Long-term cognitive impairment is one of the most common complications of critical illness among survivors who receive mechanical ventilation. Recommended oxygen targets during mechanical ventilation ...vary among international guidelines. Different oxygen targets during mechanical ventilation have the potential to alter long-term cognitive function due to cerebral hypoxemia or hyperoxemia. Whether higher, intermediate or lower SpO
targets are associated with better cognitive function at 12-month follow-up is unknown.
The
ragmatic
nvestigation of optima
xygen
argets (PILOT) trial is an ongoing pragmatic, cluster-randomised, cluster-crossover trial comparing the effect of a higher SpO
target (target 98%, goal range 96%-100%), an intermediate SpO
target (target 94%, goal range 92%-96%) and a lower SpO
target (target 90%, goal range 88%-92%) on clinical outcomes in mechanically ventilated patients admitted to the medical intensive care unit at a single centre in the USA. For this ancillary study of long-term
ognitive
utcomes (CO-PILOT), survivors of critical illness who are in the PILOT trial and who do not meet exclusion criteria for CO-PILOT are approached for consent. The anticipated number of patients for whom assessment of long-term cognition will be performed in CO-PILOT is 612 patients over 36 months of enrolment. Cognitive, functional and quality of life assessments are assessed via telephone interview at approximately 12 months after enrolment in PILOT. The primary outcome of CO-PILOT is the telephone version of the Montreal Cognitive Assessment. A subset of patients will also complete a comprehensive neuropsychological telephone battery to better characterise the cognitive domains affected.
The CO-PILOT ancillary study was approved by the Vanderbilt Institutional Review Board. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.
T cells play a crucial role in viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. MicroRNA (miR) has ...been implicated as a key regulator controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4 super(+) T-cell responses through overexpression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with overexpression of DUSP6 was observed in CD4 super(+) T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 overexpression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4 super(+) T cells led to improved T-cell responses including enhanced CD25 and CD69 expression, increased interleukin-2 expression, and improved proliferation of CD4 super(+) T cells derived from chronically HCV-infected individuals. Conclusion: Since a decline of miR-181a concomitant with DUSP6 overexpression is the signature marker for age-associated T-cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T-cell aging through miR-181a-regulated DUSP6 signaling and reveal new targets for therapeutic rejuvenation of impaired T-cell responses during chronic viral infection. (Hepatology 2015; 61:1163-1173)
We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic ...risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.
T cells play a crucial role for viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. microRNAs (miR) ...have been implicated as key regulators controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4
+
T cell responses via over-expression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with over-expression of DUSP6 were observed in CD4
+
T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 over-expression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4
+
T cells led to improved T cell responses including enhanced CD25 and CD69 expressions, increased IL-2 expression, and improved proliferation of CD4
+
T cells derived from chronically HCV-infected individuals. Since a decline of miR-181a concomitant with DUSP6 over-expression are the signature markers for age-associated T cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T cell aging via miR-181a-regulated DUSP6 signaling, and reveal new targets for therapeutic rejuvenation of impaired T cell responses during chronic viral infection.
The electrochemical conversion of CO
to methane provides a means to store intermittent renewable electricity in the form of a carbon-neutral hydrocarbon fuel that benefits from an established global ...distribution network. The stability and selectivity of reported approaches reside below technoeconomic-related requirements. Membrane electrode assembly-based reactors offer a known path to stability; however, highly alkaline conditions on the cathode favour C-C coupling and multi-carbon products. In computational studies herein, we find that copper in a low coordination number favours methane even under highly alkaline conditions. Experimentally, we develop a carbon nanoparticle moderator strategy that confines a copper-complex catalyst when employed in a membrane electrode assembly. In-situ XAS measurements confirm that increased carbon nanoparticle loadings can reduce the metallic copper coordination number. At a copper coordination number of 4.2 we demonstrate a CO
-to-methane selectivity of 62%, a methane partial current density of 136 mA cm
, and > 110 hours of stable operation.
Purpose To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy ( super(1)H-MRS) ...can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. Materials and Methods At 7T MR, we acquired super(1)H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n=26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. Results Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs greater than or equal to 0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r sub((24))=-0.37; P<0.05), and a gender effect was noted on glutamine and glutathione. Conclusion The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals. J. MAGN. RESON. IMAGING 2016; 43:88-98.
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