Implications of using different methods to characterise anticoagulant control in patients with second generation mechanical heart valve prostheses.

OBJECTIVE:Characterisation of anticoagulant control is fundamental to investigations of its association with clinical outcome. Anticoagulant control depends on several factors. This paper aims to illustrate the implications of different methods for measuring and analysing anticoagulant control in patients with second generation mechanical heart valve prostheses. METHODS:International normalised ratio (INR) data collected during the 10-year follow-up of a randomised controlled trial were analysed. We considered the influence of: 3 different target INR ranges; anticoagulant control expressed as the proportion of INR readings (PoR) vs. anticoagulant control follow-up time (PoT); 3 ways of describing the profile of anticoagulant control over time. RESULTS:Different target INR ranges dramatically influenced derived measures of anticoagulant control; the PoT within the target range varied from 88% for the widest to 28% for narrowest range. Overall distributions of PoR and PoT observations were similar but differed by up to ± 20% for individuals; PoT exceeded PoR when control was good but was less than PoR when control was poor. Classifying PoT outside the target range showed that widely varying combinations of PoT too high and too low are possible across individuals. CONCLUSIONS:Researchers' choices about methods for measuring and quantifying anticoagulant control markedly influence the values derived from INR readings. The use of different methods across studies makes it difficult or impossible to compare findings and to establish an evidence base for clinical practice. Methods for quantifying anticoagulant control should be standardised

Polynomials, Riemann surfaces, and reconstructing missing-energy events

We consider the problem of reconstructing energies, momenta, and masses in collider events with missing energy, along with the complications introduced by combinatorial ambiguities and measurement errors. Typically, one reconstructs more than one value and we show how the wrong values may be correlated with the right ones. The problem has a natural formulation in terms of the theory of Riemann surfaces. We discuss examples including top quark decays in the Standard Model (relevant for top quark mass measurements and tests of spin correlation), cascade decays in models of new physics containing dark matter candidates, decays of third-generation leptoquarks in composite models of electroweak symmetry breaking, and Higgs boson decay into two tau leptons.Comment: 28 pages, 6 figures; version accepted for publication, with discussion of Higgs to tau tau deca

Exploring the roles of urinary HAI-1, EpCAM and EGFR in bladder cancer prognosis and risk stratification

Objectives: To investigate whether elevated urinary HAI-1, EpCAM and EGFR are independent prognostic biomarkers within non-muscle-invasive bladder cancer (NMIBC) patients, and have utility for risk stratification to facilitate treatment decisions. Results: After accounting for EAU risk group in NMIBC patients, the risk of BC-specific death was 2.14 times higher (95% CI: 1.08 to 4.24) if HAI-1 was elevated and 2.04 times higher (95% CI: 1.02 to 4.07) if EpCAM was elevated. The majority of events occurred in the high-risk NMIBC group and this is where the biggest difference is seen in the survival curves when plotted for EAU risk groups separately. In MIBC patients, being elevated for any of the three biomarkers was significantly associated with BC-specific mortality after accounting for other risk factors, HR = 4.30 (95% CI: 1.85 to 10.03). Patients and Methods: Urinary levels of HAI-1, EpCAM and EGFR were measured by ELISA in 683 and 175 patients with newly-diagnosed NMIBC and MIBC, respectively, recruited to the Bladder Cancer Prognosis Programme. Associations between biomarkers and progression, BC-specific mortality and all-cause mortality were evaluated using univariable and multivariable Cox regression models, adjusted for European Association of Urology (EAU) NMIBC risk groups. The upper 25% of values for each biomarker within NMIBC patients were considered as elevated. Exploratory analyses in urine from MIBC patients were also undertaken. Conclusion: Urinary HAI-1 and EpCAM are prognostic biomarkers for NMIBC patients. These biomarkers have potential to guide treatment decisions for high-risk NMIBC patients. Further analyses are required to define the roles of HAI-1, EpCAM and EGFR in MIBC patients

Persistence in epidemic metapopulations: quantifying the rescue effects for measles, mumps, rubella and whooping cough

Metapopulation rescue effects are thought to be key to the persistence of many acute immunizing infections. Yet the enhancement of persistence through spatial coupling has not been previously quantified. Here we estimate the metapopulation rescue effects for four childhood infections using global WHO reported incidence data by comparing persistence on island countries vs all other countries, while controlling for key variables such as vaccine cover, birth rates and economic development. The relative risk of extinction on islands is significantly higher, and approximately double the risk of extinction in mainland countries. Furthermore, as may be expected, infections with longer infectious periods tend to have the strongest metapopulation rescue effects. Our results quantitate the notion that demography and local community size controls disease persistence

Propofol cardioplegia: A single-center, placebo-controlled, randomized controlled trial

OBJECTIVES: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is an effective treatment for coronary artery and aortic valve diseases. However, the myocardium sustains reperfusion injury after ischemic cardioplegic arrest. Our objective was to assess the benefits of supplementing cardioplegia solution with the general anesthetic propofol in patients undergoing either coronary artery bypass grafting (CABG) or aortic valve replacement (AVR). METHODS: A single-center, double-blind randomized controlled trial was carried out to compare cardioplegia solution supplemented with propofol (concentration 6 μg/mL) versus intralipid (placebo). The primary outcome was cardiac troponin T release over the first 48 hours after surgery. RESULTS: We recruited 101 participants (51 in the propofol group, 50 in the intralipid group); 61 underwent CABG and 40 underwent AVR. All participants were followed to 3 months. Cardiac troponin T release was on average 15% lower with propofol supplementation (geometric mean ratio, 0.85; 95% confidence interval [CI], 0.73-1.01; P = .051). There were no differences for CABG participants but propofol-supplemented participants undergoing AVR had poorer postoperative renal function (geometric mean ratio, 1.071; 95% CI, 1.019-1.125; P = .007), with a trend toward longer intensive care stay (median, 89.5 vs 47.0 hours; hazard ratio, 0.58; 95% CI, 0.31-1.09; P = .09) and fewer with perfect health (based on the EQ-5D health utility index) at 3 months (odds ratio, 0.26; 95% CI, 0.06-1.05; P = .058) compared with the intralipid group. Safety profiles were similar. There were no deaths. CONCLUSIONS: Propofol supplementation in cardioplegia appears to be cardioprotective. Its influence on early clinical outcomes may differ between CABG and AVR surgery. A larger, multicenter study is needed to confirm or refute these suggestions

siRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo

Oncogene-specific downregulation mediated by RNA interference (RNAi) is a promising avenue for cancer therapy. In addition to specific gene silencing, in vivo RNAi treatment with short interfering RNAs (siRNAs) can initiate immune activation through innate immune receptors including Toll-like receptors, (TLRs) 7 and 8. Two recent studies have shown that activation of innate immunity by addition of tri-phosphate motifs to oncogene-specific siRNAs, or by co-treatment with CpG oligos, can potentiate siRNA antitumor effects. To date, there are no reports on applying such approach against human papillomavirus (HPV)-driven cancers. Here, we characterized the antitumor effects of non-modified siRNAs that can target a specific oncogene and/or recruit the innate immune system against HPV-driven tumors. Following the characterization of silencing efficacy and TLR7 immunostimulatory potential of 15 siRNAs targeting the HPV type 16 E6/E7 oncogenes, we identified a bifunctional siRNA sequence that displayed both potent gene silencing and active immunostimulation effect. In vivo systemic administration of this siRNA resulted in reduced growth of established TC-1 tumors in C57BL/6 mice. Ablation of TLR7 recruitment via 2′O-methyl modification of the oligo backbone reduced these antitumor effects. Further, a highly immunostimulatory, but non-HPV targeting siRNA was also able to exert antitumoral effects although for less prolonged time compared with the bifunctional siRNA. Collectively, our work demonstrates for the first time that siRNA-induced immunostimulation can have antitumoral effects against HPV-driven tumors in vivo, even independent of gene silencing efficacy

Control of telomere length by a trimming mechanism that involves generation of t-circles

Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric circles (t-circles). Telomeric DNA was observed in promyelocytic leukemia bodies, but no intertelomeric copying or telomere exchange events were identified, and there was no increase in telomere dysfunction-induced foci. These data indicate that human cells possess a mechanism to negatively regulate telomere length by trimming telomeric DNA from the chromosome ends, most likely by t-loop resolution to form t-circles. Additionally, these results indicate that some phenotypic characteristics attributed to alternative lengthening of telomeres (ALT) result from increased mean telomere length, rather than from the ALT mechanism itself

Controls on the cadmium isotope composition of modern marine sediments

Continental margin sediments have been identified as the dominant sink in the marine budget of cadmium (Cd). The isotopic composition of this important output flux is, however, unknown. Here we present, with measurements on the Argentine continental margin, the first observational constraints on the isotopic composition of Cd in modern marine oxic and sub-oxic sediments. We identify two main removal mechanisms of Cd; in organic material, and by sulfide formation. Surface margin sediments (0–0.5 cm), with dissolved O2 below detection from ∼0.5 cm, are isotopically lighter than overlying oxygenated waters. A mass balance for these surface sediments indicates that Cd is present dominantly as organically-bound particulate Cd. In sub-surface sediments, Cd concentrations increase in the zone of nitrate reduction, and attain similar isotopic compositions as the water that overlies the sediment (i.e. ∼0.35‰ in deep waters). These observations are consistent with a downward diffusive flux of seawater Cd and redox-driven quantitative removal of that Cd during sulfide precipitation. In combination, these two routes of Cd removal lead to burial of isotopically light organic Cd in margin sub-oxic sediments that enables the global isotopic Cd budget to be balanced

Destabilization of the thermohaline circulation by transient perturbations to the hydrological cycle

We reconsider the problem of the stability of the thermohaline circulation as described by a two-dimensional Boussinesq model with mixed boundary conditions. We determine how the stability properties of the system depend on the intensity of the hydrological cycle. We define a two-dimensional parameters' space descriptive of the hydrology of the system and determine, by considering suitable quasi-static perturbations, a bounded region where multiple equilibria of the system are realized. We then focus on how the response of the system to finite-amplitude surface freshwater forcings depends on their rate of increase. We show that it is possible to define a robust separation between slow and fast regimes of forcing. Such separation is obtained by singling out an estimate of the critical growth rate for the anomalous forcing, which can be related to the characteristic advective time scale of the system.Comment: 37 pages, 8 figures, submitted to Clim. Dy