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Δευτέρα 19 Ιουνίου 2017

Cross-Linkable and Dual Functional Hybrid Polymeric Electron Transporting Layer for High-Performance Inverted Polymer Solar Cells

A cross-linkable dual functional polymer hybrid electron transport layer (ETL) is developed by simply adding an amino-functionalized polymer dopant (PN4N) and a light crosslinker into a commercialized n-type semiconductor (N2200) matrix. It is found that the resulting hybrid ETL not only has a good solvent resistance, facilitating multilayers device fabrication but also exhibits much improved electron transporting/extraction properties due to the doping between PN4N and N2200. As a result, by using PTB7-Th:PC71BM blend as an active layer, the inverted device based on the hybrid ETL can yield a prominent power conversion efficiency of around 10.07%. More interestingly, photovoltaic property studies of bilayer devices suggest that the absorption of the hybrid ETL contributes to photocurrent and hence the hybrid ETL simultaneously acts as both cathode interlayer material and an electron acceptor. The resulting inverted polymer solar cells function like a novel device architectures with a combination of a bulk heterojunction device and miniature bilayer devices. This work provides new insights on function of ETLs and may be open up a new direction for the design of new ETL materials and novel device architectures to further improve device performance.

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Cross-linkable dual functional hybrid electron transport layers are developed and can work as both cathode interlayer and light harvesting layer in polymer solar cells, which enhance electron collection and contribute to photocurrent production in the resulting devices. These results may provide new directions for the design of multifunctional interface materials and novel device architectures.



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Retraction: ‘Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells’ by Nobuyuki Kikuno, Hiroaki Shiina, Shinji Urakami, Ken Kawamoto, Hiroshi Hirata, Yuichiro Tanaka, Shahana Majid, Mikio Igawa and Rajvir Dahiya

The above article, published online on 22 April 2008 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, Prof. Peter Lichter, and John Wiley & Sons Ltd. The retraction has been agreed due to errors identified in Figs, 3, 4, and 5. The concerns about these figures cannot be resolved because the original data can no longer be retrieved.

Reference

Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Majid S, Igawa M and Dahiya R. (2008), Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells. Int J Cancer, 123:552560. DOI: 10.1002/ijc.23590



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Resonance frequency analysis of dental implants placed at the posterior maxilla varying the surface treatment only: A randomized clinical trial

Abstract

Background

Chemical modifications of the dental implant surface that improve the wettability result in a faster and better osseointegration.

Purpose

The aim of this randomized clinical trial was to evaluate the implant stability quotient (ISQ) of implants with similar designs, treated with 2 surfaces, sandblasted acid-etched (SAE) and hydrophilic SAE, within the initial 16 weeks of healing.

Material and methods

A total of 64 implants (32 SAE—control group and 32 modified SAE—test group) with the same design, length, and diameter (conical and compressive, 4.3 × 10 mm) were inserted into the posterior maxillae of 21 patients partially edentulous. The ISQ values were collected at post-surgery (T0), 1 week (T1), 2 weeks (T2), 3 weeks (T3), 5 weeks (T4), 8 weeks (T5), 12 weeks (T6), and 16 weeks (T7).

Results

None of the implants failed. Test group presented ISQ values higher than the control group (ANOVA—P < .01) from T5 to T7. When comparing groups regarding the amount of time required to achieve ISQ ≥ 70 as a reference, there was a statistically significant difference (cox regression—P < .01), and a hazard ratio of 2.24 (CI 1.62-3.11). At the 1-year follow-up, there was a drop out of 1 patient, and 2 implants were no longer evaluated. Survival rate for both groups was 100% at the 1-year follow-up.

Conclusions

The current study suggests that implants with hydrophilic surface (modified SAE) integrate faster than implants with SAE surface. The stability gain of the test group was 2.24 times faster than the control group after 5 weeks of evaluation at the posterior region of the edentulous maxillae.



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Incidental findings of implant complications on postimplantation CBCTs: A cross-sectional study

Abstract

Background

Survival rates of dental implants are reported to be very high and seem to indicate minimal complications related to dental implants.

Purpose

The aim of this report was to evaluate in a cross-sectional study the prevalence of implant positioning complications as appears in postimplantation Cone-Beam Computerized Tomography (CBCT) in two of the major imaging facilities in Bucharest, Romania.

Methods

Demographic and implant data was collected from two of the three main CBCT facilities in Bucharest, Romania. All postimplantation CBCT imaging were assessed and evaluated for the presence of different implant positioning related complications. Data were entered into Excel spreadsheet and analyzed statistically.

Results

Of the 2323 CBCT's that were analyzed, a total of 160 (6.89%) presented with implant positioning related complications. Out of those, 62 cases revealed penetration of the implant to adjacent anatomic structure. More specifically, there were 21 instances of sinus penetration, 19 instances of nasal cavity penetration, 9 instances of inferior alveolar canal penetration, and 13 instances of lingual plate perforations. There were also 15 cases of adjacent tooth injury noted.

Conclusions

Despite the popularity of dental implants, the surgical placement of these implants is not a riskless procedure. Implant mal-positioning might be life-threatening and can lead to serious bleeding, airway obstruction, and unnecessary postoperative surgeries. Complications of dental implants are not obsolete and dental implant associated problems may not be apparent immediately. Surgeons must have proper training and use evidenced-based treatment planning in order to prevent dental implant complications.



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Observational Study of Neural Respiratory Drive During Sleep at High Altitude

High Altitude Medicine & Biology , Vol. 0, No. 0.


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Inhibition of NF-κB activity by aminoguanidine alleviates neuroinflammation induced by hyperglycemia

Abstract

Neuroinflammation is a key feature of cerebral complication which is associated with diabetes mellitus (DM). Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of neuroinflammation. However, how iNOS facilitates the development of inflammation in brain is still unidentified. The aim of the present study was to investigate the association of iNOS and neuroinflammation in diabetic mice, and elucidate the potential mechanisms underlying aminoguanidine (AG), the selective inhibitor of iNOS, protected neurons against inflammation in diabetic mice. In present experiment, diabetic mice model were established by a single intraperitoneal injection of streptozotocin (STZ). AG was administered to diabetic mice for ten weeks after this disease induction. Then we measured iNOS activity in the serum and brain, detected the glial fibrillary acidic protein (GFAP) and ionised calcium binding adaptor molecule-1 (Iba-1) expressions in the brain. Moreover, nuclear factor-kappa B (NF-κB) in cytoplasm and nucleus were tested by IP and WB. Results revealed that high expression of iNOS in serum and brain could be reversed by AG treatment. Furthermore, AG could also inhibit GFAP and Iba-1 expressions, and NF-κB nuclear translocation by inhibiting it from binding to iNOS in cytoplasm. Our findings indicated that iNOS can combine with NF-κB in cytoplasm and promote its nuclear transfer in diabetic mice. Furthermore, AG decreased neuroinflammation through inhibiting iNOS activity and reducing NF-κB nuclear translocation by promoting its dissociation with iNOS in cytoplasm.



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Familiar Faces Look Happier Than Unfamiliar Ones

People tend to perceive faces they are familiar with as looking happier than unfamiliar faces, even when the faces objectively express the same emotion to the same degree, according to new research published in Psychological Science, a journal of the Association for Psychological Science.

"We show that familiarity with someone else's face affects the happiness you perceive in subsequent facial expressions from that person," says researcher Evan Carr of Columbia Business School. "Our findings suggest that familiarity—just having 'expertise' with someone else's face through repeated exposure—not only influences traditional ratings of liking, attractiveness, etc. but also impacts 'deeper' perceptions of the actual emotion you can extract from that person."

The fact that people tend to prefer things they're familiar with—whether people, objects, or other stimuli—has been demonstrated many times in research studies, in many different ways. But a fundamental question remains: Why do we prefer familiar things? Is it knowing that something is familiar that engenders positive feelings? Or could it be that familiarity actually leads us to perceive stimuli more positively?

Carr conducted this research at the University of California, San Diego in the Department of Psychology with colleagues Timothy F. Brady and Piotr Winkielman. They hypothesized that familiarity might guide our fundamental perceptual processes in a bottom-up fashion, selectively enhancing the positive features of a stimulus. To test this hypothesis, they designed two experiments that examined how people responded to familiar and unfamiliar faces.

In the first experiment, the researchers morphed images of male and female faces to create faces that varied in the type and degree of emotion expressed. This process resulted in a continuum of morphed faces that ranged from 50% angry to neutral to 50% happy. The researchers then divided the images into two sets.

A total of 50 undergraduate student participants came to the lab for a "memory task." Each participant saw a series of images—the neutral expressions from one of the two image sets—and was tasked with tracking the color and number of squares that appeared randomly on some images. This task allowed the researchers to expose the participants to some of the faces in the full set of morphs without explicitly calling their attention to the faces.

Participants then viewed a series of face pairs in a perceptual task, where they had to indicate whether the happier face was above or below the line shown on screen. Importantly, each pair included a familiar and an unfamiliar face and the faces showed the same objective level of emotion.

The results were revealing: Participants were more likely to identify the familiar face as the happier one in the pair, despite the fact that the faces showed the same emotion to the same degree.

And they were increasingly more likely to choose the familiar face as the positive features in the faces increased. That is, participants were more likely to identify the familiar face as happier when the faces were 50% happy than when they were 25% happy. Their selections did not show a bias toward familiarity, however, when the faces were angry.

In a second experiment, Carr and colleagues asked 40 undergraduate participants to look at a series of faces and decide whether each face was either "happy or angry." The participants also estimated on a scale of 0% to 100% how happy the face looked.

The results replicated those of the first experiment: Participants were more likely to identify familiar faces as happy compared with unfamiliar ones, but only when the faces were emotionally neutral or positive. And their estimates of how happy the faces were increased as the positive features increased.

The data indicated that familiarity actually shifted how participants perceived the emotional content of the faces – that is, a familiar face needed to have fewer objectively happy features for it to be classified as happy compared with an unfamiliar face.

The two experiments show that familiarity specifically shapes how we perceive the positive aspects of a stimulus – that is, familiarity makes faces on the happy side of neutral appear more "smiley" but it doesn't make faces on the angry side of neutral appear any less "frowny."

Ultimately, the findings underscore how flexible emotion-perception processes are.

"Emotion perception isn't only the 'formulaic' combination of facial features, it also dynamically incorporates cues specific to the individual you're trying to decode," says Carr.  "Even the judgment of 'how happy someone looks' is inherently subjective to some extent, depending on your previous experience with the person along with the type of expression you're judging."



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The absence of CD56 expression can differentiate papillary thyroid carcinoma from other thyroid lesions

http://orlhealth.blogspot.com/2017/06/the-absence-of-cd56-expression-can.html

The neural cell adhesion molecule CD56 is an antigen important for the differentiation of the follicular epithelium. Recent studies have reported low or absent expression of CD56 in papillary thyroid carcinoma (PTC) and its presence in normal thyroid tissue, benign thyroid lesions, and most follicular non-PTC tumors. Aim: We wish to estimate the value of CD56 in the differentiation of PTC (including follicular variant-PTC [FV-PTC]) from other nontumoral lesions and follicular thyroid neoplasias. Settings and Design: This was a retrospective, case–control study. Subjects and Methods: We analyzed the expression of CD56 in normal thyroid follicular tissue, 15 nonneoplastic thyroid lesions (nodular hyperplasia, Graves' disease, and chronic lymphocytic thyroiditis/Hashimoto), and 38 thyroid follicular cell neoplasms (25 cases of PTC). The immunohistochemical reactions were performed on sections stained with anti-CD56 antibody. Statistical Analysis Used: We used the Chi-square test, values of P< 0.05 being considered statistically significant. Risk analysis was applied on these studied groups, by calculating the odds ratio (OR) value. Results: Our results indicated that CD56 immunoexpression had differentiated PTC from benign nonneoplastic lesions (P = 0.002), as well as from follicular neoplasias (P = 0.046). There were no significant differences regarding CD56 expression between FV-PTC and classical PTC (P = 0.436). The immunoexpression of CD56 has differentiated PTC from other thyroid non-PTC lesions (P < 0.001), with 26.4 OR value. Conclusions: CD56 has been proved to be a useful marker in the diagnosis of PTC, including FV-PTC. Its absence can help differentiate FV-PTC from other thyroid nodules with follicular patterns.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Editorial Board



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Masthead



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Table of Contents



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In This Issue



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Phaeohyphomycosis breast masquerading as fibroadenoma in a young teenage girl

Phaeohyphomycosis is an unusual granulomatous fungal infection, observed in immunocompromised or diabetic patients; however, it is even rarer in immunocompetent patients. Cytological findings of the same have been infrequently reported. The histopathological diagnosis or fungal culture helps in definitive diagnosis to identify the exact fungal species. Hereby, we report a rare case of invasive fungal infection in a breast lump in a young female, presenting as fibroadenoma breast. Fine needle aspiration cytology from the breast lesion showed the presence of septate acute-angled branching fungal hyphae with focal pigmentation, morphologically suggestive of phaeohyphomycosis which was positive with fungal stains. This was later confirmed on biopsy as histopathology slides showed the presence of prominent pigmented fungal hyphae. The pus culture from needle aspirate also showed phaeohyphomycotic fungal organism delineating the species Exophiala dermatitidis. Aspiration cytology is crucial for the diagnosis of fungal infection in such cases. An appropriate diagnosis will help in early detection and treatment of such infections as these are usually associated with high morbidity and mortality.



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Metastatic tonsillar squamous cell carcinoma masquerading as a pancreatic cystic tumor and diagnosed by EUS-guided FNA

Abstract

Metastatic carcinoma to the pancreas is uncommon and head and neck squamous carcinoma metastatic to the pancreas is extremely rare. Metastatic squamous cell carcinoma to the pancreas presents a unique diagnostic challenge: in addition to mimicking the rare primary squamous cell carcinoma of the pancreas based on cytologic, histologic, and immunohistochemical features, it may be mistaken for a cystic neoplasm of the pancreas because of its high predilection for cystic degeneration in metastatic sites. Herein, we report a case of tonsillar squamous cell carcinoma with a cystic pancreatic metastasis diagnosed by ultrasound-guided fine needle aspiration biopsy (EUS-FNA). This represents a third reported case of metastatic squamous cell carcinoma to the pancreas from the head and neck region. Metastatic squamous cell carcinoma should be considered in the differential diagnosis of EUS-FNA during evaluation of pancreatic cystic lesion.



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Estimated Blood Loss: In the Equation of the Beholder

imageNo abstract available

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Determination of Perioperative Blood Loss: Accuracy or Approximation?

imageBACKGROUND: Various different interventions can be used to reduce surgical blood loss; however, there is no "gold standard" for accurately measuring the volume of perioperative blood loss, and this makes it difficult to assess the efficacy of these interventions. METHODS: We used data from a previous multicenter double-blind randomized clinical trial in patients undergoing total hip arthroplasty in which we compared 2 regimens for administering tranexamic acid versus placebo. We assessed direct measures (external blood loss) and indirect estimates (using the formulas of Bourke, Gross, Mercuriali, and Camarasa and a new formula we have developed) using analysis of variance to compare estimated volumes of blood loss among the study groups. In addition, intraclass correlation coefficients (ICCs) and Bland–Altman diagrams were used to compare the estimated volumes of blood loss obtained with each formula. RESULTS: The mean estimated external blood loss was 909 ± 324 mL, and the mean estimates of blood loss calculated using the formulas of Gross, Bourke and Smith, and Camarasa were 1308 ± 555, 1091 ± 454, and 1641 ± 945 mL, respectively, whereas we obtained a value of 1511 ± 919 mL with the new formula at day 2. In all cases, the results favored the use of tranexamic acid (P

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Irregular Outcomes: Predictors of New Atrial Fibrillation After Noncardiac Surgery

imageNo abstract available

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Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study

imageBACKGROUND: Despite the frequency of new clinically important atrial fibrillation (AF) after noncardiac surgery and its increased association with the risk of stroke at 30 days, there are limited data informing their prediction, association with outcomes, and management. METHODS: We used the data from the PeriOperative ISchemic Evaluation trial to determine, in patients undergoing noncardiac surgery, the association of new clinically important AF with 30-day outcomes, and to assess management of these patients. We also aimed to derive a clinical prediction rule for new clinically important AF in this population. We defined new clinically important AF as new AF that resulted in symptoms or required treatment. We recorded an electrocardiogram 6 to 12 hours postoperatively and on the 1st, 2nd, and 30th days after surgery. RESULTS: A total of 211 (2.5% [8351 patients]; 95% confidence interval, 2.2%–2.9%) patients developed new clinically important AF within 30 days of randomization (8140 did not develop new AF). AF was independently associated with an increased length of hospital stay by 6.0 days (95% confidence interval, 3.5–8.5 days) and vascular complications (eg, stroke or congestive heart failure). The usage of an oral anticoagulant at the time of hospital discharge among patients with new AF and a CHADS2 score of 0, 1, 2, 3, and ≥4 was 6.9%, 10.2%, 23.0%, 9.4%, and 33.3%, respectively. Two independent predictors of patients developing new clinically important AF were identified (ie, age and surgery). The prediction rule included the following factors and assigned weights: age ≥85 years (4 points), age 75 to 84 years (3 points), age 65 to 74 years (2 points), intrathoracic surgery (3 points), major vascular surgery (2 points), and intra-abdominal surgery (1 point). The incidence of new AF based on scores of 0 to 1, 2, 3 to 4, and 5 to 6 was 0.5%, 1.0%, 3.1%, and 5.3%, respectively. CONCLUSIONS: Age and surgery are independent predictors of new clinically important AF in the perioperative setting. A minority of patients developing new clinically important AF with high CHADS2 scores are discharged on an oral anticoagulant. There is a need to develop effective and safe interventions to prevent this outcome and to optimize the management of this event when it occurs.

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FOXO transcription factors at the interface of metabolism and cancer

Abstract

Diabetes refers to a group of metabolic diseases characterized by impaired insulin signalling and high blood glucose. A growing body of epidemiological evidence links diabetes to several types of cancer but the underlying molecular mechanisms are poorly understood. The signalling cascade connecting insulin and FOXO proteins provides a compelling example for a conserved pathway at the interface between insulin signalling and cancer. FOXOs are transcription factors that orchestrate programs of gene expression known to control a variety of processes in response to cellular stress. Genes regulated by this family of proteins are involved in the regulation of cellular energy production, oxidative stress resistance and cell viability and proliferation. Accordingly, FOXO factors have been shown to play an important role in the suppression of tumour growth and in the regulation of metabolic homeostasis. There is emerging evidence that deregulation of FOXO factors might account for the association between insulin resistance-related metabolic disorders and cancer. This article is protected by copyright. All rights reserved.



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The Academic Conference as a Chilly Climate for Women: Effects of Gender Representation on Experiences of Sexism, Coping Responses, and Career Intentions

Abstract

Across many disciplines, women are underrepresented in faculty positions relative to men. The present research focuses on the academic conference as a setting because it is a gateway to an academic career and a context in which women might experience sexism. We surveyed 329 presenters (63% women) from three U.S. national academic conferences, which differed in women-to-men ratios, about their perceptions of the conference climate, their coping tactics (e.g., gender performance, silence, or voice), and their intentions to exit the conference or academia. The greater the representation of women at the conference relative to men, the less likely were women to perceive sexism and to feel they had to behave in a masculine manner in that setting. In contrast, women who perceived the conference as sexist and felt silenced also expressed increased intentions to exit from academic careers. Men's perceptions of sexism predicted increased intentions to exit from that particular conference, but not from academia. Because conferences signal the norms of a discipline, it is important to explore their climates as they relate to gender. Perhaps especially for new and aspiring female academics, they may signal devalued status and lack of fit and as such play an inadvertent role in the "leaky pipeline." We discuss strategies that conference organizers could implement to mitigate sexist climates, including broader inclusion of women in speaking and leadership roles and explicit attention to cues that women belong.



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Did the suicide barrier work after all? Revisiting the Bloor Viaduct natural experiment and its impact on suicide rates in Toronto

Objective

This research aims to determine the long-term impact of the Bloor Street Viaduct suicide barrier on rates of suicide in Toronto and whether media reporting had any impact on suicide rates.

Design

Natural experiment.

Setting

City of Toronto, Canada; records at the chief coroner's office of Ontario 1993–2003 (11 years before the barrier) and 2004–2014 (11 years after the barrier).

Participants

5403 people who died by suicide in the city of Toronto.

Main outcome measure

Changes in yearly rates of suicide by jumping at Bloor Street Viaduct, other bridges including nearest comparison bridge and walking distance bridges, and buildings, and by other means.

Results

Suicide rates at the Bloor Street Viaduct declined from 9.0 deaths/year before the barrier to 0.1 deaths/year after the barrier (incidence rate ratio (IRR) 0.005, 95% CI 0.0005 to 0.19, p=0.002). Suicide deaths from bridges in Toronto also declined significantly (IRR 0.53, 95% CI 0.40 to 0.71, p<0.0001). Media reports about suicide at the Bloor Street Viaduct were associated with an increase in suicide-by-jumping from bridges the following year.

Conclusions

The current study demonstrates that, over the long term, suicide-by-jumping declined in Toronto after the barrier with no associated increase in suicide by other means. That is, the barrier appears to have had its intended impact at preventing suicide despite a short-term rise in deaths at other bridges that was at least partially influenced by a media effect. Research examining barriers at other locations should interpret short-term results with caution.



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Ocular myasthenic syndrome, adverse reaction to omalizumab? A case report



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Evidence for Adaptive Introgression of Disease Resistance Genes Among Closely Related Arabidopsis Species

The generation and maintenance of functional variation in the pathogen defense system of plants is central to the constant evolutionary battle between hosts and parasites. If a species is susceptible to a given pathogen, hybridisation and subsequent introgression of a resistance allele from a related species can potentially be an important source of new immunity and is therefore expected to be selected for in a process referred to as adaptive introgression. Here we survey sequence variation in ten resistance (R) genes and compare with 37 reference genes in natural populations of the two closely related and interfertile species Arabidopsis lyrata and A. halleri. The R-genes are highly polymorphic in both species and show clear signs of trans-species polymorphisms. We show that A. lyrata and A. halleri have had a history of limited introgression for the reference genes. For the R-genes the introgression rate has been significantly higher than for the reference genes, resulting in fewer fixed differences between species and a higher sharing of identical haplotypes. We conclude that R-genes likely cross the species boundaries at a higher rate than reference genes and therefore also that some of the increased diversity and trans-specific polymorphisms in R-genes is due to adaptive introgression.



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A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma

Purpose: <p>While stereotactic body radiation therapy (SBRT) can reduce tumor volumes in metastatic renal cell carcinoma (mRCC) patients, little is known regarding the immunomodulatory effects of high-dose radiation in the tumor microenvironment. The main objectives of this pilot study were to assess the safety and feasibility of nephrectomy following SBRT treatment of mRCC patients and analyze the immunological impact of high-dose radiation.</p> <br /><br />Experimental Design: Human RCC cell lines were irradiated and evaluated for immunomodulation. In a single-arm feasibility study, mRCC patients were treated with 15 Gray (Gy) SBRT at the primary lesion in a single fraction followed 4 weeks later by cytoreductive nephrectomy. RCC specimens were analyzed for tumor-associated antigen (TAA) expression and T cell infiltration. The trial has reached accrual (ClinicalTrials.gov identifier: NCT01892930).<br /><br />Results: RCC cells treated in vitro with radiation had increased TAA expression compared to untreated tumor cells. Fourteen patients received SBRT followed by surgery and treatment was well tolerated. SBRT-treated tumors had increased expression of the immunomodulatory molecule calreticulin and TAA (CA9, 5T4, NY-ESO-1, and MUC-1). Ki67+ proliferating CD8+ T cells and FOXP3+ cells were increased in SBRT-treated patient specimens in tumors and at the tumor-stromal interface compared with archived patient specimens.<br /><br />Conclusions: It is feasible to perform nephrectomy following SBRT with acceptable toxicity. Following SBRT, patient RCC tumors have increased expression of calreticulin, TAA, as well as a higher percentage of proliferating T cells compared to archived RCC tumors. Collectively, these studies provide evidence of immunomodulation following SBRT in mRCC.



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Dose-Finding Methods: Moving Away from the 3+3 to Include Richer Outcomes

The most commonly used method for dose-finding, the 3+3, has poor performances. New adaptive designs are more efficient. Nevertheless, they have reached a maximum performance level, and further improvement requires either larger sample sizes, or outcomes measures richer than the simplistic severe toxicity measured at cycle 1.



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Postnatal Growth in a Cohort of Sardinian Intrauterine Growth-Restricted Infants

Recent studies have shown that infants with intrauterine growth restriction (IUGR) undergo catch-up growth during infancy. The aim of our study was to evaluate the postnatal growth in a cohort of IUGR infants born in a tertiary-level Obstetric University Hospital of Northern Sardinia. An observational retrospective study was conducted on 12 IUGR (group A) and 12 control infants (group B) by measuring the anthropometric parameters of weight (), length () and head circumference (HC) from birth to the 3rd postnatal year. At birth, significant differences were found between group A and group B with regard to all the auxological parameters (, mean 1846.6 versus 3170.8 g, p

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Mechanisms of primary drug resistance in FGFR1 amplified lung cancer

Purpose: <br />The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.<br />Experimental Design: <br />To investigate possible mechanisms of resistance to FGFR inhibition we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR-inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.<br />Results: <br />The FGFR inhibitor resistant cells were cross-resistant and characterized by sustained mitogen-activated protein kinase (MAPK) pathway activation. In drug resistant H1581 cells we identified NRAS amplification and DUSP6 deletion, leading to MAPK-pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 out of 20 (15%) primary human FGFR1 amplified SQLC specimens. By contrast, drug resistant DMS114 cells exhibited transcriptional up-regulation of MET that drove MAPK-pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.<br />Conclusions:<br />We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment.



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Fractionated dosing improves preclinical therapeutic index of pyrrolobenzodiazepine-containing antibody drug conjugates

                Purpose:  To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBD) antibody drug conjugates (ADCs) without compromising anti-tumor activity.  <p>                Experimental design:   A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models.  The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast and gastric cancer by comparing anti-tumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer.  The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys).    </p> <p>Results:  Observations of similar anti-tumor activity in mice treated with single or fractionated dosing suggests that anti-tumor activity of PBD ADCs is more closely related to total exposure (AUC, area under the curve) than peak drug concentrations (Cmax).  In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with Cmax than AUC </p>                 Conclusions:  We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy.  These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further.



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Patient-derived interstitial fluids and predisposition to aggressive sporadic breast cancer through collagen remodeling and inactivation of p53.

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiological examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors.<br /><br />Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells. <br /><br />Results: <p>We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also down-regulates RYBP, leading to degradation of p53. Further, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation.</p> <br /><br />Conclusions:Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers



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The impact of gyrB and eis mutations in improving second-line drug resistance detection among Mycobacterium tuberculosis isolates from Georgia [PublishAheadOfPrint]

SETTING: The country of Georgia has a high burden of multi- and extensively drug-resistant tuberculosis (XDR-TB).

OBJECTIVE: To evaluate whether the detection of mutations in gyrB and eis genes increased the sensitivity of detecting phenotypic resistance to ofloxacin and kanamycin or capreomycin as compared to use of the first generation MTBDRsl assay alone which evaluates for mutations in gyrA and rrs genes.

DESIGN: A retrospective study of storedMycobacterium tuberculosis isolates. All isolates underwent DNA sequencing of resistance determining regions.

RESULTS: Among 112 M. tuberculosisisolates with DNA extraction, targeted sequencing was successfully performed for each gene as follows:gyrA – 98%; gyrB – 96%; rrs – 93% and for the eis gene and its promoter - 93%.The specificity and hence positive predictive value ofgyrA and gyrB mutations for detecting ofloxacin resistance were 100%. The addition of gyrB mutations increased the sensitivity of phenotypic ofloxacin resistance detection by 13% (75 to 88%).All rrs resistant conferring mutations were A1401G and this mutation had a low sensitivity (40% and 18%) and high specificity (95% and 100%) in predicting phenotypic capreomycinand kanamycin resistance, respectively. The eisC-14T mutation increased the sensitivity of phenotypic kanamycin resistant by 9% (18 to 27%) and was found solely in kanamycin phenotypic resistance isolates.

CONCLUSIONS: Our data showed that the inclusion of eis C-14T and gyrB mutations in addition to mutations rrs and gyrAgenes improves the sensitivity of phenotypic ofloxacin and kanamycin resistance, respectively.



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Treatment of experimental visceral leishmaniasis with single-dose liposomal amphotericin B - pharmacodynamics and biodistribution at different stages of disease [PublishAheadOfPrint]

Visceral leishmaniasis is a neglected tropical disease, which causes significant morbidity and mortality worldwide. Characterising the pharmacokinetics and pharmacodynamics of anti-leishmanial drugs in pre-clinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of AmBisome® in L. donovani infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome® >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 hours and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome® was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome® was administered at the advanced stage of infection and when compared to uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani infected livers and spleens. Taken together our data suggests that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single dose AmBisome® to L. donovani infected mice. Plasma levels were not reflective of changes in drug levels in tissues.



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Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae [PublishAheadOfPrint]

We determined imipenem, imipenem-relebactam, ceftazidime and ceftazidime-avibactam minimum inhibitory concentrations (MICs) against 100 CRE isolates that underwent whole genome sequencing. KPCs were the most common carbapenemases. Forty-six isolates carried ESBLs. With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against MBL-producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (p<0.0001), and showed a trend to independent association with higher ceftazidime-avibactam MICs (p=0.07). Presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (p<0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity, and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.



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In Vitro Activity of Delafloxacin and Microbiological Response Against Fluoroquinolone Susceptible and Non-Susceptible S. aureus Isolates from two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) [PublishAheadOfPrint]

Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad spectrum in vitro activity, including Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and percent microbiological response in subjects infected with fluoroquinolone susceptible and non-susceptible S. aureus isolates was determined from two global Phase 3 studies of delafloxacin versus vancomycin plus aztreonam in ABSSSI. Patients were enrolled in 23 countries predominately in the US but also Eastern Europe, South America and Asia. The microbiological intent-to-treat population (MITT) included 1042 patients from which 685 S. aureus isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, N. Liberty, IA). Comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Non-susceptibility to these antibiotics was determined using CLSI breakpoints. S. aureus isolates were 33.7% levofloxacin non-susceptible (FQ-NS). The delafloxacin MIC90 values against levofloxacin non-susceptible S. aureus, MRSA and MSSA were all 0.25 μg/mL. Delafloxacin demonstrated high rates of microbiological response against FQ-NS isolates as well as isolates with documented mutations in the Quinolone Resistance Determining Region (QRDR). S. aureus were eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin treated patients. Similar eradication rates were observed for delafloxacin-treated subjects with levofloxacin non-susceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). 98.6% microbiological response rates were observed with delafloxacin treated subjects with S. aureus isolates with mutations in S84L in gyrA/S80Y in parC, the most commonly observed mutation in global phase 3 studies. The data suggest that delafloxacin could be a good treatment option for S. aureus ABSSSI isolates where high rates of ciprofloxacin and levofloxacin non-susceptibility are observed including MRSA.



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Bioavailability of lumefantrine is significantly enhanced with a novel formulation approach: A randomized, open-label pharmacokinetic study in healthy volunteers [PublishAheadOfPrint]

The artemether-lumefantrine combination requires food intake for optimal absorption of lumefantrine. In an attempt to enhance bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In Part 1, relative bioavailability of the two SDF variants was compared with the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In Part 2, pharmacokinetics of lumefantrine from both SDF variants was evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions.

The bioavailability of lumefantrine from SDF variant-1 and variant-2 increased up to ~48-fold and ~24-fold, respectively, relative to the conventional formulation. Both variants demonstrated positive food effect and less than proportional increase in exposure between 480 mg and 960 mg doses.

Most AEs were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant-2. No clinically-significant treatment-emergent changes were noted in vital signs, ECG, or laboratory blood assessments.

The Solid Dispersion Formulation enhances lumefantrine bioavailability to a significant extent and SDF variant-1 is superior to SDF variant-2.



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A low molecular weight alginate oligosaccharide disrupts pseudomonal microcolony formation and enhances antibiotic effectiveness [PublishAheadOfPrint]

In chronic respiratory disease the formation of dense, 3-dimensional 'micro colonies' by Pseudomonas aeruginosa within the airway plays an important role in contributing to resistance to treatment. An in vitro biofilm model of pseudomonal microcolony formation using artificial sputum (AS) medium was established to study the effects of low molecular weight alginate oligomers (OligoG CF-5/20) on pseudomonal growth, microcolony formation and the efficacy of colistin. The studies employed clinical cystic fibrosis (CF) isolates (n=3) and reference non-mucoid and mucoid multi-drug resistant (MDR) CF isolates (n=7). Bacterial growth, biofilm development and disruption were studied using cell-viability assays and image analysis using scanning electron- and confocal laser scanning microscopy. Pseudomonal growth in AS medium was associated with increased ATP production (p<0.05) and the formation (at 48 h) of discrete (>10 μm) microcolonies. In conventional growth medium, colistin retained an ability to inhibit growth of planktonic bacteria, although the MIC was increased (0.1 to 0.4 μg/ml) in AS medium versus. In contrast, in an established biofilm model in the AS medium, the efficacy of colistin was decreased. OligoG CF-5/20 (≥2%) treatment however, induced dose-dependent biofilm disruption (p<0.05), and led to colistin retaining its antimicrobial activity (p<0.05). Whilst circular dichroism indicated that OligoG CF-5/20 did not change the orientation of the alginate carboxyl groups, mass-spectrometry demonstrated that the oligomers induced dose-dependent (>0.2%; p<0.05) reductions in pseudomonal quorum sensing signaling. These findings reinforce the potential clinical significance of microcolony formation in the CF lung, and highlight a novel approach to treat MDR pseudomonal infections.



http://ift.tt/2tHD8sw

Genome Evolution to Penicillin Resistance in Serotype 3 Streptococcus pneumoniae by Capsular Switching [PublishAheadOfPrint]

Streptococcus pneumoniae of serotype 3 was collected from cases of invasive pneumococcal disease (n = 124) throughout Japan from April 2010 to March 2013. A penicillin-resistant S. pneumoniae (PRSP) isolate from an adult patient, KK0981 of serotype 3, was identified among these strains. Whole-genome analysis characterized this PRSP as a recombinant strain derived from PRSP of serotype 23F with the cps-locus (20.3 kb) replaced by that of a penicillin-susceptible strain of serotype 3.



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Bactericidal and sterilizing activity of a novel regimen with bedaquiline, pretomanid, moxifloxacin and pyrazinamide in a murine model of tuberculosis [PublishAheadOfPrint]

New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) + pretomanid (PMD) + pyrazinamide (PZA) and of PMD + moxifloxacin (MXF) + PZA shorten the treatment duration necessary to prevent relapse by 2-3 and 1-2 months, respectively, compared with the current first-line regimen in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored to identify the optimal regimens and treatment times and to infer the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse free after two months of treatment. PZA could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA or BDQ from the beginning required approximately 0.5, 1 or 2 months of additional treatment to attain the same outcome.



http://ift.tt/2tHJqIi

Genome wide analysis of the antimicrobial peptides in Python bivittatus and characterization of cathelicidins with potent antimicrobial activity and low cytotoxicity [PublishAheadOfPrint]

In this study, we sought to identify novel antimicrobial peptides (AMPs) in Python bivittatus through bioinformatic analyses of publicly available genome information and experimental validation. In our analysis of the python genome, we identified 29 AMP-related candidate sequences. Of these, we selected five cathelicidin-like sequences and subjected them to further in silico analyses. The results showed that these sequences likely have antimicrobial activity. The sequences were named Pb-CATH1–Pb-CATH5 according to their sequence similarity to previously reported snake cathelicidins. We predicted their molecular structure, and then chemically synthesized the mature peptide for three putative cathelicidins and subjected them to biological activity tests. Interestingly, all three peptides showed potent antimicrobial effects against Gram-negative bacteria, but very weak activity against Gram-positive bacteria. Remarkably, Pb-CATH4 showed potent activity against antibiotic-resistance clinical isolates and also possess very low hemolytic activity and cytotoxicity. Pb-CATH4 also showed considerable serum stability. Electron microscopic analysis indicated that Pb-CATH4 exerts its effects via toroidal pore preformation. Structural comparison of the cathelicidins identified in this study to previously reported ones revealed that these Pb-CATHs are representatives of a new group of reptilian cathelicidins lacking the acidic connecting domain. Furthermore, Pb-CATH4 possesses a completely different mature peptide sequence compared to previously described reptilian cathelicidins. These new AMPs may be candidates for the development of alternatives to or complements of antibiotics to control multi-drug resistant pathogens.



http://ift.tt/2tHwTVz

The combined effect of the Cfr methyltransferase and ribosomal protein L3 mutations on resistance to ribosome targeting antibiotics [PublishAheadOfPrint]

Several groups of antibiotics inhibit bacterial growth by binding to bacterial ribosomes. Mutations in the ribosomal protein L3 have been associated with resistance to linezolid and tiamulin, which both bind at the peptidyl transferase center in the ribosome. Resistance to these and other antibiotics also occurs through methylation of 23S ribosomal RNA at position A2503 by the methyltransferase Cfr. The mutations in L3 and the cfr gene have been found together in clinical isolates, raising the question whether they provide a combined effect on antibiotic resistance or growth. We transformed a plasmid borne cfr gene into an uL3 depleted E. coli strain containing either wild type L3 or one of the seven L3 mutations: G147R, Q148F, N149S, N149D, N149R, Q150L, or T151P expressed from plasmid coded rplC genes. The L3 mutations are well tolerated with small to moderate decreases in growth rate. The presence of Cfr has a very minor influence on growth rate. The resistance of the transformants against linezolid, tiamulin, florfenicol, and synercid was measured by minimum inhibitory concentration assays. The resistance from Cfr is in all cases stronger than the effects from the L3 mutations but various effects were obtained from the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. The susceptibility to linezolid and tiamulin varies highly between the L3 mutations while no significant effects are seen for florfenicol and synercid. This study underscores the complex interplay between various resistance mechanisms and cross-resistance, even from antibiotics with overlapping binding sites.



http://ift.tt/2tHIOCB

Rapid and consistent evolution of colistin resistance in XDR Pseudomonas aeruginosa during morbidostat culture [PublishAheadOfPrint]

Colistin is a last resort antibiotic commonly used against multidrug-resistant strains of Pseudomonas aeruginosa. To investigate the potential for in-situ evolution of resistance against colistin and to map the molecular targets of colistin resistance, we exposed two P. aeruginosa isolates to colistin using a continuous culture device known as morbidostat. As a result, colistin resistance reproducibly increased 10-fold within ten days, and 100-fold within 20 days, along with highly stereotypic, yet strain specific mutation patterns. The majority of mutations hit the pmrAB two component signaling system and genes involved in lipopolysaccharide (LPS) synthesis, including lpxC, pmrE, and migA. We tracked the frequencies of all arising mutations by whole genome deep sequencing every 3-4 days to provide a detailed picture of the dynamics of resistance evolution, including competition and displacement among multiple resistant sub-populations. In seven out of 18 cultures, we observed mutations in mutS along with a mutator phenotype that seemed to facilitate resistance evolution.



http://ift.tt/2sK4eBO

Identification of a novel antibacterial compound 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol active against persisters of Pseudomonas aeruginosa [PublishAheadOfPrint]

Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen as a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current report is focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group and, due to an increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells and elimination of these cells would therefore significantly improve patient outcome. In this study, a small-molecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters as compared to treatment with the antibiotic alone. Based on early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 106-fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel anti-persister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.



http://ift.tt/2sK3koV

{beta}-Lactam Antibiotics with a High Affinity for PBP2 Act Synergistically with the FtsZ-Targeting Agent TXA707 against Methicillin-Resistant Staphylococcus aureus [PublishAheadOfPrint]

Methicillin-resistant Staphylococcus aureus (MRSA) is a multi-drug resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. Here we present results that demonstrate differing extents of synergy between TXA707 and a broad range of β-lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each β-lactam, we determined the binding affinities of the β-lactam antibiotics for each of the four native penicillin binding proteins (PBPs) of S. aureus using a fluorescence anisotropy competition assay. A comparison of the resulting PBP binding affinities with our corresponding synergy results reveals that β-lactams with a high affinity for PBP2 afford the greatest degree of synergy with TXA707 against MRSA. In addition, we present fluorescence and electron microscopy studies that suggest a potential mechanism underlying the synergy between TXA707 and the β-lactam antibiotics. In this connection, our microscopy results show a disruption of septum formation in TXA707-treated MRSA cells, with a concomitant mislocalization of the PBPs from mid-cell to non-productive peripheral sites. Viewed as a whole, our results indicate that PBP2-targeting β-lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections.



http://ift.tt/2tHoTE3

Antimicrobial Susceptibility Trends Among Staphylococcus aureus from United States Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program (2010-2016) [PublishAheadOfPrint]

We evaluated trends in Staphylococcus aureus antimicrobial susceptibility in United States hospitals in the 2010-2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. MRSA rates decreased from 50.0% (2010) to 42.2% (2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against MSSA and MRSA (97.2% susceptible) with no marked variations.



http://ift.tt/2tHwT81

Ceftazidime-Avibactam and Aztreonam an interesting strategy to Overcome {beta}-Lactam Resistance Conferred by Metallo-{beta}-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa [PublishAheadOfPrint]

We have read with great interest Marshal S. et al. regarding the efficacy of the ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM) combination on metallo- β -lactamases producing Enterobacteriaceae (1)....



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Loss of C-5 sterol desaturase activity results in increased resistance to azole and echinocandin antifungals in a clinical isolate of Candida parapsilosis [PublishAheadOfPrint]

Among emerging non-albicans Candida species, C. parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatment of such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting the susceptibility of azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate including upregulation of ergosterol biosynthesis pathway genes ERG2, ERG5, ERG6, ERG11, ERG24, ERG25, and UPC2. Whole-genome sequencing revealed the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins.



http://ift.tt/2tHttBX

Topical antimicrobial treatments can elicit shifts to resident skin bacterial communities and reduce colonization by Staphylococcus aureus competitors [PublishAheadOfPrint]

The skin microbiome is a complex ecosystem with important implications for cutaneous health and disease. Topical antibiotics and antiseptics are often employed to preserve the balance of this population, and inhibit colonization by more pathogenic bacteria. Despite their widespread use, however, the impact of these interventions on broader microbial communities remains poorly understood. Here we report the longitudinal effects of topical antibiotics and antiseptics on skin bacterial communities and their role in Staphylococcus aureus colonization resistance. In response to antibiotics, cutaneous populations exhibited an immediate shift in bacterial residents, an effect that persisted for multiple days post-treatment. By contrast, antiseptics elicited only minor changes to skin bacterial populations, with few changes to the underlying microbiota. While variable in scope, both antibiotics and antiseptics were found to decrease colonization by commensal Staphylococcus spp. by sequencing- and culture-based methods, an effect which was highly dependent on baseline levels of Staphylococcus. Because Staphylococcus residents have been shown to compete with the skin pathogen S. aureus, we also tested whether treatment could influence S. aureus levels at the skin surface. We found that treated mice were more susceptible to exogenous association with S. aureus, and that precolonization with the same Staphylococcus residents that were previously disrupted by treatment could reduce S. aureus levels by over 100-fold. In all, this study indicates that antimicrobial drugs can alter skin bacterial residents, and that these alterations can have critical implications for cutaneous host defense.



http://ift.tt/2sJGuhm

Occurrence of clinically important lineages, including the ST131 C1-M27 subclone, among extended-spectrum {beta}-lactamase-producing Escherichia coli in wastewater [PublishAheadOfPrint]

Contamination of environmental waters by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBLEC) is of great concern. Wastewater treatment plants (WWTPs) and hospitals release large amounts of ESBLEC into the environment. In the present study, we isolated ESBLEC strains from wastewater collected from a WWTP and a hospital in Japan and performed whole-genome sequencing to characterize these strains. Genomic analysis of 54 strains (32 from the WWTP and 22 from hospital wastewater) revealed the occurrence of clinically important clonal groups with extraintestinal pathogenic E. coli status in both WWTP and hospital wastewater. Fine-scale phylogenetic analysis was performed to further characterize 15 sequence type 131 (ST131) complex strains (11 from the WWTP and 4 from hospital wastewater). These ST131 complex strains were comprised of different subgroups: clade A (n = 2), C1-M27 (n = 8), and C1 (non-C1-M27) (n = 1) for strains from the WWTP, and clade A (n = 2), C1-M27 (n = 1), and C1 (non-C1-M27) (n = 1) for strains from hospital wastewater. The results indicate that ESBLEC strains belonging to clinically important lineages, including the C1-M27 clade, may disseminate into the environment through wastewater, highlighting the need to monitor for antibiotic-resistance in wastewater.



http://ift.tt/2tHILGV

Pharmacokinetics, Safety, and Tolerability of Single Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers [PublishAheadOfPrint]

The pharmacokinetics, safety, and tolerability of intravenous (IV) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1 hour IV infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 hours after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g IV were: Cmax= 44.3 ± 7.6 and 370 ± 61.9 μg/mL, Tmax= 1.1 ± 0.05 and 1.08 ± 0.01 h, Vd= 29.7 ± 5.7 and 31.5 ± 10.4 liters, CL= 8.7 ± 1.7 and 7.8 ± 1.4 liters/h, CLR= 6.6 ± 1.9 and 6.3 ± 1.6 liters/h, AUC0-= 120 ± 28.5 and 1060 ± 192 μg⋅h/mL, and t1/2= 2.4 ± 0.4 and 2.8 ± 0.6 h, respectively. After oral administration the parameters were: Cmax= 26.8 ± 6.4 μg/mL, Tmax= 2.25 ± 0.4 h, Vd/F= 204 ± 70.7 liters, CL/F= 17 ± 4.7 liters/h, CLR= 6.5 ± 1.8 liters/h, AUC0-= 191 ± 57.6 μg⋅h/mL, and t1/2= 9.04 ± 4.5 h, respectively. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1 g IV dose. Approximately 74% and 80% of the 1 g and 8 g IV doses were excreted unchanged in the urine by 48 hours, compared to 37% after oral administration, with the majority of this excretion occurring by 12 hours regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of IV fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.



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Pyrazinamide susceptibility and pncA mutation profile of Mycobacterium tuberculosis among multi-drug resistant tuberculosis patients in Bangladesh [PublishAheadOfPrint]

Pyrazinamide (PZA) is a front line anti-tuberculosis (anti-TB) drug used in both first and second line treatment regimen. However, due to complex laboratory requirements, the PZA susceptibility test is rarely performed leading to the scarcity of data. Bangladesh is both a high TB and multi-drug resistant (MDR-TB) burden country but to our knowledge the published data on PZA susceptibility is limited, especially among MDR-TB patients. We aimed to analyze the PZA susceptibility pattern of Mycobacterium tuberculosis (MTB) isolates from MDR-TB patients and to correlate pncA mutation with PZA resistance in Bangladesh. A total of 169 confirmed MDR-TB isolates from a pool of specimens collected in a nationwide surveillance study were included in this analysis. All the isolates were tested for phenotypic PZA susceptibility in BACTEC MGIT culture medium and pncA gene was sequenced. We also correlated different clinical information and treatment outcomes with PZA susceptibility. We found that 45% isolates were phenotypically PZA resistant. The sequencing of pncA gene revealed high concordance (82.2%) with phenotypic results. A total of 64 different mutations were found and 9 isolates harbored multiple mutations. We detected 27 new pncA mutations. We did not find any significant correlation between different clinical categories, genetic lineage or treatment outcome groups with PZA susceptibility. Considering turnaround time, sequencing would be the more feasible option to determine PZA susceptibility and further studies to investigate the minimum inhibitory concentration of PZA should be conducted to figure out an effective dose of the drug.



http://ift.tt/2tHgArB

DNA Damage and Repair Biomarkers of Immunotherapy Response [Reviews]

DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.

Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 1–19. ©2017 AACR.



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Glucose catabolism in liver tumors induced by c-MYC can be sustained by various PKM1/PKM2 ratios and pyruvate kinase activities

Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Due to differential regulation of enzymatic activities, PKM2 but not PKM1 has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC over-expression in murine livers did not affect c-MYC induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC-induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC-induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process.

http://ift.tt/2tmb9iu

Infection exposure promotes ETV6-RUNX1 precursor B cell leukemia via impaired H3K4 demethylases

<p>ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/peripheral cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB-ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss-of-function resulted in increased levels of H3K4me3, which co-precipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB-ALL after infection exposure and offer the possibility of novel therapeutic approaches.

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Evolution of ventral hernia repair

Abstract

Purpose

The aim of this review was to look at relevant data and research on the evolution of ventral hernia repair.

Methods

Resources including books, research, guidelines, and online articles were reviewed to provide a concise history of and data on the evolution of ventral hernia repair.

Results

The evolution of ventral hernia repair has a very long history, from the recognition of ventral hernias to its current management, with significant contributions from different authors. Advances in surgery have led to more cases of ventral hernia formation, and this has required the development of new techniques and new materials for ventral hernia management. The biocompatibility of prosthetic materials has been important in mesh development. The functional anatomy and physiology of the abdominal wall has become important in ventral hernia management. New techniques in abdominal wall closure may prevent or reduce the incidence of ventral hernia in the future.

Conclusion

The management of ventral hernia is continuously evolving as it responds to new demands and new technology in surgery.



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Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines

The aim of this review is to update the safety of low-intensity electric stimulation based on available published research and clinical data in animal models and in human studies until the end of 2016. The essentials of the present manuscript were agreed upon at a two-day safety conference held in Göttingen, Germany on 6-7th September, 2016. Participants included research and clinical experts from neurophysiology, neurology, cognitive neuroscience and psychiatry. Representatives of transcranial electrical stimulation (TES) equipment manufacturers contributed to regulatory issues.

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Degeneration of the vestibular nerve in unilateral Meniere’s disease evaluated by galvanic vestibular-evoked myogenic potentials

The staging system of Meniere's disease utilizes audiograms to probe cochlear dysfunction. We explored the addition of galvanic vestibular-evoked myogenic potentials (VEMP) to further explore vestibular function.

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Exam 1: Comparison of Endoscopic Dilation vs Surgery for Anastomotic Stricture in Patients With Crohn's Disease Following Ileocolonic Resection



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Report and Abstracts for 17 th Spring ACCP Conference with Training Workshops, and Technology Exhibits



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Obesity and Risk of NAFLD: A Comparison of Bioelectrical Impedance Analysis and Conventional Derived Anthropometric Measures



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Radial Endoscopic Ultrasound for the Diagnosis of Chronic Schistosomiasis in the Colorectum



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Increasing Burden of Liver Cancer Despite Extensive Use of Antiviral Agents in a Hepatitis B Virus-Endemic Population

ABSTRACT

Most mortalities from liver disease and liver cancer worldwide are attributable to hepatitis B virus (HBV) and hepatitis C virus. Despite remarkable advances in the treatment of HBV over past decades, limited population-level data are available regarding its impact on burden of liver disease and liver cancer. Mortality data from liver disease and liver cancer were obtained from national death certificate database of Korea, a HBV-endemic country, between 1999 and 2013, and were analyzed by Joinpoint analysis. For liver disease, number of annual deaths decreased by 62.3% (95% confidence interval [CI]: 62.0-62.6), crude death rate (CDR) decreased by 64.6% (95% CI: 64.3-64.9) from 21.2 to 7.5 per 100,000 population, and age-standardized death rate (ADR) declined by 75.0% (95% CI: 74.7-75.3), between 1999 and 2013. In contrast, for liver cancer, number of annual deaths increased by 17.8% (95% CI: 17.6-18.0) and CDR increased by 10.2% (95% CI: 10.0-10.4) from 20.5 to 22.6, although ADR decreased by 26.9% (95% CI: 26.6 − 27.2). The annual number of patients receiving oral antiviral agents against HBV increased from 1,716 to 187,226 during the study period. The increase in mean age at death from liver disease was significantly greater than that from liver cancer (8.8 years vs 6.1 years: P=0.02). Conclusion: Marked reduction in liver disease mortality by widespread use of antiviral treatments against HBV may increase the life expectancy and number of patients at risk of developing liver cancer, inadvertently leading to increased burden of liver cancer in a HBV-endemic population. The competing nature between death from liver disease and that from liver cancer should be carefully considered in establishing a health care policy. This article is protected by copyright. All rights reserved.



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A Novel Cause of Chronic Viral Meningoencephalitis: Cache Valley Virus

Abstract

Objective: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next-generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients.

Methods: We present the case of a 34 year-old man with X-linked agammaglobulinemia from Australia suffering from three years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next-generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen.

Results: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next-generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue.

Interpretation: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in three immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multi-organ failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Indeed, our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next-generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. This article is protected by copyright. All rights reserved.



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Structural plasticity of the ventral stream and aphasia recovery

Abstract

Re-strengthening of the residual language network is likely crucial for speech recovery in post-stroke aphasia. Eight participants with chronic aphasia received intensive speech therapy for three weeks, with standardized naming tests and brain MRIs before and after therapy. Kurtosis-based diffusion tensor tractography was used to measure mean kurtosis (MK) along a segment of the inferior longitudinal fasciculus (ILF). Therapy related reduction in the number of semantic but not phonemic errors was associated with strengthening (renormalization) of ILF MK (r=-0.90, P<0.05 corrected), suggesting that speech recovery is related to structural plasticity of linguistic specific components of the residual language network. This article is protected by copyright. All rights reserved.



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Setting Performance Standards for Technical and Nontechnical Competence in General Surgery

imageObjectives: The objectives of this study were to (1) create a technical and nontechnical performance standard for the laparoscopic cholecystectomy, (2) assess the classification accuracy and (3) credibility of these standards, (4) determine a trainees' ability to meet both standards concurrently, and (5) delineate factors that predict standard acquisition. Background: Scores on performance assessments are difficult to interpret in the absence of established standards. Methods: Trained raters observed General Surgery residents performing laparoscopic cholecystectomies using the Objective Structured Assessment of Technical Skill (OSATS) and the Objective Structured Assessment of Non-Technical Skills (OSANTS) instruments, while as also providing a global competent/noncompetent decision for each performance. The global decision was used to divide the trainees into 2 contrasting groups and the OSATS or OSANTS scores were graphed per group to determine the performance standard. Parametric statistics were used to determine classification accuracy and concurrent standard acquisition, receiver operator characteristic (ROC) curves were used to delineate predictive factors. Results: Thirty-six trainees were observed 101 times. The technical standard was an OSATS of 21.04/35.00 and the nontechnical standard an OSANTS of 22.49/35.00. Applying these standards, competent/noncompetent trainees could be discriminated in 94% of technical and 95% of nontechnical performances (P

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Meta-analysis of determinants of survival following treatment of recurrent hepatocellular carcinoma

Abstract

Background

Intrahepatic recurrence of hepatocellular carcinoma (HCC) following resection is common. However, no current consensus guidelines exist to inform management decisions in these patients. Systematic review and meta-analysis of survival following different treatment modalities may allow improved treatment selection. This review aimed to identify the optimum treatment strategies for HCC recurrence.

Methods

A systematic review, up to September 2016, was conducted in accordance with MOOSE guidelines. The primary outcome was the hazard ratio for overall survival of different treatment modalities. Meta-analysis of different treatment modalities was carried out using a random-effects model, with further assessment of additional prognostic factors for survival.

Results

Nineteen cohort studies (2764 patients) were included in final data analysis. The median 5-year survival rates after repeat hepatectomy (525 patients), ablation (658) and transarterial chemoembolization (TACE) (855) were 35·2, 48·3 and 15·5 per cent respectively. Pooled analysis of ten studies demonstrated no significant difference between overall survival after ablation versus repeat hepatectomy (hazard ratio 1·03, 95 per cent c.i. 0·68 to 1·55; P = 0·897). Pooled analysis of seven studies comparing TACE with repeat hepatectomy showed no statistically significant difference in survival (hazard ratio 1·61, 0·99 to 2·63; P = 0·056).

Conclusion

Based on these limited data, there does not appear to be a significant difference in survival between patients undergoing repeat hepatectomy or ablation for recurrent HCC. The results also identify important negative prognostic factors (short disease-free interval, multiple hepatic metastases and large hepatic metastases), which may influence choice of treatment.



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Yoga, Physical Therapy, or Education for Chronic Low Back Pain



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CONSORT Statement for Randomized Trials of Nonpharmacologic Treatments: A 2017 Update and a CONSORT Extension for Nonpharmacologic Trial Abstracts

Incomplete and inadequate reporting is an avoidable waste that reduces the usefulness of research. The CONSORT (Consolidated Standards of Reporting Trials) Statement is an evidence-based reporting guideline that aims to improve research transparency and reduce waste. In 2008, the CONSORT Group developed an extension to the original statement that addressed methodological issues specific to trials of nonpharmacologic treatments (NPTs), such as surgery, rehabilitation, or psychotherapy. This article describes an update of that extension and presents an extension for reporting abstracts of NPT trials. To develop these materials, the authors reviewed pertinent literature published up to July 2016; surveyed authors of NPT trials; and conducted a consensus meeting with editors, trialists, and methodologists.Changes to the CONSORT Statement extension for NPT trials include wording modifications to improve readers' understanding and the addition of 3 new items. These items address whether and how adherence of participants to interventions is assessed or enhanced, description of attempts to limit bias if blinding is not possible, and specification of the delay between randomization and initiation of the intervention. The CONSORT extension for abstracts of NPT trials includes 2 new items that were not specified in the original CONSORT Statement for abstracts. The first addresses reporting of eligibility criteria for centers where the intervention is performed and for care providers. The second addresses reporting of important changes to the intervention versus what was planned. Both the updated CONSORT extension for NPT trials and the CONSORT extension for NPT trial abstracts should help authors, editors, and peer reviewers improve the transparency of NPT trial reports.

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Yoga and Low Back Pain: No Fool's Tool

A randomized trial by Saper and colleagues examines whether yoga is noninferior to physical therapy for treating patients with low back pain. The editorialists discuss the findings and highlight the importance of recognizing both the varying pathophysiology of low back pain and the modesty of treatment benefits when studying the effectiveness of interventions.

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The Effect of Emphasizing Patient, Societal, and Institutional Harms of Inappropriate Antibiotic Prescribing on Physician Support of Financial Penalties: A Randomized Trial



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Yoga, Physical Therapy, or Education for Chronic Low Back Pain A Randomized Noninferiority Trial

Background:
Yoga is effective for mild to moderate chronic low back pain (cLBP), but its comparative effectiveness with physical therapy (PT) is unknown. Moreover, little is known about yoga's effectiveness in underserved patients with more severe functional disability and pain.
Objective:
To determine whether yoga is noninferior to PT for cLBP.
Design:
12-week, single-blind, 3-group randomized noninferiority trial and subsequent 40-week maintenance phase. (ClinicalTrials.gov: NCT01343927)
Setting:
Academic safety-net hospital and 7 affiliated community health centers.
Participants:
320 predominantly low-income, racially diverse adults with nonspecific cLBP.
Intervention:
Participants received 12 weekly yoga classes, 15 PT visits, or an educational book and newsletters. The maintenance phase compared yoga drop-in classes versus home practice and PT booster sessions versus home practice.
Measurements:
Primary outcomes were back-related function, measured by the Roland Morris Disability Questionnaire (RMDQ), and pain, measured by an 11-point scale, at 12 weeks. Prespecified noninferiority margins were 1.5 (RMDQ) and 1.0 (pain). Secondary outcomes included pain medication use, global improvement, satisfaction with intervention, and health-related quality of life.
Results:
One-sided 95% lower confidence limits were 0.83 (RMDQ) and 0.97 (pain), demonstrating noninferiority of yoga to PT. However, yoga was not superior to education for either outcome. Yoga and PT were similar for most secondary outcomes. Yoga and PT participants were 21 and 22 percentage points less likely, respectively, than education participants to use pain medication at 12 weeks. Improvements in yoga and PT groups were maintained at 1 year with no differences between maintenance strategies. Frequency of adverse events, mostly mild self-limited joint and back pain, did not differ between the yoga and PT groups.
Limitations:
Participants were not blinded to treatment assignment. The PT group had disproportionate loss to follow-up.
Conclusion:
A manualized yoga program for nonspecific cLBP was noninferior to PT for function and pain.
Primary Funding Source:
National Center for Complementary and Integrative Health of the National Institutes of Health.

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Effects of age on the reproductive performance of different males and females in bighead carp Hypophthalmichthys nobilis (Richardson, 1845)

Abstract

The age of fish can affect reproductive performance in relation to the gamete quality and productivity which might be expected to be changed in older individuals. The consideration can be important in artificial propagation in relation to the selection of broodstock. We determined the age-related changes in male and female reproductive characteristics of the bighead carp Hypophthalmichthys nobilis and then we examined the effects of age on the male and female reproductive fitness in terms of fertilization, hatching, and larvae survival rate. A total of eight 3–4-year-old males and eight 4–5-year-old females were crossed using a factorial breeding design. Fertilization, hatching, and larvae survival rates were counted. We found no significant difference between 3 and 4 year olds in the sperm motility traits, density, and spermatocrit, but significant differences (p < 0.05) were observed in the ionic composition (mainly Na+, K+, Ca2+, Mg2+), acid phosphatase, and glucose level. The quantitative characteristics between two age groups (4 and 5-year-olds) of the females showed significant differences (p < 0.05) in total weight of stripped egg, ovarian weight, and relative fecundity, while no significant differences were found in egg size, absolute fecundity, and gonadosomatic index (GSI). In fertilization trials, we found that male age strongly influences fertilization (p < 0.05), embryonic development (p < 0.05), and larval survivability (p < 0.001), while significant female effects, as well as male and female interactions (p < 0.001 for all) were only observed for 7 days post-hatching larval survivability. One-way ANOVA showed significant differences among the fertilization (F = 3.797, p = 0.05), hatching (F = 4.802, p = 0.03), and larvae survival rate (F = 32.94, p = 0.001). Our results suggest that crosses between 4-year-old males and 5-year-old females of bighead carp achieved the best reproductive output.



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Calcein-acetoxymethy ester enhances the antitumor effects of doxorubicin in nonsmall cell lung cancer by regulating the TopBP1/p53RR pathway.

Calcein acetoxymethyl ester (calcein-AM) treatment has been reported to exert antitumor effects in certain cancer cells; however, the detailed mechanism of action of calcein-AM in cancers remains unclear, especially in nonsmall cell lung cancer (NSCLC). This study focused on the function and mechanism of action of calcein-AM in NSCLC. We used cell viability assays, western blotting, and EdU proliferation assay combined with calcein-AM treatment or siRNA interference to investigate the role of topoisomerase II[beta] binding protein 1 (TopBP1) and p53 in NSCLC chemotherapy. We found that calcein-AM has antitumor effects in lung cancer and enhances the antitumor effects of doxorubicin in NSCLC. Furthermore, we found that TopBP1, which we previously showed was involved in doxorubicin resistance through upregulation of aberrant p53, was involved in calcein-AM-mediated increased doxorubicin sensitivity. Doxorubicin upregulated the expression of aberrant p53. Calcein-AM repressed the expression of TopBP1, which resulted in reduced expression of aberrant p53 and disrupted the antiapoptotic activity mediated by the TopBP1/mutp53 pathway in NSCLC. Together, our findings show that calcein-AM, the cell-permeable derivative of calcein, exerts significant antitumor effects in NSCLC, and can enhance the antitumor effect of doxorubicin by regulating the TopBP1/mutp53 pathway. These findings provide novel insight into lung cancer treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Complete remission of intrathecal metastases with lorlatinib therapy in a heavily pretreated ALK-positive lung cancer patient.

Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later. Local recurrence was managed by chemotherapy and crizotinib after the patient was included in a named patient use programme in 2012. Over the following years, the patient repeatedly developed lesions at different sites in the brain and spinal cord. Partial remission was obtained twice with local irradiation. When the next-generation ALK tyrosine kinase inhibitors became available, her treatment was switched to brigatinib, which again induced partial remission. Another episode of intrathecal progression prompted the prescription of the third-generation ALK tyrosine kinase inhibitor lorlatinib. This treatment has resulted in complete remission in the patient. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Krebs Cycle



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In severe aortic stenosis with intermediate surgical risk, TAVR was noninferior to SAVR for death or disabling stroke



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Extracranial Carotid Disease and Effect of Intra-arterial Treatment in Patients With Proximal Anterior Circulation Stroke in MR CLEAN

Background:
The presence of extracranial carotid disease (ECD) is associated with less favorable clinical outcomes in patients with acute ischemic stroke caused by intracranial proximal occlusion. Acute intra-arterial treatment (IAT) in the setting of extracranial and intracranial lesions is considered challenging, and whether it yields improved outcomes remains uncertain.
Objective:
To examine whether the presence of ECD modified the effect of IAT for intracranial proximal anterior circulation occlusion.
Design:
Prespecified subgroup analysis of a randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands. (Trial registrations: NTR1804 [Netherlands Trial Register] and ISRCTN10888758)
Setting:
16 hospitals in the Netherlands.
Patients:
Acute ischemic stroke caused by proximal intracranial arterial occlusion of the anterior circulation. Extracranial carotid disease was defined as cervical internal carotid artery stenosis (>50%) or occlusion.
Intervention:
IAT treatment versus no IAT.
Measurements:
The primary outcome was functional outcome, as measured by the modified Rankin Scale at 90 days and reported as adjusted common odds ratio (acOR) for a shift in direction of a better outcome. Multivariable ordinal logistic regression analysis with an interaction term was used to estimate treatment effect modification by ECD.
Results:
The overall acOR was 1.67 (95% CI, 1.21 to 2.30) in favor of the intervention. The acOR was 3.1 (CI, 1.7 to 5.8) in the prespecified subgroup of patients with ECD versus 1.3 (CI, 0.9 to 1.9) in patients presenting without ECD. Both acORs are in favor of the intervention (P for interaction = 0.07).
Limitation:
The study was not powered for subgroup analysis.
Conclusion:
Intra-arterial treatment may be at least as effective in patients with ECD as in those without ECD, and it should not be withheld in these complex patients with acute ischemic stroke.
Primary Funding Source:
Dutch Heart Foundation, AngioCare BV, Medtronic/Covidien/EV3, MEDAC Gmbh/LAMEPRO, Penumbra, Stryker, and Top Medical/Concentric.

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Prevalence of Elevated Cardiovascular Risks in Young Adults



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Prevalence of Elevated Cardiovascular Risks in Young Adults: A Cross-sectional Analysis of National Health and Nutrition Examination Surveys

Background:
The 2013 cholesterol management guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) recommend lipid screening in all adults older than 20 years to identify those at increased risk for atherosclerotic cardiovascular disease (ASCVD). Statins may be considered for patients with elevated 10-year risk (>5%) or a low-density lipoprotein cholesterol (LDL-C) level of 4.92 mmol/L (190 mg/dL) or greater.
Objective:
To describe the prevalence of elevated ASCVD risk among nondiabetic adults younger than 50 years.
Design:
Cross-sectional.
Setting:
NHANES (National Health and Nutrition Examination Survey), 1999 to 2000 through 2011 to 2012.
Participants:
Adults aged 30 to 49 years without known ASCVD or diabetes.
Measurements:
10-year ASCVD risk was estimated by using the 2013 ACC/AHA ASCVD risk calculator. Participants were subdivided by age, sex, and history of smoking and hypertension. The percentages of adults in each subgroup with a 10-year ASCVD risk greater than 5% and of those with an LDL-C level of 4.92 mmol/L (190 mg/dL) or greater were estimated. Low-prevalence subgroups were defined as those in which a greater than 1% prevalence of elevated cardiovascular risk could be ruled out (that is, the upper 95% confidence bound for prevalence was ≤1%).
Results:
Overall, 9608 NHANES participants representing 67.9 million adults were included, with approximately half (47.12%, representing 32 million adults) in low-prevalence subgroups. In the absence of smoking or hypertension, 0.09% (95% CI, 0.02% to 0.35%) of adult men younger than 40 years and 0.04% (CI, 0.0% to 0.26%) of adult women younger than 50 years had an elevated risk. Among other subgroups, 0% to 75.9% of participants had an increased risk. Overall, 2.9% (CI, 2.3% to 3.5%) had an LDL-C level of 4.92 mmol/L (190 mg/dL) or greater.
Limitation:
No information was available regarding cardiovascular outcomes.
Conclusion:
In the absence of risk factors, the prevalence of increased ASCVD risk is low among women younger than 50 and men younger than 40 years.
Primary Funding Source:
None.

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Review: Compared with systolic BP target of



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Early Versus Delayed Feeding in Patients With Acute Pancreatitis A Systematic Review

Background:
Acute pancreatitis is among the most common and costly reasons for hospitalization in the United States. Bowel rest, pain control, and intravenous fluids are the cornerstones of treatment, but early feeding might also be beneficial.
Purpose:
To compare length of hospital stay, mortality, and readmission in adults hospitalized with pancreatitis who received early versus delayed feeding.
Data Sources:
MEDLINE via Ovid, EMBASE, the Cochrane Library, CINAHL, and Web of Science through January 2017.
Study Selection:
Two authors independently reviewed and selected studies if they were randomized clinical trials, included adults hospitalized with acute pancreatitis, and compared early versus delayed feeding (≤48 vs. >48 hours after hospitalization).
Data Extraction:
Two investigators independently extracted study data and rated risk of bias using the Cochrane Collaboration tool.
Data Synthesis:
Eleven randomized trials (8 peer-reviewed publications, 3 abstract-only presentations) that included 948 patients were eligible. Seven trials (3 with low risk of bias) enrolled patients with mild to moderate pancreatitis. Four trials (1 with low risk of bias) included patients with predicted severe pancreatitis. Routes used for early feeding included oral (4 studies), nasogastric (2 studies), nasojejunal (4 studies), and oral or nasoenteric (1 study). Among patients with mild to moderate pancreatitis, early feeding was associated with reduced length of stay in 4 of 7 studies (including 2 of 3 with low risk of bias). Other outcomes were heterogeneous and variably reported, but no study showed an increase in adverse events with early feeding. Among patients with severe pancreatitis, limited evidence revealed no statistically significant difference in outcomes between early and delayed feeding.
Limitation:
Heterogeneity of feeding protocols and outcomes, scant data, and unclear or high risk of bias in several studies.
Conclusion:
Limited data suggest that early feeding in patients with acute pancreatitis does not seem to increase adverse events and, for patients with mild to moderate pancreatitis, may reduce length of hospital stay.
Primary Funding Source:
None. (PROSPERO: CRD42015016193)

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