A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacologic therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. Clinical Trial Registration - http://clinicaltrials.gov Unique identifier: NCT01873950

Perturbations of nuclear C*-algebras

Kadison and Kastler introduced a natural metric on the collection of all C*-subalgebras of the bounded operators on a separable Hilbert space. They conjectured that sufficiently close algebras are unitarily conjugate. We establish this conjecture when one algebra is separable and nuclear. We also consider one-sided versions of these notions, and we obtain embeddings from certain near inclusions involving separable nuclear C*-algebras. At the end of the paper we demonstrate how our methods lead to improved characterisations of some of the types of algebras that are of current interest in the classification programme.Comment: 45 page

In vivo investigation of ear canal pulse oximetry during hypothermia

Pulse oximeters rely on the technique of photoplethysmography (PPG) to estimate arterial oxygen saturation (SpO(Formula presented.)). In conditions of poor peripheral perfusion such as hypotension, hypothermia, and vasoconstriction, the PPG signals detected are often weak and noisy, or in some cases unobtainable. Hence, pulse oximeters produce erroneous SpO(Formula presented.) readings in these circumstances. The problem arises as most commercial pulse oximeter probes are designed to be attached to peripheral sites such as the finger or toe, which are easily affected by vasoconstriction. In order to overcome this problem, the ear canal was investigated as an alternative site for measuring reliable SpO(Formula presented.) on the hypothesis that blood flow to this central site is preferentially preserved. A novel miniature ear canal PPG sensor was developed along with a state of the art PPG processing unit to investigate PPG measurements from the bottom surface of the ear canal. An in vivo study was carried out in 15 healthy volunteers to validate the developed technology. In this comparative study, red and infrared PPGs were acquired from the ear canal and the finger of the volunteers, whilst they were undergoing artificially induced hypothermia by means of cold exposure (10 (Formula presented.)C). Normalised Pulse Amplitude (NPA) and SpO(Formula presented.) was calculated from the PPG signals acquired from the ear canal and the finger. Good quality baseline PPG signals with high signal-to-noise ratio were obtained from both the PPG sensors. During cold exposure, significant differences were observed in the NPA of the finger PPGs. The mean NPA of the red and infrared PPGs from the finger have dropped by >80%. Contrary to the finger, the mean NPA of red and infrared ear canal PPGs had dropped only by 0.2 and 13% respectively. The SpO(Formula presented.)s estimated from the finger sensor have dropped below 90% in five volunteers (failure) by the end of the cold exposure. The ear canal sensor, on the other hand, had only failed in one volunteer. These results strongly suggest that the ear canal may be used as a suitable alternative site for monitoring PPGs and arterial blood oxygen saturation at times were peripheral perfusion is compromised

The Impact of Global Warming and Anoxia on Marine Benthic Community Dynamics: an Example from the Toarcian (Early Jurassic)

The Pliensbachian-Toarcian (Early Jurassic) fossil record is an archive of natural data of benthic community response to global warming and marine long-term hypoxia and anoxia. In the early Toarcian mean temperatures increased by the same order of magnitude as that predicted for the near future; laminated, organic-rich, black shales were deposited in many shallow water epicontinental basins; and a biotic crisis occurred in the marine realm, with the extinction of approximately 5% of families and 26% of genera. High-resolution quantitative abundance data of benthic invertebrates were collected from the Cleveland Basin (North Yorkshire, UK), and analysed with multivariate statistical methods to detect how the fauna responded to environmental changes during the early Toarcian. Twelve biofacies were identified. Their changes through time closely resemble the pattern of faunal degradation and recovery observed in modern habitats affected by anoxia. All four successional stages of community structure recorded in modern studies are recognised in the fossil data (i.e. Stage III: climax; II: transitional; I: pioneer; 0: highly disturbed). Two main faunal turnover events occurred: (i) at the onset of anoxia, with the extinction of most benthic species and the survival of a few adapted to thrive in low-oxygen conditions (Stages I to 0) and (ii) in the recovery, when newly evolved species colonized the re-oxygenated soft sediments and the path of recovery did not retrace of pattern of ecological degradation (Stages I to II). The ordination of samples coupled with sedimentological and palaeotemperature proxy data indicate that the onset of anoxia and the extinction horizon coincide with both a rise in temperature and sea level. Our study of how faunal associations co-vary with long and short term sea level and temperature changes has implications for predicting the long-term effects of “dead zones” in modern oceans

Improvements in survival of the uncemented Nottingham Total Shoulder prosthesis: a prospective comparative study

<p>Abstract</p> <p>Background</p> <p>The uncemented Nottingham Total Shoulder Replacement prosthesis system (Nottingham TSR) was developed from the previous BioModular^®shoulder prosthesis taking into consideration the causes of the initial implant's failure.</p> <p>We investigated the impact of changes in the design of Nottingham TSR prosthesis on its survivorship rate.</p> <p>Methods</p> <p>Survivorship analyses of three types of uncemented total shoulder arthroplasty prostheses (BioModular^®, initial Nottingham TSR and current Nottingham TSR systems with 11, 8 and 4 year survivorship data respectively) were compared. All these prostheses were implanted for the treatment of disabling pain in the shoulder due to primary and secondary osteoarthritis or rheumatoid arthritis. Each type of the prosthesis studied was implanted in consecutive group of patients – 90 patients with BioModular^®system, 103 with the initial Nottingham TSR and 34 patients with the current Nottingham TSR system.</p> <p>The comparison of the annual cumulative survivorship values in the compatible time range between the three groups was done according to the paired <it>t </it>test.</p> <p>Results</p> <p>The 8-year and 11-year survivorship rates for the initially used modified BioModular^®uncemented prosthesis were relatively low (75.6% and 71.7% respectively) comparing to the reported survivorship of the conventional cemented implants. The 8-year survivorship for the uncemented Nottingham TSR prosthesis was significantly higher (81.8%), but still not in the desired range of above 90%, that is found in other cemented designs. Glenoid component loosening was the main factor of prosthesis failure in both prostheses and mainly occurred in the first 4 postoperative years. The 4-year survivorship of the currently re-designed Nottingham TSR prosthesis, with hydroxylapatite coating of the glenoid baseplate, was significantly higher, 93.1% as compared to 85.1% of the previous Nottingham TSR.</p> <p>Conclusion</p> <p>The initial Nottingham shoulder prosthesis showed significantly higher survivorship than the BioModular^®uncemented prosthesis, but lower than expected. Subsequently re-designed Nottingham TSR system presented a high short term survivorship rate that encourages its ongoing use</p

Reducing unnecessary prescriptions of antibiotics for acute cough: Adaptation of a leaflet aimed at Turkish immigrants in Germany

<p>Abstract</p> <p>Background</p> <p>The reduction in the number of unnecessary prescriptions of antibiotics has become one of the most important objectives for primary health care. German GPs report that they are under "pressure to prescribe" antibiotics particularly in consultations with Turkish immigrants. And so a qualitative approach was used to learn more about the socio-medical context of Turkish patients in regard to acute coughs. A German leaflet designed to improve the doctor-patient communication has been positively tested and then adapted for Turkish patients.</p> <p>Methods</p> <p>The original leaflet was first translated into Turkish. Then 57 patients belonging to 8 different GPs were interviewed about the leaflet using a semi-standardised script. The material was audio recorded, fully transcribed, and analysed by three independent researchers. As a first step a comprehensive content analysis was performed. Secondly, elements crucial to any Turkish version of the leaflet were identified.</p> <p>Results</p> <p>The interviews showed that the leaflets' messages were clearly understood by all patients irrespective of age, gender, and educational background. We identified no major problems in the perception of the translated leaflet but identified several minor points which could be improved. We found that patients were starting to reconsider their attitudes after reading the leaflet.</p> <p>Conclusion</p> <p>The leaflet successfully imparted relevant and new information to the target patients. A qualitative approach is a feasible way to prove general acceptance and provides additional information for its adaptation to medico-cultural factors.</p