Adaptation au codage CIM-10 de 15 indicateurs de la sécurité des patients proposés par l'Agence étasunienne pour la recherche et la qualité des soins de santé (AHRQ) [ICD-10 adaptation of 15 Agency for Healthcare Research and Quality patient safety indicators].

BACKGROUND: In the United States, the Agency for Healthcare Research and Quality (AHRQ) has developed 20 Patient Safety Indicators (PSIs) to measure the occurrence of hospital adverse events from medico-administrative data coded according to the ninth revision of the international classification of disease (ICD-9-CM). The adaptation of these PSIs to the WHO version of ICD-10 was carried out by an international consortium. METHODS: Two independent teams transcoded ICD-9-CM diagnosis codes proposed by the AHRQ into ICD-10-WHO. Using a Delphi process, experts from six countries evaluated each code independently, stating whether it was "included", "excluded" or "uncertain". During a two-day meeting, the experts then discussed the codes that had not obtained a consensus, and the additional codes proposed. RESULTS: Fifteen PSIs were adapted. Among the 2569 proposed diagnosis codes, 1775 were unanimously adopted straightaway. The 794 remaining codes and 2541 additional codes were discussed. Three documents were prepared: (1) a list of ICD-10-WHO codes for the 15 adapted PSIs; (2) recommendations to the AHRQ for the improvement of the nosological frame and the coding of PSI with ICD-9-CM; (3) recommendations to the WHO to improve ICD-10. CONCLUSIONS: This work allows international comparisons of PSIs among the countries using ICD-10. Nevertheless, these PSIs must still be evaluated further before being broadly used.

Lung cancer mortality in European men: Trends and predictions.

Lung cancer mortality in men from the European Union (EU) peaked in the late 1980s at an age-standardised (world standard population) rate over 53/100,000 and declined subsequently to reach 44/100,000 in the early 2000s. To provide a comprehensive picture of recent trends in male lung cancer mortality in Europe, we analyzed available data from the World Health Organization up to 2009 and predicted future rates to 2015. Lung cancer mortality rates in EU men continued to fall over recent years, to reach a value of 41.1/100,000 in 2005-2009. The fall was similar at all-ages and in middle-aged men (less than 2% per year over most recent years), but was appreciably larger in young men (aged 20-44years, over 5% per year). A favourable trend is thus likely to be maintained in the foreseeable future, although the predicted overall EU rate in 2015 is still over 35/100,000, i.e., higher than the US rate in 2007 (33.7/100,000). Over most recent calendar years, overall male lung cancer rates were around 35-40/100,000 in western Europe, as compared to over 50/100,000 in central and eastern Europe. Within western Europe, lung cancer rates were lower in northern countries such as Sweden, but also Finland and the UK (below 30/100,000), where the tobacco-related epidemic started earlier and rates have long been declining, whereas mortality was high in Belgium (51.6), France (42.3), the Netherlands and Spain (around 43.0), where the epidemic started later but is persisting. Widespread measures for smoking control and cessation in middle-aged European men, i.e., in the generations where smoking prevalence used to be high, would lead to appreciable reductions in male lung cancer mortality in the near future. This is particularly urgent in central and eastern European countries.

Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome.

Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.

Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response.

Anti-CTLA-4 treatment improves the survival of patients with advanced-stage melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an approved treatment for patients with metastatic disease, it remains unknown by which mechanism it boosts tumor-specific T cell activity. In particular, it is unclear whether treatment amplifies previously induced T cell responses or whether it induces new tumor-specific T cell reactivities. Using a combination ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility complex (pMHC) combinatorial coding, we monitored immune reactivity against a panel of 145 melanoma-associated epitopes in a cohort of patients receiving anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated that anti-CTLA-4 treatment induces a significant increase in the number of detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking contrast, the magnitude of both virus-specific and melanoma-specific T cell responses that were already detected before start of therapy remained unaltered by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.

Disegni come documento e disegni come monumento : Giovanni Ciampini, Sebastiano Resta e la fortuna del Medioevo artistico nella Roma di Bellori

La tesi di Dottorato, condotta in accordo di colutela tra l'Università di Roma Tor Vergata e l'UNIL di Losanna, ha affrontato l'analisi di un gruppo di undici disegni custodia presso la National Gallery of Scotland di Edimburgo, copie di alcuni dei più significativi mosaici medioevali delle chiese di Roma, ricostruendone la genesi, quindi le vicende legate alla committenza, e il percorso collezionistico. I disegni scozzesi, oggetto di un importante articolo di Julian Gardner pubblicato sul Burlington Magatine nel 1973, furono commissionati intorno agli anni Settanta del XVII secolo dall'antiquario romano Giovanni Giustino Ciampini (1633-1698) in connessione alla stesura della sua opera di erudizione più avvertita e famosa: i Vetera Mommenta in' quibus praecipue Musiva Opera, sacrarum, profanan,mque, Aedìum structura, ac nonnulli antiqui ritus dissertationibus iconìbusque illustrantur. La composizione dei Vetera Mommenta - un'opera riccamente illustrata che nasce per rispondere alle esigenze della ideologia della Chiesa di Roma in un momento di rinnovata crisi del sistema - impone a Ciampini di porsi da un lato nella prospettiva della più alta tradizione antiquaria cinque e seicentesca, di cui recupera i metodi di lettura e di analisi applicati allo studio delle monete e dei monumenti antichi interpretati quali prove per la ricostruzione storica, e dall'altra, come è emerso dalle mie ricerche, lo pone immediatamente in contatto con gli avamposti del più moderno metodo di indagine storica e filologica applicato alle fonti e ai documenti della storia ecclesiastica, inaugurato dall'ambiente bollandista e inaurino. I monumenti paleocristiani e medioevali assumono in quest'ottica lo status di 'fatti incontestabili', le fonti primarie attraverso le quali Ciampini ricuce le tappe salienti della storia della Chiesa, da Costantino fino al XV secolo. Nel 1700 le copie di Edimburgo arrivano nelle mani del mercante e connoisseur milanese il padre oratoriano Sebastiano Resta (1635-1714), di stanza a Roma presso la Chiesa Nuova della Vallicella dal 1660, che decide di rilegarle tutte insieme in un volume da donare al suo maggiore acquirente e patrono, il vescovo di Arezzo Giovanni Matteo Marchetti. Come spiega Resta in alcune sue lettere, il presente avrebbe dovuto costituire insieme una curiosità ed offrire un confronto: infatti «le copie delli mosaici di Roma che erano di Monsignor Ciampini» - afferma Resta - avrebbero mostrato al Marchetti «le maniere di que' tempi gottici, barbari e divoti de cristiani e [fatto] spiccare i secoli seguenti». Questa indagine infatti ha fatto riemergere aspetti della precoce attenzione di Sebastiano Resta per l'arte dei "secoli bassi", mai debitamente affrontata dagli studi. E' infatti sulla scorta di una profonda conoscenza dei testi della letteratura artistica, e in connessione alla esplosione vivacissima della controversia Malvasia/Baldinucci sul primato del risorgere delle arti in Toscana, che Sebastiano a partire dagli anni Ottanta del Seicento comincia a meditare sul Medioevo artistico con il fine di spiegare l'evoluzione del linguaggio tecnico e formale che ha condotto alla perfezione dell'atte moderna. In questa prospettiva ι disegni del XIV e XV secolo che egli riuscì ad intercettare sul mercato valgono quali testimonianze delle maniere degli artefici più antichi e sono imbastiti nei molteplici album che Resta compone nel rispetto della successione cronologica dei presunti autori, e ordinati in base alle scuole pittoriche di pertinenza. La tesi permette perciò di descrivere nelle loro diverse specificità: da un lato il modo dei conoscitori come Resta, interessati nell'opera al dato stilistico, con immediate e sensibili ricadute sul mercato, e disposti anche con passione a ricercare i documenti relativi all'opera in quanto pressati dall'urgenza di collocarla nella sequenza cronologica dello sviluppo del linguaggio formale e tecnico; dall'altro gli antiquari come Ciampini e come Bianchini, per i quali le opere del passato valgono come prove irrefutabili della ricostruzione storica, e divengono quindi esse stesse, anche nel loro statuto di copia, documento della stona. Sono due approcci che si manifestano nel Seicento, e talvolta in una medesima persona, come mostra il caso anche per questo cruciale di Giovati Pietro Bellori, ma che hanno radici cinquecentesche, di cui i protagonisti di queste vicende sono ben consapevoli: e se dietro Resta c'è palesemente Vasari, dietro Ciampini e soprattutto Bianchini c'è la più alta tradizione antiquaria del XVI secolo, da Antonio Augustin a Fulvio Orsini.

Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience.

BACKGROUND: Uveal melanoma exhibits a high incidence of metastases; and, to date, there is no systemic therapy that clearly improves outcomes. The anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab is a standard of care for metastatic melanoma; however, the clinical activity of CTLA-4 inhibition in patients with metastatic uveal melanoma is poorly defined. METHODS: To assess ipilimumab in this setting, the authors performed a multicenter, retrospective analysis of 4 hospitals in the United States and Europe. Clinical characteristics, toxicities, and radiographic disease burden, as determined by central, blinded radiology review, were evaluated. RESULTS: Thirty-nine patients with uveal melanoma were identified, including 34 patients who received 3 mg/kg ipilimumab and 5 who received 10 mg/kg ipilimumab. Immune-related response criteria and modified World Health Organization criteria were used to assess the response rate (RR) and the combined response plus stable disease (SD) rate after 12 weeks, after 23 weeks, and overall (median follow-up, 50.4 weeks [12.6 months]). At week 12, the RR was 2.6%, and the response plus SD rate was 46.%; at week 23, the RR was 2.6%, and the response plus SD rate was 28.2%. There was 1 complete response and 1 late partial response (at 100 weeks after initial SD) for an immune-related RR of 5.1%. Immune-related adverse events were observed in 28 patients (71.8%) and included 7 (17.9%) grade 3 and 4 events. Immune-related adverse events were more frequent in patients who received 10 mg/kg ipilimumab than in those who received 3 mg/kg ipilimumab. The median overall survival from the first dose of ipilimumab was 9.6 months (95% confidence interval, 6.3-13.4 months; range, 1.6-41.6 months). Performance status, lactate dehydrogenase level, and an absolute lymphocyte count ≥ 1000 cells/μL at week 7 were associated significantly with survival. CONCLUSIONS: In this multicenter, retrospective analysis of 4 hospitals in the United States and Europe of patients with uveal melanoma, durable responses to ipilimumab and manageable toxicity were observed.

Oxidative and glycogenolytic cCapacities within the developing chick heart.

Cardiac morphogenesis and function are known to depend on both aerobic and anaerobic energy-producing pathways. However, the relative contribution of mitochondrial oxidation and glycogenolysis, as well as the determining factors of oxygen demand in the distinct chambers of the embryonic heart, remains to be investigated. Spontaneously beating hearts isolated from stage 11, 20, and 24HH chick embryos were maintained in vitro under controlled metabolic conditions. O(2) uptake and glycogenolytic rate were determined in atrium, ventricle, and conotruncus in the absence or presence of glucose. Oxidative capacity ranged from 0.2 to 0.5 nmol O(2)/(h.microg protein), did not depend on exogenous glucose, and was the highest in atria at stage 20HH. However, the highest reserves of oxidative capacity, assessed by mitochondrial uncoupling, were found at the youngest stage and in conotruncus, representing 75 to 130% of the control values. At stage 24HH, glycogenolysis in glucose-free medium was 0.22, 0.17, and 0.04 nmol glucose U(h.microg protein) in atrium, ventricle, and conotruncus, respectively. Mechanical loading of the ventricle increased its oxidative capacity by 62% without altering glycogenolysis or lactate production. Blockade of glycolysis by iodoacetate suppressed lactate production but modified neither O(2) nor glycogen consumption in substrate-free medium. These findings indicate that atrium is the cardiac chamber that best utilizes its oxidative and glycogenolytic capacities and that ventricular wall stretch represents an early and major determinant of the O(2) uptake. Moreover, the fact that O(2) and glycogen consumptions were not affected by inhibition of glyceraldehyde-3-phosphate dehydrogenase provides indirect evidence for an active glycerol-phosphate shuttle in the embryonic cardiomyocytes.

Art et Observance à Venise : les Dominicains et leurs artistes (1391-1545)

L'Observance est le premier mouvement de réforme avant la Contre-réforme promu par l'Eglise elle-même, dès la fin du XlVème siècle. Visant à restaurer une plus grande observance de la Règle au sein des Ordres religieux, par l'importance accordée à la vie commune, à la formation intellectuelle de ses membres et à l'oraison mentale, elle joue un rôle de premier plan dans la vie des cités au XVème siècle. Tantôt instrument du pouvoir civil tantôt de la papauté, elle est un acteur fondamental dans le panorama urbain, aspirant à contrôler la vie religieuse des laïcs, grâce à ses prédicateurs et son intense activité pastorale, fondée sur l'édition de traités dévotionnels et de manuels pour la prière. L'objet de cette thèse est l'étude des relations entre ce mouvement de réforme religieuse et la production artistique, afin de comprendre la contribution de l'Observance aux transformations importantes que l'image de culte tant publique que privée connaît entre le XVème et le XVIème siècle. Elle montre que l'Observance et les formes de dévotion qu'elle promeut participent non seulement des choix iconographiques mais également formels, et pose la question de l'existence et de la définition d'une esthétique observante. L'analyse se concentre sur la ville de Venise et les Dominicains à partir de 1391, date de l'introduction de l'Observance dans la cité, jusqu'en 1545, qui marque le début du Concile de Trente. La perspective diachronique adoptée a permis de révéler une véritable politique artistique de l'Observance dominicaine, qui fait un usage réfléchi et conscient des images. Celles-ci permettent, d'une part de décliner l'identité de l'Ordre de diverses manières en fonction de la situation religieuse et historique et des destinataires, d'autre part de contrôler et informer la dévotion du fidèle. La perspective diachronique éclaire également comment l'Observance dominicaine a fait face à des mouvements religieux importants, qui promeuvent des pratiques dévotionnelles christocentriques, fondées sur un rapport direct et individuel avec le divin. Il s'agit au XVème siècle de la Devotio moderna, puis au XVIème siècle de la Réforme protestante, mais aussi des divers mouvements de spiritualité évangélique dont Venise est un centre de diffusion. Pour un Ordre voué à la défense de la papauté et de l'Eglise, ces formes de dévotion individuelles constituaient des menaces auxquelles il fallait opposer des formes de dévotion individuelles contrôlées. A cette fin, l'utilisation des images s'est révélée un instrument puissant. Après une première partie historique qui offre une reconstruction de certaines églises dominicaines détruites et établit un corpus d'oeuvres, les rapports de l'Observance et des oeuvres d'art sont analysés selon trois angles d'approche. Le premier se concentre sur la question des femmes, et aborde le problème de l'utilisation des images dans la direction spirituelle des nonnes ainsi que dans la construction d'une identité féminine dominicaine. Le deuxième prend en considération l'utilisation des images dans la dévotion privée des frères eux-mêmes. Le troisième et dernier angle d'approche concerne l'utilisation des images pour définir l'identité de l'Ordre face aux représentants des autorités politiques et religieuses, mais aussi des fidèles.

Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells.

A comprehensive understanding of the complex, autologous cellular interactions and regulatory mechanisms that occur during normal dendritic cell (DC)-stimulated immune responses is critical to optimizing DC-based immunotherapy. We have found that mature, immunogenic human monocyte-derived DCs (moDCs) up-regulate the immune-inhibitory enzyme, indoleamine 2,3-dioxygenase (IDO). Under stringent autologous culture conditions without exogenous cytokines, mature moDCs expand regulatory T cells (Tregs) by an IDO-dependent mechanism. The priming of resting T cells with autologous, IDO-expressing, mature moDCs results in up to 10-fold expansion of CD4(+)CD25(bright)Foxp3(+)CD127(neg) Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and endogenous interleukin-2. Cytofluorographically sorted CD4(+) CD25(bright)Foxp3(+) Tregs inhibit as much as 80% to 90% of DC-stimulated autologous and allogeneic T-cell proliferation, in a dose-dependent manner at Treg:T-cell ratios of 1:1, 1:5, and as low as 1:25. CD4(+)CD25(bright)Foxp3(+) Tregs also suppress the generation of cytotoxic T lymphocytes specific for the Wilms tumor antigen 1, resulting in more than an 80% decrease in specific target cell lysis. Suppression by Tregs is both contact-dependent and transforming growth factor-beta-mediated. Although mature moDCs can generate Tregs by this IDO-dependent mechanism to limit otherwise unrestrained immune responses, inhibition of this counter-regulatory pathway should also prove useful in sustaining responses stimulated by DC-based immunotherapy.

How many diagnosis fields are needed to capture safety events in administrative data? Findings and recommendations from the WHO ICD-11 Topic Advisory Group on Quality and Safety

OBJECTIVE: As part of the WHO ICD-11 development initiative, the Topic Advisory Group on Quality and Safety explores meta-features of morbidity data sets, such as the optimal number of secondary diagnosis fields. DESIGN: The Health Care Quality Indicators Project of the Organization for Economic Co-Operation and Development collected Patient Safety Indicator (PSI) information from administrative hospital data of 19-20 countries in 2009 and 2011. We investigated whether three countries that expanded their data systems to include more secondary diagnosis fields showed increased PSI rates compared with six countries that did not. Furthermore, administrative hospital data from six of these countries and two American states, California (2011) and Florida (2010), were analysed for distributions of coded patient safety events across diagnosis fields. RESULTS: Among the participating countries, increasing the number of diagnosis fields was not associated with any overall increase in PSI rates. However, high proportions of PSI-related diagnoses appeared beyond the sixth secondary diagnosis field. The distribution of three PSI-related ICD codes was similar in California and Florida: 89-90% of central venous catheter infections and 97-99% of retained foreign bodies and accidental punctures or lacerations were captured within 15 secondary diagnosis fields. CONCLUSIONS: Six to nine secondary diagnosis fields are inadequate for comparing complication rates using hospital administrative data; at least 15 (and perhaps more with ICD-11) are recommended to fully characterize clinical outcomes. Increasing the number of fields should improve the international and intra-national comparability of data for epidemiologic and health services research, utilization analyses and quality of care assessment.

Climatic and biotic upheavals following the end-Permian mass extinction

Recovery from the end-Permian mass extinction is frequently described as delayed(1-3), with complex ecological communities typically not found in the fossil record until the Middle Triassic epoch. However, the taxonomic diversity of a number of marine groups, ranging from ammonoids to benthic foraminifera, peaked rapidly in the Early Triassic(4-10). These variations in biodiversity occur amidst pronounced excursions in the carbon isotope record, which are compatible with episodes of massive CO2 outgassing from the Siberian Large Igneous Province(4,11-13). Here we present a high-resolution Early Triassic temperature record based on the oxygen isotope composition of pristine apatite from fossil conodonts. Our reconstruction shows that the beginning of the Smithian substage of the Early Triassic was marked by a cooler climate, followed by an interval of warmth lasting until the Spathian substage boundary. Cooler conditions resumed in the Spathian. We find the greatest increases in taxonomic diversity during the cooler phases of the early Smithian and early Spathian. In contrast, a period of extreme warmth in the middle and late Smithian was associated with floral ecological change and high faunal taxonomic turnover in the ocean. We suggest that climate upheaval and carbon-cycle perturbations due to volcanic outgassing were important drivers of Early Triassic biotic recovery.

Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab.

Metastatic melanoma has a poor prognosis with high resistance to chemotherapy and radiation. Recently, the anti-CTLA-4 antibody ipilimumab has demonstrated clinical efficacy, being the first agent to significantly prolong the overall survival of inoperable stage III/IV melanoma patients. A major aim of patient immune monitoring is the identification of biomarkers that predict clinical outcome. We studied circulating myeloid-derived suppressor cells (MDSC) in ipilimumab-treated patients to detect alterations in the myeloid cell compartment and possible correlations with clinical outcome. Lin(-) CD14(+) HLA-DR(-) monocytic MDSC were enriched in peripheral blood of melanoma patients compared to healthy donors (HD). Tumor resection did not significantly alter MDSC frequencies. During ipilimumab treatment, MDSC frequencies did not change significantly compared to baseline levels. We observed high inter-patient differences. MDSC frequencies in ipilimumab-treated patients were independent of baseline serum lactate dehydrogenase levels but tended to increase in patients with severe metastatic disease (M1c) compared to patients with metastases in skin or lymph nodes only (M1a), who had frequencies comparable to HD. Interestingly, clinical responders to ipilimumab therapy showed significantly less lin(-) CD14(+) HLA-DR(-) cells as compared to non-responders. The data suggest that the frequency of monocytic MDSC may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilimumab treatment. Prospective clinical trials assessing MDSC frequencies as potential biomarkers are warranted to validate these observations.