Evolutionarily derived networks to inform disease pathways

ABSTRACT

Methods to identify genes or pathways associated with complex diseases are often inadequate to elucidate most risk because they make implicit and oversimplified assumptions about underlying models of disease etiology. These can lead to incomplete or inadequate conclusions. To address this, we previously developed human phenotype networks (HPN), linking phenotypes based on shared biology. However, such visualization alone is often uninterpretable, and requires additional filtering. Here, we expand the HPN to include another method, evolutionary triangulation (ET). ET utilizes the hypothesis that alleles affecting disease risk in multiple populations are distributed consistently with differences in disease prevalence and compares allele frequencies among populations and their relationship to phenotype prevalence. We hypothesized that combining these methods will increase our ability to detect genetic patterns of association in complex diseases. We combined HPN and ET to identify network patterns associated with type 2 diabetes mellitus (T2DM), a leading cause of death worldwide. Fasting glucose, a continuous trait, was used as a proxy for T2DM and differs significantly among continental populations. The combined method identified several diabetes-related traits and several phenotypes related to cardiovascular diseases, for which diabetes is a major risk factor. ET-HPN found more phenotypes related to our target and related phenotypes than the application of either method alone. Not only could we detect phenotype connections related to T2DM, but we also identified phenotypes that are distributed in parallel to it, e.g., amyotrophic lateral sclerosis. Our analyses showed that ET-filtered HPN provides information that neither technique can individually.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2ynESth

Mendelian randomization with fine-mapped genetic data: Choosing from large numbers of correlated instrumental variables

ABSTRACT

Mendelian randomization uses genetic variants to make causal inferences about the effect of a risk factor on an outcome. With fine-mapped genetic data, there may be hundreds of genetic variants in a single gene region any of which could be used to assess this causal relationship. However, using too many genetic variants in the analysis can lead to spurious estimates and inflated Type 1 error rates. But if only a few genetic variants are used, then the majority of the data is ignored and estimates are highly sensitive to the particular choice of variants. We propose an approach based on summarized data only (genetic association and correlation estimates) that uses principal components analysis to form instruments. This approach has desirable theoretical properties: it takes the totality of data into account and does not suffer from numerical instabilities. It also has good properties in simulation studies: it is not particularly sensitive to varying the genetic variants included in the analysis or the genetic correlation matrix, and it does not have greatly inflated Type 1 error rates. Overall, the method gives estimates that are less precise than those from variable selection approaches (such as using a conditional analysis or pruning approach to select variants), but are more robust to seemingly arbitrary choices in the variable selection step. Methods are illustrated by an example using genetic associations with testosterone for 320 genetic variants to assess the effect of sex hormone related pathways on coronary artery disease risk, in which variable selection approaches give inconsistent inferences.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2xulN9r

An Advanced Multifunctional Hydrogel-Based Dressing for Wound Monitoring and Drug Delivery

Wound management is a major global challenge and poses a significant financial burden to the healthcare system due to the rapid growth of chronic diseases such as diabetes, obesity, and aging population. The ability to detect pathogenic infections and release drug at the wound site is of the utmost importance to expedient patient care. Herein, this study presents an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site. This study demonstrates the ability of GelDerm to detect bacterial infections using in vitro and ex vivo tests with accuracies comparable to the commercially available systems. Wireless interfaces to digital image capture hardware such as smartphones serve as a means for quantitation and enable the patient to record the wound condition at home and relay the information to the healthcare personnel for following treatment strategies. Additionally, the dressing is integrated within commercially available patches and can be placed on the wound without chemical or physical irritation. This study demonstrates the ability of GelDerm to eradicate bacteria by the sustained release of antibiotics. The proposed technology holds great promise in managing chronic and acute injuries caused by trauma, surgery, or diabetes.

The ability to detect pathogenic infections and release drug at the wound site is of the utmost importance to expedient wound management. Herein, this study presents an advanced multifunctional dressing (GelDerm) capable of colorimetric measurement of pH, an indicator of bacterial infection, and release of antibiotic agents at the wound site.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2ylPJ6Y

Comparison of nonoperative and surgical management of renal trauma: Can we predict when nonoperative management fails? — Corrigendum

No abstract available

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2yB9urS

Using systematic review in occupational safety and health

Evaluation of scientific evidence is critical in developing recommendations to reduce risk. Healthcare was the first scientific field to employ a systematic review approach for synthesizing research findings to support evidence-based decision-making and it is still the largest producer and consumer of systematic reviews. Systematic reviews in the field of occupational safety and health are being conducted, but more widespread use and adoption would strengthen assessments. In 2016, NIOSH asked RAND to develop a framework for applying the traditional systematic review elements to the field of occupational safety and health. This paper describes how essential systematic review elements can be adapted for use in occupational systematic reviews to enhance their scientific quality, objectivity, transparency, reliability, utility, and acceptability.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2wfcIjq

Delayed sternal closure does not reduce complications associated with coagulopathy and right ventricular failure after left ventricular assist device implantation

Abstract

Delayed sternal closure (DSC) is occasionally adopted after implantation of left ventricular assist device (LVAD). Recent studies suggest that DSC be used for high risk group of patients with coagulopathy, hemodynamic instability or right ventricular failure. However, whether DSC is efficacious for bleeding complication or right ventricular failure is not known. This study is single center analysis of 52 patients, who underwent LVAD implantation. Of those 52 patients, 40 consecutive patients underwent DSC routinely. The sternum was left open with vacuum assist device after implantation of LVAD. Perioperative outcome of the patients who underwent routine DSC were compared with 12 patients who had immediate sternal closure (IC). Mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level of IC group and DSC group were 2.7 and 2.6, respectively. Postoperative bleeding (643 vs. 1469 ml, p < 0.001), duration of inotropic support (109 vs. 172 h, p = 0.034), and time to extubation (26 vs. 52 h, p = 0.005) were significantly increased in DSC group. Length of ICU stay (14 vs. 15 days, p = 0.234) and hospital stay (28 vs. 20 days, p = 0.145) were similar. Incidence of right ventricular failure and tamponade were similar in the two groups. Routine DSC after implantation of an LVAD did not prove to be beneficial in reducing complications associated with coagulopathy and hemodynamic instability including cardiac tamponade or right ventricular failure. We suggest that DSC be selectively applied for patients undergoing LVAD implant.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2wO9hVj

Fluoride-catalyzed Nucleophilic Addition of PhSCF2SiMe3 to Isatins: Synthesis of 3-(1',1'-Difluoroalkyl)-3-hydroxyindolin-2-ones

Synthesis of 3-(1',1'-difluoroalkyl)-3-hydroxyindolin-2-ones employing α,α-difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF2SiMe3) as a gem-difluoromethylene building block is described. The reaction entailed fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 to isatin derivatives followed by reductive cleavage of a phenylsulfanyl group leading to 3-(difluoromethyl)-3-hydroxyindolin-2-ones in good yields. Under similar reduction conditions, in the presence of activated olefins, an intermolecular radical trapping reactions took place to yield 3-(1',1'-difluoroalkyl)-3-hydroxyindolin-2-ones.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2fL8v0w