Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism.

In patients with venous thromboembolism (VTE), assessment of the risk of fatal recurrent VTE and fatal bleeding during anticoagulation may help to guide intensity and duration of therapy. We aimed to provide estimates of the case-fatality rate (CFR) of recurrent VTE and major bleeding during anticoagulation in a 'real life' population, and to assess these outcomes according to the initial presentation of VTE and its etiology. The study included 41,826 patients with confirmed VTE from the RIETE registry who received different durations of anticoagulation (mean 7.8 ± 0.6 months). During 27,110 patient-years, the CFR was 12.1% (95% CI, 10.2-14.2) for recurrent VTE, and 19.7% (95% CI, 17.4-22.1) for major bleeding. During the first three months of anticoagulant therapy, the CFR of recurrent VTE was 16.1% (95% CI, 13.6-18.9), compared to 2.0% (95% CI, 0-4.2) beyond this period. The CFR of bleeding was 20.2% (95% CI, 17.5-23.1) during the first three months, compared to 18.2% (95% CI, 14.0-23.2) beyond this period. The CFR of recurrent VTE was higher in patients initially presenting with PE (18.5%; 95% CI, 15.3-22.1) than in those with DVT (6.3%; 95% CI, 4.5-8.6), and in patients with provoked VTE (16.3%; 95% CI, 13.6-19.4) than in those with unprovoked VTE (5.5%; 95% CI, 3.5-8.0). In conclusion, the CFR of recurrent VTE decreased over time during anticoagulation, while the CFR of major bleeding remained stable. The CFR of recurrent VTE was higher in patients initially presenting with PE and in those with provoked VTE.

Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism.

Background: In haemodynamically stable patients with acute symptomatic pulmonary embolism (PE), studies have not evaluated the usefulness of combining the measurement of cardiac troponin, transthoracic echocardiogram (TTE), and lower extremity complete compression ultrasound (CCUS) testing for predicting the risk of PE-related death. Methods: The study assessed the ability of three diagnostic tests (cardiac troponin I (cTnI), echocardiogram, and CCUS) to prognosticate the primary outcome of PE-related mortality during 30 days of follow-up after a diagnosis of PE by objective testing. Results: Of 591 normotensive patients diagnosed with PE, the primary outcome occurred in 37 patients (6.3%; 95% CI 4.3% to 8.2%). Patients with right ventricular dysfunction (RVD) by TTE and concomitant deep vein thrombosis (DVT) by CCUS had a PE-related mortality of 19.6%, compared with 17.1% of patients with elevated cTnI and concomitant DVT and 15.2% of patients with elevated cTnI and RVD. The use of any two-test strategy had a higher specificity and positive predictive value compared with the use of any test by itself. A combined three-test strategy did not further improve prognostication. For a subgroup analysis of high-risk patients, according to the pulmonary embolism severity index (classes IV and V), positive predictive values of the two-test strategies for PE-related mortality were 25.0%, 24.4% and 20.7%, respectively. Conclusions: In haemodynamically stable patients with acute symptomatic PE, a combination of echocardiography (or troponin testing) and CCUS improved prognostication compared with the use of any test by itself for the identification of those at high risk of PE-related death.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

MP2RAGE Multiple Sclerosis Magnetic Resonance Imaging at 3 T.

OBJECTIVES: Lesion detection and characterization in multiple sclerosis (MS) are an essential part of its clinical diagnosis and an important research field. In this pilot study, we applied the recently introduced two inversion-contrast magnetization-prepared rapid gradient echo sequence (MP2RAGE) to patients with early-stage MS.¦MATERIALS AND METHODS: The MP2RAGE is a 3-dimensional (3D) magnetization-prepared rapid gradient echo derivative providing homogeneous T1 weighting and simultaneous T1 mapping. The MP2RAGE performance was compared with that of 2 clinical routine sequences (2D fluid-attenuated inversion recovery [FLAIR] and 3D magnetization-prepared rapid gradient echo [MP-RAGE]) and 2 state-of-the art clinical research sequences (the 3D FLAIR-SPACE [sampling perfection with application-optimized contrasts by using different flip-angle evolutions], a fluid-attenuated variable flip-angle fast spin echo technique, and the 3D double-inversion recovery SPACE). A cohort of 10 early-stage female MS patients (age, 31.6 ± 4.7 years; disease duration, 3.8 ± 1.9 years; median expanded disability status scale score, 1.75) and 10 age- and gender-matched controls were enrolled after approval of the local institutional review board was obtained. Multiple sclerosis lesions were identified and assigned to brain locations and tissue types by two experienced physicians in all 5 contrasts. Subsequently, lesions were manually delineated for comparison and statistical analysis of lesion count, volume and quantitative measures.¦RESULTS AND CONCLUSIONS: The results show that the 3D T1-weighted high-resolution MP2RAGE contrast provides a sensitive means for MS lesion assessment. The additional quantitative T1 relaxation time maps obtained with the MP2RAGE provide further potential diagnostic and prognostic information that could help (a) to better discriminate lesion subtypes and (b) to stage and predict the activity and the evolution of MS. Results also indicate that the T2-weighted double-inversion recovery and FLAIR-SPACE contrasts are attractive complements to the MP2RAGE for lesion detection.

L'hépatectomie réglée. A propos de 18 cas opérés dans un hôpital périphérique [Standardized hepatectomy. 18 cases operated in a peripheral hospital]

Hepatectomy has long been a formidable surgical procedure because the risk of hemorrhage it can involve. With a better understanding of hepatic anatomy, left hepatectomy, right hepatectomy and segmental hepatic resections have been standardized. Between January 1989 and December 1992, 18 hepatectomies were performed on 16 patients in the Department of Surgery, General Hospital, La Chaux-de-Fonds, Switzerland. The mean age of the patients was 65. The surgical indications were: hepatic metastases 11 (61%); gallbladder or biliary duct neoplasm 4 (22%); hydatic cyst 3 (17%). 11 segmental resection, 3 left hepatectomies, 2 right hepatectomies, 2 pericystectomies were performed. Blood loss during these operations averaged 2800 ml. Surgical complications appeared in 6 cases (hemorrhage 1, postoperative effusion 4, sepsis 1). One patient died within 30 days (mortality 5%). Hepatectomy is nowadays a safe procedure. It can be performed in a general hospital with a trained surgical team and an efficient intensive care unit

Traitement mini-invasif sous contrôle scanner et fluoroscopique de la lyse isthmique vertébrale : une nouvelle technique.

Objectifs: Evaluer la faisabilité, les résultats préliminaires à court et long terme du vissage percutané de vissage trans -isthmique sous anesthésie locale et contrôle scannerdes lyses isthmiques de bas grades.Matériels et méthodes: Etude prospective monocentrique réalisée sur 10 patients ayant une lyse isthmique grade 1 et 2 résistant au traitement médical conventionnel. Une évaluationclinique était réalisée à un mois, 3 mois, 6 mois et un an post-opératoire par un évaluateur indépendant. L'indication est posée en concertation avec le service dechirurgie orthopédique.Résultats: Les lyses isthmiques étaient situées en L5-S1 avec 6 grades 1 et 4 grades 2. L'échelle analogique de la douleur (VAS) variait de 6 a 9 avec une moyenne de 7,8.L'indication opératoire chirurgicale était posée pour tous les patients par arthrodèse postérieure lombo -sacree. Pour chaque patient 2 vis étaient positionnées soitun total de 20 vis. Un suivi clinique était réalisé de 28 a 36 mois. L'EVA et ODI diminuaient de 7,8 +/- 1,7 à 1,9 +/- 1,2 et de 62,3 +/- 17,2 à 15,1 +/- 6,0respectivement. L'ensemble des résultats était stable dans le temps en particulier à long terme.Conclusion: La fixation précise de la lyse isthmique améliore la symptomatologie et probablement évite un glissement vertébral plus important , un suivi à plus long terme surune serie de patients plus importante devrait confirmer cette hypothèse.

Prevalence of measured and reported multimorbidity in a representative sample of the Swiss population.

BACKGROUND: Little is known on the prevalence of multimorbidity (MM) in the general population. We aimed to assess the prevalence of MM using measured or self-reported data in the Swiss population. METHODS: Cross-sectional, population-based study conducted between 2003 and 2006 in the city of Lausanne, Switzerland, and including 3714 participants (1967 women) aged 35 to 75 years. Clinical evaluation was conducted by thoroughly trained nurses or medical assistants and the psychiatric evaluation by psychologists or psychiatrists. For psychiatric conditions, two definitions were used: either based on the participant's statements, or on psychiatric evaluation. MM was defined as presenting ≥2 morbidities out of a list of 27 (self-reported - definition A, or measured - definition B) or as the Functional Comorbidity Index (FCI) using measured data - definition C. RESULTS: The overall prevalence and (95% confidence interval) of MM was 34.8% (33.3%-36.4%), 56.3% (54.6%-57.9%) and 22.7% (21.4%-24.1%) for definitions A, B and C, respectively. Prevalence of MM was higher in women (40.2%, 61.7% and 27.1% for definitions A, B and C, respectively, vs. 28.7%, 50.1% and 17.9% in men, p < 0.001); Swiss nationals (37.1%, 58.8% and 24.8% for definitions A, B and C, respectively, vs. 31.4%, 52.3% and 19.7% in foreigners, all p < 0.001); elderly (>65 years: 67.0%, 70.0% and 36.7% for definitions A, B and C, respectively, vs. 23.6%, 50.2% and 13.8% for participants <45 years, p < 0.001); participants with lower educational level; former smokers and obese participants. Multivariate analysis confirmed most of these associations: odds ratio (95% Confidence interval) 0.55 (0.47-0.64), 0.61 (0.53-0.71) and 0.51 (0.42-0.61) for men relative to women for definitions A, B and C, respectively; 1.27 (1.09-1.49), 1.29 (1.11-1.49) and 1.41 (1.17-1.71) for Swiss nationals relative to foreigners, for definitions A, B and C, respectively. Conversely, no difference was found for educational level for definitions A and B and abdominally obese participants for all definitions. CONCLUSIONS: Prevalence of MM is high in the Lausanne population, and varies according to the definition or the data collection method.

PAR2 Promotes Vaccine-Induced Protection Against Helicobacter Infection in Mice.

BACKGROUND & AIMS: Protective immunization limits Helicobacter infection of mice by undetermined mechanisms. Protease-activated receptor 2 (PAR2) signaling is believed to regulate immune and inflammatory responses. We investigated the role of PAR2 in vaccine-induced immunity against Helicobacter infection. METHODS: Immune responses against Helicobacter infection were compared between vaccinated PAR2(-/-) and wild-type (WT) mice. Bacterial persistence, gastric pathology, and inflammatory and cellular responses were assessed using the rapid urease test (RUT), histologic analyses, quantitative polymerase chain reaction, and flow cytometry, respectively. RESULTS: Following vaccination, PAR2(-/-) mice did not have reductions in Helicobacter felis infection (RUT values were 0.01 ± 0.01 for WT mice and 0.11 ± 0.13 for PAR2(-/-) mice; P < .05). The vaccinated PAR2(-/-) mice had reduced inflammation-induced stomach tissue damage (tissue damage scores were 8.83 ± 1.47 for WT mice and 4.86 ± 1.35 for PAR2(-/-) mice; P < .002) and reduced T-helper (Th)17 responses, based on reduced urease-induced interleukin (IL)-17 secretion by stomach mononuclear cells (5182 ± 1265 pg/mL for WT mice and 350 ± 436 pg/mL for PAR2(-/-) mice; P < .03) and reduced recruitment of CD4(+) IL-17(+) T cells into the gastric mucosa of PAR2(-/-) mice following bacterial challenge (3.7% ± 1.5% for WT mice and 2.6% ± 1.1% for PAR2(-/-) mice; P < .05). In vitro, H felis-stimulated dendritic cells (DCs) from WT mice induced greater secretion of IL-17 by ovalbumin-stimulated OT-II transgenic CD4(+) T cells compared with DCs from PAR2(-/-) mice (4298 ± 347 and 3230 ± 779; P < .04), indicating that PAR2(-/-) DCs are impaired in priming of Th17 cells. Adoptive transfer of PAR2(+/+) DCs into vaccinated PAR2(-/-) mice increased vaccine-induced protection (RUT values were 0.11 ± 0.10 and 0.26 ± 0.15 for injected and noninjected mice, respectively; P < .03). CONCLUSIONS: PAR2 activates DCs to mediate vaccine-induced protection against Helicobacter infection in mice.

Clinical management and outcome of histologically verified adult brainstem gliomas in Switzerland: a retrospective analysis of 21 patients.

Because of low incidence, mixed study populations and paucity of clinical and histological data, the management of adult brainstem gliomas (BSGs) remains non-standardized. We here describe characteristics, treatment and outcome of patients with exclusively histologically confirmed adult BSGs. A retrospective chart review of adults (age >18 years) was conducted. BSG was defined as a glial tumor located in the midbrain, pons or medulla. Characteristics, management and outcome were analyzed. Twenty one patients (17 males; median age 41 years) were diagnosed between 2004 and 2012 by biopsy (n = 15), partial (n = 4) or complete resection (n = 2). Diagnoses were glioblastoma (WHO grade IV, n = 6), anaplastic astrocytoma (WHO grade III, n = 7), diffuse astrocytoma (WHO grade II, n = 6) and pilocytic astrocytoma (WHO grade I, n = 2). Diffuse gliomas were mainly located in the pons and frequently showed MRI contrast enhancement. Endophytic growth was common (16 vs. 5). Postoperative therapy in low-grade (WHO grade I/II) and high-grade gliomas (WHO grade III/IV) consisted of radiotherapy alone (three in each group), radiochemotherapy (2 vs. 6), chemotherapy alone (0 vs. 2) or no postoperative therapy (3 vs. 1). Median PFS (24.1 vs. 5.8 months; log-rank, p = 0.009) and mOS (30.5 vs. 11.5 months; log-rank, p = 0.028) was significantly better in WHO grade II than in WHO grade III/IV tumors. Second-line therapy considerably varied. Histologically verification of adult BSGs is feasible and has an impact on postoperative treatment. Low-grade gliomas can simple be followed or treated with radiotherapy alone. Radiochemotherapy with temozolomide can safely be prescribed for high-grade gliomas without additional CNS toxicities.

Cardiorenal end points in a trial of aliskiren for type 2 diabetes.

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Water-Stable Aggregates and Associated Carbon in a Subtropical Rice Soil Under Variable Tillage

ABSTRACT Tillage systems can influence C sequestration by changing aggregate formation and C distribution within the aggregate. This study was undertaken to explore the impact of no-tillage without straw (NT-S) and with straw (NT+S), and moldboard plow without straw (MP-S) and with straw (MP+S), on soil aggregation and aggregate-associated C after six years of double rice planting in a Hydragric Anthrosol in Guangxi, southwest of China. Soil samples of 0.00-0.05, 0.05-0.20 and 0.20-0.30 m layers were wet-sieved and divided into four aggregate-size classes, >2 mm, 2.00-0.25 mm, 0.25-0.053 and <0.053 mm, respectively, for measuring aggregate associated C and humic and fulvic acids. Results showed that the soil organic carbon (SOC) stock in bulk soil was 40.2-51.1 % higher in the 0.00-0.05 m layer and 11.3-17.0 % lower in the 0.05-0.20 m layer in NT system (NT+S and NT-S) compared to the MP system (MP+S and MP-S), respectively. However, no statistical difference was found across the whole 0.00-0.30 m layer. The NT system increased the proportion of >2 mm aggregate fraction and reduced the proportion of <0.053 mm aggregates in both 0.00-0.05 and 0.05-0.20 m layers. The SOC concentration, SOC stock and humic and fulvic acids within the >0.25 mm macroaggregate fraction also significantly increased in the 0.00-0.5 m layer in NT system. However, those within the 2.00-0.25 mm aggregate fraction were significantly reduced in the 0.05-0.200 m layer under NT system. Straw incorporation increased not only the SOC stock in bulk soil, but also the proportion of macroaggregate, aggregate associated with SOC and humic and fulvic acids concentration within the aggregate. The effect of straw on C sequestration might be dependent on the location of straw incorporation. In conclusion, the NT system increased the total SOC accumulation and humic and fulvic acids within macroaggregates, thus contributing to C sequestration in the 0.00-0.05 m layer.

Comparison of thermogenic activity induced by the new sympathomimetic Ro 16-8714 between normal and obese subjects.

In a previous study, we demonstrated that the new beta-adrenoceptor agonist Ro 16-8714 possesses thermogenic property in normal male volunteers. The aim of the present study was to compare the metabolic response of lean vs obese individuals to a similar dose of this compound. Following an overnight fast, Ro 16-8714 (0.17 mg/kg fat free mass) or a placebo was given per os to six normal-weight subjects and to six moderately obese subjects. The rate of energy expenditure (EE) and the substrate utilization were determined by indirect calorimetry (hood system) before and for 6 h following the drug administration. Heart rate and blood pressure as well as plasma glucose, insulin and free fatty acid (FFA) concentrations were also measured at regular intervals throughout the study. The increment relative to base-line (mean +/- s.e.m.) in EE was similar in the two groups and averaged 4.0 +/- 1.4 per cent and 12.2 +/- 1.4 per cent with placebo and with Ro 16-8714 respectively in lean subjects, whereas the values reached 3.5 +/- 1.2 per cent and 14.4 +/- 2.0 per cent in obese subjects. Heart rate, systolic blood pressure, insulin and FFA were increased without any significant difference between the two groups. This study shows that Ro 16-8714 is a potent thermogenic agent both in normal and obese subjects.