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Παρασκευή 7 Σεπτεμβρίου 2018

A Structured Compensation Plan Improves But Does Not Erase the Sex Pay Gap in Surgery

imageObjective: The aim of this study is to examine the relationship between the sex pay gap in a large academic department of surgery and a recently instituted structured compensation plan. Summary of Background Data: A recent large study found that after controlling for measures of academic and clinical productivity, male physicians earned nearly $20,000 more annually than female physicians. Increased salary transparency has been proposed as a method to reduce this disparity. Methods: A new structured compensation plan was developed to improve transparency of compensation and financial viability of each division. The total compensations of each faculty member before and after the new compensation plan were calculated. Salaries were compared with the Association of Academic Medical Colleges (AAMC) median value based on specialty, region, academic rank, stratified by sex and compared. Work relative value units (wRVUs) were calculated for each faculty member during the entire study period, stratified by sex and compared. Results: Among 44 eligible surgeons (33 men and 11 women), a sex pay gap existed with male surgeon salaries significantly higher than female surgeon salaries [56% (8 to 213) vs 26% (1 to 64); P

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Abdominal obesity, glucose intolerance and decreased high-density lipoprotein cholesterol as components of the metabolic syndrome are associated with the development of colorectal cancer

Abstract

Metabolic syndrome (MetS) and its components has been thought to be involved in the development of colorectal cancer (CRC). However, the results is often inconsistent according to gender or anatomical location of tumor. This study aimed to investigate the association between MetS and its components and CRC development by gender and tumor location. We evaluated the data of 22,809,722 Korean individuals of the National semi-compulsive cohort who underwent regular health check-ups between 2009 and 2012. Compared to subjects without MetS components, the hazard ratio for CRC development in patients with MetS was 1.22 (95% Confidence Interval [CI] 1.20–1.24) and this association was more prominent in men than in women (HR 1.41 95% CI 1.37–1.44 vs. HR 1.23 95% CI 1.20–1.27, P for interaction < 0.001). Left-sided colon cancers were more associated with MetS among men compared to women (HR 1.70, 95% CI 1.61–1.80 vs. HR 1.43, 95% CI 1.33–1.54), while right colon cancers showed a stronger association with MetS among women than men (HR 1.63, 95% CI 1.49–1.78 vs. HR 1.34, 95% CI 1.24–1.44) (all P for interaction < 0.001, respectively). Having two MetS components was still associated with CRC development and the association was the highest when two of glucose intolerance, abdominal obesity and low high-density lipoprotein cholesterol (HDL-C) combined. Individuals with glucose intolerance, abdominal obesity or low HDL-C levels, may need to undergo thorough screening for CRC even if they do not meet the diagnostic MetS criteria.



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Cannabis for the Treatment of Epilepsy: an Update

Abstract

Purpose of Review

For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.

Recent Findings

While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD's inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD.

Summary

Understanding of CBD's efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.



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Survival strategies of cancerous cells: a novel perspective

Future Oncology, Ahead of Print.


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Pancreatic cancer: let us focus on cachexia, not just sarcopenia!

Future Oncology, Ahead of Print.


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Inhibition of Suicidal Erythrocyte Death by Chronic Hypoxia

High Altitude Medicine &Biology, Ahead of Print.


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Ribociclib with an Aromatase Inhibitor for Previously Untreated, HR-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Abstract

The National Institute for Health and Care Excellence, as part of the institute's single technology appraisal process, invited the manufacturer of ribociclib (Kisqali®, Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer's decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3–not reached) vs. 14.7 months (95% confidence interval 13.0–16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft® Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.



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Cost-Effectiveness Analysis of Patiromer and Spironolactone Therapy in Heart Failure Patients with Hyperkalemia

Abstract

Background and Objective

Certain patients with heart failure (HF) are unable to tolerate spironolactone therapy due to hyperkalemia. Patiromer is a novel agent used to treat hyperkalemia and has been shown to be efficacious, safe, and well-tolerated. The potential clinical outcomes and economic value of using patiromer and spironolactone in patients with HF unable to otherwise tolerate spironolactone due to hyperkalemia are unclear. The objective of this analysis was to model the potential pharmacoeconomic value of using patiromer and spironolactone in patients with a history of hyperkalemia that prevents them from utilizing spironolactone.

Methods

We performed a cost-effectiveness analysis of treatment with patiromer, spironolactone, and an angiotensin-converting enzyme inhibitor (ACEI) in patients with New York Heart Association (NYHA) class III–IV HF compared with ACEI alone. A Markov model was constructed to simulate a cohort of 65-year-old patients diagnosed with HF from the payer perspective across the lifetime horizon. Clinical inputs were derived from the RALES and OPAL-HK randomized trials of spironolactone and patiromer, respectively. Utility estimates and costs were derived from the literature and list prices. Outcomes assessed included hospitalization, life expectancy, and quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analyses were performed to test the robustness of the model findings.

Results

Treatment with patiromer–spironolactone–ACEI was projected to increase longevity compared with ACEI alone (5.29 vs. 4.62 life-years gained, respectively), greater QALYs (2.79 vs. 2.60), and costs (US$28,200 vs. US$18,200), giving an ICER of US$52,700 per QALY gained. The ICERs ranged from US$40,000 to US$85,800 per QALY gained in 1-way sensitivity analyses.

Conclusion

Our results suggest that the use of spironolactone–patiromer–ACEI may provide clinical benefit and good economic value in patients with NYHA class III–IV HF unable to tolerate spironolactone due to hyperkalemia.



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One Method, Many Methodological Choices: A Structured Review of Discrete-Choice Experiments for Health State Valuation

Abstract

Background

Discrete-choice experiments (DCEs) are used in the development of preference-based measure (PBM) value sets. There is considerable variation in the methodological approaches used to elicit preferences.

Objective

Our objective was to carry out a structured review of DCE methods used for health state valuation.

Methods

PubMed was searched until 31 May 2018 for published literature using DCEs for health state valuation. Search terms to describe DCEs, the process of valuation and preference-based instruments were developed. English language papers with any study population were included if they used DCEs to develop or directly inform the production of value sets for generic or condition-specific PBMs. Assessment of paper quality was guided by the recently developed Checklist for Reporting Valuation Studies. Data were extracted under six categories: general study information, choice task and study design, type of designed experiment, modelling and analysis methods, results and discussion.

Results

The literature search identified 1132 published papers, and 63 papers were included in the review. Paper quality was generally high. The study design and choice task formats varied considerably, and a wide range of modelling methods were employed to estimate value sets.

Conclusions

This review of DCE methods used for developing value sets suggests some recurring limitations, areas of consensus and areas where further research is required. Methodological diversity means that the values should be seen as experimental, and users should understand the features of the value sets produced before applying them in decision making.



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Editorial: Thematic issue on bacterial protein export: from fundamentals to applications



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Recent advances in the microbial hydroxylation and reduction of soy isoflavones

ABSTRACT
Soy isoflavones are naturally occurring phytochemicals, which are biotransformed into functional derivatives through oxidative and reductive metabolic pathways of diverse microorganisms. Such representative derivatives, ortho-dihydroxyisoflavones (ODIs) and equols, have attracted great attention for their versatile health benefits since they were found from soybean fermented foods and human intestinal fluids. Recently, scientists in food technology, nutrition and microbiology began to understand their correct biosynthetic pathways and nutraceutical values, and have attempted to produce the valuable bioactive compounds using microbial fermentation and whole-cell/enzyme-based biotransformation. Furthermore, artificial design of microbial catalysts and/or protein engineering of oxidoreductases were also conducted to enhance production efficiency and regioselectivity of products. This minireview summarizes and introduces the past year's studies and recent advances in notable production of ODIs and equols, and provides information on available microbial species and their catalytic performance with perspectives on industrial application.

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Stenotrophomonas maltophilia mutant lacking flagella remains virulent in DBA/2N mice but is less efficient in stimulating TNF-α expression

ABSTRACT
To understand the role of flagella of Stenotrophomonas maltophilia in lung infections, DBA/2N mice were challenged with aflagellate fliI mutant and colonization, invasion and persistence, lung damage and inflammatory response compared, on days 1 and 3 post-exposure (p.e.), with that of the isogenic wild-type (wt). Following exposure to nebulized bacterial suspension, mice infected with wt and fliI strains showed a comparable trend in body weight change, pulmonary persistence, lung damage and mortality rate over the study period considered. Interestingly, although on day 1 p.e. both strains colonized near all the spleens, on day 3 p.e. wt strain persisted in 40% of spleens, whereas fliI mutant was completely cleared. No significant differences were found in MIP-2, IFN-γ and IL-6 pulmonary levels between groups over time, except for TNF-α whose levels on day 1 p.e. were significantly higher in mice infected with flagellated wt strain. Overall, our results indicate that in S. maltophilia flagella and motility might not represent virulence traits involved in the pathogenesis of lung infection. However, the evidence for a specific flagellar-induced TNF-α response warrants further study.

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Discovery of QTL Alleles for Grain Shape in the Japan-MAGIC Rice Population Using Haplotype Information

A majority of traits are determined by multiple quantitative trait loci (QTLs) that can have pleiotropic effects. A multi-parent advanced generation inter-cross (MAGIC) population is well suited for genetically analyzing the effects of multiple QTLs on traits of interest because it contains a higher number of QTL alleles than a biparental population. We previously produced the JAPAN-MAGIC (JAM) population, derived from eight rice (Oryza sativa L.) cultivars with high yield and biomass in Japan, and developed the method of genome-wide association study (GWAS) using haplotype information on the JAM lines. This method was effective for identifying major genes such as Waxy for eating quality and Sd1 for culm length. Here, we show that haplotype-based GWAS is also effective for the evaluation of multiple QTLs with small effects on rice grain shape in the JAM lines. Although both the haplotype- and SNP-based GWAS identified multiple QTLs for grain length and width, the sum of the estimated trait values of each allele for the QTLs detected by haplotype-based GWAS had higher correlation with observed values than those detected by SNP-based GWAS, indicating high-accuracy QTL detection in the haplotype-based GWAS. Furthermore, the study revealed pleiotropic effects of some QTL regions in regulation of grain shape, suggesting that the haplotype-based GWAS using the JAM lines is an effective means to evaluate the main and side effects of haplotypes at each QTL. Information on the pleiotropic effects of haplotypes on various traits will be useful for designing ideal lines in a breeding program.



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Natural Genetic Variation in Yeast Reveals That NEDD4 Is a Conserved Modifier of Mutant Polyglutamine Aggregation

A feature common to late onset proteinopathic disorders is an accumulation of toxic protein conformers and aggregates in affected tissues. In the search for potential drug targets, many studies used high-throughput screens to find genes that modify the cytotoxicity of misfolded proteins. A complement to the latter approach is to focus on strategies that use protein aggregation as a phenotypic readout to identify pathways that control aggregate formation and maintenance. Here we use natural variation between strains of budding yeast to genetically map loci that influence the aggregation of a polyglutamine-containing protein derived from a mutant form of huntingtin, the causative agent in Huntington disease. Linkage analysis of progeny derived from a cross between wild and laboratory yeast strains revealed two polymorphic loci that modify polyglutamine aggregation. One locus contains the gene RFU1 which modifies ubiquitination states of misfolded proteins targeted by the E3-ubiquitin ligase complex Rsp5. Activity of the Rsp5 complex, and the mammalian homolog NEDD4, are critical in maintaining protein homeostasis in response to proteomic stress. Our analysis also showed linkage of aggregation phenotype to a distinct locus containing a gene encoding the Rsp5-interacting Bul2 protein. Allele-swap experiments validated the impact of both RFU1 and BUL2 on huntingtin aggregation. Furthermore, we found that the nematode C. elegans' ortholog of Rsp5, wwp-1, also negatively regulates polyglutamine aggregation. Knockdown of the NEDD4 in human cells likewise altered polyglutamine aggregation. Taken together, these results implicate conserved processes involving the ubiquitin regulation network that regulate protein aggregation and provide novel therapeutic targets for polyglutamine and other protein folding diseases.



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Bulked-Segregant Analysis Coupled to Whole Genome Sequencing (BSA-Seq) for Rapid Gene Cloning in Maize

Forward genetics remains a powerful method for revealing the genes underpinning organismal form and function, and for revealing how these genes are tied together in gene networks. In maize, forward genetics has been tremendously successful, but the size and complexity of the maize genome made identifying mutant genes an often arduous process with traditional methods. The next generation sequencing revolution has allowed for the gene cloning process to be significantly accelerated in many organisms, even when genomes are large and complex. Here, we describe a bulked-segregant analysis sequencing (BSA-Seq) protocol for cloning mutant genes in maize. Our simple strategy can be used to quickly identify a mapping interval and candidate single nucleotide polymorphisms (SNPs) from whole genome sequencing of pooled F2 individuals. We employed this strategy to identify narrow odd dwarf as an enhancer of teosinte branched1, and to identify a new allele of defective kernel1. Our method provides a quick, simple way to clone genes in maize.



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Capmatinib plus Gefitinib Is Active in EGFR-Mutant MET-Amplified Tumors [Research Watch]

Capmatinib plus gefitinib had a 27% to 29% response rate in patients who progressed on prior EGFR TKI therapy.



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The lncRNA NORAD Contributes to the Maintenance of Genomic Stability [Research Watch]

NORAD binds to RBMX to facilitate the assembly of a topoisomerase I complex termed NARC1.



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Mutations and Targeted Drugs Alter RAS Signaling Dynamics in Cancer [Research Watch]

Oncogenic mutations and targeted drugs promote slow deactivation of activated RAS signaling.



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Ewing Sarcoma Gene Fusions Can Be Generated via Chromoplexy [Research Watch]

EWSR1–ETS fusions can arise by a sudden burst of complex, loop-like rearrangements termed chromoplexy.



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Exposure to Toxic Metals May Up Cardiovascular Disease Risk

FRIDAY, Sept. 7, 2018 -- Exposure to arsenic, lead, cadmium, and copper is associated with elevated risk of clinical cardiovascular disease outcomes, according to a review and meta-analysis published online Aug. 29 in The BMJ. Rajiv Chowdhury,...

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MERTK promotes resistance to irreversible EGFR tyrosine kinase inhibitors in non-small cell lung cancers expressing wild-type EGFR-family members

Purpose: Lung cancer is the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and over 60% express wild-type EGFR (wtEGFR); however, EGFR tyrosine kinase inhibitors (TKIs) have limited effect in most patients with wtEGFR tumors. We previously identified MERTK tyrosine kinase as a potential therapeutic target in NSCLC and developed MRX-2843, a novel MERTK-selective inhibitor with favorable properties for clinical translation. The goal of the current study is to determine if MERTK and EGFR inhibitor combination therapy could provide anti-tumor efficacy against wtEGFR NSCLC. Experimental Design: An unbiased screen of 378 kinase inhibitors was conducted to identify synergistic interactions with MRX-2843 and biochemical and therapeutic effects were determined in vitro and in vivo. Results: Numerous irreversible EGFR TKIs, including CO-1686 and osimertinib, synergized with MRX-2843 to inhibit wtEGFR NSCLC cell expansion, irrespective of driver oncogene status. CO-1686 and MRX-2843 combination therapy inhibited MERTK, wtEGFR, and ERBB2/ERBB3 and decreased downstream PI3K-AKT, MAPK-ERK, and AURORA kinase (AURK) signaling more effectively than single agents. Inhibition of PI3K, AKT or AURK, but not MEK, synergized with CO-1686 to inhibit tumor cell expansion, suggesting their roles as key redundant resistance pathways. Treatment with MRX-2843 and CO-1686 or osimertinib prevented xenograft growth while single agents had limited effect. Tumor growth inhibition was durable even after treatment with combination therapy was stopped. Conclusions: Our data support the application of MRX-2843 in combination with an irreversible EGFR TKI as a novel strategy for treatment of patients with wtEGFR NSCLC.



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American Academy of Pediatrics Updates Car Seat Guidance

FRIDAY, Sept. 7, 2018 -- The American Academy of Pediatrics' updated car seat guidelines recommend children remain in a rear-facing car safety seat as long as possible, according to policy statement published online Aug. 30 in Pediatrics. Dennis R....

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Southwest Passengers May Have Been Exposed to Measles

FRIDAY, Sept. 7, 2018 -- Passengers and crew on four Southwest Airlines flights within Texas in late August are being notified that they may have been exposed to measles. Officials said a passenger who took the four flights over two days was later...

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Influenza Caused Emirates Flight to Be Briefly Quarantined at JFK

FRIDAY, Sept. 7, 2018 -- The mysterious illness that kept a plane away from the terminal after some passengers reported feeling sick has been confirmed as the flu, according to the New York City Department of Health and Mental Hygiene. Emirates...

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Physician Assistants Match Medical Residents in ICU Skills

FRIDAY, Sept. 7, 2018 -- Physician assistants (PAs) exhibit equal performance on clinical skills as medical residents (MRs) with six to 24 months of experience in the intensive care unit (ICU), according to a study recently published in the Journal...

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Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (CDK2), is central to the initiation of DNA replication at the G1/S checkpoint. Tight temporal control of cyclin E is essential to the coordination of cell-cycle processes and the maintenance of genome integrity. Overexpression of cyclin E in human tumors was first observed in the 1990s and led to the identification of oncogenic roles for deregulated cyclin E in experimental models. A decade later, low-molecular-weight cyclin E (LMW-E) isoforms were observed in aggressive tumor subtypes. Compared with full-length cyclin E, LMW-E hyperactivates CDK2 through increased complex stability and resistance to the endogenous inhibitors p21CIP1 and p27KIP1. LMW-E is predominantly generated by neutrophil elastase–mediated proteolytic cleavage, which eliminates the N-terminal cyclin E nuclear localization signal and promotes cyclin E's accumulation in the cytoplasm. Compared with full-length cyclin E, the aberrant localization and unique stereochemistry of LMW-E dramatically alters the substrate specificity and selectivity of CDK2, increasing tumorigenicity in experimental models. Cytoplasmic LMW-E, which can be assessed by IHC, is prognostic of poor survival and predicts resistance to standard therapies in patients with cancer. These patients may benefit from therapeutic modalities targeting the altered biochemistry of LMW-E or its associated vulnerabilities. Cancer Res; 1–11. ©2018 AACR.

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Specific Targeting of Oncogenes Using CRISPR Technology

In recent decades, tools of molecular biology have enabled researchers to genetically modify model organisms, including human cells. RNAi, zinc-finger nucleases, transcription activator–like effector nucleases, CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats and CRISPR-associated protein 9), retro- or lentiviral gene transfer, and many other methods can be utilized to remove genes, add genes, or change their expression. Within the same timeframe, survival rates for many highly malignant tumor diseases have not improved substantially. If modern medicine could apply even a subset of research methods in clinical management, which are already well established and controllable in basic research laboratories, this could strongly impact patients' prognosis. CRISPR-Cas9 is a method to precisely target and manipulate genomic loci and recent studies have attempted to use this method as a genetic treatment for Duchenne muscular dystrophy, blood disorders, autosomal-dominant hearing loss, and cancer. Some of these approaches target mutant genomic sequences specifically and try to avoid affecting the respective normal loci. Considering obvious genetic risks opposing the objected benefits, data are needed to show whether CRISPR technology is suitable as a future cancer therapy approach or not. Here, we develop strategies for the specific targeting of viral cancer drivers and oncogenes activated by mutation, using the latest CRISPR technology. Cancer Res; 1–7. ©2018 AACR.

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Impact of preoperative biopsy on severe submucosal fibrosis on endoscopic submucosal dissection for colorectal laterally spreading tumors: a propensity score analysis

It is thought that preoperative biopsy for superficial-type colorectal tumors should be avoided because submucosal fibrosis caused by biopsy makes endoscopic mucosal resection impossible. However, few studies have reported the influence of biopsy on colorectal endoscopic submucosal dissection (ESD). This study aimed to examine the effect of biopsy on submucosal fibrosis and treatment outcomes of ESD for laterally spreading tumors (LSTs).

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Lamivudine prophylaxis prevents hepatitis B virus reactivation in anti-HBc positive patients under rituximab for non–Hodgkin lymphoma

A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non–Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation.

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Patterns of progression after 68Ga-PSMA-ligand PET/CT-guided radiotherapy for recurrent prostate cancer

We demonstrated in 108 patients with increased prostate-specific antigen levels, who received 68Ga-PSMA-ligand PET/CT-guided radiotherapy (RT) for recurrent oligometastatic disease after primary therapy for prostate cancer (PCa) that PSMA-ligand PET/CT-guided RT for relapsed PCa with limited tumor burden allowed individualized treatment approaches, provided effective local control and considerably prolonged biochemical progression-free survival. The PSMA-ligand PET/CT patterns of progression revealed a shift in the pattern of metastases towards skeletal involvement and distant lymph node metastases.

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Intrinsic Network Reactivity Differentiates Levels of Consciousness in Comatose Patients

Coma and other disorders of consciousness (DOC) is associated with profound reductions in wakefulness and awareness (Bruno et al., 2011; Giacino et al., 2014; Laureys, 2005). Linking these behavioral markers with specific injury attributes remains a persistent clinical challenge (McGee et al., 2016). Electroencephalographic recordings offer the potential to help to disassociate underlying causes of DOC by revealing systematic electrophysiological correlates of injury and behavior (Sitt et al., 2014; Sebastiano et al., 2015).

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Circumstances of Death among Undocumented Immigrants Who Rely on Emergency-Only Hemodialysis



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Variations in 24-Hour BP Profiles in Cohorts of Patients with Kidney Disease around the World: The I-DARE Study

Background and objectives

Ambulatory BP is increasingly recognized as a better measure of the risk for adverse outcomes related to hypertension, an important comorbidity in patients with CKD. Varying definitions of white-coat and masked hypertension have made it difficult to evaluate differences in prevalence of these BP patterns across CKD cohorts.

Design, setting, participants, & measurements

The International Database of Ambulatory BP in Renal Patients collaborative group established a large database of demographic, clinical, and ambulatory BP data from patients with CKD from cohorts in Italy, Spain, the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension Cohort Study (AASK) in the United States, and the CKD Japan Cohort (CKD-JAC). Participants (n=7518) with CKD were included in the present analyses. Cutoffs for defining controlled BP were 140/90 mm Hg for clinic and 130/80 mm Hg for 24-hour ambulatory BP.

Results

Among those with controlled clinic BP, compared with CKD-JAC, AASK participants were more likely to have masked hypertension (prevalence ratio [PR], 1.21; 95% confidence interval [95% CI], 1.04 to 1.41) whereas CRIC (PR, 0.82; 0.72 to 0.94), Italian (PR, 0.73; 0.56 to 0.95), and Spanish participants (PR, 0.75; 0.64 to 0.88) were less likely. Among those with elevated clinic BP, AASK participants were more likely to have sustained hypertension (PR, 1.22; 95% CI, 1.13 to 1.32) whereas Italian (PR, 0.78; 0.70 to 0.87) and Spanish participants (PR, 0.89; 0.82 to 0.96) were less likely, although CRIC participants had similar prevalence as CKD-JAC. Prevalence of masked and sustained hypertension was elevated in males, patients with diabetes, participants on four or more antihypertensives, and those with moderate-to-severe proteinuria.

Conclusions

In a large, multinational database, the prevalence of masked and sustained hypertension varied across cohorts independent of important comorbidities.



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Two-Year Observational Study of Bloodstream Infection Rates in Hemodialysis Facility Patients with and without Catheters

Background and objectives

Bloodstream infection rates of patients on hemodialysis with catheters are greater than with other vascular accesses and are an important quality measure. Our goal was to compare relative bloodstream infection rates of patients with and without catheters as a quality parameter among the facilities providing hemodialysis.

Design, setting, participants, & measurements

We used CROWNWeb and National Healthcare Safety Network data from all 179 Medicare facilities providing adult outpatient hemodialysis in New England for >6 months throughout 2015–2016 (mean, 12,693 patients per month). There was a median of 60 (interquartile range, 43–93) patients per facility, with 17% having catheters.

Results

Among the five batch-submitting dialysis organizations, the bloodstream infection rate in patients with a catheter in four organizations had adjusted risk ratios of 1.44 (95% confidence interval, 1.07 to 1.93) to 1.91 (95% confidence interval, 1.39 to 2.63) times relative to the reference dialysis provider group (P<0.001). The percentage of catheters did not explain the difference in bloodstream infection rates among dialysis provider organizations. The bloodstream infection rates in patients with a catheter were negatively correlated with the facility's proportion of this patient group. Facilities with <10%, 10%–14.9%, 15%–19.9%, and ≥20% catheter patients had bloodstream infection rates of 4.4, 2.2, 1.9, and 1.5 per 100 patient-months, respectively, in that patient group (adjusted P<0.001). This difference was not seen in patients without catheters. There was no effect of facility patient census or season of the year.

Conclusions

A study of the adult outpatient hemodialysis facilities in New England in 2015–2016 found that four dialysis provider groups had significantly higher bloodstream infection rates in patients with a catheter than the best-performing dialysis provider group. Hemodialysis facilities with lower proportions of patients with a catheter have significantly higher bloodstream infection rates in this patient group than facilities with >20% catheters, a finding that did not explain the difference among provider organizations.



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Clinical and Economic Benefits of Antimicrobial Stewardship Programs in Hemodialysis Facilities: A Decision Analytic Model

Background and objectives

Infections caused by multidrug-resistant organisms and Clostridium difficile are associated with substantial morbidity and mortality as well as excess costs. Antimicrobial exposure is the leading cause for these infections. Approximately 30% of antimicrobial doses administered in outpatient hemodialysis facilities are considered unnecessary. Implementing an antimicrobial stewardship program in outpatient hemodialysis facilities aimed at improving prescribing practices would have important clinical and economic benefits.

Design, setting, participants, & measurements

We developed a decision analytic model of antimicrobial use on the clinical and economic consequences of implementing a nationwide antimicrobial stewardship program in outpatient dialysis facilities. The main outcomes were total antimicrobial use, infections caused by multidrug-resistant organisms and C. difficile, infection-related mortality, and total costs. The analysis considered all patients on outpatient hemodialysis in the United States. The value of implementing antimicrobial stewardship programs, assuming a 20% decrease in unnecessary antimicrobial doses, was calculated as the incremental differences in clinical end points and cost outcomes. Event probabilities, antimicrobial regimens, and health care costs were informed by publicly available sources.

Results

On a national level, implementation of antimicrobial stewardship programs was predicted to result in 2182 fewer infections caused by multidrug-resistant organisms and C. difficile (4.8% reduction), 629 fewer infection-related deaths (4.6% reduction), and a cost savings of $106,893,517 (5.0% reduction) per year. The model was most sensitive to clinical parameters as opposed to antimicrobial costs.

Conclusions

The model suggests that implementation of antimicrobial stewardship programs in outpatient dialysis facilities would result in substantial reductions in infections caused by multidrug-resistant organisms and C. difficile, infection-related deaths, and costs.



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A Patient with Hemodialysis Access Problems



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Gut-Derived Metabolites and Chronic Kidney Disease: The Forest (F)or the Trees?



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Regulatory Considerations for Hemodiafiltration in the United States

Online hemodiafiltration provides greater removal of higher molecular weight uremic retention solutes than conventional high-flux hemodialysis. However, online hemodiafiltration is used sparsely in the United States in part because of a paucity of delivery systems cleared for clinical use by the US Food and Drug Administration. Although a pathway for regulatory approval exists in the United States, concerns remain, particularly regarding online production of the large volumes of sterile, nonpyrogenic substitution fluid infused directly into the bloodstream to maintain fluid balance. Clearly defined testing protocols, acceptable to Food and Drug Administration, will be useful to show that an online hemodiafiltration system is capable of routinely achieving a sterility assurance level of 10–6 and nonpyrogenic levels of endotoxin. Large-scale clinical experience has shown that systems providing this level of performance when combined with certain design features, such as redundancy, and an appropriate quality management process can routinely and safely produce substitution fluid for online hemodiafiltration.



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Incident Atrial Fibrillation and the Risk of Stroke in Adults with Chronic Kidney Disease: The Stockholm CREAtinine Measurements (SCREAM) Project

Background and objectives

Patients with CKD have a high risk of atrial fibrillation. Both CKD and atrial fibrillation are associated with higher risk of stroke and death. However, the effect of incident atrial fibrillation on stroke risk among patients with CKD is unknown.

Design, setting, participants, & measurements

Our study included adults with CKD (eGFR<60 ml/min per 1.73 m2) without previously documented atrial fibrillation who had been in contact with health care in Stockholm, Sweden during 2006–2011. Incident atrial fibrillation was identified by administrative diagnostic codes in outpatient or inpatient care and treated as a time-updated exposure in the analysis of stroke and death risk. Stroke events and deaths were ascertained from regional and national registers with complete coverage. Covariates included demographics, comorbidities, therapeutic procedures, and medications. Multivariable Cox regression analysis and competing risk analysis (accounting for death) were used to estimate the association between incident atrial fibrillation and stroke.

Results

Among 116,184 adults with CKD, 13,412 (12%) developed clinically recognized atrial fibrillation during a mean follow-up of 3.9 years (interquartile range, 2.3–5.7 years). Incidence of atrial fibrillation increased across lower eGFR strata: from 29.4 to 46.3 atrial fibrillations per 1000 person-years in subjects with eGFR=45–60 and <30 ml/min per 1.73 m2, respectively; 1388 (53.8 per 1000 person-years) cases of stroke and 5592 (205.1 per 1000 person-years) deaths occurred after incident atrial fibrillation compared with 6850 (16.6 per 1000 person-years) cases of stroke and 28,613 (67.5 per 1000 person-years) deaths during periods without atrial fibrillation. After adjustment, incident atrial fibrillation was associated with higher risk of stroke (hazard ratio, 2.00; 95% confidence interval, 1.88 to 2.14) and death (hazard ratio, 1.76; 95% confidence interval, 1.71 to 1.82). This was attributed to both ischemic stroke (hazard ratio, 2.11; 95% confidence interval, 1.96 to 2.28) and intracranial bleeds (hazard ratio, 1.64; 95% confidence interval, 1.42 to 1.90). Stroke risk was similar across all eGFR strata. In competing risk analyses accounting for death, the association between incident atrial fibrillation and stroke was attenuated but remained higher (subhazard ratio, 1.49; 95% confidence interval, 1.39 to 1.60).

Conclusions

Patients with CKD who develop atrial fibrillation are at higher risk of stroke and death.



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Mapping Progress in Reducing Cardiovascular Risk with Kidney Disease: A Focus on Heart Failure



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Association of Urinary Biomarkers of Kidney Injury with Estimated GFR Decline in HIV-Infected Individuals following Tenofovir Disoproxil Fumarate Initiation

Background and objectives

Tenofovir disoproxil fumarate (tenofovir) is associated with elevated concentrations of biomarkers of kidney damage and dysfunction in individuals with HIV. The relationship of these kidney biomarkers with longitudinal kidney function decline is unknown.

Design, setting, participants, & measurements

We evaluated associations of 14 urinary biomarkers of kidney injury with changes in eGFR among 198 men and women with HIV who initiated tenofovir between 2009 and 2015 in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Urinary biomarkers included albumin-to-creatinine ratio, α-1-microglobulin, β-2-microglobulin, cystatin C, kidney injury molecule-1 (KIM-1), IL-18, neutrophil gelatinase–associated lipocalin (NGAL), clusterin, osteopontin, uromodulin, monocyte chemoattractant protein-1, EGF, trefoil factor 3, and chitinase 3-like protein 1. We used multivariable linear mixed-effect models controlling for demographics, traditional kidney disease risk factors, and HIV-related risk factors to evaluate associations of baseline biomarkers with first-year changes in eGFR, and associations of year 1 and first-year change in biomarkers with changes in eGFR from year 1 to year 3. We used the least absolute shrinkage and selection operator method to identify a parsimonious set of biomarkers jointly associated with changes in eGFR.

Results

Median eGFR before tenofovir initiation was 103 (interquartile range, 88–116) ml/min per 1.73 m2. During the first year of tenofovir use, eGFR decreased on average by 9.2 (95% confidence interval, 6.5 to 11.9) ml/min per 1.73 m2 and was stable afterward (decrease of 0.62; 95% confidence interval, –0.85 to 2.1 ml/min per 1.73 m2 per year). After multivariable adjustment, higher baseline β-2-microglobulin, KIM-1, and clusterin were associated with larger first-year eGFR declines, whereas higher baseline uromodulin was associated with a smaller eGFR decline. First-year increase in urinary cystatin C and higher year 1 IL-18 were associated with larger annual eGFR declines from year 1 to year 3. The parsimonious models identified higher pre-tenofovir clusterin and KIM-1, lower pre-tenofovir uromodulin, and higher year 1 IL-18 as jointly associated with larger eGFR declines.

Conclusions

Urinary biomarkers of kidney injury measured before and after tenofovir initiation are associated with subsequent changes in eGFR in individuals with HIV.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_28_CJASNPodcast_18_9_S.mp3



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IgA Nephropathy Susceptibility Loci and Disease Progression

Background and objectives

At least 20 susceptibility loci of IgA nephropathy have been identified by genome-wide association studies to date. Whether these loci were associated with disease progression is unclear.

Design, setting, participants, & measurements

We enrolled 613 adult patients with IgA nephropathy for a follow-up of ≥12 months. All 20 IgA nephropathy susceptibility loci were selected and their tag single nucleotide polymorphisms (SNPs) were genotyped. After strict quality control, 16 SNPs and 517 patients with IgA nephropathy were eligible for subsequent analysis. Progression was defined as ESKD or 50% decrease in eGFR. A stepwise Cox regression analysis of all SNPs on Akaike information criterion was performed to select the best model.

Results

A four-SNP model, rs11150612 (ITGAM-ITGAX), rs7634389 (ST6GAL1), rs2412971 (HORMAD2), and rs2856717 (HLA-DQ/DR), was selected as the best predictive model. The genetic risk score calculated on the basis of the four SNPs was independently associated with disease progression before (hazard ratio [HR], 1.65; 95% confidence interval [95% CI], 1.29 to 2.12) and after adjustment by a recently reported clinical model (HR, 1.29; 95% CI, 1.03 to 1.62) or clinical–pathologic model (HR, 1.35; 95% CI, 1.03 to 1.77). Compared with low genetic risk, patients with middle genetic risk had a 2.12-fold (95% CI, 1.33 to 3.40) increase of progression risk, whereas patients with high genetic risk had 3.61-fold (95% CI, 2.00 to 6.52) progression risk increase. In addition, incorporation of genetic risk score could potentially increase discrimination of the clinical model (c-statistic increase from 0.83 to 0.86) or the clinical–pathologic model (c-statistic increase from 0.82 to 0.85) in predicting 5-year progression risk.

Conclusions

The four-SNP genetic risk score was independently associated with IgA nephropathy progression and could enhance the performance of clinical and clinical–pathologic risk models.



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The ABCs in the Mapping Progress in Reducing Cardiovascular Risk with Kidney Disease: An Introductory Remark on Expert Perspectives



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Dementia, Alzheimers Disease, and Mortality after Hemodialysis Initiation

Background and objectives

Older patients with ESKD experience rapid declines in executive function after initiating hemodialysis; these impairments might lead to high rates of dementia and Alzheimer's disease in this population. We estimated incidence, risk factors, and sequelae of diagnosis with dementia and Alzheimer's disease among older patients with ESKD initiating hemodialysis.

Design, setting, participants, & measurements

We studied 356,668 older (age ≥66 years old) patients on hemodialysis (January 1, 2001 to December 31, 2013) from national registry data (US Renal Data System) linked to Medicare. We estimated the risk (cumulative incidence) of diagnosis of dementia and Alzheimer's disease and studied factors associated with these disorders using competing risks models to account for death, change in dialysis modality, and kidney transplant. We estimated the risk of subsequent mortality using Cox proportional hazards models.

Results

The 1- and 5-year risks of diagnosed dementia accounting for competing risks were 4.6% and 16% for women, respectively, and 3.7% and 13% for men, respectively. The corresponding Alzheimer's disease diagnosis risks were 0.6% and 2.6% for women, respectively, and 0.4% and 2.0% for men, respectively. The strongest independent risk factors for diagnosis of dementia and Alzheimer's disease were age ≥86 years old (dementia: hazard ratio, 2.11; 95% confidence interval, 2.04 to 2.18; Alzheimer's disease: hazard ratio, 2.11; 95% confidence interval, 1.97 to 2.25), black race (dementia: hazard ratio, 1.70; 95% confidence interval, 1.67 to 1.73; Alzheimer's disease: hazard ratio, 1.78; 95% confidence interval, 1.71 to 1.85), women (dementia: hazard ratio, 1.10; 95% confidence interval, 1.08 to 1.12; Alzheimer's disease: hazard ratio, 1.12; 95% confidence interval, 1.08 to 1.16), and institutionalization (dementia: hazard ratio, 1.36; 95% confidence interval, 1.33 to 1.39; Alzheimer's disease: hazard ratio, 1.10; 95% confidence interval, 1.05 to 1.15). Older patients on hemodialysis with a diagnosis of dementia were at 2.14-fold (95% confidence interval, 2.07 to 2.22) higher risk of subsequent mortality; those with a diagnosis of Alzheimer's disease were at 2.01-fold (95% confidence interval, 1.89 to 2.15) higher mortality risk.

Conclusions

Older patients on hemodialysis are at substantial risk of diagnosis with dementia and Alzheimer's disease, and carrying these diagnoses is associated with a twofold higher mortality.



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Mapping Progress in Reducing Cardiovascular Risk with Kidney Disease: Managing Volume Overload



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Characteristics of Colon-Derived Uremic Solutes

Background and objectives

Colon microbial metabolism produces solutes that are normally excreted in the urine and accumulate in the plasma when the kidneys fail. This study sought to further identify and characterize human colon-derived uremic solutes.

Design, setting, participants, & measurements

Colon-derived solutes normally excreted in the urine were identified by comparing urine from controls (n=17) and patients with total colectomies (n=12), using an established metabolomic platform. Colon-derived solutes that accumulate in kidney failure were then identified by comparing the plasma of the control patients with that of patients on dialysis (n=14).

Results

Ninety-one urinary solutes were classified as colon-derived on the basis of the finding of a urine excretion rate at least four-fold higher in control patients than in patients with total colectomies. Forty-six were solutes with known chemical structure, 35 of which had not previously been identified as colon-derived. Sixty of the colon-derived solutes accumulated in the plasma of patients with ESKD to a degree greater than urea and were therefore classified as uremic. The estimated urinary clearance for 27 out of the 32 colon-derived solutes for which clearance could be calculated exceeded that of creatinine, consistent with tubular secretion. Sulfatase treatment revealed that 42 out of the 91 colon-derived solutes detected were likely conjugates.

Conclusions

Metabolomic analysis identified numerous colon-derived solutes that are normally excreted in human urine. Clearance by tubular secretion limits plasma levels of many colon-derived solutes.



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Association of Preexisting Arterial Intimal Hyperplasia with Arteriovenous Fistula Outcomes

Background and objectives

Preoperative arterial function is associated with arteriovenous fistula (AVF) development. Because arterial pathology may correlate with its function, preexisting arterial intimal hyperplasia may be associated with AVF development.

Design, setting, participants, & measurements

Vascular specimens obtained from 125 patients (with minimal 2 mm arterial diameter and 2.5 mm venous diameter) undergoing AVF creation were quantified for arterial intimal hyperplasia, arterial medial fibrosis, arterial microcalcification, and venous intimal hyperplasia. A 6-week postoperative ultrasound quantified AVF diameter, blood flow, and stenosis. Clinical AVF maturation was assessed using a predefined protocol. In a prospective cohort study design, we investigated the association of preexisting arterial intimal hyperplasia with the postoperative AVF diameter, blood flow, stenosis, and clinical maturation failure, after controlling for baseline demographics, comorbidities, and preoperative vein diameter. Additional analyses evaluated whether other vascular pathologies interacted with arterial intimal hyperplasia in affecting AVF outcomes.

Results

The median intimal thickness of the native artery was 22.0 μm (interquartile range, 14.8–37.1 μm). The median postoperative AVF diameter was 4.8 (interquartile range, 3.7–6.8) mm, blood flow was 796 (interquartile range, 413–1036) ml/min, and stenosis was present in 37 out of 98 patients with ultrasound data (38%). AVF nonmaturation occurred in 37 out of 125 patients (30%). Preexisting arterial intimal thickness was not significantly associated with AVF blood flow (–12 ml/min; 95% confidence interval [95% CI], –55 to 30 ml/min), diameter (–0.04 mm; 95% CI, –0.21 to 0.14 mm), stenosis (odds ratio, 0.93; 95% CI, 0.75 to 1.14), or clinical maturation failure (odds ratio, 1.07; 95% CI, 0.90 to 1.28), all per 10 μm increase. There was no significant interaction of preexisting arterial intimal thickness and postoperative AVF outcomes with arterial medial fibrosis, arterial microcalcification, or venous intimal hyperplasia.

Conclusions

Preexisting arterial intimal hyperplasia is not associated with the 6-week AVF blood flow, diameter or stenosis, or clinical maturation when the preoperative arterial diameter is ≥2 mm.



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Management of the Incidental Kidney Mass in the Nephrology Clinic



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Postoperative Ultrasound, Unassisted Maturation, and Subsequent Primary Patency of Arteriovenous Fistulas

Background and objectives

Postoperative ultrasound is commonly used to assess arteriovenous fistula (AVF) maturation for hemodialysis, but its utility for predicting unassisted AVF maturation or primary AVF patency for hemodialysis has not been well defined. This study assessed the predictive value of postoperative AVF ultrasound measurements for these clinical AVF outcomes.

Design, setting, participants, & measurements

We queried a prospective vascular access database to identify 246 patients on catheter-dependent hemodialysis who underwent AVF creation between 2010 and 2016 and obtained a postoperative ultrasound within 90 days. Multivariable logistic regression was used to evaluate the association of clinical characteristics and postoperative ultrasound measurements with unassisted AVF maturation. A receiver operating characteristic curve estimated the predictive value of these factors for unassisted AVF maturation. Finally, multivariable survival analysis was used to identify factors associated with primary AVF patency in patients with unassisted AVF maturation.

Results

Unassisted AVF maturation occurred in 121 out of 246 patients (49%), assisted maturation in 55 patients (22%), and failure to mature in 70 patients (28%). Using multivariable logistic regression, unassisted AVF maturation was associated with AVF blood flow (odds ratio [OR], 1.30; 95% confidence interval [95% CI], 1.18 to 1.45 per 100 ml/min increase; P<0.001), forearm location (OR, 0.37; 95% CI, 0.08 to 1.78; P=0.21), presence of stenosis (OR, 0.45; 95% CI, 0.23 to 0.88; P=0.02); AVF depth (OR, 0.88; 95% CI, 0.77 to 1.00 per 1 mm increase; P=0.05), and AVF location interaction with depth (OR, 0.50; 95% CI, 0.28 to 0.84; P=0.02). The area under the receiver operating characteristic curve, using all these factors, was 0.84 (95% CI, 0.79 to 0.89; P<0.001). Primary AVF patency in patients with unassisted maturation was associated only with AVF diameter (hazard ratio, 0.84; 95% CI, 0.76 to 0.94 per 1 mm increase; P=0.002).

Conclusions

Unassisted AVF maturation is predicted by AVF blood flow, location, depth, and stenosis. AVF patency after unassisted maturation is predicted only by the postoperative AVF diameter.



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Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease

Pharmacokinetics and pharmacodynamics follow the logic of cause and consequence. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. Reversible effects are capacity-limited and saturable whereas irreversible effects are limited only by the number of viable targets. In the case of receptor-mediated and reversible effects a threshold and a ceiling concentration can be defined. Antimicrobial drugs with concentration-dependent action are distinguished from drugs with time-dependent action. Concentration-dependent effects are associated with a high ceiling concentration and the target is the high peak. Time-dependent effects are associated with a high threshold concentration and the target is the high trough. During kidney dysfunction, alterations of drug response are usually attributed to pharmacokinetic but rarely to pharmacodynamic changes. Dose adjustment calculations, therefore, tacitly presume that pharmacodynamic parameters remain unchanged while only pharmacokinetic parameters are altered in kidney failure. Kidney dysfunction influences the pharmacokinetic parameters of at least 50% of all essential drugs. Clinicians usually consider pharmacokinetics when kidney disease is found, but pharmacodynamics is as important. Alterations of pharmacodynamic parameters are conceivable but only rarely reported in kidney failure. Sometimes surprising dosing adjustments are needed when pharmacodynamic concepts are brought into the decision process of which dose to choose. Pharmacokinetics and pharmacodynamics should both be considered when any dosing regimen is determined.



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The Effect of Increasing Dialysate Magnesium on Serum Calcification Propensity in Subjects with End Stage Kidney Disease: A Randomized, Controlled Clinical Trial

Background and objectives

Serum calcification propensity is a novel functional test that quantifies the functionality of the humeral system of calcification control. Serum calcification propensity is measured by T50, the time taken to convert from primary to secondary calciprotein particle in the serum. Lower T50 represents higher calcification propensity and is associated with higher risk of cardiovascular events and death in patients with ESKD. Increasing magnesium in serum increases T50, but so far, no clinical trials have investigated whether increasing serum magnesium increases serum calcification propensity in subjects with ESKD.

Design, setting, participants, & measurements

We conducted a single-center, randomized, double-blinded, parallel group, controlled clinical trial, in which we examined the effect of increasing dialysate magnesium from 1.0 to 2.0 mEq/L for 28 days compared with maintaining dialysate magnesium at 1.0 mEq/L on T50 in subjects undergoing hemodialysis for ESKD. The primary end point was the value of T50 at the end of the intervention.

Results

Fifty-nine subjects were enrolled in the trial, and of these, 57 completed the intervention and were analyzed for the primary outcome. In the standard dialysate magnesium group, T50 was 233±81 minutes (mean±SD) at baseline (mean of days –7 and 0) and 229±93 minutes at follow-up (mean of days 21 and 28), whereas in the high dialysate magnesium group, T50 was 247±69 minutes at baseline and 302±66 minutes at follow-up. The difference in T50 between the two groups at follow-up (primary analysis) was 73 minutes (between-group difference; 95% confidence interval, 30 to 116; P<0.001), and the between-group difference in serum magnesium was 0.88 mg/dl (95% confidence interval, 0.66 to 1.10; P=0.001).

Conclusions

Increasing dialysate magnesium increases T50 and hence, decreases calcification propensity in subjects undergoing maintenance hemodialysis.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_21_CJASNPodcast_18_9_B.mp3



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Gastric Kaposi Sarcoma



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Double balloon enteroscopy assisted diagnosis of malignancy arising from Meckel’s Diverticulum



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Cost Effectiveness of Universal Screening for HCV Infection in the Era of Direct-Acting, Pangenotypic Treatment Regimens

Most persons infected with hepatitis C virus (HCV) in the United States (US) were born from 1945 through 1965—testing is recommended for this cohort. However, HCV incidence is increasing among younger persons in many parts of the country and treatment is recommended for all adults with HCV infection. We aimed to estimate the cost effectiveness of universal 1-time screening for HCV infection in all adults living in the US and to determine the prevalence of HCV antibody above which HCV testing is cost-effective.

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Brunner’s gland hamartoma arising from the pyloric ring



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Pancreatic carcinoma discovered by Sister Mary Joseph’s nodules



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Transplantation of a Gitelman Syndrome Kidney Ameliorates Hypertension: A Case Report

Gitelman syndrome is caused by inactivating mutations of the gene that encodes the renal sodium/chloride cotransporter (NCC; encoded by SLC12A3), resulting in hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Renal salt wasting commonly provokes mild hypotension. The paucity of previous kidney transplants from donors with known tubulopathies suggests that such conditions may be considered contraindications to donation. A 76-year-old man received a live unrelated kidney transplant from a donor with known Gitelman syndrome secondary to a pathogenic mutation of SLC12A3.

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Estimated GFR and Hospital-Acquired Infections Following Major Surgery

Low estimated glomerular filtration rate (eGFR) increases infection risk, but its contribution to hospital-acquired infection following major surgery is unknown.

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Use of Renin-Angiotensin System Blockade in Advanced CKD: An NKF-KDOQI Controversies Report

Multiple clinical trials have demonstrated that renin-angiotensin system (RAS) blockade with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers effectively reduces chronic kidney disease (CKD) progression. However, most clinical trials excluded participants with advanced CKD (ie, estimated glomerular filtration rate [eGFR]<30mL/min/1.73m2). It is acknowledged that initiation of RAS blockade is often associated with an acute reduction in eGFR, which is thought to be functional, but may result in long-term preservation of kidney function through the reductions in glomerular intracapillary pressure conferred by these agents.

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Never Thought I Would

I hate getting older. I should be proud of every grey hair, but I'm not. So I avoid those cameras (all of them now, it seems) that showcase the lines on my face and my sagging neck. I no longer time my daily runs. And I keep in touch with old friends, who make me feel as if we're all still 20.

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Longitudinal Self-Management and/or Transition Readiness per the TRxANSITION Index among Patients with Chronic Conditions in Pediatric or Adult Care Settings

To evaluate the roles of key individual, family, and illness characteristics on the levels of and gains in longitudinal healthcare transition (HCT) readiness in the pediatric setting and/or self-management skills (SMS) in the adult-focused setting, we used a large dataset with longitudinal measurements from 2006 to 2015.

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Applying the neonatal Early-Onset Sepsis calculator in cases of clinical chorioamnionitis at or after 34 weeks of gestation

Carola et al questioned the diagnostic utility and hence the safety of the neonatal Early-Onset Sepsis (EOS) calculator.1 In a retrospectively studied cohort of 1159 infants born to mothers with clinical chorioamnionitis, the calculator would have missed 2 of 5 infants with culture-proven, early-onset sepsis.

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Superion, TriTech, Zuercher, and Aptean’s Public Sector Business merge to form CentralSquare Technologies

LAKE MARY, Fla. — Created by the merger of four innovative software businesses, CentralSquare Technologies launched today as an industry leading provider of public sector software. The completed merger brings together the capabilities of Superion, TriTech Software Systems along with Zuercher Technologies, and the public sector and healthcare business of Aptean. CentralSquare today provides...

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Correlative Light Electron Microscopy (CLEM) for Tracking and Imaging Viral Protein Associated Structures in Cryo-immobilized Cells

A correlative light electron microscopy (CLEM) method is applied to image virus-induced intracellular structures via electron microscopy (EM) in cells that are previously selected by light microscopy (LM). LM and EM are combined as a hybrid imaging approach to achieve an integrated view of virus-host interactions.

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Ferric Chloride-induced Canine Carotid Artery Thrombosis: A Large Animal Model of Vascular Injury

Here, we present the modifications necessary to a well characterized and commonly used small animal ferric chloride-induced (FeCl3) carotid artery injury model for use in a large animal vascular injury model. The resulting model can be utilized for pre-clinical trial assessment of both prophylactic and thrombolytic pharmacological and mechanical interventions.

https://ift.tt/2oNYKCY

Characterization of Thymus-dependent and Thymus-independent Immunoglobulin Isotype Responses in Mice Using Enzyme-linked Immunosorbent Assay

In this paper, we describe a protocol to characterize T-dependent and T-independent immunoglobulin (Ig) isotype responses in mice using ELISA. This method used alone or in combination with flow cytometry will allow researchers to identify differences in B cell-mediated Ig isotype responses in mice following T-dependent and T-independent antigen immunization.

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Patient care: First and last impressions make the difference

Positive beginning and ending patient interactions fall into the "serial positioning effect" and can boost patient care reviews

https://ift.tt/2vLEBBy

Adding Fish Oil in Pregnancy May Lead to Higher Child BMI

FRIDAY, Sept. 7, 2018 -- Supplementation with n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) in pregnancy leads to higher body mass index (BMI) in offspring at age 6 years, but no increase in the proportion of obese children, according to a...

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Social Determinants Linked to Provision of Primary Care

FRIDAY, Sept. 7, 2018 -- Social determinants are associated with provision of primary care services, according to a study recently published in the Annals of Family Medicine. Alan Katz, M.B.Ch.B., from the University of Manitoba in Canada, and...

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With New Persistent Opioid Use, Most Early Scripts From Surgeons

FRIDAY, Sept. 7, 2018 -- Among surgical patients who develop new persistent opioid use, surgeons provide the majority of opioid prescriptions in the first few months after surgery, but by nine to 12 months post-surgery, most prescriptions are from...

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Personalized Weighting Could Enhance Hospital Rating Tools

FRIDAY, Sept. 7, 2018 -- The weighting systems that underlie hospital performance rating tools should incorporate the needs, values, and preferences of patients, according to a perspective article published in the Aug. 30 issue of the New England...

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Metabolite Analysis IDs Pathways Associated With WTC-Lung Injury

FRIDAY, Sept. 7, 2018 -- Machine learning approaches to metabolite analysis can predict key pathways contributing to lung function loss associated with World Trade Center Lung Injury (WTC-LI), according to a small study published online Sept. 3 in...

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Greater CAD Incidence, Heart Mass in Firefighter Cardiac Arrests

FRIDAY, Sept. 7, 2018 -- Most cardiac fatalities among firefighters have evidence of coronary heart disease and increased heart mass, according to a study published online Sept. 5 in the Journal of the American Heart Association. Denise L. Smith,...

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X-Rays, Blood Tests Not Advised for Children's Concussions

FRIDAY, Sept. 7, 2018 -- Routine X-rays and blood tests should not be used to diagnose children's concussions, new U.S. government guidelines say. The guidelines were published online Sept. 4 in JAMA Pediatrics. Computed tomography scans may be...

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Increased Corticomotor Excitability ID'd in Restless Legs

FRIDAY, Sept. 7, 2018 -- For patients with restless leg syndrome (RLS), the primary motor cortex (M1) exhibits hyperexcitability, which is associated with disease severity, according to a study published recently in Sleep Medicine. Rachel Marie E....

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AAP Updates Recommendations for Pediatric Flu Vaccination

FRIDAY, Sept. 7, 2018 -- All children and adolescents are advised to undergo annual influenza immunization, ideally with an inactivated influenza vaccine, according to a policy statement published online Sept. 3 in Pediatrics. Yvonne A. Maldonado,...

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Bigger Cut in Smoke Exposure for Immediate Nicotine Reduction

FRIDAY, Sept. 7, 2018 -- Immediate reduction of nicotine in cigarettes leads to significantly greater decreases in biomarkers of smoke exposure than gradual reductions in nicotine levels, according to a study published in the Sept. 4 issue of the...

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Generation and Control of Electrohydrodynamic Flows in Aqueous Electrolyte Solutions

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The rectification of ion transport pathways is an effective method to generate one-directional ion-dragged electrohydrodynamic flows. By setting an ion-exchange membrane in a flow channel, an electrically polarized condition is generated and causes a liquid flow to be driven when an electric field is externally applied.

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Fat-Water Phantoms for Magnetic Resonance Imaging Validation: A Flexible and Scalable Protocol

The purpose of this work is to describe a protocol for creating a practical fat-water phantom that can be customized to produce phantoms with varying fat percentages and volumes.

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A Colorimetric Method for Measuring Iron Content in Plants

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We present a simple and reliable protocol for measuring iron content in plant tissues using the colorimetric Prussian Blue method.

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Exosomes May Help Tumors Evade Immune System

A new study has identified what may be an important and previously unknown route by which tumors evade the immune system: They secrete small membrane-encased sacs, called exosomes, studded with a protein that dials down the immune response.



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Harnessing the Power of the Crowd Could Improve Screening Accuracy

Averaging the results from two independent participants improved screening accuracy, whether participants were looking at baggage scans or mammograms, according to findings published in Psychological Science, a journal of the Association for Psychological Science.

The research findings, reported by researchers at Brunel University, suggest that having multiple screeners could improve the detection of rare items in real-world contexts, such as airport security, radiology and military reconnaissance.

"There is a known problem with detecting rare targets," said study author Jennifer E Corbett, an honorary lecturer for Brunel's College of Health and Life Sciences. "When you go to the airport, they always seem to find the bottle of water in your bag – it's a very common item, so people have a mental template. They'll just find it. But with rare targets like weapons and guns, people see these far less frequently, so are more likely to miss them."

This is an animation showing an example of the mammogram screening task

Can you tell which of these mammograms shows a tumor? Check your answers below. Source: Brunel University

Corbett, who coauthored the paper with Brunel researcher Jaap Munneke, says the problem lies with the human visual system, which is only capable of processing a few objects in detail at any given moment. The brain averages out redundant and specific information, filling in the spaces based on prior knowledge. As a result, infrequent objects – those that the observers aren't expecting to see – are often missed.

However, two people independently looking at the same scan perceive it differently, significantly increasing the possibility of infrequent items being spotted.

"We found that when we pair the estimates of two people who don't know they're working together – they have no interaction whatsoever – there is a huge improvement in detection, just by capitalizing on the diversity of people's judgments," said Corbett.

To test their ideas, Corbett and Munneke conducted two experiments – one which challenged participants to undertake airport screening and the other mammogram screening.

In the airport screening experiment, 16 participants, who had no experience with security screening, saw an image containing nine objects for half a second. They then indicated whether they'd like to call the image back, based on whether they detected a target object.

"The experiment tested weapons detection as well as simple detection tasks," said Corbett. "We found that not only did pairing observers estimates improve detection in both types of tasks, but that pairing individuals' estimates from the simple task in a way that maximized the decorrelated patterns actually improved the performance in the separate weapons task."

The researchers discovered that when they paired the detections of two people who worked individually and independently, they not only saw an increase in the detection of rare objects, but also a reduction in the likelihood of harmless items being wrongly flagged as suspicious.

For the second experiment, 18 participants learned how to identify a tumor on a mammogram. They then saw 400 unique scans, 5% of which had a tumor present, and then another 400, of which 50% had a tumor present.

In both cases, a significant increase in detection rate was observed when two individuals' results were averaged.

"The task is not so different between airport scanner and a radiologist – the idea is you're looking for something you have knowledge of but see infrequently," said Corbett. "It doesn't matter though whether it's a tumor or a weapon or something else, averaging two different perceptions of the same scene increases detection."

The researchers say their detection method is a marked improvement over those currently used in airport and radiological screening, as it significantly reduces the time someone needs to look at a scan.

"The method we propose is probably the best candidate for maximizing the resources of a limited pool of highly trained experts needing to detect rare targets in a lot of images," said Corbett. "Obviously the limit here is that it requires a second set of eyes, but we're now looking for ways to use a deep-learning algorithm to cover the aspects of the images which are causing these decorrelations. We can then pair a single person with the algorithm."

All data have been made publicly available via the Open Science Framework. The complete Open Practices Disclosure for this article is available online. This article has received the badge for Open Data.

This image shows the answers to the sample mammogram screening task

Correct answers. Source: Brunel University



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Role of plasmid plasticity and mobile genetic elements in the entomopathogen Bacillus thuringiensis serovar israelensis

Abstract
Bacillus thuringiensis is a well-known biopesticide that has been used for more than 80 years. This spore-forming bacterium belongs to the group of Bacillus cereus that also includes, among others, emetic and diarrheic pathotypes of B. cereus, the animal pathogen Bacillus anthracis and the psychrotolerant Bacillus weihenstephanensis. B. thuringiensis is rather unique since it has adapted its lifestyle as an efficient pathogen of specific insect larvae. One of the peculiarities of B. thuringiensis strains is the extent of their extrachromosomal pool, with strains harbouring more than 10 distinct plasmid molecules. Among the numerous serovars of B. thuringiensis, 'israelensis' is certainly emblematic since its host spectrum is apparently restricted to dipteran insects like mosquitoes and black flies, vectors of human and animal diseases such as malaria, yellow fever or river blindness. In this review, the putative role of the mobile gene pool of B. thuringiensis serovar israelensis in its pathogenicity and dedicated lifestyle is reviewed, with specific emphasis on the nature, diversity and potential mobility of its constituents. Variations among the few related strains of B. thuringiensis serovar israelensis will also be reported and discussed in the scope of this specialized insect pathogen, whose lifestyle in the environment remains largely unknown.

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Evaluation of Diagnostic Accuracy and a Practical Algorithmic Approach for the Diagnosis of Renal Masses by FNA

Cancer Cytopathology, EarlyView.


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Fabrication of a Multiplexed Artificial Cellular MicroEnvironment Array

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This article describes the detailed methodology to prepare a Multiplexed Artificial Cellular MicroEnvironment (MACME) array for high-throughput manipulation of physical and chemical cues mimicking in vivo cellular microenvironments and to identify the optimal cellular environment for human pluripotent stem cells (hPSCs) with single-cell profiling.

https://ift.tt/2N074hG

A Method for Investigating Change Blindness in Pigeons (Columba Livia)

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Change blindness is a phenomenon of visual attention, whereby changes to a visual display go unnoticed under certain specific circumstances. This protocol describes a variation on the flicker paradigm for investigating change blindness that is appropriate and effective for research with pigeons.

https://ift.tt/2M8NCtx

A new look at molecular biology of breast cancer

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New insights into the pelagic microorganisms involved in the methane cycle in the meromictic Lake Pavin through metagenomics

Abstract
Advances in metagenomics have given rise to the possibility of obtaining genome sequences from uncultured microorganisms, even for those poorly represented in microbial community, thereby providing important means to study their ecology and evolution. In this study, metagenomic sequencing was carried out at four sampling depths having different oxygen concentrations or environmental conditions in the water column of Lake Pavin. By analyzing the sequenced reads and matching the contigs to the proxy genomes of the closest cultivated relatives, we evaluated the metabolic potential of the dominant planktonic species involved in the methane cycle. We demonstrated that methane-producing communities were dominated by the genus Methanoregula while methane-consuming communities were dominated by the genus Methylobacter, thus confirming prior observations. Our work allowed the reconstruction of a draft of their core metabolic pathways. Although hydrogenotrophs, the presence of the genes required for acetate activation in the methanogen genome were also detected. Regarding methanotrophy, Methylobacter was present in the same areas as the non-methanotrophic, methylotrophic Methylotenera, which could suggest a relationship between these two groups. Furthermore, the presence of a large gene inventory for nitrogen metabolism (nitrate transport, denitrification, nitrite assimilation and nitrogen fixation, for instance) was detected in the Methylobacter genome.

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Metagenomic sequencing provides insights into microbial detoxification in the guts of small mammalian herbivores (Neotoma spp.)

Abstract
Microbial detoxification of plant toxins influences the use ofplants as food sources by herbivores. Stephen's woodrats (Neotoma stephensi) specialize on juniper, which is defended by oxalate, phenolics, and monoterpenes, while closely related N. albigula specialize on cactus, which only contains oxalate. Woodrats maintain two gut chambers harboring dense microbial communities: a foregut chamber proximal to the major site of toxin absorption, and a cecal chamber in their hindgut. We performed several experiments to investigate the location and nature of microbial detoxification in the woodrat gut. First, we measured toxin concentrations across gut chambers of N. stephensi. Compared to food material, oxalate concentrations were immediately lower in the foregut, while concentrations of terpenes remained high in the foregut, and were lowest in the cecal chamber. We conducted metagenomic sequencing of the foregut chambers of both woodrat species and and cecal chambers of N. stephensi to compare microbial functions. We found that most genes associated with detoxification were more abundant in the cecal chambers of N. stephensi. However, some genes associated with degradation of oxalate and phenolic compounds were more abundant in the foregut chambers. Thus, microbial detoxification may take place in various chambers depending on the class of chemical compound.

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Transcriptional regulation of the ferric aerobactin receptor gene by a GntR-like repressor IutR in Vibrio furnissii

Abstract
We found that Vibrio furnissii can utilize aerobactin (AERO) as a xenosiderophore. A homology search of its genome revealed that this bacterium possesses genes encoding an AERO-mediated iron acquisition system similar to that of Vibrio vulnificus. The system consists of the ABC transporter gene vatCDB, the GntR-type transcriptional repressor gene iutR, and the outer membrane receptor gene iutA. The functions of the vatCDB operon and iutA in V. furnissii were confirmed by the inability of the corresponding deletion mutants to utilize AERO. Reverse transcription-quantitative PCR revealed that iutA transcription under iron-limiting conditions was extensively activated by the addition of AERO to the growth medium; therefore, we focused on elucidating this phenomenon. Electrophoretic mobility shift and DNase I footprinting assays revealed that glutathione S-transferase-fused IutR (GST-IutR) bound directly to a specific palindromic sequence in the iutA promoter region. However, GST-IutR did not bind to this sequence when either AERO or ferric AERO was present in the assay mixture. These in vitro findings suggest that, under iron-limiting conditions, iutA transcription in V. furnissii is artfully regulated both by IutR, acting as a direct repressor of iutA, and by AERO, acting as an effector for IutR, leading to the derepression of iutA transcription.

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Age-dependent changes in GI physiology and microbiota: time to reconsider?

Our life expectancy is increasing, leading to a rise in the ageing population. Ageing is associated with a decline in physiological function and adaptive capacity. Altered GI physiology can affect the amount and types of nutrients digested and absorbed as well as impact the intestinal microbiota. The intestinal microbiota is considered a key player in our health, and a variety of studies have reported that microbiota composition is changing during ageing. Since ageing is associated with a decline in GI function and adaptive capacity, it is crucial to obtain insights into this decline and how this is related to the intestinal microbiota in the elderly. Hence, in this review we focus on age-related changes in GI physiology and function, changes of the intestinal microbiota with ageing and frailty, how these are associated and how intestinal microbiota-targeted interventions may counteract these changes.



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Join the 2nd annual NY Tactical EMS Expo

MELVILLE, N.Y. – The 2nd Annual NY Tactical EMS Expo is coming to Long Island January 5th and 6th, 2019, at the Huntington Hilton Expo Center in Melville, NY. The expo will feature 2 events under 1 roof bringing together the best training and products in the fields of EMS, Fire and Law Enforcement. There is 10,000 square feet of vendors, exhibits and public safety trade show featuring...

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Implementing crew resource management tactics in emergency medicine

CRM strategies include a consensus among crew members and confirmed communications that make tasks more efficient

https://ift.tt/2NpYoAd

Use checklists to counter the effects of fatigue, improve patient care

Avoid missteps, reduce errors and give hospital staff an in-depth preview of a patient's condition

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Pancreaticojejunostomy with or without reinforcement after pancreaticoduodenectomy: surgical technique of ligamentum teres hepatis wrap around pancreaticojejunostomy

Abstract

In a previous issue of the Journal, Zhong et al. reported a retrospective study that compared the perioperative outcomes of the mesh-reinforced pancreaticojejunostomy with conventional pancreaticojejunostomy. They concluded that mesh-reinforced pancreaticojejunostomy was a safe and effective technique, as it provided a safe anchor site for suture, thus reducing the risk of pancreatic leakage. Considering these encouraging results, we present a further simple technique using ligamentum teres hepatis wrap around pancreatojejunostomy for prevention of postoperative pancreatic fistula after pancreaticoduodenectomy.



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Primary classic Hodgkin lymphoma of the ileum and Epstein-Barr virus mucocutaneous ulcer of the colon: two entities compared

Abstract

Primary classic Hodgkin lymphoma of the gastrointestinal tract represents a rare occurrence. A full patient's work-up is essential in order to exclude a secondary intestinal involvement. Histologically Epstein-Barr virus mucocutaneous ulcer closely resembles Hodgkin lymphoma. The differential diagnosis between these two entities is relevant, since both the therapeutic approach and the clinical behavior are different. Herein, we describe a case of primary classic Hodgkin lymphoma arising in the ileum and a case of Epstein-Barr virus mucocutaneous ulcer of the colon, focusing on the main clinicopathological differences.



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Cancers, Vol. 10, Pages 319: Impact of Tumor Regression Grade as a Major Prognostic Factor in Locally Advanced Rectal Cancer after Neoadjuvant Chemoradiotherapy: A Proposal for a Modified Staging System

Cancers, Vol. 10, Pages 319: Impact of Tumor Regression Grade as a Major Prognostic Factor in Locally Advanced Rectal Cancer after Neoadjuvant Chemoradiotherapy: A Proposal for a Modified Staging System

Cancers doi: 10.3390/cancers10090319

Authors: Changhoon Song Joo-Hyun Chung Sung-Bum Kang Duck-Woo Kim Heung-Kwon Oh Hye Seung Lee Jin Won Kim Keun-Wook Lee Jee Hyun Kim Jae-Sung Kim

There is ongoing debate regarding the significance of complete or near-complete response after neoadjuvant chemoradiotherapy (CRT) for rectal cancer. This study assessed the prognostic value of the Dworak tumor regression grade (TRG) following neoadjuvant CRT and surgery primarily in patients with pathological stage (ypStage) II and III rectal cancer. The records of 331 patients who underwent neoadjuvant CRT followed by total mesorectal excision between 2004 and 2015 were retrospectively reviewed. Patients were categorized as having a good response (GR, TRG 3/4, n = 122) or a poor response (PR, TRG 1/2, n = 209). At a median follow-up of 65 months, five-year disease-free survival (DFS) was higher in the GR group than in the PR group (91.3% vs. 66.6%, p &lt; 0.001). Patients with a GR and ypStage II disease had a five-year DFS that was indistinguishable from that of patients with ypStage 0–I disease (92.3% vs. 90.7%, p = 0.885). Likewise, patients with a GR and ypStage III disease had a five-year DFS similar to those with ypStage II disease (76.0% vs. 75.9%, p = 0.789). A new modified staging system that incorporates grouped TRG (GR vs. PR) was developed. The prognostic performance of this modified stage and the ypStage was compared with the Harrell C statistic. C statistic of the modified stage was higher than that of the ypStage (0.784 vs. 0.757, p = 0.012). The results remained robust after multivariate Cox regression analyses. In conclusion, a GR to neoadjuvant CRT is an independent predictor of good DFS and overall survival and further stratifies patients so as to estimate the risk of recurrence and survival among patients with ypStage II and III rectal cancer.



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Cancers, Vol. 10, Pages 318: Nutrition Impact Symptoms Are Prognostic of Quality of Life and Mortality after Surgery for Oesophageal Cancer

Cancers, Vol. 10, Pages 318: Nutrition Impact Symptoms Are Prognostic of Quality of Life and Mortality after Surgery for Oesophageal Cancer

Cancers doi: 10.3390/cancers10090318

Authors: Poorna Anandavadivelan Lena Martin Therese Djärv Asif Johar Pernilla Lagergren

We aimed to clarify the influence of nutritional problems after surgery for oesophageal cancer on functional health related quality of life (HRQOL) and survival. A prospective nationwide cohort of oesophageal cancer patients operated 2001–2005 in Sweden with 6 months postoperative follow up was used. Nutritional problems were categorized as low/moderate/severe/very severe based on weight loss and nutrition impact symptoms. An ANCOVA model calculated mean score differences (MD) with 95% confidence intervals (CI) of global quality of life (QOL), social and physical function scores, stratified by preoperative body mass index (BMI) &lt;25 and ≥25. A Cox proportional hazards model produced hazard ratios (HR) with 95% CI for overall 5-year survival. Of 358 patients, 196 (55%) had preoperative BMI ≥25. Very severe and severe nutritional problems were associated with worse HRQOL in both BMI groups. E.g. MD's for global QOL among 'very severe' group was −29 (95% CI −39–−19) and −20 (95% CI −29–−11) for &lt;25 and ≥25 BMI, respectively, compared to the 'low' group. Overall 5-year survival among 'very severe' and BMI ≥ 25 was worse; HR 4.6 (95% CI 1.4–15.6). Intense nutritional problems negatively impact postoperative HRQOL and combined with preoperative BMI ≥ 25 are associated with poorer 5-year overall survival representing a group needing greater clinical attention.



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Sepsis alert: How to diagnose septic shock

Decreasing mortality through recognizing, reporting, and treating sepsis in the field

https://ift.tt/2wPts29

Implementing crew resource management tactics in emergency medicine

CRM strategies include a consensus among crew members and confirmed communications that make tasks more efficient

https://ift.tt/2NWAKs8

Sepsis alert: How to diagnose septic shock

Decreasing mortality through recognizing, reporting, and treating sepsis in the field

https://ift.tt/2wPts29

Cancers, Vol. 10, Pages 317: Transcriptome Signatures of Canine Mammary Gland Tumors and Its Comparison to Human Breast Cancers

Cancers, Vol. 10, Pages 317: Transcriptome Signatures of Canine Mammary Gland Tumors and Its Comparison to Human Breast Cancers

Cancers doi: 10.3390/cancers10090317

Authors: Kang-Hoon Lee Hyoung-Min Park Keun-Hong Son Tae-Jin Shin Je-Yoel Cho

Breast cancer (BC)/mammary gland carcinoma (MGC) is the most frequently diagnosed and leading cause of cancer-related mortality in both women and canines. To better understand both canine MGC and human BC-specific genes, we sequenced RNAs obtained from eight pairs of carcinomas and adjacent normal tissues in dogs. By comprehensive transcriptome analysis, 351 differentially expressed genes (DEGs) were identified in overall canine MGCs. Based on the DEGs, comparative analysis revealed correlation existing among the three histological subtypes of canine MGC (ductal, simple, and complex) and four molecular subtypes of human BC (HER2+, ER+, ER&amp;HER2+, and TNBC). Eight DEGs shared by all three subtypes of canine MGCs had been previously reported as cancer-associated genes in human studies. Gene ontology and pathway analyses using the identified DEGs revealed that the biological processes of cell proliferation, adhesion, and inflammatory responses are enriched in up-regulated MGC DEGs. In contrast, fatty acid homeostasis and transcription regulation involved in cell fate commitment were down-regulated in MGC DEGs. Moreover, correlations are demonstrated between upstream promoter transcripts and DEGs. Canine MGC- and subtype-enriched gene expression allows us to better understand both human BC and canine MGC, yielding new insight into the development of biomarkers and targets for both diseases.



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A Bayesian robust Kalman smoothing framework for state-space models with uncertain noise statistics

The classical Kalman smoother recursively estimates states over a finite time window using all observations in the window. In this paper, we assume that the parameters characterizing the second-order statistic...

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Joys and challenges of relationships in Scotland and New Zealand rural midwifery: A multicentre study

Publication date: Available online 7 September 2018

Source: Women and Birth

Author(s): Susan Crowther, Ruth Deery, Rea Daellenbach, Lorna Davies, Andrea Gilkison, Mary Kensington, Jean Rankin

Abstract
Background

Globally there are challenges meeting the recruitment and retention needs for rural midwifery. Rural practice is not usually recognised as important and feelings of marginalisation amongst this workforce are apparent. Relationships are interwoven throughout midwifery and are particularly evident in rural settings. However, how these relationships are developed and sustained in rural areas is unclear.

Aim

To study the significance of relationships in rural midwifery and provide insights to inform midwifery education.

Methods/design

Multi-centre study using online surveys and discussion groups across New Zealand and Scotland. Descriptive and template analysis were used to organise, examine and analyse the qualitative data.

Findings

Rural midwives highlighted how relationships with health organisations, each other and women and their families were both a joy and a challenge. Social capital was a principal theme. Subthemes were (a) working relationships, (b) respectful communication, (c) partnerships, (d) interface tensions, (e) gift of time facilitates relationships.

Conclusions

To meet the challenges of rural practice the importance of relationship needs acknowledging. Relationships are created, built and sustained at a distance with others who have little appreciation of the rural context. Social capital for rural midwives is thus characterised by social trust, community solidarity, shared values and working together for mutual benefit. Rural communities generally exhibit high levels of social capital and this is key to sustainable rural midwifery practice.

Implications

Midwives, educationalists and researchers need to address the skills required for building social capital in rural midwifery practice. These skills are important in midwifery pre- and post-registration curricula.



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Gestational diabetes and postnatal depressive symptoms: A prospective cohort study in Western China

Publication date: Available online 6 September 2018

Source: Women and Birth

Author(s): Jonathan K.L. Mak, Andy H. Lee, Ngoc Minh Pham, Li Tang, Xiong-Fei Pan, Colin W. Binns, Xin Sun

Abstract
Background

Gestational diabetes mellitus (GDM) can lead to adverse birth outcomes, but its effect on postnatal depression has not been thoroughly investigated, especially in Asian populations.

Aim

To determine the prospective association between GDM and postnatal depressive symptoms in Western China.

Methods

A prospective cohort study of 1449 mothers was conducted in Chengdu, capital city of Sichuan Province. GDM was diagnosed during pregnancy using oral glucose tolerance tests. Maternal depressive symptoms were measured at 32–37 weeks of gestation, then at one and three months after giving birth using a validated Chinese version of the Edinburgh Postnatal Depression Scale (EPDS). Associations between the postnatal EPDS scores, GDM status and blood glucose levels were assessed by multivariable mixed-effects regression models, accounting for baseline EPDS scores of the cohort and other confounding factors.

Findings

Compared to the non-GDM group (n = 1220), women with GDM (n = 229, 15.8%) reported significantly higher mean EPDS scores at both 1-month (p = 0.02) and 3-month (p < 0.01) postpartum. Similarly, high levels of fasting, 1-h and 2-h blood glucose levels during pregnancy were associated with increased EPDS scores. Mixed-effects models further confirmed the positive association between GDM status and postnatal depressive symptoms, even though the mean EPDS scores decreased substantially over the three time points.

Conclusion

Chinese women with GDM were more susceptible to postnatal depression than others without the condition, despite their depressive symptoms reducing over time after childbirth. It is thus important to raise awareness of postnatal depression amongst healthcare professionals who care for women with GDM.



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Eagerness to use an immature technology: Humans have a habit of trusting algorithms without troubling themselves to think about consequences

From WSJ:

Don't Believe the Algorithm: Blind faith in machines (and machine learning) has left us vulnerable to biased and incoherent AI. The solution? A healthy dose of skepticism and human oversight.

The mathematican who wrote the WSJ artucle had the following suggestion:

"USE 'MAGIC' TO SPOT BOGUS ALGORITHMS -- Whenever you see a story about an algorithm, replace buzzwords like "machine learning," "artificial intelligence" and "neural network" with the word "magic." Does everything still make grammatical sense? Is any of the meaning lost? If not, I'd be worried that something smells like bull—. Because I'm afraid—long into the foreseeable future—we're not going to "solve world hunger with magic" or "use magic to write the perfect screenplay" any more than we are with AI."

References:

Don't Believe the Algorithm, WSJ.

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Astrocytic degeneration in chronic traumatic encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated head traumas. Using immunohistochemistry for glial fibrillary acidic protein as a marker, plus automated quantitative analysis, we examined the characteristics and extent of astrogliosis present in stage III and IV CTE, along with Alzheimer's disease (AD), and frontotemporal dementia (FTD) cases. Astrogliosis in CTE patients was more diffuse compared to that of AD and FTD patients, which was concentrated in the sulcal depths. Of 14 patients with CTE, 10 exhibited signs of a degenerating astrocyte pathology, characterized by beaded, broken astrocytic processes. This astrocytic degeneration was typically found to be diffuse throughout the white matter, although two cases demonstrated astrocytic degeneration in the gray matter. The degeneration was also observed in 2 of 3 AD and 2 of 3 FTD brains, with overall similar characteristics across diseases. There was minimal to no astrocytic degeneration in six age-matched controls with no neurodegenerative disease. We found that the extent of the white matter astrocytic degeneration was strongly correlated with the level of overall astrogliosis in both the white and gray matter. However, astrocytic degeneration was not correlated with the overall extent of tau pathology. Specifically, there was no correlation between levels of p-tau in the sulcal depths and astrocytic degeneration in the white matter adjacent to the sulcal depths. Thus, astrocytic degeneration and overall astrogliosis appear to represent distinct pathological features of CTE. Further investigation into these astroglial pathologies could provide new insights into underlying disease mechanisms and represent a potential target for in vivo assessment of CTE as well as other neurodegenerative disorders.



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