Valproate Protein Binding Is Highly Variable in ICU Patients and Not Predicted by Total Serum Concentrations: A Case Series and Literature Review

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/1/phar1912-sup-0001-SupInfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/2/phar1912_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136503/3/phar1912.pd

Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFβ-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated

Development of a fidelity measure for research on the effectiveness of the Ayres Sensory Integration intervention.

OBJECTIVE: We developed a reliable and valid fidelity measure for use in research on Ayres Sensory Integration (ASI) intervention. METHOD: We designed a fidelity instrument to measure structural and process aspects of ASI intervention. Because scoring of process involves subjectivity, we conducted a series of reliability and validity studies on the process section. Raters were trained to score therapist strategies observed in video recordings of adult-child dyads. We examined content validity through expert ratings. RESULTS: Reliability of the process section was strong for total fidelity score (ICC = .99, Cronbach\u27s alpha = .99) and acceptable for most items. Total score significantly differentiated ASI from four alternative interventions. Expert ratings indicated strong agreement that items in the structural and process sections represent ASI intervention. CONCLUSION. The Ayres Sensory Integration Fidelity Measure has strong content validity. The process section is reliable and valid when scored by trained raters with expertise in ASI

Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression

AbstractNkx2.2 and Arx are essential pancreatic transcription factors. Nkx2.2 is necessary for the appropriate specification of the islet alpha, beta, PP and epsilon cell lineages, whereas Arx is required to form the correct ratio of alpha, beta, delta and PP cells. To begin to understand the cooperative functions of Nkx2.2 and Arx in the development of endocrine cell lineages, we generated progenitor cell-specific deletions of Arx on the Nkx2.2 null background. The analysis of these mutants demonstrates that expansion of the ghrelin cell population in the Nkx2.2 null pancreas is not dependent on Arx; however, Arx is necessary for the upregulation of ghrelin mRNA levels in Nkx2.2 mutant epsilon cells. Alternatively, in the absence of Arx, delta cell numbers are increased and Nkx2.2 becomes essential for the repression of somatostatin gene expression. Interestingly, the dysregulation of ghrelin and somatostatin expression in the Nkx2.2/Arx compound mutant (Nkx2.2null;ArxΔpanc) results in the appearance of ghrelin+/somatostatin+ co-expressing cells. These compound mutants also revealed a genetic interaction between Nkx2.2 and Arx in the regulation of the PP cell lineage; the PP cell population is reduced when Nkx2.2 is deleted but is restored back to wildtype numbers in the Nkx2.2null;ArxΔpanc mutant. Moreover, conditional deletion of Arx in specific pancreatic cell populations established that the functions of Arx are necessary in the Neurog3+ endocrine progenitors. Together, these experiments identify novel genetic interactions between Nkx2.2 and Arx within the endocrine progenitor cells that ensure the correct specification and regulation of endocrine hormone-producing cells

Two-photon Lithography for 3D Magnetic Nanostructure Fabrication

Ferromagnetic materials have been utilised as recording media within data storage devices for many decades. Confinement of the material to a two dimensional plane is a significant bottleneck in achieving ultra-high recording densities and this has led to the proposition of three dimensional (3D) racetrack memories that utilise domain wall propagation along nanowires. However, the fabrication of 3D magnetic nanostructures of complex geometry is highly challenging and not easily achievable with standard lithography techniques. Here, by using a combination of two-photon lithography and electrochemical deposition, we show a new approach to construct 3D magnetic nanostructures of complex geometry. The magnetic properties are found to be intimately related to the 3D geometry of the structure and magnetic imaging experiments provide evidence of domain wall pinning at a 3D nanostructured junction

Goal attainment scaling as a measure of meaningful outcomes for children with sensory integration disorders.

Goal attainment scaling (GAS) is a methodology that shows promise for application to intervention effectiveness research and program evaluation in occupational therapy (Dreiling & Bundy, 2003; King et al., 1999; Lannin, 2003; Mitchell & Cusick, 1998). This article identifies the recent and current applications of GAS to occupational therapy for children with sensory integration dysfunction, as well as the process, usefulness, and problems of application of the GAS methodology to this population. The advantages and disadvantages of using GAS in single-site and multisite research with this population is explored, as well as the potential solutions and future programs that will strengthen the use of GAS as a measure of treatment effectiveness, both in current clinical practice and in much-needed larger, multisite research studies

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006–2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1–2) versus poor (CPC 3–5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46–0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.publishedVersio

Fidelity in sensory integration intervention research.

OBJECTIVE: We sought to assess validity of sensory integration outcomes research in relation to fidelity (faithfulness of intervention to underlying therapeutic principles). METHOD: We identified core sensory integration intervention elements through expert review and nominal group process. Elements were classified into structural (e.g., equipment used, therapist training) and therapeutic process categories. We analyzed 34 sensory integration intervention studies for consistency of intervention descriptions with these elements. RESULTS: Most studies described structural elements related to therapeutic equipment and interveners\u27 profession. Of the 10 process elements, only 1 (presentation of sensory opportunities) was addressed in all studies. Most studies described fewer than half of the process elements. Intervention descriptions in 35% of the studies were inconsistent with one process element, therapist-child collaboration. CONCLUSION: Validity of sensory integration outcomes studies is threatened by weak fidelity in regard to therapeutic process. Inferences regarding sensory integration effectiveness cannot be drawn with confidence until fidelity is adequately addressed in outcomes research

The association of partial pressures of oxygen and carbon dioxide with neurological outcome after out-of-hospital cardiac arrest: an explorative International Cardiac Arrest Registry 2.0 study

Background Exposure to extreme arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) following the return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) is common and may affect neurological outcome but results of previous studies are conflicting. Methods Exploratory study of the International Cardiac Arrest Registry (INTCAR) 2.0 database, including 2162 OHCA patients with ROSC in 22 intensive care units in North America and Europe. We tested the hypothesis that exposure to extreme PaO2 or PaCO2 values within 24 h after OHCA is associated with poor neurological outcome at discharge. Our primary analyses investigated the association between extreme PaO2 and PaCO2 values, defined as hyperoxemia (PaO2 > 40 kPa), hypoxemia (PaO2  6.7 kPa) and hypocapnemia (PaCO2  40 kPa with PaCO2  6.7 kPa and neurological outcome. To define a cut point for the onset of poor neurological outcome, we tested a model with increasing and decreasing PaO2 levels and decreasing PaCO2 levels. Cerebral Performance Category (CPC), dichotomized to good (CPC 1–2) and poor (CPC 3–5) was used as outcome measure. Results Of 2135 patients eligible for analysis, 700 were exposed to hyperoxemia or hypoxemia and 1128 to hypercapnemia or hypocapnemia. Our primary analyses did not reveal significant associations between exposure to extreme PaO2 or PaCO2 values and neurological outcome (P = 0.13–0.49). Our secondary analyses showed no significant associations between combinations of PaO2 and PaCO2 and neurological outcome (P = 0.11–0.86). There was no PaO2 or PaCO2 level significantly associated with poor neurological outcome. All analyses were adjusted for relevant co-variates. Conclusions Exposure to extreme PaO2 or PaCO2 values in the first 24 h after OHCA was common, but not independently associated with neurological outcome at discharge.publishedVersio