Capturing diagnosis-timing in ICD-coded hospital data: recommendations from the WHO ICD-11 topic advisory group on quality and safety.

PURPOSE: To develop a consensus opinion regarding capturing diagnosis-timing in coded hospital data. METHODS: As part of the World Health Organization International Classification of Diseases-11th Revision initiative, the Quality and Safety Topic Advisory Group is charged with enhancing the capture of quality and patient safety information in morbidity data sets. One such feature is a diagnosis-timing flag. The Group has undertaken a narrative literature review, scanned national experiences focusing on countries currently using timing flags, and held a series of meetings to derive formal recommendations regarding diagnosis-timing reporting. RESULTS: The completeness of diagnosis-timing reporting continues to improve with experience and use; studies indicate that it enhances risk-adjustment and may have a substantial impact on hospital performance estimates, especially for conditions/procedures that involve acutely ill patients. However, studies suggest that its reliability varies, is better for surgical than medical patients (kappa in hip fracture patients of 0.7-1.0 versus kappa in pneumonia of 0.2-0.6) and is dependent on coder training and setting. It may allow simpler and more precise specification of quality indicators. CONCLUSIONS: As the evidence indicates that a diagnosis-timing flag improves the ability of routinely collected, coded hospital data to support outcomes research and the development of quality and safety indicators, the Group recommends that a classification of 'arising after admission' (yes/no), with permitted designations of 'unknown or clinically undetermined', will facilitate coding while providing flexibility when there is uncertainty. Clear coding standards and guidelines with ongoing coder education will be necessary to ensure reliability of the diagnosis-timing flag.

Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: effect of Anticoagulation and Its Timing: the RAF Study.

BACKGROUND AND PURPOSE: The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. METHODS: The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. RESULTS: Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30-0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively (P=0.003). CONCLUSIONS: Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants.

Regulation of bistable ICEclc transfer in pseudomonas knackmussii B13

L'élément génétique intégratif et conjugatif auto-transférable de 103 kb qui se trouve dans le génome de Pseudomonas knackmussii B13 (ICEc/c) confère la capacité de dégrader le 3-chlorobenzoate et le 2-aminophénol. L'élément ICE c/c peut être transféré par conjugaison de la souche B13 à diverses bêta- et gamma- protéobactéries. Seule une sous-population de 3 à 5% des cellules transfère l'élément, les cellules dites "compétentes pour le transfert". L'acquisition de la compétence pour le transfert est vraisemblablement la conséquence d'une régulation bistable, conduisant une partie des cellules au transfert de l'élément ICE c/c tandis que, dans les autres, l'élément reste quiescent et ne se transfère pas. À ce jour, les mécanismes et les acteurs moléculaires qui régulent l'activation bistable de l'élément sont restés inconnus. Mon travail de doctorat visait à identifier les éléments bistables du régulon de la compétence pour le transfert et d'analyser les fondements moléculaires de la bistabilité de l'élément ICE c/c chez P. knackmussii. Le premier chapitre introduit le thème du transfert génétique horizontal avec un accent particulier sur les éléments intégratifs et conjugatifs (ICE) et ICEcIc. L'état actuel des connaissances sur l'organisation génétique, la régulation, l'intégration et le transfert de différents modèles de ICEs est exposé en détail. En outre, je m'étends sur les phénomènes d'hétérogénéité et de bistabilité phénotyplques, qu'on peut distinguer dans une population isogénique dans des conditions de culture homogènes, et qui sont susceptibles de jouer un rôle dans le transfert de l'élément ICE c/c, dans la mesure où il ne s'active et n'est transférable que dans une très petite sous-population de cellules. Dans le chapitre 2, je présente une analyse globale des régions promotrices minimales des gènes appartenant au régulon de la compétence pour le transfert de l'élément ICE c/c. Nous avons étudié les caractéristiques d'expression des promoteurs et, s'ils s'avéraient bistables, leur activation dans le temps par comparaison avec le mutant lntB13. Pour ce faire, nous avons utilisé des fusions de promoteurs avec des gènes rapporteurs et testé l'expression bistable chez P. knackmussii par microscopie à épifluorescence. Pour six promoteurs présentant une expression bistable, nous avons employé de la microscopie temporelle pour déterminer la chronologie de leur expression par rapport à Pint et PinR. Parmi eux, nous avons identifié deux gènes exprimés précocement et trois gènes exprimés tardivement dans le processus d'acquisition de la compétence de transfert. Dans le chapitre 3, j'expose une analyse d'expression génétique pour l'un des groupes de gènes dont la transcription est la plus élevée dans la région conservée de ICE c/c, les gènes orf81655-orf68241 contenus dans une région de 14 kb. Nous montrons d'abord que cet opéron fait partie du même régulon bistable que intB13 et inrR et analysons les caractéristiques génétiques qui conduisent à une transcription élevée. Nous étudions les fonctions biologiques de ce groupe de gènes par des délétlons ciblées et montrons que certaines d'entre elles empêchent le transfert de l'élément. Nous approfondissons la caractérlsatlon de I'orf8l655 en construisant une fusion transcrlptionnelle avec le gène codant pour la protéine fluorescente verte (egfp) (en utilisant le système minl-Tn5). L'expression de Vorf81655 dans des cellules individuelles est comparée au signal mesuré par hybridation in situ en fluorescence (FISH) sur le ARN messager du gène. En utilisant FISH, des délétlons du promoteur et de l'analyse directe de transcription, nous avons localisé la région promotrice du groupe de gènes. En outre, nous avons utilisé des mutations dirigées pour comprendre la bistabilité de cette région promotrice, caractérisée par une transcription très élevée et une traduction lente de l'ARN messager.  Dans le chapitre 4, nous nous efforçons de comprendre comment la bistabilité est générée au sein du régulon te de l'élément ICE c/c. Pour ce faire, nous avons tenté de reconstituer une expression bistable, dans un hôte qui ne présente pas de bistabilité naturellement, à partir d'éléments génétiques individuels. L'hôte choisi est Pseudomonas putida dans lequel nous avons introduit une copie unique de Pint, PinR ou PaipA fusionnés à la egfp, construits qui permettent d'observer l'apparition de bistabilité. Nous avons ensuite construit différents assemblages de composants génétiques de l'élément ICE c/c, en nous concentrant sur la région parA-inrR. En effet, nous avons pu démontrer qu'une expression bistable apparaît dans P. putida grâce à ces éléments en l'absence de l'élément ICE c/c complet. À noter que la plupart des construits génétiques activent PaipA ou P|,,R, mais qu'un seul recrée la bistabilité de Pint, ce qui suggère que la région parA-inrR permet à la fois d'engendrer la bistabilité et d'opérer la transition entre les promoteurs précoces et les promoteurs tardifs du régulon de la bistabilité. Dans le chapitre 5, nous concluons sur une discussion de la pertinence de nos résultats et sur de futures perspectives de recherche. -- The 103-kb self-transmissible integrative and conjugative element (ICE) of Pseudomonas knackmussii B13 (ICEc/c) confers the capacity to degrade 3- chlorobenzoate and 2-aminophenol. ICEc/c can be conjugated from strain B13 to a variety of Beta- and Gammaproteobacteria. Interestingly, ICE c/c transfer is observed in a subpopulatlon of cells (3-5%) only, the so-called 'transfer competent' cells. The formation of transfer competence (tc) is thought to be the consequence of a 'bistable' decision, which forces those cells to follow the developmental path which leads to ICEc/c transfer, whereas in others ICE c/c remains silent and does not transfer. So far, the mechanisms and molecular partners generating this bistable transfer activation in cells of P. knackmussii B13 remain mostly unidentified. This thesis aimed at understanding the extent of the tc bistability regulon and to dissect the molecular basis of bistabillty formation of ICEc/c in P. knackmussii. The first chapter is a general Introduction on horizontal gene transfer (HGT) with particular emphasis on ICEs and ICE c/c. The emphasis is made on the current knowledge about the HGT gene organization, regulation and specific integration and transfer aspects of the different ICEs models. Furthermore, I focus on the phenomena of phenotypic heterogeneity and bistability (the property of two distinguishable phenotypes existing within an isogenic population under homogeneous conditions), which may play a particular role in ICEc/c behaviour, since ICE activation and transfer only occurs in a very small subpopulation of cells. In Chapter Two, I focus on a global analysis of the different core promoters that might belong to the ICEc/c tc pathway regulon. We studied both expression patterns of ICEc/c promoters and, once being identified as "bistable", their temporal activation compared to that of intB13. In order to do this, we used promoter reporter fusions and tested blstability expression in P. knackmussii using epifluorescence microscopy. For the 6 promoters that showed bistable expression, we used time-lapse microscopy to study the timing of promoter expression in comparison to that of P,,,t or PlnR. We could establish two "early" and 3 "late" phase promoters in the process of transfer competence. In Chapter Three, I focused my attention on analysis of gene expression of one of the most highly transcribed gene clusters in the conserved core region of ICEc/c, a 14-kb gene cluster formed by the genes orf81655-orf68241. First we showed that this operon is part of the same bistability 'regulon' as intB13 and inrR, and analysed the genetic features that lead to high transcription. We studied the potential biological function of this cluster for ICE c/c by making specific gene deletions, showing that some interrupt ICEc/c transfer. We further analysed the orfdl655 promoter by constructing transcriptional egfp fusion reporter strains using the miniTn5 delivery system. Expression of the orf81655 promoter in single cells was compared to signals measured by Fluorescence In Situ Hybridization (FISH) on orfSl655 mRNA. We localized the promoter region of the gene cluster using FISH, promoter deletions, and by direct transcript analysis. We further used site-directed mutagenesis to understand the bistability character of the promoter region and the extremely high transcription but low translation from this mRNA. In Chapter Four, we set out to understand how bistability is generated in the tc pathway of ICEc/c. For this we tried rebuilding bistable expression from ICEc/c individual gene components in a host, which normally does not display bistability. As host we used P. putida without ICEc/c but with a single copy Pint-, PlnR- or PalpA- egfp fusion that enabled us to verify bistability formation. Subsequently, we built different assemblages of ICEc/c gene components, focusing on the parA-inrR region. Indeed, we found that bistable expression can be build from those components in P. putida without ICEc/c. Interestingly, most genetic constructs activated PaipA or PlnR, but only one resulted in bistable activation of PinT. This suggests that the parA-inrR region acts as a bistability "generator", but also as a bistability "relay" from early to late promoters in the tc pathway hierarchy. In the final fifth chapter, we conclude with a discussion of the relevance of the present thesis and the resulting perspectives for future studies.

A cellular system for spatial signal decoding in chemical gradients.

Directional cell growth requires that cells read and interpret shallow chemical gradients, but how the gradient directional information is identified remains elusive. We use single-cell analysis and mathematical modeling to define the cellular gradient decoding network in yeast. Our results demonstrate that the spatial information of the gradient signal is read locally within the polarity site complex using double-positive feedback between the GTPase Cdc42 and trafficking of the receptor Ste2. Spatial decoding critically depends on low Cdc42 activity, which is maintained by the MAPK Fus3 through sequestration of the Cdc42 activator Cdc24. Deregulated Cdc42 or Ste2 trafficking prevents gradient decoding and leads to mis-oriented growth. Our work discovers how a conserved set of components assembles a network integrating signal intensity and directionality to decode the spatial information contained in chemical gradients.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Prosthetic joint infections : A retrospective study on the timing of reimplantation in a two-stage exchange

Different therapeutic options for prosthetic joint infections exist, but surgery remains the key. With a two-stage exchange procedure, a success rate above 90% can be expected. Currently, there is no consensus regarding the optimal duration between explantation and the reimplantation in a two-stage procedure. The aim of this study was to retrospectively compare treatment outcomes between short-interval and long-interval two-stage exchanges. Patients having a two-stage exchange of a hip or knee prosthetic joint infection at Lausanne University Hospital (Switzerland) between 1999 and 2013 were included. The satisfaction of the patient, the function of the articulation and the eradication of infection, were compared between patients having a short (2 to 4 weeks) versus a long (4 weeks and more) interval during a two-stage procedure. Patient satisfaction was defined as good if the patient did not have pain and bad if the patient had pain. Functional outcome was defined good if the patient had a prosthesis in place and could walk, medium if the prosthesis was in place but the patient could not walk, and bad if the prosthesis was no longer in place. Infection outcome was considered good if there had been no re-infection and bad if there had been a re-infection of the prosthesis 145 patients (100 hips, 45 knees) were identified with a median age of 68 years (range 19-103). The median hospital stay was 58 days (range 10-402). The median follow-up was 12.9 months (range 0.5-152). 28 % and 72 % of the patients had a short-interval and long-interval exchange of the prosthesis, respectively. Patient satisfaction, functional outcome and infection outcome for patients having a short versus a long interval are reported in the Table. The patient satisfaction was higher when a long interval was performed whereas the functional and infection outcomes were higher when a short interval was performed. According to this study a short-interval exchange appears preferable to a long interval, especially in the view of treatment effectiveness and functional outcome.

Timing History: The Introduction of Graphical Analysis in 19th Century British Economics

The introduction of time-series graphs into British economics in the 19th century depended on the « timing » of history. This involved reconceptualizing history into events which were both comparable and measurable and standardized by time unit. Yet classical economists in Britain in the early 19th century viewed history as a set of heterogenous and complex events and statistical tables as giving unrelated facts. Both these attitudes had to be broken down before time-series graphs could be brought into use for revealing regularities in economic events by the century's end.

The EXS Domain of PHO1 Participates in the Response of Shoots to Phosphate Deficiency via a Root-to-Shoot Signal.

The response of shoots to phosphate (Pi) deficiency implicates long-distance communication between roots and shoots, but the participating components are poorly understood. We have studied the topology of the Arabidopsis (Arabidopsis thaliana) PHOSPHATE1 (PHO1) Pi exporter and defined the functions of its different domains in Pi homeostasis and signaling. The results indicate that the amino and carboxyl termini of PHO1 are both oriented toward the cytosol and that the protein spans the membrane twice in the EXS domain, resulting in a total of six transmembrane α-helices. Using transient expression in Nicotiana benthamiana leaf, we demonstrated that the EXS domain of PHO1 is essential for Pi export activity and proper localization to the Golgi and trans-Golgi network, although the EXS domain by itself cannot mediate Pi export. In contrast, removal of the amino-terminal hydrophilic SPX domain does not affect the Pi export capacity of the truncated PHO1 in N. benthamiana. While the Arabidopsis pho1 mutant has low shoot Pi and shows all the hallmarks associated with Pi deficiency, including poor shoot growth and overexpression of numerous Pi deficiency-responsive genes, expression of only the EXS domain of PHO1 in the roots of the pho1 mutant results in a remarkable improvement of shoot growth despite low shoot Pi. Transcriptomic analysis of pho1 expressing the EXS domain indicates an attenuation of the Pi signaling cascade and the up-regulation of genes involved in cell wall synthesis and the synthesis or response to several phytohormones in leaves as well as an altered expression of genes responsive to abscisic acid in roots.

Timing of visual stimuli in V1 and V5/MT: fMRI and TMS

Time perception is used in our day-to-day activities. While we understand quite well how our brain processes vision, touch or taste, brain mechanisms subserving time perception remain largely understudied. In this study, we extended an experiment of previous master thesis run by Tatiana Kenel-Pierre. We focused on time perception in the range of milliseconds. Previous studies have demonstrated the involvement of visual areas V1 and V5/MT in the encoding of temporal information of visual stimuli. Based on these previous findings the aim of the present study was to understand if temporal information was encoded in V1 and extrastriate area V5/MT in different spatial frames i.e., head- centered versus eye-centered. To this purpose we asked eleven healthy volunteers to perform a temporal discrimination task of visual stimuli. Stimuli were presented at 4 different spatial positions (i.e., different combinations of retinotopic and spatiotopic position). While participants were engaged in this task we interfered with the activity of the right dorsal V1 and the right V5/MT with transcranial magnetic stimulation (TMS). Our preliminary results showed that TMS over both V1 and V5/MT impaired temporal discrimination of visual stimuli presented at specific spatial coordinates. But whereas TMS over V1 impaired temporal discrimination of stimuli presented in the lower left quadrant, TMS over V5/MT affected temporal discrimination of stimuli presented at the top left quadrant. Although it is always difficult to draw conclusions from preliminary results, we could tentatively say that our data seem to suggest that both V1 and V5/MT encode visual temporal information in specific spatial frames.

Perception du timing pubertaire et comportements à risque chez des adolescents suisses

Il faut distinguer timing pubertaire objectif (TPO ; comparaison du timing pubertaire réel d'un sujet avec celui d'un groupe de référence) et timing pubertaire subjectif (TPS ; perception subjective par le sujet de son timing pubertaire par rapport à celui de ses pairs). Chez l'adolescente, la ménarche est couramment utilisée comme marqueur du TPO. La littérature s'intéressant aux variations physiologiques (normales) du timing pubertaire montre qu'un TPO précoce est corrélé chez les adolescentes avec de nombreux problèmes de santé (p.ex. dépression, abus de substances, comportements à risques, niveau d'études inférieur). Un TPO tardif chez l'adolescente serait quant à lui associé à une meilleure réussite scolaire. Les diverses hypothèses expliquant ces corrélations sont brièvement décrites dans notre travail. Certaines hypothèses impliquent des facteurs objectifs tels les changements du corps à la puberté, alors que d'autres privilégient des facteurs plus subjectifs, dans le registre de la perception de soi. A ce jour, la littérature ne s'est que très peu intéressée au TPS en soi. Une adolescente percevant son timing pubertaire comme précoce est-elle à risque même si sa puberté survient objectivement au même âge que la majorité de ses pairs ? L'objectif de ce travail est de rechercher d'éventuelles corrélations entre TPS et adoption de comportements à risque chez des adolescentes rapportant un TPO dans la moyenne. Nos données proviennent de l'enquête SMASH 2002, une étude par questionnaire auto-administré conduite parmi un échantillon de 7548 adolescentes et adolescents suisses âgés de 16-20 ans. Des 3658 adolescentes de l'échantillon initial, nous ne sélectionnons que les 1003 d'entre elles qui ont répondu à la question sur le TPS et qui ont rapporté un âge à la ménarche de 13 ans, soit la moyenne et la médiane de l'âge à la ménarche rapporté par les 3658 adolescentes de l'échantillon initial. Ces 1003 adolescentes sélectionnées sont considérées comme ayant un TPO dans la moyenne. Ces 1003 adolescentes sont séparées en 3 groupes en fonction de leur TPS (précoce/correspondant à la moyenne/tardif). A l'aide d'analyses bivariées et logistiques, nous comparons ces 3 groupes en termes d'adoption de comportements à risque dans le champ de la sexualité (précocité des rapports sexuels) et dans celui de la consommation de substances (tabac, cannabis, drogues dures). Nos résultats montrent principalement qu'une perception de précocité pubertaire est associée avec une précocité des premiers rapports sexuels et de l'usage de drogues dures. A l'inverse, les adolescentes percevant leur puberté comme tardive rapportent moins fréquemment des rapports sexuels avant 16 ans que les adolescentes percevant leur puberté comme dans la moyenne. Les implications cliniques sont les suivantes : face à une adolescente percevant sa puberté comme étant ou ayant été précoce, le praticien devrait investiguer l'existence de comportements à risque même si la puberté survient ou est survenue à un âge similaire à ce qui est retrouvé chez la majorité des pairs. En effet, notre étude suggère que même si cette adolescente se trompe en percevant sa puberté comme précoce, la probabilité de comportements à risque est augmentée dans le champ de la sexualité et de la consommation de substances. Nos résultats suggèrent aussi que l'association retrouvée dans la littérature entre précocité objective de la puberté et comportements à risque chez les adolescentes n'est pas uniquement médiée par les changements corporels pubertaires mais qu'un facteur psychologique tel que la perception subjective est également impliqué.