Hepatocyte-derived biomarkers predict liver-related events at 2 years in Child-Pugh class A alcohol-related cirrhosis.

BACKGROUND & AIMS: In patients with compensated alcohol-related cirrhosis, reliable prognostic biomarkers are lacking. Keratin-18 and hepatocyte-derived large extracellular vesicle (lEV) concentrations reflect disease activity, but their ability to predict liver-related events is unknown. METHODS: We measured plasma keratin-18 and hepatocyte lEV concentrations in 500 patients with Child-Pugh class A alcohol-related cirrhosis. The ability of these hepatocyte-derived biomarkers, alone or combined with model for end-stage liver disease (MELD) and FibroTest scores, to predict liver-related events at 2 years was analyzed, taking into account the alcohol consumption at inclusion and during follow-up. RESULTS: Keratin-18 and hepatocyte lEV concentrations increased with alcohol consumption. In patients without active alcohol consumption at enrollment (n = 419), keratin-18 concentration predicted liver-related events at 2 years, independently of FibroTest and MELD. Patients with both keratin-18 concentrations >285 U/L and FibroTest >0.74 had a 24% cumulative incidence of liver-related events at 2 years, vs. 5% to 14% in other groups of patients. Similar results were obtained when combining keratin-18 concentrations >285 U/L with MELD >10. In patients with active alcohol consumption at enrollment (n = 81), hepatocyte lEVs predicted liver-related events at 2 years, independently of FibroTest and MELD. Patients with both hepatocyte lEV concentrations >50 U/L and FibroTest >0.74 had a 62% cumulative incidence of liver-related events at 2 years, vs. 8% to 13% in other groups of patients. Combining hepatocyte lEV concentrations >50 U/L with MELD >10 had a lower discriminative ability. Similar results were obtained when using decompensation of cirrhosis, defined according to Baveno VII criteria, as an endpoint. CONCLUSION: In patients with Child-Pugh class A alcohol-related cirrhosis, combining hepatocyte-derived biomarkers with FibroTest or MELD scores identifies patients at high risk of liver-related events, and could be used for risk stratification and patient selection in clinical trials. IMPACT AND IMPLICATIONS: In patients with compensated alcohol-related cirrhosis, reliable predictors of outcome are lacking. In patients with Child-Pugh class A alcohol-related cirrhosis, combining hepatocyte-derived biomarkers (keratin-18 and hepatocyte-large extracellular vesicles) with FibroTest or MELD scores identifies those at high risk of liver-related events at 2 years. The identified patients at high risk of liver-related events are the target-of-choice population for intensive surveillance (e.g., referral to tertiary care centers; intensive control of risk factors) and inclusion in clinical trials.

Correlation between safety attitudes and early adoption of cognitive aids in the German culture sphere: a multicenter survey study.

BACKGROUND: Cognitive Aids (checklists) are a common tool to improve patient safety. But the factors for their successful implementation and continuous use are not yet fully understood. Recent publications suggest safety culture to play a key role in this context. However, the effects on the outcome of implementation measures remain unclear. Hospitals and clinics that are involved in cognitive aid development and research might have significantly different safety cultures than their counterparts, resulting in skewed assessments of proper implementation. Therefore, the objective of this study was to assess the correlation between cognitive aid implementation and safety attitudes of staff members in early adopting and later adopting clinics. METHODS: An online survey of the Safety Attitudes Questionnaire (SAQ) was carried out in German anaesthesiology departments during the initial implementation of a new checklist for emergencies during anesthesia ("eGENA" app). Subsequently an analysis between subgroups ("eGENA" app usage and occupation), with Kruskal-Wallis- and Mann-Whitney-U-Tests was carried out for the general SAQ, as well as it six subscales. RESULTS: Departments that introduced "eGENA" app (Median 3,74, IQR 0,90) reported a significantly higher median SAQ (U (NeGENA = 6, Nnon eGENA = 14) = 70,0, z = 2,31, p = 0,02, r = 0,516) than their counterparts (Median 2,82, IQR 0,77) with significant differences in the dimensions teamwork climate, work satisfaction, perception of management and working conditions. CONCLUSION: Early adopters of cognitive aids are likely to show a significantly higher perception of safety culture in the SAQ. Consequently, successful implementation steps from these settings might not be sufficient in different clinics. Therefore, further investigation of the effects of safety culture on cognitive aid implementation should be conducted.

How novice and expert anaesthetists understand expertise in anaesthesia: a qualitative study.

BACKGROUND: The development of expertise in anaesthesia requires personal contact between a mentor and a learner. Because mentors often are experienced clinicians, they may find it difficult to understand the challenges novices face during their first months of clinical practice. As a result, novices' perspectives may be an important source of pedagogical information for the expert. The aim of this study was to explore novice and expert anaesthetists understanding of expertise in anaesthesia using qualitative methods. METHODS: Semi-structured interviews were conducted with 9 novice and 9 expert anaesthetists from a German University Hospital. Novices were included if they had between 3 and 6 months of clinical experience and experts were determined by peer assessment. Interviews were intended to answer the following research questions: What do novices think expertise entails and what do they think they will need to become an expert? What do experts think made them the expert person and how did that happen? How do both groups value evidence-based standards and how do they negotiate following written guidance with following one's experience? RESULTS: The clinical experience in both groups differed significantly (novices: 4.3 mean months vs. experts: 26.7 mean years; p < 0.001). Novices struggled with translating theoretical knowledge into action and found it difficult to talk about expertise. Experts no longer seem to remember being challenged as novice by the complexity of routine tasks. Both groups shared the understanding that the development of expertise was a socially embedded process. Novices assumed that written procedures were specific enough to address every clinical contingency whereas experts stated that rules and standards were essentially underspecified. For novices the challenge was less to familiarise oneself with written standards than to learn the unwritten, quasi-normative rules of their supervising consultant(s). Novices conceptualized decision making as a rational, linear process whereas experts added to this understanding of tacit knowledge and intuitive decision making. CONCLUSIONS: Major qualitative differences between a novice and an expert anaesthetist's understanding of expertise can create challenges during the first months of clinical training. Experts should be aware of the problems novices may have with negotiating evidence-based standards and quasi-normative rules.

The influence of different patient positions during rapid induction with severe regurgitation on the volume of aspirate and time to intubation: a prospective randomised manikin simulation study.

BACKGROUND: Aspiration is a main contributor to morbidity and mortality in anaesthesia. The ideal patient positioning for rapid sequence induction remains controversial. A head-down tilt and full cervical spine extension (Sellick) might prevent aspiration but at the same time compromise airway management. We aimed to determine the influence of three different positions during induction of general anaesthesia on the volume of aspirate and on participants' airway management. METHODS: Eighty-four anaesthetic trainees and consultants participated in a prospective randomised simulation study. Anaesthesia was induced in reverse Trendelenburg position (+ 15°) in a manikin capable of dynamic fluid regurgitation. Participants were randomised to change to Trendelenburg position (- 15°) a) as soon as regurgitation was noticed, b) as soon as 'patient' had been anaesthetised, and c) as soon as 'patient' had been anaesthetised and with full cervical spine extension (Sellick). Primary endpoints were the aspirated volume and the time to intubation. Secondary endpoints were ratings of the laryngoscopic view and the intubation situation (0-100 mm). RESULTS: Combining head-down tilt with Sellick position significantly reduced aspiration (p < 0.005). Median time to intubate was longer in Sellick position (15 s [8-30]) as compared with the head in sniffing position (10 s [8-12.5]; p < 0.05). Participants found laryngoscopy more difficult in Sellick position (39.3 ± 27.9 mm) as compared with the sniffing position (23.1 ± 22.1 mm; p < 0.05). Both head-down tilt intubation situations were considered equally difficult: 34.8 ± 24.6 mm (Sniffing) vs. 44.2 ± 23.1 mm (Sellick; p = n.s). CONCLUSIONS: In a simulated setting, using a manikin-based simulator capable of fluid regurgitation, a - 15° head-down tilt with Sellick position reduced the amount of aspirated fluid but increased the difficulty in visualising the vocal cords and prolonged the time taken to intubate. Assessing the airway management in the identical position in healthy patients without risk of aspiration might be a promising next step to take.

Applying the human factors analysis and classification system to critical incident reports in anaesthesiology.

BACKGROUND: The Human Factors Analysis and Classification System (HFACS) was developed as a practical taxonomy to investigate and analyse the human contribution to accidents and incidents. Based on Reason's "Swiss Cheese Model", it considers individual, environmental, leadership and organizational contributing factors in four hierarchical levels. The aim of this study was to assess the applicability of a modified HFACS taxonomy to incident reports from a large, anonymous critical incident database with the goal of gaining valuable insight into underlying, more systemic conditions and recurring schemes that might add important information for future incident avoidance. METHODS: We analysed 50 reports from an anonymous, anaesthesiologic, single-centre Critical Incident Reporting System using a modified HFACS-CIRS taxonomy. The 19 HFACS categories were further subdivided into a total of 117 nanocodes representing specific behaviours or preconditions for incident development. RESULTS: On an individual level, the most frequent contributions were decision errors, attributed to inadequate risk assessment or critical-thinking failure. Communication and Coordination, mostly due to inadequate or ineffective communication, was contributory in two-thirds of reports. Half of the reports showed contributory complex interactions in a sociotechnical environment. Ratability scores were noticeably lower for categories evaluating leadership and organizational influences, necessitating careful interpretation. CONCLUSIONS: We applied the HFACS taxonomy to the analysis of CIRS reports in anaesthesiology. This constitutes a structured approach that, especially when applied to a large data set, might help guide future mitigation and intervention strategies to reduce critical incidents and improve patient safety. Improved, more structured reporting templates could further optimize systematic analysis.

Does an electronic cognitive aid have an effect on the management of severe gynaecological TURP syndrome? A prospective, randomised simulation study.

BACKGROUND: Lack of familiarity with the content of current guidelines is a major factor associated with non-compliance by clinicians. It is conceivable that cognitive aids with regularly updated medical content can guide clinicians' task performance by evidence-based practices, even if they are unfamiliar with the actual guideline. Acute hyponatraemia as a consequence of TURP syndrome is a rare intraoperative event, and current practice guidelines have changed from slow correction to rapid correction of serum sodium levels. The primary objective of this study was to compare the management of a simulated severe gynaecological transurethral resection of the prostate (TURP) syndrome under spinal anaesthesia with either: an electronic cognitive aid, or with management from memory alone. The secondary objective was to assess the clinical relevance and participant perception of the usefulness of the cognitive aid. METHODS: Anaesthetic teams were allocated to control (no cognitive aid; n = 10) or intervention (cognitive aid provided; n = 10) groups. We identified eight evidence-based management tasks for severe TURP syndrome from current guidelines and subdivided them into acute heart failure (AHF)/pulmonary oedema tasks (5) and acute hyponatraemia tasks (3). Implementation of the treatment steps was measured by scoring task items in a binary fashion (yes/no). To assess whether or not the cognitive aid had prompted a treatment step, participants from the cognitive aid group were questioned during debriefing on every single treatment step. At the end of the simulation, session participants were asked to complete a survey. RESULTS: Teams in the cognitive aid group considered evidence-based treatment steps significantly more often than teams of the control group (96% vs. 50% for 'AHF/pulmonary oedema' p < 0.001; 79% vs. 12% for 'acute hyponatraemia' p < 0.001). Without the cognitive aid, performance would have been comparable across both groups. Nurses, trainees, and consultants derived equal benefit from the cognitive aid. CONCLUSIONS: The cognitive aid improved the implementation of evidence-based practices in a simulated intraoperative scenario. Cognitive aids with current medical content could help to close the translational gap between guideline publication and implementation in acute patient care. It is important that the cognitive aid should be familiar, in a format that has been used in practice and training.

The effect of an electronic cognitive aid on the management of ST-elevation myocardial infarction during caesarean section: a prospective randomised simulation study.

BACKGROUND: Cognitive aids have come to be viewed as promising tools in the management of perioperative critical events. The majority of published simulation studies have focussed on perioperative crises that are characterised by time pressure, rare occurrence, or complex management steps (e.g., cardiac arrest emergencies, management of the difficult airway). At present, there is limited information on the usefulness of cognitive aids in critical situations with moderate time pressure and complexity. Intraoperative myocardial infarction may be an emergency to which these limitations apply. METHODS: Anaesthetic teams were allocated to control (no cognitive aid; n = 10) or intervention (cognitive aid provided; n = 10) groups. The primary aim of this study was to compare cognitive aid versus memory for intraoperative ST-elevation myocardial infarction (STEMI) management in a simulation of caesarean delivery under spinal anaesthesia. We identified nine evidence-based metrics of essential care from current guidelines and subdivided them into mandatory (high level of evidence; no interference with surgery) and optional (lower class of recommendation; possible impact on surgery) tasks. Six clinically relevant tasks were added by consensus. Implementation of these steps was measured by scoring task items in a binary fashion (yes/no). The interval between the diagnosis of STEMI and the first contact with the cardiac catheterisation lab was measured. To determine whether or not the cognitive aid had prompted an action, participants from the cognitive aid group were interviewed during debriefing on every single treatment step. At the end of the simulation, session participants were asked to complete a survey. RESULTS: The presence of the cognitive aid did not shorten the time interval until the cardiac catheterisation lab was contacted. The availability of the cognitive aid improved task performance in the tasks identified from the guidelines (93% vs. 69%; p < 0.001) as well as overall task performance (87.5% vs. 59%; p < 0.001). The observed difference in performance can be attributed to the use of the cognitive aid, as performance from memory alone would have been comparable across both groups. Trainees appeared to derive greater benefit from the cognitive aid than did consultants and nurses. CONCLUSIONS: The management of intraoperative ST-elevation myocardial infarction can be improved if teams use a cognitive aid. Trainees appeared to derive greater benefit from the cognitive aid than did consultants and nurses.

Intraoral microvascular anastomosis for segmental mandibular reconstruction following removal of an ameloblastoma.

Cases of immediate bony microvascular reconstruction following segmental mandibulectomy in children are hard to find in the current literature. Moreover, microvascular segmental mandibular reconstruction that adopts an intraoral anastomosis technique has not been described so far. Therefore, the present clinical report aims at extending the armamentarium of bony microvascular reconstruction in pediatric cases of segmental mandibulectomy by highlighting an intraoral microvascular anastomosing technique.A 6-year-old boy, who suffered from an ameloblastoma of the mural type in the mandible, received a radical segmental mandibular resection because of the high recurrence rate of this tumor entity. Immediate reconstruction was carried out with a fibular double-barrel graft. Microvascular anastomoses were performed in an end-to-end fashion with the facial artery and vein as recipient vessels. The postoperative course was uneventful. There was no impairment of speech, deglutition, mastication, and facial nerve function. The facial appearance remained unobtrusive. On removal of the reconstruction plate 3 months after the reconstruction procedure, bleeding from the reconstructed mandibular segment indicated vascularization of the graft.It seems that segmental mandibulectomy and simultaneous microvascular bony reconstruction do not necessarily lead to impaired function as far as speech, deglutition, and mastication are concerned. Instead, the intraoral anastomosis technique allows waiving extraoral skin incisions and subsequent scarring, leaving the facial appearance unchanged and unobtrusive. Especially, the potential risk of stigmatization of the patient is avoided. Therefore, decision making in the choice of 1 or the other reconstruction option following segmental mandibulectomy should always consider the adoption of an intraoral anastomosing technique.

TMEM45A is essential for hypoxia-induced chemoresistance in breast and liver cancer cells.

BACKGROUND: Hypoxia is a common characteristic of solid tumors associated with reduced response to radio- and chemotherapy, therefore increasing the probability of tumor recurrence. The aim of this study was to identify new mechanisms responsible for hypoxia-induced resistance in breast cancer cells. METHODS: MDA-MB-231 and HepG2 cells were incubated in the presence of taxol or etoposide respectively under normoxia and hypoxia and apoptosis was analysed. A whole transcriptome analysis was performed in order to identify genes whose expression profile was correlated with apoptosis. The effect of gene invalidation using siRNA was studied on drug-induced apoptosis. RESULTS: MDA-MB-231 cells incubated in the presence of taxol were protected from apoptosis and cell death by hypoxia. We demonstrated that TMEM45A expression was associated with taxol resistance. TMEM45A expression was increased both in MDA-MB-231 human breast cancer cells and in HepG2 human hepatoma cells in conditions where protection of cells against apoptosis induced by chemotherapeutic agents was observed, i.e. under hypoxia in the presence of taxol or etoposide. Moreover, this resistance was suppressed by siRNA-mediated silencing of TMEM45A. Kaplan Meier curve showed an association between high TMEM45A expression and poor prognostic in breast cancer patients. Finally, TMEM45 is highly expressed in normal differentiated keratinocytes both in vitro and in vivo, suggesting that this protein is involved in epithelial functions. CONCLUSION: Altogether, our results unravel a new mechanism for taxol and etoposide resistance mediated by TMEM45A. High levels of TMEM45A expression in tumors may be indicative of potential resistance to cancer therapy, making TMEM45A an interesting biomarker for resistance.

The impact of "To Err Is Human" on patient safety in anesthesiology. A bibliometric analysis of 20 years of research.

Background: Patient safety gained public notoriety following the 1999 report of the Institute of Medicine: To Err is Human - Building a Safer Health System which summarized a culminated decades' worth of research that had so far been largely ignored. The aim of this study was to analyze the report's impact on patient safety research in anesthesiology. Methods: A bibliometric analysis was performed on all anesthesiologic publications from 2000 to 2019 that referenced To Err Is Human. In bibliometric literature, references are understood to represent an author's conscious decision to express a relationship between his own manuscript and the cited document. Results: The anesthesiologic data base contained 1.036 publications. The journal with the most references to the IOM report is Anesthesia & Analgesia. By analyzing author keywords and patterns of collaboration, changes in the patient safety debate and its core themes in anesthesiology over time could be visualized. The generic notion of "error," while initially a central topic in the scientific discourse, was subsequently replaced by terms representing a more granular, team-oriented, and educational approach. Patient safety research in anesthesia, while profiting from a certain intellectual and conceptual head start, showed a discursive shift toward more managerial, quality-management related topics as observed in the health care system as a whole. Conclusions: Over the last 20 years, the research context expanded from the initial focus set forth by the IOM report, which ultimately led to an underrepresentation of research on critical incident reporting and systemic approaches to safety. Important collaborations with safety researchers from outside of health care dating back to the 1990's were gradually reduced, while previous research within anesthesiology was aligned with a broader, more managerial patient safety agenda.

Role of extracellular vesicles in atherosclerosis: An update.

Extracellular vesicles (EVs) are membrane particles released by most cell types in response to different stimuli. They are composed of a lipid bilayer that encloses a wide range of bioactive material, including proteins and nucleic acids. EVs have garnered increasing attention over recent years, as their role in intercellular communication has been brought to light. As such, they have been found to regulate pathophysiologic pathways like inflammation, angiogenesis, or senescence, and are therefore implicated in key aspects atherosclerosis initiation and progression. Interestingly, EVs appear to have a multifaceted role; depending on their cargo, they can either facilitate or hamper the development of atherosclerotic lesions. In this review, we examine how EVs of varying origins may be implicated in the different phases of atherosclerotic lesion development. We also discuss the need to standardize isolation and analysis procedures to fully fulfil their potential as biomarkers and therapeutics for cardiovascular diseases.

Cell-specific targeting of extracellular vesicles through engineering the glycocalyx.

Extracellular vesicles (EVs) are promising carriers for the delivery of a variety of chemical and biological drugs. However, their efficacy is limited by the lack of cellular specificity. Available methods to improve the tissue specificity of EVs predominantly rely on surface display of proteins and peptides, largely overlooking the dense glycocalyx that constitutes the outermost layer of EVs. In the present study, we report a reconfigurable glycoengineering strategy that can endogenously display glycans of interest on EV surface. Briefly, EV producer cells are genetically engineered to co-express a glycosylation domain (GD) inserted into the large extracellular loop of CD63 (a well-studied EV scaffold protein) and fucosyltransferase VII (FUT7) or IX (FUT9), so that the engineered EVs display the glycan of interest. Through this strategy, we showcase surface display of two types of glycan ligands, sialyl Lewis X (sLeX) and Lewis X, on EVs and achieve high specificity towards activated endothelial cells and dendritic cells, respectively. Moreover, the endothelial cell-targeting properties of sLeX-EVs were combined with the intrinsic therapeutic effects of mesenchymal stem cells (MSCs), leading to enhanced attenuation of endothelial damage. In summary, this study presents a reconfigurable glycoengineering strategy to produce EVs with strong cellular specificity and highlights the glycocalyx as an exploitable trait for engineering EVs.

[Extracellular vesicles and cardiovascular diseases]. / Vésicules extracellulaires et maladies cardiovasculaires.

Cardiovascular diseases remain the leading cause of death globally. There is therefore a need to develop new approaches for the treatment and early detection of these ailments. In the past decades, extracellular vesicles (EVs) have attracted significant attention as their role in intercellular communication has been brought to light. They have been shown to regulate pathways such as cellular inflammation or angiogenesis, and are therefore involved in key aspects of cardiovascular pathophysiology. Interestingly, EVs appear to have a multifaceted role which depends on their origin and cargo. Though at times deleterious, they have also been proposed as promising diagnostic tools and potential therapeutics. This review highlights recent advances in the role of extracellular vesicles in cardiovascular pathologies.

TITLE: Vésicules extracellulaires et maladies cardiovasculaires. ABSTRACT: Les maladies cardiovasculaires constituent la principale cause de décès dans le monde. Il est donc urgent de développer de nouvelles approches pour le traitement et la détection de ces maladies. Les vésicules extracellulaires (VE) ont attiré une attention considérable au vu de leur rôle dans la communication intercellulaire. Elles régulent en effet des processus clés comme l'inflammation ou l'angiogenèse, et sont donc impliquées dans de nombreux aspects de la physiopathologie cardiovasculaire. Les VE semblent avoir une action complexe qui dépend de leur origine et de leur contenu. Bien que leur présence soit parfois délétère, elles sont également considérées comme des outils diagnostiques et thérapeutiques potentiels. Cette revue résume les avancées récentes dans la compréhension du rôle des VE dans les maladies cardiovasculaires.

PathEx: a novel multi factors based datasets selector web tool.

BACKGROUND: Microarray experiments have become very popular in life science research. However, if such experiments are only considered independently, the possibilities for analysis and interpretation of many life science phenomena are reduced. The accumulation of publicly available data provides biomedical researchers with a valuable opportunity to either discover new phenomena or improve the interpretation and validation of other phenomena that partially understood or well known. This can only be achieved by intelligently exploiting this rich mine of information. DESCRIPTION: Considering that technologies like microarrays remain prohibitively expensive for researchers with limited means to order their own experimental chips, it would be beneficial to re-use previously published microarray data. For certain researchers interested in finding gene groups (requiring many replicates), there is a great need for tools to help them to select appropriate datasets for analysis. These tools may be effective, if and only if, they are able to re-use previously deposited experiments or to create new experiments not initially envisioned by the depositors. However, the generation of new experiments requires that all published microarray data be completely annotated, which is not currently the case. Thus, we propose the PathEx approach. CONCLUSION: This paper presents PathEx, a human-focused web solution built around a two-component system: one database component, enriched with relevant biological information (expression array, omics data, literature) from different sources, and another component comprising sophisticated web interfaces that allow users to perform complex dataset building queries on the contents integrated into the PathEx database.

Functional analysis: evaluation of response intensities--tailoring ANOVA for lists of expression subsets.

BACKGROUND: Microarray data is frequently used to characterize the expression profile of a whole genome and to compare the characteristics of that genome under several conditions. Geneset analysis methods have been described previously to analyze the expression values of several genes related by known biological criteria (metabolic pathway, pathology signature, co-regulation by a common factor, etc.) at the same time and the cost of these methods allows for the use of more values to help discover the underlying biological mechanisms. RESULTS: As several methods assume different null hypotheses, we propose to reformulate the main question that biologists seek to answer. To determine which genesets are associated with expression values that differ between two experiments, we focused on three ad hoc criteria: expression levels, the direction of individual gene expression changes (up or down regulation), and correlations between genes. We introduce the FAERI methodology, tailored from a two-way ANOVA to examine these criteria. The significance of the results was evaluated according to the self-contained null hypothesis, using label sampling or by inferring the null distribution from normally distributed random data. Evaluations performed on simulated data revealed that FAERI outperforms currently available methods for each type of set tested. We then applied the FAERI method to analyze three real-world datasets on hypoxia response. FAERI was able to detect more genesets than other methodologies, and the genesets selected were coherent with current knowledge of cellular response to hypoxia. Moreover, the genesets selected by FAERI were confirmed when the analysis was repeated on two additional related datasets. CONCLUSIONS: The expression values of genesets are associated with several biological effects. The underlying mathematical structure of the genesets allows for analysis of data from several genes at the same time. Focusing on expression levels, the direction of the expression changes, and correlations, we showed that two-step data reduction allowed us to significantly improve the performance of geneset analysis using a modified two-way ANOVA procedure, and to detect genesets that current methods fail to detect.

A benchmark for statistical microarray data analysis that preserves actual biological and technical variance.

BACKGROUND: Recent reanalysis of spike-in datasets underscored the need for new and more accurate benchmark datasets for statistical microarray analysis. We present here a fresh method using biologically-relevant data to evaluate the performance of statistical methods. RESULTS: Our novel method ranks the probesets from a dataset composed of publicly-available biological microarray data and extracts subset matrices with precise information/noise ratios. Our method can be used to determine the capability of different methods to better estimate variance for a given number of replicates. The mean-variance and mean-fold change relationships of the matrices revealed a closer approximation of biological reality. CONCLUSIONS: Performance analysis refined the results from benchmarks published previously.We show that the Shrinkage t test (close to Limma) was the best of the methods tested, except when two replicates were examined, where the Regularized t test and the Window t test performed slightly better. AVAILABILITY: The R scripts used for the analysis are available at http://urbm-cluster.urbm.fundp.ac.be/~bdemeulder/.

Meta-analysis of archived DNA microarrays identifies genes regulated by hypoxia and involved in a metastatic phenotype in cancer cells.

BACKGROUND: Metastasis is a major cancer-related cause of death. Recent studies have described metastasis pathways. However, the exact contribution of each pathway remains unclear. Another key feature of a tumor is the presence of hypoxic areas caused by a lack of oxygen at the center of the tumor. Hypoxia leads to the expression of pro-metastatic genes as well as the repression of anti-metastatic genes. As many Affymetrix datasets about metastasis and hypoxia are publicly available and not fully exploited, this study proposes to re-analyze these datasets to extract new information about the metastatic phenotype induced by hypoxia in different cancer cell lines. METHODS: Affymetrix datasets about metastasis and/or hypoxia were downloaded from GEO and ArrayExpress. AffyProbeMiner and GCRMA packages were used for pre-processing and the Window Welch t test was used for processing. Three approaches of meta-analysis were eventually used for the selection of genes of interest. RESULTS: Three complementary approaches were used, that eventually selected 183 genes of interest. Out of these 183 genes, 99, among which the well known JUNB, FOS and TP63, have already been described in the literature to be involved in cancer. Moreover, 39 genes of those, such as SERPINE1 and MMP7, are known to regulate metastasis. Twenty-one genes including VEGFA and ID2 have also been described to be involved in the response to hypoxia. Lastly, DAVID classified those 183 genes in 24 different pathways, among which 8 are directly related to cancer while 5 others are related to proliferation and cell motility. A negative control composed of 183 random genes failed to provide such results. Interestingly, 6 pathways retrieved by DAVID with the 183 genes of interest concern pathogen recognition and phagocytosis. CONCLUSION: The proposed methodology was able to find genes actually known to be involved in cancer, metastasis and hypoxia and, thus, we propose that the other genes selected based on the same methodology are of prime interest in the metastatic phenotype induced by hypoxia.

Data Model Requirements for a Digital Cognitive Aid for Anesthesia to Support Intraoperative Crisis Management.

OBJECTIVE: The aim of this study is to define data model requirements supporting the development of a digital cognitive aid (CA) for intraoperative crisis management in anesthesia, including medical emergency text modules (text elements) and branches or loops within emergency instructions (control structures) as well as their properties, data types, and value ranges. METHODS: The analysis process comprised three steps: reviewing the structure of paper-based CAs to identify common text elements and control structures, identifying requirements derived from content, design, and purpose of a digital CA, and validating requirements by loading exemplary emergency checklist data into the resulting prototype data model. RESULTS: The analysis of paper-based CAs identified 19 general text elements and two control structures. Aggregating these elements and analyzing the content, design and purpose of a digital CA revealed 20 relevant data model requirements. These included checklist tags to enable different search options, structured checklist action steps (items) in groups and subgroups, and additional information on each item. Checklist and Item were identified as two main classes of the prototype data model. A data object built according to this model was successfully integrated into a digital CA prototype. CONCLUSION: To enable consistent design and interactivity with the content, presentation of critical medical information in a digital CA for crisis management requires a uniform structure. So far it has not been investigated which requirements need to be met by a data model for this purpose. The results of this study define the requirements and structure that enable the presentation of critical medical information. Further research is needed to develop a comprehensive data model for a digital CA for crisis management in anesthesia, including supplementation of requirements resulting from simulation studies and feasibility analyses regarding existing data models. This model may also be a useful template for developing data models for CAs in other medical domains.