Πέμπτη, 31 Μαΐου 2018

Acoustic Field-Assisted Particle Patterning for Smart Polymer Composite Fabrication in Stereolithography

3D Printing and Additive Manufacturing, Ahead of Print.

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Genotyping by Sequencing of 393 Sorghum bicolor BTx623 x IS3620C Recombinant Inbred Lines Improves Sensitivity and Resolution of QTL Detection

We describe a genetic map with a total of 381 bins of 616 genotyping by sequencing (GBS)-based SNP markers in a F6-F8 recombinant inbred line (RIL) population of 393 individuals derived from crossing S. bicolor BTx623 to S. bicolor IS3620C, a guinea line substantially diverged from BTx623. Five segregation distorted regions were found with four showing enrichment for S. bicolor alleles, suggesting possible selection during formation of this RIL population. A quantitative trait locus (QTL) study with this number of individuals, tripled relative to prior studies of this cross, provided resources, validated previous findings, and demonstrated improved power to detect plant height and flowering time related QTLs relative to other published studies. An unexpected low correlation between flowering time and plant height permitted us to separate QTLs for each trait and provide evidence against pleiotropy. Ten non- random syntenic regions conferring QTLs for the same trait suggest that those QTLs may represent alleles at genes functioning in the same manner since the 96 million year ago genome duplication that created these syntenic relationships, while syntenic regions conferring QTLs for different trait may suggest sub-functionalization after duplication. Collectively, this study provides resources for marker-assisted breeding, as well as a framework for fine mapping and subsequent cloning of major genes for important traits such as plant height and flowering time in sorghum.

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Involvement of YAP-1, the Homolog of Yes-Associated Protein, in the Wnt-Mediated Neuronal Polarization in Caenorhabditis elegans

Guidance molecules, receptors, and downstream signaling pathways involved in the asymmetric neuronal cell migration and process outgrowth have been identified from genetic studies using model organisms, most of which are evolutionarily conserved. In the nematode Caenorhabditis elegans, the roles of Wnt ligands and their receptors in the polarization of specific sets of neurons along the anterior-posterior (A-P) body axis have been well elucidated, but their downstream effectors are relatively unknown. Here, we report yap-1, encoding an evolutionarily conserved transcriptional co-activator, as a novel player in the Wnt-mediated asymmetric development of specific neurons in C. elegans. We found that the loss of yap-1 activity failed to restrict the dendritic extension of ALM neurons to the anterior orientation, which is similar to the phenotype caused by defective cwn-1 and cwn-2 Wnt gene activities. Cell-specific rescue experiments showed that yap-1 acts in the cell autonomous manner to polarize ALM dendrites. We also found that subcellular localization of YAP-1 was spatio-temporally regulated. The loss of yap-1 in Wnt-deficient mutants did not increase the severity of the ALM polarity defect of the mutants. Wnt-deficient animals displayed abnormal subcellular localization of YAP-1 in touch receptor neurons, suggesting that yap-1 may act downstream of the cwn-1/cwn-2 Wnt ligands for the ALM polarization process. Together, we have identified a new role for YAP-1 in neuronal development and our works will contribute to further understanding of intracellular events in neuronal polarization during animal development.

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Excitability tests using high-density surface-EMG: A novel approach to studying single motor units

Excitability in single human motor axons was studied extensively by Joseph Bergmans in the 1970s (Bergmans, 1970). In his early pioneering work, single motor unit action potential (MUAP) responses were recorded using surface electromyography (EMG). His approach involved major challenges: isolating electrically recruited single MUAP responses and monitoring the threshold manually by careful investigation of the motor units' all-or-none activity. The introduction of automated threshold tracking techniques (Bostock et al.

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Small fibre neuropathy in mitochondrial diseases explored with sudoscan

Peripheral nervous system (PNS) is highly dependent on energy metabolism, and consequently, mitochondrial dysfunction can contribute to peripheral neuropathy. In fact, mitochondria play a key role in the pathophysiology of the PNS for the involvement in the release of energy in the form of ATP to maintain ionic gradients, preserve the integrity of axonal cytoskeletal elements, transport cellular components along the extended lengths of axons, sustain of exocytosis/recycling of synaptic vesicles at axonal terminals, and for the regulation of the Ca2+ homeostasis (Persson et al., 2016).

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Long-term outcomes in patients with ulnar neuropathy at the elbow treated according to the presumed aetiology

In our previous publications (Omejec and Podnar, 2015, 2016b), we presented evidence that idiopathic ulnar neuropathy at the elbow (UNE) mainly consists of two conditions occurring 2-5 cm apart. In the first condition, affecting about 15% of UNE patients (Omejec and Podnar, 2016b), the ulnar nerve is entrapped 2-3 cm distal to the medial epicondyle (ME) under the humeroulnar aponeurosis (HUA), i.e., in the cubital tunnel (Omejec and Podnar, 2015). In the second condition, affecting the majority (about 85%) of patients (Omejec and Podnar, 2016b), the lesion is located at the ME or up to 4 cm proximally in the retrocondylar groove (RTC) (Omejec and Podnar, 2015).

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Septic Sacroiliitis in a 53-year-old Adult: A Case Report

A 53-year-old female with no significant past medical history presented with 10/10 right buttock pain that radiated to the right groin. With no reported recent injury, the absence of fever, and no identifiable risk factors, an infectious etiology including septic sacroiliitis is at the end spectrum of the differential. Septic sacroiliitis (SSI) is a rare condition with nonspecific findings that can lead to major complications, including death. To our knowledge, there are only four recent major literature reviews on SSI, with most cases reported to have at least one risk factor or clinical sign indicating the possibility of an infectious etiology.

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Validity, reliability and responsiveness of the Spanish version of the OPTIMAL instrument

The Outpatient Physical Therapy Improvement in Movement Assessment Log (OPTIMAL) is a self-report instrument developed to measure the ability to perform mobility actions.

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A Case Report of Aphonogelia following Recovery from Severe Traumatic Brain Injury

During rehabilitation from a severe traumatic brain injury, a 16-year-old woman became aware that she had lost the ability to laugh out loud. This rare phenomenon has previously been described as "aphonogelia." A discussion of therapeutic avenues which were explored with this patient is the first case, to our knowledge, of aphonogelia following a traumatic brain injury is presented.

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Cytotoxic Effects of Nonionic Iodinated Contrast Agent on Human Adipose-derived Mesenchymal Stem Cells

Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for degenerative spine conditions. However, cell therapy for painful spine degeneration presently requires use of contrast agents during fluoroscopy-guided injections and the effects of these agents on MSCs represents a gap in knowledge.

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Successful conservative treatment of type 3 injury (ductal injury) developing after ERCP


Publication date: Available online 31 May 2018
Source:Arab Journal of Gastroenterology
Author(s): Rahman Şenocak, Ali Kağan Coşkun, Şahin Kaymak, Yusuf Serdar Sakin
Although endoscopic retrograde cholangio-pancreatography (ERCP) is considered a safe procedure, it is associated with complications such as pancreatitis, bleeding and perforation of the bile duct, pancreatic duct and duodenum. In recent years, successful conservative treatment in selected patients with complications have increased. We present a case with successful conservative treatment of rare injury (type 3) developing after ERCP.

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Extrapolation of significant genes and transcriptional regulatory networks involved in Zea mays in response in UV-B stress


A wide range of plant species growth influenced when they exposed to solar UV-B radiation. Leaves of the plant are highly affected by UV-B radiation lead to the reduction in the growth of the plant. Current work demonstrates the comparative transcriptional changes and visible symptoms occurred in the maize leaf growth zone (GZ). Primary objective of this study was to identify differentially expressed genes (DEGs) responsible for leaf growth and their association in the transcriptional regulatory network under UV-B stress. Whole transcriptomic data was analysed and the quality check was tested for each sample and further genome-wide mapping and DEGs were performed. Gene Ontology (GO) based functional annotation, associated transcriptional networks and molecular pathways were annotated. Reduction in cell production due to UV-B stress causes a decrease in leaf's length and size was observed. Further, the specific role of the DEGs, in UV-B signalling pathways and other molecular functions responsible for leaf cell death was discovered. Results also infer that the major changes occurred in the cell cycle, transcriptional regulation, post-transcriptional modification, phytohormones, flavonoids biosynthesis, and chromatin remodeling. UV-B signalling pathways and the transcriptional regulatory networks infer the different molecular steps along with downstream transcriptional and post-transcriptional control of metabolic enzymes used in long-term memory adoption and attainment resistance to UV-B stress identified. Effects of UV-B radiation on leaf growth was noted in this study. UV-B stress response genes and associated transcriptional regulatory networks were identified, can be used in developing the marker assist UB-B stress tolerant genotypes of the maize.

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A Catalogue of Putative cis-Regulatory Interactions Between Long Non-coding RNAs and Proximal Coding Genes Based on Correlative Analysis Across Diverse Human Tumors

Antisense transcripts and other long non-coding RNAs are pervasive in mammalian cells, and some of these molecules have been proposed to regulate proximal protein-coding genes in cis. For example, non-coding transcription can contribute to inactivation of tumor suppressor genes in cancer, and antisense transcripts have been implicated in the epigenetic inactivation of imprinted genes. However, our knowledge is still limited and more such regulatory interactions likely await discovery. Here, we make use of available gene expression data from a large compendium of human tumors to generate hypotheses regarding non-coding-to-coding cis-regulatory relationships with emphasis on negative associations, as these are less likely to arise for reasons other than cis-regulation. We document a large number of possible regulatory interactions, including 193 coding/non-coding pairs that show expression patterns compatible with negative cis-regulation. Importantly, by this approach we capture several known cases, and many of the involved coding genes have known roles in cancer. Our study provides a large catalog of putative non-coding/coding cis-regulatory pairs that may serve as a basis for further experimental validation and characterization.

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TAS2R38 Predisposition to Bitter Taste Associated with Differential Changes in Vegetable Intake in Response to a Community-Based Dietary Intervention

Although vegetable consumption associates with decreased risk for a variety of diseases, few Americans meet dietary recommendations for vegetable intake. TAS2R38 encodes a taste receptor that confers bitter taste sensing from chemicals found in some vegetables. Common polymorphisms in TAS2R38 lead to coding substitutions that alter receptor function and result in the loss of bitter taste perception. Our study examined whether bitter taste perception TAS2R38 diplotypes associated with vegetable consumption in participants enrolled in either an enhanced or a minimal nutrition counseling intervention. DNA was isolated from the peripheral blood cells of study participants (N = 497) and analyzed for polymorphisms. Vegetable consumption was determined using the Block Fruit and Vegetable screener. We tested for differences in the frequency of vegetable consumption between intervention and genotype groups over time using mixed effects models. Baseline vegetable consumption frequency did not associate with bitter taste diplotypes (P = 0.937), however after six months of the intervention, we observed an interaction between bitter taste diplotypes and time (P = 0.046). Participants in the enhanced intervention increased their vegetable consumption frequency (P = 0.020) and within this intervention group, the bitter non-tasters and intermediate-bitter tasters had the largest increase in vegetable consumption. In contrast, in the minimal intervention group, the bitter tasting participants reported a decrease in vegetable consumption. Bitter-non tasters and intermediate-bitter tasters increased vegetable consumption in either intervention more than those who perceive bitterness. Future precision medicine applications could consider genetic variation in bitter taste perception genes when designing dietary interventions.

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Whole Genome Sequence of an Edible and Potential Medicinal Fungus, Cordyceps guangdongensis

Cordyceps guangdongensis is an edible fungus which was approved as a novel food by the Chinese Ministry of Public Health in 2013. It also has a broad prospect of application in pharmaceutical industries, with many medicinal activities. In this study, the whole genome of C. guangdongensis GD15, a single spore isolate from a wild strain, was sequenced and assembled with Illumina and PacBio sequencing technology. The generated genome is 29.05 Mb in size, comprising nine scaffolds with an average GC content of 57.01%. It is predicted to contain a total of 9150 protein-coding genes. Sequence identification and comparative analysis indicated that the assembled scaffolds contained two complete chromosomes and four single-end chromosomes, showing a high level assembly. Gene annotation revealed a diversity of transposons that could contribute to the genome size and evolution. Besides, approximately 15.57% and 12.01% genes involved in metabolic processes were annotated by KEGG and COG respectively. Genes belonging to CAZymes accounted for 3.15% of the total genes. In addition, 435 transcription factors, involved in various biological processes, were identified. Among the identified transcription factors, the fungal transcription regulatory proteins (18.39%) and fungal-specific transcription factors (19.77%) represented the two largest classes of transcription factors. This genomic resource provided a new insight into better understanding the relevance of phenotypic characters and genetic mechanisms in C. guangdongensis.

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A Cloning-Free Method for CRISPR/Cas9-Mediated Genome Editing in Fission Yeast

The CRISPR/Cas9 system, which relies on RNA-guided DNA cleavage to induce site-specific DNA double-strand breaks, is a powerful tool for genome editing. This system has been successfully adapted for the fission yeast Schizosaccharomyces pombe by expressing Cas9 and the single-guide RNA (sgRNA) from a plasmid. In the procedures published to date, the cloning step that introduces a specific sgRNA target sequence into the plasmid is the most tedious and time-consuming. To increase the efficiency of applying the CRISPR/Cas9 system in fission yeast, we here developed a cloning-free procedure that uses gap repair in fission yeast cells to assemble two linear DNA fragments, a gapped Cas9-encoding plasmid and a PCR-amplified sgRNA insert, into a circular plasmid. Both fragments contain only a portion of the ura4 or bsdMX marker so that only the correctly assembled plasmid can confer uracil prototrophy or blasticidin resistance. We show that this gap-repair-based and cloning-free CRISPR/Cas9 procedure permits rapid and efficient point mutation knock-in, endogenous N-terminal tagging, and genomic sequence deletion in fission yeast.

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An RNAi Screen Identifies New Genes Required for Normal Morphogenesis of Larval Chordotonal Organs

The proprioceptive chordotonal organs (ChO) of a fly larva respond to mechanical stimuli generated by muscle contractions and consequent deformations of the cuticle. The ability of the ChO to sense the relative displacement of its epidermal attachment sites likely depends on the correct mechanical properties of the accessory (cap and ligament) and attachment cells that connect the sensory unit (neuron and scolopale cell) to the cuticle. The genetic programs dictating the development of ChO cells with unique morphologies and mechanical properties are largely unknown. Here we describe an RNAi screen that focused on the ChO's accessory and attachment cells and was performed in 2nd instar larvae to allow for phenotypic analysis of ChOs that had already experienced mechanical stresses during larval growth. Nearly one thousand strains carrying RNAi constructs targeting more than 500 candidate genes were screened for their effects on ChO morphogenesis. The screen identified 31 candidate genes whose knockdown within the ChO lineage disrupted various aspects of cell fate determination, cell differentiation, cellular morphogenesis and cell-cell attachment. Most interestingly, one phenotypic group consisted of genes that affected the response of specific ChO cell types to developmental organ stretching, leading to abnormal pattern of cell elongation. The 'cell elongation' group included the transcription factors Delilah and Stripe, implicating them for the first time in regulating the response of ChO cells to developmental stretching forces. Other genes found to affect the pattern of ChO cell elongation, such as αTub85E, β1Tub56D, Tbce, CCT8, mys, Rac1 and shot, represent putative effectors that link between cell-fate determinants and the realization of cell-specific mechanical properties.

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Functional Analysis of Hif1 Histone Chaperone in Saccharomyces cerevisiae

The Hif1 protein in the yeast Saccharomyces cerevisie is an evolutionarily conserved H3/H4-specific chaperone and a subunit of the nuclear Hat1 complex that catalyzes the acetylation of newly synthesized histone H4. Hif1, as well as its human homolog NASP, has been implicated in an array of chromatin-related processes including histone H3/H4 transport, chromatin assembly and DNA repair. In this study, we elucidate the functional aspects of Hif1. Initially we establish the wide distribution of Hif1 homologs with an evolutionarily conserved pattern of four tetratricopeptide repeats (TPR) motifs throughout the major fungal lineages and beyond. Subsequently, through targeted mutational analysis, we demonstrate that the acidic region that interrupts the TPR2 is essential for Hif1 physical interactions with the Hat1/Hat2-complex, Asf1, and with histones H3/H4. Furthermore, we provide evidence for the involvement of Hif1 in regulation of histone metabolism by showing that cells lacking HIF1 are both sensitive to histone H3 over expression, as well as synthetic lethal with a deletion of histone mRNA regulator LSM1. We also show that a basic patch present at the extreme C-terminus of Hif1 is essential for its proper nuclear localization. Finally, we describe a physical interaction with a transcriptional regulatory protein Spt2, possibly linking Hif1 and the Hat1 complex to transcription-associated chromatin reassembly. Taken together, our results provide novel mechanistic insights into Hif1 functions and establish it as an important protein in chromatin-associated processes.

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The Atypical Rho GTPase CHW-1 Works with SAX-3/Robo To Mediate Axon Guidance in Caenorhabditis elegans

During development, neuronal cells extend an axon toward their target destination in response to a cue to form a properly functioning nervous system. Rho proteins, Ras-related small GTPases that regulate cytoskeletal organization and dynamics, cell adhesion, and motility, are known to regulate axon guidance. Despite extensive knowledge about canonical Rho proteins (RhoA/Rac1/Cdc42), little is known about the Caenorhabditis elegans (C. elegans) atypical Cdc42-like family members CHW-1 and CRP-1 in regards to axon pathfinding and neuronal migration. chw-1(Chp/Wrch) encodes a protein that resembles human Chp (Wrch-2/RhoV) and Wrch-1 (RhoU), and crp-1 encodes for a protein that resembles TC10 and TCL. Here, we show that chw-1 works redundantly with crp-1 and cdc-42 in axon guidance. Furthermore, proper levels of chw-1 expression and activity are required for proper axon guidance. When examining CHW-1 GTPase mutants, we found that the native CHW-1 protein is likely partially activated, and mutations at a conserved residue (position 12 using Ras numbering, position 18 in CHW-1) alter axon guidance and neural migration. Additionally, we showed that chw-1 genetically interacts with the guidance receptor sax-3 in PDE neurons. Finally, in VD/DD motor neurons, chw-1 works downstream of sax-3 to control axon guidance. In summary, this is the first study implicating the atypical Rho GTPases chw-1 and crp-1 in axon guidance. Furthermore, this is the first evidence of genetic interaction between chw-1 and the guidance receptor sax-3. These data suggest that chw-1 is likely acting downstream and/or in parallel to sax-3 in axon guidance.

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RNA Polymerase II Transcription Attenuation at the Yeast DNA Repair Gene, DEF1, Involves Sen1-Dependent and Polyadenylation Site-Dependent Termination

Termination of RNA Polymerase II (Pol II) activity serves a vital cellular role by separating ubiquitous transcription units and influencing RNA fate and function. In the yeast Saccharomyces cerevisiae, Pol II termination is carried out by cleavage and polyadenylation factor (CPF-CF) and Nrd1-Nab3-Sen1 (NNS) complexes, which operate primarily at mRNA and non-coding RNA genes, respectively. Premature Pol II termination (attenuation) contributes to gene regulation, but there is limited knowledge of its prevalence and biological significance. In particular, it is unclear how much crosstalk occurs between CPF-CF and NNS complexes and how Pol II attenuation is modulated during stress adaptation. In this study, we have identified an attenuator in the DEF1 DNA repair gene, which includes a portion of the 5'-untranslated region (UTR) and upstream open reading frame (ORF). Using a plasmid-based reporter gene system, we conducted a genetic screen of 14 termination mutants and their ability to confer Pol II read-through defects. The DEF1 attenuator behaved as a hybrid terminator, relying heavily on CPF-CF and Sen1 but without Nrd1 and Nab3 involvement. Our genetic selection identified 22 cis-acting point mutations that clustered into four regions, including a polyadenylation site efficiency element that genetically interacts with its cognate binding-protein Hrp1. Outside of the reporter gene context, a DEF1 attenuator mutant increased mRNA and protein expression, exacerbating the toxicity of a constitutively active Def1 protein. Overall, our data support a biologically significant role for transcription attenuation in regulating DEF1 expression, which can be modulated during the DNA damage response.

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Genetic Loci Governing Androgenic Capacity in Perennial Ryegrass (Lolium perenne L.)

Immature pollen can be induced to switch developmental pathways from gametogenesis to embryogenesis and subsequently regenerate into homozygous, diploid plants. Such androgenic production of doubled haploids is particularly useful for species where inbreeding is hampered by effective self-incompatibility systems. Therefore, increasing the generally low androgenic capacity of perennial ryegrass (Lolium perenne L.) germplasm would enable the efficient production of homozygous plant material, so that a more effective exploitation of heterosis through hybrid breeding schemes can be realized. Here, we present the results of a genome-wide association study in a heterozygous, multiparental population of perennial ryegrass (n = 391) segregating for androgenic capacity. Genotyping-by-sequencing was used to interrogate gene- dense genomic regions and revealed over 1,100 polymorphic sites. Between one and 10 quantitative trait loci (QTL) were identified for anther response, embryo and total plant production, green and albino plant production and regeneration. Most traits were under polygenic control, although a major QTL on linkage group 5 was associated with green plant regeneration. Distinct genetic factors seem to affect green and albino plant recovery. Two intriguing candidate genes, encoding chromatin binding domains of the developmental phase transition regulator, Polycomb Repressive Complex 2, were identified. Our results shed the first light on the molecular mechanisms behind perennial ryegrass microspore embryogenesis and enable marker-assisted introgression of androgenic capacity into recalcitrant germplasm of this forage crop of global significance.

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Rapid Integration of Multi-copy Transgenes Using Optogenetic Mutagenesis in Caenorhabditis elegans

Stably transmitted transgenes are indispensable for labeling cellular components and manipulating cellular functions. In Caenorhabditis elegans, transgenes are generally generated as inheritable multi-copy extrachromosomal arrays, which can be stabilized in the genome through a mutagenesis-mediated integration process. Standard methods to integrate extrachromosomal arrays primarily use protocols involving ultraviolet light plus trimethylpsoralen or gamma- or X-ray irradiation, which are laborious and time-consuming. Here, we describe a one-step integration method, following germline-mutagenesis induced by mini Singlet Oxygen Generator (miniSOG). Upon blue light treatment, miniSOG tagged to histone (Histone-miniSOG) generates reactive oxygen species (ROS) and induces heritable mutations, including DNA double-stranded breaks. We demonstrate that we can bypass the need to first establish extrachromosomal transgenic lines by coupling microinjection of desired plasmids with blue light illumination on Histone-miniSOG worms to obtain integrants in the F3 progeny. We consistently obtained more than one integrant from 12 injected animals in two weeks. This optogenetic approach significantly reduces the amount of time and labor for transgene integration. Moreover, it enables to generate stably expressed transgenes that cause toxicity in animal growth.

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Accounting for Genotype-by-Environment Interactions and Residual Genetic Variation in Genomic Selection for Water-Soluble Carbohydrate Concentration in Wheat

Abiotic stress tolerance traits are often complex and recalcitrant targets for conventional breeding improvement in many crop species. This study evaluated the potential of genomic selection to predict water-soluble carbohydrate concentration (WSCC), an important drought tolerance trait, in wheat under field conditions. A panel of 358 varieties and breeding lines constrained for maturity was evaluated under rainfed and irrigated treatments across two locations and two years. Whole-genome marker profiles and factor analytic mixed models were used to generate genomic estimated breeding values (GEBVs) for specific environments and environment groups. Additive genetic variance was smaller than residual genetic variance for WSCC, such that genotypic values were dominated by residual genetic effects rather than additive breeding values. As a result, GEBVs were not accurate predictors of genotypic values of the extant lines, but GEBVs should be reliable selection criteria to choose parents for intermating to produce new populations. The accuracy of GEBVs for untested lines was sufficient to increase predicted genetic gain from genomic selection per unit time compared to phenotypic selection if the breeding cycle is reduced by half by the use of GEBVs in off-season generations. Further, genomic prediction accuracy depended on having phenotypic data from environments with strong correlations with target production environments to build prediction models. By combining high-density marker genotypes, stress-managed field evaluations, and mixed models that model simultaneously covariances among genotypes and covariances of complex trait performance between pairs of environments, we were able to train models with good accuracy to facilitate genetic gain from genomic selection.

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A High-Quality Reference Genome for the Invasive Mosquitofish Gambusia affinis Using a Chicago Library

The western mosquitofish, Gambusia affinis, is a freshwater poecilid fish native to the southeastern United States but with a global distribution due to widespread human introduction. Gambusia affinis has been used as a model species for a broad range of evolutionary and ecological studies. We sequenced the genome of a male G. affinis to facilitate genetic studies in diverse fields including invasion biology and comparative genetics. We generated Illumina short read data from paired-end libraries and in vitro proximity-ligation libraries. We obtained 54.9x coverage, N50 contig length of 17.6 kb, and N50 scaffold length of 6.65 Mb. Compared to two other species in the Poeciliidae family, G. affinis has slightly fewer genes that have shorter total, exon, and intron length on average. Using a set of universal single-copy orthologs in fish genomes, we found 95.5% of these genes were complete in the G. affinis assembly. The number of transposable elements in the G. affinis assembly is similar to those of closely related species. The high-quality genome sequence and annotations we report will be valuable resources for scientists to map the genetic architecture of traits of interest in this species.

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Subtle Perturbations of the Maize Methylome Reveal Genes and Transposons Silenced by Chromomethylase or RNA-Directed DNA Methylation Pathways

DNA methylation is a chromatin modification that can provide epigenetic regulation of gene and transposon expression. Plants utilize several pathways to establish and maintain DNA methylation in specific sequence contexts. The chromomethylase (CMT) genes maintain CHG (where H = A, C or T) methylation. The RNA-directed DNA methylation (RdDM) pathway is important for CHH methylation. Transcriptome analysis was performed in a collection of Zea mays lines carrying mutant alleles for CMT or RdDM-associated genes. While the majority of the transcriptome was not affected, we identified sets of genes and transposon families sensitive to context-specific decreases in DNA methylation in mutant lines. Many of the genes that are up-regulated in CMT mutant lines have high levels of CHG methylation, while genes that are differentially expressed in RdDM mutants are enriched for having nearby mCHH islands, implicating context-specific DNA methylation in the regulation of expression for a small number of genes. Many genes regulated by CMTs exhibit natural variation for DNA methylation and transcript abundance in a panel of diverse inbred lines. Transposon families with differential expression in the mutant genotypes show few defining features, though several families up-regulated in RdDM mutants show enriched expression in endosperm tissue, highlighting the potential importance for this pathway during reproduction. Taken together, our findings suggest that while the number of genes and transposon families whose expression is reproducibly affected by mild perturbations in context-specific methylation is small, there are distinct patterns for loci impacted by RdDM and CMT mutants.

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Phylogenetic and Phylogenomic Definition of Rhizopus Species

Phylogenomic approaches have the potential to improve confidence about the inter-relationships of species in the order Mucorales within the fungal tree of life. Rhizopus species are especially important as plant and animal pathogens and bioindustrial fermenters for food and metabolite production. A dataset of 192 orthologous genes was used to construct a phylogenetic tree of 21 Rhizopus strains, classified into four species isolated from habitats of industrial, medical and environmental importance. The phylogeny indicates that the genus Rhizopus consists of three major clades, with R. microsporus as the basal species and the sister lineage to R. stolonifer and two closely related species R. arrhizus and R. delemar. A comparative analysis of the mating type locus across Rhizopus reveals that its structure is flexible even between different species in the same genus, but shows similarities between Rhizopus and other mucoralean fungi. The topology of single-gene phylogenies built for two genes involved in mating is similar to the phylogenomic tree. Comparison of the total length of the genome assemblies showed that genome size varies by as much as threefold within a species and is driven by changes in transposable element copy numbers and genome duplications.

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Effect of Larval Nutrition on Maternal mRNA Contribution to the Drosophila Egg

Embryonic development begins under the control of maternal gene products, mRNAs and proteins that the mother deposits into the egg; the zygotic genome is activated some time later. Maternal control of early development is conserved across metazoans. Gene products contributed by mothers are critical to many early developmental processes, and set up trajectories for the rest of development. Maternal deposition of these factors is an often-overlooked aspect of parental investment. If the mother experiences challenging environmental conditions, such as poor nutrition, previous studies in Drosophila melanogaster have demonstrated a plastic response wherein these mothers may produce larger eggs to buffer the offspring against the same difficult environment. This additional investment can produce offspring that are more fit in the challenging environment. With this study, we ask whether D. melanogaster mothers who experience poor nutrition during their own development change their gene product contribution to the egg. We perform mRNA-Seq on eggs at a stage where all mRNAs are maternally derived, from mothers with different degrees of nutritional limitation. We find that nutritional limitation produces similar transcript changes at all degrees of limitation tested. Genes that have lower transcript abundance in nutritionally limited mothers are those involved in translation, which is likely one of the most energetically costly processes occurring in the early embryo. We find an increase in transcripts for transport and localization of macromolecules, and for the electron transport chain. The eggs produced by nutrition-limited mothers show a plastic response in mRNA deposition, which may better prepare the future embryo for development in a nutrition-limited environment.

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Stonewall and Brickwall: Two Partially Redundant Determinants Required for the Maintenance of Female Germline in Drosophila

Proper specification of germline stem cells (GSCs) in Drosophila ovaries depends on niche derived non-autonomous signaling and cell autonomous components of transcriptional machinery. Stonewall (Stwl), a MADF-BESS family protein, is one of the cell intrinsic transcriptional regulators involved in the establishment and/or maintenance of GSC fate in Drosophila ovaries. Here we report identification and functional characterization of another member of the same protein family, CG3838/ Brickwall (Brwl) with analogous functions. Loss of function alleles of brwl exhibit age dependent progressive degeneration of the developing ovarioles and loss of GSCs. Supporting the conclusion that the structural deterioration of mutant egg chambers is a result of apoptotic cell death, activated caspase levels are considerably elevated in brwl- ovaries. Moreover, as in the case of stwl mutants, on several instances, loss of brwl activity results in fusion of egg chambers and misspecification of the oocyte. Importantly, brwl phenotypes can be partially rescued by germline specific over-expression of stwl arguing for overlapping yet distinct functional capabilities of the two proteins. Taken together with our phylogenetic analysis, these data suggest that brwl and stwl likely share a common MADF-BESS ancestor and they are expressed in overlapping spatiotemporal domains to ensure robust development of the female germline.

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The Pseudokinase Domain of Saccharomyces cerevisiae Tra1 Is Required for Nuclear Localization and Incorporation into the SAGA and NuA4 Complexes

Tra1 is an essential component of the SAGA/SLIK and NuA4 complexes in S. cerevisiae, recruiting these co-activator complexes to specific promoters. As a PIKK family member, Tra1 is characterized by a C-terminal phosphoinositide 3-kinase (PI3K) domain. Unlike other PIKK family members (e.g., Tor1, Tor2, Mec1, Tel1), Tra1 has no demonstrable kinase activity. We identified three conserved arginine residues in Tra1 that reside proximal or within the cleft between the N- and C-terminal subdomains of the PI3K domain. To establish a function for Tra1's PI3K domain and specifically the cleft region, we characterized a tra1 allele where these three arginine residues are mutated to glutamine. The half-life of the Tra1$${}_{\hbox{ Q }3}$$ protein is reduced but its steady state level is maintained at near wild-type levels by a transcriptional feedback mechanism. The tra1$${}_{Q\mathit{3}}$$ allele results in slow growth under stress and alters the expression of genes also regulated by other components of the SAGA complex. Tra1$${}_{\hbox{ Q }3}$$ is less efficiently transported to the nucleus than the wild-type protein. Likely related to this, Tra1$${}_{\hbox{ Q }3}$$ associates poorly with SAGA/SLIK and NuA4. The ratio of Spt7SLIK to Spt7SAGA increases in the tra1$${}_{Q\mathit{3}}$$ strain and truncated forms of Spt20 become apparent upon isolation of SAGA/SLIK. Intragenic suppressor mutations of tra1$${}_{Q\mathit{3}}$$ map to the cleft region further emphasizing its importance. We propose that the PI3K domain of Tra1 is directly or indirectly important for incorporating Tra1 into SAGA and NuA4 and thus the biosynthesis and/or stability of the intact complexes.

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Mapping of Leaf Rust Resistance Genes and Molecular Characterization of the 2NS/2AS Translocation in the Wheat Cultivar Jagger

Winter wheat cultivar 'Jagger' was recently found to have an alien chromosomal segment 2NS that has Lr37, a gene conferring resistance against leaf rust caused by Puccinia triticina. The objective of this study was to map and characterize the gene(s) for seedling leaf rust resistance in Jagger. The recombinant inbred line (RIL) population of Jagger x '2174' was inoculated with leaf rust pathogen THBJG and BBBDB, and evaluated for infection type (IT) response. A major quantitative trait locus (QTL) for THBJG and BBBDB was coincidently mapped to chromosome arm 2AS, and the QTL accounted for 56.6–66.2% of total phenotypic variation in infection type (IT) response to THBJG, and 72.1–86.9% to BBBDB. The causal gene for resistance to these rust races was mapped to the 2NS segment in Jagger. The 2NS segment was located in a region of approximately 27.8 Mb starting from the telomere of chromosome arm 2AS, based on the sequences of the A genome in tetraploid wheat. The Lr17a gene on chromosome arm 2AS was delimited to 3.1 Mb in the genomic region, which was orthologous to the 2NS segment. Therefore, the Lr37 gene in the 2NS segment can be pyramided with other effective resistance genes, rather than Lr17a in wheat, to improve resistance to rust diseases.

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diploS/HIC: An Updated Approach to Classifying Selective Sweeps

Identifying selective sweeps in populations that have complex demographic histories remains a difficult problem in population genetics. We previously introduced a supervised machine learning approach, S/HIC, for finding both hard and soft selective sweeps in genomes on the basis of patterns of genetic variation surrounding a window of the genome. While S/HIC was shown to be both powerful and precise, the utility of S/HIC was limited by the use of phased genomic data as input. In this report we describe a deep learning variant of our method, diploS/HIC, that uses unphased genotypes to accurately classify genomic windows. diploS/HIC is shown to be quite powerful even at moderate to small sample sizes.

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Regulation of Global Transcription in Escherichia coli by Rsd and 6S RNA

In Escherichia coli, the sigma factor 70 directs RNA polymerase to transcribe growth-related genes, while 38 directs transcription of stress response genes during stationary phase. Two molecules hypothesized to regulate RNA polymerase are the protein Rsd, which binds to 70, and the non-coding 6S RNA which binds to the RNA polymerase-70 holoenzyme. Despite multiple studies, the functions of Rsd and 6S RNA remain controversial. Here we use RNA-Seq in five phases of growth to elucidate their function on a genome-wide scale. We show that Rsd and 6S RNA facilitate 38 activity throughout bacterial growth, while 6S RNA also regulates widely different genes depending upon growth phase. We discover novel interactions between 6S RNA and Rsd and show widespread expression changes in a strain lacking both regulators. Finally, we present a mathematical model of transcription which highlights the crosstalk between Rsd and 6S RNA as a crucial factor in controlling sigma factor competition and global gene expression.

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The effects of codon usage on the formation of secondary structures of nucleocapsid protein of peste des petits ruminants virus


The nucleocapsid (N) protein of peste des petits ruminants virus (PPRV) with a conserved amino acid usage pattern plays an important role in viral replication. The primary objective of this study was to estimate roles of synonymous codon usages of PPRV N gene and tRNA abundances of host in the formation of secondary structure of N protein. The potential effects of synonymous codon usages of N gene and tRNA abundances of host on shaping different folding units (α-helix, β-strand and the coil) in N protein were estimated, based on the information about the modeling secondary structure of PPRV N protein. The synonymous codon usage bias was found in different folding units in PPRV N protein. To better understand the role of translation speed caused by variant tRNA abundances in shaping the specific folding unit in N protein, we modeled the changing trends of tRNA abundance at the transition boundaries from one folding unit to another folding unit (β-strand → coil, coil → β-strand, α-helix → coil, coil → α-helix). The obvious fluctuations of tRNA abundance were identified at the two transition boundaries (β-strand → coil and coil → β-strand) in PPRV N protein. Our findings suggested that viral synonymous codon usage bias and cellular tRNA abundance variation might have potential effects on the formation of secondary structure of PPRV N protein.

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Cognitive reappraisal of snake and spider pictures: An event-related potentials study

Publication date: Available online 30 May 2018
Source:International Journal of Psychophysiology
Author(s): Sandra J.E. Langeslag, Jan W. van Strien
Fear of snakes and spiders are common animal phobias. Emotion regulation can change the response to emotional stimuli, including snakes and spiders. It is well known that emotion regulation modulates the late positive potential (LPP), which reflects sustained motivated attention. However, research concerning the effect of emotion regulation on the early posterior negativity (EPN), which reflects early selective attention, is scarce. The present research question was whether the EPN and LPP amplitudes are modulated by regulation of emotional responses to snake and spider stimuli. Emotion up- and down-regulation were expected to enhance and reduce the LPP amplitude, respectively, but emotion regulation was not expected to modulate the EPN amplitude. Female participants passively viewed snake, spider, and bird pictures, and up- and down-regulated their emotional responses to the snake and spider pictures using self-focused reappraisal, while their electroencephalogram was recorded. There were EPNs for snakes and spiders vs. birds, as well as for snakes vs. spiders. The LPP amplitude tended to be enhanced for snakes and spiders compared to birds. Most importantly, the LPP amplitude was larger in the up-regulate than in the down-regulate condition for both snakes and spiders, but there was no evidence that the EPN amplitude was modulated by emotion regulation. This suggests that emotion regulation modulated sustained motivated attention, but not early selective attention, to snakes and spiders. The findings are in line with the notion that the emotional modulation of the EPN is more automatic than the emotional modulation of the LPP.

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Genotype imputation for Han Chinese population using Haplotype Reference Consortium as reference


Genotype imputation is now routinely performed in genomic analysis. Reference panel size, that is, the number of haplotypes in the reference panel, has been well established to be one major driving factor of imputation accuracy. For that reason, huge efforts have been made worldwide to provide large reference panels, with the Haplotype Reference Consortium (HRC) being currently the largest available in the public domain. The imputation performance of HRC, whose major samples are Europeans, has been mainly evaluated in Europeans. We conducted whole-genome genotype imputation on two independent genome-wide genotyping datasets, one with 1000 European samples and the other with 1000 Han Chinese samples. We compared the results obtained using HRC with those using Phase III of the 1000 Genomes Project (1000G) reference panel. For the European dataset, using HRC improved imputation quality, especially for rare variants with minor allele-frequency (MAF) < 0.1%. However, 1000G demonstrates better performance in the Han Chinese dataset, in both imputation quality and number of well-imputed variants. We validated the performance of 1000G reference panel in a second, independent cohort of Han Chinese (N = 2402). Our study showcases the limitations of HRC for Han Chinese populations, strongly suggesting the necessity of building population-specific reference panels.

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Τετάρτη, 30 Μαΐου 2018

Choosing Wisely in pediatric anesthesia: An interpretation from the German Scientific Working Group of Paediatric Anaesthesia (WAKKA)

Pediatric Anesthesia, EarlyView.

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Whole-genome RNAi screen identifies methylation-related genes influencing lipid metabolism in Caenorhabditis elegans


Publication date: Available online 30 May 2018
Source:Journal of Genetics and Genomics
Author(s): Xiaotong Zhu, Yangli Liu, Hong Zhang, Pingsheng Liu
Lipid droplets (LDs) are highly conserved multifunctional cellular organelles and aberrant lipid storage in LDs can lead to many metabolic diseases. However, the molecular mechanisms governing lipid dynamic changes remain elusive, and the high-throughput screen of genes influencing LD morphology was limited by lacking specific LD marker proteins in the powerful genetic tool Caenorhabditis elegans. In this study, we established a new method to conduct whole-genome RNAi screen using LD resident protein DHS-3 as a LD marker, and identified 78 genes involved in significant LD morphologic changes. Among them, mthf-1, as well as a series of methylation-related genes, was found dramatically influencing lipid metabolism. SREBP-1 and SCD1 homologs in C. elegans were involved in the lipid metabolic change of mthf-1(RNAi) worms, and the regulation of ATGL-1 also contributed to it by decreasing triacylglycerol (TAG) hydrolysis. Overall, this study not only identified important genes involved in LD dynamics, but also provided a new tool for LD study using C. elegans, with implications for the study of lipid metabolic diseases.

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CORL Expression in the Drosophila Central Nervous System Is Regulated by Stage Specific Interactions of Intertwined Activators and Repressors

CORL proteins (SKOR in mice and Fussel in humans) are a subfamily of central nervous system (CNS) specific proteins related to Sno/Ski oncogenes. Their developmental and homeostatic roles are largely unknown. We previously showed that Drosophila CORL (dCORL; fussel in Flybase) functions between the Activin receptor Baboon and Ecdysone Receptor-B1 (EcR-B1) activation in mushroom body neurons of third instar larval brains. To better understand dCORL regulation and function we generated a series of reporter genes. We examined the embryonic and larval CNS and found that dCORL is regulated by stage specific interactions between intertwined activators and repressors spanning numerous reporters. The reporter AH.lacZ, which contains sequences 7-11kb upstream of dCORL exon1, reflects dCORL brain expression at all stages. Surprisingly, AH.lacZ is not present in EcR-B1 expressing mushroom body neurons. In larvae AH.lacZ is coexpressed with Elav and the transcription factor Drifter as well as in dILP2 insulin producing cells of the pars intercerebralis. The presence of dCORL in insulin producing cells suggests that dCORL functions non-autonomously in the regulation of EcR-B1 mushroom body activation via the modulation of insulin signaling. Overall, the high level of sequence conservation seen in all CORL/SKOR/Fussel family members and their common CNS-specificity suggest that similarly complex regulation and a potential function in insulin signaling are associated with SKOR/Fussel proteins in mammals.

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Bayesian Networks Predict Neuronal Transdifferentiation

We employ the language of Bayesian networks to systematically construct gene-regulation topologies from deep-sequencing single-nucleus RNA-Seq data for human neurons. From the perspective of the cell-state potential landscape, we identify attractors that correspond closely to different neuron subtypes. Attractors are also recovered for cell states from an independent data set confirming our models accurate description of global genetic regulations across differing cell types of the neocortex (not included in the training data). Our model recovers experimentally confirmed genetic regulations and community analysis reveals genetic associations in common pathways. Via a comprehensive scan of all theoretical three-gene perturbations of gene knockout and overexpression, we discover novel neuronal trans-differrentiation recipes (including perturbations of SATB2, GAD1, POU6F2 and ADARB2) for excitatory projection neuron and inhibitory interneuron subtypes.

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A Collection of Transgenic Medaka Strains for Efficient Site-Directed Transgenesis Mediated by phiC31 Integrase

Genetic analysis is facilitated by the efficient production of transgenic strains expressing a DNA of interest as a single copy at a designated chromosomal location. However, technical progress toward this goal in medaka fish (Oryzias latipes), a vertebrate model organism, has been slow. It is well known that phiC31 integrase enables efficient site-directed transgenesis by catalyzing the recombination of an attP DNA motif in a host genome with an attB motif in a targeting vector. This system was pioneered in medaka using the Sleeping Beauty transposon system, and the attP site was established at three chromosomal locations. However, this number appeared insufficient with regard to genetic linkage between the attP-landing site and a genetically modified locus of interest. Here, to establish a collection of transgenic strains of medaka, we introduced an attP motif into the medaka genome using the Ac/Ds maize transposon system and established 12 independent transgenic strains harboring a single copy of the attP motif in at least 11 of the 24 medaka chromosomes. We designed an attB-targeting vector that was integrated efficiently and precisely into the attP-landing site, and with which the DNA of interest was efficiently transmitted to germline cells. Extraneous sequences in the integrants derived from the bacterial backbone of the attB-targeting vector as well as a transgenic fluorescence marker present in the attP-landing site were removable through flippase-mediated recombination. Further, an advanced targeting vector with a heart-specific recombination marker served as a useful tool for easily screening phiC31 integrase-mediated recombinant G0 embryos, leading to the efficient establishment of transgenic strains. Thus, our resources advance genetic research in medaka.

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Upregulation of dNTP Levels After Telomerase Inactivation Influences Telomerase-Independent Telomere Maintenance Pathway Choice in Saccharomyces cerevisiae

In 10-15% of cancers, telomere length is maintained by a telomerase-independent, recombination-mediated pathway called alternative lengthening of telomeres (ALT). ALT mechanisms were first seen, and have been best studied, in telomerase-null Saccharomyces cerevisiae cells called "survivors". There are two main types of survivors. Type I survivors amplify Y' subtelomeric elements while type II survivors, similar to the majority of human ALT cells, amplify the terminal telomeric repeats. Both types of survivors require Rad52, a key homologous recombination protein, and Pol32, a non-essential subunit of DNA polymerase . A number of additional proteins have been reported to be important for either type I or type II survivor formation, but it is still unclear how these two pathways maintain telomeres. In this study, we performed a genome-wide screen to identify novel genes that are important for the formation of type II ALT-like survivors. We identified 23 genes that disrupt type II survivor formation when deleted. 17 of these genes had not been previously reported to do so. Several of these genes (DUN1, CCR4, and MOT2) are known to be involved in the regulation of dNTP levels. We find that dNTP levels are elevated early after telomerase inactivation and that this increase favors the formation of type II survivors.

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The Antitumor Mechanism of Paeonol on CXCL4/CXCR3-B Signals in Breast Cancer Through Induction of Tumor Cell Apoptosis

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.

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Bile acids and FXR in functional gastrointestinal disorders

Functional Gastrointestinal Disorders (FGIDs), such as Irritable Bowel Syndrome (IBS) and Chronic Constipation (CC), are commonly diagnosed conditions in clinical practice which create a substantial global burden. Since the Farnesoid X Receptor (FXR) and bile acids (BAs) are responsible for maintaining homeostasis in the GI tract, any disturbances in the expression of FXR or the composition of BAs may contribute to the development of the GI symptoms. Alterations in the mechanism of action of FXR directly affect the BAs pool and account for increased intestinal permeability and changes in abundance and diversity of gut microbiota leading to intestinal dysmotility.

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Long-term Follow-up in Adults with Coeliac Disease: Predictors and Effect on Health Outcomes

Guidelines recommend regular follow-up in coeliac disease, but effect of this on long-term outcomes remains unclear.

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Meta-analysis comparing the efficacy and adverse events of biologics and thiopurines for Crohn's Disease after surgery for ulcerative colitis

Long-term inflammatory complications of IPAA include Crohn's Disease (CD) or "CD-like" (CDL) condition. We performed a meta-analysis to evaluate the efficacy of anti-tumor necrosis factor (anti-TNF) with or without immunomodulator (IM) therapy in this group of patients.

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Antibiotic Resistance in Czech Urban Wastewater Treatment Plants: Microbial and Molecular Genetic Characterization

Microbial Drug Resistance, Ahead of Print.

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Impact of Franseen needle on rapid onsite evaluation and histological examination following endoscopic ultrasonography-guided tissue acquisition in patients with splenic malignant lymphoma

Publication date: Available online 30 May 2018
Source:Arab Journal of Gastroenterology
Author(s): Tesshin Ban, Hiroshi Kawakami, Yoshimasa Kubota, Yuichiro Sato
Rapid onsite evaluation (ROSE) following endoscopic ultrasonography (EUS)-guided fine-needle aspiration contributes to the establishment of a diagnosis for various organs. Newly designed three-plane symmetric needles for EUS-guided fine-needle biopsy (EUS-FNB), such as the Franseen needle, have been developed to enable histological core tissue acquisition. However, EUS-guided tissue acquisition for hypervascular splenic lesions remains challenging. Tissue acquisition in cases of splenic malignant lymphoma by using a conventional needle with multiple strokes and suction may result in indeterminate ROSE due to blood contamination and tiny fragments of lymphoma tissue, whereas EUS-FNB by using the Franseen needle with a minimal number of strokes with suction demonstrates qualified specimens for the ROSE as well as histological examination. For splenic malignant lymphomas, EUS-FNB by using the Franseen needle with a limited number of strokes may facilitate qualified specimen acquisition.

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The Cost Effectiveness of Minimally Invasive Spine Surgery in the Treatment of Adult Degenerative Scoliosis: A Comparison of Trans-psoas and Open Techniques

: Surgical treatment improves quality of life in patients with adult degenerative scoliosis (ADS). However, open ADS surgeries are complex, large magnitude operations associated with a high rate of complications. The lateral trans-psoas interbody fusion technique is a less invasive alternative to open ADS surgery, but less invasive techniques tend to be more expensive. The objective of this study was to evaluate the cost-effectiveness of the trans-psoas technique for patients with ADS over a 12-month time horizon from a public payer perspective.

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The impact of prophylactic intraoperative vancomycin powder on microbial profile, antibiotic regimen, length of stay, and reoperation rate in elective spine surgery

: There is growing concern that the microbial profile of surgical site infection (SSI) in the setting of prophylactic vancomycin powder may favor more resistant and uncommon organisms.

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Elevated Glycohemoglobin HbA1c is Associated with Low Back Pain in Non-Overweight Diabetics

Low back pain (LBP) is a common complaint in clinical practice of multifactorial origin. Although obesity has been thought to contribute to LBP primarily by altering the distribution of mechanical loads on the spine, the additional contribution of obesity-related conditions such as diabetes mellitus (DM) to LBP has not been thoroughly examined.

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3D-Printed Poly(ɛ-caprolactone)/Graphene Scaffolds Activated with P1-Latex Protein for Bone Regeneration

3D Printing and Additive Manufacturing, Ahead of Print.

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Ketamine Anesthesia Does Not Improve Depression Scores in Electroconvulsive Therapy: A Randomized Clinical Trial

Background: Although interest in ketamine use during electroconvulsive therapy (ECT) has increased, studies have been equivocal with regard to its efficacy. The aims of this clinical trial were to evaluate ketamine's antidepressive effects in ECT as a primary anesthetic, determine ketamine's tolerability when compared with standard anesthesia, and determine if plasma brain-derived neurotrophic factor (BDNF) is necessary for treatment response. Materials and Methods: Adults meeting criteria for treatment-resistant depression undergoing index course ECT received either methohexital (1 to 2 mg/kg) or ketamine (1 to 2 mg/kg) anesthesia in this dual-arm double-blinded randomized clinical trial (NCT02752724). The primary outcome of this study is change in depression questionnaire scores before and after ECT. Seizure data, depression severity using self-reported and clinician-assessed questionnaires, cognitive scoring, and plasma BDNF concentrations were obtained before and after completion of ECT. Results: There were no differences in seizure lengths, hemodynamics, or seizure stimuli between the ketamine (n=23;138 ECTs) and methohexital (n=27;159 ECTs) groups. Depression scores improved similarly after ECT in both groups. In the methohexital group, 15% of patients failed to achieve adequate seizures and were switched to ketamine and 26% were converted to bilateral ECT stimulus, whereas all ketamine patients achieved adequate seizures and only 4% required bilateral stimulus. Plasma BDNF increased after ECT only in the ketamine group. Conclusions: Our data show that ketamine does not significantly improve depression when compared with methohexital as a single induction agent for ECT, increases serum BDNF and does not increase rates of post-ECT agitation. Ketamine use in ECT may have some benefits for some patients that are not captured through standard depression assessment questionnaires alone. This work was supported in part by a Pilot Project Award #850 from the United States Department of Veterans Affairs. The content does not represent the views of the United States Department of Veterans Affairs or the United States Government. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors have no conflicts of interest to disclose. Address correspondence to: Charles William Carspecken, MD, MSc, MBA, Department of Anesthesiology and Critical Care, University of Pennsylvania, Hospital of the University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104 (e-mail: charles.carspecken@uphs.upenn.edu). Received March 2, 2018 Accepted April 23, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

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Efficacy of Malignant Hyperthermia Association of the United States–Recommended Methods of Preparation for Malignant Hyperthermia-Susceptible Patients Using Dräger Zeus Anesthesia Workstations and Associated Costs

BACKGROUND: The objective of this study was to assess the efficacy and cost of Malignant Hyperthermia Association of the United States–recommended methods for preparing Dräger Zeus anesthesia workstations (AWSs) for the malignant hyperthermia-susceptible patient. METHODS: We studied washout profiles of sevoflurane, isoflurane, and desflurane in 3 Zeus AWS following 3 preparation methods. AWS was primed with 1.2 minimum alveolar concentration anesthetic for 2 hours using 2 L/min fresh gas flow, 500 mL tidal volume, and 12/min respiratory rate. Two phases of washout were performed: high flow (10 L/min) until anesthetic concentration was

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What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome

Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-α-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy. Accepted for publication April 16, 2018. Funding: Institutional and/or departmental. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to W. Jonathan Dunkman, MD, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to william.dunkman@duke.edu. © 2018 International Anesthesia Research Society

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Automated Assessment of Existing Patient’s Revised Cardiac Risk Index Using Algorithmic Software

BACKGROUND: Previous work in the field of medical informatics has shown that rules-based algorithms can be created to identify patients with various medical conditions; however, these techniques have not been compared to actual clinician notes nor has the ability to predict complications been tested. We hypothesize that a rules-based algorithm can successfully identify patients with the diseases in the Revised Cardiac Risk Index (RCRI). METHODS: Patients undergoing surgery at the University of California, Los Angeles Health System between April 1, 2013 and July 1, 2016 and who had at least 2 previous office visits were included. For each disease in the RCRI except renal failure—congestive heart failure, ischemic heart disease, cerebrovascular disease, and diabetes mellitus—diagnosis algorithms were created based on diagnostic and standard clinical treatment criteria. For each disease state, the prevalence of the disease as determined by the algorithm, International Classification of Disease (ICD) code, and anesthesiologist's preoperative note were determined. Additionally, 400 American Society of Anesthesiologists classes III and IV cases were randomly chosen for manual review by an anesthesiologist. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve were determined using the manual review as a gold standard. Last, the ability of the RCRI as calculated by each of the methods to predict in-hospital mortality was determined, and the time necessary to run the algorithms was calculated. RESULTS: A total of 64,151 patients met inclusion criteria for the study. In general, the incidence of definite or likely disease determined by the algorithms was higher than that detected by the anesthesiologist. Additionally, in all disease states, the prevalence of disease was always lowest for the ICD codes, followed by the preoperative note, followed by the algorithms. In the subset of patients for whom the records were manually reviewed, the algorithms were generally the most sensitive and the ICD codes the most specific. When computing the modified RCRI using each of the methods, the modified RCRI from the algorithms predicted in-hospital mortality with an area under the receiver operating characteristic curve of 0.70 (0.67–0.73), which compared to 0.70 (0.67–0.72) for ICD codes and 0.64 (0.61–0.67) for the preoperative note. On average, the algorithms took 12.64 ± 1.20 minutes to run on 1.4 million patients. CONCLUSIONS: Rules-based algorithms for disease in the RCRI can be created that perform with a similar discriminative ability as compared to physician notes and ICD codes but with significantly increased economies of scale. Accepted for publication March 5, 2018. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. I. S. Hofer and A. Mahajan are working with counsel to patent the algorithms for the diseases described in this article. Reprints will not be available from the authors. Address correspondence to Ira S. Hofer, MD, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at University of California, Los Angeles, 757 Westwood Plaza, Los Angeles, CA 90095. Address e-mail to ihofer@mednet.ucla.edu. © 2018 International Anesthesia Research Society

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Pain Medicine Board Review

No abstract available

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Assessing the Association Between Blood Loss and Postoperative Hemoglobin After Cesarean Delivery: A Prospective Study of 4 Blood Loss Measurement Modalities

BACKGROUND: Visual estimation and gravimetric methods are commonly used to quantify the volume of blood loss during cesarean delivery (CD). However, the correlation between blood loss and post-CD hemoglobin (Hb) is poorly studied, and it is unclear whether the correlation varies according to how blood loss is measured. METHODS: After obtaining Institutional Review Board approval, we performed a prospective study of 61 women undergoing CD to assess the relations between post-CD Hb and blood loss measured using 4 modalities: gravimetric blood loss measurement (gBL), visual blood loss estimation by a blinded obstetrician (oBL) and anesthesiologist (aBL), and the Triton System (tBL). Hb was measured preoperatively and within 10 minutes after CD. gBL was quantified as blood volume in a suction canister in addition to the weight of blood-soaked sponges. tBL was measured with the Triton System by photographing blood-soaked sponges and suction canister contents. To assess the relation between blood loss and post-CD Hb, we performed correlation analyses and compared the magnitude of the correlations across the 4 measurement modalities using William t test. A Bonferroni correction was set to identify a statistically significant correlation (P

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Intraoperative Methadone in Same-Day Ambulatory Surgery: A Randomized, Double-Blinded, Dose-Finding Pilot Study

BACKGROUND: Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery. METHODS: A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects. RESULTS: Median (interquartile range) methadone doses were 6 (5–6) and 9 (8–9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3–11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1–3.3; P

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Phentolamine Reverses Epinephrine-Enhanced Skin Antinociception of Dibucaine in Rats

BACKGROUND: The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture. METHODS: We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug–drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine. RESULTS: We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007–0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435–0.560] μmol) (P

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Mixing Studies in Patients With Prolonged Activated Partial Thromboplastin Time or Prothrombin Time

BACKGROUND: Patients presenting for surgery may have isolated or combined prolonged activated partial thromboplastin time (aPTT) and/or prothrombin time (PT). In patients not receiving anticoagulants or with no identifiable cause for abnormal clot formation, a mixing study is performed. The index of circulating anticoagulant (ICA) has been used to predict the presence of an inhibitor, usually a lupus anticoagulant. METHODS: We retrospectively reviewed the results of mixing studies performed at Northwestern Memorial Hospital, between January 1, 2010 and February 29, 2012. We determined the number of samples that normalized or remained prolonged, the clotting factors associated with prolonged test results, and the presence of coagulation inhibitors. We calculated the ICA in the samples with prolonged aPTT and PT to determine its ability to predict a lupus anticoagulant. The primary comparison of interest was the diagnostic utility of the ICA at cutoff values of 11% for predicting the presence of lupus anticoagulant. RESULTS: There were 269 mixing studies performed: 131 samples with prolonged aPTT; 95 with prolonged PT; and 43 with both prolonged aPTT and prolonged PT. Of the samples with a prolonged aPTT, 55 of 131 (42%) normalized, 36 of 131 (27%) partially corrected, and 40 of 131 (31%) remained prolonged. Thirty-three of 95 samples (35%) with prolonged PT normalized, while 62 of 95 (65%) remained prolonged. Eight of 43 (19%) mixing studies of patients with prolonged PT and aPTT normalized; the aPTT normalized, but the PT remained prolonged in 17 of 43 (39%); the PT normalized, but the aPTT remained prolonged in 7 of 43 (16%); and both tests remained prolonged in 11 of 43 (26%) samples. Prolongations in the aPTT were primarily associated with low activities of CF XII, while the majority of the prolongations in PT were secondary to low activities in CF VII. Combined prolongations were secondary to deficiencies in both the intrinsic and extrinsic as well as the common pathways. An ICA >11% had 100% (95% CI, 59%–100%) sensitivity, 53% (95% CI, 35%–70%) specificity, and 77% (95% CI, 62%–92%) accuracy in predicting the presence of lupus anticoagulant in patients with prolonged aPTT. CONCLUSIONS: Normalization of the aPTT and PT in a mixing study was associated with low clotting factor activity. The ICA may be helpful in predicting the presence of a lupus anticoagulant. As anesthesiologists take ownership of the perioperative surgical home, we need to understand the clinical implications of the results of mixing studies. Accepted for publication April 12, 2018. Funding: Departmental. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Honorio T. Benzon, MD, Northwestern University Feinberg School of Medicine, 251 E Huron, Feinberg Pavilion, 5–704, Chicago, IL 60611. Address e-mail to h-benzon@northwestern.edu. © 2018 International Anesthesia Research Society

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Opening the Black Box: Understanding the Science Behind Big Data and Predictive Analytics

Big data, smart data, predictive analytics, and other similar terms are ubiquitous in the lay and scientific literature. However, despite the frequency of usage, these terms are often poorly understood, and evidence of their disruption to clinical care is hard to find. This article aims to address these issues by first defining and elucidating the term big data, exploring the ways in which modern medical data, both inside and outside the electronic medical record, meet the established definitions of big data. We then define the term smart data and discuss the transformations necessary to make big data into smart data. Finally, we examine the ways in which this transition from big to smart data will affect what we do in research, retrospective work, and ultimately patient care. Accepted for publication March 22, 2018. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Ira S. Hofer, MD, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Los Angeles, CA 90095. Address e-mail to ihofer@mednet.ucla.edu. © 2018 International Anesthesia Research Society

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Reversing Cholinergic Bronchoconstriction by Common Inotropic Agents: A Randomized Experimental Trial on Isolated Perfused Rat Lungs

BACKGROUND: The ability of inotropic agents to alter airway reactivity and lung tissue mechanics has not been compared in a well-controlled experimental model. Therefore, we compared the potential to alter lung tissue viscoelasticity and bronchodilator effects of commonly used inotropic agents in an isolated perfused rat lung model. METHODS: After achieving steady state lung perfusion, sustained bronchoconstriction was induced by acetylcholine (ACh). Isolated rat lungs were then randomly allocated to 6 groups treated with either saline vehicle (n = 8) or incremental concentrations of inotropes (adrenaline, n = 8; dopamine, n = 7; dobutamine, n = 7; milrinone, n = 8; or levosimendan, n = 6) added to the whole-blood perfusate. Airway resistance (Raw), lung tissue damping (G), and elastance were measured under baseline conditions, during steady-state ACh-induced constriction and for each inotrope dose. RESULTS: No change in Raw was observed after addition of the saline vehicle. Raw was significantly lower after addition of dopamine (maximum difference [95% CI] of 29 [12–46]% relative to the saline control, P = .004), levosimendan (58 [39–77]%, P

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The Effect of Labor Epidural Analgesia on Breastfeeding Outcomes: A Prospective Observational Cohort Study in a Mixed-Parity Cohort

BACKGROUND: The effect of labor epidural analgesia (LEA) on successful breastfeeding has been evaluated in several studies with divergent results. We hypothesized that LEA would not influence breastfeeding status 6 weeks postpartum in women who intended to breastfeed in an environment that encourages breastfeeding. METHODS: In this prospective observational cohort study, a total of 1204 women intending to breastfeed, delivering vaginally with or without LEA, were included; breastfeeding was recorded at 3 days and 6 weeks postpartum. Primary outcome was breastfeeding at 6 weeks, and the χ2 test was used for comparisons between women delivering with and without LEA, according to parity status and previous breastfeeding experience. Total epidural fentanyl dose and oxytocin use (yes/no) were recorded. A multivariable logistic regression was performed to assess factors affecting breastfeeding at 6 weeks. RESULTS: The overall breastfeeding rate at 6 weeks was 76.9%; it was significantly lower among women delivering with LEA (74.0%) compared with women delivering without LEA (83.4%; P

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Readiness for Discharge After Foot and Ankle Surgery Using Peripheral Nerve Blocks: A Randomized Controlled Trial Comparing Spinal and General Anesthesia as Supplements to Nerve Blocks

BACKGROUND: Neuraxial anesthesia is often viewed as superior to general anesthesia but may delay discharge. Comparisons do not typically use multimodal analgesics and nerve blockade. Combining nerve blockade with general anesthesia may reduce pain, opioid consumption, and nausea. We hypothesized that general anesthesia (with nerve blocks) would lead to earlier readiness for discharge, compared to spinal anesthesia (with nerve blocks). METHODS: All patients underwent ambulatory foot and ankle surgery, with a predicted case duration of 1–3 hours. All patients received popliteal and adductor canal nerve blocks using bupivacaine and dexamethasone. No intraoperative opioids were administered. All patients received ondansetron, dexamethasone, ketamine, and ketorolac. Patients, data collectors, and the data analyst were not informed of group assignment. Patients were randomized to spinal or general anesthesia with concealed allocation. Spinal anesthesia was performed with mepivacaine and accompanied with propofol sedation. After general anesthesia was induced with propofol, a laryngeal mask airway was inserted, followed by sevoflurane and propofol. Time until ready for discharge, the primary outcome, was compared between groups after adjusting for age and surgery time using multivariable unconditional quantile regression. Secondary outcomes compared at multiple timepoints were adjusted for multiple comparisons using the Holm–Bonferroni step-down procedure. RESULTS: General anesthesia patients were ready for discharge at a median of 39 minutes earlier (95% confidence interval, 2–75; P = .038) versus spinal anesthesia patients. Patients in both groups met readiness criteria for discharge substantially before actual discharge. Pain scores at rest were higher among general anesthesia patients 1 hour after leaving the operating room (adjusted difference in means, 2.1 [95% confidence interval, 1.0–3.2]; P

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In Response

No abstract available

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Opioid Use Disorders: Perioperative Management of a Special Population

Opioid-related overdose deaths have reached epidemic levels within the last decade. The efforts to prevent, identify, and treat opioid use disorders (OUDs) mostly focus on the outpatient setting. Despite their frequent overrepresentation, less is known about the inpatient management of patients with OUDs. Specifically, the perioperative phase is a very vulnerable time for patients with OUDs, and little has been studied on the optimal management of acute pain in these patients. The preoperative evaluation should aim to identify those with OUDs and assess factors that may interfere with OUD treatment and pain management. Efforts should be made to provide education and assistance to patients and their support systems. For those who are actively struggling with opioid use, the perioperative phase can be an opportunity for engagement and to initiate treatment. Buprenorphine, methadone, and naltrexone medication treatment for OUD and opioid tolerance complicate perioperative pain management. A multidisciplinary team approach is crucial to provide clinically balanced pain relief without jeopardizing the patient's recovery. This article reviews the existing literature on the perioperative management of patients with OUDs and provides clinical suggestions for the optimal care of this patient population. Accepted for publication March 22, 2018. Funding:None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Emine Nalan Ward, MD, Department of Psychiatry, Massachusetts General Hospital, 16 Blossom St, Boston, MA 02114. Address e-mail to enward@partners.org. © 2018 International Anesthesia Research Society

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The Use of Hydroxyethyl Starch 130/0.4 in Surgery Patients

No abstract available

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Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events

Objective We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. Participants and methods Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. Results Analyses included 167 cases with grade 2 or greater efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7×10−4). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9×10−27). Conclusion Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics. Correspondence to David W. Haas, MD, Vanderbilt Health, One Hundred Oaks, 719 Thompson Lane, Suite 47183, Nashville, TN 37204, USA Tel: +1 615 936 8594; fax: +1 615 936 2644; e-mail: david.haas@vanderbilt.edu Received December 11, 2017 Accepted May 10, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A comparison of the incidence of supraventricular arrhythmias between thoracic paravertebral and intercostal nerve blocks in patients undergoing thoracoscopic surgery: A randomised trial

BACKGROUND Postoperative supraventricular arrhythmias are common in patients after thoracoscopic lobectomy. Inadequate pain control has long been recognised as a significant risk factor for arrhythmias. The performance of ultrasound-guided (USG) thoracic paravertebral block (PVB) is increasing as an ideal technique for postoperative analgesia. OBJECTIVE We conducted this study to evaluate whether a single-shot USG thoracic PVB would result in fewer postoperative supraventricular tachycardias (SVT) than intercostal nerve blocks (ICNBs) after thoracoscopic pulmonary resection. DESIGN A randomised controlled study. SETTING A single university hospital. PATIENTS Sixty-eight patients undergoing thoracoscopic lobectomy were randomised into two equal groups of 34. INTERVENTIONS For postoperative pain control, all patients received a total of 0.3 ml kg−1 of a mixture containing 0.5% ropivacaine and 1/200 000 epinephrine after placement of needles for either a single thoracic PVB or two individual ICNBs, both guided by ultrasound. Data were obtained during the first 48 postoperative hours. MAIN OUTCOME MEASURES The primary outcome was the incidence of SVT after thoracoscopic pulmonary resection. RESULTS During the first 48 postoperative hours, the incidences of SVT and atrial fibrillation were lower in the USG thoracic PVB group (14.7 vs. 46.9%, P = 0.004 and 3.0 vs. 18.8%, P = 0.037, respectively). The requirement for β-receptor blockade was more frequent in the ICNBs group than in the PVB group (5.9 vs. 25%, P = 0.033). CONCLUSION After placement of the needle using ultrasound guidance, a single-shot thoracic PVB is a well tolerated and effective technique to reduce the incidences of postoperative SVT and atrial fibrillation in patients undergoing thoracoscopic pulmonary resection. TRIAL REGISTRATION https://ift.tt/2LGPFWU, registration number: ChiCTR-IOR-17010952. Correspondence to Ying Cao, MD, PhD, School of Pharmacological Science, Southern Medical University, Guangzhou 510515, China Tel: +86 20 36591230; fax: +86 20 36591350; e-mail: yingcao1986@163.com © 2018 European Society of Anaesthesiology

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Safety of moderate-to-deep sedation performed by sedation practitioners: A national prospective observational study

BACKGROUND In the Netherlands, a significant proportion of moderate-to-deep sedation is performed by sedation practitioners under the indirect supervision of an anaesthesiologist but there are limited safety data available. OBJECTIVE To estimate the rate of sedation-related adverse events and patient relevant outcomes (PRO). DESIGN This was a prospective national observational study. Data were collected with a modified adverse event reporting tool from the International Sedation Task Force of the World Society of Intravenous Anaesthesia. SETTING A total of 24 hospitals in the Netherlands where moderate-to-deep sedation was performed by sedation practitioners from the 1 February 2015 to 1 March 2016. PATIENTS Consecutive adults undergoing moderate-to-deep sedation for gastrointestinal, pulmonary and cardiac procedures. INTERVENTION Observation: Analysis included descriptive statistics and a multivariate logistic regression model for an association between adverse events and PRO. MAIN OUTCOME MEASURES The primary outcome was the rate of unfavourable PRO (admission to ICU, permanent neurological deficit, pulmonary aspiration or death). Secondary outcome was the rate of moderate-to-good PRO (unplanned hospital admission or escalation of care). Composite outcome was the sum of all primary and secondary outcomes. RESULTS A total of 11 869 patients with a median age of 64 years [interquartile range 51 to 72] were included. ASA physical score distribution was: first, 19.1%; second, 57.6%; third, 21.6%; fourth, 1.2%. Minimal adverse events occurred in 1517 (12.8%), minor adverse events in 113 (1.0%) and major adverse events in 80 instances (0.7%). Primary outcome: Five (0.04%) unfavourable PRO were observed; four patients needing admission to the intensive care unit; and one died. Secondary outcome: 12 (0.1%) moderate-to-good PRO were observed. Moderate and major adverse events were associated with the composite outcome [3.7 (95% confidence interval 1.1 to 11.9) and 40.6 (95% confidence interval 11.0 to 150.4)], but not minimal or minor adverse events. CONCLUSION Moderate-to-deep sedation performed by trained sedation practitioners has a very low rate of unfavourable outcome. Correspondence to Benedikt Preckel, Department of Anaesthesia, Academic Medical Centre, Meibergdreef 9, 1105 AZ, 1100 DD Amsterdam, The Netherlands Tel: +00 31 205669111; fax: +00 31 206979441; e-mail: b.preckel@amc.nl © 2018 European Society of Anaesthesiology

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Challenges of bringing a new sedative to market!

Purpose of review The current review examines the success and failures of the development of new hypnotic compounds for the human market. One of the important aspects is that one of the key present agents, propofol, is considered by many anaesthesiologists as 'the ideal'. However, all drugs have adverse or side-effects. Recent findings The last 30 years since the introduction of propofol has seen many new compounds evaluated; but as at the present time, only three agents may achieve a pivotal position in the market – fospropofol (a sedative agent which may have a role in endoscopic surgery); remimazolam (a short-acting benzodiazepine) whose development is also being focused on the sedation rather than anaesthesia market; and the pregnane steroid, alfaxalone (an anaesthetic agent first introduced in 1972, but withdrawn in 1984 because of adverse allergic reactions to the solvent, Cremophor EL) now solvented in a cyclodextrin. Summary Studies of these three agents thus far have shown that none of them has any major adverse side-effects; all have properties which warrant further clinical evaluation. Correspondence to John W. Sear, 6 Whites Forge, Abingdon, Appleton OXON OX13 5LG, UK. E-mail: john.sear@gtc.ox.ac.uk Copyright © 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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