Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C

BACKGROUND/AIMS: While several risk factors for the histological progression of chronic hepatitis C have been identified, the contribution of HCV genotypes to liver fibrosis evolution remains controversial. The aim of this study was to assess independent predictors for fibrosis progression. METHODS: We identified 1189 patients from the Swiss Hepatitis C Cohort database with at least one biopsy prior to antiviral treatment and assessable date of infection. Stage-constant fibrosis progression rate was assessed using the ratio of fibrosis Metavir score to duration of infection. Stage-specific fibrosis progression rates were obtained using a Markov model. Risk factors were assessed by univariate and multivariate regression models. RESULTS: Independent risk factors for accelerated stage-constant fibrosis progression (>0.083 fibrosis units/year) included male sex (OR=1.60, [95% CI 1.21-2.12], P<0.001), age at infection (OR=1.08, [1.06-1.09], P<0.001), histological activity (OR=2.03, [1.54-2.68], P<0.001) and genotype 3 (OR=1.89, [1.37-2.61], P<0.001). Slower progression rates were observed in patients infected by blood transfusion (P=0.02) and invasive procedures or needle stick (P=0.03), compared to those infected by intravenous drug use. Maximum likelihood estimates (95% CI) of stage-specific progression rates (fibrosis units/year) for genotype 3 versus the other genotypes were: F0-->F1: 0.126 (0.106-0.145) versus 0.091 (0.083-0.100), F1-->F2: 0.099 (0.080-0.117) versus 0.065 (0.058-0.073), F2-->F3: 0.077 (0.058-0.096) versus 0.068 (0.057-0.080) and F3-->F4: 0.171 (0.106-0.236) versus 0.112 (0.083-0.142, overall P<0.001). CONCLUSIONS: This study shows a significant association of genotype 3 with accelerated fibrosis using both stage-constant and stage-specific estimates of fibrosis progression rates. This observation may have important consequences for the management of patients infected with this genotype.

The effect of pulsed jet lavage in vertebroplasty on injection forces of PMMA bone cement: an animal study

Percutaneous vertebroplasty, comprising of the injection of polymethylmethacrylate (PMMA) into vertebral bodies, is an efficient procedure to stabilize osteoporotic compression fractures as well as other weakening lesions. Besides fat embolism, cement leakage is considered to be one of the major and most severe complications during percutaneous vertebroplasty. The viscosity of the PMMA during injection plays a key role in this context. It was shown in vitro that the best way to lower the risk of cement leakage is to inject the cement at higher viscosity, which is requires high injection forces. Injection forces can be reduced by applying a newly developed lavage technique as it was shown in vitro using human cadaver vertebrae. The purpose of this study was to prove the in vitro results in an in vivo model. The investigation was incorporated in an animal study that was performed to evaluate the cardiovascular reaction on cement augmentation using the lavage technique. Injection forces were measured with instrumentation for 1 cc syringes, additionally acquiring plunger displacement. Averaged injection forces measured, ranged from 12 to 130 N and from 28 to 140 N for the lavage group and the control group, respectively. Normalized injection forces (by viscosity and injection speed) showed a trend to be lower for the lavage group in comparison to the control group (P = 0.073). In conclusion, the clinical relevance on the investigated lavage technique concerning lowering injection forces was only shown by trend in the performed animal study. However, it might well be that the effect is more pronounced for osteoporotic vertebral bodies.

An in-situ surface electrochemistry approach toward whole-cell studies: Charge transfer between Geobacter sulfurreducens and electrified metal/electrolyte interfaces through linker molecules

Electrochemical reactivity and structure properties of electrogenic bacteria, Geobacter sulfurreducens (Gs) were studied to explore the heterogeneous electron transfer at the bacteria/electrode interface using electrochemical and in-situ spectroscopic techniques. The redox behavior of Gs adsorbed on a gold electrode, which is modified with a ω-functionalized self-assembled monolayer (SAM) of alkanethiols, depends strongly on the terminal group. The latter interacts directly with outermost cytochromes embedded into the outer membrane of the Gs cells. The redox potential of bacterial cells bound electrostatically to a carboxyl-terminated SAM is close to that observed for bacteria attached to a bare gold electrode, revealing a high electronic coupling at the cell/SAM interface. The redox potentials of bacterial cells adsorbed on amino- and pyridyl-terminated SAMs are significantly different suggesting that the outermost cytochromes changes their conformation upon adsorption on these SAMs. No redox activity of Gs was found with CH3-, N(CH3)3+- and OH-terminated SAMs. Complementary in-situ spectroscopic studies on bacteria/SAMs/Au electrode assemblies were carried out to monitor structure changes of the bacterial cells upon polarization. Spectro-electrochemical techniques revealed the electrochemical turnover of the oxidized and reduced states of outer membrane cytochromes (OMCs) in Gs, providing evidence that the OMCs are responsible for the direct electron transfer to metal electrodes, such as gold or silver, during the electricity production. Furthermore, we observed spectroscopic signatures of the native structure of the OMCs and no conformational change during the oxidation/reduction process of the microorganisms. These findings indicate that the carboxyl-anchoring group provides biocompatible conditions for the outermost cytochromes of the Gs, which facilitate the heterogeneous electron transfer at the microorganism/electrode interface.

Frailty and risk for heart failure in older adults: the health, aging, and body composition study

OBJECTIVE The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. BACKGROUND Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. METHODS We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. RESULTS Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). CONCLUSIONS Frailty is independently associated with risk of HF in older adults.

Dreidimensionale Bewegungserfassung mit Consumer-Highspeedkameras: Eine Systementwicklung unter besonderer Berücksichtigung der Messunsicherheit

Schwerpunkt dieser Arbeit ist die Entwicklung und der Test eines auf Consumer-Highspeedkameras basierenden Bewegungserfassungssystems. Consumer-Kameras sind flexibler einsetzbar als kommerzielle Bewegungserfassungssysteme, zugleich kostengünstiger und werden daher oft in der sportwissenschaftlichen Forschung verwendet. Durch ihren Einsatz entstehen jedoch prinzipbedingt höhere Messunsicherheiten, deren Bestimmung in der vorliegenden Arbeit ein besonderer Stellenwert eingeräumt wird. Nach einem Überblick über aktuelle Bewegungserfassungssysteme und deren Genauigkeiten folgt eine Betrachtung der Messunsicherheit aus metrologischer Perspektive. Anschließend werden die Prozesse der Bilderfassung bei digitalen Consumer-Kameras sowie die zur Modellierung des Kameraabbildungsverhaltens notwendigen Parameteridentifikationsmethoden dargestellt. Diese reichen vom häufig genutzten DLT-Verfahren über Methoden mit Verzeichnungskorrektur bis zu Bündelausgleichsverfahren. Im Anschluss werden die für die verwendeten Kameras geeigneten Methoden auf Basis funktionaler Hardwaretests ausgewählt und weitere für das Bewegungserfassungssystem notwendige Softwarekomponenten diskutiert. Dazu gehören neben der automatisierten Video- und Bildverarbeitung, spezielle Verfahren zur Korrektur von Consumer-Kamera-spezifischen Abweichungen, z.B. die Korrektur von Rolling-Shutter-Verzerrungen. Im zweiten Teil der Arbeit richtet sich der Fokus auf die Simulation der Effekte von Parameterungenauigkeiten auf die Systemgenauigkeit sowie auf die Validierung und den Test des implementierten Systems. Dabei konnte die Rekonstruktionsgenauigkeit von 11.86mm bei einer Referenzrahmenkalibration durch den Einsatz der Kalibrationsmethode mit Bündelausgleichsverfahren von Svoboda u. a. (2005) auf maximal 4.126mm (M=0.073 mm; SD=1.486 mm) reduziert werden. Diese Methode erlaubt zudem eine einfachere Kalibration größerer Messvolumen ohne aufwändige Referenzrahmen und ist daher ideal für den sportwissenschaftlichen Einsatz geeignet. Ein weiteres Ergebnis der Arbeit ist die theoretische Ableitung der Fehlerfortpflanzung für die Prozessschritte der Bewegungserfassung. In Kombination mit der entwickelten Simulationsumgebung wird damit die Grundlage für eine Prädiktion der erreichbaren Messunsicherheit bereits vor der eigentlichen Messung gelegt.

How fluids bend: the elastic expansion for higher-dimensional black holes

Hydrodynamics can be consistently formulated on surfaces of arbitrary co-dimension in a background space-time, providing the effective theory describing long-wavelength perturbations of black branes. When the co-dimension is non-zero, the system acquires fluid-elastic properties and constitutes what is called a fluid brane. Applying an effective action approach, the most general form of the free energy quadratic in the extrinsic curvature and extrinsic twist potential of stationary fluid brane configurations is constructed to second order in a derivative expansion. This construction generalizes the Helfrich-Canham bending energy for fluid membranes studied in theoretical biology to the case in which the fluid is rotating. It is found that stationary fluid brane configurations are characterized by a set of 3 elastic response coefficients, 3 hydrodynamic response coefficients and 1 spin response coefficient for co-dimension greater than one. Moreover, the elastic degrees of freedom present in the system are coupled to the hydrodynamic degrees of freedom. For co-dimension-1 surfaces we find a 8 independent parameter family of stationary fluid branes. It is further shown that elastic and spin corrections to (non)-extremal brane effective actions can be accounted for by a multipole expansion of the stress-energy tensor, therefore establishing a relation between the different formalisms of Carter, Capovilla-Guven and Vasilic-Vojinovic and between gravity and the effective description of stationary fluid branes. Finally, it is shown that the Young modulus found in the literature for black branes falls into the class predicted by this approach - a relation which is then used to make a proposal for the second order effective action of stationary blackfolds and to find the corrected horizon angular velocity of thin black rings.

Laufzeitverlängerung von Atomkraftwerken - Nein, Danke!? Der Einfluss medialer Kommunikation auf Einstellungen zur Atomkraft

In dieser Studie wurde der Einfluss der individuellen Mediennutzung auf Einstellungen gegenüber Atomkraft am Beispiel der im Jahr 2010 geplanten Laufzeitverlängerung deutscher Atomkraftwerke untersucht. Die Studie wurde im Zwei-Methoden-Design durchgeführt. In einer repräsentativen Telefonbefragung wurden die Einstellungen und das Mediennutzungsverhalten von n=551 Thüringern erhoben. Die Argumente in der Berichterstattung für bzw. gegen eine Laufzeitverlängerung wurden durch eine quantitative Inhaltsanalyse von n=480 Medienbeiträgen erfasst. Bei der Datenverknüpfung wurden Variablen zum individuellen Medieninput an Argumenten aus der Berichterstattung gebildet. Auf Basis dieser Variablen wurden dann Einstellungseffekte geprüft. Die Befunde zeigten, dass der individuelle Medieninput an Argumenten die Einstellungen gegenüber Atomkraft sowohl mittel- als auch langfristig beeinflusste. Deutlich wurde auch, dass sich Einstellungen gegenüber der Laufzeitverlängerung besser durch generelle Einstellungen zu Atomkraft, Energie und Politik vorhersagen ließen, als durch die individuelle Nutzung medialer Kommunikationsinhalte.

L’archéologie entre glaciers et sommets. Dernières découvertes dans les Alpes Bernoises (Cantons de Berne et du Valais, Suisse)

Connus sous le nom populaire de palafittes, les habitats préhistoriques construits sur les rives des lacs subalpins du Néolithique à l’aube de l’âge du Fer (entre 5300 et 700 av. J.-C.) offrent des informations exceptionnelles sur l’évolution culturelle d’une importante région européenne, grâce à la préservation remarquable des matériaux organiques, en particulier du bois. À partir de la deuxième moitié du XXe siècle, le perfectionnement des techniques de fouille subaquatiques et de la dendrochronologie permettront la construction d’un schéma chronologique précis pour l’Europe nord-alpine. Les recherches contribueront à des observations d’ordre écologique à l’échelle locale et régionale et à l’identification des rythmes de développement des villages. Sous l’égide de l'UNESCO, les années 2010 verront la constitution d’un inventaire vaste et uniforme des sites préhistoriques des lacs circumalpins, classés Patrimoine culturel mondial en juin 2011. De nombreux objets préhistoriques, romains et médiévaux ont été découverts entre 2003 et 2010, au Schnidejoch, un col des Alpes bernoises occidentales à 2756 m d’altitude, à la frontière entre les cantons de Berne et du Valais. Les hautes températures de l'été 2003 ont provoqué la fonte d'un petit champ de glace et mis en lumière les vestiges. Les recherches ont été programmées à la suite d’une série d’informations fournies par des randonneurs. Les objets en matière organique (bois, écorce de bouleau, cuir, fibres végétales) revêtent une très grande importance car ils ont permis l’obtention de plus d’une cinquantaine de datations radiocarbone ; elles indiquent le passage du col entre la moitié du Ve millénaire av. J.-C. et l’année 1000 de notre ère. En outre, les séries de datations suggèrent l’alternance de périodes de praticabilité et d’inaccessibilité du col. Le Schnidejoch est actuellement le plus ancien témoignage de la traversée des Alpes, reliant l‘Oberland bernois par les vallées de la Simme et du Rhône.

Two Stable Equilibria of the Atlantic Subpolar Gyre

The cyclonic circulation of the Atlantic subpolar gyre is a key mechanism for North Atlantic climate variability on a wide range of time scales. It is generally accepted that it is driven by both cyclonic winds and buoyancy forcing, yet the individual importance and dynamical interactions of the two contributions remain unclear. The authors propose a simplified four-box model representing the convective basin of the Labrador Sea and its shallow and deep boundary current system, the western subpolar gyre. Convective heat loss drives a baroclinic flow of relatively light water around the dense center. Eddy salt flux from the boundary current to the center increases with a stronger circulation, favors the formation of dense waters, and thereby sustains a strong baroclinic flow, approximately 10%–25% of the total. In contrast, when the baroclinic flow is not active, surface waters may be too fresh to convect, and a buoyancy-driven circulation cannot develop. This situation corresponds to a second stable circulation mode. A hysteresis is found for variations in surface freshwater flux and the salinity of the near-surface boundary current. An analytical solution is presented and analyzed.

Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study.

BACKGROUND Clinical prognostic groupings for localised prostate cancers are imprecise, with 30-50% of patients recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in prostate cancer to improve risk stratification and complement clinical prognostic factors. METHODS We used DNA-based indices alone or in combination with intra-prostatic hypoxia measurements to develop four prognostic indices in 126 low-risk to intermediate-risk patients (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering Cancer Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk patients. We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying patients for risk of biochemical relapse 5 years after primary treatment. FINDINGS Biochemical relapse was associated with indices of tumour hypoxia, genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for prostate cancer, which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4·5 [95% CI 2·1-9·8]; p=0·00013; area under the receiver operator curve [AUC] 0·70 [95% CI 0·65-0·76]) and radical prostatectomy (4·0 [1·6-9·7]; p=0·0024; AUC 0·57 [0·52-0·61]) patients with prostate cancer, and its effect is magnified by intratumoral hypoxia (3·8 [1·2-12]; p=0·019; AUC 0·67 [0·61-0·73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6·1 [95% CI 2·0-19]; p=0·0015; AUC 0·74 [95% CI 0·65-0·83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk patients who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2·9 [95% CI 1·4-6·0]; p=0·0039; AUC 0·68 [95% CI 0·63-0·73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION This is the first study of cancer outcome to integrate DNA-based and microenvironment-based failure indices to predict patient outcome. Patients exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING Movember Foundation, Prostate Cancer Canada, Ontario Institute for Cancer Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, Cancer Research UK, Cambridge Cancer Charity, Prostate Cancer UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret Cancer Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian Cancer Society.

Antibiotic resistance and phylogenetic characterization of Acinetobacter baumannii strains isolated from commercial raw meat in Switzerland.

The spread of antibiotic-resistant bacteria through food has become a major public health concern because some important human pathogens may be transferred via the food chain. Acinetobacter baumannii is one of the most life-threatening gram-negative pathogens; multidrug-resistant (MDR) clones of A. baumannii are spreading worldwide, causing outbreaks in hospitals. However, the role of raw meat as a reservoir of A. baumannii remains unexplored. In this study, we describe for the first time the antibiotic susceptibility and fingerprint (repetitive extragenic palindromic PCR [rep-PCR] profile and sequence types [STs]) of A. baumannii strains found in raw meat retailed in Switzerland. Our results indicate that A. baumannii was present in 62 (25.0%) of 248 (CI 95%: 19.7 to 30.9%) meat samples analyzed between November 2012 and May 2013, with those derived from poultry being the most contaminated (48.0% [CI 95%: 37.8 to 58.3%]). Thirty-nine strains were further tested for antibiotic susceptibility and clonality. Strains were frequently not susceptible (intermediate and/or resistant) to third- and fourth-generation cephalosporins for human use (i.e., ceftriaxone [65%], cefotaxime [32%], ceftazidime [5%], and cefepime [2.5%]). Resistance to piperacillin-tazobactam, ciprofloxacin, colistin, and tetracycline was sporadically observed (2.5, 2.5, 5, and 5%, respectively), whereas resistance to carbapenems was not found. The strains were genetically very diverse from each other and belonged to 29 different STs, forming 12 singletons and 6 clonal complexes (CCs), of which 3 were new (CC277, CC360, and CC347). RepPCR analysis further distinguished some strains of the same ST. Moreover, some A. baumannii strains from meat belonged to the clonal complexes CC32 and CC79, similar to the MDR isolates responsible for human infections. In conclusion, our findings suggest that raw meat represents a reservoir of MDR A. baumannii and may serve as a vector for the spread of these pathogens into both community and hospital settings.

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.