Πέμπτη, 26 Ιουλίου 2018

Downregulation of Long Noncoding RNA HOTAIR and EZH2 Induces Apoptosis and Inhibits Proliferation, Invasion, and Migration of Human Breast Cancer Cells

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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Pinnacle EMS 2018 Quick Take: The power of collaboration for EMS leaders

Jay Fitch, Ph.D., tells Pinnacle leaders that collaboration with colleagues and frenemies is critical to greater operational success

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Downregulation of Long Noncoding RNA HOTAIR and EZH2 Induces Apoptosis and Inhibits Proliferation, Invasion, and Migration of Human Breast Cancer Cells

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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mTOR Complex 1 Implicated in Aphid/Buchnera Host/Symbiont Integration

Obligate nutritional endosymbioses are arguably the most intimate of all interspecific associations. While many insect nutritional endosymbioses are well studied, a full picture of how two disparate organisms, a bacterial endosymbiont and a eukaryotic host, are integrated is still lacking. The mTOR pathway is known to integrate nutritional conditions with cell growth and survival in eukaryotes. Characterization and localization of amino acid transporters in aphids suggest the mTOR pathway as point of integration between an aphid host and its amino acid-provisioning endosymbiont Buchnera aphidicola. The mTOR pathway is unannotated in aphids and unstudied in any nutritional endosymbiosis. We annotated mTOR pathway genes in two aphid species, Acyrthosiphon pisum and Myzus persicae, using both BLASTp searches and Hidden Markov Models. Using previously collected RNAseq data we constructed new reference transcriptomes for bacteriocyte, gut, and whole insect tissue for three lines of M. persicae. Annotation of the mTOR pathway identified homologs of all known invertebrate mTOR genes in both aphid species with some duplications. Differential expression analysis showed that genes specific to the amino acid-sensitive mTOR Complex 1 were more highly expressed in bacteriocytes than genes specific to the amino acid-insensitive mTOR Complex 2. Almost all mTOR genes involved in sensing amino acids showed higher expression in bacteriocytes than in whole insect tissue. When compared to gut, the putative glutamine/arginine sensing transporter ACYPI000333, an ortholog of SLC38A9, showed 6.5 times higher expression in bacteriocytes. Our results suggest that the mTOR pathway may be functionally important in mediating integration of Buchnera into aphid growth and reproduction.



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Transcriptome Analysis of Four Arabidopsis thaliana Mediator Tail Mutants Reveals Overlapping and Unique Functions in Gene Regulation

The Mediator complex is a central component of transcriptional regulation in Eukaryotes. The complex is structurally divided into four modules known as the head, middle, tail and kinase modules, and in Arabidopsis thaliana, comprises 28-34 subunits. Here, we explore the functions of four Arabidopsis Mediator tail subunits, MED2, MED5a/b, MED16, and MED23, by comparing the impact of mutations in each on the Arabidopsis transcriptome. We find that these subunits affect both unique and overlapping sets of genes, providing insight into the functional and structural relationships between them. The mutants primarily exhibit changes in the expression of genes related to biotic and abiotic stress. We find evidence for a tissue specific role for MED23, as well as in the production of alternative transcripts. Together, our data help disentangle the individual contributions of these MED subunits to global gene expression and suggest new avenues for future research into their functions.



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BGGE: A New Package for Genomic-Enabled Prediction Incorporating Genotype x Environment Interaction Models

One of the major issues in plant breeding is the occurrence of genotype x environment (GE) interaction. Several models have been created to understand this phenomenon and explore it. In the genomic era, several models were employed to improve selection by using markers and account for GE interaction simultaneously. Some of these models use special genetic covariance matrices. In addition, the scale of multi-environment trials is getting larger, and this increases the computational challenges. In this context, we propose an R package that, in general, allows building GE genomic covariance matrices and fitting linear mixed models, in particular, to a few genomic GE models. Here we propose two functions: one to prepare the genomic kernels accounting for the genomic GE and another to perform genomic prediction using a Bayesian linear mixed model. A specific treatment is given for sparse covariance matrices, in particular, to block diagonal matrices that are present in some GE models in order to decrease the computational demand. In empirical comparisons with Bayesian Genomic Linear Regression (BGLR), accuracies and the mean squared error were similar; however, the computational time was up to five times lower than when using the classic approach. Bayesian Genomic Genotype x Environment Interaction (BGGE) is a fast, efficient option for creating genomic GE kernels and making genomic predictions.



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Pinnacle EMS Quick Take: Why transitions of care are an important patient safety opportunity

Transitions of care are critical opportunities to communicate patient assessment and treatment information to other healthcare providers

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Pinnacle EMS Quick Take: EMS leaders challenged ‘to make tomorrow better than today’

John O'Leary, a survivor of 100 percent TBSA burn as a child, delivered an inspiring opening keynote to Pinnacle EMS conference attendees

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Pinnacle EMS Quick Take: Why transitions of care are an important patient safety opportunity

Transitions of care are critical opportunities to communicate patient assessment and treatment information to other healthcare providers

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Rehabilitation Outcomes of Patients with Severe Disability After Stroke

Publication date: Available online 26 July 2018

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Domenico Scrutinio, Pietro Guida, Bernardo Lanzillo, Chiara Ferretti, Anna Loverre, Nicola Montrone, Simona Spaccavento

Abstract.
Objective

To characterize rehabilitation outcomes of patients with severe post-stroke motor impairment (MI) and develop a predictive model for treatment failure.

Design

Retrospective cohort study. Correlates of treatment failure, defined as the persistence of severe MI following rehabilitation, were identified using logistic regression analysis. Then, an integer-based scoring rule was developed from the logistic model.

Setting

Three specialized inpatient rehabilitation facilities.

Participants

1,265 patients classified as Case-Mix Groups (CMG) 0108, 0109, and 0110 of the Medicare classification system.

Interventions

Not applicable.

Main Outcome Measure

Change in the severity of MI, as assessed by the Functional Independence Measure (FIM), from admission to discharge,

Results

Median FIM-motor score increased from 17 (Interquartile range [IQR] 14-23) to 38 (IQR, 25-55) points. Median proportional recovery, as expressed by FIM-motor effectiveness, was 26% (IQR, 12-47). Median FIM-motor change was 18 (IQR, 9-34) points. 38.5% patients achieved the Minimal Clinically Important Difference. 18.6% and 38.5% of the patients recovered to a stage of either mild (FIM-motor ≥62) or moderate (FIM-motor 38-to-61) MI, respectively. All between-CMG differences were statistically significant. Outcomes have also been analyzed according to classification systems used in Australia and Canada. The scoring rule had an AUC of 0.833 (95% CIs 0.808-0.858). Decision curve analysis displayed large net benefit of using the risk score compared with the "treat all" strategy.

Conclusions

This study provides a snapshot of rehabilitation outcomes in a large cohort of patients with severe post-stroke MI, thus filling a gap in knowledge. The scoring rule accurately identified the patients at risk for treatment failure.



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Multiple confounders influence the association between low-grade systemic inflammation and musculoskeletal pain. A call for a prudent interpretation of the literature

Our understanding of the multiple systems and their interactions that contribute to musculoskeletal pain has evolved considerably in recent years. There is a large interest in the role of the immune system in both acute and persistent musculoskeletal pain states [1,2]. Systemically elevated levels of proinflammatory cytokines and chemokines have been revealed in people with musculoskeletal pain. This low-grade inflammation has been demonstrated in various musculoskeletal conditions, such as low back pain [1], neck pain [2] and radicular pain [3].

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The next generation in surgical research for patients with spinal metastases

Since the landmark randomized trial of Patchell and colleagues was published in 2005 [1], enthusiasm for surgical intervention as a treatment for patients with spinal metastases has increased substantially [2–5]. This, combined with parallel improvements in adjuvant therapies, enhanced perioperative safety, efficiency and surgical techniques have culminated in the fact that spine surgical procedures are now considered viable treatment options for individuals who little more than a decade ago would not have been deemed candidates for anything beyond palliative care, let alone a major operative event [4,5].

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Forelimb morphology and substrate use in extant Cercopithecidae and the fossil primate community of the Hadar sequence, Ethiopia

Publication date: Available online 26 July 2018

Source: Journal of Human Evolution

Author(s): Amy L. Rector, Marie Vergamini

Abstract

It is suggested that joint architecture of the extant cercopithecid forelimb differentiates terrestrial from arboreal quadrupedal species. Linear dimensions of forelimb joint morphology have also been used to assign fossil species to locomotor categories. However, many primates use a mix of terrestrial and arboreal behaviors, which can be problematic when developing models of behavior reconstruction using morphological variation. The current study uses multivariate analyses to identify morphology related to substrate use in primates, including determination of semiterrestriality. Measurements collected from distal humeri and proximal ulnae of 49 extant cercopithecid primate species were selected based on studies indicating that they could individually predict substrate use. Analyses including one-way analysis of variance, principal components, and discriminant functions were conducted to assess their ability to differentiate between arboreal and terrestrial substrate use. The functions created in these analyses are then applied to data from fossil specimens from the Hadar sequence, Ethiopia, sampling both the Hadar and overlying Busidima Formations, to retrodict possible substrate behavior of fossil monkeys at Hadar through time. As this study is designed to identify function and behavior rather than phylogeny, the taxonomic assignment of the fossil specimens is sometimes uncertain, but substrate behavior can still be inferred. Results suggest that substrate use, including semiterrestrial behavior, in extant and extinct primates can be inferred successfully from multivariate analyses based on joint morphology of the monkey elbow. This study reveals that the ecological distribution of primarily terrestrial fossil primate species of the Hadar sequence is comparable to modern-day communities in habitats similar to those reconstructed for the Hadar members.



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Characterizing functional consequences of DNA copy number alterations in breast and ovarian tumors by spaceMap

Publication date: Available online 26 July 2018

Source: Journal of Genetics and Genomics

Author(s): Christopher J. Conley, Umut Ozbek, Pei Wang, Jie Peng

Abstract

We propose a novel conditional graphical model — spaceMap — to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation of DNA copy number alterations (CNAs) on downstream protein levels in tumors. Through a penalized multivariate regression framework, spaceMap jointly models high dimensional protein levels as responses and high dimensional CNAs as predictors. In this setup, spaceMap infers an undirected network among proteins together with a directed network encoding how CNAs perturb the protein network. spaceMap can be applied to learn other types of regulatory relationships from high dimensional molecular profiles, especially those exhibiting hub structures. Simulation studies show spaceMap has greater power in detecting regulatory relationships over competing methods. Additionally, spaceMap includes a network analysis toolkit for biological interpretation of inferred networks. We applied spaceMap to the CNAs, gene expression and proteomics data sets from CPTAC-TCGA breast (n=77) and ovarian (n=174) cancer studies. Each cancer exhibited disruption of 'ion transmembrane transport' and 'regulation from RNA polymerase II promoter' by CNA events unique to each cancer. Moreover, using protein levels as a response yields a more functionally-enriched network than using RNA expressions in both cancer types. The network results also help to pinpoint crucial cancer genes and provide insights on the functional consequences of important CNA in breast and ovarian cancers. The R package spaceMap — including vignettes and documentation — is hosted on https://topherconley.github.io/spacemap.



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Employment stability in the first 5 years after moderate to severe traumatic brain injury

Publication date: Available online 26 July 2018

Source: Archives of Physical Medicine and Rehabilitation

Author(s): Dominic DiSanto, Raj Kumar, Shannon B. Juengst, Tessa Hart, Therese M. O'Neil-Pirozzi, Nathan Zasler, Thomas A. Novack, Christina Dillahunt-Aspillaga, Kristin M. Graham, Bridget A. Cotner, Amanda Rabinowitz, Sureyya Dikmen, Janet Niemeier, Matthew R. Kesinger, Amy K. Wagner

Abstract
Objective

To characterize employment stability and identify predictive factors of employment stability in working-age individuals after moderate to severe traumatic brain injury (TBI) that may be clinically addressed.

Design

Longitudinal observational study of an inception cohort from the Traumatic Brain Injury Model Systems National Database (TBIMS-NDB) using data at years 1, 2, and 5 post-TBI.

Setting

Inpatient rehabilitation centers with telephone follow-up.

Participants

Individuals enrolled in the TBIMS-NDB since 2001, aged 18 to 59, with employment data at two or more follow-up interviews at years 1, 2, and 5 (N=5,683).

Interventions

Not applicable.

Main Outcome Measure

Employment stability, categorized using post-TBI employment data as no paid employment (53.25%), stably (27.20%), delayed (10.24%), or unstably (9.31%) employed.

Results

Multinomial regression analyses identified predictive factors of employment stability, including younger age, white race, less severe injuries, pre-injury employment, higher annual earnings, male sex, higher education, transportation independence post-injury, and no anxiety or depression at 1-year post-TBI.

Conclusions

Employment stability serves as an important measure of productivity post-TBI. Psychosocial, clinical, environmental, and demographic factors predict employment stability post-TBI. Notable predictors include transportation independence as well as presence of anxiety and depression at year 1 post-TBI as potentially modifiable intervention targets.



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Asthma is not associated with the need for surgery in Crohn’s disease when controlling for smoking status: A population-based cohort study

Clinical Epidemiology

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Virologic control and severity of liver disease determine survival after radiofrequency ablation of hepatocellular carcinoma on cirrhosis

Digestive and Liver Diseases

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Risk assessment of lymph node metastases in early gastric adenocarcinoma fulfilling expanded endoscopic resection criteria

Gastrointestinal Endoscopy

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Cbt modulates Foxo activation by positively regulating insulin signaling in Drosophila embryos

Publication date: Available online 26 July 2018

Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Author(s): Verónica Muñoz-Soriano, Yaiza Belacortu, Francisco José Sanz, Cristina Solana-Manrique, Luke Dillon, Carmen Suay-Corredera, Marina Ruiz-Romero, Montserrat Corominas, Nuria Paricio

Abstract

In late Drosophila embryos, the epidermis exhibits a dorsal hole as a consequence of germ band retraction. It is sealed during dorsal closure (DC), a morphogenetic process in which the two lateral epidermal layers converge towards the dorsal midline and fuse. We previously demonstrated the involvement of the Cbt transcription factor in Drosophila DC. However its molecular role in the process remained obscure. In this study, we used genomic approaches to identify genes regulated by Cbt as well as its direct targets during late embryogenesis. Our results reveal a complex transcriptional circuit downstream of Cbt and evidence that it is functionally related with the Insulin/insulin-like growth factor signaling pathway. In this context, Cbt may act as a positive regulator of the pathway, leading to the repression of Foxo activity. Our results also suggest that the DC defects observed in cbt embryos could be partially due to Foxo overactivation and that a regulatory feedback loop between Foxo and Cbt may be operating in the DC context.



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Regulation of multiple abiotic stress tolerance by LexA in the cyanobacterium Anabaena sp. strain PCC7120

Publication date: Available online 26 July 2018

Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Author(s): Arvind Kumar, Anurag Kirti, Hema Rajaram

Abstract

The paradigm of involvement of LexA in regulation of only SOS-response in bacteria through the down-regulation of DNA repair genes was challenged in the unicellular cyanobacterium, Synechocystis PCC6803, wherein it was originally shown not to be associated with DNA repair and later also involved in management of carbon-starvation through up-regulation of C-metabolism genes. In the filamentous cyanobacterium, Anabaena sp. strain PCC7120, global stress management role for LexA and a consensus LexA-binding box (AnLexA-box) has been established using a LexA-overexpressing recombinant strain, AnlexA+. High levels of LexA rendered Anabaena cells sensitive to different DNA damage and oxidative stress-inducing agents, through the transcriptional down-regulation of the genes involved in DNA repair and alleviation of oxidative stress. LexA overexpression enhanced the ability of Anabaena to tolerate C-depletion, induced by inhibiting photosynthesis, by up-regulating genes involved in C-fixation and down-regulating those involved in C-breakdown, while maintaining the overall photosynthetic efficiency. A consensus LexA-binding box, AnLexA-box [AGT-N4–11-ACT] was identified upstream of both up- and down-regulated genes using a subset of Anabaena genes identified on the basis of proteomic analysis of AnlexA+ strain along with a few DNA repair genes. A short genome search revealed the presence of AnLexA box in at least 40 more genes, with functional roles in fatty acid biosynthesis, toxin-antitoxin systems in addition to DNA repair, oxidative stress, metal tolerance and C-metabolism. Thus, Anabaena LexA modulates the tolerance to multitude of stresses through transcriptional up/down-regulation of their functional genes directly by binding to the AnLexA Box present in their promoter region.

Graphical abstract

Unlabelled Image



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Longitudinal gait assessment in a stiff person syndrome

Stiff person syndrome (SPS) is an autoimmune disorder with multiple clinical presentations, all characterized by generalized or focal muscular stiffness leading to abnormal postures and movements. To date, no standardized treatments are available; also, the outcome measures are mainly clinical based and unstandardized, limiting the reliability of clinical trials. In this case study, we used the eight-camera motion capture system for gait analysis (GA) to outline the gait features and track the clinical evolution of a young patient with SPS receiving a personalized multimodal therapy. GA was accurate in reflecting clinical changes over a 7-week-long period, thus representing a potential source for objective biomarkers in SPS. Therefore, future studies focusing on either the natural history or the treatment of SPS could adopt GA for reliable outocome measures, confirming this preliminary observation. *Tommaso Schirinzi and Andrea Sancesario contributed equally to the writing of this article. Correspondence to Tommaso Schirinzi, MD, Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children Hospital, Piazza Sant'Onofrio, Rome 00133, Italy Tel: +39 066 8591; fax: +39 066 859 3377; e-mail: t.schirinzi@yahoo.com Received May 7, 2018 Accepted June 25, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Influence of Nasal Tip Lifting on the Incidence of the Tracheal Tube Pathway Passing Through the Nostril During Nasotracheal Intubation: A Randomized Controlled Trial.

Influence of Nasal Tip Lifting on the Incidence of the Tracheal Tube Pathway Passing Through the Nostril During Nasotracheal Intubation: A Randomized Controlled Trial.

Anesth Analg. 2018 Jul 21;:

Authors: Kim H, Lee JM, Lee J, Hwang JY, Chang JE, No HJ, Won D, Choi S, Min SW

Abstract
BACKGROUND: For safe nasotracheal intubation without middle turbinate injury, the tracheal tube should pass through the lower pathway, which is beneath the inferior turbinate and immediately above the nasal floor of the nostril. The purpose of this study was to assess the influence of nasal tip lifting on the incidence of passing preformed nasal Ring-Adair-Elwyn (RAE) tubes through the lower pathway during nasotracheal intubation.
METHODS: Patients were randomly assigned to a "nasal tip lifting group" or a "neutral group." For patients in the nasal tip lifting group, an investigator pulled the nasal tip in a cephalad direction when inserting a preformed nasal RAE tube into the nostril after induction of anesthesia. For patients in the neutral group, a tube was inserted with the nasal tip in a neutral position. The pathway by which the tube passed in each patient was identified using a fiberscope. The incidence of the tube passing through the lower pathway was compared between the 2 groups. The incidence of epistaxis was also evaluated.
RESULTS: Eighty-six patients were enrolled and completed the study protocol. The incidence of the tracheal tube passing through the lower pathway was significantly higher in the nasal tip lifting group (79.1%) than in the neutral group (51.2%) (relative risk, 1.55; 95% confidence interval, 1.11-2.15; P = .007). Although the incidence of epistaxis was not different between the groups (18.6% vs 32.6%; P = .138), it was lower when the tracheal tube passed nasal cavity through the lower pathway (14.3%) than the upper pathway (46.7%), regardless of the randomized group with adjustment for potentially confounding variables (odds ratio, 0.19; 95% confidence interval, 0.07-0.54; P = .002).
CONCLUSIONS: The nasal tip lifting maneuver helped to guide preformed nasal RAE tubes into the lower pathway during nasotracheal intubation.

PMID: 30044295 [PubMed - as supplied by publisher]



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An Ultrasound-Guided Lateral Approach for Proximal Sciatic Nerve Block: A Randomized Comparison With the Anterior Approach and a Cadaveric Evaluation

Background and Objectives The lateral and anterior approaches for proximal sciatic nerve (SN) block can be used in patients lying supine. We assume that the posterior femoral cutaneous nerve (PFCN) is simultaneously blocked more often via the lateral approach than via the anterior approach, given the proximity of these 2 nerves at the injection level. However, locating the SN is difficult when using the original landmark-based lateral approach. We have introduced ultrasound guidance to alleviate the technical difficulty of the lateral approach and tested the hypothesis that an ultrasound-guided lateral approach would achieve PFCN block more often than the ultrasound-guided anterior approach for SN block. Methods Forty consecutive patients undergoing knee surgery were randomly allocated to receive an SN block using an ultrasound-guided lateral or anterior approach. The primary outcome was the frequency of PFCN block 30 minutes after SN block. Secondary outcomes included the frequency of SN block, nerve depth, needle depth, and time taken to perform the block. We also assessed the spread of injectate by the lateral approach in 4 cadaveric legs. Results The frequency of PFCN block 30 minutes after SN block was higher with the lateral approach than with the anterior approach (60% vs 15%, P = 0.008). The frequency of SN block was comparable between the groups. Dye reached the PFCN in all cadaveric specimens. Conclusions The ultrasound-guided lateral approach for proximal SN block can be performed as successfully as the anterior approach and provides PFCN block more often than the anterior approach. Clinical Trial Registration: This study was registered at UMIN Clinical Trials Registry, identifier UMIN000026748. Accepted for publication March 25, 2018. Address correspondence to: Takayuki Yoshida, MD, PhD, Department of Anesthesiology, Kansai Medical University Hospital, 2-3-1 Shin-machi, Hirakata-city, Osaka 573-1191, Japan (e-mail: ytaka@mac.com). The authors declare no conflict of interest. Copyright © 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Windshield Wiper in the Shoulder: Ultrasound Imaging for the Proximal Rotator Cuff Interval

No abstract available

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Dexamethasone concentration affecting rocuronium-induced neuromuscular blockade and sugammadex reversal in a rat phrenic nerve-hemidiaphragm model: An ex vivo study

BACKGROUND The concentration range of dexamethasone that inhibits neuromuscular blockade (NMB) and sugammadex reversal remains unclear. OBJECTIVE To evaluate the effects of dexamethasone on rocuronium-induced NMB and sugammadex reversal. DESIGN Ex vivo study. SETTING Asan Institute for Life Sciences, Asan Medical Center, Korea, from July 2015 to November 2015. ANIMALS One hundred sixty male Sprague–Dawley rats. INTERVENTIONS We assessed the effect of four concentrations of dexamethasone [0, 0.5, 5 (clinical concentrations) and 50 μg ml−1 (experimental concentration)] on partial NMB on 40 phrenic nerve–hemidiaphragm preparations (n=10 per concentration). Once the first twitch of train-of-four (TOF) had been depressed by 50% with rocuronium, dexamethasone was administered. To assess the effect of dexamethasone on sugammadex reversal, 120 phrenic nerve–hemidiaphragm preparations were used in three subexperiments (n=40 per experiment), using three administration regimens of rocuronium–equimolar sugammadex: a single dose, a split-dose (split 1/2 and 1/2) and a reduced split-dose (split 1/2 and 1/4). After complete NMB was achieved, dexamethasone and sugammadex were administered. MAIN OUTCOME MEASURES The change in the first twitch height, the recovery time to a TOF ratio at least 0.9, and the TOF ratio at 30 min were evaluated. RESULTS There were no significant differences in the first twitch height among groups (P = 0.532). With a single dose of sugammadex, dexamethasone did not affect the recovery time to a TOF ratio at least 0.9 (P = 0.070). After using a split-dose of sugammadex, the recovery time to a TOF ratio at least 0.9 was delayed only at a concentration of 50 μg ml−1 of dexamethasone. With a reduced split-dose of sugammadex, the TOF ratio at 30 min was lowered only by a concentration of 50 μg ml−1 of dexamethasone (P 

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Paediatric Coeliac Disease: Increasing Incidence or Increased Awareness?

No abstract available

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A New Paradigm in the Treatment of Eosinophilic Esophagitis: Proton Pump Inhibitors Are Safe, Aim for “Deep Remission”

imageNo abstract available

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Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care—An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition

imageBackground: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. Results: These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. Conclusions: These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

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Systematic Review: The Epidemiology, Natural History, and Burden of Alagille Syndrome

imageBackground and Aim: Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end-stage liver disease and death. The aim of the study was to perform the first systematic review of the epidemiology, natural history, and burden of ALGS with a focus on the liver component. Methods: Electronic databases and proceedings from key congresses were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines. This analysis included publications reporting epidemiology, natural history, economic burden or health-related quality of life (HRQoL) outcomes in patients with ALGS. Results: Of 525 screened publications, 20 met the inclusion criteria. Liver-related features included cholestasis (87%–100% of patients), jaundice (66%–85%), and cirrhosis (44%–95%). Between 15% and 47% of patients underwent liver transplantation and 4% to 14% received partial biliary diversion. Pruritus affected the majority of patients (59%–88%, of whom up to 45% had severe pruritus) and manifested during the first 10 years of life. Children with ALGS had significantly impaired HRQoL compared with healthy controls and those with other diseases. Itching was the symptom that most affected children with ALGS. No study assessed the economic burden of ALGS. Conclusions: Our findings consolidate information on the clinical course of ALGS, and highlight gaps in knowledge, most notably the absence of any research on the economic consequences of the disease. Further research is needed to establish the incidence of genetically confirmed ALGS. Disease-specific tools are also needed to improve the measurement of symptoms, such as itching, and better understand the impact of ALGS on HRQoL.

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Factors Associated With Length of Stay and 30-Day Revisits in Pediatric Acute Pancreatitis

imageObjective: The objective of the study was to identify factors associated with length of stay (LOS) and 30-day hospital revisit for patients hospitalized with acute pancreatitis (AP). Method: Multicenter, retrospective cohort study using the Pediatric Health Information System database. Multilevel linear and logistic regression was used to identify factors independently associated with the primary outcome variables of LOS and 30-day hospital revisit in children aged 1 and 18 years discharged with a primary discharge diagnosis of AP from participating hospitals between 2008 and 2013. Results: For the 7693 discharges, median LOS was 4 days (interquartile range 3–7 days) and 30-day revisit rate 17.6% (n = 1356). Discharges were primarily girls (55%), Caucasian (46%), and 6 years old or older (85%). On multilevel regression, factors independently associated with both longer LOS and higher revisit odds included malignant and gastrointestinal complex chronic conditions (CCCs) and total parenteral nutrition use while hospitalized. Male gender was associated with both lower LOS (adjusted length of stay = −0.6 days, 95% confidence interval [CI] = −0.8 to −0.4) and decreased revisit odds (aOR 0.85; 95% CI = 0.74 to 0.97). Hispanic ethnicity was associated with increased LOS (adjusted length of stay = +0.8 days, 95% CI = +0.5 to +1.1), but no change in revisit odds. Conclusions: Certain demographic and clinical factors, including gender, ethnicity, and type of CCC, were independently associated with LOS and risk of 30-day hospital revisit for pediatric AP. Children with malignant and gastrointestinal CCCs who require total parenteral nutrition are at highest risk for both longer LOS and hospital revisit when admitted with AP. These patient populations may benefit from intensive care coordination when hospitalized for AP.

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Neurodevelopmental Outcomes in Children With Liver Diseases: a Systematic Review

imageObjective: The aim of the study was to determine the neurodevelopmental outcomes of children with liver diseases based on a systematical review of the literature. Method: A literature search according to the PRISMA statement was conducted using predefined search terms in PubMed, Cochrane Library, and PsycINFO. The inclusion criterion was studies published from 2000 onwards that reported on the neurodevelopmental outcomes of term-born children with liver diseases. A narrative synthesis was done to appraise the studies. Results: Twenty-five studies were included (1913 children), 19 of which described children after liver transplantation (LTx; 1372 children). Sixty-seven percentage of the studies on children with liver diseases who survived with their native livers showed low-average or abnormal scores on specific subscales of cognitive and behavioral measures. In studies on children after LTx, this was 82%. After LTx, 83% of studies demonstrated impaired outcomes on behavior, whereas 42% of children received special education. Motor development was impaired in 82% of studies in children with native liver and after LTx. Limitations: Studies were heterogenic because of sample sizes, etiology of liver disease and type of assessment tools used. Conclusions: More than two-third of included studies showed neurodevelopmental deficits in children with liver diseases, affecting all neurodevelopmental areas. Knowledge on risk factors for impaired neurodevelopment is limited and lack of long-term follow-up is worrying, especially considering the increasing survival rates, resulting in more at-risk patients. Studying early predictors and risk factors of abnormal developmental trajectories of children with liver diseases is indicated to assess strategies to improve their long-term neurodevelopmental outcomes.

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Early Administration of N-acetylcysteine in the Treatment of Clove Oil Ingestion

imageNo abstract available

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Pediatric Liver Transplant Teams Coping With Patient Death

imageObjectives: Coping with patient death among pediatric liver transplant teams has received little attention despite general recognition of the potentially negative emotional consequences associated with such loss. The purpose of this study was to investigate the ways in which members of pediatric liver transplant teams cope with the death of patients on the waitlist and post-transplant and the institutional resources available to facilitate this coping. Methods: Participants included 120 physicians, nurses, and mental health professionals from multiple transplant centers across the United States. Participants completed an online questionnaire that assessed the availability of formal coping resources at their institutions, informal sources of support used to cope with patient death, and as indices of coping, bereavement, and emotional exhaustion symptoms experienced. Results: Debriefing, the most commonly offered support, was available to about half (55.8%) of the sample; yet, nearly all respondents (98.3%) indicated that debriefing would be useful. On average, bereavement and emotional exhaustion levels were comparable to normative data, but patterns of coping varied based on participants' position within the transplant team. For participants who reported that debriefing was available at their institutions, emotional exhaustion was lower. Conclusions: Overall, formal supports were inconsistently offered to pediatric transplant team members. Team members expressed high acceptability for debriefing, which has been associated with benefits in other populations, and findings indicated better coping in the transplant setting when it was offered.

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Celiac Diasease–associated lncRNA Named HCG14 Regulates NOD1 Expression in Intestinal Cells

imageObjective: The aim of the study is to identify additional celiac disease associated loci in the major histocompatibility complex (MHC) independent from classical HLA risk alleles (HLA-DR3-DQ2) and to characterize their potential functional impact in celiac disease pathogenesis at the intestinal level. Methods: We performed a high-resolution single-nucleotide polymorphism (SNP) genotyping of the MHC region, comparing HLA-DR3 homozygous celiac patients and non-celiac controls carrying a single copy of the B8-DR3-DQ2 conserved extended haplotype. Expression level of potential novel risk genes was determined by RT-PCR in intestinal biopsies and in intestinal and immune cells isolated from control and celiac individuals. Small interfering RNA-driven silencing of selected genes was performed in the intestinal cell line T84. Results: MHC genotyping revealed 2 associated SNPs, one located in TRIM27 gene and another in the non-coding gene HCG14. After stratification analysis, only HCG14 showed significant association independent from HLA-DR-DQ loci. Expression of HCG14 was slightly downregulated in epithelial cells isolated from duodenal biopsies of celiac patients, and eQTL analysis revealed that polymorphisms in HCG14 region were associated with decreased NOD1 expression in duodenal intestinal cells. Conclusions: We have successfully employed a conserved extended haplotype-matching strategy and identified a novel additional celiac disease risk variant in the lncRNA HCG14. This lncRNA seems to regulate the expression of NOD1 in an allele-specific manner. Further functional studies are needed to clarify the role of HCG14 in the regulation of gene expression and to determine the molecular mechanisms by which the risk variant in HCG14 contributes to celiac disease pathogenesis.

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Transjugular Intrahepatic Portosystemic Shunt Insertion for the Management of Portal Hypertension in Children

imageObjectives: the aim of the study was to describe our 20-year experience with transjugular intrahepatic portosystemic shunt (TIPSS) procedures for children with resistant portal hypertension (PHTN). Methods: Retrospective review of all children that had a TIPSS performed at Birmingham Children's Hospital from January 1, 1995 to January 1, 2015. Results: Forty children underwent 42 attempted TIPSS for resistant PHTN with recurrent variceal bleeding (n = 35), refractory ascites (n = 4), and hypersplenism (n = 1). Median age at operation was 12 years (range 7 months–17 years). Thirty-four procedures were elective and 8 were emergency cases. TIPSS was established in 33 cases (79%). Median portal venous pressure reduction was 10 mmHg. Variceal bleeding ceased in 27 (96%) and ascites improved in all. Clinical improvement following TIPSS enabled 7 children to be bridged to transplantation and 7 others to become suitable for transplantation. The 1-year and 5-year survival with TIPSS was 57% and 35%, respectively. Child-Pugh score C was an independent risk factor for adverse outcome (Likelihood ratio (LR) = 8.0; 95% confidence interval (CI) 2.7 to 23.5; P = 0.001). There were 6 major complications: hepatic artery thrombosis and infarction (n = 1), hepatic artery pseudoaneurysm (n = 1), bile leak (n = 1), and hepatic encephalopathy (n = 3). Encephalopathy was resistant to medical treatment in 2 cases, necessitating staged closure in 1. Ten patients (30%) required intervention to maintain TIPSS patency. The 1-year and 5-year freedom from reintervention was 71% and 55%, respectively. Conclusions: A TIPSS is highly successful in controlling symptoms in children with resistant PHTN and facilitating liver transplantation. It is technically demanding and not without risk. Patients must be appropriately selected and counselled.

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Environmental Enteropathy, Micronutrient Adequacy, and Length Velocity in Nepalese Children: the MAL-ED Birth Cohort Study

imageObjectives: Environmental enteropathy (EE) is likely associated with growth retardation in children, but the association between EE and length velocity z score (LVZ) has not been investigated. The objective of the study was to assess associations between fecal markers for intestinal inflammation and LVZ and whether these associations were influenced by micronutrient adequacy among 9 to 24 months old children in Bhaktapur, Nepal. Methods: Data were divided into 5 time slots (9–12, 12–15, 15–18, 18–21, and 21–24 months). Anthropometric measurement and dietary assessment (by 24 hour recall) were performed monthly. Mean nutrient density adequacy was calculated based on nutrient density adequacy of 10 micronutrients (thiamin, riboflavin, niacin, vitamin B6, folate, vitamin C, vitamin A, calcium, iron, and zinc). Anti-1-antitrypsin (AAT), myeloperoxidase (MPO), and neopterin (NEO) were measured in stool samples collected at the beginning of each time slot. An EE score was calculated based on all 3 fecal markers. Associations between AAT, MPO, NEO and EE score and LVZ were assessed by multiple linear regression analyses and Generalized Estimating Equations models. Results: Associations between fecal markers and EE score and LVZ were generally weak. EE score and MPO for 3-month and MPO for 6-month growth periods were significantly associated with LVZ from 9 to 24 months. These associations were slightly modified by mean nutrient density adequacy. Conclusions: EE score and MPO were significantly associated with LVZ in 9 to 24 months old Nepali children. Further studies to establish the usefulness of AAT, MPO, and NEO in assessing EE and growth retardation are warranted.

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Comparison of Transjugular Liver Biopsy and Percutaneous Liver Biopsy With Tract Embolization in Pediatric Patients

imagePurpose: The aim of the study was to compare safety and efficacy of transjugular liver biopsy (TJLB) and percutaneous liver biopsy (PLB) with tract embolization in pediatric patients with liver disease. Materials and Methods: TJLB and PLB between December 2009 and October 2015 were retrospectively reviewed. Primary endpoints were adequate sampling and complication rate. Patient age, weight, coagulation factors, ascites, blood transfusions, adequacy of biopsy sample, number of biopsy samples, and complications were compared. Results: There were 39 TJLB (average age 10.6 years) and 120 PLB (average age 7.1 years) (P value

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Endoscopic Management Postcholedochoduodenostomy for Choledochal Cysts

imageNo abstract available

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Competitively Selected Donor Fecal Microbiota Transplantation: Butyrate Concentration and Diversity as Measures of Donor Quality

imageIn this prospective cohort study, we examine the feasibility of a protocol to optimize microbiota for fecal microbiota transplantation (FMT). Donor stool metrics generally accepted as markers of gut health were used to select a stool donor based on superior microbial diversity, balanced constitution of Bacteroidetes versus Firmicutes and high concentration of fecal butyrate. Selected donor microbiota was then administered via FMT. A total of 10 patients with median age of 12 years with recurrent Clostridium difficile infection received the intervention. The rate of recurrence-free resolution with 1-2 FMTs was 100% at Week 10. With a single FMT, 80% of patients cleared Clostridium difficile infection without recurrence, whereas 20% of patients required a single re-treatment. No serious adverse events occurred. Microbiota sequencing revealed that recipients' gut microbiota phylogenic diversity increased by 72-hours post-transplantation, with sustainment over 10-week follow-up. This study highlights the feasibility of purposefully selecting the most ideal microbiota for transplantation.

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Prediction of Large Varices in Children With Cirrhosis: Platelets, Bilirubin, or Etiology?

No abstract available

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Dilation of Esophageal Stricture in a Pediatric Patient Using Functional Lumen Imaging Probe Technology Without the Use of Fluoroscopy

imageNo abstract available

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Towards Better Diagnosis and Monitoring of Eosinophilic Esophagitis

No abstract available

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Barriers and Facilitators to a Good Bowel Preparation for Colonoscopy in Children: A Qualitative Study

imageBackground: A well-visualized colon during colonoscopy has a direct impact on interpretation of findings and need for repeat procedure. Studies have been conducted in the adult population to assess factors contributing to improved bowel preparation. The primary aim of this study was to determine barriers and facilitators to good preparation in children. Methods: A qualitative descriptive approach was utilized. Children age 2 to 18 years old, and their parents were recruited from the McMaster University Gastroenterology clinic from May 2015 to January 2016. Semistructured interviews were conducted assessing the understanding of the preparation protocol, and the compliance and tolerability of the preparation. A thematic analysis was conducted. Results: Eleven families participated (7 children and 14 parents). Fifty percent of the children were under 11 years of age, and 73% were undergoing bowel preparation for the first time. Participants identified 26 subthemes, which were categorized into 4 broad themes. Barriers included confusion regarding mixing of the preparation and allowable diet during the preparation day, as well as lack of clarity on expected stool end goals. Facilitators included ease of access of the gastroenterology team, small volume of liquid mixed with the preparation, few adverse effects, and the provision of an understandable handout. Parental motivation to achieve a good outcome was also a facilitator. Conclusions: This is the first qualitative study focusing on children undergoing a home bowel preparation for a colonoscopy. Being able to identify barriers and facilitators will allow gastroenterologists to improve the quality of bowel preparation and overall experience for the pediatric population.

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Recommendations for Diagnosis and Management of Autoimmune Pancreatitis in Childhood: Consensus From INSPPIRE

imageObjectives: Autoimmune pancreatitis (AIP) represents a complex immune-mediated pancreas disorder. Pediatric AIP (P-AIP) is rare. We have recently summarized the characteristic features of P-AIP. We now aim to develop recommendation statements to standardize the diagnostic and therapeutic approach to P-AIP and facilitate future research in the field. Methods: A panel of pediatric gastroenterologists participating in the International Study Group of Pediatric Pancreatitis: In search for a cuRE was formed to discuss and then vote on 15 recommendation statements. A consensus of at least 80% was obtained following 3 voting rounds and revision of the statements. Results: We have now generated 15 statements to help standardize the approach to diagnosis and management of P-AIP. Conclusions: The first P-AIP recommendation statements developed by the International Study Group of Pediatric Pancreatitis: In search for a cuRE group are intended to bring standardization to the diagnosis and treatment of this rare childhood disorder. These statements may help guide a uniform approach to patient care and facilitate future research studies.

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Single Balloon–assisted Colonoscopy for Placement of Colonic Manometry Catheters: Initial Experience in Children

imageObjectives: Colonic manometry is used frequently in children with long standing and difficult to manage constipation to aid in management decisions. Accurate analysis requires placement of the colonic manometry catheter in the colon without looping. This is technically difficult due to the long-standing nature of the constipation in most patients leading to sigmoid and other colonic redundancy. Single balloon colonoscopy has been successfully used in adult in cases of difficult colonoscopy. We report the first series of single balloon–assisted colonoscopy for performing difficult colonoscopy in children and placing colonic manometry catheters. Methods: Retrospective chart review was performed to identify patients undergoing the procedure. All patients had prior preparation with nasogastric golytely. Results: Using the single balloon technique, 36 patients underwent placement of the colonic manometry catheter (ages ranging from 3 to 16 years, weights 12 to 95 kg). Catheter placement was successful in all cases with procedure times of 20 to 105 minutes. No major complications were noted. Conclusions: This is the first reported series of using single balloon–assisted colonoscopy to perform difficult colonoscopy in children and place colonic manometry catheters. It may have other therapeutic implications in children such as removal of polyps or placement of similar catheters.

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