Physician satisfaction with transition from CPOE to paper-based prescription.

INTRODUCTION: In January 2015, Rouen University Hospital's information system experienced serious issues. It was necessary to rapidly switch from the computerized provider order entry (CPOE) system towards a paper-based order entry (PBOE) system. This was an opportunity to evaluate prescriber opinion on the two provider order entry (POE) systems. METHODS: All residents were asked to fill an augmented version of the POE satisfaction and usage survey for both POE systems. The results were compared to identify the strengths and weaknesses of each system. RESULTS: Fifty-one respondents had used the CPOE system and the PBOE system. Overall, satisfaction was higher with PBOE than CPOE (odds ratio (OR)=3.74; p<0.001). Usability (OR=4.00; p<0.001), reliability (OR=8.54; p<0.001), time consumption (OR=0.50; p<0.05 - survey statement was formulated negatively), and communication with nurses (OR=14.27; p<0.0001) reached statistically better agreement. The more experience with CPOE the more residents were disillusioned with the reliability (OR=6.55; p<0.01), the usability (OR=5.68; p<0.01) and the patient safety (OR=0.27; p<0.05 - survey statement was formulated negatively) of CPOE. Although safety issues were reported for both systems, the causes were different; PBOE imposed frequent rewriting of the order while CPOE lack of usability might be unsafe. Another important issue with both POE systems was time consumption. CONCLUSION: Residents did not report any increase in safety issues with the rapid switch from CPOE to PBOE. They even seemed more satisfied with the rollback to paper, which remains a possible degraded mode in case of health information technology collapse.

Some Innovative Approaches for Public Health and Epidemiology Informatics.

OBJECTIVES: Summarize excellent current research published in 2015 in the field of Public Health and Epidemiology Informatics. METHODS: The complete 2015 literature concerning public health and epidemiology informatics has been searched in PubMed and Web of Science, and the returned references were reviewed by the two section editors to select 14 candidate best papers. These papers were then peer-reviewed by external reviewers to allow the editorial team an enlightened selection of the best papers. RESULTS: Among the 1,272 references retrieved from PubMed and Web of Science, three were finally selected as best papers. The first one presents a language agnostic approach for epidemic event detection in news articles. The second paper describes a system using big health data gathered by a statewide system to forecast emergency department visits. The last paper proposes a rather original approach that uses machine learning to solve the old issue of outbreak detection and prediction. CONCLUSIONS: The increasing availability of data, now directly from health systems, will probably lead to a boom in public health surveillance systems and in large-scale epidemiologic studies.

[Benefits and usability of a pharmaceutical record in medical practice. A survey of hospital doctors and pharmacists (MATRIX study)]. / Intérêt et utilisabilité du dossier pharmaceutique en pratique médicale. Enquête auprès de médecins et pharmaciens hospitaliers (étude MATRIX).

BACKGROUND: To evaluate the impact of the pharmaceutical patient record use in emergency, geriatric and anaesthesia and intensive care departments, an experimentation was launched in 2013 in 55 hospitals. The purpose of the study was to assess the opinions of physicians and pharmacists about the benefits and usability of the patient pharmaceutical record. METHODS: An e-mailed self-administered questionnaire was sent to all the pharmacists, anaesthesiologists, geriatricians and emergency physicians of the 55 hospitals involved in the patient pharmaceutical record experimentation. The questionnaire assessed the usability of the patient pharmaceutical record using the "System Usability Scale", as well as its use, its benefits and limitations perceived in clinical practice, and overall user satisfaction. Questionnaires were collected from November 2014 to January 2015. RESULTS: Ninety-six questionnaires were collected, from 47 hospitals, representing 86% of the hospitals involved in the experimentation. The patient pharmaceutical record was effectively operational in 36 hospitals. Data from 73 questionnaires filled by physicians and pharmacists with potential experience with the patient pharmaceutical record were used for evaluation. Forty-two respondents were pharmacists (57%) and 31 were physicians (43%), including 13 geriatricians, 11 emergency physicians and 7 anaesthesiologists. Patient pharmaceutical record overall usability score was 62.5 out of 100. It did not vary with the profession or seniority of the respondent. It was positively correlated with the frequency of use. More than half of respondents reported that they never or uncommonly used the patient pharmaceutical record. The length of access to data period was considered as insufficient. Main obstacles to more utilization of the patient pharmaceutical record were the lack of information about the dosage of dispensed drugs, the low number of patients in possession of their health card and the low number of patients with an activated patient pharmaceutical record. CONCLUSION: Two years after the beginning of the experiment aiming to broaden the access to the patient pharmaceutical record to physicians, these first evaluation results are encouraging. The evaluation of the consequences of the access to the patient pharmaceutical record for physicians remains necessary.

Searching for rare diseases in PubMed: a blind comparison of Orphanet expert query and query based on terminological knowledge.

BACKGROUND: Despite international initiatives like Orphanet, it remains difficult to find up-to-date information about rare diseases. The aim of this study is to propose an exhaustive set of queries for PubMed based on terminological knowledge and to evaluate it versus the queries based on expertise provided by the most frequently used resource in Europe: Orphanet. METHODS: Four rare disease terminologies (MeSH, OMIM, HPO and HRDO) were manually mapped to each other permitting the automatic creation of expended terminological queries for rare diseases. For 30 rare diseases, 30 citations retrieved by Orphanet expert query and/or query based on terminological knowledge were assessed for relevance by two independent reviewers unaware of the query's origin. An adjudication procedure was used to resolve any discrepancy. Precision, relative recall and F-measure were all computed. RESULTS: For each Orphanet rare disease (n = 8982), there was a corresponding terminological query, in contrast with only 2284 queries provided by Orphanet. Only 553 citations were evaluated due to queries with 0 or only a few hits. There were no significant differences between the Orpha query and terminological query in terms of precision, respectively 0.61 vs 0.52 (p = 0.13). Nevertheless, terminological queries retrieved more citations more often than Orpha queries (0.57 vs. 0.33; p = 0.01). Interestingly, Orpha queries seemed to retrieve older citations than terminological queries (p < 0.0001). CONCLUSION: The terminological queries proposed in this study are now currently available for all rare diseases. They may be a useful tool for both precision or recall oriented literature search.

Toward a formalization of the process to select IMIA Yearbook best papers.

BACKGROUND: Each year, the International Medical Informatics Association Yearbook recognizes significant scientific papers, labelled as "best papers", published the previous year in the subfields of biomedical informatics that correspond to the different section topics of the journal. For each section, about fifteen pre-selected "candidate" best papers are externally peer-reviewed to select the actual best papers. Although based on the available literature, little is known about the pre-selection process. OBJECTIVE: To move toward an explicit formalization of the candidate best papers selection process to reduce variability in the literature search across sections and over years. METHODS: A methodological framework is proposed to build for each section topic specific queries tailored to PubMed and Web of Science citation databases. The two sets of returned papers are merged and reviewed by two independent section editors and citations are tagged as "discarded", "pending", and "kept". A protocolized consolidation step is then jointly conducted to resolve conflicts. A bibliographic software tool, BibReview, was developed to support the whole process. RESULTS: The proposed search strategy was fully applied to the Decision Support section of the 2013 edition of the Yearbook. For this section, 1124 references were returned (689 PubMed-specific, 254 WoS-specific, 181 common to both databases) among which the 15 candidate best papers were selected. CONCLUSIONS: The search strategy for determining candidate best papers for an IMIA Yearbook's section is now explicitly specified and allows for reproducibility. However, some aspects of the whole process remain reviewer-dependent, mostly because there is no characterization of a "best paper".

Managing free text for secondary use of health data.

OBJECTIVE: To summarize the best papers in the field of Knowledge Representation and Management (KRM). METHODS: A comprehensive review of medical informatics literature was performed to select some of the most interesting papers of KRM and natural language processing (NLP) published in 2013. RESULTS: Four articles were selected, one focuses on Electronic Health Record (EHR) interoperability for clinical pathway personalization based on structured data. The other three focus on NLP (corpus creation, de-identification, and co-reference resolution) and highlight the increase in NLP tools performances. CONCLUSION: NLP tools are close to being seriously concurrent to humans in some annotation tasks. Their use could increase drastically the amount of data usable for meaningful use of EHR.

Knowledge representation and management: towards an integration of a semantic web in daily health practice.

OBJECTIVE: To summarize the best papers in the field of Knowledge Representation and Management (KRM). METHODS: A synopsis of the four selected articles for the IMIA Yearbook 2013 KRM section is provided, as well as highlights of current KRM trends, in particular, of the semantic web in daily health practice. The manual selection was performed in three stages: first a set of 3,106 articles, then a second set of 86 articles followed by a third set of 15 articles, and finally the last set of four chosen articles. RESULTS: Among the four selected articles (see Table 1), one focuses on knowledge engineering to prevent adverse drug events; the objective of the second is to propose mappings between clinical archetypes and SNOMED CT in the context of clinical practice; the third presents an ontology to create a question-answering system; the fourth describes a biomonitoring network based on semantic web technologies. CONCLUSION: These four articles clearly indicate that the health semantic web has become a part of daily practice of health professionals since 2012. In the review of the second set of 86 articles, the same topics included in the previous IMIA yearbook remain active research fields: Knowledge extraction, automatic indexing, information retrieval, natural language processing, management of health terminologies and ontologies.

Ubiquitination precedes internalization and proteolytic cleavage of plasma membrane-bound glycine receptors.

The inhibitory glycine receptor (GlyR) in developing spinal neurones is internalized efficiently upon antagonist inhibition. Here we used surface labeling combined with affinity purification to show that homopentameric alpha1 GlyRs generated in Xenopus oocytes are proteolytically nicked into fragments of 35 and 13 kDa upon prolonged incubation. Nicked GlyRs do not exist at the cell surface, indicating that proteolysis occurs exclusively in the endocytotic pathway. Consistent with this interpretation, elevation of the lysosomal pH, but not the proteasome inhibitor lactacystin, prevents GlyR cleavage. Prior to internalization, alpha1 GlyRs are conjugated extensively with ubiquitin in the plasma membrane. Our results are consistent with ubiquitination regulating the endocytosis and subsequent proteolysis of GlyRs residing in the plasma membrane. Ubiquitin-conjugating enzymes thus may have a crucial role in synaptic plasticity by determining postsynaptic receptor numbers.

BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization.

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

D2/D3 dopamine receptor heterodimers exhibit unique functional properties.

Evidence for heterodimerization has recently been provided for dopamine D(1) and adenosine A(1) receptors as well as for dopamine D(2) and somatostatin SSTR(5) receptors. In this paper, we have studied the possibility that D(2) and D(3) receptors interact functionally by forming receptor heterodimers. Initially, we split the two receptors at the level of the third cytoplasmic loop into two fragments. The first, containing transmembrane domains (TM) I to V and the N-terminal part of the third cytoplasmic loop, was named D(2trunk) or D(3trunk), and the second, containing the C-terminal part of the third cytoplasmic loop, TMVI and TMVII, and the C-terminal tail, was named D(2tail) or D(3tail). Then we defined the pharmacological profiles of the homologous (D(2trunk)/D(2tail) and D(3trunk)/D(3tail)) as well as of the heterologous (D(2trunk)/D(3tail) and D(3trunk)/D(2tail)) cotransfected receptor fragments. The pharmacological profile of the cross-cotransfected fragments was different from that of the native D(2) or D(3) receptors. In most cases, the D(3trunk)/D(2tail) was the one with the highest affinity for most agonists and antagonists. Moreover, we observed that all of these receptor fragments reduced the expression of the wild type dopamine D(2) and D(3) receptors, suggesting that D(2) and D(3) receptors can form complexes with these fragments and that these complexes bind [(3)H]nemonapride less efficiently or are not correctly targeted to the membrane. In a second set of experiments, we tested the ability of the split and the wild type receptors to inhibit adenylyl cyclase (AC) types V and VI. All of the native and split receptors inhibited AC-V and AC-VI, with the exception of D(3), which was unable to inhibit AC-VI. We therefore studied the ability of D(2) and D(3) to interact functionally with one another to inhibit AC-VI. We found that with D(2) alone, R-(+)-7-hydroxydypropylaminotetralin hydrobromide inhibited AC-VI with an IC(50) of 2.05 +/- 0.15 nm, while in the presence of D(2) and D(3) it inhibited AC-VI with an IC(50) of 0.083 +/- 0.011 nm. Similar results were obtained with a chimeric cyclase made from AC-V and AC-VI. Coimmunoprecipitation experiments indicate that D(2) and D(3) receptors are capable of physical interaction.

Thermodynamics of Na+ binding to coagulation serine proteases.

The sodium binding to serine proteases triggers a conformational change in the proteins that enhances the catalytic activity of the enzymes. The interaction of the cation with the protein is mediated by the hydrogen-bonding network of water molecules that embed the Na+ site. We pointed out the crucial role of the insertion loop 186a-d and the I16-D194 ion pair in the stabilization of sodium binding pocket in thrombin. This paper contributes to better explain the molecular mechanism of sodium binding for different serine proteases leading to the identification of the structural changes necessary to engineer a functional Na+ site and regulate catalytic activity in serine proteases.

Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1.

Abuse of cannabis is frequent among the young and is suspected to precipitate schizophrenia in vulnerable subjects. Cannabinoid receptor (CB1) is particularly concentrated in dopamine-modulated areas of the nervous system. An association between an AAT polymorphism of the CB1 gene and intravenous drug abuse has been previously reported, but not with schizophrenia. In a French Caucasian population, we compared the distribution of a single-base polymorphism revealed by MspI within the first exon of the CB1 gene in patients with schizophrenia (n = 102) and ethnic- and gender-matched controls (n = 63). No significant difference was seen in the allele or genotype distribution between the whole sample of schizophrenic patients and controls. However, we found a borderline lack of allele g and a significant lack of gg genotype in the non-substance-abusing patients compared to substance-abusing patients, the latter being similar to the controls. These results are the first report of an significant association between CB1 receptor and a subtype of schizophrenia. Studies are needed to confirm and further explore the precise role of the cannabinoid system in schizophrenia.

Identification of a binding site for quaternary amines in factor Xa.

In the process of characterizing the Na(+)-binding properties of factor Xa, a specific inhibition of this enzyme by quaternary amines was identified, consistent with previous observations. The binding occurs with K(i) in the low millimolar range, with trimethylphenylammonium (TMPA) showing the highest specificity. Binding of TMPA inhibits substrate hydrolysis in a competitive manner, does not inhibit the binding of p-aminobenzamidine to the S1 pocket, and is positively linked to Na(+) binding. Inhibition by TMPA is also seen in thrombin and tissue plasminogen activator (tPA), though to a lesser extent compared to factor Xa. Computer modeling using the crystal structure of factor Xa suggests that TMPA binds to the S2/S3 specificity sites, with its hydrophobic moiety making van der Waals interactions with the side chains of Y99, F174, and W215, and the charged amine coupling electrostatically with the carboxylates of E97. Site-directed mutagenesis of factor Xa, thrombin, and tPA confirms the predictions drawn by docking calculations and reveal a dominant role for residue Y99. Binding of TMPA to factor Xa is drastically (25-fold) reduced by the Y99T replacement. Likewise, the Y99L substitution compromises binding of TMPA to tPA. On the other hand, the affinity of TMPA is enhanced 4-fold in thrombin with the substitution L99Y. The identification of a binding site for quaternary amines in factor Xa has a bearing on the rational design of selective inhibitors of this clotting enzyme.

Molecular determinants of glycine receptor subunit assembly.

The inhibitory glycine receptor (GlyR) is a pentameric transmembrane protein composed of homologous alpha and beta subunits. Single expression of alpha subunits generates functional homo-oligomeric GlyRs, whereas the beta subunit requires a co-expressed alpha subunit to assemble into hetero-oligomeric channels of invariant stoichiometry (alpha(3)beta(2)). Here, we identified eight amino acid residues within the N-terminal region of the alpha1 subunit that are required for the formation of homo-oligomeric GlyR channels. We show that oligomerization and N-glycosylation of the alpha1 subunit are required for transit from the endoplasmic reticulum to the Golgi apparatus and later compartments, and that addition of simple carbohydrate side chains occurs prior to GlyR subunit assembly. Our data are consistent with both intersubunit surface and conformational differences determining the different assembly behaviour of GlyR alpha and beta subunits.

Additive effects of beta chain mutations in low oxygen affinity hemoglobin betaF41Y,K66T.

In order to decrease significantly the oxygen affinity of human hemoglobin, we have associated the mutation betaF41Y with another point mutation also known to decrease the oxygen affinity of Hb. We have synthesized a recombinant Hb (rHb) with two mutations in the beta chains: rHb betaF41Y,K66T. In the absence of 2, 3-diphosphoglycerate, additive effects of the mutations are evident, since the doubly mutated Hb exhibits a larger decrease in oxygen affinity than for the individual single mutations. In the presence of 2,3-diphosphoglycerate, the second mutation did not significantly increase the P(50) value relative to the single mutations. However, the kinetics of CO binding still indicate combined effects on the allosteric equilibrium, as evidenced by more of the slow bimolecular phase characteristic of binding to the deoxy conformation. Dimer-tetramer equilibrium studies indicate an increase in stability of the mutants relative to rHb A; the double mutant rHb betaF41Y, K66T at pH 7.5 showed a K(4,2) value of 0.26 microM. Despite the lower oxygen affinity, the single mutant betaF41Y and double mutant betaF41Y,K66T show only a moderate increase of 20% in the autoxidation rate. These mutations are thus of interest in developing a Hb-based blood substitute.

Structural, functional, and genetic characterization of Gastrophilus hemoglobin.

Hemoglobin of Gastrophilus intestinalis (Insecta, Diptera), was purified and characterized. At least two isoforms have been identified by isoelectrofocusing, mass spectrometry, and genomic Southern blotting. Functional studies show a high oxygen affinity due to a low ligand dissociation rate (koff = 2.4 s-1) and a relatively high autoxidation rate (t1/2 = 1.6/h). The globins were separated under denaturing conditions, and the sequence of Hb1 (Mr = 17,965 +/- 2) was determined at the protein and DNA level. The open reading frame codes for a polypeptide of 150 amino acids. Although the globin is distantly related to globins from other species, it has a low penalty score against globin templates. Freshly isolated hemoglobin was crystallized from polyethylene glycol. Crystals contain two hemoglobin molecules per asymmetric unit. Solution of the three-dimensional structure by molecular replacement could not be achieved, possibly due to the presence of three protein isoforms in the crystals. In order to determine its three-dimensional structure, G. intestinalis Hb1 was overexpressed in Escherichia coli, resulting in a fully functional molecule as confirmed by ligand binding affinity. The globin gene contains two introns at positions D7.0 and G7.0. The D7.0 intron is unprecedented, suggesting that globin gene evolution is much more complex than originally thought.

Coexpression of dopamine D1 and D3 receptors in islands of Calleja and shell of nucleus accumbens of the rat: opposite and synergistic functional interactions.

Using double in situ hybridization, we found extensive coexpression of dopamine D1 and D3 receptor (D1R and D3R) mRNAs in neurons of the island of Calleja major (ICjM) and ventromedial shell of nucleus accumbens (ShV), respectively. Thus, at least 79 and 63% of D3R mRNA-expressing neurons in ICjM and ShV also expressed the D1R mRNA. Coexpression of D1R and D3R mRNAs was found to occur in substance P (SP) mRNA-expressing neurons in both areas, suggesting SP mRNA as a marker of the activity of coexpressing neurons. Administration of SKF 38393, a D1R receptor agonist, increased c-fos mRNA in ICjM, whereas administration of quinpirole, a D2R/D3R agonist, decreased it; SCH 23390, a D1 R antagonist and nafadotride, a preferential D3R antagonist, given alone, had effects opposite to those of the corresponding agonists. These data indicate that basal c-fos expression in ICjM is maintained by endogenous dopamine acting tonically upon two receptor subtypes subserving opposite effects on the same cell. However, in ShV, whereas SKF 38393 also increased c-fos mRNA, quinpirole had no effect, a difference presumably reflecting the lower fraction of neurons coexpressing D1R and D3R in this area. In contrast, in ShV from reserpine-treated rats, SKF 38393 increased SP mRNA and quinpirole potentiated this effect. These contrasting interactions of D1R- and D3R-mediated signalling events, i.e. in either opposite or synergistic directions, most likely occurring at the single cell level, may serve to increase the dopamine response threshold of the target cells in ICjM and to maintain a strong tonic activity of ShV neurons.

Synthesized allosteric effectors of the hemoglobin molecule: a possible mechanism for improved erythrocyte oxygen release capability in hemoglobinopathy H disease.

Patients with the nondeletion genotype of hemoglobinopathy H (HbH or beta4) disease have higher proportions of HbH and more severe tissue hypoxia than patients with the deletion genotype. Because these patients' red blood cells (RBCs) contain mainly two Hb species, HbH and HbA, the high proportion of HbA can be exploited by lowering its oxygen affinity; this would probably increase oxygen delivery to the RBCs and improve the patients' clinical phenotype. Allosteric effectors that induce a low-affinity Hb may be useful in this regard. We investigated the effect of a bezafibrate derivative, RSR-4, on the oxygen affinity of RBCs and purified hemolysates containing HbA and HbH. This allosteric effector crosses RBC membranes and binds reversibly to the alpha-chains of deoxy-Hb, decreasing hemoglobin oxygen affinity. The blood used was obtained from a patient with HbH disease (alphaTSaudi homozygote) whose HbH level was 33.5% as measured by high-performance liquid chromatography. Oxygen binding studies were performed in RBCs and purified hemolysates. RBCs incubated in the presence of 500 microM RSR-4 (2-[[[(3,5-dichloroanilino)-carbonyl]methyl]phenoxy]-2-methylpropi onic acid) in standard conditions (pH 7.4, 0.14 M NaCl, 37 degrees C) displayed an increase in their P50 value from 14.5 to 35.2 mm Hg. Oxygen binding studies in purified stripped hemolysates (pH 7.2, 0.1 M NaCl, 25 degrees C) showed that addition of both 500 microM RSR-4 and 1 mM of 2,3 diphosphoglycerate (DPG) led to an 11-fold decrease in oxygen affinity, whereas the addition of the natural effector DPG or RSR-4 alone produced a 2.7- and 5.7-fold decrease, respectively. In both cases, the oxygen equilibrium curves (OECs) were biphasic due to the presence of the noncooperative, high-oxygen-affinity HbH (beta4) component. After addition of RSR-4, the lower part of the OEC (corresponding to HbH) was not shifted compared with the upper part (corresponding to HbA). These results were confirmed by kinetic studies of CO recombination. Both experiments demonstrated that RSR-4 does not affect beta4 Hb. Our findings provide an experimental model for lowering the oxygen affinity of HbA in HbH-containing cells and suggest that the oxygen delivery capability of the latter would be thereby improved.