Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org)

Lettuce (Lactuca sativa) productivity influenced by microbial inocula under nitrogen-limited conditions in aquaponics.

The demand for food will outpace productivity of conventional agriculture due to projected growth of the human population, concomitant with shrinkage of arable land, increasing scarcity of freshwater, and a rapidly changing climate. While aquaponics has potential to sustainably supplement food production with minimal environmental impact, there is a need to better characterize the complex interplay between the various components (fish, plant, microbiome) of these systems to optimize scale up and productivity. Here, we investigated how the commonly-implemented practice of continued microbial community transfer from pre-existing systems might promote or impede productivity of aquaponics. Specifically, we monitored plant growth phenotypes, water chemistry, and microbiome composition of rhizospheres, biofilters, and fish feces over 61-days of lettuce (Lactuca sativa var. crispa) growth in nitrogen-limited aquaponic systems inoculated with bacteria that were either commercially sourced or originating from a pre-existing aquaponic system. Lettuce above- and below-ground growth were significantly reduced across replicates treated with a pre-existing aquaponic system inoculum when compared to replicates treated with a commercial inoculum. Reduced productivity was associated with enrichment in specific bacterial genera in plant roots, including Pseudomonas, following inoculum transfer from pre-existing systems. Increased productivity was associated with enrichment of nitrogen-fixing Rahnella in roots of plants treated with the commercial inoculum. Thus, we show that inoculation from a pre-existing system, rather than from a commercial inoculum, is associated with lower yields. Further work will be necessary to test the putative mechanisms involved

Developing core sets for persons following amputation based on the International Classification of Functioning, Disability and Health as a way to specify functioning

Amputation is a common late stage sequel of peripheral vascular disease and diabetes or a sequel of accidental trauma, civil unrest and landmines. The functional impairments affect many facets of life including but not limited to: Mobility; activities of daily living; body image and sexuality. Classification, measurement and comparison of the consequences of amputations has been impeded by the limited availability of internationally, multiculturally standardized instruments in the amputee setting. The introduction of the International Classification of Functioning, Disability and Health (ICF) by the World Health Assembly in May 2001 provides a globally accepted framework and classification system to describe, assess and compare function and disability. In order to facilitate the use of the ICF in everyday clinical practice and research, ICF core sets have been developed that focus on specific aspects of function typically associated with a particular disability. The objective of this paper is to outline the development process for the ICF core sets for persons following amputation. The ICF core sets are designed to translate the benefits of the ICF into clinical routine. The ICF core sets will be defined at a Consensus conference which will integrate evidence from preparatory studies, namely: (a) a systematic literature review regarding the outcome measures of clinical trails and observational studies, (b) semi-structured patient interviews, (c) international experts participating in an internet-based survey, and (d) cross-sectional, multi-center studies for clinical applicability. To validate the ICF core sets field-testing will follow. Invitation for participation: The development of ICF Core Sets is an inclusive and open process. Anyone who wishes to actively participate in this process is invited to do so

MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome.

Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30-50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.-19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort

A hazard analysis method for systematic identification of safety requirements for user interface software in medical devices

© Springer International Publishing AG (outside the US) 2017. Formal methods technologies have the potential to verify the usability and safety of user interface (UI) software design in medical devices, enabling significant reductions in use errors and consequential safety incidents with such devices. This however depends on comprehensive and verifiable safety requirements to leverage these techniques for detecting and preventing flaws in UI software that can induce use errors. This paper presents a hazard analysis method that extends Leveson’s System Theoretic Process Analysis (STPA) with a comprehensive set of causal factor categories, so as to provide developers with clear guidelines for systematic identification of use-related hazards associated with medical devices, their causes embedded in UI software design, and safety requirements for mitigating such hazards. The method is evaluated with a case study on the Gantry-2 radiation therapy system, which demonstrates that (1) as compared to standard STPA, our method allowed us to identify more UI software design issues likely to cause use-related hazards; and (2) the identified UI software design issues facilitated the definition of precise, verifiable safety requirements for UI software, which could be readily formalized in verification tools such as Prototype Verification System (PVS).- U.S. Food and Drug Administration(NORTE-01-0145-FEDER-000016)Sandy Weininger (FDA), Scott Thiel (Navigant Consulting, Inc.), Michelle Jump (Stryker), Stefania Gnesi (ISTI/CNR) and the CHI+MED team (www.chi-med.ac.uk) provided useful feedback and inputs. Paolo Masci’s work is supported by the North Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement, and by the European Regional Development Fund (ERDF) within Project “NORTE-01-0145-FEDER-000016”.info:eu-repo/semantics/publishedVersio

Low sensitivity of a urine LAM-ELISA in the diagnosis of pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>The development and evaluation of rapid and accurate new diagnostic tools is essential to improve tuberculosis (TB) control in developing countries. In a previous study, the first release of a urine LAM-ELISA by Chemogen (Portland, USA) has been evaluated with a promising sensitivity and specificity for the diagnosis of pulmonary TB. In the present study, the now commercially available assay has been clinically assessed regarding its diagnostic value alone and in combination with clinical co-factors.</p> <p>Methods</p> <p>The test was applied to two urine samples from 291 consecutively enrolled Tanzanian patients with suspected pulmonary tuberculosis. The participants were subsequently assigned to classification groups according to microbiological, clinical and radiological findings at recruitment and during a maximum follow up period of 56 days.</p> <p>Results</p> <p>Only 35 out of 69 pulmonary TB cases -confirmed by smear microscopy and/or solid culture and/or liquid culture- showed at least one positive LAM-ELISA result (sensitivity 50.7%). The sensitivity was noticeably higher in females (66.7%) and in HIV positive participants (62.0%). The specificity amounted to 87.8% and was determined in participants with negative results in all microbiological tests and with sustained recovery under antibiotic treatment at day 56. Correlation with urinalysis revealed that proteinuria was significantly and positively associated with LAM-positivity (<it>P </it>= 0.026).</p> <p>Conclusion</p> <p>This commercially available generation of LAM-ELISA does not appear to be useful as an independent diagnostic test for pulmonary tuberculosis. The question whether the assay is suitable as a supplemental device in the diagnosis of HIV-associated TB, requires further investigations.</p

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Mechanisms Underlying Stage-1 TRPL Channel Translocation in Drosophila Photoreceptors

Background: TRP channels function as key mediators of sensory transduction and other cellular signaling pathways. In Drosophila, TRP and TRPL are the light-activated channels in photoreceptors. While TRP is statically localized in the signaling compartment of the cell (the rhabdomere), TRPL localization is regulated by light. TRPL channels translocate out of the rhabdomere in two distinct stages, returning to the rhabdomere with dark-incubation. Translocation of TRPL channels regulates their availability, and thereby the gain of the signal. Little, however, is known about the mechanisms underlying this trafficking of TRPL channels. Methodology/Principal Findings: We first examine the involvement of de novo protein synthesis in TRPL translocation. We feed flies cycloheximide, verify inhibition of protein synthesis, and test for TRPL translocation in photoreceptors. We find that protein synthesis is not involved in either stage of TRPL translocation out of the rhabdomere, but that re-localization to the rhabdomere from stage-1, but not stage-2, depends on protein synthesis. We also characterize an ex vivo eye preparation that is amenable to biochemical and genetic manipulation. We use this preparation to examine mechanisms of stage-1 TRPL translocation. We find that stage-1 translocation is: induced with ATP depletion, unaltered with perturbation of the actin cytoskeleton or inhibition of endocytosis, and slowed with increased membrane sterol content. Conclusions/Significance: Our results indicate that translocation of TRPL out of the rhabdomere is likely due to protei

Using the realized relationship matrix to disentangle confounding factors for the estimation of genetic variance components of complex traits

Background: In the analysis of complex traits, genetic effects can be confounded with non-genetic effects, especially when using full-sib families. Dominance and epistatic effects are typically confounded with additive genetic and non-genetic effects. This confounding may cause the estimated genetic variance components to be inaccurate and biased