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  • 1
    Online Resource
    Online Resource
    Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 145, No. 5 ( 2022-02), p. 357-370
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 145, No. 5 ( 2022-02), p. 357-370
    Abstract: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.121.055117
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    Plasma coadministration improves resuscitation with tranexamic acid or prothrombin complex in a porcine hemorrhagic shock model
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of Trauma and Acute Care Surgery Vol. 85, No. 1 ( 2018-7), p. 91-100
    Details
    In: Journal of Trauma and Acute Care Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 85, No. 1 ( 2018-7), p. 91-100
    Abstract: Traumatic coagulopathy has now been well characterized and carries high rates of mortality owing to bleeding. A "factor-based" resuscitation strategy using procoagulant drugs and factor concentrates in lieu of plasma is being used by some, but with little evidentiary support. We sought to evaluate and compare resuscitation strategies using combinations of tranexamic acid (TXA), prothrombin complex concentrate (PCC), and fresh frozen plasma (FFP). METHODS Sixty adult swine underwent 35% blood volume hemorrhage combined with a truncal ischemia-reperfusion injury to produce uniform shock and coagulopathy. Animals were randomized to control (n = 12), a single-agent group (TXA, n = 10; PCC, n = 8; or FFP, n = 6) or combination groups (TXA-FFP, n = 10; PCC-FFP, n = 8; TXA-PCC, n = 6). Resuscitation was continued to 6 hours. Key outcomes included hemodynamics, laboratory values, and rotational thromboelastometry. Results were compared between all groups, with additional comparisons between FFP and non-FFP groups. RESULTS All 60 animals survived to 6 hours. Shock was seen in all animals, with hypotension (mean arterial pressure, 44 mm Hg), tachycardia (heart rate, 145), acidosis (pH 7.18; lactate, 11), anemia (hematocrit, 17), and coagulopathy (fibrinogen, 107). There were clear differences between groups for mean pH ( p = 0.02), international normalized ratio ( p 〈 0.01), clotting time (CT; p 〈 0.01), lactate ( p = 0.01), creatinine ( p 〈 0.01), and fibrinogen ( p = 0.02). Fresh frozen plasma groups had significantly improved resuscitation and clotting parameters (Figures), with lower lactate at 6.5 versus 8.4 ( p = 0.04), and increased fibrinogen at 126 versus 95 ( p 〈 0.01). Rotational thromboelastometry also demonstrated shortened CT at 60 seconds in the FFP group vs 65 seconds in the non-FFP group ( p = 0.04). CONCLUSION When used to correct traumatic coagulopathy, combinations of FFP with TXA or PCC were superior in improving acidosis, coagulopathy, and CT than when these agents are given alone or in combination without plasma. Further validation of pure factor-based strategies is needed.
    Type of Medium: Online Resource
    ISSN: 2163-0763 , 2163-0755
    URL: Article
    DOI: 10.1097/TA.0000000000001942
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2651313-4
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  • 3
    Online Resource
    Online Resource
    Mobile forward-looking infrared technology allows rapid assessment of resuscitative endovascular balloon occlusion of the aorta in hemorrhage and blackout conditions
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of Trauma and Acute Care Surgery Vol. 85, No. 1 ( 2018-7), p. 25-32
    Details
    In: Journal of Trauma and Acute Care Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 85, No. 1 ( 2018-7), p. 25-32
    Abstract: Objective assessment of final resuscitative endovascular balloon occlusion of the aorta (REBOA) position and adequate distal aortic occlusion is critical in patients with hemorrhagic shock, especially as feasibility is being increasingly investigated in the prehospital setting. We propose that mobile forward-looking infrared (FLIR) thermal imaging is a fast, reliable, and noninvasive method to assess REBOA position and efficacy in scenarios applicable to battlefield and prehospital care. METHODS Ten swine were randomized to a 40% hemorrhage group (H, n = 5) or nonhemorrhage group (NH, n = 5). Three experiments were completed after Zone I placement of a REBOA catheter. Resuscitative endovascular balloon occlusion of the aorta was deployed for 30 minutes in all animals followed by randomized continued deployment versus sham in both light and blackout conditions. Forward-looking infrared images and hemodynamic data were obtained. Images were presented to 62 blinded observers for assessment of REBOA inflation status. RESULTS There was no difference in hemodynamic or laboratory values at baseline. The H group was significantly more hypotensive (mean arterial pressure 44 vs. 60 mm Hg, p 〈 0.01), vasodilated (systemic vascular resistance 634 vs. 938dyn·s/cm 5 , p = 0.02), and anemic (hematocrit 12 vs. 23.2%, p 〈 0.01). Hemorrhage group animals remained more hypotensive, anemic, and acidotic throughout all three experiments. There was a significant difference in the temperature change (Δ Temp ) measured by FLIR between animals with REBOA inflated versus not inflated (5.7°C vs. 0.7°C, p 〈 0.01). The H and NH animals exhibited equal magnitudes of Δ Temp in both inflated and deflated states. Blinded observer analysis of FLIR images correctly identified adequate REBOA inflation and aortic occlusion 95.4% at 5 minutes and 98.8% at 10 minutes (positive predictive value at 5 minutes = 99% and positive predictive value at 10 minutes = 100%). CONCLUSIONS Mobile thermal imaging is an easy, rapid, and reliable method for assessing distal perfusion after occlusion by REBOA. Smartphone-based FLIR technology allows for confirmation of adequate REBOA placement at the point of care, and performance was not degraded in the setting of major hemorrhage or blackout conditions.
    Type of Medium: Online Resource
    ISSN: 2163-0763 , 2163-0755
    URL: Article
    DOI: 10.1097/TA.0000000000001932
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 4
    Online Resource
    Online Resource
    Metabolic Risk Status and Second-Generation Antipsychotic Drug Selection : A Retrospective Study of Commercially Insured Patients
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Journal of Clinical Psychopharmacology Vol. 29, No. 1 ( 2009-02), p. 26-32
    Details
    In: Journal of Clinical Psychopharmacology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 1 ( 2009-02), p. 26-32
    Type of Medium: Online Resource
    ISSN: 0271-0749
    URL: Article
    DOI: 10.1097/JCP.0b013e31819294cb
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 2057059-4
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  • 5
    Online Resource
    Online Resource
    Staghorn Calculi: Analysis of Treatment Results between Initial Percutaneous Nephrostolithotomy and Extracorporeal Shock Wave Lithotripsy Monotherapy with Reference to Surface Area
    Ovid Technologies (Wolters Kluwer Health) ; 1992
    In:  Journal of Urology Vol. 147, No. 5 ( 1992-05), p. 1219-1225
    Details
    In: Journal of Urology, Ovid Technologies (Wolters Kluwer Health), Vol. 147, No. 5 ( 1992-05), p. 1219-1225
    Type of Medium: Online Resource
    ISSN: 0022-5347 , 1527-3792
    URL: Article
    DOI: 10.1016/S0022-5347(17)37522-5
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1992
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  • 6
    Online Resource
    Online Resource
    Determination of ambulatory blood pressure control in treated patients with controlled office blood pressures
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Blood Pressure Monitoring Vol. 5, No. 5 ( 2000-10), p. 263-269
    Details
    In: Blood Pressure Monitoring, Ovid Technologies (Wolters Kluwer Health), Vol. 5, No. 5 ( 2000-10), p. 263-269
    Type of Medium: Online Resource
    ISSN: 1359-5237
    URL: Article
    DOI: 10.1097/00126097-200010000-00003
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 2029920-5
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  • 7
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    Online Resource
    The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Journal of Trauma and Acute Care Surgery Vol. 85, No. 1S ( 2018-7), p. S44-S48
    Details
    In: Journal of Trauma and Acute Care Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 85, No. 1S ( 2018-7), p. S44-S48
    Abstract: The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model. METHODS The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage. RESULTS Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 μg/mL. CONCLUSION Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations. LEVEL OF EVIDENCE Therapeutic, level II.
    Type of Medium: Online Resource
    ISSN: 2163-0763 , 2163-0755
    URL: Article
    DOI: 10.1097/TA.0000000000001861
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 8
    Online Resource
    Online Resource
    Smartphone-based mobile thermal imaging technology to assess limb perfusion and tourniquet effectiveness under normal and blackout conditions
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Journal of Trauma and Acute Care Surgery Vol. 83, No. 6 ( 2017-12), p. 1129-1135
    Details
    In: Journal of Trauma and Acute Care Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 83, No. 6 ( 2017-12), p. 1129-1135
    Abstract: Over the past decade, there has been a resurgence of tourniquet use in civilian and military settings. Several key challenges include assessment of limb perfusion and adequacy of tourniquet placement, particularly in the austere or prehospital environments. We investigated the utility of thermal imaging to assess adequacy of tourniquet placement. METHODS The FLIR ONE smartphone-based thermal imager was utilized. Ten swine underwent tourniquet placement with no associated hemorrhage (n = 5) or with 40% hemorrhage (n = 5). Experiment 1 simulated proper tourniquet application, experiment 2 had one of two tourniquets inadequately tightened, and experiment 3 had one of two tourniquets inadequately tightened while simulating blackout-combat conditions. Static images were taken at multiple time points up to 30 minutes. Thermal images were then presented to blinded evaluators who assessed adequacy of tourniquet placement. RESULTS The mean core temperature was 38.3 °C in non-hemorrhaged animals versus 38.2 °C in hemorrhaged animals. Hemorrhaged animals were more hypotensive ( p = 0.001), anemic ( p 〈 0.001), vasodilated ( p = 0.008), and had a lower cardiac output ( p = 0.007) compared to non-hemorrhaged animals. The thermal imaging temperature reading decreased significantly after proper tourniquet placement in all animals, with no difference between hemorrhaged and non-hemorrhaged groups at 30 minutes ( p = 0.23). Qualitative thermal image analysis showed clearly visible perfusion differences in all animals between baseline, adequate tourniquet, and inadequate tourniquet in both hemorrhaged and non-hemorrhaged groups. Ninety-eight percent of blinded evaluators (n = 62) correctly identified adequate and inadequate tourniquet placement at 5 minutes. Images in blackout conditions showed no adverse impact on thermal measurements or in the ability to accurately characterize perfusion and tourniquet adequacy. CONCLUSIONS A simple handheld smartphone-based forward looking infrared radiometry device demonstrated a high degree of accuracy, reliability, and ease of use for assessing limb perfusion. Forward looking infrared radiometry also allowed for rapid and reliable identification of adequate tourniquet placement that was not affected by major hemorrhage or blackout conditions.
    Type of Medium: Online Resource
    ISSN: 2163-0763 , 2163-0755
    URL: Article
    DOI: 10.1097/TA.0000000000001639
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 9
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    Online Resource
    The Serum Proteome and Ursodeoxycholic Acid Response in Primary Biliary Cholangitis
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hepatology Vol. 74, No. 6 ( 2021-12), p. 3269-3283
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 6 ( 2021-12), p. 3269-3283
    Abstract: Stratified therapy has entered clinical practice in primary biliary cholangitis (PBC), with routine use of second‐line therapy in nonresponders to first‐line therapy with ursodeoxycholic acid (UDCA). The mechanism for nonresponse to UDCA remains, however, unclear and we lack mechanistic serum markers. The UK‐PBC study was established to explore the biological basis of UDCA nonresponse in PBC and identify markers to enhance treatment. Approach and Results Discovery serum proteomics (Olink) with targeted multiplex validation were carried out in 526 subjects from the UK‐PBC cohort and 97 healthy controls. In the discovery phase, untreated PBC patients (n = 68) exhibited an inflammatory proteome that is typically reduced in scale, but not resolved, with UDCA therapy (n = 416 treated patients). Nineteen proteins remained at a significant expression level (defined using stringent criteria) in UDCA‐treated patients, six of them representing a tightly linked profile of chemokines (including CCL20, known to be released by biliary epithelial cells (BECs) undergoing senescence in PBC). All showed significant differential expression between UDCA responders and nonresponders in both the discovery and validation cohorts. A linear discriminant analysis, using serum levels of C‐X‐C motif chemokine ligand 11 and C‐C motif chemokine ligand 20 as markers of responder status, indicated a high level of discrimination with an AUC of 0.91 (CI, 0.83‐0.91). Conclusions UDCA under‐response in PBC is characterized by elevation of serum chemokines potentially related to cellular senescence and was previously shown to be released by BECs in PBC, suggesting a potential role in the pathogenesis of high‐risk disease. These also have potential for development as biomarkers for identification of high‐risk disease, and their clinical utility as biomarkers should be evaluated further in prospective studies.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.32011
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1472120-X
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  • 10
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    Surrogate Humane Endpoints in Small Animal Models of Acute Lung Injury: A Modified Delphi Consensus Study of Researchers and Laboratory Animal Veterinarians*
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Critical Care Medicine Vol. 49, No. 2 ( 2021-02), p. 311-323
    Details
    In: Critical Care Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 49, No. 2 ( 2021-02), p. 311-323
    Abstract: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. Design: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. Setting: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. Subjects: None. Interventions: None. Measurements and Main Results: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. Conclusions: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.
    Type of Medium: Online Resource
    ISSN: 0090-3493
    URL: Article
    DOI: 10.1097/CCM.0000000000004734
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2034247-0
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