Heart rate variability predicts 30-day all-cause mortality in intensive care units

Background: Autonomic nervous function, as quantified by heart rate variability (HRV), has shown promise in predicting clinically important outcomes in the critical care setting; however, there is debate concerning its utility. HRV analysis was assessed as a practical tool for outcome prediction in two South African hospitals and compared with Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring.Method: In a dual centre, prospective, observational cohort study of patients admitted to the intensive care units (ICU) of two hospitals in KwaZulu-Natal, South Africa frequency domain HRV parameters were explored as predictors of: all-cause mortality at 30 days after admission; ICU stay duration; the need for invasive ventilation; the need for inotrope/vasopressor therapy; and the need for renal replacement therapy. The predictive ability of HRV parameters against the APACHE II score for the study outcomes was also compared.Results: A total of 55 patients were included in the study. Very low frequency power (VLF) was shown to predict 30-day mortality in ICU (odds ratio 0.6; 95% confidence interval 0.396–0.911). When compared with APACHE II, VLF remained a significant predictor of outcome, suggesting that it adds a unique component of prediction. No HRV parameters were predictive for the other secondary outcomes.Conclusion: This study found that VLF independently predicted all-cause mortality at 30 days after ICU admission. VLF provided additional predictive ability above that of the APACHE II score. As suggested by this exploratory analysis larger multi-centre studies seem warranted.Keywords: APACHE II, autonomic nervous system, critical care, heart rate variability, mortalit

High Intensity Interval Training in High Risk Individuals: A Systematic Review of the Literature

Purpose: This systematic review of the literature (SRL) aims to demonstrate that high intensity interval training is an effective, safe, and more efficient training protocol as compared to continuous moderate intensity exercise in patients with COPD or HFhttps://jdc.jefferson.edu/dptcapstones/1005/thumbnail.jp

\u3ci\u3eStaphylococcus aureus\u3c/i\u3e Hyaluronidase Is a CodY-Regulated Virulence Factor

Staphylococcus aureus is a Gram-positive pathogen that causes a diverse range of bacterial infections. Invasive S. aureus strains secrete an extensive arsenal of hemolysins, immunomodulators, and exoenzymes to cause disease. Our studies have focused on the secreted enzyme hyaluronidase (HysA), which cleaves the hyaluronic acid polymer at the β-1,4 glycosidic bond. In the study described in this report, we have investigated the regulation and contribution of this enzyme to S. aureus pathogenesis. Using the Nebraska Transposon Mutant Library (NTML), we identified eight insertions that modulate extracellular levels of HysA activity. Insertions in the sigB operon, as well as in genes encoding the global regulators SarA and CodY, significantly increased HysA protein levels and activity. By altering the availability of branched-chain amino acids, we further demonstrated CodY-dependent repression of HysA activity. Additionally, through mutation of the CodY binding box upstream of hysA, the repression of HysA production was lost, suggesting that CodY is a direct repressor of hysA expression. To determine whether HysA is a virulence factor, a ΔhysA mutant of a community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 strain was constructed and found to be attenuated in a neutropenic, murine model of pulmonary infection. Mice infected with this mutant strain exhibited a 4-log-unit reduction in bacterial burden in their lungs, as well as reduced lung pathology and increased levels of pulmonary hyaluronic acid, compared to mice infected with the wild-type, parent strain. Taken together, these results indicate that S. aureus hyaluronidase is a CodY-regulated virulence factor

Towards Value-Sensitive Learning Analytics Design

To support ethical considerations and system integrity in learning analytics, this paper introduces two cases of applying the Value Sensitive Design methodology to learning analytics design. The first study applied two methods of Value Sensitive Design, namely stakeholder analysis and value analysis, to a conceptual investigation of an existing learning analytics tool. This investigation uncovered a number of values and value tensions, leading to design trade-offs to be considered in future tool refinements. The second study holistically applied Value Sensitive Design to the design of a recommendation system for the Wikipedia WikiProjects. To proactively consider values among stakeholders, we derived a multi-stage design process that included literature analysis, empirical investigations, prototype development, community engagement, iterative testing and refinement, and continuous evaluation. By reporting on these two cases, this paper responds to a need of practical means to support ethical considerations and human values in learning analytics systems. These two cases demonstrate that Value Sensitive Design could be a viable approach for balancing a wide range of human values, which tend to encompass and surpass ethical issues, in learning analytics design.Comment: The 9th International Learning Analytics & Knowledge Conference (LAK19

Two new ArrayTrack libraries for personalized biomedical research

<p>Abstract</p> <p>Background</p> <p>Recent advances in high-throughput genotyping technology are paving the way for research in personalized medicine and nutrition. However, most of the genetic markers identified from association studies account for a small contribution to the total risk/benefit of the studied phenotypic trait. Testing whether the candidate genes identified by association studies are causal is critically important to the development of personalized medicine and nutrition. An efficient data mining strategy and a set of sophisticated tools are necessary to help better understand and utilize the findings from genetic association studies. </p> <p>Description</p> <p>SNP (single nucleotide polymorphism) and QTL (quantitative trait locus) libraries were constructed and incorporated into ArrayTrack, with user-friendly interfaces and powerful search features. Data from several public repositories were collected in the SNP and QTL libraries and connected to other domain libraries (genes, proteins, metabolites, and pathways) in ArrayTrack. Linking the data sets within ArrayTrack allows searching of SNP and QTL data as well as their relationships to other biological molecules. The SNP library includes approximately 15 million human SNPs and their annotations, while the QTL library contains publically available QTLs identified in mouse, rat, and human. The QTL library was developed for finding the overlap between the map position of a candidate or metabolic gene and QTLs from these species. Two use cases were included to demonstrate the utility of these tools. The SNP and QTL libraries are freely available to the public through ArrayTrack at <url>http://www.fda.gov/ArrayTrack</url>. </p> <p>Conclusions</p> <p>These libraries developed in ArrayTrack contain comprehensive information on SNPs and QTLs and are further cross-linked to other libraries. Connecting domain specific knowledge is a cornerstone of systems biology strategies and allows for a better understanding of the genetic and biological context of the findings from genetic association studies. </p

Role of CD44 in clear cell renal cell carcinoma invasiveness after antiangiogenic treatment

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia, Universitat de Barcelona, 2017. Tutor/a: Joan Carles Rodríguez Rubio.[eng] During last century, big effort to understand the biochemical basis of cancer was carried out. One of the principal branches of these cancer investigations used drugs to prevent the formation of new blood vessels –process called angiogenesis– responsible for the nutrients supply of the tumour. These drugs are generally called antiangiogenics. It was discovered that some types of tumour have or develop resistance to these drugs when treatment was long enough. For that reason, mechanisms of resistance, aggressiveness, invasion and/or metastasis after the treatment are nowadays relevant to study. Recently, a protein that could be involved in the increased invasiveness of tumour cells after the antiangiogenic treatment appeared. This project collects some evidence that indicates that this protein, called CD44, might play a role in the increased invasion after antiangiogenic treatment in mouse models of renal carcinoma.[cat] Durant l’últim segle, s’ha fet un gran esforç per aprofundir en la basant bioquímica de la investigació contra el càncer. Una de les branques principals d’aquesta investigació utilitza fàrmacs que prevenen la formació de nous vasos sanguinis –procés anomenat angiogènesis- encarregats de nodrir el tumor. Aquests fàrmacs es diuen generalment antiangiogènics. S’ha descobert que alguns tipus de tumor tenen o desenvolupen resistència a aquests fàrmacs quan el tractament és prou llarg. Per aquesta raó, actualment s’està investigant profundament quins són els mecanismes pels quals apareix aquesta resistència, així com també perquè els tumors es tornen més agressius, invasius i/o metastàtics després del tractament. Recentment s’ha descobert una proteïna que podria estar involucrada en l’augment de la invasivitat de les cèl·lules tumorals després del tractament antiangiogènic. Aquest treball recull algunes de les evidències que apunten cap al paper de la proteïna CD44 en l’increment de la invasió tumoral post-tractament amb fàrmacs antiangiogènics en models ratolins de càncer renal

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN