Einsatz nicht-steroidaler Antirheumatika bei akuter Gicht [Use of non-steroidal antirheumatic drugs in acute gout]

Hintergrund : Ein akuter Gichtanfall entsteht durchdas Ausfällen von Mononatriumkristallenaus der Synovialflüssigkeit unddie dadurch bedingte Entzündung einesoder mehrerer Gelenke.Mitunter kommt es auch zur Bildung der Kristalle direkt im Gewebe. Das Erscheinungsbild der Gichterkrankung umfasst neben akuten Gichtanfällen die asymptomatische Hyperurikämie und chronische Gicht-Arthritis; extraartikulär kann sich eine Uratnephropathie bzw. Urolithiasis ausbilden. Bei akuten Gichtanfällen kommen die klassischen NSAR (z.B. Diclofenac) sowie die selektiven Cyclooxygenase-2-Hemmer (COX-2-Hemmer oder Coxibe) zum Einsatz. Beide Substanzgruppen scheinen das gleiche Risikoprofil und klinische Effektivität zu besitzen. Der Einsatz sollte kurzzeitig in maximal möglicher Dosierung erfolgen. Bei komorbiden Patienten z.B. mit kardiovaskulären Erkrankungen, Niereninsuffizienz, Status nach gastrointestinalem Ulkus oder Blutung ist der Einsatz von NSAR eingeschränkt. Bisher wurde der Nutzen und die Sicherheit von klassischen NSAR und COX-2-Hemmer in der Behandlung von akuten Gichtanfällen nicht systematisch untersucht.

Impact of case management on frequent users' quality of life : a randomized, controlled trial (FM 286)

Introduction: Frequent emergency department (ED) users are often vulnerable patients with many risk factors affecting their quality of life (QoL). The aim of this study was to examine to what extent a case management intervention improved frequent ED users' QoL. Methods: Data were part of a randomized, controlled trial designed to improve frequent ED users' QoL at the Lausanne University Hospital. A total of 194 frequent ED users (≥ 5 attendances during the previous 12 months; ≥ 18 years of age) were randomly assigned to the control or the intervention group. Participants in the intervention group received a case management intervention (i.e. counseling and assistance concerning social determinants of health, substance-use disorders, and access to the health-care system). QoL was evaluated using the WHOQOL-BREF at baseline and twelve months later. Four dimensions of QoL were retained: physical health, psychological health, social relationship, and environment, with scores ranging from 0 (low QoL) to 100 (high QoL).

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.

Patients' characteristics associated with the decision of "do not attempt cardiopulmonary resuscitation" order in a Swiss hospital

Présentation En accord avec la loi suisse, seul le patient peut décider de la notification, dans son dossier, d'un ordre de «non réanimation » (DNACPR) en cas d'arrêt cardio-respiratoire. L'équipe médicale peut exceptionnellement prendre une telle décision, si elle juge qu'une réanimation n'a aucune chance d'aboutir. Les mécanismes menant à ce processus de décision n'ont pas encore été complètement investigués, en particulier en Suisse. Enjeu Notre étude vise à déterminer la prévalence de l'ordre de «non réanimation» après l'admission, l'auteur de cette décision, ainsi que son association avec certaines caractéristiques propres aux patients : le sexe, l'âge, la situation familiale, la nationalité, la religion, le nombre et le type de comorbidités. Nous cherchons ainsi à mieux définir quels sont les facteurs importants dans ce processus décisionnel complexe où le jugement médical, ainsi que l'information apportée aux patients sont primordiaux. Contexte de recherche Nous avons effectué une étude observationnelle sur une durée de 6 semaines, en analysant les formulaires d'admission de 194 patients hospitalisés dans le service de médecine interne du CHUV, dans les 72 heures après leur admission. Résultats L'étude montre que plus de la moitié des 194 dossiers de patients analysés ont un ordre de « non réanimation » (DNACPR) (53%). 27% de ces décisions ont été prises par les patients eux-mêmes, 12% par leur représentant thérapeutique/famille et 61% par les équipes médicales. Nous trouvons une association statistiquement significative entre l'ordre DNACPR et l'âge, avec un âge moyen de 80.7 +-10.8 ans dans le groupe « non réanimation » versus 67.5 +- 15.1 ans dans le groupe « réanimation », entre l'ordre DNACPR et une pathologie oncologique, quel que soit le stade de cette dernière, ainsi qu'entre l'ordre DNACPR et la religion protestante. Une analyse de sous-groupe montre que l'âge, ainsi que la pathologie oncologique sont statistiquement significatifs lors de l'analyse des décisions prises par les équipes médicales. La religion protestante est, quant à elle, significative lors de l'analyse des décisions prises par le patient ou son représentant. Perspectives Contrairement aux publications passées, cette étude montre une prédominance de l'ordre de «non réanimation » (DNACPR) à l'admission dans un service de médecine interne, principalement sur décision médicale. La plupart des patients ont été jugés incapables de discernement sur la question ou n'ont tout simplement pas été impliqués dans le processus décisionnel. Une réflexion doit avoir lieu afin de prendre des mesures de sensibilisation auprès des équipes médicales et d'approfondir la formation médicale et éthique sur le sujet de la détermination de l'attitude de réanimation. D'autres études qualitatives permettraient de mieux comprendre les motivations ayant mené à ces nombreuses décisions médicales, ainsi que les critères importants pour les patients.

The Effect of Cigarette Smoking on Diabetic Peripheral Neuropathy: A Systematic Review and Meta-Analysis.

OBJECTIVE: Studies suggest that smoking may be a risk factor for the development of microvascular complications such as diabetic peripheral neuropathy (DPN). The objective of this study was to assess the relationship between smoking and DPN in persons with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: A systematic review of the PubMed, Embase, and Cochrane clinical trials databases was conducted for the period from January 1966 to November 2014 for cohort, cross-sectional and case-control studies that assessed the relationship between smoking and DPN. Separate meta-analyses for prospective cohort studies and case-control or cross-sectional studies were performed using random effects models. RESULTS: Thirty-eight studies (10 prospective cohort and 28 cross-sectional) were included. The prospective cohort studies included 5558 participants without DPN at baseline. During follow-up ranging from 2 to 10 years, 1550 cases of DPN occurred. The pooled unadjusted odds ratio (OR) of developing DPN associated with smoking was 1.26 (95% CI 0.86-1.85; I(2) = 74%; evidence grade: low strength). Stratified analyses of the prospective studies revealed that studies of higher quality and with better levels of adjustment and longer follow-up showed a significant positive association between smoking and DPN, with less heterogeneity. The cross-sectional studies included 27,594 participants. The pooled OR of DPN associated with smoking was 1.42 (95% CI 1.21-1.65; I(2) = 65%; evidence grade: low strength). There was no evidence of publication bias. CONCLUSIONS: Smoking may be associated with an increased risk of DPN in persons with diabetes. Further studies are needed to test whether this association is causal and whether smoking cessation reduces the risk of DPN in adults with diabetes.

Spontaneous cell polarization: Feedback control of Cdc42 GTPase breaks cellular symmetry.

Spontaneous polarization without spatial cues, or symmetry breaking, is a fundamental problem of spatial organization in biological systems. This question has been extensively studied using yeast models, which revealed the central role of the small GTPase switch Cdc42. Active Cdc42-GTP forms a coherent patch at the cell cortex, thought to result from amplification of a small initial stochastic inhomogeneity through positive feedback mechanisms, which induces cell polarization. Here, I review and discuss the mechanisms of Cdc42 activity self-amplification and dynamic turnover. A robust Cdc42 patch is formed through the combined effects of Cdc42 activity promoting its own activation and active Cdc42-GTP displaying reduced membrane detachment and lateral diffusion compared to inactive Cdc42-GDP. I argue the role of the actin cytoskeleton in symmetry breaking is not primarily to transport Cdc42 to the active site. Finally, negative feedback and competition mechanisms serve to control the number of polarization sites.

Validation of and comparison between a semidistributed rainfall-runoff hydrological model (PREVAH) and a spatially distributed snow-evolution model (SnowModel) for snow cover prediction in mountain ecosystems

Snow cover is an important control in mountain environments and a shift of the snow-free period triggered by climate warming can strongly impact ecosystem dynamics. Changing snow patterns can have severe effects on alpine plant distribution and diversity. It thus becomes urgent to provide spatially explicit assessments of snow cover changes that can be incorporated into correlative or empirical species distribution models (SDMs). Here, we provide for the first time a with a lower overestimation comparison of two physically based snow distribution models (PREVAH and SnowModel) to produce snow cover maps (SCMs) at a fine spatial resolution in a mountain landscape in Austria. SCMs have been evaluated with SPOT-HRVIR images and predictions of snow water equivalent from the two models with ground measurements. Finally, SCMs of the two models have been compared under a climate warming scenario for the end of the century. The predictive performances of PREVAH and SnowModel were similar when validated with the SPOT images. However, the tendency to overestimate snow cover was slightly lower with SnowModel during the accumulation period, whereas it was lower with PREVAH during the melting period. The rate of true positives during the melting period was two times higher on average with SnowModel with a lower overestimation of snow water equivalent. Our results allow for recommending the use of SnowModel in SDMs because it better captures persisting snow patches at the end of the snow season, which is important when modelling the response of species to long-lasting snow cover and evaluating whether they might survive under climate change.

Fatal Events in Cancer Patients Receiving Anticoagulant Therapy for Venous Thromboembolism.

In cancer patients treated for venous thromboembolism (VTE), including deep-vein thrombosis (DVT) and pulmonary embolism (PE), analyzing mortality associated with recurrent VTE or major bleeding is needed to determine the optimal duration of anticoagulation.This was a cohort study using the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) Registry database to compare rates of fatal recurrent PE and fatal bleeding in cancer patients receiving anticoagulation for VTE.As of January 2013, 44,794 patients were enrolled in RIETE, of whom 7911 (18%) had active cancer. During the course of anticoagulant therapy (mean, 181 ± 210 days), 178 cancer patients (4.3%) developed recurrent PE (5.5 per 100 patient-years; 95% CI: 4.8-6.4), 194 (4.7%) had recurrent DVT (6.2 per 100 patient-years; 95% confidence interval [CI]: 5.3-7.1), and 367 (8.9%) bled (11.3 per 100 patient-years; 95% CI: 10.2-12.5). Of 4125 patients initially presenting with PE, 43 (1.0%) died of recurrent PE and 45 (1.1%) of bleeding; of 3786 patients with DVT, 19 (0.5%) died of PE, and 55 (1.3%) of bleeding. During the first 3 months of anticoagulation, there were 59 (1.4%) fatal PE recurrences and 77 (1.9%) fatal bleeds. Beyond the third month, there were 3 fatal PE recurrences and 23 fatal bleeds.In RIETE cancer patients, the rate of fatal recurrent PE or fatal bleeding was much higher within the first 3 months of anticoagulation therapy.

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study.

BACKGROUND: The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. METHODS: FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. FINDINGS: Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). INTERPRETATION: Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. FUNDING: ViiV Healthcare and Shionogi & Co.