Platelet Function in Patients with Diabetes Mellitus: From a Theoretical to a Practical Perspective

Patients with diabetes mellitus have an increased prevalence of vascular disease. Pathologic thrombosis associated with atherosclerotic plaque rupture is a major cause of morbidity and mortality. Platelets are intimately involved in the initiation and propagation of thrombosis. Evidence suggests that platelets from patients with type 2 diabetes have increased reactivity and baseline activation compared to healthy controls. We review the pathophysiology of platelet hyperreactivity in DM patients and its implications in clinical practice, with particular focus on acute coronary syndromes, percutaneous coronary intervention, and novel antiplatelet agents

Implementation of the "FASTHUG" concept decreases the incidence of ventilator-associated pneumonia in a surgical intensive care unit

<p>Abstract</p> <p>Background</p> <p>Ventilator-associated pneumonia (VAP) is a leading cause of morbidity and mortality in critically ill patients. The Institute for Healthcare Improvement 100,000 Lives Campaign made VAP a target of prevention and performance improvement. Additionally, the Joint Commission on Accreditation of Health Organizations' 2007 Disease Specific National Patient Safety Goals included the reduction of healthcare-associated infections. We report implementation of a performance improvement project that dramatically reduced our VAP rate that had exceeded the 90^thpercentile nationally.</p> <p>Methods</p> <p>From 1 January 2004 to 31 December 2005 a performance improvement project was undertaken to decrease our critical care unit VAP rate. In year one (2004) procedural interventions were highlighted: aggressive oral care, early extubation, management of soiled or malfunctioning respiratory equipment, hand washing surveillance, and maximal sterile barrier precautions. In year two (2005) an evaluative concept called FASTHUG (daily evaluation of patients' feeding, analgesia, sedation, thromboembolic prophylaxis, elevation of the head of the bed, ulcer prophylaxis, and glucose control) was implemented. To determine the long-term effectiveness of such an intervention a historical control period (2003) and the procedural intervention period of 2004, i.e., the pre-FASTHUG period (months 1–24) were compared with an extended post-FASTHUG period (months 25–54).</p> <p>Results</p> <p>The 2003 surgical intensive care VAP rate of 19.3/1000 ventilator-days served as a historical control. Procedural interventions in 2004 were not effective in reducing VAP, p = 0.62. However, implementation of FASTHUG in 2005, directed by a critical care team, resulted in a rate of 7.3/1000 ventilator-days, p ≤ .01. The median pneumonia rate was lower after implementation of FASTHUG when compared to the historical control year (p = .028) and the first year after the procedural interventions (p = .041) using follow-up pairwise comparisons. The pre-FASTHUG period (2003–2004, months 1–24) when compared with an extended post-FASTHUG period (2005–2007, 25–54 months) also demonstrated a significant decrease in the VAP rate, p = .0004. This reduction in the post-FASTHUG period occurred despite a rising Severity of Illness index in critically ill patients, p = .001.</p> <p>Conclusion</p> <p>Implementation of the FASTHUG concept, in the daily evaluation of mechanically ventilated patients, significantly decreased our surgical intensive care unit VAP rate.</p

Transcriptomic analysis in pediatric spinal ependymoma reveals distinct molecular signatures

Pediatric spinal ependymomas (SEPN) are important albeit uncommon malignant central nervous system tumors with limited treatment options. Our current knowledge about the underlying biology of these tumors is limited due to their rarity. To begin to elucidate molecular mechanisms that give rise to pediatric SEPN, we compared the transcriptomic landscape of SEPNs to that of intracranial ependymomas using genome-wide mRNA and microRNA (miRNA) expression profiling in primary tumour samples. We found that pediatric SEPNs are characterized by increased expression of genes involved in developmental processes, oxidative phosphorylation, cellular respiration, electron transport chain, and cofactor metabolic process. Next, we compared pediatric spinal and intracranial ependymomas with the same tumours in adults and found a relatively low number of genes in pediatric tumours that were shared with adult tumours (12.5%). In contrast to adult SEPN, down-regulated genes in pediatric SEPN were not enriched for position on chromosome 22. At the miRNA level, we found ten miRNAs that were perturbed in pediatric SEPN and we identified regulatory relationships between these miRNAs and their putative targets mRNAs using the integrative miRNA-mRNA network and predicted miRNA target analysis. These miRNAs include the oncomiR hsa-miR-10b and its family member hsa-miR-10a, both of which are upregulated and target chromatin modification genes that are down regulated in pediatric SEPN. The tumor suppressor, hsa-miR-124, was down regulated in pediatric SEPN and it normally represses genes involved in cell-cell communication and metabolic processes. Together, our findings suggest that pediatric SEPN is characterized by a distinct transcriptional landscape from that of pediatric intracranial EPNs or adult tumors (both SEPNs and intracranial EPNs). Although confirmatory studies are needed, our study reveals novel molecular pathways that may drive tumorigenesis and could serve as biomarkers or rational therapeutic targets

HMGA1 Induces Intestinal Polyposis in Transgenic Mice and Drives Tumor Progression and Stem Cell Properties in Colon Cancer Cells

Although metastatic colon cancer is a leading cause of cancer death worldwide, the molecular mechanisms that enable colon cancer cells to metastasize remain unclear. Emerging evidence suggests that metastatic cells develop by usurping transcriptional networks from embryonic stem (ES) cells to facilitate an epithelial-mesenchymal transition (EMT), invasion, and metastatic progression. Previous studies identified HMGA1 as a key transcription factor enriched in ES cells, colon cancer, and other aggressive tumors, although its role in these settings is poorly understood.To determine how HMGA1 functions in metastatic colon cancer, we manipulated HMGA1 expression in transgenic mice and colon cancer cells. We discovered that HMGA1 drives proliferative changes, aberrant crypt formation, and intestinal polyposis in transgenic mice. In colon cancer cell lines from poorly differentiated, metastatic tumors, knock-down of HMGA1 blocks anchorage-independent cell growth, migration, invasion, xenograft tumorigenesis and three-dimensional colonosphere formation. Inhibiting HMGA1 expression blocks tumorigenesis at limiting dilutions, consistent with depletion of tumor-initiator cells in the knock-down cells. Knock-down of HMGA1 also inhibits metastatic progression to the liver in vivo. In metastatic colon cancer cells, HMGA1 induces expression of Twist1, a gene involved in embryogenesis, EMT, and tumor progression, while HMGA1 represses E-cadherin, a gene that is down-regulated during EMT and metastatic progression. In addition, HMGA1 is among the most enriched genes in colon cancer compared to normal mucosa.Our findings demonstrate for the first time that HMGA1 drives proliferative changes and polyp formation in the intestines of transgenic mice and induces metastatic progression and stem-like properties in colon cancer cells. These findings indicate that HMGA1 is a key regulator, both in metastatic progression and in the maintenance of a stem-like state. Our results also suggest that HMGA1 or downstream pathways could be rational therapeutic targets in metastatic, poorly differentiated colon cancer

Integrative molecular characterization of pediatric spinal ependymoma: the UK Children’s Cancer and Leukaemia Group study

BackgroundPediatric spinal ependymomas (SP-EPNs) are rare primary central nervous system tumors with heterogeneous clinical course. Considering that ependymomas in children are biologically distinct from their adult counterparts, this study aimed to define the molecular landscape of SP-EPNs in children.MethodsIn this retrospective study, we have collected tumor samples from 27 SP-EPN patients younger than 18 years and carried out the histological review, DNA methylation, and gene expression profiling.ResultsUnsupervised analyses with methylation profiles revealed 2 subgroups where all grade I tumors (n = 11) were in Group 1, but the grade II/III tumors split into 2 groups (n = 7 in Group 1 and n = 9 in Group 2). The Heidelberg classifier assigned Group 1 tumors as spinal myxopapillary ependymomas (SP-MPEs), 5 Group 2 tumors as SP-EPNs, and failed to classify 4 Group 2 tumors. Copy numbers derived from DNA methylation arrays revealed subgroup-specific genetic alterations and showed that SP-EPN tumors lack MYCN amplification. Gene expression profiling revealed distinct transcriptomic signatures, including overexpression of genes involved in oxidative phosphorylation in SP-MPEs that were validated by Western blot analysis. We discovered widespread decreases in DNA methylation at enhancer regions that are associated with the expression of oncogenic signaling pathways in SP-MPEs. Furthermore, transcription factor motifs for master regulators, including HNF1B, PAX3, and ZIC3, were significantly overrepresented in probes specific to distal regulatory regions in SP MPEs.Conclusion Our findings show substantial heterogeneity in pediatric SP-EPN and uncover novel enhancers and transcriptional pathways specific to the SP-MPE subgroup, providing a foundation for future therapeutic strategies

Applying the quality improvement collaborative method to process redesign: a multiple case study

<p>Abstract</p> <p>Background</p> <p>Despite the widespread use of quality improvement collaboratives (QICs), evidence underlying this method is limited. A QIC is a method for testing and implementing evidence-based changes quickly across organisations. To extend the knowledge about conditions under which QICs can be used, we explored in this study the applicability of the QIC method for process redesign.</p> <p>Methods</p> <p>We evaluated a Dutch process redesign collaborative of seventeen project teams using a multiple case study design. The goals of this collaborative were to reduce the time between the first visit to the outpatient's clinic and the start of treatment and to reduce the in-hospital length of stay by 30% for involved patient groups. Data were gathered using qualitative methods, such as document analysis, questionnaires, semi-structured interviews and participation in collaborative meetings.</p> <p>Results</p> <p>Application of the QIC method to process redesign proved to be difficult. First, project teams did not use the provided standard change ideas, because of their need for customised solutions that fitted with context-specific causes of waiting times and delays. Second, project teams were not capable of testing change ideas within short time frames due to: the need for tailoring changes ideas and the complexity of aligning interests of involved departments; small volumes of involved patient groups; and inadequate information and communication technology (ICT) support. Third, project teams did not experience peer stimulus because they saw few similarities between their projects, rarely shared experiences, and did not demonstrate competitive behaviour. Besides, a number of project teams reported that organisational and external change agent support was limited.</p> <p>Conclusions</p> <p>This study showed that the perceived need for tailoring standard change ideas to local contexts and the complexity of aligning interests of involved departments hampered the use of the QIC method for process redesign. We cannot determine whether the QIC method would have been appropriate for process redesign. Peer stimulus was non-optimal as a result of the selection process for participation of project teams by the external change agent. In conclusion, project teams felt that necessary preconditions for successful use of the QIC method were lacking.</p

Development and validation of a risk model for predicting adverse drug reactions in older people during hospital stay: Brighton Adverse Drug Reactions Risk (BADRI) model

BACKGROUND: Older patients are at an increased risk of developing adverse drug reactions (ADR). Of particular concern are the oldest old, which constitute an increasingly growing population. Having a validated clinical tool to identify those older patients at risk of developing an ADR during hospital stay would enable healthcare staff to put measures in place to reduce the risk of such an event developing. The current study aimed to (1) develop and (2) validate an ADR risk prediction model. METHODS: We used a combination of univariate analysis and multivariate binary logistic regression to identify clinical risk factors for developing an ADR in a population of older people from a UK teaching hospital. The final ADR risk model was then validated in a European population (European dataset). RESULTS: Six-hundred-ninety patients (median age 85 years) were enrolled in the development stage of the study. Ninety-five reports of ADR were confirmed by independent review in these patients. Five clinical variables were identified through multivariate analysis and included in our final model; each variable was attributed a score of 1. Internal validation produced an AUROC of 0.74, a sensitivity of 80%, and specificity of 55%. During the external validation stage the AUROC was 0.73, with sensitivity and specificity values of 84% and 43% respectively. CONCLUSIONS: We have developed and successfully validated a simple model to use ADR risk score in a population of patients with a median age of 85, i.e. the oldest old. The model is based on 5 clinical variables (≥8 drugs, hyperlipidaemia, raised white cell count, use of anti-diabetic agents, length of stay ≥12 days), some of which have not been previously reported

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Although the <it>high mobility group A1 </it>(<it>HMGA1</it>) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. <it>HMGA1 </it>functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, <it>HMGA1 </it>is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from <it>HMGA1a </it>transgenic mice at different stages in tumorigenesis.</p> <p>Results</p> <p>RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.</p> <p>Conclusions</p> <p>We found that <it>HMGA1 </it>induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. <it>HMGA1 </it>also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into <it>HMGA1 </it>function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant <it>HMGA1 </it>expression.</p

Multilevel psychometric properties of the AHRQ hospital survey on patient safety culture

<p>Abstract</p> <p>Background</p> <p>The Agency for Healthcare Research and Quality (AHRQ) <it>Hospital Survey on Patient Safety Culture </it>was designed to assess staff views on patient safety culture in hospital settings. The purpose of this study was to examine the multilevel psychometric properties of the survey.</p> <p>Methods</p> <p>Survey data from 331 U.S. hospitals with 2,267 hospital units and 50,513 respondents were analyzed to examine the psychometric properties of the survey's items and composites. Item factor loadings, intraclass correlations (ICCs), design effects, internal consistency reliabilities, and multilevel confirmatory factor analyses (MCFA) were examined as well as intercorrelations among the survey's composites.</p> <p>Results</p> <p>Psychometric analyses confirmed the multilevel nature of the data at the individual, unit and hospital levels of analysis. Results provided overall evidence supporting the 12 dimensions and 42 items included in the AHRQ <it>Hospital Survey on Patient Safety Culture </it>as having acceptable psychometric properties at all levels of analysis, with a few exceptions. The Staffing composite fell slightly below cutoffs in a number of areas, but is conceptually important given its impact on patient safety. In addition, one hospital-level model fit indicator for the Supervisor/Manager Expectations & Actions Promoting Patient Safety composite was low (CFI = .82), but all other psychometrics for this scale were good. Average dimension intercorrelations were moderate at .42 at the individual level, .50 at the unit level, and .56 at the hospital level.</p> <p>Conclusions</p> <p>Psychometric analyses conducted on a very large database of hospitals provided overall support for the patient safety culture dimensions and items included in the AHRQ <it>Hospital Survey on Patient Safety Culture</it>. The survey's items and dimensions overall are psychometrically sound at the individual, unit, and hospital levels of analysis and can be used by researchers and hospitals interested in assessing patient safety culture. Further research is needed to study the criterion-related validity of the survey by analysing the relationship between patient safety culture and patient outcomes and studying how to improve patient safety culture.</p