Motivation: Next-generation sequencing (NGS) has enabled whole genome and transcriptome single nucleotide variant (SNV) discovery in cancer. NGS produces millions of short sequence reads that, once ...aligned to a reference genome sequence, can be interpreted for the presence of SNVs. Although tools exist for SNV discovery from NGS data, none are specifically suited to work with data from tumors, where altered ploidy and tumor cellularity impact the statistical expectations of SNV discovery. Results: We developed three implementations of a probabilistic Binomial mixture model, called SNVMix, designed to infer SNVs from NGS data from tumors to address this problem. The first models allelic counts as observations and infers SNVs and model parameters using an expectation maximization (EM) algorithm and is therefore capable of adjusting to deviation of allelic frequencies inherent in genomically unstable tumor genomes. The second models nucleotide and mapping qualities of the reads by probabilistically weighting the contribution of a read/nucleotide to the inference of a SNV based on the confidence we have in the base call and the read alignment. The third combines filtering out low-quality data in addition to probabilistic weighting of the qualities. We quantitatively evaluated these approaches on 16 ovarian cancer RNASeq datasets with matched genotyping arrays and a human breast cancer genome sequenced to >40× (haploid) coverage with ground truth data and show systematically that the SNVMix models outperform competing approaches. Availability: Software and data are available at http://compbio.bccrc.ca Contact: sshah@bccrc.ca Supplemantary information: Supplementary data are available at Bioinformatics online.
The rapid growth in the number of mobile health applications could have profound significance in the prevention of disease or in the treatment of patients with chronic disease such as diabetes.
The ...objective of this study was to describe the characteristics of the most common mobile health care applications available in the Apple iTunes marketplace.
We undertook a descriptive analysis of a sample of applications in the "health and wellness" category of the Apple iTunes Store. We characterized each application in terms of its health factor and primary method of user engagement. The main outcome measures of the analysis were price, health factors, and methods of user engagement.
Among the 400 applications that met the inclusion criteria, the mean price of the most frequently downloaded paid applications was US $2.24 (SD $1.30), and the mean price of the most currently available paid applications was US $2.27 (SD $1.60). Fitness/training applications were the most popular (43.5%, 174/400). The next two most common categories were health resource (15.0%, 60/400) and diet/caloric intake (14.3%, 57/400). Applications in the health resource category constituted 5.5% (22/400) of the applications reviewed. Self-monitoring was the most common primary user engagement method (74.8%, 299/400). A total of 20.8% (83/400) of the applications used two or more user engagement approaches, with self-monitoring and progress tracking being the most frequent.
Most of the popular mobile health applications focus on fitness and self-monitoring. The approaches to user engagement utilized by these applications are limited and present an opportunity to improve the effectiveness of the technology.
We developed and clinically validated a hybrid capture next generation sequencing assay to detect somatic alterations and microsatellite instability in solid tumors and hematologic malignancies. This ...targeted oncology assay utilizes tumor-normal matched samples for highly accurate somatic alteration calling and whole transcriptome RNA sequencing for unbiased identification of gene fusion events. The assay was validated with a combination of clinical specimens and cell lines, and recorded a sensitivity of 99.1% for single nucleotide variants, 98.1% for indels, 99.9% for gene rearrangements, 98.4% for copy number variations, and 99.9% for microsatellite instability detection. This assay presents a wide array of data for clinical management and clinical trial enrollment while conserving limited tissue.
Background Acute COVID-19-related myocardial, pulmonary, and vascular pathology and how these relate to each other remain unclear. To our knowledge, no studies have used complementary imaging ...techniques, including molecular imaging, to elucidate this. We used multimodality imaging and biochemical sampling in vivo to identify the pathobiology of acute COVID-19. Specifically, we investigated the presence of myocardial inflammation and its association with coronary artery disease, systemic vasculitis, and pneumonitis. Methods and Results Consecutive patients presenting with acute COVID-19 were prospectively recruited during hospital admission in this cross-sectional study. Imaging involved computed tomography coronary angiography (identified coronary disease), cardiac 2-deoxy-2-fluorine-18fluoro-D-glucose positron emission tomography/computed tomography (identified vascular, cardiac, and pulmonary inflammatory cell infiltration), and cardiac magnetic resonance (identified myocardial disease) alongside biomarker sampling. Of 33 patients (median age 51 years, 94% men), 24 (73%) had respiratory symptoms, with the remainder having nonspecific viral symptoms. A total of 9 patients (35%, n=9/25) had cardiac magnetic resonance-defined myocarditis. Of these patients, 53% (n=5/8) had myocardial inflammatory cell infiltration. A total of 2 patients (5%) had elevated troponin levels. Cardiac troponin concentrations were not significantly higher in patients with and without myocarditis (8.4 ng/L interquartile range, IQR: 4.0-55.3 versus 3.5 ng/L IQR: 2.5-5.5;
=0.07) or myocardial cell infiltration (4.4 ng/L IQR: 3.4-8.3 versus 3.5 ng/L IQR: 2.8-7.2;
=0.89). No patients had obstructive coronary artery disease or vasculitis. Pulmonary inflammation and consolidation (percentage of total lung volume) was 17% (IQR: 5%-31%) and 11% (IQR: 7%-18%), respectively. Neither were associated with the presence of myocarditis. Conclusions Myocarditis was present in a third patients with acute COVID-19, and the majority had inflammatory cell infiltration. Pneumonitis was ubiquitous, but this inflammation was not associated with myocarditis. The mechanism of cardiac pathology is nonischemic and not attributable to a vasculitic process. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN12154994.
•White coats are laundered much less frequently than surgical scrubs.•White coats and scrubs are commonly colonized with multidrug resistant organisms.•Data regarding contamination based on fabric ...type are variable in findings.•Scrubs impregnated with antimicrobial substances can potentially reduce contamination.•Laundering practices have a varying degree of efficacy in reducing contamination.
Horizontal transmission of bacteria, especially multidrug-resistant organisms (MDROs), remains an important concern in hospitals worldwide. Some studies have implicated provider attire in the transmission of organisms within hospitals, whereas others have suggested that evidence supporting this notion is limited.
PubMed was searched for publications between 1990 and 2018 to identify studies of bacterial contamination of, or dissemination of, bacteria from physician, nursing, or trainee attire, with a specific focus on white coats and surgical scrubs. A total of 214 articles were identified. Of these, 169 were excluded after abstract review and 33 were excluded after in-depth full manuscript review.
Twenty-two articles were included: 16 (73%) cross-sectional studies, 4 (18%) randomized controlled trials, and 2 (9%) cohort studies. Results are organized by microbial contaminants, antibiotic resistance, types of providers, fabric type, antimicrobial coating, and laundering practices. Provider attire was commonly colonized by MDROs, with white coats laundered less frequently than scrubs. Studies revealed considerable differences among fabrics used and laundering practices.
Findings suggest that provider attire is a potential source of pathogenic bacterial transmission in health care settings. However, data confirming a direct link between provider attire and health care–associated infections remain limited. Suggestions outlined in this article may serve as a guideline to reduce the spread of bacterial pathogens, including MDROs, that have the potential to precipitate hospital-acquired infections.
The rapidly advancing field of digital health technologies provides a great opportunity to radically transform the way clinical trials are conducted and to shift the clinical trial paradigm from a ...site‐centric to a patient‐centric model. Merck’s (Kenilworth, NJ) digitally enabled clinical trial initiative is focused on introduction of digital technologies into the clinical trial paradigm to reduce patient burden, improve drug adherence, provide a means of more closely engaging with the patient, and enable higher quality, faster, and more frequent data collection. This paper will describe the following four key areas of focus from Merck’s digitally enabled clinical trials initiative, along with corresponding enabling technologies: (i) use of technologies that can monitor and improve drug adherence (smart dosing), (ii) collection of pharmacokinetic (PK), pharmacodynamic (PD), and biomarker samples in an outpatient setting (patient‐centric sampling), (iii) use of digital devices to collect and measure physiological and behavioral data (digital biomarkers), and (iv) use of data platforms that integrate digital data streams, visualize data in real‐time, and provide a means of greater patient engagement during the trial (digital platform). Furthermore, this paper will discuss the synergistic power in implementation of these approaches jointly within a trial to enable better understanding of adherence, safety, efficacy, PK, PD, and corresponding exposure‐response relationships of investigational therapies as well as reduced patient burden for clinical trial participation. Obstacle and challenges to adoption and full realization of the vision of patient‐centric, digitally enabled trials will also be discussed.
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•The first high-resolution crystal structure of human IgG3 Fc has been solved.•Effect of GlcNAc2Man5 (Man5) high mannose type glycosylation on IgG Fc structure was ...analyzed.•Interactions of the N297 glycan with the Fc are demonstrated to be important for binding to FcγRIIIA.•IgG3 Fc structure provides basis for IgG3-Arg435 effects on protein A and FcRn binding.•IgG3 Fc crystal structure helps to explain some of the unique properties of this IgG subclass.
Immunoglobulin G (IgG) consists of four subclasses in humans: IgG1, IgG2, IgG3 and IgG4, which are highly conserved but have unique differences that result in subclass-specific effector functions. Though IgG1 is the most extensively studied IgG subclass, study of other subclasses is important to understand overall immune function and for development of new therapeutics. When compared to IgG1, IgG3 exhibits a similar binding profile to Fcγ receptors and stronger activation of complement. All IgG subclasses are glycosylated at N297, which is required for Fcγ receptor and C1q complement binding as well as maintaining optimal Fc conformation. We have determined the crystal structure of homogenously glycosylated human IgG3 Fc with a GlcNAc2Man5 (Man5) high mannose glycoform at 1.8Å resolution and compared its structural features with published structures from the other IgG subclasses. Although the overall structure of IgG3 Fc is similar to that of other subclasses, some structural perturbations based on sequence differences were revealed. For instance, the presence of R435 in IgG3 (and H435 in the other IgG subclasses) has been implicated to result in IgG3-specific properties related to binding to protein A, protein G and the neonatal Fc receptor (FcRn). The IgG3 Fc structure helps to explain some of these differences. Additionally, protein-glycan contacts observed in the crystal structure appear to correlate with IgG3 affinity for Fcγ receptors as shown by binding studies with IgG3 Fc glycoforms. Finally, this IgG3 Fc structure provides a template for further studies aimed at engineering the Fc for specific gain of function.
Systematic annotation of gene regulatory elements is a major challenge in genome science. Direct mapping of chromatin modification marks and transcriptional factor binding sites genome-wide has ...successfully identified specific subtypes of regulatory elements. In Drosophila several pioneering studies have provided genome-wide identification of Polycomb response elements, chromatin states, transcription factor binding sites, RNA polymerase II regulation and insulator elements; however, comprehensive annotation of the regulatory genome remains a significant challenge. Here we describe results from the modENCODE cis-regulatory annotation project. We produced a map of the Drosophila melanogaster regulatory genome on the basis of more than 300 chromatin immunoprecipitation data sets for eight chromatin features, five histone deacetylases and thirty-eight site-specific transcription factors at different stages of development. Using these data we inferred more than 20,000 candidate regulatory elements and validated a subset of predictions for promoters, enhancers and insulators in vivo. We identified also nearly 2,000 genomic regions of dense transcription factor binding associated with chromatin activity and accessibility. We discovered hundreds of new transcription factor co-binding relationships and defined a transcription factor network with over 800 potential regulatory relationships.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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