| 41. |
- Kosova, E. C., et al.
(author)
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Vorapaxar in patients with coronary artery bypass grafting: Findings from the TRA 2 degrees P-TIMI 50 trial
- 2017
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In: European heart journal. Acute cardiovascular care. - : Oxford University Press (OUP). - 2048-8726 .- 2048-8734. ; 6:2, s. 164-172
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Journal article (peer-reviewed)abstract
- BACKGROUND: Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for the reduction of cardiovascular death, myocardial infarction, and stroke in stable patients with prior atherothrombosis, who have not had a prior stroke or transient ischemic attack. The aims of this study were to investigate: 1) the role of vorapaxar in patients with severe coronary artery disease treated previously with coronary artery bypass grafting (CABG); and 2) safety in patients undergoing CABG while receiving vorapaxar. METHODS: TRA 2 degrees P-TIMI 50 was a randomized, double-blinded, placebo-controlled trial of vorapaxar in 26,449 stable patients with prior atherothrombosis followed for a median of 30 months. We 1) investigated the efficacy of vorapaxar among patients with a history of CABG prior to randomization (n=2942); and 2) assessed the safety among 367 patients who underwent a new CABG during the trial. RESULTS: Patients with a prior CABG were at higher risk for cardiovascular death, myocardial infarction, or stroke at three years compared with patients without a prior CABG (13.7% vs. 7.8%, p<0.001). Among patients with a prior CABG, vorapaxar significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke (11.9% vs. 15.6%, hazard ratio 0.71, 95% confidence interval 0.58-0.88, p=0.001; number-needed-to-treat = 27). In patients undergoing CABG while receiving vorapaxar, the rate of Thrombolysis in Myocardial Infarction CABG major bleeding was 6.3% vs. 4.1% with placebo (hazard ratio 1.53, 95% confidence interval 0.58-4.01, p=0.39). CONCLUSIONS: In patients with a prior CABG, vorapaxar significantly reduced the risk of recurrent major cardiovascular events. In patients undergoing CABG while receiving vorapaxar, bleeding risk appeared similar to that seen in the overall trial population.
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| 42. |
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| 43. |
- Panyard, D. J., et al.
(author)
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Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer's disease
- 2023
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In: Alzheimers & Dementia. - 1552-5260.
-
Journal article (peer-reviewed)abstract
- INTRODUCTIONA hallmark of Alzheimer's disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODSWe conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTSWe identified 61 proteins significantly associated with the AT category (P < 5.46 x 10(-5)) and 636 significant protein-biomarker associations (P < 6.07 x 10(-6)). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSIONThese results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTSCerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing.Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins.Key glucose/carbon metabolism protein associations independently replicated.CSF proteome outperformed other omics data in predicting amyloid/tau positivity.CSF metabolomics identified and replicated a succinylcarnitine-phosphorylated tau association.
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| 44. |
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| 45. |
- Yang, Liyun, 1992-, et al.
(author)
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Impact of Procedure Type, Case Duration, and Adjunctive Equipment on Surgeon Intraoperative Musculoskeletal Discomfort
- 2020
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In: Journal of the American College of Surgeons. - : ELSEVIER SCIENCE INC. - 1072-7515 .- 1879-1190. ; 230:4, s. 554-560
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Journal article (peer-reviewed)abstract
- BACKGROUND: Surgeons are at high risk of developing musculoskeletal disorders. STUDY DESIGN: This study was designed to identify risk factors and assess intraoperative physical stressors using subjective and objective measures, including type of procedure and equipment used. Wearable sensors and pre- and postoperation surveys were analyzed. RESULTS: Data from 116 cases (34 male and 19 female surgeons) were collected across surgical specialties. Surgeons reported increased pain in the neck, upper, and lower back both during and after operations. High-stress intraoperative postures were also revealed by the real-time measurement in the neck and back. Surgical duration also impacted physical pain and fatigue. Open procedures had more stressful physical postures than laparoscopic procedures. Loupe usage negatively impacted neck postures. CONCLUSIONS: This study highlights the fact that musculoskeletal disorders are common in surgeons and characterizes surgeons' intraoperative posture as well as surgeon pain and fatigue across specialties. Defining intraoperative ((C) 2020 The Author(s). Published by Elsevier Inc. on behalf of the American College of Surgeons.
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| 46. |
- Barrenäs, Fredrik, et al.
(author)
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Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy
- 2021
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:7
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Journal article (peer-reviewed)abstract
- Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in similar to 55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8(+) T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8(+) T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8(+) T cells to mediate protection against SIV challenge.
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| 47. |
- Collins, J.W., et al.
(author)
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Assessing intra-operative ergonomics and workload in robotic surgery using inertia measuring unit sensors and validated questionnaires
- 2016
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In: European urology. Supplement. - : Elsevier BV. - 1569-9056 .- 1878-1500. ; 15:7, s. 247-247
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Journal article (peer-reviewed)abstract
- INTRODUCTION & OBJECTIVES: Robotic approaches have revolutionized radical prostatectomy surgery. The 3D vision and 10 fold magnification provide surgeons improved anatomical vision and more precise instrument control compared to open or laparoscopic techniques. However, the potential benefits of robotic techniques may have trade-offs in increased mental and physical demands for the surgeons. The assisting surgeon, also has the added workload of maintaining working postures that do not impede the robotic arms. This study implemented an innovative motion tracking tool along with validated workload questionnaires to assess the ergonomics and workload for both assisting and console surgeons during robotic surgery. MATERIAL & METHODS: Ten individual surgeons (6 console surgeons and 4 assistant surgeons) performed 15 robotic prostatectomy cases while wearing inertia measurement units (IMUs) to track neck, shoulder, and torso motion during each case. Postoperatively, participants completed a validated workload questionnaire (NASA-TLX). Analysis of variance was performed on all response variables that do not violate the assumption of normality to identify the impact of surgeon role (Console vs Assistant). RESULTS: Twenty-six questionnaires were completed from 13 assisting and 13 console surgeons over the 15 cases. Selfreported mental demand was 41% higher for surgeons at the console than assisting (p<0.05), but physical demand was not statistically different. Post-operative pain was reported highest for the right shoulder and neck and this was more frequently seen in the console surgeons. On IMU readings, the assisting surgeon experienced high neck flexion (>10 degrees) duration over 42% of the procedure compared to only 24% in the console surgeon. In general, surgeons posture on the console was primarily static resulting in fewer movements compared to assisting surgeons. Table 1 summarizes posture movements and durations of static postures. CONCLUSIONS: Postures were more ergonomic during console tasks than assisting by the operating table. However, the console constrains postures leading to static postural loads that have been associated with musculoskeletal symptoms for the neck, torso and shoulders.
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| 48. |
- Deming, Y., et al.
(author)
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Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk
- 2023
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3406-3416
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Journal article (peer-reviewed)abstract
- IntroductionApolipoprotein E (APOE) epsilon 4-carrier status or epsilon 4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE epsilon 2 or heterogeneous effect of epsilon 2, epsilon 3, and epsilon 4 haplotypes. MethodsWe leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). ResultsThe APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE epsilon 4-carrier status and epsilon 4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DiscussionThe APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.
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| 49. |
- Melsen, Wilhelmina G., et al.
(author)
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Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies
- 2013
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In: The Lancet. Infectious Diseases. - 1474-4457. ; 13:8, s. 665-671
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Journal article (peer-reviewed)abstract
- Background Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. Methods We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. Findings Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20-29 and simplified acute physiology score [SAPS 2] 35-58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1.13 (95% CI 0.98-1.31). The overall daily risk of discharge after ventilator-associated pneumonia was 0.74 (0-68-0.80), leading to an overall cumulative risk for dying in the ICU of 2.20 (1.91-2.54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2.97,95% CI 2-24-3-94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2.49 [1.81-3-44] for patients with APACHE scores of 20-29 and 2.72 [1.95-3.78] for those with SAPS 2 scores of 35-58). Interpretation The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay.
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| 50. |
- Mudaliar, S., et al.
(author)
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Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
- 2013
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In: Gastroenterology. - : Elsevier BV. - 0016-5085. ; 145:3, s. 574-582
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Obeticholic acid (OCA; INT-747, 6 alpha-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. METHODS: We performed a double-blind, placebocontrolled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemiceuglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7 alpha-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. RESULTS: When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of gamma-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7 alpha-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. CONCLUSIONS: In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592.
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