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  • 2017  (9)
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  • 2017  (9)
  • 1
    Language: English
    In: Disease models & mechanisms, 01 April 2017, Vol.10(4), pp.425-437
    Description: Molecular mechanisms underlying development of acute pneumonitis and/or late fibrosis following thoracic irradiation remain poorly understood. Here, we hypothesize that heterogeneity in disease progression and phenotypic expression of radiation-induced lung disease (RILD) across murine strains presents an opportunity to better elucidate mechanisms driving tissue response toward pneumonitis and/or fibrosis. Distinct differences in disease progression were observed in age- and sex-matched CBA/J, C57L/J and C57BL/6J mice over 1 year after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 h post-exposure demonstrated 〉5000 genes to be differentially expressed (twofold change) between strains with early versus late onset of disease. An immediate divergence in early tissue response between radiation-sensitive and -resistant strains was observed. In pneumonitis-prone C57L/J mice, differentially expressed genes were enriched in proinflammatory pathways, whereas in fibrosis-prone C57BL/6J mice, genes were enriched in pathways involved in purine and pyrimidine synthesis, DNA replication and cell division. At 24 h post-WTLI, different patterns of cellular damage were observed at the ultrastructural level among strains but microscopic damage was not yet evident under light microscopy. These data point toward a fundamental difference in patterns of early pulmonary tissue response to WTLI, consistent with the macroscopic expression of injury manifesting weeks to months after exposure. Understanding the mechanisms underlying development of RILD might lead to more rational selection of therapeutic interventions to mitigate healthy tissue damage.
    Keywords: Gene Expression Profiling ; Lung Fibrosis ; Murine Strain Differences ; Radiation Pneumonitis ; Disease Progression ; Gene Expression Profiling ; Lung Diseases -- Genetics ; Radiation Injuries -- Genetics
    ISSN: 17548403
    E-ISSN: 1754-8411
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  • 2
    Language: English
    In: Sports medicine (Auckland, N.Z.), July 2017, Vol.47(7), pp.1437-1451
    Description: The natural history of mild traumatic brain injury (TBI) or concussion remains poorly defined and no objective biomarker of physiological recovery exists for clinical use. The National Collegiate Athletic Association (NCAA) and the US Department of Defense (DoD) established the Concussion Assessment, Research and Education (CARE) Consortium to study the natural history of clinical and neurobiological recovery after concussion in the service of improved injury prevention, safety and medical care for student-athletes and military personnel. The objectives of this paper were to (i) describe the background and driving rationale for the CARE Consortium; (ii) outline the infrastructure of the Consortium policies, procedures, and governance; (iii) describe the longitudinal 6-month clinical and neurobiological study methodology; and (iv) characterize special considerations in the design and implementation of a multicenter trial. Beginning Fall 2014, CARE Consortium institutions have recruited and enrolled 23,533 student-athletes and military service academy students (approximately 90% of eligible student-athletes and cadets; 64.6% male, 35.4% female). A total of 1174 concussions have been diagnosed in participating subjects, with both concussion and baseline cases deposited in the Federal Interagency Traumatic Brain Injury Research (FITBIR) database. Challenges have included coordinating regulatory issues across civilian and military institutions, operationalizing study procedures, neuroimaging protocol harmonization across sites and platforms, construction and maintenance of a relational database, and data quality and integrity monitoring. The NCAA-DoD CARE Consortium represents a comprehensive investigation of concussion in student-athletes and military service academy students. The richly characterized study sample and multidimensional approach provide an opportunity to advance the field of concussion science, not only among student athletes but in all populations at risk for mild TBI.
    Keywords: Athletes ; Athletic Injuries ; Military Personnel ; Students ; Brain Concussion -- Diagnosis ; Universities -- Organization & Administration
    ISSN: 01121642
    E-ISSN: 1179-2035
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  • 3
    In: Hepatology Communications, 2017, Vol.2(1), p.29-34
    Description: Only a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin‐like phospholipase domain‐containing protein 3 ( PNPLA3 ) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well‐characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P 〈 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation. ( Hepatology Communications 2018;2:29–34)
    Keywords: Brief Report ; Brief Reports
    E-ISSN: 2471-254X
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  • 4
    In: Hepatology, August 2017, Vol.66(2), pp.575-590
    Description: Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty‐eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL‐6], IL‐8, interferon gamma–induced protein 10, IL‐4, IL‐9, IL‐10, fibroblast growth factor 2, IL‐7, IL‐15, and transforming growth factor alpha) but lower levels of the anti‐inflammatory macrophage‐derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon‐gamma in response to T‐cell stimulation. Up‐regulated IL‐6, IL‐8, CD38, and CD69 and down‐regulated macrophage‐derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL‐6, IL‐8, CD38, and CD69 were reduced, whereas levels of macrophage‐derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL‐8, IL‐10, fibroblast growth factor 2, and IL‐7 remained higher. : AH patients were in a highly immune‐dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (H 2017;66:575–590).
    Keywords: Monocytes ; Chemokines ; Lymphocytes T ; Hepatitis ; Cytokines ; Liver Diseases ; Interleukin 9 ; Cd4 Antigen ; Fibroblast Growth Factor 2 ; Interleukin 8 ; Interleukin 10 ; Interleukin 7 ; Interleukin 6 ; Fibroblast Growth Factor ; Interleukin 15 ; Cd38 Antigen ; Interleukin 4 ; Cd86 Antigen ; Inflammation ; Cd69 Antigen ; Growth Factors ; Drinking Behavior ; Fibroblasts ; Chemokines ; Macrophage-Derived Chemokine ; Histocompatibility Antigen HLA ; Tumor Necrosis Factor-Tnf ; Alcohol ; Antigens ; Lymphocytes B ; Hepatitis ; Cd80 Antigen ; Macrophages ; Immune Response;
    ISSN: 0270-9139
    E-ISSN: 1527-3350
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  • 5
    In: Alcoholism: Clinical and Experimental Research, December 2017, Vol.41(12), pp.2000-2006
    Description: The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects’ demographics with their adherence to follow‐up appointments were examined. Three hundred eight‐seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two‐thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two‐thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6‐ and 12‐month follow‐up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis. Recruitment and retention of patients with alcohol use disorders in clinical trials is difficult; we report factors related to recruitment of patients with alcoholic hepatitis into observational and treatment trials. Approximately 35% of patients in the observational study returned for 6 and 12 months followup visits. We did not identify any biopsychosocial correlates of retention. Half of the patients eligible for the treatment trials could be recruited. These data may guide design, power analyses, and execution of future studies.
    Keywords: Alcoholic Hepatitis ; Recruitment ; Retention ; Clinical Trial ; Model For End‐Stage Liver Disease Score
    ISSN: 0145-6008
    E-ISSN: 1530-0277
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  • 6
    Language: English
    Description: The role of design in the formation of the Silicon Valley ecosystem of innovation. The role of design in the formation of the Silicon Valley ecosystem of innovation.California's Silicon Valley is home to the greatest concentration of designers in the world: corporate design offices at flagship technology...
    Keywords: Art And Design ; History Of Art ; History Of Specific Companies / Corporate History ; California ; Industrial / Commercial Art & Design
    ISBN: 9780262533591
    Source: VLeBooks
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  • 7
    Language: English
    In: Interpretation, 02/24/2017, pp.1-4
    Keywords: Sedimentary Petrology ; Economic Geology, Geology Of Energy Sources ; Asia ; China ; Clastic Rocks ; Depositional Environment ; Far East ; Lacustrine Environment ; Natural Gas ; Ordos Basin ; Petroleum ; Resources ; Sedimentary Rocks ; Shale ; Shale Gas ; Shale Oil;
    ISSN: 2324-8858
    E-ISSN: 2324-8866
    Source: Society of Exploration Geophysicists (SEG, includes EEGS) (via CrossRef)
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  • 8
    Language: English
    In: Mayo Clinic Proceedings: Innovations, Quality & Outcomes, July 2017, Vol.1(1), pp.37-48
    Description: To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; 〈.001), and this association between regular coffee drinking and lower risk of AH persisted after controlling for relevant covariates (odds ratio=0.26; 95% CI, 0.15-0.46). Time-dependent receiver operating characteristic curve analysis revealed that Model for End-Stage Liver Disease; Maddrey Discriminant Function; age, serum bilirubin, international normalized ratio, and serum creatinine; and Child-Pugh scores all provided similar discrimination performance at 30 days (area under the curve=0.73-0.77). Alcoholic hepatitis remains highly fatal, with 1-year mortality of 25%. Regular coffee consumption was associated with lower risk of AH in heavy drinkers.
    Keywords: Abic ; Ah ; Aic ; Alt ; Ast ; Auc ; BMI ; CP ; Hr ; Inr ; Iqr ; Mdf ; Meld ; Na ; OR ; ROC ; Stopah ; Treat ; Wbc;
    ISSN: 2542-4548
    E-ISSN: 2542-4548
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  • 9
    Language: English
    In: JACC: Heart Failure, May 2017, Vol.5(5), pp.317-326
    Description: The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction 〈35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.
    Keywords: Bosentan ; Clinical Trial ; Endothelin ; Heart Failure ; Placebo ; Medicine
    ISSN: 2213-1779
    E-ISSN: 2213-1787
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