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Article ; Online: Order Set Usage is Associated With Lower Hospital Mortality in Patients With Sepsis.

Dale, Christopher R / Schoepflin Sanders, Shelley / Chang, Shu Ching / Pandhair, Omar / Diggs, Naomi G / Woodruff, Whitney / Selander, David N / Mark, Nicholas M / Nurse, Sarah / Sullivan, Mark / Mezaraups, Liga / O'Mahony, D Shane

Critical care explorations

2023 Volume 5, Issue 5, Page(s) e0918

Abstract: The Surviving Sepsis Campaign recommends standard operating procedures for patients with sepsis. Real-world evidence about sepsis order set implementation is limited.: Objectives: To estimate the effect of sepsis order set usage on hospital mortality.! ...

Abstract	The Surviving Sepsis Campaign recommends standard operating procedures for patients with sepsis. Real-world evidence about sepsis order set implementation is limited. Objectives: To estimate the effect of sepsis order set usage on hospital mortality. Design: Retrospective cohort study. Setting and participants: Fifty-four acute care hospitals in the United States from December 1, 2020 to November 30, 2022 involving 104,662 patients hospitalized for sepsis. Main outcomes and measures: Hospital mortality. Results: The sepsis order set was used in 58,091 (55.5%) patients with sepsis. Initial mean sequential organ failure assessment score was 0.3 lower in patients for whom the order set was used than in those for whom it was not used (2.9 sd [2.8] vs 3.2 [3.1], Conclusions and relevance: In a cohort of patients hospitalized with sepsis, order set use was independently associated with lower hospital mortality. Order sets can impact large-scale quality improvement efforts.
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Journal Article
ISSN	2639-8028
ISSN (online)	2639-8028
DOI	10.1097/CCE.0000000000000918
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Article: Ambulatory Risk Models for the Long-Term Prevention of Sepsis: Retrospective Study.

Lee, Jewel Y / Molani, Sevda / Fang, Chen / Jade, Kathleen / O'Mahony, D Shane / Kornilov, Sergey A / Mico, Lindsay T / Hadlock, Jennifer J

JMIR medical informatics

2021 Volume 9, Issue 7, Page(s) e29986

Abstract: Background: Sepsis is a life-threatening condition that can rapidly lead to organ damage and death. Existing risk scores predict outcomes for patients who have already become acutely ill.: Objective: We aimed to develop a model for identifying ... ...

Abstract	Background: Sepsis is a life-threatening condition that can rapidly lead to organ damage and death. Existing risk scores predict outcomes for patients who have already become acutely ill. Objective: We aimed to develop a model for identifying patients at risk of getting sepsis within 2 years in order to support the reduction of sepsis morbidity and mortality. Methods: Machine learning was applied to 2,683,049 electronic health records (EHRs) with over 64 million encounters across five states to develop models for predicting a patient's risk of getting sepsis within 2 years. Features were selected to be easily obtainable from a patient's chart in real time during ambulatory encounters. Results: The models showed consistent prediction scores, with the highest area under the receiver operating characteristic curve of 0.82 and a positive likelihood ratio of 2.9 achieved with gradient boosting on all features combined. Predictive features included age, sex, ethnicity, average ambulatory heart rate, standard deviation of BMI, and the number of prior medical conditions and procedures. The findings identified both known and potential new risk factors for long-term sepsis. Model variations also illustrated trade-offs between incrementally higher accuracy, implementability, and interpretability. Conclusions: Accurate implementable models were developed to predict the 2-year risk of sepsis, using EHR data that is easy to obtain from ambulatory encounters. These results help advance the understanding of sepsis and provide a foundation for future trials of risk-informed preventive care.
Language	English
Publishing date	2021-07-08
Publishing country	Canada
Document type	Journal Article
ZDB-ID	2798261-0
ISSN	2291-9694
ISSN	2291-9694
DOI	10.2196/29986
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Article ; Online: Phase 2, randomized, double-blind, placebo-controlled multi-center trial of the clinical and biological effects of anti-CD14 treatment in hospitalized patients with COVID-19 pneumonia.

Mabrey, F Linzee / Nian, Hui / Yu, Chang / Barnes, Elizabeth M / Malhotra, Uma / Mikacenic, Carmen / Goldstein, Julia / O'Mahony, D Shane / Garcia-Diaz, Julia / Finn, Patricia / Voelker, Kirk / Morrell, Eric D / Self, Wesley H / Becker, Patrice M / Martin, Thomas R / Wurfel, Mark M

EBioMedicine

2023 Volume 93, Page(s) 104667

Abstract: Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target.: Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a ... ...

Abstract	Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target. Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo. All participants received remdesivir. The primary outcome was time-to-resolution of illness, defined as improvement on the 8-point NIH-Ordinal COVID-19 Scale to category ≤3. Secondary endpoints were safety and exploratory endpoints were pro-inflammatory and antiviral mediators in serum on days 0-5 & 7. The trial was stopped after 40 patients were randomized and treated due to slow enrollment. Findings: 40 participants were randomized and treated with IC14 (n = 20) or placebo (n = 20). The median time-to-recovery was 6 days (95% CI, 5-11) in the IC14 group vs. 5 days (95% CI, 4-10) in the Placebo group (recovery rate ratio: 0.77 (95% CI, 0.40, 1.48) (log-rank p = 0.435). The number of adverse events was similar in each group, and no IC14-attributable secondary infections occurred. In repeated-measures mixed-effects analyses, IC14 treatment increased serum sCD14 concentrations, an expected pharmacodynamic effect. Pre-planned, exploratory analyses suggested that IC14 treatment decreased the trajectories of circulating MIP-1β and TNF-α. Interpretation: IC14 treatment did not improve time-to-resolution of illness in hypoxemic patients with COVID-19 in this small trial. Results of exploratory analyses suggested IC14 had biologic effects that warrant future clinical investigation. Funding: National Institute of Allergy and Infectious Diseases.
MeSH term(s)	Adult ; Humans ; COVID-19 ; SARS-CoV-2 ; Administration, Intravenous ; Double-Blind Method ; Treatment Outcome
Language	English
Publishing date	2023-06-17
Publishing country	Netherlands
Document type	Randomized Controlled Trial ; Clinical Trial, Phase II ; Multicenter Study ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104667
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Article ; Online: A Two-Biomarker Model Predicts Mortality in the Critically Ill with Sepsis.

Mikacenic, Carmen / Price, Brenda L / Harju-Baker, Susanna / O'Mahony, D Shane / Robinson-Cohen, Cassianne / Radella, Frank / Hahn, William O / Katz, Ronit / Christiani, David C / Himmelfarb, Jonathan / Liles, W Conrad / Wurfel, Mark M

American journal of respiratory and critical care medicine

2017 Volume 196, Issue 8, Page(s) 1004–1011

Abstract: Rationale: Improving the prospective identification of patients with systemic inflammatory response syndrome (SIRS) and sepsis at low risk for organ dysfunction and death is a major clinical challenge.: Objectives: To develop and validate a ... ...

Abstract	Rationale: Improving the prospective identification of patients with systemic inflammatory response syndrome (SIRS) and sepsis at low risk for organ dysfunction and death is a major clinical challenge. Objectives: To develop and validate a multibiomarker-based prediction model for 28-day mortality in critically ill patients with SIRS and sepsis. Methods: A derivation cohort (n = 888) and internal test cohort (n = 278) were taken from a prospective study of critically ill intensive care unit (ICU) patients meeting two of four SIRS criteria at an academic medical center for whom plasma was obtained within 24 hours. The validation cohort (n = 759) was taken from a prospective cohort enrolled at another academic medical center ICU for whom plasma was obtained within 48 hours. We measured concentrations of angiopoietin-1, angiopoietin-2, IL-6, IL-8, soluble tumor necrosis factor receptor-1, soluble vascular cell adhesion molecule-1, granulocyte colony-stimulating factor, and soluble Fas. Measurements and main results: We identified a two-biomarker model in the derivation cohort that predicted mortality (area under the receiver operator characteristic curve [AUC], 0.79; 95% confidence interval [CI], 0.74-0.83). It performed well in the internal test cohort (AUC, 0.75; 95% CI, 0.65-0.85) and the external validation cohort (AUC, 0.77; 95% CI, 0.72-0.83). We determined a model score threshold demonstrating high negative predictive value (0.95) for death. In addition to a low risk of death, patients below this threshold had shorter ICU length of stay, lower incidence of acute kidney injury, acute respiratory distress syndrome, and need for vasopressors. Conclusions: We have developed a simple, robust biomarker-based model that identifies patients with SIRS/sepsis at low risk for death and organ dysfunction.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Angiopoietins/blood ; Biomarkers/blood ; Cohort Studies ; Critical Illness/mortality ; Female ; Granulocyte Colony-Stimulating Factor/blood ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Prospective Studies ; Sepsis/blood ; Sepsis/mortality ; Systemic Inflammatory Response Syndrome/blood ; Tumor Necrosis Factor-alpha/blood ; Vascular Cell Adhesion Molecule-1/blood
Chemical Substances	Angiopoietins ; Biomarkers ; Tumor Necrosis Factor-alpha ; Vascular Cell Adhesion Molecule-1 ; Granulocyte Colony-Stimulating Factor (143011-72-7)
Language	English
Publishing date	2017-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201611-2307OC
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Article ; Online: Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome.

Morrell, Eric D / O'Mahony, D Shane / Glavan, Bradford J / Harju-Baker, Susanna / Nguyen, Catherine / Gunderson, Scott / Abrahamson, Aaron / Radella, Frank / Rona, Gail / Black, R Anthony / Wurfel, Mark M

American journal of respiratory cell and molecular biology

2017 Volume 58, Issue 1, Page(s) 117–125

Abstract: Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with ... ...

Abstract	Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single-nucleotide polymorphisms covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT (Fluid and Catheter Treatment Trial) study, and tested for associations between MAP3K1 single-nucleotide polymorphisms and ventilator-free days (VFDs) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (Seattle, WA). We found the variant allele of rs832582 (MAP3K1
MeSH term(s)	Adolescent ; Adult ; Aged ; Alleles ; Amino Acid Substitution ; Cytokines/genetics ; Cytokines/immunology ; Cytokines/metabolism ; Female ; Humans ; MAP Kinase Kinase Kinase 1/genetics ; MAP Kinase Kinase Kinase 1/immunology ; MAP Kinase Kinase Kinase 1/metabolism ; Male ; Middle Aged ; Mutation, Missense ; Polymorphism, Single Nucleotide ; Respiratory Distress Syndrome, Adult/enzymology ; Respiratory Distress Syndrome, Adult/genetics ; Respiratory Distress Syndrome, Adult/immunology ; Respiratory Distress Syndrome, Adult/mortality
Chemical Substances	Cytokines ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25) ; MAP3K1 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2017-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2017-0030OC
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Article ; Online: Medical complexity and pediatric emergency department and inpatient utilization.

O'Mahony, Lila / O'Mahony, D Shane / Simon, Tamara D / Neff, John / Klein, Eileen J / Quan, Linda

Pediatrics

2013 Volume 131, Issue 2, Page(s) e559–65

Abstract: Objectives: To characterize the use of and disposition from a tertiary pediatric emergency department (PED) by children with chronic conditions with varying degrees of medical complexity.: Methods: We conducted a retrospective cohort study using a ... ...

Abstract	Objectives: To characterize the use of and disposition from a tertiary pediatric emergency department (PED) by children with chronic conditions with varying degrees of medical complexity. Methods: We conducted a retrospective cohort study using a dataset of all registered PED patient visits at Seattle Children's Hospital from January 1, 2008, through December 31, 2009. Children's medical complexity was classified by using a validated algorithm (Clinical Risk Group software) into nonchronic and chronic conditions: episodic chronic, lifelong chronic, progressive chronic, and malignancy. Outcomes included PED length of stay (LOS) and disposition. Logistic regression generated age-adjusted odds ratios (AOR) of admission with 95% confidence intervals (CIs). Results: PED visits totaled 77 748; 20% (15 433) of which were for children with chronic conditions. Compared with visits for children without chronic conditions, those for children with chronic conditions had increased PED LOS (on average, 79 minutes longer; 95% CI 77-81; P < .0001) and hospital (51% vs 10%) and PICU (3.2% vs 0.1%) admission rates (AOR 10.3, 95% CI 9.9-10.7 to hospital and AOR 25.0, 95% CI 17.0-36.0 to PICU). Admission rates and PED LOS increased with increasing medical complexity. Conclusions: Children with chronic conditions comprise a significant portion of annual PED visits in a tertiary pediatric center; medical complexity is associated with increased PED LOS and hospital or PICU admission. Clinical Risk Group may have utility in identifying high utilizers of PED resources and help support the development of interventions to facilitate optimal PED management, such as pre-arrival identification and individual emergency care plans.
MeSH term(s)	Adolescent ; Algorithms ; Cause of Death ; Child ; Child, Preschool ; Chronic Disease/epidemiology ; Chronic Disease/mortality ; Chronic Disease/therapy ; Cohort Studies ; Cooperative Behavior ; Electronic Health Records/statistics & numerical data ; Emergency Service, Hospital/statistics & numerical data ; Female ; Health Services Needs and Demand/statistics & numerical data ; Hospitalization/statistics & numerical data ; Hospitals, Pediatric/statistics & numerical data ; Humans ; Infant ; Interdisciplinary Communication ; International Classification of Diseases ; Length of Stay/statistics & numerical data ; Male ; Patient Care Team/statistics & numerical data ; Retrospective Studies ; Software ; Tertiary Care Centers/statistics & numerical data ; Utilization Review/statistics & numerical data ; Washington ; Young Adult
Language	English
Publishing date	2013-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	207677-9
ISSN	1098-4275 ; 0031-4005
ISSN (online)	1098-4275
ISSN	0031-4005
DOI	10.1542/peds.2012-1455
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Article ; Online: Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages.

O'Mahony, D Shane / Pham, Uyenvy / Iyer, Ramesh / Hawn, Thomas R / Liles, W Conrad

International journal of medical sciences

2008 Volume 5, Issue 1, Page(s) 1–8

Abstract: Human Toll-like receptors (TLRs) comprise a family of proteins that recognizes pathogen-associated molecular patterns (PAMPs) and initiates host innate immune responses. Neutrophils, monocytes, and macrophages are critical cellular components of the ... ...

Abstract	Human Toll-like receptors (TLRs) comprise a family of proteins that recognizes pathogen-associated molecular patterns (PAMPs) and initiates host innate immune responses. Neutrophils, monocytes, and macrophages are critical cellular components of the human innate immune system. Proinflammatory cytokines, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interferon-gamma (IFN-gamma), have been shown to up-regulate microbicidal activity in these effector cells of innate immunity. Currently, the cellular and molecular mechanisms responsible for these effects are not completely understood. We hypothesized that these cytokines may up-regulate TLR expression as a mechanism to facilitate microbial recognition and augment the innate immune response. Using quantitative realtime rt-PCR technology, we examined constitutive expression of TLR2, TLR4, TLR5, and TLR9 mRNA and the effects of G-CSF, GM-CSF, M-CSF, and IFN-gamma on TLR mRNA expression in purified populations of normal human neutrophils, monocytes, and monocyte-derived macrophages. Relative constitutive expression of TLR2, TLR4, and TLR9 was similar in neutrophils and monocytes. Constitutive expression of TLR5 was less in neutrophils compared to monocytes. Constitutive expression of TLR4 was greater and that of TLR9 lower in monocyte-derived macrophages compared to monocytes. Of the cytokines examined, IFN-gamma and GM-CSF caused the greatest effects on TLR expression. IFN- gamma up-regulated TLR2 and TLR4 in neutrophils and monocytes. GM-CSF up-regulated expression of TLR2 and TLR4 in neutrophils and TLR2 in monocytes. TLR5 was down-regulated by inflammatory cytokines in monocytes. These results suggest a potential role for IFN- gamma and/or GM-CSF as therapeutic immunomodulators of the host defense to infection.
MeSH term(s)	Cell Culture Techniques ; Cells, Cultured ; Cytokines/genetics ; Cytokines/physiology ; Gene Expression Regulation/immunology ; Granulocyte Colony-Stimulating Factor/genetics ; Granulocyte Colony-Stimulating Factor/physiology ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Granulocyte-Macrophage Colony-Stimulating Factor/physiology ; Humans ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Interferon-gamma/physiology ; Macrophage Activation ; Macrophage Colony-Stimulating Factor/genetics ; Macrophage Colony-Stimulating Factor/physiology ; Macrophages/immunology ; Macrophages/physiology ; Monocytes/immunology ; Monocytes/physiology ; Neutrophil Activation ; Neutrophils/immunology ; Neutrophils/physiology ; RNA, Messenger/metabolism ; Recombinant Proteins/metabolism ; Toll-Like Receptor 2/metabolism ; Toll-Like Receptor 2/physiology ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptor 4/physiology ; Toll-Like Receptor 5/metabolism ; Toll-Like Receptor 5/physiology ; Toll-Like Receptor 9/metabolism ; Toll-Like Receptor 9/physiology ; Toll-Like Receptors/metabolism ; Toll-Like Receptors/physiology
Chemical Substances	Cytokines ; RNA, Messenger ; Recombinant Proteins ; Toll-Like Receptor 2 ; Toll-Like Receptor 4 ; Toll-Like Receptor 5 ; Toll-Like Receptor 9 ; Toll-Like Receptors ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; Macrophage Colony-Stimulating Factor (81627-83-0) ; Interferon-gamma (82115-62-6) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2008-01-04
Publishing country	Australia
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2151424-0
ISSN	1449-1907 ; 1449-1907
ISSN (online)	1449-1907
ISSN	1449-1907
DOI	10.7150/ijms.5.1
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Book ; Online: Covid-19 in Critically Ill Patients in the Seattle Region — Case Series

Bhatraju, Pavan K / Ghassemieh, Bijan J / Nichols, Michelle / Kim, Richard / Jerome, Keith R / Nalla, Arun K / Greninger, Alexander L / Pipavath, Sudhakar / Wurfel, Mark M / Evans, Laura / Kritek, Patricia M / West, T. Eoin / Luks, Andrew / Gerbino, Anthony / Dale, Chris R / Goldman, Jason D / O'Mahony, D Shane / Mikacenic, Carmen

Articles, Abstracts, and Reports

2020

Abstract: BACKGROUND Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. METHODS We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed ... ...

Abstract	BACKGROUND Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. METHODS We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up. RESULTS We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU. CONCLUSIONS During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.)
Keywords	2019-nCoV ; Infectious Disease ; covid19
Subject code	610
Publishing date	2020-03-30T07:00:00Z
Publisher	Providence St. Joseph Health Digital Commons
Publishing country	us
Document type	Book ; Online
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Book ; Online: Covid-19 in Critically Ill Patients in the Seattle Region - Case Series.

Bhatraju, Pavan K / Ghassemieh, Bijan J / Nichols, Michelle / Kim, Richard / Jerome, Keith R / Nalla, Arun K / Greninger, Alexander L / Pipavath, Sudhakar / Wurfel, Mark M / Evans, Laura / Kritek, Patricia A / West, T Eoin / Luks, Andrew / Gerbino, Anthony / Dale, Chris / Goldman, Jason D / O'Mahony, D Shane / Mikacenic, Carmen

Articles, Abstracts, and Reports

2020

Abstract: BACKGROUND: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. METHODS: We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed ...

Abstract	BACKGROUND: Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. METHODS: We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up. RESULTS: We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU. CONCLUSIONS: During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.).
Keywords	2019-nCoV ; Critical Care ; Infectious Disease ; Pulmonology ; covid19
Subject code	610
Publishing date	2020-03-30T07:00:00Z
Publisher	Providence St. Joseph Health Digital Commons
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome.

Tejera, Paula / O'Mahony, D Shane / Owen, Caroline A / Wei, Yongyue / Wang, Zhaoxi / Gupta, Kushagra / Su, Li / Villar, Jesus / Wurfel, Mark / Christiani, David C

American journal of respiratory cell and molecular biology

2014 Volume 51, Issue 2, Page(s) 262–272

Abstract: Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an ... ...

Abstract	Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an association between single-nucleotide polymorphism (SNP) rs2664581 in the PI3 gene, increased risk of acute respiratory distress syndrome (ARDS) and pre-elafin circulating levels. This study aims to validate the legitimacy of this association by using a cohort of patients who met the criteria for systemic inflammatory response syndrome and were at risk of developing ARDS (n = 840). A comprehensive functional study of SNPs in PI3 gene was also performed. Luciferase assays and electrophoretic mobility shift assays were conducted to determine the functional relevance of promoter region variants. The effect of the coding SNP rs2664581 on the neutrophil elastase inhibitory activity and transglutaminase binding properties of pre-elafin was also investigated. The variant allele of rs2664581 (C) was significantly associated with increased ARDS risk, mainly among subjects with sepsis (odds ratio = 1.44; 95% confidence interval = 1.04-1.99; P = 0.0276, adjusted by age, sex, and Acute Physiology and Chronic Health Evaluation III). Pre-elafin recombinant protein carrying the amino acid change associated with rs2664581 (Thr34Pro, mutant protein [MT]) had greater capacity to undergo transglutaminase-mediated cross-linking to immobilized fibronectin than wild-type protein in vitro (P < 0.003). No differences were observed in the neutrophil elastase inhibitory activities of wild-type versus MT proteins. In addition, the risk allele-promoter construct had significantly lower cytokine-induced transcriptional activity. Electrophoretic mobility shift assay results indicated a differential binding of nuclear proteins to the G and A alleles of SNP -338G > A. Our results confirm the association between SNP rs2664581 and enhanced risk of ARDS, further supporting the role of PI3 in ARDS development. SNPs in the PI3 locus may act synergistically by regulating PI3 gene expression and pre-elafin biological functions.
MeSH term(s)	Adult ; Aged ; Binding Sites ; Case-Control Studies ; Cell Line, Tumor ; Cytokines/metabolism ; Elafin/genetics ; Elafin/metabolism ; Female ; Fibronectins/metabolism ; Gene Expression Regulation ; Gene Frequency ; Genes, Reporter ; Genetic Association Studies ; Genetic Predisposition to Disease ; Haplotypes ; Humans ; Leukocyte Elastase/metabolism ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Phenotype ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Protein Binding ; Respiratory Distress Syndrome/genetics ; Respiratory Distress Syndrome/metabolism ; Risk Factors ; Systemic Inflammatory Response Syndrome/genetics ; Systemic Inflammatory Response Syndrome/metabolism ; Transcription, Genetic ; Transfection ; Transglutaminases/metabolism
Chemical Substances	Cytokines ; Elafin ; Fibronectins ; PI3 protein, human ; Transglutaminases (EC 2.3.2.13) ; Leukocyte Elastase (EC 3.4.21.37)
Language	English
Publishing date	2014-03-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Validation Study
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2013-0238OC
Database	MEDical Literature Analysis and Retrieval System OnLINE

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