Effects of Web-Based Instruction on Nursing Students' Arithmetical and Drug Dosage Calculation Skills

Drug dosage calculation skill is critical for all nursing students to ensure patient safety, particularly during clinical practice. The study purpose was to evaluate the effectiveness of Web-based instruction on improving nursing students' arithmetical and drug dosage calculation skills using a pretest-posttest design. A total of 63 nursing students participated. Data were collected through the Demographic Information Form, and the Arithmetic Skill Test and Drug Dosage Calculation Skill Test were used as pre and posttests. The pretest was conducted in the classroom. A Web site was then constructed, which included audio presentations of lectures, quizzes, and online posttests. Students had Web-based training for 8 weeks and then they completed the posttest. Pretest and posttest scores were compared using the Wilcoxon test and correlation coefficients were used to identify the relationship between arithmetic and calculation skills scores. The results demonstrated that Web-based teaching improves students' arithmetic and drug dosage calculation skills. There was a positive correlation between the arithmetic skill and drug dosage calculation skill scores of students. Web-based teaching programs can be used to improve knowledge and skills at a cognitive level in nursing students.

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Design and Evaluation of a Web-Based Symptom Monitoring Tool for Heart Failure

Heart failure is a chronic condition where symptom recognition and between-visit communication with providers are critical. Patients are encouraged to track disease-specific data, such as weight and shortness of breath. Use of a Web-based tool that facilitates data display in graph form may help patients recognize exacerbations and more easily communicate out-of-range data to clinicians. The purposes of this study were to (1) design a Web-based tool to facilitate symptom monitoring and symptom recognition in patients with chronic heart failure and (2) conduct a usability evaluation of the Web site. Patient participants generally had a positive view of the Web site and indicated it would support recording their health status and communicating with their doctors. Clinician participants generally had a positive view of the Web site and indicated it would be a potentially useful adjunct to electronic health delivery systems. Participants expressed a need to incorporate decision support within the site and wanted to add other data, for example, blood pressure, and have the ability to adjust font size. A few expressed concerns about data privacy and security. Technologies require careful design and testing to ensure they are useful, usable, and safe for patients and do not add to the burden of busy providers.

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Standard Occupational Classification Codes: An Update

No abstract available

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The Inherent Challenges of Using Large Data Sets in Healthcare Research: Experiences of an Interdisciplinary Team

No abstract available

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Accuracy and Efficiency of Recording Pediatric Early Warning Scores Using an Electronic Physiological Surveillance System Compared With Traditional Paper-Based Documentation

Pediatric Early Warning Scores are advocated to assist health professionals to identify early signs of serious illness or deterioration in hospitalized children. Scores are derived from the weighting applied to recorded vital signs and clinical observations reflecting deviation from a predetermined "norm." Higher aggregate scores trigger an escalation in care aimed at preventing critical deterioration. Process errors made while recording these data, including plotting or calculation errors, have the potential to impede the reliability of the score. To test this hypothesis, we conducted a controlled study of documentation using five clinical vignettes. We measured the accuracy of vital sign recording, score calculation, and time taken to complete documentation using a handheld electronic physiological surveillance system, VitalPAC Pediatric, compared with traditional paper-based charts. We explored the user acceptability of both methods using a Web-based survey. Twenty-three staff participated in the controlled study. The electronic physiological surveillance system improved the accuracy of vital sign recording, 98.5% versus 85.6%, P

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Development of a Web Exercise Video for Patients With Shoulder Problems

The purpose of this study was to develop a Web video designed to promote regular shoulder joint exercise on a continuous basis among patients with shoulder joint disease. This is a methodological research. A shoulder joint exercise video was developed through the five stages of the ADDIE model: analysis, design, development, implementation, and evaluation. The video demonstrates exercises that stretch and strengthen the joints and muscles of the shoulders. Stretching exercises include the pendulum, forward elevation, outer rotation, crossover arm stretch, inner rotation, and the sleeper; strengthening exercises include dumbbell exercises, a chair exercise, wall push-ups, and rowing. This Web exercise video can be used as an educational resource for preventing shoulder joint diseases by middle-aged and elderly people and those seeking to restore shoulder joint function damaged by shoulder joint diseases.

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Nurses’ Attitudes Toward Meaningful Use Technologies: An Integrative Review

Nurses comprise the largest segment of the healthcare workforce. As such, their perceptions of any new technology are important to understand, as it may ultimately mean the difference between acceptance and rejection of a product. The three-stage meaningful use program is intended to help improve and standardize data capture and advance clinical processes to improve patient and population outcomes in the US. With more than 471 000 healthcare providers having already received meaningful use incentive payments totaling more than $20 billion as of June 2015, it is critical to understand how these technologies are being viewed and utilized in practice. Understanding nurses' attitudes toward healthcare technology may help drive acceptance, as well as maximize the inherent potential of the new technologies toward improving patient care. Thus, the purpose of this integrative review is to highlight what is known about nurses' attitudes toward meaningful use technologies.

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Nurses’ Attitudes Toward Meaningful Use Technologies: An Integrative Review

No abstract available

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HIF-1α, MDM2, CDK4, and p16 expression in ischemic fasciitis, focusing on its ischemic condition

Abstract

Ischemic fasciitis is a benign myofibroblastic lesion, occurring in the sacral region or proximal thigh of elderly or bedridden individuals. The pathogenesis of ischemic fasciitis is thought to be based on ischemic condition; however, it has never been demonstrated. In this study, we examined the expression of ischemia-associated proteins in ischemic fasciitis by immunohistochemical and genetic methods. Specifically, this study aimed to reveal the expression of HIF-1α, MDM2, CDK4, p16, and gene amplification of MDM2 gene. Seven cases of ischemic fasciitis from among the soft-tissue tumors registered at our institution were retrieved. Histopathological findings were as follows: poorly demarcated nodular masses, a proliferation of spindle-shaped fibroblastic or myofibroblastic cells with oval nuclei and eosinophilic or pale cytoplasm, zonal fibrinous deposition, pseudocystic degeneration, granulation-like proliferation of capillary vessels, ganglion-like cells, myxoid or hyalinized stroma, and chronic inflammatory infiltration. Immunohistochemically, the spindle cells were positive for HIF-1α (7/7 cases), MDM2 (4/7 cases), CDK4 (4/7 cases), p16 (7/7 cases), p53 (2/7 case), cyclin D1 (7/7 cases), and alpha-smooth muscle actin (6/7 cases). Neither MDM2 gene amplification nor USP6 gene split signal was detected in any case. Overexpression of the above proteins may be associated with the pathogenic mechanism of ischemic fasciitis. It is noted that the immunohistochemical positivity of MDM2, CDK4, and p16 do not necessarily indicate malignant neoplasm such as dedifferentiated liposarcoma.

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Role of DNA methylation in the dietary restriction mediated cellular memory

Abstract

An important facet of dietary restriction (DR) that has been largely overlooked is that DR can have early effects that create a cellular memory, which persists even when DR is discontinued. The goal of this study was to determine if DNA methylation played a role in the cellular memory of DR by examining the effect of short-term DR on gene expression and DNA methylation and determining if the changes in expression and DNA methylation persist when DR is discontinued and mice returned to ad libitum (AL) feeding. We show that DR can induce substantial changes in gene expression within 1 month of its implementation in various tissues, and more interestingly, ~19–50% of these changes in gene expression persist across the tissues even when DR is discontinued. We then determined whether DR induced changes in DNA methylation in the promoter of three candidate genes identified from our gene expression analysis (Pomc, Hsph1, and Nts1) that correlated with the changes in the expression of these genes. Decreased methylation at three specific CG sites in the promoter of the Nts1 gene encompassing the distal consensus AP-1 site was correlated with increased Nts1 expression. Both the promoter hypomethylation and increased Nts1 expression persisted even after DR was discontinued and mice fed AL, supporting our hypothesis that DNA methylation could play a role in the memory effect of DR. The changes in DNA methylation in the Nts1 gene are likely to occur in intestinal stem cells and could play a role in preserving the intestinal stem cell pool in DR mice.

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Allergens labeling on French processed foods – an Oqali study

Abstract

The French Observatory of Food Quality (Oqali) aims at collecting all nutritional data provided on labels of processed foods (nutritional information and composition), at branded products level, in order to follow nutritional labeling changes over time. This study carries out an overview of allergens labeling frequencies by distinguishing allergens used in recipes from those listed on precautionary statements, for the fourteen allergen categories for which labeling is mandatory according to European legislation. 17,309 products were collected, between 2008 and 2012, from 26 food categories. Products were classified per family and type of brand (national brands, retailer brands, entry-level retailer brands, hard discount, and specialized retailer brands). Allergenic ingredients were identified from ingredients lists and precautionary statements. 73% of the 17,309 products studied contained at least one allergen in their ingredients list and 39% had a precautionary statement for one or more allergens. Milk (53%), gluten (41%), and egg (22%) were the most commonly used allergens in ingredients lists. For precautionary statement, nuts (20%), egg (14%), peanut (13%), soybean (12%), and milk (11%) were the most common allergens listed. Precautionary statement was most frequently found among first-price products (hard discount and entry-level retailer brands). National brands seemed to use it less frequently. For all these results, differences depended both on food categories and allergen categories. This study will enable to follow allergens labeling and their use as ingredients over time, particularly by assessing an hypothetical increase in allergens presence in processed food.

This study provides a first overview of the allergens used in recipes and precautionary statements on 17,309 French processed foodstuffs, in order to follow changes in uses and labeling practices over time.

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The Immune Phenotype of Three Drosophila Leukemia Models

Many leukemia patients suffer from dysregulation of their immune system, making them more susceptible to infections and leading to general weakening (cachexia). Both adaptive and innate immunity are affected. The fruitfly Drosophila melanogaster has an innate immune system including cells of the myeloid lineage (hemocytes). To study Drosophila immunity and physiology during leukemia we established three models by driving expression of a dominant-active version of the Ras oncogene (Ras^V12) alone or combined with knockdowns of tumor suppressors in Drosophila hemocytes. Our results show that phagocytosis, hemocytes migration to wound sites, wound sealing and survival upon bacterial infection of leukemic lines are similar to wild type. We find that in all leukemic models the two major immune pathways (Toll and Imd) are dysregulated. Toll-dependent signaling is activated to comparable extents as after wounding wild type larvae, leading to a proinflammatory status. In contrast, Imd signaling is suppressed. Finally, we notice that adult tissue formation is blocked and degradation of cell masses during metamorphosis of leukemic lines, which is akin to the state of cancer-dependent cachexia. To further analyze the immune competence of leukemic lines we used a natural infection model that involves insect-pathogenic nematodes. We identified two leukemic lines, which were sensitive to nematode infections. Further characterization demonstrates that despite the absence of behavioral abnormalities at the larval stage, leukemic larvae show reduced locomotion in the presence of nematodes. Taken together this work establishes new Drosophila models to study the physiological- immune- and behavioral consequences of various forms of leukemia.

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Construction of a Recyclable Genetic Maker and Serial Gene Deletions in the Human Pathogenic Mucorales Mucor circinelloides

Mucor circinelloides is a human pathogen, biofuel producer, and model system that belongs to a basal fungal lineage; however, the genetics of this fungus are limited. In contrast to ascomycetes and basidiomycetes, basal fungal lineages have been understudied. This may be caused by a lack of attention given to these fungi, as well as limited tools for genetic analysis. Nonetheless, the importance of these fungi as pathogens and model systems has increased. M. circinelloides is one of a few genetically tractable organisms in the basal fungi, but it is far from a robust genetic system when compared to model fungi in the subkingdom dikarya. One problem is the organism is resistant to drugs utilized to select for dominant markers in other fungal transformation systems. Thus, we developed a blaster recyclable marker system by using the pyrG gene (encoding an orotidine-5'-phosphate decarboxylase, ortholog of URA3 in Saccharomyces cerevisiae). A 237-bp fragment downstream of the pyrG gene was tandemly incorporated into the upstream region of the gene, resulting in construction of a pyrG-dpl237 marker. To test the functionality of the pyrG-dpl237 marker, we disrupted the carp gene that is involved in carotenoid synthesis in pyrG^- mutant background. The resulting carRP::pyrG-dpl237 mutants exhibit a white-colony phenotype due to lack of carotene, whereas wild-type displays yellowish colonies. The pyrG marker was then successfully excised, generating carRP-dpl237 on 5-FOA medium. The mutants became auxotrophic and require uridine for growth. We then disrupted the calcineurin B regulatory subunit cnbR gene in the carRP::dpl237 strain, generating mutants with the alleles carRP::dpl237 and cnbR::pyrG. These results demonstrate that the recyclable marker system is fully functional, and therefore the pyrG-dpl237 marker can be used for sequential gene deletions in M. circinelloides.

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Pursuing Research Careers in Pediatrics: Hope Springs Eternal

In the last decade or more, we have heard and told the sobering tales of single digit pay lines at the National Institutes of Health (NIH) and dwindling support for research at our institutions. Given these harsh realities, it has seemed somewhat disingenuous to encourage trainees and junior faculty to pursue careers as physician scientists. As a result, the pipeline of physician-scientists has been shrinking.1 Nevertheless, several events and new realities are causing us to adopt a much more optimistic outlook.

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Simulation Testing of Pediatric Rapid Response Teams: Can Simulation Be Used to Determine the Best Team Structure?

Medical simulation and rapid response teams (RRTs) are 2 subjects whose application and effectiveness have been criticized. However, both are increasingly being integrated and expanded into the healthcare environment, including institutions that care for children. Added to this predicament is the constant effort to restructure responsibilities among healthcare providers including within medical response teams. Furthermore, there are no studies using simulation scenarios to compare the performance of RRTs led by intensivists-in-training and nurse practitioners (NPs).

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Early Intervention for Functional Somatic Symptoms Using Psychological Interventions Highlights the Need for a Medical Home Care Model for Pediatric Patients

Bonvanie et al1 explored the effectiveness of psychological interventions on the impact of physical symptoms reported by children and teens ages 6-18 years. The analysis was accomplished by performing a systematic review of the literature combining studies and analyzing data in a meta-analysis. The authors note that clear recommendations for how to approach a variety of physical complaints in the pediatric population is not known, and no best practice is established. As more evidence becomes available, it is prudent to evaluate the effectiveness of a variety of psychological approaches and to try to determine if certain complaints respond better or worse to different interventions and modalities.

http://ift.tt/2pj6HhZ

Missed Opportunities for Hepatitis A Vaccination, National Immunization Survey-Child, 2013

To quantify the number of missed opportunities for vaccination with hepatitis A vaccine in children and assess the association of missed opportunities for hepatitis A vaccination with covariates of interest.

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The Highs and Lows of Fetal Programming for Fatty Liver Disease

Birth weight is determined by a multitude of factors, such as maternal health, parity, nutritional status, genetics, as well as socioeconomic status.1-4 In utero exposures that directly affect birth weight also have epigenetic consequences for the offspring.5,6 As a result, birth weight is a marker of health, as well as an indicator of future disease risk, as suggested by the Barker hypothesis.7 Low and high birth weights (LBW and HBW), typically in conjunction with rapid weight gain early in life, have been associated with obesity8 and features of metabolic dysregulation,9 such as diabetes,10 hypertension,11 dyslipidemia,12 and atherosclerosis13 in late childhood or adulthood.

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Management of a large cystic lymphangioma causing intestinal obstruction

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Oral L-tyrosine supplementation augments the vasoconstriction response to whole body cooling in older adults

Abstract

L-tyrosine is the primary substrate for noradrenaline biosynthesis within sympathetic axon terminals. Under stressful conditions requiring increased catecholamine production, axonal L-tyrosine concentration may limit the full expression of the sympathetic effector response and this may be particularly evident in older adults. We hypothesize that oral L-tyrosine supplementation will increase the sympathetic response to whole-body cooling and muscle metaboreflex activation. In a randomized, double-blind design, eleven young (Y = 24 ± 1 years) and eleven older (O = 68 ± 4 years) participants ingested either 150 mg kg⁻¹ of L-tyrosine or placebo prior to commencing 30 minutes of whole-body cooling to induce a gradual decline in skin temperature from 34 to 30.5°C. Laser Doppler flux (LDF) was measured at the ventral forearm and cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percent change from baseline (%ΔCVC). Two minutes of static handgrip exercise (35% MVC) followed by 3 minutes of post-exercise ischaemia was implemented before and toward the end of the cooling bout. Tyrosine supplementation did not affect blood pressure or heart rate responses to exercise or post-exercise ischaemia. However, the blunted VC response to whole-body cooling in older adults (Placebo: Y = 39 ± 5; O = 16 ± 2 %ΔCVC; P < 0.05) was augmented after tyrosine supplementation (Tyrosine: Y = 40 ± 4; O = 32 ± 5 %ΔCVC; P < 0.05). These results suggest that L-tyrosine bioavailability may limit thermoregulatory function in an older population.

This article is protected by copyright. All rights reserved

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The RNA-Binding Protein SYNCRIP Promotes Leukemogenesis [Research Watch]

Depletion of the RNA-binding protein (RBP) SYNCRIP promotes leukemic cell differentiation and apoptosis.

http://ift.tt/2qBCGOj

IFN{gamma} Acts on Endothelial Cells to Promote Tumor Regression [Research Watch]

IFN induces vascular regression and tumor ischemia to initiate tumor regression.

http://ift.tt/2pj0Ucf

Bacterial Metabolism Alters the Efficacy of Chemotherapeutics [Research Watch]

Bacteria alter the response to the chemotherapeutics 5-FU, FUDR, capecitabine, and CPT in C. elegans.

http://ift.tt/2qBpjO6

Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency

The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infectio...

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Correction to: Cancer Biother Radiopharm 2017;32(3):101–110

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Intracranial lesion as onset symptom in a patient with early undifferentiated connective tissue disease: a case report

Undifferentiated connective tissue disease (UCTD) is widely considered to be a distinct clinical entity, and now divided into two subgroups: stable UCTD and early UCTD. The most frequent onset symptoms of UCTD...

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Clinical value of R-spondins in triple-negative and metaplastic breast cancers

Clinical value of R-spondins in triple-negative and metaplastic breast cancers

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.131

Authors: F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni & I Bièche

http://ift.tt/2p33eID

Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data

Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.128

Authors: Chikuma Hamada, Takuji Okusaka, Takaaki Ikari, Hiroyuki Isayama, Junji Furuse, Hiroshi Ishii, Yousuke Nakai, Shogo Imai & Shota Okamura

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Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer

Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.132

Authors: Steffen Wagner, Claus Wittekindt, Shachi Jenny Sharma, Nora Wuerdemann, Theresa Jüttner, Miriam Reuschenbach, Elena-Sophie Prigge, Magnus von Knebel Doeberitz, Stefan Gattenlöhner, Ernst Burkhardt, Jörn Pons-Kühnemann & Jens Peter Klussmann

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One-carbon metabolism in cancer

One-carbon metabolism in cancer

British Journal of Cancer advance online publication, May 4 2017. doi:10.1038/bjc.2017.118

Authors: Alice C Newman & Oliver D K Maddocks

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Melicope ptelefolia leaf extracts exhibit antioxidant activity and exert anti-proliferative effect with apoptosis induction on four different cancer cell lines

Melicope ptelefolia is a well-known herb in a number of Asian countries. It is often used as vegetable salad and traditional medicine to address various ailments. However, not many stu...

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Castanea sativa Mill. bark extract exhibits chemopreventive properties triggering extrinsic apoptotic pathway in Jurkat cells

Chemoprevention represents the possibility to prevent, stop or reverse the cancerogenetic process. In this context the interest towards natural extracts and botanical drugs has constantly grown due to their ph...

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HeartWare Splice Kit Intended to Repair the Driveline of its Ventricular Assist Device by Medtronic: Recall - May Cause Electrical Issues or Pump Stops

[Posted 05/05/2017] AUDIENCE: Cardiology, Risk Manager, Transplantation, Nursing, Patient ISSUE: Medtronic is recalling the driveline splice kit due to a design problem that would prevent the repaired cable assembly from withstanding excessive force...

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Avoiding Preventable Complications in Hospitalized Patients with CKD

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Proteins in Preservation Fluid as Predictors of Delayed Graft Function in Kidneys from Donors after Circulatory Death

Background and objectives

Kidney transplantation is the preferred treatment for ESRD, and donor kidney shortage urges proper donor-recipient matching. Zero-hour biopsies provide predictive values for short- and long-term transplantation outcomes, but are invasive and may not reflect the entire organ. Alternative, more representative methods to predict transplantation outcome are required. We hypothesized that proteins accumulating in preservation fluid during cold ischemic storage can serve as biomarkers to predict post-transplantation graft function.

Design, setting, participants, & measurements

Levels of 158 proteins were measured in preservation fluids from kidneys donated after circulatory death (Maastricht category III) collected in two Dutch centers (University Medical Center Utrecht and Erasmus Medical Center Rotterdam) between 2013 and 2015. Five candidate biomarkers identified in a discovery set of eight kidneys with immediate function (IF) versus eight with delayed graft function (DGF) were subsequently analyzed in a verification set of 40 additional preservation fluids to establish a prediction model.

Results

Variables tested for their contribution to a prediction model included five proteins (leptin, periostin, GM-CSF, plasminogen activator inhibitor-1, and osteopontin) and two clinical parameters (recipient body mass index [BMI] and dialysis duration) that distinguished between IF and DGF in the discovery set. Stepwise multivariable logistic regression provided a prediction model on the basis of leptin and GM-CSF. Receiver operating characteristic analysis showed an area under the curve (AUC) of 0.87, and addition of recipient BMI generated a model with an AUC of 0.89, outperforming the Kidney Donor Risk Index and the DGF risk calculator, showing AUCs of 0.55 and 0.59, respectively.

Conclusions

We demonstrate that donor kidney preservation fluid harbors biomarkers that, together with information on recipient BMI, predict short-term post-transplantation kidney function. Our approach is safe, easy, and performs better than current prediction algorithms, which are only on the basis of clinical parameters.

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A Population-Based Analysis of Quality Indicators in CKD

Background and objectives

Awareness of CKD remains low in comparison with other chronic diseases, such as diabetes, leading to low use of preventive medications and appropriate testing. The objective of this study was to evaluate the quality of care provided to people with and at risk of CKD.

Design, setting, participants, & measurements

We conducted a population-based analysis of all Albertans with eGFR=15–59 ml/min per 1.73 m² between April 1, 2011 and March 31, 2012 as well as patients with diabetes (as of March 31, 2012). We assessed multiple quality indicators in people with eGFR=15–59 ml/min per 1.73 m², including appropriate risk stratification with albuminuria testing and preventive medication use and screened people with diabetes using urine albumin-to-creatinine ratio and serum creatinine measurements.

Results

Among 96,480 adults with eGFR=15–59 ml/min per 1.73 m², we found that 17.0% of those without diabetes were appropriately risk stratified with a measure of albuminuria compared with 64.2% of those with diabetes (P<0.001). Of those with eGFR=15–59 ml/min per 1.73 m² and moderate or severe albuminuria, 63.2% of those without diabetes received an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker compared with 82.1% in those with diabetes (P<0.001). Statin use was also significantly lower in patients with eGFR=15–59 ml/min per 1.73 m² without diabetes (39.2%) compared with those with diabetes (64.6%; P<0.001). Among 235,649 adults with diabetes, only 41.8% received a urine albumin-to-creatinine ratio and 73.2% received a serum creatinine measurement over 1 year.

Conclusions

We identified large gaps in care, especially in those with CKD but no diabetes. The largest gap was in the prescription of guideline-concordant medication in those with CKD as well as appropriate screening for albuminuria in those with diabetes. Our work illustrates the importance of measuring health system performance as the first step in a quality improvement process to improve care and outcomes in CKD.

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HeartWare Splice Kit Intended to Repair the Driveline of its Ventricular Assist Device by Medtronic: Recall - May Cause Electrical Issues or Pump Stops

[Posted 05/05/2017] AUDIENCE: Cardiology, Risk Manager, Transplantation, Nursing, Patient ISSUE: Medtronic is recalling the driveline splice kit due to a design problem that would prevent the repaired cable assembly from withstanding excessive force...

http://ift.tt/2p5jxV7

Changes in the Profile of Endovascular Procedures Performed in Freestanding Dialysis Access Centers over 15 Years

Background and objectives

Marked changes occurred in the vascular access profile of patients receiving hemodialysis in the United States over the 15-year period of 2001–2015. This study was undertaken to evaluate how these changes have affected dialysis access maintenance and salvage procedures performed in freestanding dialysis access centers and to examine the effectiveness, efficiency, and safety of these procedures in this setting.

Design, setting, participants, & measurements

Data were collected from freestanding, dedicated dialysis access centers operating under a common system of management. Data were available on 689,676 dialysis access procedures. Data relating to case mix, procedure outcome, procedural time, and intraprocedural and immediate postprocedural complications were analyzed.

Results

The arteriovenous procedure profile changed from one characterized by approximately equal numbers of angioplasties and thrombectomies performed on arteriovenous grafts (AVGs) to one characterized primarily by angioplasties performed on arteriovenous fistulas. The percentage of angioplasties performed throughout the study was significantly greater than thrombectomies, with a mean of 67.9% versus 32.1% (P<0.001). Interventional procedures did not decrease with increasing arteriovenous fistula utilization in prevalent patients receiving dialysis. The incidence roughly paralleled the increasing prevalence of this type of access. A decreasing percentage of AVG utilization resulted in a progressive, roughly parallel, but disproportionately higher, decrease in the percentage of AVG procedures (P<0.001). A progressive improvement in procedure outcomes and a decrease in complication rates and procedure times were observed (P<0.001 for each). A progressive decrease in tunneled dialysis catheter placement was also observed.

Conclusions

The procedure profile treated in freestanding, dedicated dialysis access centers changed significantly over 15 years, reflecting the changes that have occurred in the vascular access profile of the dialysis population.

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New Organ Allocation System for Combined Liver-Kidney Transplants and the Availability of Kidneys for Transplant to Patients with Stage 4-5 CKD

A new proposal has been created for establishing medical criteria for organ allocation in recipients receiving simultaneous liver-kidney transplants. In this article, we describe the new policy, elaborate on the points of greatest controversy, and offer a perspective on the policy going forward. Although we applaud the fact that simultaneous liver-kidney transplant activity will now be monitored and appreciate the creation of medical criteria for allocation in simultaneous liver-kidney transplants, we argue that some of the criteria proposed, especially those for allocating a kidney to a liver recipient with AKI, are too liberal. We call on the nephrology community to follow the consequences of this new policy and push for a re-examination of the longstanding policy of allocating kidneys to multiorgan transplant recipients before all other candidates. The charge to protect our system of equitable organ allocation is very challenging, but it is a challenge that we must embrace.

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Can Preservation Fluid Biomarkers Predict Delayed Graft Function in Transplanted Kidneys?

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Adverse Outcomes Associated with Preventable Complications in Hospitalized Patients with CKD

Background

and objectives Patients with CKD are at risk of hospital-acquired complications (HACs). We sought to determine the association of preventable HACs with mortality, length of stay (LOS), and readmission.

Design, setting, participants, & measurements

All adults hospitalized from April of 2003 to March of 2008 in Alberta were characterized by kidney function and occurrence of preventable HACs. CKD was defined by eGFR<60 ml/min per 1.73 m² and/or albumin-to-creatinine ratio >3–30 mg/mmol for >3 months in the time frame from 365 to 90 days before admission. Regression models examined the association of HACs with outcomes.

Results

Of 536,549 hospitalizations, 8.5% (n=45,733) had CKD and 9.8% of patients with CKD had one or more potentially preventable HAC. In patients with potentially preventable HACs, proportions of death within index hospitalization and from discharge to 90 days were 17.7% and 6.8%, respectively. In patients with CKD, comparing with those hospitalizations without potentially preventable HACs, the adjusted odds ratio (OR) of mortality during index hospitalization and from hospital discharge to 90 days in patients with one or more preventable HAC was 4.67 (95% confidence interval [95% CI], 4.17 to 5.22) and 1.08 (95% CI, 0.94 to 1.25), respectively. Median incremental LOS in patients with one or more preventable HAC was 9.86 days (95% CI, 9.25 to 10.48). The OR for readmission with preventable HAC was 1.24 (95% CI, 1.15 to 1.34). In a cohort with and without CKD, the adjusted ORs of mortality during index hospitalization in patients with CKD and no preventable HACs, patients without CKD and with preventable HACs, and patients with CKD and preventable HACs were 2.22 (95% CI, 1.69 to 2.94), 5.26 (95% CI, 4.98 to 5.55), and 9.56 (95% CI, 7.23 to 12.56), respectively (referenced to patients without CKD or preventable HACs).

Conclusions

Preventable HACs are associated with higher mortality, incremental LOS, and greater risk of readmission, especially in people with CKD. Targeted strategies to reduce complications should be a high priority.

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Association of CKD with Outcomes Among Patients Undergoing Transcatheter Aortic Valve Implantation

Background and objectives

Despitethe multiple depicted associations of CKD with reduced cardiovascular and overall prognoses, the association of CKD with outcome of patients undergoing transcatheter aortic valve implantation has still not been well described.

Design, setting, participants, & measurements

Data from all hospitalized patients who underwent transcatheter aortic valve implantation procedures between January 1, 2010 and December 31, 2013 in Germany were evaluated regarding influence of CKD, even in the earlier stages, on morbidity, in-hospital outcomes, and costs.

Results

A total of 28,716 patients were treated with transcatheter aortic valve implantation. A total of 11,189 (39.0%) suffered from CKD. Patients with CKD were predominantly women; had higher rates of comorbidities, such as coronary artery disease, heart failure at New York Heart Association 3/4, peripheral artery disease, and diabetes; and had a 1.3-fold higher estimated logistic European System for Cardiac Operative Risk Evaluation value. In-hospital mortality was independently associated with CKD stage ≥3 (up to odds ratio, 1.71; 95% confidence interval, 1.35 to 2.17; P<0.05), bleeding was independently associated with CKD stage ≥4 (up to odds ratio, 1.82; 95% confidence interval, 1.47 to 2.24; P<0.001), and AKI was independently associated with CKD stages 3 (odds ratio, 1.83; 95% confidence interval, 1.62 to 2.06) and 4 (odds ratio, 2.33; 95% confidence interval, 1.92 to 2.83 both P<0.001). The stroke risk, in contrast, was lower for patients with CKD stages 4 (odds ratio, 0.23; 95% confidence interval, 0.16 to 0.33) and 5 (odds ratio, 0.24; 95% confidence interval, 0.15 to 0.39; both P<0.001). Lengths of hospital stay were, on average, 1.2-fold longer, whereas reimbursements were, on average, only 1.03-fold higher in patients who suffered from CKD.

Conclusions

This analysis illustrates for the first time on a nationwide basis the association of CKD with adverse outcomes in patients who underwent transcatheter aortic valve implantation. Thus, classification of CKD stages before transcatheter aortic valve implantation is important for appropriate risk stratification.

http://ift.tt/2pK1Gli

An Elderly Man with Fatigue, Dyspnea, and Kidney Failure

http://ift.tt/2qJzjSL

Understanding Histolopathologic Characteristics to Predict Renal Outcomes in Lupus Nephritis

http://ift.tt/2qJzptB

Clinical and Histopathologic Characteristics Associated with Renal Outcomes in Lupus Nephritis

Background and objectives

The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal outcome in LN outside the framework of the classification.

Design, setting, participants, & measurements

Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft–Gault (normalized to a body surface area of 1.73 m²) and Schwartz formulas were used to calculate eGFR for adults and children, respectively.

Results

During median follow-up of 9.9 years (25th–75th percentile, 5.9–13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio [HR], 1.04 per %; 95% confidence interval [95% CI], 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m²; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m² per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (–0.4 ml/min per 1.73 m² per %; 95% CI, –0.6 to –0.2) and age (–0.8 ml/min per 1.73 m² per year; 95% CI, –1.2 to –0.4).

Conclusion

The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.

http://ift.tt/2pK17bk

Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial

Background and objectives

Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting.

Design, setting, participants, & measurements

In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping.

Results

Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m²) from baseline to 8 weeks, was –4 (–25 to 32) in the probenecid group (P=0.83), –4 (–16 to 9) in the allopurinol group (P=0.32), and 1 (–21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was –1.6±10.1 with probenecid (P=0.43), –0.4±6.1 with allopurinol (P=0.76), and 0.5±6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively.

Conclusions

In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.

http://ift.tt/2pK1X7Q

Qualitative Interviews Exploring Palliative Care Perspectives of Latinos on Dialysis

Background and objectives

Compared with non-Latino whites with advanced illness, Latinos are less likely to have an advance directive or to die with hospice services. To improve palliative care disparities, international ESRD guidelines call for increased research on culturally responsive communication of advance care planning (ACP). The objective of our study was to explore the preferences of Latino patients receiving dialysis regarding symptom management and ACP.

Design, setting, participants, & measurements

Qualitative study design using semistructured face-to-face interviews of 20 Latinos on hemodialysis between February and July of 2015. Data were analyzed using thematic analysis.

Results

Four themes were identified: Avoiding harms of medication (fear of addiction and damage to bodies, effective distractions, reliance on traditional remedies, fatalism: the sense that one's illness is deserved punishment); barriers and facilitators to ACP: faith, family, and home (family group decision-making, family reluctance to have ACP conversations, flexible decision-making conversations at home with family, ACP conversations incorporating trust and linguistic congruency, family-first and faith-driven decisions); enhancing wellbeing day-to-day (supportive relationships, improved understanding of illness leads to adherence, recognizing new self-value, maintaining a positive outlook); and distressing aspects of living with their illness (dietary restriction is culturally isolating and challenging for families, logistic challenges and socioeconomic disadvantage compounded by health literacy and language barriers, required rapid adjustments to chronic illness, demanding dialysis schedule).

Conclusions

Latinos described unique cultural preferences such as avoidance of medications for symptom alleviation and a preference to have family group decision-making and ACP conversations at home. Understanding and integrating cultural values and preferences into palliative care offers the potential to improve disparities and achieve quality patient-centered care for Latinos with advanced illness.

http://ift.tt/2qJAFNx

Risk of Febuxostat-Associated Myopathy in Patients with CKD

Background and objectives

Febuxostat, a nonpurine xanthine oxidase inhibitor, is widely used to treat hyperuricemia. Although febuxostat-associated rhabdomyolysis was reported in some patients with CKD, the association between CKD and febuxostat-associated myopathy remains uncertain.

Design, setting, participants, & measurements

Our retrospective cohort study included 1332 patients using febuxostat in Taipei Medical University–Wanfang Hospital from February of 2014 to January of 2016. The primary predictor was time-averaged eGFR as calculated by the equation proposed by the 2009 Chronic Kidney Disease Epidemiology Collaboration. The outcome was febuxostat-associated myopathy defined as elevated creatine kinase levels during febuxostat use that were not attributed to other muscular injuries.

Results

The median duration of febuxostat use was 224 days (25th, 75th percentiles: 86, 441.5 days). Of 1332 study participants, 1222 (91.7%) had CKD; the median eGFR was 20.8 ml/min per 1.73 m² (25th, 75th percentiles: 9.0, 35.4 ml/min per 1.73 m²). Forty-one of the participants had febuxostat-associated myopathy (3.2%). All patients with myopathy had CKD, and the incident rate was 0.013 (95% confidence interval, 0.01 to 0.02) events per 100 patient-days in patients with CKD. Of 41 patients with myopathy, 37 had myositis, and four had rhabdomyolysis. Myopathy resolved in 17 patients who withdrew from treatment and eight patients who continued febuxostat treatment. Among the evaluated predictors, multivariate analysis showed that only the lowest eGFR tertile was significantly associated with myopathy in febuxostat users. The odds ratio of the lowest eGFR tertile to the highest tertile was 4.21 (95% confidence interval, 1.7 to 10.43). This finding remained consistent among subgroups stratified by age, sex, diabetes status, coronary artery disease, and statin or fibrate use.

Conclusions

Patients with severely reduced eGFR had higher risk of myopathy with treatment of febuxostat. Regular monitoring of creatine kinase level is suggested for early detection of febuxostat-associated myopathy, particularly in patients with CKD.

http://ift.tt/2pK1FxK

Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function

Background and objective

Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c–lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood.

Design, setting, participants, & measurements

This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m², eGFR≥60 to <90 ml/min per 1.73 m², and eGFR≥90 ml/min per 1.73 m²).

Results

Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (P value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (P value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients.

Conclusions

The HbA1c–lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated via nonglucosuric-dependent mechanisms.

http://ift.tt/2qJMbs6

Update on Lupus Nephritis

SLE is a chronic inflammatory disease that affects the kidneys in about 50% of patients. Lupus nephritis is a major risk factor for overall morbidity and mortality in SLE, and despite potent anti-inflammatory and immunosuppressive therapies still ends in CKD or ESRD for too many patients. This review highlights recent updates in our understanding of disease epidemiology, genetics, pathogenesis, and treatment in an effort to establish a framework for lupus nephritis management that is patient-specific and oriented toward maintaining long-term kidney function in patients with lupus.

http://ift.tt/2pJUh5o

Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study

Background and objectives

CKD is an important risk factor for cardiovascular disease (CVD) and death. We investigated whether select urine kidney injury biomarkers were associated with higher risk of heart failure (HF), CVD, and death in persons with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Design, setting, participants, & measurements

Urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, and N-acetyl-β-d-glucosaminidase were measured in urine of a subset of CRIC participants (n=2466). We used Cox proportional hazards regression to examine associations between these biomarkers indexed to urinary creatinine (Cr) and (1) HF, (2) a composite of atherosclerotic CVD events (myocardial infarction, ischemic stroke, or peripheral artery disease), and (3) all-cause death.

Results

At baseline, mean age of study participants was 59.5±10.8 years, 46% were women, and 34% had a self-reported history of any CVD. Median follow-up was 6.5 (interquartile range, 5.6–6.8) years. A total of 333 HF events, 282 atherosclerotic CVD events, and 440 deaths were observed during a median follow-up of 6.5 (interquartile range, 5.6–6.8) years. Those in the highest two quintiles of KIM-1/Cr levels had a higher risk of HF relative to the lowest quintile (quintile 5 versus quintile 1 adjusted hazard ratio [aHR] of 1.73 [95% confidence interval, 1.05 to 2.85]). N-acetyl-β-d-glucosaminidase/Cr was associated with HF in continuous analyses (aHR per log SD higher 1.18 [95% confidence interval, 1.01 to 1.38]). Only KIM-1/Cr was independently associated with atherosclerotic CVD events (aHR per log SD higher 1.21 [95% confidence interval, 1.02 to 1.41]), whereas both KIM-1/Cr (quintile 5 versus quintile 1 aHR of 1.56 [95% confidence interval, 1.06 to 2.31]) and neutrophil gelatinase-associated lipocalin/Cr (quintile 5 versus quintile 1 aHR of 1.82 [95% confidence interval, 1.19 to 2.8]) were associated with all-cause death.

Conclusions

Selected urine kidney injury biomarkers were independently associated with higher risk of HF, CVD events, and death in CRIC. Among the biomarkers examined, only KIM-1/Cr was associated with each outcome. Further work is needed to determine the utility of these biomarkers to improve risk prediction for these adverse outcomes.

http://ift.tt/2qJD9eC

The Use of a Multidimensional Measure of Dialysis Adequacy--Moving beyond Small Solute Kinetics

Urea removal has become a key measure of the intensity of dialysis treatment for kidney failure. Small solute removal, exemplified by Kt/V_urea, has been broadly applied as a means to quantify the dose of thrice weekly hemodialysis. Yet, the reliance on small solute clearances alone as a measure of dialysis adequacy fails fully to quantify the intended clinical effects of dialysis therapy. This review aims to (1) understand the strengths and limitations of small solute kinetics as a surrogate marker of dialysis dose, and (2) present the prospect of a more comprehensive construct for dialysis dose, one that considers more broadly the goals of ESRD care to maximize both quality of life and survival. On behalf of the American Society of Nephrology Dialysis Advisory Group, we propose the need to ascertain the validity and utility of a multidimensional measure that moves beyond small solute kinetics alone to quantify optimal dialysis derived from both patient-reported and comprehensive clinical and dialysis-related measures.

http://ift.tt/2pK3c71

Immunogenicity of Augmented Compared With Standard Dose Hepatitis B Vaccine in Pediatric Patients on Dialysis: a Midwest Pediatric Nephrology Consortium Study

Background and objectives

Patients on maintenance dialysis have a higher risk of unresponsiveness to hepatitis B vaccination and loss of hepatitis B immunity. Adult guidelines recommend augmented dosing (40 mcg/dose), resulting in improved response in adults. We sought to determine whether children on dialysis mount a similar antibody response when given standard or augmented dosing of hepatitis B vaccine.

Design, setting, participants, & measurements

This is a retrospective review of patients on dialysis aged <19 years from May 1, 2008 to May 1, 2013 at 12 pediatric dialysis units. Hepatitis B surface antibody (HBsAb) titers ≥10 mIU/ml were defined as protective.

Results

A total of 187 out of 417 patients received one or more hepatitis B vaccine boosters. The median age was 13 years; the cohort was 57% boys and 59% white. Booster dose or HBsAb titers were missing in 17 patients. Conversion to protective HBsAb titers was achieved in 135 out of 170 patients (79%) after their first single-dose booster or multidose booster series. In patients receiving a single-dose booster, the response rate was 53% (nine out of 17) after a 10 mcg dose, 86% (65 out of 76) after a 20 mcg dose, and 65% (17 out of 26) after a 40 mcg hepatitis B vaccine dose. In patients receiving a multidose booster series, the response rate was 95% (19 out of 20) after a 10 mcg/dose series, 83% (20 out of 24) after a 20 mcg/dose series, and 71% (five out of seven) after a 40 mcg/dose series. Patients receiving a multidose booster series had a response rate of 86% (44 out of 51), compared with 76% (91 out of 119) in patients receiving a single-dose booster (P=0.21). Twenty-seven patients received more than one single-dose booster or multidose series, and 26 out of 27 (96%) eventually gained immunity after receiving one to three additional single-dose boosters or multidose booster series.

Conclusions

There was no clear gradient of increasing seroconversion rate with increasing vaccine dose in this cohort of pediatric patients on dialysis.

http://ift.tt/2qJTro3

CYP450 genotype and aggressive behavior on selective serotonin reuptake inhibitors

Pharmacogenomics Ahead of Print.


http://ift.tt/2qJF17g

Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing

Pharmacogenomics Ahead of Print.


http://ift.tt/2pJUSUR

Serum clomipramine and desmethylclomipramine levels in a CYP2C19 and CYP2D6 intermediate metabolizer

Pharmacogenomics Ahead of Print, Pages 00-00.


http://ift.tt/2qK1kcY

Polymorphisms associated with etanercept response in moderate-to-severe plaque psoriasis

Pharmacogenomics Ahead of Print.


http://ift.tt/2pK8sHH

OCT1 genetic variants are associated with postoperative morphine-related adverse effects in children

Pharmacogenomics Ahead of Print.


http://ift.tt/2qJJK8X

Pharmacogenomics in pediatric acute lymphoblastic leukemia: promises and limitations

Pharmacogenomics Ahead of Print.


http://ift.tt/2pJUQfH

Understanding cancer lineage plasticity: reversing therapeutic resistance in metastatic prostate cancer

Pharmacogenomics Ahead of Print.


http://ift.tt/2qJJrei

Analysis of Cell Suspensions Isolated from Solid Tissues by Spectral Flow Cytometry

This article describes spectral cytometry, a new approach in flow cytometry that uses the shapes of emission spectra to distinguish fluorochromes. An algorithm replaces compensations and can treat auto-fluorescence as an independent parameter. This new approach allows for the proper analysis of cells isolated from solid organs.

http://ift.tt/2p5B9Am

Poppers retinopathy

Joshua Luis<br />Mar 7, 2016; 2016:bcr2016214442-bcr2016214442<br />case-report

http://ift.tt/2p5BlQ9

Use of ticagrelor in human pregnancy, the first experience

Marjan Verbruggen<br />Nov 25, 2015; 2015:bcr2015212217-bcr2015212217<br />case-report

http://ift.tt/2qMqnvf

Heterotopic ossification of the elbows in a major petrol burn

Shahriar Raj Zaman<br />Aug 27, 2012; 2012:bcr0320126027-bcr0320126027<br />case-report

http://ift.tt/2qMFxk4

Maxillary sinusitis with pulmonary tuberculosis

Rashmi Upadhyay<br />Aug 1, 2014; 2014:bcr2014203952-bcr2014203952<br />case-report

http://ift.tt/2qMoQVN

Pleural effusion caused by a malpositioned umbilical venous catheter in a neonate

Thangaraj Abiramalatha<br />Oct 30, 2015; 2015:bcr2015212705-bcr2015212705<br />case-report

http://ift.tt/2p5j6dj

Cutaneous and pleural involvement in a patient with multiple myeloma

Olfa Saidane<br />Oct 5, 2015; 2015:bcr2015211197-bcr2015211197<br />case-report

http://ift.tt/2qMGZmE

Molecular detection of Schizophyllum commune in a case of allergic fungal rhinosinusitis

Prashant Gupta<br />May 24, 2015; 2015:bcr2015209955-bcr2015209955<br />case-report

http://ift.tt/2p5JDaz

Steroid unresponsive anti-NMDA receptor encephalitis during pregnancy successfully treated with plasmapheresis

Lokesh Shahani<br />Apr 29, 2015; 2015:bcr2014208823-bcr2014208823<br />case-report

http://ift.tt/2qMBPHh

Actinomyces meyeri brain abscess following dental extraction

U Clancy<br />Apr 13, 2015; 2015:bcr2014207548-bcr2014207548<br />case-report

http://ift.tt/2p5JEeD

Rothia aeria: a great mimicker of the Nocardia species

Takeshi Saraya<br />Dec 3, 2014; 2014:bcr2014206349-bcr2014206349<br />case-report

http://ift.tt/2qMv5sS

Potential involvement of Campylobacter curvus and Haemophilus parainfluenzae in preterm birth

George Louis Mendz<br />Oct 1, 2014; 2014:bcr2014205282-bcr2014205282<br />case-report

http://ift.tt/2p58qvA

Calvarial and cutaneous metastasis as the primary presentation of a renal cell carcinoma

Tarun Jindal<br />May 19, 2014; 2014:bcr2013202830-bcr2013202830<br />case-report

http://ift.tt/2p5E9Nd

Fatal Bipolaris spicifera infection in an immunosuppressed child

Carlos G Teran<br />Feb 3, 2014; 2014:bcr2013009703-bcr2013009703<br />case-report

http://ift.tt/2qMqkQ5

Subcutaneous endometriosis: a rare cause of deep dyspareunia

Aruna Nigam<br />Jan 6, 2014; 2014:bcr2013202230-bcr2013202230<br />case-report

http://ift.tt/2p5tT7G

Quetiapine-induced manic episode: a paradox for contemplation

Sundar Gnanavel<br />Dec 4, 2013; 2013:bcr2013201761-bcr2013201761<br />case-report

http://ift.tt/2qMrsTE

Enterobius vermicularis infection of the ovary

George Powell<br />Oct 31, 2013; 2013:bcr2013201146-bcr2013201146<br />case-report

http://ift.tt/2p5iHry

Primary disseminated extrahepatic abdominal hydatid cyst: a rare disease

Jitendra Kumar Kushwaha<br />May 30, 2012; 2012:bcr0220125808-bcr0220125808<br />case-report

http://ift.tt/2p5teD5

Autoimmune pernicious anaemia as a cause of collapse, heart failure and marked panyctopaenia in a young patient

Justin Carey<br />May 8, 2012; 2012:bcr0120125576-bcr0120125576<br />case-report

http://ift.tt/2qMpumg

Still dizzy after all these years: a 90-year-old woman with a 54-year history of dizziness

Alina Smirnova<br />Sep 15, 2011; 2011:bcr0520114247-bcr0520114247<br />case-report

http://ift.tt/2p5rU2V

Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model

Abstract

Clearance of amyloid-beta (Aβ) from the brain is an important therapeutic strategy for Alzheimer's disease (AD). Current studies mainly focus on the central approach of Aβ clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in clearing brain-derived Aβ, suggesting that the peripheral approach of removing Aβ from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces brain Aβ burden and attenuates AD-type pathologies and cognitive impairments. Thirty patients with newly diagnosed CKD were enrolled. The plasma Aβ concentrations of the patients were measured before and after peritoneal dialysis. APP/PS1 mice were subjected to peritoneal dialysis once a day for 1 month from 6 months of age (prevention study) or 9 months of age (treatment study). The Aβ in the interstitial fluid (ISF) was collected using microdialysis. Behavioural performance, long-term potentiation (LTP), Aβ burden and other AD-type pathologies were measured after 1 month of peritoneal dialysis. Peritoneal dialysis significantly reduced plasma Aβ levels in both CKD patients and APP/PS1 mice. Aβ levels in the brain ISF of APP/PS1 mice immediately decreased after reduction of Aβ in the blood during peritoneal dialysis. In both prevention and treatment studies, peritoneal dialysis substantially reduced Aβ deposition, attenuated other AD-type pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, and synaptic dysfunction, and rescued the behavioural deficits of APPswe/PS1 mice. Importantly, the Aβ phagocytosis function of microglia was enhanced in APP/PS1 mice after peritoneal dialysis. Our study suggests that peritoneal dialysis is a promising therapeutic method for AD, and Aβ clearance using a peripheral approach could be a desirable therapeutic strategy for AD.

http://ift.tt/2qJAdyB

'Crochetage sign on ECG in secundum ASD: clinical significance

Pranab Jyoti Bhattacharyya<br />Oct 8, 2016; 2016:bcr2016217817-bcr2016217817<br />case-report

http://ift.tt/2pJJkkq

Multimer-PAGE: A Method for Capturing and Resolving Protein Complexes in Biological Samples

A method for stabilizing and separating native protein complexes from unmodified tissue lysate using an amine-reactive protein cross-linker coupled to a novel two-dimensional polyacrylamide gel electrophoresis (PAGE) system is presented.

http://ift.tt/2pOQJQ5

Cancers, Vol. 9, Pages 44: HGF/Met Signaling in Cancer Invasion: The Impact on Cytoskeleton Remodeling

The invasion of cancer cells into surrounding tissue and the vasculature is essential for tumor metastasis. Increasing evidence indicates that hepatocyte growth factor (HGF) induces cancer cell migration and invasion. A broad spectrum of mechanisms underlies cancer cell migration and invasion. Cytoskeletal reorganization is of central importance in the development of the phenotype of cancer cells with invasive behavior. Through their roles in cell mechanics, intracellular trafficking, and signaling, cytoskeleton proteins participate in all essential events leading to cell migration. HGF has been involved in cytoskeleton assembly and reorganization, and its role in regulating cytoskeleton dynamics is still expanding. This review summarizes our current understanding of the role of HGF in regulating cytoskeleton remodeling, distribution, and interactions.

http://ift.tt/2qIrahl

Nanoparticles Create Effective CAR T Cells in Living Mice

Researchers have developed a method to genetically engineer cancer-fighting immune cells in living animals using nanoparticles that carry DNA. The new study shows that the resulting immune cells, known as CAR T cells, eliminated leukemia in mice.

http://ift.tt/2q7WBEQ

Identification of Plant Ice-binding Proteins Through Assessment of Ice-recrystallization Inhibition and Isolation Using Ice-affinity Purification

This paper outlines the identification of ice-binding proteins from freeze-tolerant plants through the assessment of ice-recrystallization inhibition activity and subsequent isolation of native IBPs using ice-affinity purification.

http://ift.tt/2phH6WW

Contribution of QSM Imaging to the Diagnosis of the Rare Syndrome of Leukoencephalopathy with Cysts and Calcification (LCC)

Abstract

We describe the typical computed tomography (CT) and magnetic resonance imaging (MRI) characteristics in a rare case of adult leukoencephalopathy with calcifications and cysts (LCC). In addition, we describe the specific findings of quantified susceptibility mapping (QSM) in this case, relate it to known histopathological findings, and point out possible advantages of this method.

http://ift.tt/2qAw7M1

Value of Flat-detector Computed Tomography Angiography with Intravenous Contrast Media Injection in the Evaluation and Treatment of Acutely Ruptured Aneurysms of the AcomA complex: A Single Center Experience in 15 Cases

Abstract

Objective

To illustrate the added value of flat-detector computed tomography angiography with intravenous contrast media injection (intravenous FDCTA) in the evaluation of complex A1/A2/AcomA aneurysms.

Patients and Methods

We retrospectively reviewed 15 patients with ruptured aneurysms. In each patient, an intravenous FDCTA was performed and its diagnostic value investigated.

Results

In all patients, FDCTA contributed relevant additional information concerning the anatomy of the A1/A2/AcomA complex and the relationship of the aneurysm neck to these vascular structures, which could not be gained by 2D- and 3D-DSA, and changed the management in 33% of the patients (5 out of 15). In an additional 5 cases, knowledge of the detailed anatomy was helpful to plan the exact stent position.

Conclusion

In case of complex A1/A2/AcomA aneurysms, intravenous FDCTA is an effective option to visualize the exact location of the aneurysm neck and the relationship between the aneurysm and the adjacent vessels. Thus, it is of significant added value in the precise planning of a therapeutic strategy.

http://ift.tt/2pODsVB

Hepatitis B virus X protein: TRIMming antiviral defences in hepatocytes

Humans and viruses have coevolved over thousands of years; however, very few viruses are able to manifest as chronic infections with most being cleared after an acute course. Consequently, success of the human species has relied on a functional immune system that is capable of fighting off most viral pathogens. The heptatitis B virus (HBV)  is one of the most successful viruses to establish chronic infection in man with over 300 million individuals currently infected worldwide and over 2 billion humans having been infected by this virus.1 These numbers underscore the tremendous ability of HBV to thwart the human immune system and establish chronic infection. In this issue of Gut, Lim et al2 have provided evidence for a new mechanism through which HBV is able to establish and maintain chronic infection.

They specifically examine the role of the enigmatic HBx protein3 in the regulation of TRIM22,...

http://ift.tt/2qAXN3v

Chromosomal instability in HCC: a key function for checkpoint kinase 2

The German cytologist Theodor Boveri proposed about 100 years ago that cancer is caused by an abnormal distribution of microscopic bodies called chromosomes. At that time, researchers had no idea of the cellular component for inheritance and challenged his hypothesis. Meanwhile, genomic instability is viewed as a hallmark of cancer1 and an alternative model for cancer formation was put forward that proposed acquisition of a 'mutator' phenotype as the initiating event. Although supported by the vast plasticity of sequence changes and chromosomal aberrations in individual cells of single tumours, these observations did not solve the issue whether the 'mutator' phenotype is a precondition or a consequence of tumourigenesis.

The 'mutator' phenotype is causative for genomic instability, an umbrella term for small DNA structure variations, microsatellite instability and chromosomal instability (CIN).2 The latter affects chromosome number and structure and is a characteristic feature of many cancer types including hepatocellular...

http://ift.tt/2qJ1dyo

Plunge Freezing: A Tool for the Ultrastructural and Immunolocalization Studies of Suspension Cells in Transmission Electron Microscopy

This manuscript describes an easy-to-use and low-cost cryofixation method for visualizing suspension cells by transmission electron microscopy.

http://ift.tt/2pIYWor

From Pine Cones to Read Clouds: Rescaffolding the Megagenome of Sugar Pine (Pinus lambertiana)

We investigate the utility and scalability of new read cloud technologies to improve the draft genome assemblies of the colossal, and largely repetitive, genomes of conifers. Synthetic long read technologies have existed in various forms as a means of reducing complexity and resolving repeats since the outset of genome assembly. Recently, technologies that combine subhaploid pools of high molecular weight DNA with barcoding on a massive scale have brought new efficiencies to sample preparation and data generation. When combined with inexpensive light shotgun sequencing, the resulting data can be used to scaffold large genomes. The protocol is efficient enough to consider routinely for even the largest genomes. Conifers represent the largest reference genome projects executed to date. The largest of these is that of the conifer Pinus lambertiana (sugar pine), with a genome size of 31 billion bp. In this paper, we report on the molecular and computational protocols for scaffolding the P. lambertiana genome using the library technology from 10x Genomics. At 247,000 bp, the NG50 of the existing reference sequence is the highest scaffold contiguity among the currently published conifer assemblies; this new assembly's NG50 is 1.94 million bp, an eightfold increase.

http://ift.tt/2qJbElx

Genotype Calling from Population-Genomic Sequencing Data

Genotype calling plays important roles in population-genomic studies, which have been greatly accelerated by sequencing technologies. To take full advantage of the resultant information, we have developed maximum-likelihood (ML) methods for calling genotypes from high-throughput sequencing data. As the statistical uncertainties associated with sequencing data depend on depths of coverage, we have developed two types of genotype callers. One approach is appropriate for low-coverage sequencing data, and incorporates population-level information on genotype frequencies and error rates pre-estimated by an ML method. Performance evaluation using computer simulations and human data shows that the proposed framework yields less biased estimates of allele frequencies and more accurate genotype calls than current widely used methods. Another type of genotype caller applies to high-coverage sequencing data, requires no prior genotype-frequency estimates, and makes no assumption on the number of alleles at a polymorphic site. Using computer simulations, we determine the depth of coverage necessary to accurately characterize polymorphisms using this second method. We applied the proposed method to high-coverage (mean 18x) sequencing data of 83 clones from a population of Daphnia pulex. The results show that the proposed method enables conservative and reasonably powerful detection of polymorphisms with arbitrary numbers of alleles. We have extended the proposed method to the analysis of genomic data for polyploid organisms, showing that calling accurate polyploid genotypes requires much higher coverage than diploid genotypes.

http://ift.tt/2q7Feny

Modulating Crossover Frequency and Interference for Obligate Crossovers in Saccharomyces cerevisiae Meiosis

Meiotic crossover frequencies show wide variation among organisms. But most organisms maintain at least one crossover per homolog pair (obligate crossover). In Saccharomyces cerevisiae, previous studies have shown crossover frequencies are reduced in the mismatch repair related mutant mlh3 and enhanced in a meiotic checkpoint mutant pch2 by up to twofold at specific chromosomal loci, but both mutants maintain high spore viability. We analyzed meiotic recombination events genome-wide in mlh3, pch2, and mlh3 pch2 mutants to test the effect of variation in crossover frequency on obligate crossovers. mlh3 showed ~30% genome-wide reduction in crossovers (64 crossovers per meiosis) and loss of the obligate crossover, but nonexchange chromosomes were efficiently segregated. pch2 showed ~50% genome-wide increase in crossover frequency (137 crossovers per meiosis), elevated noncrossovers as well as loss of chromosome size dependent double-strand break formation. Meiotic defects associated with pch2 did not cause significant increase in nonexchange chromosome frequency. Crossovers were restored to wild-type frequency in the double mutant mlh3 pch2 (100 crossovers per meiosis), but obligate crossovers were compromised. Genetic interference was reduced in mlh3, pch2, and mlh3 pch2. Triple mutant analysis of mlh3 pch2 with other resolvase mutants showed that most of the crossovers in mlh3 pch2 are made through the Mus81-Mms4 pathway. These results are consistent with a requirement for increased crossover frequencies in the absence of genetic interference for obligate crossovers. In conclusion, these data suggest crossover frequencies and the strength of genetic interference in an organism are mutually optimized to ensure obligate crossovers.

http://ift.tt/2qIYFA5

A New Reference Genome Assembly for the Microcrustacean Daphnia pulex

Comparing genomes of closely related genotypes from populations with distinct demographic histories can help reveal the impact of effective population size on genome evolution. For this purpose, we present a high quality genome assembly of Daphnia pulex (PA42), and compare this with the first sequenced genome of this species (TCO), which was derived from an isolate from a population with >90% reduction in nucleotide diversity. PA42 has numerous similarities to TCO at the gene level, with an average amino acid sequence identity of 98.8 and >60% of orthologous proteins identical. Nonetheless, there is a highly elevated number of genes in the TCO genome annotation, with ~7000 excess genes appearing to be false positives. This view is supported by the high GC content, lack of introns, and short length of these suspicious gene annotations. Consistent with the view that reduced effective population size can facilitate the accumulation of slightly deleterious genomic features, we observe more proliferation of transposable elements (TEs) and a higher frequency of gained introns in the TCO genome.

http://ift.tt/2qJ41LT

A Bayesian Poisson-lognormal Model for Count Data for Multiple-Trait Multiple-Environment Genomic-Enabled Prediction

When a plant scientist wishes to make genomic-enabled predictions of multiple traits measured in multiple individuals in multiple environments, the most common strategy for performing the analysis is to use a single trait at a time taking into account genotype x environment interaction (G x E), because there is a lack of comprehensive models that simultaneously take into account the correlated counting traits and G x E. For this reason, in this study we propose a multiple-trait and multiple-environment model for count data. The proposed model was developed under the Bayesian paradigm for which we developed a Markov Chain Monte Carlo (MCMC) with noninformative priors. This allows obtaining all required full conditional distributions of the parameters leading to an exact Gibbs sampler for the posterior distribution. Our model was tested with simulated data and a real data set. Results show that the proposed multi-trait, multi-environment model is an attractive alternative for modeling multiple count traits measured in multiple environments.

http://ift.tt/2qJ9SRs

Dynamic Notch Signaling Specifies Each Cell Fate in Drosophila Spermathecal Lineage

Spermathecae are glandular organs in the insect female reproductive tract that play essential roles in insect reproduction; however, the molecular mechanism involved in their development is largely unknown. Drosophila spermathecae consist of class-III secretory units, in which each secretory cell (SC) discharges its products to the central lumen through an end-apparatus and a canal. Secretory unit formation in Drosophila spermathecae utilizes a fixed cell lineage, in which each secretory unit precursor (SUP) divides to produce one pIIb cell and one pIIa cell. The former differentiates into an apical cell (AC), whereas the latter divides again to produce an SC and a basal cell (BC). It is unclear how each cell acquires its identity and contributes to secretory unit formation. Here, we demonstrate that Notch signaling is required and sufficient for the specification of lumen epithelial precursors (LEPs; vs. SUPs), pIIb (vs. pIIa), and SCs (vs. BCs) sequentially. To our surprise, Notch activation in LEPs and SCs apparently utilizes different ligand mechanisms. In addition, Notch signaling both suppresses and activates transcription factors Hindsight (Hnt) and Cut during spermathecal lineage specification, supporting the notion that Notch signaling can have opposite biological outcomes in different cellular environments. Furthermore, LEP-derived epithelial cells (ECs) and ACs show distinct cellular morphology and are essential for securing secretory units to the epithelial lumen. Our work demonstrates, for the first time, the dynamic role of Notch signaling in binary cell fate determination in Drosophila spermathecae and the role of ECs and ACs in secretory unit formation.

http://ift.tt/2q7WadN

TheCellMap.org: A Web-Accessible Database for Visualizing and Mining the Global Yeast Genetic Interaction Network

Providing access to quantitative genomic data is key to ensure large-scale data validation and promote new discoveries. TheCellMap.org serves as a central repository for storing and analyzing quantitative genetic interaction data produced by genome-scale Synthetic Genetic Array (SGA) experiments with the budding yeast Saccharomyces cerevisiae. In particular, TheCellMap.org allows users to easily access, visualize, explore, and functionally annotate genetic interactions, or to extract and reorganize subnetworks, using data-driven network layouts in an intuitive and interactive manner.

http://ift.tt/2qJd7Zc

Reliable CRISPR/Cas9 Genome Engineering in Caenorhabditis elegans Using a Single Efficient sgRNA and an Easily Recognizable Phenotype

CRISPR/Cas9 genome engineering strategies allow the directed modification of the Caenorhabditis elegans genome to introduce point mutations, generate knock-out mutants, and insert coding sequences for epitope or fluorescent tags. Three practical aspects, however, complicate such experiments. First, the efficiency and specificity of single-guide RNAs (sgRNA) cannot be reliably predicted. Second, the detection of animals carrying genome edits can be challenging in the absence of clearly visible or selectable phenotypes. Third, the sgRNA target site must be inactivated after editing to avoid further double-strand break events. We describe here a strategy that addresses these complications by transplanting the protospacer of a highly efficient sgRNA into a gene of interest to render it amenable to genome engineering. This sgRNA targeting the dpy-10 gene generates genome edits at comparatively high frequency. We demonstrate that the transplanted protospacer is cleaved at the same time as the dpy-10 gene. Our strategy generates scarless genome edits because it no longer requires the introduction of mutations in endogenous sgRNA target sites. Modified progeny can be easily identified in the F1 generation, which drastically reduces the number of animals to be tested by PCR or phenotypic analysis. Using this strategy, we reliably generated precise deletion mutants, transcriptional reporters, and translational fusions with epitope tags and fluorescent reporter genes. In particular, we report here the first use of the new red fluorescent protein mScarlet in a multicellular organism. wrmScarlet, a C. elegans-optimized version, dramatically surpassed TagRFP-T by showing an eightfold increase in fluorescence in a direct comparison.

http://ift.tt/2q7Mf88

Distinct Patterns of Gene Gain and Loss: Diverse Evolutionary Modes of NBS-Encoding Genes in Three Solanaceae Crop Species

Plant resistance conferred by nucleotide binding site (NBS)-encoding resistance genes plays a key role in the defense against various pathogens throughout the entire plant life cycle. However, comparative analyses for the systematic evaluation and determination of the evolutionary modes of NBS-encoding genes among Solanaceae species are rare. In this study, 447, 255, and 306 NBS-encoding genes were identified from the genomes of potato, tomato, and pepper, respectively. These genes usually clustered as tandem arrays on chromosomes; few existed as singletons. Phylogenetic analysis indicated that three subclasses [TNLs (TIR-NBS-LRR), CNLs (CC-NBS-LRR), and RNLs (RPW8-NBS-LRR)] each formed a monophyletic clade and were distinguished by unique exon/intron structures and amino acid motif sequences. By comparing phylogenetic and systematic relationships, we inferred that the NBS-encoding genes in the present genomes of potato, tomato, and pepper were derived from 150 CNL, 22 TNL, and 4 RNL ancestral genes, and underwent independent gene loss and duplication events after speciation. The NBS-encoding genes therefore exhibit diverse and dynamic evolutionary patterns in the three Solanaceae species, giving rise to the discrepant gene numbers observed today. Potato shows a "consistent expansion" pattern, tomato exhibits a pattern of "first expansion and then contraction," and pepper presents a "shrinking" pattern. The earlier expansion of CNLs in the common ancestor led to the dominance of this subclass in gene numbers. However, RNLs remained at low copy numbers due to their specific functions. Along the evolutionary process of NBS-encoding genes in Solanaceae, species-specific tandem duplications contributed the most to gene expansions.

http://ift.tt/2q7BcM5

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2. While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice.

http://ift.tt/2qJ9UZA

Accurate Classification of Protein Subcellular Localization from High-Throughput Microscopy Images Using Deep Learning

High-throughput microscopy of many single cells generates high-dimensional data that are far from straightforward to analyze. One important problem is automatically detecting the cellular compartment where a fluorescently-tagged protein resides, a task relatively simple for an experienced human, but difficult to automate on a computer. Here, we train an 11-layer neural network on data from mapping thousands of yeast proteins, achieving per cell localization classification accuracy of 91%, and per protein accuracy of 99% on held-out images. We confirm that low-level network features correspond to basic image characteristics, while deeper layers separate localization classes. Using this network as a feature calculator, we train standard classifiers that assign proteins to previously unseen compartments after observing only a small number of training examples. Our results are the most accurate subcellular localization classifications to date, and demonstrate the usefulness of deep learning for high-throughput microscopy.

http://ift.tt/2q7Glnm

Aging Effects of Caenorhabditis elegans Ryanodine Receptor Variants Corresponding to Human Myopathic Mutations

Delaying the decline in skeletal muscle function will be critical to better maintenance of an active lifestyle in old age. The skeletal muscle ryanodine receptor, the major intracellular membrane channel through which calcium ions pass to elicit muscle contraction, is central to calcium ion balance and is hypothesized to be a significant factor for age-related decline in muscle function. The nematode Caenorhabditis elegans is a key model system for the study of human aging, and strains were generated with modified C. elegans ryanodine receptors corresponding to human myopathic variants linked with malignant hyperthermia and related conditions. The altered response of these strains to pharmacological agents reflected results of human diagnostic tests for individuals with these pathogenic variants. Involvement of nerve cells in the C. elegans responses may relate to rare medical symptoms concerning the central nervous system that have been associated with ryanodine receptor variants. These single amino acid modifications in C. elegans also conferred a reduction in lifespan and an accelerated decline in muscle integrity with age, supporting the significance of ryanodine receptor function for human aging.

http://ift.tt/2qJhpQ8

Genomic Comparison of Indigenous African and Northern European Chickens Reveals Putative Mechanisms of Stress Tolerance Related to Environmental Selection Pressure

Global climate change is increasing the magnitude of environmental stressors, such as temperature, pathogens, and drought, that limit the survivability and sustainability of livestock production. Poultry production and its expansion is dependent upon robust animals that are able to cope with stressors in multiple environments. Understanding the genetic strategies that indigenous, noncommercial breeds have evolved to survive in their environment could help to elucidate molecular mechanisms underlying biological traits of environmental adaptation. We examined poultry from diverse breeds and climates of Africa and Northern Europe for selection signatures that have allowed them to adapt to their indigenous environments. Selection signatures were studied using a combination of population genomic methods that employed F_ST, integrated haplotype score (iHS), and runs of homozygosity (ROH) procedures. All the analyses indicated differences in environment as a driver of selective pressure in both groups of populations. The analyses revealed unique differences in the genomic regions under selection pressure from the environment for each population. The African chickens showed stronger selection toward stress signaling and angiogenesis, while the Northern European chickens showed more selection pressure toward processes related to energy homeostasis. The results suggest that chromosomes 2 and 27 are the most diverged between populations and the most selected upon within the African (chromosome 27) and Northern European (chromosome 2) birds. Examination of the divergent populations has provided new insight into genes under possible selection related to tolerance of a population's indigenous environment that may be baselines for examining the genomic contribution to tolerance adaptions.

http://ift.tt/2q7IYFR

Schizosaccharomyces pombe MutS{alpha} and MutL{alpha} Maintain Stability of Tetra-Nucleotide Repeats and Msh3 of Hepta-Nucleotide Repeats

Defective mismatch repair (MMR) in humans is associated with colon cancer and instability of microsatellites, that is, DNA sequences with one or several nucleotides repeated. Key factors of eukaryotic MMR are the heterodimers MutSα (Msh2-Msh6), which recognizes base-base mismatches and unpaired nucleotides in DNA, and MutLα (Mlh1-Pms1), which facilitates downstream steps. In addition, MutSβ (Msh2-Msh3) recognizes DNA loops of various sizes, although our previous data and the data presented here suggest that Msh3 of Schizosaccharomyces pombe does not play a role in MMR. To test microsatellite stability in S. pombe and hence DNA loop repair, we have inserted tetra-, penta-, and hepta-nucleotide repeats in the ade6 gene and determined their Ade⁺ reversion rates and spectra in wild type and various mutants. Our data indicate that loops with four unpaired nucleotides in the nascent and the template strand are the upper limit of MutSα- and MutLα-mediated MMR in S. pombe. Stability of hepta-nucleotide repeats requires Msh3 and Exo1 in MMR-independent processes as well as the DNA repair proteins Rad50, Rad51, and Rad2^FEN1. Most strikingly, mutation rates in the double mutants msh3 exo1 and msh3 rad51 were decreased when compared to respective single mutants, indicating that Msh3 prevents error prone processes carried out by Exo1 and Rad51. We conclude that Msh3 has no obvious function in MMR in S. pombe, but contributes to DNA repeat stability in MMR-independent processes.

http://ift.tt/2qJ8pdZ

Genotyping-by-Sequencing Facilitates a High-Density Consensus Linkage Map for Aegilops umbellulata, a Wild Relative of Cultivated Wheat

High-density genetic maps are useful to precisely localize QTL or genes that might be used to improve traits of nutritional and/or economical importance in crops. However, high-density genetic maps are lacking for most wild relatives of crop species, including wheat. Aegilops umbellulata is a wild relative of wheat known for its potential as a source of biotic and abiotic stress resistance genes. In this work, we have developed a framework consensus genetic map using two biparental populations derived from accessions PI 298905, PI 542369, PI 5422375, and PI 554395. The framework map comprised 3009 genotype-by-sequence SNPs with a total map size of 948.72 cM. On average, there were three SNPs per centimorgan for each chromosome. Chromosome 1U was the shortest (66.5 cM), with only 81 SNPs, whereas the remaining chromosomes had between 391 and 591 SNP markers. A total of 2395 unmapped SNPs were added to the linkage maps through a recombination frequency approach, and increased the number of SNPs placed on the consensus map to a total of 5404 markers. Segregation distortion was disproportionally high for chromosome 1U for both populations used to construct component linkage maps, and thus segregation distortion could be one of the probable reasons for the exceptionally reduced linkage size for chromosome 1U. From comparative analysis, Ae. umbellulata chromosomes except 4U showed moderate to strong collinearity with corresponding homeologous chromosomes of hexaploid wheat and barley. The present consensus map may serve as a reference map in QTL mapping and validation projects, and also in genome assembly to develop a reference genome sequence for Ae. umbellulata.

http://ift.tt/2q7Ae2d

Extensive Copy Number Variation in Fermentation-Related Genes Among Saccharomyces cerevisiae Wine Strains

Due to the importance of Saccharomyces cerevisiae in wine-making, the genomic variation of wine yeast strains has been extensively studied. One of the major insights stemming from these studies is that wine yeast strains harbor low levels of genetic diversity in the form of single nucleotide polymorphisms (SNPs). Genomic structural variants, such as copy number (CN) variants, are another major type of variation segregating in natural populations. To test whether genetic diversity in CN variation is also low across wine yeast strains, we examined genome-wide levels of CN variation in 132 whole-genome sequences of S. cerevisiae wine strains. We found an average of 97.8 CN variable regions (CNVRs) affecting ~4% of the genome per strain. Using two different measures of CN diversity, we found that gene families involved in fermentation-related processes such as copper resistance (CUP), flocculation (FLO), and glucose metabolism (HXT), as well as the SNO gene family whose members are expressed before or during the diauxic shift, showed substantial CN diversity across the 132 strains examined. Importantly, these same gene families have been shown, through comparative transcriptomic and functional assays, to be associated with adaptation to the wine fermentation environment. Our results suggest that CN variation is a substantial contributor to the genomic diversity of wine yeast strains, and identify several candidate loci whose levels of CN variation may affect the adaptation and performance of wine yeast strains during fermentation.

http://ift.tt/2qINmYL

asymptoticMK: A Web-Based Tool for the Asymptotic McDonald-Kreitman Test

The McDonald–Kreitman (MK) test is a widely used method for quantifying the role of positive selection in molecular evolution. One key shortcoming of this test lies in its sensitivity to the presence of slightly deleterious mutations, which can severely bias its estimates. An asymptotic version of the MK test was recently introduced that addresses this problem by evaluating polymorphism levels for different mutation frequencies separately, and then extrapolating a function fitted to that data. Here, we present asymptoticMK, a web-based implementation of this asymptotic MK test. Our web service provides a simple R-based interface into which the user can upload the required data (polymorphism and divergence data for the genomic test region and a neutrally evolving reference region). The web service then analyzes the data and provides plots of the test results. This service is free to use, open-source, and available at http://ift.tt/2oZqczP. We provide results from simulations to illustrate the performance and robustness of the asymptoticMK test under a wide range of model parameters.

http://ift.tt/2q7Cnef

Paternal Induction of Hybrid Dysgenesis in Drosophila melanogaster Is Weakly Correlated with Both P-Element and hobo Element Dosage

Transposable elements (TEs) are virtually ubiquitous components of genomes, yet they often impose significant fitness consequences on their hosts. In addition to producing specific deleterious mutations by insertional inactivation, TEs also impose general fitness costs by inducing DNA damage and participating in ectopic recombination. These latter fitness costs are often assumed to be dosage-dependent, with stronger effects occurring in the presence of higher TE copy numbers. We test this assumption in Drosophila melanogaster by considering the relationship between the copy number of two active DNA transposons, P-element and hobo element, and the incidence of hybrid dysgenesis, a sterility syndrome associated with transposon activity in the germline. By harnessing a subset of the Drosophila Genetic Reference Panel (DGRP), a group of fully-sequenced D. melanogaster strains, we describe quantitative and structural variation in P-elements and hobo elements among wild-derived genomes and associate these factors with hybrid dysgenesis. We find that the incidence of hybrid dysgenesis is associated with both P-element and hobo element copy number in a dosage-dependent manner. However, the relationship is weak for both TEs, suggesting that dosage alone explains only a small part of TE-associated fitness costs.

http://ift.tt/2q7D5Z6

Identification of QTLs for 14 Agronomically Important Traits in Setaria italica Based on SNPs Generated from High-Throughput Sequencing

Foxtail millet (Setaria italica) is an important crop possessing C4 photosynthesis capability. The S. italica genome was de novo sequenced in 2012, but the sequence lacked high-density genetic maps with agronomic and yield trait linkages. In the present study, we resequenced a foxtail millet population of 439 recombinant inbred lines (RILs) and developed high-resolution bin map and high-density SNP markers, which could provide an effective approach for gene identification. A total of 59 QTL for 14 agronomic traits in plants grown under long- and short-day photoperiods were identified. The phenotypic variation explained ranged from 4.9 to 43.94%. In addition, we suggested that there may be segregation distortion on chromosome 6 that is significantly distorted toward Zhang gu. The newly identified QTL will provide a platform for sequence-based research on the S. italica genome, and for molecular marker-assisted breeding.

http://ift.tt/2qAuKx7

Change in carbohydrate antigen 19-9 level as a prognostic marker of overall survival in locally advanced pancreatic cancer treated with concurrent chemoradiotherapy

Abstract

Purpose

To investigate the significance of carbohydrate antigen 19-9 (CA19-9) levels for survival in locally advanced pancreatic cancer (LAPC) treated with concurrent chemoradiotherapy (CCRT).

Methods/patients

We retrospectively reviewed data from 97 LAPC patients treated with CCRT between 2000 and 2013. CA19-9 levels (initial and post-CCRT) and their changes [{(post-CCRT CA19-9 level − initial CA19-9 level)/(initial CA19-9 level)} × 100] were analyzed for overall survival. A cut-off point of 37 U/mL was used to analyze initial and post-CCRT CA19-9 levels. In order to define an optimal cut-off point for change in CA19-9 level, the maxstat package of R was applied.

Results

Median overall survival was 14.7 months (95% CI 13.4–16.0), and the 2-year survival rate was 16.5%. The estimated optimal cut-off point of CA19-9 level change was 94.4%. On univariate analyses, CA19-9 level change between initial and post-CCRT was significantly correlated with overall survival (median survival time 9.7 vs 16.3 months, p < 0.001). Multivariate analyses confirmed that CA19-9 level change from initial to post-CCRT was the only prognostic factor (p < 0.001).

Conclusions

Change in CA19-9 level between initial and post-CCRT was a significant prognostic marker for overall survival in LAPC treated with CCRT. A CA19-9 level increase >94.4% might serve as a surrogate marker for poor survival in patients with LAPC undergoing CCRT, and the prognostic power surpassed other CA19-9 variables including initial and post-CCRT values.

http://ift.tt/2phNTQk

Reconstruction in Breast Conservation Therapy—Single Tertiary Care Institution Experience with 472 Patients

Abstract

Breast conservation therapy (BCT) is now internationally accepted treatment for early breast cancer. Despite of high incidence of carcinoma breast in India, BCT rates are very low as compared to the west. In this article, we wish to share our experience of breast conservation with oncoplasty in Indian women. A retrospective analysis of case records of patients treated with oncoplastic breast conservation from January 2009 to June 2014 in a single surgical oncology unit in a tertiary cancer institute. Demographic patient data, stage of disease, location of primary tumour, use of neo-adjuvant chemotherapy if received, tumour size and breast size ratio, reconstruction method used, post-operative complications and aesthetic score of patients were analysed. Various methods of oncoplasty and partial breast reconstruction used are discussed. Four hundred and seventy-two patient records were found suitable for analysis. Most common stage of presentation was T2N0 in 189 patients (40%). Forty-one patients received neo-adjuvant chemotherapy (NACT). Tumour arising in upper outer quadrant was most common site, seen in 268 (56.7%). The most common method of reconstruction was volume displacement, done in 57.6% patients. Overall surgical complications included wound infection with or without dehiscence, seroma formation, partial flap necrosis and fat necrosis. Cosmesis was found to be excellent in 23.09% and good in 58.47% at 6-month follow-up. Breast conservation with oncoplasty is oncologically safe for early breast cancer treatment and has good cosmetic outcome with high patient satisfaction rates.

Its practice should be encouraged in Indian set-up also.

http://ift.tt/2pOg4rd

Why is digital pathology in cytopathology lagging behind surgical pathology?

http://ift.tt/2pOqiYt

Consistency and reproducibility of next-generation sequencing and other multigene mutational assays: A worldwide ring trial study on quantitative cytological molecular reference specimens

BACKGROUND

Molecular testing of cytological lung cancer specimens includes, beyond epidermal growth factor receptor (EGFR), emerging predictive/prognostic genomic biomarkers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA). Next-generation sequencing (NGS) and other multigene mutational assays are suitable for cytological specimens, including smears. However, the current literature reflects single-institution studies rather than multicenter experiences.

METHODS

Quantitative cytological molecular reference slides were produced with cell lines designed to harbor concurrent mutations in the EGFR, KRAS, NRAS, BRAF, and PIK3CA genes at various allelic ratios, including low allele frequencies (AFs; 1%). This interlaboratory ring trial study included 14 institutions across the world that performed multigene mutational assays, from tissue extraction to data analysis, on these reference slides, with each laboratory using its own mutation analysis platform and methodology.

RESULTS

All laboratories using NGS (n = 11) successfully detected the study's set of mutations with minimal variations in the means and standard errors of variant fractions at dilution points of 10% (P = .171) and 5% (P = .063) despite the use of different sequencing platforms (Illumina, Ion Torrent/Proton, and Roche). However, when mutations at a low AF of 1% were analyzed, the concordance of the NGS results was low, and this reflected the use of different thresholds for variant calling among the institutions. In contrast, laboratories using matrix-assisted laser desorption/ionization–time of flight (n = 2) showed lower concordance in terms of mutation detection and mutant AF quantification.

CONCLUSIONS

Quantitative molecular reference slides are a useful tool for monitoring the performance of different multigene mutational assays, and this could lead to better standardization of molecular cytopathology procedures. Cancer Cytopathol 2017. © 2017 American Cancer Society.

http://ift.tt/2qAoIwc