

Assessment of the adequacy of oxygen delivery.

PURPOSE OF REVIEW: This article reviews the recent literature pertaining to assessment of the adequacy of oxygen delivery in critically ill patients with circulatory shock. RECENT FINDINGS: The assessment of the adequacy of oxygen delivery has traditionally involved measurement of lactate, central (or mixed) venous oxygen saturation (ScvO2), and global hemodynamic markers such as mean arterial pressure and cardiac index. The search for noninvasive, reliable, and sensitive methods to detect derangements in oxygen delivery and utilization continues. Recent studies focus on near-infrared spectroscopy (NIRS) to assess regional tissue oxygenation, as well as bedside ultrasound techniques to assess the macrovascular hemodynamic factors in oxygen delivery. SUMMARY: In this article, we review physiologic principles of global oxygen delivery, and discuss the bedside approach to assessing the adequacy of oxygen delivery in critically ill patients. Although there have been technological advances in the assessment of oxygen delivery, we revisit and emphasize the importance of a 'tried and true' method - the physical examination. Also potentially important in the evaluation of oxygen delivery is the utilization of biomarkers (e.g., lactate, ScvO2, NIRS). In complementary fashion, bedside ultrasound for hemodynamic assessment may augment the physical examination and biomarkers, and represents a potentially important adjunct for assessing the adequacy of oxygen delivery.

Critical Care Delivery: The Importance of Process of Care and ICU Structure to Improved Outcomes: An Update From the American College of Critical Care Medicine Task Force on Models of Critical Care.

In 2001, the Society of Critical Care Medicine published practice model guidelines that focused on the delivery of critical care and the roles of different ICU team members. An exhaustive review of the additional literature published since the last guideline has demonstrated that both the structure and process of care in the ICU are important for achieving optimal patient outcomes. Since the publication of the original guideline, several authorities have recognized that improvements in the processes of care, ICU structure, and the use of quality improvement science methodologies can beneficially impact patient outcomes and reduce costs. Herein, we summarize findings of the American College of Critical Care Medicine Task Force on Models of Critical Care: 1) An intensivist-led, high-performing, multidisciplinary team dedicated to the ICU is an integral part of effective care delivery; 2) Process improvement is the backbone of achieving high-quality ICU outcomes; 3) Standardized protocols including care bundles and order sets to facilitate measurable processes and outcomes should be used and further developed in the ICU setting; and 4) Institutional support for comprehensive quality improvement programs as well as tele-ICU programs should be provided.

Human aldosterone synthase gene polymorphism promotes miRNA binding and regulates gene expression.

Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Like other complex diseases, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin-aldosterone system plays an important role in the regulation of blood pressure. The octapeptide angiotensin II (ANG II) is one of the most active vasopressor agents and is obtained from the precursor molecule, angiotensinogen, by the combined proteolytic action of renin and angiotensin-converting enzyme. ANG II increases the expression of aldosterone synthase (coded by Cyp11B2 gene), which is the rate-limiting enzyme in the biosynthesis of aldosterone. Previous studies have shown that increased expression of aldosterone synthase increases blood pressure and cardiac hypertrophy in transgenic mice. Human Cyp11B2 gene has a T/C polymorphism at -344 positions in its 5'-untranslated region (UTR), and the -344T allele is associated with hypertension. Human Cyp11B2 gene also has an A/G polymorphism at 735 position in its 3'-UTR (rs28491316) that is in linkage disequilibrium with single nucleotide polymorphism at -344. We show here that 1) microRNA (miR)-766 binds to the 735G-allele and not the 735A-allele of the hCyp11B2 gene and 2) transfection of miR-766 reduces the human aldosterone synthase mRNA and protein level in human adrenocortical cells H295R. These studies suggest that miR-766 may downregulate the expression of human aldosterone synthase gene and reduce blood pressure in human subjects containing -344T allele.

A haplotype of angiotensin receptor type 1 associated with human hypertension increases blood pressure in transgenic mice.

The renin-angiotensin system plays an important role in the regulation of blood pressure via angiotensin II and the angiotensin II receptor type 1 (AT1R). Human AT1R gene promoter has four SNPs: T/A at -777, T/G at -680, A/C at -214, and A/G at -119, that are in linkage disequilibrium. Variants -777T, -680T, -214A, and -119A almost always occur together (named haplotype I), and variants -777A, -680G, -214C, and -119G almost always occur together (named haplotype II) in Caucasian subjects. Genomic DNA analyses, from 388 normotensive and 374 hypertensive subjects, link haplotype I of the human AT1R (hAT1R) gene with hypertension in Caucasians (p = 0.004, χ(2) = 8.46). Our results show increased basal promoter activity of the hAT1R gene in cells (H295R and A7r5) transfected with reporter construct containing haplotype I. We also show increased binding of the transcription factor, USF2, to oligonucleotide containing nucleoside -214A as opposed to -214C. Recombineering of a 166-kb bacterial artificial chromosome containing 68 kb of the 5'-flanking region, 45 kb of the coding sequence, and 53 kb of the 3'-flanking region of the hAT1R gene was employed to generate transgenic mice with either haplotype. We show that (a) hAT1R mRNA level is increased in the kidney and heart of transgenic mice containing haplotype I as compared with haplotype II; (b) USF2 binds more strongly to the chromatin obtained from the kidney of transgenic mice containing haplotype I as compared with haplotype II; and (c) blood pressure and oxidative stress are increased in transgenic mice containing haplotype I as compared with haplotype II.