Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) estimates the risk of 30-day mortality in patients with acute pulmonary embolism (PE). We constructed a simplified version of the PESI. METHODS: The study retrospectively developed a simplified PESI clinical prediction rule for estimating the risk of 30-day mortality in a derivation cohort of Spanish outpatients. Simplified and original PESI performances were compared in the derivation cohort. The simplified PESI underwent retrospective external validation in an independent multinational cohort (Registro Informatizado de la Enfermedad Tromboembólica [RIETE] cohort) of outpatients. RESULTS: In the derivation data set, univariate logistic regression of the original 11 PESI variables led to the removal of variables that did not reach statistical significance and subsequently produced the simplified PESI that contained the variables of age, cancer, chronic cardiopulmonary disease, heart rate, systolic blood pressure, and oxyhemoglobin saturation levels. The prognostic accuracy of the original and simplified PESI scores did not differ (area under the curve, 0.75 [95% confidence interval (CI), 0.69-0.80]). The 305 of 995 patients (30.7%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.0% (95% CI, 0.0%-2.1%) compared with 10.9% (8.5%-13.2%) in the high-risk group. In the RIETE validation cohort, 2569 of 7106 patients (36.2%) who were classified as low risk by the simplified PESI had a 30-day mortality of 1.1% (95% CI, 0.7%-1.5%) compared with 8.9% (8.1%-9.8%) in the high-risk group. CONCLUSION: The simplified PESI has similar prognostic accuracy and clinical utility and greater ease of use compared with the original PESI.

Detailed 3D seismic imaging of a fault zone beneath Lake Geneva, Switzerland

An efficient high-resolution (HR) three-dimensional (3D) seismic reflection system for small-scale targets in lacustrine settings was developed. In Lake Geneva, near the city of Lausanne, Switzerland, the offshore extension of a complex fault zone well mapped on land was chosen for testing our system. A preliminary two-dimensional seismic survey indicated structures that include a thin (<40 m) layer of subhorizontal Quaternary sediments that unconformably overlie south-east-dipping Tertiary Molasse beds and a major fault zone (Paudeze Fault Zone) that separates Plateau and Subalpine Molasse (SM) units. A 3D survey was conducted over this test site using a newly developed three-streamer system. It provided high-quality data with a penetration to depths of 300 m below the water bottom of non-aliased signal for dips up to 30degrees and with a maximum vertical resolution of 1.1 m. The data were subjected to a conventional 3D processing sequence that included post-stack time migration. Tests with 3D pre-stack depth migration showed that such techniques can be applied to HR seismic surveys. Delineation of several horizons and fault surfaces reveals the potential for small-scale geologic and tectonic interpretation in three dimensions. Five major seismic facies and their detailed 3D geometries can be distinguished. Three fault surfaces and the top of a molasse surface were mapped in 3D. Analysis of the geometry of these surfaces and their relative orientation suggests that pre-existing structures within the Plateau Molasse (PM) unit influenced later faulting between the Plateau and SM. In particular, a change in strike of the PM bed dip may indicate a fold formed by a regional stress regime, the orientation of which was different from the one responsible for the creation of the Paudeze Fault Zone. This structure might have later influenced the local stress regime and caused the curved shape of the Paudeze Fault in our surveyed area.

Anti-doping testing at the 2008 European football championship.

Big sports events like the 2008 European Football Championship are a challenge for anti-doping activities, particularly when the sports event is hosted by two different countries and there are two laboratories accredited by the World Anti-Doping Agency. This challenges the logistics of sample collection as well as the chemical analyses, which must be carried out timeously. The following paper discusses the handling of whereabouts information for each athlete and the therapeutic use exemption system, experiences in sample collection and transportation of blood and urine samples, and the results of the chemical analysis in two different accredited laboratories. An overview of the analytical results of blood profiling and growth hormone testing in comparison with the distribution of the normal population is also presented.

A Missense Mutation in PRPF6 Causes Impairment of pre-mRNA Splicing and Autosomal-Dominant Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is an inherited form of retinal degeneration that leads to progressive visual-field constriction and blindness. Although the disease manifests only in the retina, mutations in ubiquitously expressed genes associated with the tri-snRNP complex of the spliceosome have been identified in patients with dominantly inherited RP. We screened for mutations in PRPF6 (NM_012469.3), a gene on chromosome 20q13.33 encoding an essential protein for tri-snRNP assembly and stability, in 188 unrelated patients with autosomal-dominant RP and identified a missense mutation, c.2185C>T (p.Arg729Trp). This change affected a residue that is conserved from humans to yeast and cosegregated with the disease in the family in which it was identified. Lymphoblasts derived from patients with this mutation showed abnormal localization of endogenous PRPF6 within the nucleus. Specifically, this protein accumulated in the Cajal bodies, indicating a possible impairment in the tri-snRNP assembly or recycling. Expression of GFP-tagged PRPF6 in HeLa cells showed that this phenomenon depended exclusively on the mutated form of the protein. Furthermore, analysis of endogenous transcripts in cells from patients revealed intron retention for pre-mRNA bearing specific splicing signals, according to the same pattern displayed by lymphoblasts with mutations in other PRPF genes. Our results identify PRPF6 as the sixth gene involved in pre-mRNA splicing and dominant RP, corroborating the hypothesis that deficiencies in the spliceosome play an important role in the molecular pathology of this disease.

A clinical prognostic model for the identification of low-risk patients with acute symptomatic pulmonary embolism and active cancer.

BACKGROUND: Physicians need a specific risk-stratification tool to facilitate safe and cost-effective approaches to the management of patients with cancer and acute pulmonary embolism (PE). The objective of this study was to develop a simple risk score for predicting 30-day mortality in patients with PE and cancer by using measures readily obtained at the time of PE diagnosis. METHODS: Investigators randomly allocated 1,556 consecutive patients with cancer and acute PE from the international multicenter Registro Informatizado de la Enfermedad TromboEmbólica to derivation (67%) and internal validation (33%) samples. The external validation cohort for this study consisted of 261 patients with cancer and acute PE. Investigators compared 30-day all-cause mortality and nonfatal adverse medical outcomes across the derivation and two validation samples. RESULTS: In the derivation sample, multivariable analyses produced the risk score, which contained six variables: age > 80 years, heart rate ≥ 110/min, systolic BP < 100 mm Hg, body weight < 60 kg, recent immobility, and presence of metastases. In the internal validation cohort (n = 508), the 22.2% of patients (113 of 508) classified as low risk by the prognostic model had a 30-day mortality of 4.4% (95% CI, 0.6%-8.2%) compared with 29.9% (95% CI, 25.4%-34.4%) in the high-risk group. In the external validation cohort, the 18% of patients (47 of 261) classified as low risk by the prognostic model had a 30-day mortality of 0%, compared with 19.6% (95% CI, 14.3%-25.0%) in the high-risk group. CONCLUSIONS: The developed clinical prediction rule accurately identifies low-risk patients with cancer and acute PE.

Fracture imaging within a granitic rock aquifer using multiple-offset single-hole and cross-hole GPR reflection data

The sparsely spaced highly permeable fractures of the granitic rock aquifer at Stang-er-Brune (Brittany, France) form a well-connected fracture network of high permeability but unknown geometry. Previous work based on optical and acoustic logging together with single-hole and cross-hole flowmeter data acquired in 3 neighbouring boreholes (70-100 m deep) has identified the most important permeable fractures crossing the boreholes and their hydraulic connections. To constrain possible flow paths by estimating the geometries of known and previously unknown fractures, we have acquired, processed and interpreted multifold, single- and cross-hole GPR data using 100 and 250 MHz antennas. The GPR data processing scheme consisting of timezero corrections, scaling, bandpass filtering and F-X deconvolution, eigenvector filtering, muting, pre-stack Kirchhoff depth migration and stacking was used to differentiate fluid-filled fracture reflections from source generated noise. The final stacked and pre-stack depth-migrated GPR sections provide high-resolution images of individual fractures (dipping 30-90°) in the surroundings (2-20 m for the 100 MHz antennas; 2-12 m for the 250 MHz antennas) of each borehole in a 2D plane projection that are of superior quality to those obtained from single-offset sections. Most fractures previously identified from hydraulic testing can be correlated to reflections in the single-hole data. Several previously unknown major near vertical fractures have also been identified away from the boreholes.

Impact of Pre-Existing Immunity on the Selection of Rare Adenovirus Vector Candidates: Implications for HIV Vaccine Development

Background: Adenovirus serotype 5 (Ad5) phase IIb vaccine trial (STEP) was prematurely stopped due to a lack of efficacy and two-fold higher incidence of HIV infection among Ad5 seropositive vaccine recipients. We have recently demonstrated that Ad5 immune complexes (Ad5 ICs)-mediated activation of the dendritic cell (DC)-T cell axis was associated with the enhancement of HIV infection in vitro. Although the direct role of Ad5 neutralizing antibodies (NAbs) in the increase of HIV susceptibility during the STEP trial is still under debate, vector-specific NAbs remain a major hurdle for vector-based gene therapies or vaccine strategies. To surmount this obstacle, vectors based on ''rare'' Ad serotypes including Ad6, Ad26, Ad36 and Ad41 were engineered.Methods: The present study aimed to determine whether Ad ICmediated DC maturation could be circumvented using these Advector candidates.Results: We found that all Ad vectors tested forming ICs with plasma containing serotype-specific NAbs had the capacity to 1) mature human DCs as monitored by the up-regulation of costimulatory molecules and the release of pro-inflammatory cytokines (TNF-a), via the stabilization of Ad capsid at endosomal but not lysosomal pH rendering Ad DNA/TLR9 interactions possible and 2) potentiate Ad-specific CD4 and CD8 T cell responses.Conclusion: In conclusion, despite a conserved DC maturation potential, the low prevalence of serotype-specific NAbs renders rare Ad vectors attractive for vaccine strategies.

Bénéfices de l'utilisation d'un test VIH rapide à la permanence PMU-FLON [Benefits of using rapid HIV testing at the PMU-FLON walk-in clinic in Lausanne].

Lab tests are frequently used in primary care to guide patient care. This is particularly the case when a severe disorder, or one that will affect patients' initial care, needs to be excluded rapidly. At the PMU-FLON walk-in clinic the use of HIV testing as recommended by the Swiss Office of Public Health was hampered by the delay in obtaining test results. This led us to introduce rapid HIV testing which provides results within 30 minutes. Following the first 250 tests the authors discuss the results as well as the benefits of rapid HIV testing in an urban walk-in clinic.

Discriminant validity and test-retest reliability of a self-administered Internet-based questionnaire testing doctors' knowledge in evidence-based medicine.

Aims and objectives  This study aimed to determine the discriminant validity and the test-retest reliability of a questionnaire testing the impact of evidence-based medicine (EBM) training on doctors' knowledge and skills. Methods  Questionnaires were sent electronically to all doctors working as residents and chief residents in two French speaking hospital networks in Switzerland. Participants completed the questionnaire twice, within a 4-week interval. The discriminant validity was examined in comparing doctors' performance according to their reported EBM previous training. Proportion of agreement between both sessions of the questionnaire, Cohen's kappa and 'uniform kappa' determined its test-retest reliability. Results  The participation rate was 9.8%/7.1% to first/second session. Performance increased according to the level of doctors' previous training in EBM. The observed proportion of agreement between both sessions was over 70% for 14/19 questions, and the 'uniform kappa' was superior to 0.60 for 15/19 questions. Conclusion  The discriminant validity and test-retest reliability of the questionnaire were satisfying. The low participation rate did not prevent the study from achieving its aims.

Sudden death: ethical and legal problems of post-mortem forensic genetic testing for hereditary cardiac diseases.

Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young. In these cases, genetic testing can be useful and does not require proxy consent if it is carried out at the request of judicial authorities as part of a forensic death investigation. Mutations in several genes are implicated in arrhythmic syndromes, including SCN5A, KCNQ1, KCNH2, RyR2, and genes causing HCM. If the victim's test is positive, this information is important for relatives who might be themselves at risk of carrying the disease-causing mutation. There is no consensus about how professionals should proceed in this context. This article discusses the ethical and legal arguments in favour of and against three options: genetic testing of the deceased victim only; counselling of relatives before testing the victim; counselling restricted to relatives of victims who tested positive for mutations of serious and preventable diseases. Legal cases are mentioned that pertain to the duty of geneticists and other physicians to warn relatives. Although the claim for a legal duty is tenuous, recent publications and guidelines suggest that geneticists and others involved in the multidisciplinary approach of sudden death (SD) cases may, nevertheless, have an ethical duty to inform relatives of SD victims. Several practical problems remain pertaining to the costs of testing, the counselling and to the need to obtain permission of judicial authorities.

Is a pre-anaesthetic information form really useful ?

Background: All patients should be fully informed about the risks and benefits of anaesthetic procedures before giving a written consent. Moreover, the satisfaction level may vary in proportion to the information given. We aimed to determine, in a single-blind randomized-controlled study, whether an information form given before the pre-anaesthetic consultation could improve perceived information, information gain and satisfaction level. Methods: Two hundred patients ASA 1-3 scheduled for an elective orthopaedic surgery were randomized into two groups: a group that received an information form before the pre-anaesthetic consultation (IF group) and a control group (no information form). A standardized questionnaire was submitted after the pre-anaesthetic consultation and after the operation. This 17-item questionnaire explored perceived information (five items), information gain (three items) and satisfaction level (nine items). The items of each topic were pooled and compared between groups. Results: One hundred and eighty-five patients (92.5%) completed the study. The IF group had better perceived information (IF group 73% vs. control group 63%, P=0.002), higher information gain (IF group 75% vs. control group 62%, P=0.001) and a higher satisfaction level (IF group 95% vs. control group 92%, P=0.048). Conclusions: Our study suggests that an information form given before the pre-anaesthetic consultation enhances perceived information, information gain and satisfaction level. Méthode Cette étude prospective randomisée en simple aveugle a été conduite à l'hôpital Orthopédique du Centre Hospitalier Universitaire Vaudois. Deux cents patients prévus pour une chirurgie élective orthopédique ont été recrutés entre avril et juin 2008 et repartis en deux groupes selon une table de randomisation : un groupe recevait une feuille d'information 30 minutes avant la consultation préanesthésique, et l'autre pas. Les patients des deux groupes étaient ensuite examinés à la consultation preoperatoire par un anesthésiste indépendant de l'étude, puis recevaient un questionnaire standardisé. Ce questionnaire, issu de questionnaires existants, et validé préalablement sur un échantillon de 50 patients, comportait 17 questions qui exploraient la perception- de l'information (5 questions), le gain d'information (3 questions) et le niveau de satisfaction (9 questions) Parmi ces 17 questions, 3 étaient posées 24 h après l'intervention chirurgicale lors d'une visite dans la chambre ou lors d'un contact téléphonique. Les réponses étaient analysées et comparées entre les deux groupes. Résultats Cent huitante-cinq patients ont terminé l'étude. Le groupe qui a reçu la feuille d'information avait une meilleure perception de l'information (73% vs 63% dans le groupe de contrôle, ρ = 0 002) un gain d'information plus élevé (75% vs. 62% dans le groupe de contrôle, ρ = 0.001) et un niveau de satisfaction plus élevé (95% vs. 92% dans le groupe de contrôle, ρ= 0.048). Discussion et conclusion Cette étude a permis de démontrer que la remise d'une feuille d'information explicative avant la consultation préanesthésique était un moyen simple et bon marché pour améliorer la perception de l'information et le niveau de satisfaction.