Ventricular tachycardia after administration of sildenafil citrate: a case report

<p>Abstract</p> <p>Background</p> <p>It has not previously been reported that sildenafil citrate causes malignant arrhythmias in humans.</p> <p>Case presentation</p> <p>A 41-year-old man developed sustained ventricular tachycardia following sildenafil citrate administration.</p> <p>Conclusion</p> <p>It cannot be dismissed that this patient experienced ventricular tachycardia as an adverse effect of sildenafil citrate administration.</p

A novel method to detect rare variants using both family and unrelated case-control data

To detect rare variants associated with a phenotype, we develop a novel statistical method that can use both family and unrelated case-control data. Unlike the currently existing methods, we first use family data to calculate weights to be given to rare variants, differentiating between concordantly affected and discordant sib pairs. These weights are then used in an association test applied to the unrelated case-control data. We applied the proposed method to the simulated sequencing data in Genetic Analysis Workshop 17 and identified two genes associated with the disease

a M. T. Akadémia által az 1886-ik évi pályázaton a Teleky-díjjal jutalmazott eredeti társadalmi tragoedia 3 felvonásban - irta Csiky Gergely

Debreczeni Városi Szinház. Kedden, 1897. évi október hó 19-én.Debreceni Egyetem Egyetemi és Nemzeti Könyvtá

Digging into the extremes: a useful approach for the analysis of rare variants with continuous traits?

The common disease/rare variant hypothesis predicts that rare variants with large effects will have a strong impact on corresponding phenotypes. Therefore it is assumed that rare functional variants are enriched in the extremes of the phenotype distribution. In this analysis of the Genetic Analysis Workshop 17 data set, my aim is to detect genes with rare variants that are associated with quantitative traits using two general approaches: analyzing the association with the complete distribution of values by means of linear regression and using statistical tests based on the tails of the distribution (bottom 10% of values versus top 10%). Three methods are used for this extreme phenotype approach: Fisher’s exact test, weighted-sum method, and beta method. Rare variants were collapsed on the gene level. Linear regression including all values provided the highest power to detect rare variants. Of the three methods used in the extreme phenotype approach, the beta method performed best. Furthermore, the sample size was enriched in this approach by adding additional samples with extreme phenotype values. Doubling the sample size using this approach, which corresponds to only 40% of sample size of the original continuous trait, yielded a comparable or even higher power than linear regression. If samples are selected primarily for sequencing, enriching the analysis by gathering a greater proportion of individuals with extreme values in the phenotype of interest rather than in the general population leads to a higher power to detect rare variants compared to analyzing a population-based sample with equivalent sample size

Large-scale risk prediction applied to Genetic Analysis Workshop 17 mini-exome sequence data

We consider the application of Efron’s empirical Bayes classification method to risk prediction in a genome-wide association study using the Genetic Analysis Workshop 17 (GAW17) data. A major advantage of using this method is that the effect size distribution for the set of possible features is empirically estimated and that all subsequent parameter estimation and risk prediction is guided by this distribution. Here, we generalize Efron’s method to allow for some of the peculiarities of the GAW17 data. In particular, we introduce two ways to extend Efron’s model: a weighted empirical Bayes model and a joint covariance model that allows the model to properly incorporate the annotation information of single-nucleotide polymorphisms (SNPs). In the course of our analysis, we examine several aspects of the possible simulation model, including the identity of the most important genes, the differing effects of synonymous and nonsynonymous SNPs, and the relative roles of covariates and genes in conferring disease risk. Finally, we compare the three methods to each other and to other classifiers (random forest and neural network)

Bunyavirus requirement for endosomal K+ reveals new roles of cellular ion channels during infection

In order to multiply and cause disease a virus must transport its genome from outside the cell into the cytosol, most commonly achieved through the endocytic network. Endosomes transport virus particles to specific cellular destinations and viruses exploit the changing environment of maturing endocytic vesicles as triggers to mediate genome release. Previously we demonstrated that several bunyaviruses, which comprise the largest family of negative sense RNA viruses, require the activity of cellular potassium (K+) channels to cause productive infection. Specifically, we demonstrated a surprising role for K+ channels during virus endosomal trafficking. In this study, we have used the prototype bunyavirus, Bunyamwera virus (BUNV), as a tool to understand why K+ channels are required for progression of these viruses through the endocytic network. We report three major findings: First, the production of a dual fluorescently labelled bunyavirus to visualize virus trafficking in live cells. Second, we show that BUNV traffics through endosomes containing high [K+] and that these K+ ions influence the infectivity of virions. Third, we show that K+ channel inhibition can alter the distribution of K+ across the endosomal system and arrest virus trafficking in endosomes. These data suggest high endosomal [K+] is a critical cue that is required for virus infection, and is controlled by cellular K+ channels resident within the endosome network. This highlights cellular K+ channels as druggable targets to impede virus entry, infection and disease

Geographical inequalities in lung cancer management and survival in South East England: evidence of variation in access to oncology services?

This study aimed to determine whether the management and survival of patients with lung cancer varied among 26 health authorities in South East England. The Thames Cancer Registry identified patients diagnosed with lung cancer (ICD-10 codes C33-C34) between 1995 and 1999. After excluding death certificate only patients, 32,818 (81%) patients were analysed. The proportions of patients receiving active treatment varied among health authorities between 5 and 17% for non-investigative surgery, 4 and 17% for any chemotherapy, 8 and 30% for any radiotherapy and 15 and 42% for any active treatment. One-year patient survival ranged from 11 to 34%. There was evidence of health authority level variation even after adjusting for case mix. Patients whose first hospital attendance was at a radiotherapy centre were more likely to receive active treatment (OR 1.72, 95% CI 1.21-2.46), chemotherapy (1.38, 1.06-1.79) or radiotherapy (1.86, 1.28-2.71). There was some evidence that patients whose first hospital attendance was at a radiotherapy centre survived longer. This study shows there is geographical inequality in the treatment given to lung cancer patients and patient survival in South East England. There was some evidence to suggest that these inequalities might be explained by variations in access to oncology services. Future studies should investigate the pathways and barriers to specialist care in this condition

Co-designing inflammatory bowel disease (Ibd) services in Scotland : findings from a nationwide survey

Background: The Scottish Government’s ambition is to ensure that health services are co-designed with the communities they serve. Crohn’s and Colitis UK and the Scottish Government acknowledged the need to review and update the current IBD care model. An online survey was conducted asking IBD patients about their experiences of the NHS care they receive. This survey was the first step of co-designing and developing a national strategy for IBD service improvement in Scotland. Aim: To explore IBD patients’ experiences of current services and make recommendations for future service development. Methods: This study was part of a wider cross-sectional on-line survey. Participants were patients with IBD across Scotland. 777 people with IBD took part in the survey. Thematic analysis of all data was conducted independently by two researchers. Results: Three key themes emerged: Quality of life: Participants highlighted the impact the disease has on quality of life and the desperate need for IBD services to address this more holistically. IBD clinicians and access: Participants recognised the need for more IBD nurses and gastroenterologists along with better access to them. Those with a named IBD nurse reported to be more satisfied with their care. An explicit IBD care pathway: Patients with IBD identified the need of making the IBD care pathway more explicit to service users. Conclusions: Participants expressed the need for a more holistic approach to their IBD care. This includes integrating psychological, counselling and dietetic services into IBD care with better access to IBD clinicians and a more explicit IBD care pathway. Keywords: Inflammatory bowel disease, Co-designing, Qualitative study, Patient survey, Crohn’s disease, Ulcerative coliti

Young off-axis volcanism along the ultraslow-spreading Southwest Indian Ridge

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 3 (2010): 286-292, doi:10.1038/ngeo824.Mid-ocean ridge crustal accretion occurs continuously at all spreading rates through a combination of magmatic and tectonic processes. Fast to slow spreading ridges are largely built by adding magma to narrowly focused neovolcanic zones. In contrast, ultraslow spreading ridge construction significantly relies on tectonic accretion, which is characterized by thin volcanic crust, emplacement of mantle peridotite directly to the seafloor, and unique seafloor fabrics with variable segmentation patterns. While advances in remote imaging have enhanced our observational understanding of crustal accretion at all spreading rates, temporal information is required in order to quantitatively understand mid-ocean ridge construction. However, temporal information does not exist for ultraslow spreading environments. Here, we utilize U-series eruption ages to investigate crustal accretion at an ultraslow spreading ridge for the first time. Unexpectedly young eruption ages throughout the Southwest Indian ridge rift valley indicate that neovolcanic activity is not confined to the spreading axis, and that magmatic crustal accretion occurs over a wider zone than at faster spreading ridges. These observations not only suggest that crustal accretion at ultraslow spreading ridges is distinct from faster spreading ridges, but also that the magma transport mechanisms may differ as a function of spreading rate.This work was supported by the following NSF grants: NSF-OCE 0137325; NSF-OCE 060383800; and NSF-OCE 062705300

The Relationship Between Therapist Effects and Therapy Delivery Factors: Therapy Modality, Dosage, and Non-completion.

To consider the relationships between, therapist variability, therapy modality, therapeutic dose and therapy ending type and assess their effects on the variability of patient outcomes. Multilevel modeling was used to analyse a large sample of routinely collected data. Model residuals identified more and less effective therapists, controlling for case-mix. After controlling for case mix, 5.8 % of the variance in outcome was due to therapists. More sessions generally improved outcomes, by about half a point on the PHQ-9 for each additional session, while non-completion of therapy reduced the amount of pre-post change by six points. Therapy modality had little effect on outcome. Patient and service outcomes may be improved by greater focus on the variability between therapists and in keeping patients in therapy to completion