bluuebunny/crossref_metadata_2025 huggingface dataset:
Dendritic plateau potentials can process spike sequences across multiple time-scales
Authors: Leugering Johannes , Nieters Pascal , Pipa Gordon
Published: July 2019

Abstract

The brain constantly processes information encoded in temporal sequences of spiking activity. This sequential activity emerges from sensory inputs as well as from the brain’s own recurrent connectivity and spans multiple dynamically changing timescales. Decoding the temporal order of spiking activity across these varying timescales is a critical function of the brain, but we do not yet understand its neural implementation. The problem is, that the passive dynamics of neural membrane potentials occur on a short millisecond timescale, whereas many cognitive tasks require the integration of information across much slower behavioral timescales. However, actively generated dendritic plateau potentials do occur on such longer timescales, and their essential role for many aspects of cognition has been firmly established by recent experiments. Here, we build on these discoveries and propose a new model of neural computation that emerges from the interaction of localized plateau potentials across a functionally compartmentalized dendritic tree. We show how this interaction offers a robust solution to the timing invariant detection and processing of sequential spike patterns in single neurons. Stochastic synaptic transmission complements the deterministic all-or-none plateau process and improves information transmission by allowing ensembles of neurons to produce graded responses to continuous combinations of features. We found that networks of such neurons can solve highly complex sequence detection tasks by breaking down long inputs into sequences of shorter, random features that can be classified reliably. These results suggest that active dendritic processes are fundamental to neural computation.
ECHO: an Application for Detection and Analysis of Oscillators Identifies Metabolic Regulation on Genome-Wide Circadian Output
Authors: De los Santos Hannah , Collins Emily J. , Mann Catherine , Sagan April W. , Jankowski Meaghan S. , Bennett Kristin P. , Hurley Jennifer M.
Published: July 2019

Motivation

Time courses utilizing genome scale data are a common approach to identifying the biological pathways that are controlled by the circadian clock, an important regulator of organismal fitness. However, the methods used to detect circadian oscillations in these datasets are not able to accommodate changes in the amplitude of the oscillations over time, leading to an underestimation of the impact of the clock on biological systems.

Results

We have created a program to efficaciously identify oscillations in large-scale datasets, called the Extended Circadian Harmonic Oscillator application, or ECHO. ECHO utilizes an extended solution of the fixed amplitude mass-spring oscillator that incorporates the amplitude change coefficient. Employing synthetic datasets, we determined that ECHO outperforms existing methods in detecting rhythms with decreasing oscillation amplitudes and recovering phase shift. Rhythms with changing amplitudes identified from published biological datasets revealed distinct functions from those oscillations that were harmonic, suggesting purposeful biologic regulation to create this subtype of circadian rhythms.

Availability

ECHO’s full interface is available athttps://github.com/delosh653/ECHO. An R package for this functionality, echo.find, can be downloaded athttps://CRAN.R-project.org/package=echo.find.

Contact

hurleyj2@rpi.edu

Supplementary information

Supplementary data are available
Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes
Authors: Baldini Federico , Hertel Johannes , Sandt Estelle , Thinnes Cyrille C. , Neuberger-Castillo Lorieza , Pavelka Lukas , Betsou Fay , Krüger Rejko , Thiele Ines ,   on behalf of the NCER-PD Consortium
Published: July 2019

Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we first analysed the gut microbiome of patients and healthy controls by 16S rRNA gene sequencing of stool samples from the Luxembourg Parkinson’s study (n=147 typical PD cases, n=162 controls). All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include: 1. eight genera and nine species changed significantly in their relative abundances between PD patients and healthy controls. 2. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. The relative abundances ofBilophilaandParaprevotellawere significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. In contrast, dopaminergic medication had no detectable effect on the PD microbiome composition. 3. Personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms and attributed to individual bacteria, such asAkkermansia muciniphilaandBilophila wardswarthia. Our results suggest that PD-associated alterations of gut microbiome could translate into functional differences affecting host metabolism and disease phenotype.
Y-chromosome haplotypes are associated with variation in size and age at maturity in male Chinook salmon
Authors: McKinney Garrett J. , Seeb James E , Pascal Carita E. , Schindler Daniel E. , Gilk-Baumer Sara E. , Seeb Lisa W.
Published: July 2019

Variation in size and age at maturity is an important component of life history that is influenced both by environmental and genetic factors. In salmonids, large size confers a direct reproductive advantage through increased fecundity and egg quality in females, while larger males gain a reproductive advantage by monopolizing access to females. In addition, variation in size and age at maturity in males can be associated with different reproductive strategies; younger smaller males may gain reproductive success by sneaking in among mating pairs. In both sexes there is a trade-off between older age and increased reproductive success and increased risk of mortality by delaying reproduction. We identified four Y-chromosome haplogroups that showed regional and population-specific variation in frequency using RADseq data for 21 populations of Alaska Chinook salmon. We then characterized the range-wide distribution of these haplogroups using GT-seq assays. These haplogroups exhibited associations with size at maturity in multiple populations suggesting that the lack of recombination between X and Y-chromosomes has allowed Y-chromosome haplogroups to capture different alleles that influence size at maturity. Ultimately, conservation of life history diversity in Chinook salmon may require conservation of Y-chromosome haplotype diversity.
A Mendelian randomization study of the role of lipoprotein subfractions in coronary artery disease
Authors: Zhao Qingyuan , Wang Jingshu , Miao Zhen , Zhang Nancy R , Hennessy Sean , Small Dylan S , Rader Daniel J
Published: July 2019

Recent genetic data can offer important insights into the roles of lipoprotein subfractions and particle sizes in preventing coronary artery disease (CAD), as previous observational studies have often reported conflicting results. In this study, we first used the LD score regression to estimate the genetic correlation of 77 subfraction traits with traditional lipid profile and identified 27 traits that may involve distinct genetic mechanisms. We then used Mendelian randomization (MR) to estimate the causal effect of these traits on the risk of CAD. In univariable MR, the concentration and content of medium high-density lipoprotein (HDL) particles showed a protective effect against coronary artery disease. The effect was not attenuated in multivariable MR that adjusted for traditional lipid profile. The multivariable MR analyses also found that small HDL particles and smaller mean HDL particle diameter may have a protective effect. We identified four genetic markers for HDL particle size and CAD.
Unsupervised identification of the internal states that shape natural behavior
Authors: Calhoun Adam J. , Pillow Jonathan W. , Murthy Mala
Published: July 2019

Internal states can shape stimulus responses and decision-making, but we lack methods to identify internal states and how they evolve over time. To address this gap, we have developed an unsupervised method to identify internal states from behavioral data, and have applied it to the study of a dynamic social interaction. During courtship, Drosophila melanogaster males pattern their songs using feedback cues from their partner. Our model uncovers three latent states underlying this behavior, and is able to predict the moment-to-moment variation in natural song patterning decisions. These distinct behavioral states correspond to different sensorimotor strategies, each of which is characterized by different mappings from feedback cues to song modes. Using the model, we show that a pair of neurons previously thought to be command neurons for song production are sufficient to drive switching between states. Our results reveal how animals compose behavior from previously unidentified internal states, a necessary step for quantitative descriptions of animal behavior that link environmental cues, internal needs, neuronal activity, and motor outputs.
Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma
Authors: Chen Kok-Siong , Bunt Jens , Bridges Caitlin R. , Lynton Zorana , Lim Jonathan W.C. , Stringer Brett W. , Rajagopal Revathi , Wong Kum-Thong , Ganesan Dharmendra , Ariffin Hany , Day Bryan W. , Richards Linda J.
Published: July 2019

Astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation and therefore could be effectors of cellular differentiation in glioblastoma. We analysed expression of family membersNFIAandNFIBusing high-grade astrocytoma mRNA expression datasets, and with immunofluorescence co-staining. Their expression is reduced in glioblastomas and is associated with differentiated and mature astrocyte-like cells at a cellular level. Furthermore, induction of NFI expression is sufficient to promote cellular differentiation in patient-derived glioblastoma xenografts. Our findings indicate that NFI proteins may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal development. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.
Meningeal lymphatic endothelial cells fulfill scavenger endothelial cell function and employ Mrc1a for cargo uptake
Authors: Padberg Yvonne , van Impel Andreas , van Lessen Max , Bussmann Jeroen , Schulte-Merker Stefan
Published: July 2019

Brain lymphatic endothelial cells (BLECs) constitute a group of loosely connected endothelial cells within the meningeal layer of the zebrafish brain. We previously reported that BLECs efficiently endocytose extracellular cargo molecules (van Lessen et al., 2017), but how this is accomplished and controlled on the molecular level remains unclear. We here compare BLECs to scavenging endothelial cells (SECs) in the embryonic cardinal vein and find them to accept an identical set of substrate molecules. While there is redundancy in the type of scavenger receptors being used, the two cell populations rely for specific substrate molecules on different cell surface receptors to mediate their physiological role: Stab2 appears more critical within SECs in the cardinal vein, while BLECs depend more on the Mrc1a receptor for internalization of cargo. Given the striking similarities to the substrate specificity of cardinal vein SECs, we postulate that BLECs qualify functionally as SECs of the brain.
Are railways detrimental to bird populations? A BDACI study on the construction of the Bothnia Line Railway
Authors: de Jong Adriaan
Published: July 2019

Railways, like roads, are commonly considered bad for birdlife, but supporting data are very scarce. We conducted a 14-year before-during-after control-impact (BDACI) study of birds in agricultural landscapes affected by the construction of the Bothnia Line Railway (BLR) in northern Sweden. The “during” phase was split into two phases, one for the true construction period and one for the years when the railway was ready but not trafficked. Avian biodiversity increased in impact sites (N=13), but not in control sites (N=6). The numbers of breeding territories decreased correspondingly in impact and control sites, but trends differed between species and sites. Developments in the Degernäs site demonstrated that mitigation could be successful. Finally, there was no support for a shying-away effect of the BLR. Territory midpoints moved closer rather than away from the railway, albeit with variable patterns for individual sites and species. Mixed effect models showed no differences in avian biodiversity between theConstruction,ReadyandTrafficphases compared withBefore, but relative increases in numbers of territories and decreases in territory midpoint distances to the BLR. The results do not support a general detrimental effect of railway construction on bird populations in terms of biodiversity loss, reduced abundances or shying-away from train traffic. More studies and the development of “Railway Ecology” are badly needed.
Formation of Phage Lysis Patterns and Implications on Co-Propagation of Phages and Motile Host Bacteria
Authors: Li Xiaochu , Gonzalez Floricel , Esteves Nathaniel , Scharf Birgit E. , Chen Jing
Published: July 2019

Coexistence of bacteriophages, or phages, and their host bacteria plays an important role in maintaining the microbial communities. In natural environments with limited nutrients, motile bacteria can actively migrate towards locations of richer resources. Although phages are not motile themselves, they can infect motile bacterial hosts and spread in space via the hosts. Therefore, in a migrating microbial community coexistence of bacteria and phages implies their co-propagation in space. Here, we combine an experimental approach and mathematical modeling to explore how phages and their motile host bacteria coexist and co-propagate. When lytic phages encountered motile host bacteria in our experimental set up, a sector-shaped lysis zone formed. Our mathematical model indicates that local nutrient depletion and the resulting inhibition of proliferation and motility of bacteria and phages are the key to formation of the observed lysis pattern. The model further reveals the straight radial boundaries in the lysis pattern as a tell-tale sign for coexistence and co-propagation of bacteria and phages. Emergence of such a pattern, albeit insensitive to extrinsic factors, requires a balance between intrinsic biological properties of phages and bacteria, which likely results from co-evolution of phages and bacteria.

Author summary

Coexistence of phages and their bacterial hosts is important for maintaining the microbial communities. In a migrating microbial community, coexistence between phages and host bacteria implies that they co-propagate in space. Here we report a novel phage lysis pattern that is indicative of this co-propagation. The corresponding mathematical model we developed highlights a crucial dependence of the lysis pattern and implied phage-bacteria co-propagation on intrinsic properties allowing proliferation and spreading of the microbes in space. Remarkably, extrinsic factors, such as overall nutrient level, do not influence phage-bacteria coexistence and co-propagation. Findings from this work have strong implications for dispersal of phages mediated by motile bacterial communities, which will provide scientific basis for the fast-growing applications of phages.
Mineral deposition and vascular invasion of hydroxyapatite reinforced collagen scaffolds seeded with human adipose-derived stem cells
Authors: Weiss-Bilka Holly E. , Meagher Matthew J. , Gargac Joshua A. , Niebur Glen L. , Roeder Ryan K. , Wagner Diane R.
Published: July 2019

Collagen-based scaffolds reinforced with hydroxyapatite (HA) are an attractive choice for bone tissue engineering because their composition mimics that of bone. We previously reported the development of compression-molded collagen-HA scaffolds that exhibited high porosity, interconnected pores, and mechanical properties that were well-suited for surgical handling and fixation. The objective of this study was to investigate the use of these novel collagen-HA scaffolds in combination with human adipose-derived stem cells (hASCs) as a template for bone formation in a subcutaneous athymic mouse model. Cell-seeded constructs were pre-treated with either control or osteogenic media. Cell-free and collagen-only groups were included, as was a clinically approved bone void filler as a control for the material. After 8 weeks implantation, cell-free collagen-HA scaffolds and those that were pre-seeded with osteogenically differentiated hASCs supported bone formation and vascular invasion at comparable rates. HA-reinforcement allowed collagen constructs to maintain their implanted shape, provided for improved cell-tissue-scaffold integration, and resulted in a more organized tissue when pre-treated in an osteogenic induction medium. Scaffold type and pre-treatment also determined osteoclast activity and therefore potential remodeling of the constructs. Results suggest that it may be necessary to match the scaffold with a particular cell type and cell-specific pre-treatment to achieve optimal bone formation.
NMR reveals light-induced changes in the dynamics of a photoswitchable fluorescent protein
Authors: Christou N. E. , Ayala I. , Giandoreggio-Barranco K. , Byrdin M. , Adam V. , Bourgeois D. , Brutscher B.
Published: July 2019

The availability of fluorescent proteins with distinct phototransformation properties is crucial for a wide range of applications in advanced fluorescence microscopy and biotechnology. To rationally design new variants optimized for specific applications, a detailed understanding of the mechanistic features underlying phototransformation is essential. At present, little is known about the conformational dynamics of fluorescent proteins at physiological temperature, and how these dynamics contribute to the observed phototransformation properties. Here, we apply high-resolution NMR spectroscopy in solution combined with in-situ sample illumination at different wavelengths to investigate the conformational dynamics of rsFolder, a GFP-derived protein that can be reversibly switched between a green fluorescent state and a non-fluorescent state. Our results add a dynamic view to the static structures obtained by X-ray crystallography. Including NMR into the analytical toolbox used for fluorescent protein research provides new opportunities for investigating the effect of mutations or changes in the environmental conditions on the conformational dynamics of phototransformable fluorescent proteins, and their correlation with the observed photochemical and photophysical properties.

Significance

Photo-transformable Fluorescent Proteins (PTFPs) are essential tools for super-resolution (SR) microscopy. In practical applications, however, researchers often encounter problems when using PTFPs in a particular cellular context, because the environmental conditions (pH, temperature, redox potential, oxygen level, viscosity, …) affect their brightness, photostability, phototransformation kinetics, etc. Rational fluorescent protein engineering exploits the mechanistic information available from structural studies, mainly X-ray crystallography, in order to design new PTFP variants with improved properties for particular applications. Here we apply NMR spectroscopy in solution to investigate the light-induced changes in conformational dynamics of rsFolder, a reversibly switchable fluorescent protein. The dynamic view offered by NMR highlights protein regions that comprise potentially interesting mutation points for future mutagenesis campaigns.
Combining random microseed matrix screening and the magic triangle for the efficient structure solution of a potential lysin from bacteriophage P68
Authors: Truong Jia Quyen , Panjikar Santosh , Shearwin-Whyatt Linda , Bruning John B. , Shearwin Keith E.
Published: July 2019

Two commonly encountered bottlenecks in the structure determination of a protein by X-ray crystallography are screening for conditions that give high-quality crystals and, in the case of novel structures, finding derivatization conditions for experimental phasing. In this study, the phasing molecule 5-amino-2,4,6-triiodoisophthalic acid (I3C) was added to a random microseed matrix screen to generate high-quality crystals derivatized with I3C in a single optimization experiment. I3C, often referred to as the magic triangle, contains an aromatic ring scaffold with three bound I atoms. This approach was applied to efficiently phase the structures of hen egg-white lysozyme and the N-terminal domain of the Orf11 protein fromStaphylococcusphage P68 (Orf11 NTD) using SAD phasing. The structure of Orf11 NTD suggests that it may play a role as a virion-associated lysin or endolysin.
Impact of abusive supervision on counterproductive work behaviors of nurses
Authors: Low Yoke May , Sambasivan Murali , Ho Jo Ann
Published: July 2019

The objectives of this research are to address the two fundamental research questions: 1) What are the antecedents that lead to counterproductive work behavior (CWB) of nurses in public hospitals? 2) How effective are the moderating roles of power distance orientation (a cultural factor) and locus of control (an individual factor) in impacting CWB? The antecedents addressed are abusive supervision and nurses’ perception of injustice. A questionnaire‐based study was conducted among 337 nurses working in six public hospitals in different departments in Malaysia. The data were analyzed using structural equation modeling. The main findings are:1) nurses perceive injustice when subjected to abusive supervision and indulge in CWB; 2) nurses with a high level of power distance orientation are less likely to perceive abusive supervision as injustice; and 3) nurses with an internal locus of control are less likely to engage in CWB. The contributions of the study are discussed.
Effect of Accelerated Storage on Fatty Acids, Thermal Properties and Bioactive Compounds of Kenaf Seed Oil
Authors: Zhang Zhen‐shan , Zhang Li‐xia , Xie Qing‐fang , Che Li‐ming
Published: July 2019

The effects of thermal oxidation at 65 °C for 24 days on oxidation indices, fatty acid positional distribution, thermal properties, vitamin E composition and sterol composition of kenaf seed oil are investigated. The results showed that total oxidation value (TOTOX) of the oil increased from initial 8.83 to 130.74 at the end of 24 days storage. Linoleic acid at sn‐1, 3 positon of kenaf seed oil was less stable than the one at sn‐2 positon. Oxidative degradation changed the melting profile of kenaf seed oil, the value of endothermic enthalpy reduced from 58.17 to 20.25 J/g after 24 days of storage. Moreover, the content of vitamin E and total sterol decreased by 84.26% and 38.47%, respectively. Tocotrienols were more stable than tocopherols during the accelerated storage. Correlation analysis indicated vitamin E content was significantly related to p‐anisidine value, while sterol content was significantly related to peroxide value.

Practical Application

Kenaf seed oil is rich in polyunsaturated fatty acids and bioactive compounds. Heating process and long‐term storage cause oil oxidation and bioactive compounds degradation. The oxidation process of kenaf seed oil is simulated with accelerated storage. The study evaluates fatty acid composition and distribution, vitamin E and sterol content, melting thermal characteristics of kenaf seed oil at different oxidation levels. The research shows the stability of fatty acid is related with its type and position in backbone of triacylglycerol molecule. There are good correlation among oxidation level, vitamin E and sterol content, and melting enthalpy value of kenaf seed oil.
Effect of Basket Geometry on the Sensory Quality and Consumer Acceptance of Drip Brewed Coffee
Authors: Frost Scott C. , Ristenpart William D. , Guinard Jean‐Xavier
Published: July 2019

In this work, discrimination tests, descriptive analysis, consumer tests, and total dissolved solids (TDS) were used to evaluate the effects of brew basket geometry on the sensory quality and consumer acceptance of drip brewed coffee. Two basic geometries, semi‐conical and flat‐bottom, were evaluated in conjunction with coffee roast and particle size. Initial discrimination tests showed that small differences in median particle size were not discernable, but that coffees brewed using either semi‐conical or flat‐bottom filter baskets were significantly different (P < 0.05, N = 45). Additionally, coffee brewed in the semi‐conical basket had significantly higher %TDS, and we estimated a sensory difference threshold of 0.24 %TDS. A subsequent descriptive analysis (DA) showed significant differences by roast for 11 attributes and by grind for six attributes. Although brewing geometry, as a single factor, was only significantly different for three independent attributes (smoke aroma, sweetness, and tobacco flavor), roast × geometry interactions were significant for six attributes (berry flavor, bitterness, burnt wood/ash, citrus flavor, earthy flavor, and sourness) and the grind × geometry interaction was significant for two attributes (bitterness and floral aroma). Attributes showing significant interactions with brewing geometry were also key drivers of consumer liking/disliking. Overall consumer liking (9‐point hedonic scale) was analyzed by cluster analysis (N = 85), which revealed four distinct preference clusters. For each cluster, a particular basket geometry and/or roast level showed lesser acceptance. Overall, the results strongly corroborate the hypothesis that basket geometry affects the sensory quality of drip brewed coffee.

Practical Application

Most Americans consume drip brewed coffee. Improving our understanding of the effects of basket geometry, roast level, and grind size on the total dissolved solids, sensory properties, and acceptability of drip brewed coffee gives producers and consumers alike an opportunity to optimize the sensory quality of their coffee.
Imaging features of undifferentiated carcinoma of the pancreas
Authors: Ishigami Kousei , Nishie Akihiro , Yamamoto Takeo , Asayama Yoshiki , Ushijima Yasuhiro , Kakihara Daisuke , Fujita Nobuhiro , Morita Koichiro , Ohtsuka Takao , Kawabe Ken , Mochidome Naoki , Honda Hiroshi
Published: July 2019

Introduction

The purpose of this retrospective study was to evaluate imaging features of undifferentiated carcinoma of the pancreas.

Methods

The study group included eight patients with surgically resected undifferentiated carcinoma of the pancreas. Multidetector‐row computed tomography (MDCT, n = 8) and magnetic resonance imaging (MRI, n = 6) findings were retrospectively reviewed.

Results

On MDCT, all eight cases were hypovascular with upstream main pancreatic duct (MPD) dilatation, and only 1 showed exophytic growth. Five cases (62.5%) showed necrosis/cystic change, and calcification was observed in two cases (25%). Calcification reflected tumour osteoid components. On MRI, haemorrhage and hemosiderin were observed in 4 of 6 (66.7%) cases. In addition, tumour thrombus in the splenic vein (n = 1) and intraductal tumour growth in the MPD (n = 2) were pathologically identified, although imaging studies only revealed 1 of these latter cases.

Conclusion

Undifferentiated carcinoma of the pancreas may present as a tumour with haemorrhagic necrosis. Coexistence of calcification, intraductal tumour growth in the MPD and tumour thrombus may support the imaging diagnosis of this entity.
A new diagnostic method using air perfusion radiography under DSA for gastric stump‐pleural fistula: Report of five cases
Authors: Wu Tao , Sun Ruimin , Zhang Mingqin , Miao Niu , Wang Huili , Yang Dongyi , Liu Yangyang , Zhou Qing
Published: July 2019

Gastric stump‐pleural fistula is a common complication following gastroesophageal anastomosis in patients diagnosed with gastric cancer. Mortality is high because of the severe subsequent relevant complications caused by the fistula. Here we report five cases of gastric stump‐pleural fistula diagnosed by air perfusion radiography under digital subtraction angiography (DSA). DSA air perfusion radiography provides a reliable basis for the development of clinical programmes; it is a simple method which does not involve any pain or trauma to the patient.
Neurobehavioral effects of neonatal opioid exposure in mice: Influence of the OPRM1 SNP
Authors: Robinson Shivon A. , Jones Alonzo D. , Brynildsen Julia K. , Ehrlich Michelle E. , Blendy Julie A.
Published: July 2019

Opioid use among pregnant women is a growing public health concern in the United States. Infants exposed to opioids in utero are at risk of exhibiting neonatal opioid withdrawal syndrome (NOWS). The biological mechanisms underlying short and long‐term consequences of in utero opioid exposure and NOWS are unknown. A potential genetic factor is a single‐nucleotide polymorphism (SNP) in the mu‐opioid receptor gene (OPRM1 A118G). Opioid exposed infants with the G‐allele spend less time in hospitals after birth. To determine whether this SNP modulates the neurobehavioral effects of neonatal opioid exposure and withdrawal, we used mice possessing the equivalent Oprm1 SNP (A112G). Pups were treated chronically with saline or morphine from postnatal days (PNDs) 1 to 14, a developmental period equivalent to the third trimester of a human pregnancy and a sensitive period for opioid exposure in rodents. Morphine treatment produced significant developmental delays regardless of genotype and increased total ultrasonic vocalizations in males during spontaneous withdrawal. Animals were aged and tested for anxiety and drug response during adolescence and adulthood, respectively. AA morphine‐treated animals showed reduced activity in the marble burying task compared with saline controls; however, this effect was absent in AG and GG animals. As adults, AA males exposed to morphine from PNDs 1 to 14 exhibited enhanced development of locomotor sensitization to morphine, whereas females showed reduced locomotor sensitization. These data suggest the involvement of the Oprm1 SNP for certain outcomes of neonatal opioid exposure and highlight the importance of considering sex and genetic variability for the prognosis of NOWS.
Access to original canal trajectory after deviation and perforation with guided endodontic assistance
Authors: Casadei Bruna de Athayde , Lara‐Mendes Sônia T.de O. , Barbosa Camila de Freitas M. , Araújo Christiane Valente , de Freitas Cristina Almeida , Machado Vinícius C. , Santa‐Rosa Caroline C.
Published: July 2019

Procedural accidents are eventualities that may occur during endodontic treatment because of lack of attention to detail or even unforeseeable situations. Knowledge of the root canal anatomy and its variations is a prerequisite for successful endodontic treatment. This case report describes an endodontic treatment where there was an intercurrence, generating deviation and perforation, which was solved with the aid of guided endodontics. A 37 years old, ASA1, was referred to the clinic for localisation and treatment of a calcified canal of the second right upper premolar. The tomographic images revealed the presence of only one canal and deviation with apical perforation. With the help of CBCT and CAD/CAM, it was possible to perform the guided access technique even after deviation and root perforation. Once again, this technique proved to be safe and predictable, allowing for a favourable prognosis in the long term.
Suicide amongst anaesthetists – an Association of Anaesthetists survey
Authors: Yentis S. M. , Shinde S. , Plunkett E. , Mortimore A.
Published: July 2019

Following a 2–3‐month period of publicity, anaesthetists were invited to participate in an online survey that was administered by a third party company on behalf of the Association of Anaesthetists and ran between 3 September and 31 October 2018. Anaesthetists working in the UK or Ireland were asked about the presence or absence of welfare/support structures or resources in their workplace in the case of mental illness, addiction and/or suicide. Anaesthetists working anywhere in the world were also asked for their experiences of a colleague's suicide, defined as a colleague's taking his or her own life – whether intentional or not – while practising as an anaesthetist in the UK or Ireland, in the same department and at the same time as the respondent. Respondents were also asked about experiences of other suicides not meeting this definition. A total of 3638 responses were received. Most respondents were unaware of the existence of policies/guidance on mental illness, addiction or suicide, or of welfare leads, within their Trust or department. A total of 1916 cases of suicide meeting the survey's definition were reported by 1397 respondents, although the actual number of discrete cases is unknown because of likely multiple reporting of the same cases. A third of respondents who reported a suicide had experience of more than one case. Most reports were of suicide in the last 10 years, and most reported cases involved anaesthetic drugs. Deficiencies were noted in the support available and in the way the deaths were handled, although examples of good support were also described. A further 1715 respondents reported suicides that did not meet the primary definition. Overall, 92% of respondents reporting suicide experienced it through work, and 41% outside of work (total > 100% as some reported both). Although unable to provide estimates of suicide rates, or numerical associations between the features of the deaths, this survey highlights the considerable emotional and mental burden of suicide on anaesthetists.
Psychological outcomes of left ventricular assist device long‐term treatment: A 2‐year follow‐up study
Authors: Voltolini Alessandra , Salvato Gerardo , Frigerio Maria , Cipriani Manlio , Perna Enrico , Pisu Mirella , Mazza Umberto
Published: July 2019

Left ventricular assist device (LVAD) is an effective therapy for patients with advanced or refractory heart failure. It may represent a temporary treatment in heart transplant (HTX) candidates (Bridge‐To‐Transplant—BTT), or a permanent therapy for patients unsuitable for HTX (Destination Therapy—DT). Living with the device may be stressful for both the patients and their caregivers. Currently, evidence on the psychological assessment of LVAD recipients, and factors influencing the patients' psychological adaptation to the device in the long‐term period is limited. Here, we explored the quality of life in 20 patients who were treated with LVAD with BTT (n = 13) or DT indication (n = 7) before (T0), 1 year (T1) and 2 years (T2) after implantation, using the EuroQoL‐5D‐5L test. We also analyzed the influence of sociodemographic (eg, age, gender) and clinical variables (eg, the INTERMACS level and number of hospital admissions) on the quality of life at T2. We found a significant improvement in the self‐perceived quality of life 2 years after LVAD implantation. Patients significantly improved in the domains of physical activity and anxiety and depression symptoms. Interestingly, we also demonstrated that the treatment indication was related to changes in self‐assessed quality of life, which improved over time in patients implanted with DT indication, whereas it decreased from T1 to T2 in patients with BTT indication. Taken together, these findings suggest that LVAD‐related emotional distress and coping strategies need to be carefully evaluated before and in the long‐term after LVAD implantation.
Numerical simulation of centrifugal and hemodynamically levitated LVAD for performance improvement
Authors: Kannojiya Vikas , Das Arup Kumar , Das Prasanta Kumar
Published: July 2019

Left ventricular assist device (LVAD) provides an effective artificial support system to the heart patients. Despite the improved life survival rate, complications like hemolysis, blood trauma, and thrombus formation still limit the performance of the blood pump. The geometrical aspects of blood pumps majorly influence the hemodynamics, therefore these devices must be carefully engineered. In this work, several versions of centrifugal blood pumps are simulated using ANSYS‐CFX to propose a best compatible design for LVAD. A hemodynamic levitation approach for the impeller is also suggested to overcome the cost and weight issue associated with the magnetic levitation. The blood flow is modeled by implementing Bird–Carreau model and its turbulence is solved using the SST turbulence model. The influence of the blade profile, blade tip width, blade numbers, and splitter blades on the hemodynamic characteristics through the pump is observed. An optimum design of centrifugal blood pump for the assistance of failed ventricle is proposed that can effectively pump the blood from the left ventricle to the ascending aorta. The proposal can be adopted by LVAD designers to have hemodynamically tuned efficient product.
Individualised dosing algorithm and personalised treatment of high‐dose rifampicin for tuberculosis
Authors: Svensson Robin J. , Niward Katarina , Davies Forsman Lina , Bruchfeld Judith , Paues Jakob , Eliasson Erik , Schön Thomas , Simonsson Ulrika S.H.
Published: July 2019

Aims

To propose new exposure targets for Bayesian dose optimisation suited for high‐dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin's auto‐induction, saturable pharmacokinetics and high interoccasion variability.

Methods

Rifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti‐mycobacterial activity in relation to rifampicin's pharmacokinetics i.e. highest plasma concentration up to 24 hours and area under the plasma concentration–time curve up to 24 hours (AUC0–24h). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10 mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC.

Results

The suggested exposure target for Bayesian dose optimisation was a steady state AUC0–24h of 181–214 h × mg/L. The observed MICs ranged from 0.016–0.125 mg/L (mode: 0.064 mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200–3000 mg (20–50 mg/kg) with a mode of 1800 mg (30 mg/kg, n = 24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0–24h‐only target.

Conclusions

A new up‐to‐date exposure target for Bayesian dose optimisation suited for high‐dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto‐induction, saturable pharmacokinetics and high between‐occasion variability of rifampicin.
Comparative assessment of budesonide‐MMX and mesalamine in active, mild‐to‐moderate ulcerative colitis: A systematic review and network meta‐analysis
Authors: Bonovas Stefanos , Nikolopoulos Georgios K. , Piovani Daniele , González‐Lorenzo Marien , Pantavou Katerina , Lytras Theodore , Peyrin‐Biroulet Laurent , Danese Silvio
Published: July 2019

Aims

The comparative efficacy, safety and tolerability of budesonide‐MMX and oral mesalamine in active, mild‐to‐moderate ulcerative colitis (UC) are unclear. We conducted a network meta‐analysis to fill this evidence gap.

Methods

We searched PubMed, Scopus, Embase, the Cochrane Library, clinical trial registries, regulatory agencies' websites and international conference proceedings, up to July 2018, to identify randomized controlled trials of adult patients with active, mild‐to‐moderate UC, comparing budesonide‐MMX or mesalamine against placebo, or against each other, or different dosing strategies, for induction of remission. Two reviewers independently abstracted study data and outcomes, and assessed each trial's risk‐of‐bias.

Results

We identified and synthesized evidence from 15 eligible trials including 4083 participants. Budesonide‐MMX 9 mg/day and mesalamine >2.4 g/day had similar efficacy for induction of clinical and endoscopic remission (OR = 0.97; 0.59–1.60), both showing superiority over placebo (OR = 2.68; 1.75–4.10, and OR = 2.75; 1.94–3.90, respectively). Furthermore, mesalamine >2.4 g/day was more efficacious than mesalamine 1.6–2.4 g/day (odds ratio = 1.27; 1.03–1.56). Secondary analyses showed that mesalamine >2.4 g/day ranks at the top among comparator treatments regarding safety (serious adverse events; surface under the cumulative ranking area [SUCRA] 79.2%) and tolerability (treatment discontinuations or withdrawals from the study due to adverse events; SUCRA 96.7%). There was no evidence of inconsistency, while heterogeneity between studies and risk of publication bias were low.

Conclusion

Budesonide‐MMX and mesalamine >2.4 g/day had similar efficacy for induction of clinical and endoscopic remission in active, mild‐to‐moderate UC; however, mesalamine >2.4 g/day showed better tolerability. Further high‐quality research is warranted.
Low‐dose ketamine provides poor analgesia for pain in redback spider envenoming
Authors: Ryan Nicole M. , James Rosemary , Downes Michael A. , Isbister Geoffrey K.
Published: July 2019

Redback spider envenoming causes severe pain lasting several days. A recent clinical trial found that antivenom is not effective. We investigated ketamine for pain in redback spider envenoming. Ten adult patients with severe pain from redback spider envenoming were administered 15 mg intravenous ketamine after standard analgesia, then up to 4 oral doses of ketamine 25– 50 mg. Three patients had a clinically significant improvement in pain compared to baseline after intravenous ketamine. Five patients had a minimal decrease in pain and 2 had no improvement. Eight patients received oral ketamine: 4 doses in 5 and 2 doses in 3. At 24 h, 3/6 patients assessed had clinically significant improvement in pain and 4/5 patients assessed at 48 h, had clinically significant improvement in pain. Six patients reported side effects, including dissociation (4) and hallucinations (2). Five patients required rescue opioids and 2 were readmitted to hospital. We found that ketamine provided no additional pain relief in redback spider envenoming, compared to standard analgesia, and resulted in unacceptable adverse effects.
Risk of secondary haematological malignancies in patients with follicular lymphoma: an analysis of 1028 patients treated in the rituximab era
Authors: Prusila Roosa E. I. , Sorigue Marc , Jauhiainen Jyrki , Mercadal Santiago , Postila Aleksi , Salmi Petteri , Tanhua Taru , Tikkanen Susanna , Kakko Sakari , Kuitunen Hanne , Pollari Marjukka , Nystrand Ilja , Kuusisto Milla E. L. , Vasala Kaija , Jantunen Esa , Korkeila Eija , Karihtala Peeter , Sancho Juan‐Manuel , Turpeenniemi‐Hujanen Taina , Kuittinen Outi
Published: July 2019

Follicular lymphoma (FL) is the most common indolent lymphoma. Currently there are many comparable treatment options available for FL. When selecting the most optimal therapy it is important to consider possible late effects of the treatment as well as survival. Secondary haematological malignancy (SHM) is a severe late effect of treatments, but the incidence of SHMs is still largely unknown. The goal of the present study was to determine the incidence of SHMs and how therapeutic decisions interfere with this risk. The study included 1028 FL patients with a median follow‐up time of 5·6 years. The 5‐year risk of SHM was 1·1% and the risk was associated with multiple lines of treatment (P = 0·016). The 5‐year risk of SHM was 0·5% after the first‐line treatment and 1·6% after the second‐line. The standardized incidence ratio (SIR) was 6·2 (95% confidence interval 3·4–10·5) for SHM overall. This retrospective study found that the risk of SHM was low after first‐line treatment in FL patients from the rituximab era. However, the risk of SHM increases with multiple lines of treatment. Therapeutic approaches should aim to achieve as long a remission as possible with first‐line treatment, thereby postponing the added risk of SHM.
What Does Prone Skateboarding in the Newborn Tell Us About the Ontogeny of Human Locomotion?
Authors: Forma Vincent , Anderson David. I. , Provasi Joëlle , Soyez Evelyne , Martial Mélina , Huet Viviane , Granjon Lionel , Goffinet François , Barbu‐Roth Marianne
Published: July 2019

The crawling behavior of sixty 2‐day‐old newborns was studied while they were supported prone on a mini skateboard and on a pediatric mattress without additional support. Analyses of the number and types of limb movements and their characteristics, the coactivation of limb pairs, and the displacement across the surface, revealed that newborns can crawl with locomotor patterns similar to those documented during quadrupedal locomotion in animals and human adults. This was particularly apparent on the skateboard. This discovery suggests that locomotor circuitry underlying quadrupedal locomotion develops during fetal life. Drawing upon other evidence for a quadrupedal organization underlying bipedal gait, we argue that early quadrupedal training may enhance interventions designed to hasten the onset of independent walking.