bluuebunny/crossref_metadata_2025 huggingface dataset:
Proinflammatory Cytokines, Mood, and Sleep in Interepisode Bipolar Disorder and Insomnia: A Pilot Study With Implications for Psychosocial Interventions
Authors: Dolsen Emily A. , Soehner Adriane M. , Harvey Allison G.
Published: September 2017

Objective

Proinflammatory cytokines are associated with bipolar disorder (BD), but less is known about how cytokines function during the interepisode period. This study examined cytokines, mood symptoms, and sleep in individuals with interepisode BD with complaints of insomnia. We also investigated the effects of a BD-specific modification of cognitive behavior therapy for insomnia (CBTI-BP) on cytokine levels.

Methods

Twenty-two adults with interepisode BD type I and insomnia were drawn from a subset of a National Institute of Mental Health funded study. Participants were randomly allocated to CBTI-BP (n = 11) or psychoeducation (n = 11). Participants completed a sleep diary, rated self-report measures of mania and depression, and provided samples assayed for interleukin (IL)-6 and tumor necrosis factor soluble receptor 2 (sTNF-R2).

Results

IL-6 was associated with mania symptoms (r
s = 0.44, p = .041) and total sleep time (r
s = −0.49, p = .026). IL-6 was related to depression symptoms at the trend level (r
s = 0.43, p = .052). sTNF-R2 was not significantly related to mood or sleep measures. From pretreatment to posttreatment, CBTI-BP compared with psychoeducation was associated with a nonsignificant, large effect size decrease in IL-6 (z = −1.61, p = .13, d = −0.78) and a nonsignificant, small-medium effect size decrease in sTNF-R2 (z = −0.79, p = .44, d = −0.38).

Conclusions

These findings provide preliminary evidence that IL-6 is related to mania symptoms and shorter total sleep time in interepisode BD. A treatment that targets sleep in BD could potentially decrease IL-6 although replication is warranted.
Infection Staging and Incidence Surveillance Applications of High Dynamic Range Diagnostic Immuno-Assay Platforms
Authors: Grebe Eduard , Welte Alex , Hall Jake , Keating Sheila M. , Facente Shelley N. , Marson Kara , Martin Jeffrey N. , Little Susan J. , Price Matthew A. , Kallas Esper G. , Busch Michael P. , Pilcher Christopher D. , Murphy Gary ,   on behalf of the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA)
Published: September 2017

Background:

Custom HIV staging assays, including the Sedia HIV-1 Limiting Antigen (LAg) Avidity EIA and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify “recent” infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and long-standing infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications.

Methods:

We tested a panel of 2500 well-characterized specimens with estimable duration of HIV infection with the 3 assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRIs), context-specific false-recent rates (FRRs) and correlation between diagnostic signal intensity and LAg measurements. Hypothetical epidemiological scenarios were constructed to evaluate utility in surveillance applications.

Results:

Over a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR ≈ 0.5% and 1.5%, respectively at MDRI ≈ 200 days), and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (relative SE ≈ 17.5% and 15%, respectively at MDRI ≈ 200 days). ARCHITECT S/CO measurements were highly correlated with LAg optical density measurements (r = 0.80), and values below 200 are strongly predictive of LAg recency and duration of infection less than 1 year.

Conclusions:

Low quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing, and its use is feasible in clinical staging and incidence surveillance applications.
Effectiveness of Bone Suppression Imaging in the Detection of Lung Nodules on Chest Radiographs
Authors: Miyoshi Tomohiro , Yoshida Junji , Aramaki Nao , Matsumura Yuki , Aokage Keiju , Hishida Tomoyuki , Kobayashi Tsuyoshi , Tsubura Shinichi , Katsuhara Shinsuke , Kasai Satoshi , Sasano Yasuhiko , Nagai Kanji , Tsuboi Masahiro
Published: September 2017

Objective:

To evaluate the effectiveness of bone suppression imaging (BSI) software in lung-nodule detection on chest radiographs (CXRs) in relation to nodule location and observer’s experience.

Materials and Methods:

The CXRs of 80 patients, of which 40 had a lung nodule (8 to 30 mm in diameter) and 40 did not have any nodules, were interpreted by 20 observers comprising of 7 pulmonologists with >10 years of experience and 13 pulmonology residents. Each patient’s image was sequentially read, first using the standard CXR and thereafter with the BSI software. The nodule location and confidence level with regard to the presence of a lung nodule were recorded. Receiver operating characteristic analysis was used to evaluate observer performance.

Results:

The average area under the curve (AUC) for the observers’ receiver operating characteristic significantly improved from 0.867 to 0.900 (P=0.004) with the use of the BSI software. The average AUC for experienced pulmonologists improved from 0.877 to 0.924 (P=0.017) for lung nodules located in the apical and peripheral areas but not for those in the inner area. The average AUC for residents improved regardless of nodule location.

Conclusion:

The use of BSI software improved the performance in lung-nodule detection on CXRs regardless of observer’s experience and was more effective for observers with limited experience.
Cleft Lip and Palate Repair
Authors: Gatti Gian Luca , Freda Nicola , Giacomina Alessandro , Montemagni Marina , Sisti Andrea
Published: September 2017

Introduction:

Cleft lip and palate is the most frequent congenital craniofacial deformity. In this article, the authors describe their experience with cleft lip and palate repair.

Methods:

Data regarding patients presenting with primary diagnosis of cleft lip and/or palate, between 2009 and 2015, were reviewed. Details including demographics, type of cleft, presence of known risk factors, surgical details, and follow-up visits were collected. Documented complications were reported. Caregivers’ satisfaction was assessed with a survey. The survey used to assess satisfaction with cleft-related features was based on the cleft evaluation profile (CEP). In addition, 4 assessors used visual analog scale (VAS) to assess the aesthetic satisfaction.

Results:

Seven hundred fifty-two patients with primary diagnosis of cleft lip and/or palate underwent surgical correction at ”S. Chiara” Hospital, 432 (57.45%) male and 320 (42.55%) female. The most common cleft types in our study were incomplete cleft palate (152 patients) and left unilateral complete cleft lip and palate (152 patients). Associated syndromes were found in 46 patients (6.12%). Cleft lip was repaired using a modified Tennison–Randall technique when the defect was unilateral, whereas a modified Mulliken technique was used for bilateral cleft lip. Cleft palate was repaired using the Bardach technique or Von Langenbeck technique at 5 to 6 months of age. Cleft lip and palate was repaired in several surgical steps. In total, complications were reported in 81 of 752 patients (14.16%). Average fathers’ satisfaction score assessed using CEP was 4.5 (lip), 4.8 (nose), 4.7 (teeth), 4.8 (bite), 4.2 (breathing), 4.6 (profile). Average mothers’ satisfaction score assessed using CEP was 4.3 (lip), 4.6 (nose), 4.4 (teeth), 4.5 (bite), 4.1 (breathing), 4.4 (profile). Average level of aesthetic satisfaction, assessed using VAS, was 8.7 (fathers), 8.1 (mothers), 7.9 (lay person), and 8.0 (senior cleft surgeon).

Conclusion:

The multidisciplinary management of children with oral cleft determinated good results, in terms of satisfaction and aesthetic appearance. From our experience, periosteoplasty and lip-adhesion are key surgical techniques.
Quality, reliability, repeatability—What about excellence?
Authors: Harrington David T.
Published: September 2017

Today, I will be giving a general overview of the quality question. I will divide quality into four topics: first essential element—data, second essential element—process, third essential element—culture, and hidden dangers. We were fairly “high on the hog” in the House of Surgery in the late 20th century but then came the Institute of Medicine (IOM) reports. Partly in response to the IOM reports, we have discussed incessantly airplanes and aircrews. However, this is not the only challenge for in addition to this quality problem, we have a cost problem. These intersecting challenges appear insurmountable, but there is hope. We need better data, better process, and an evolution of our culture. The easiest type of data to collect is process measure data. We should all be aware of Surgical Care Improvement Project (SCIP), Physician Reporting Quality System (PRQS), and Merit-Based Incentive Payment System (MIPS). On the performance measures side of the house, the National Surgical Quality Incentive Program and the University Health-System Collaborative are major initiatives. There is an abundance of data, but if we are to improve care, we also need a good process. There is increased attention into process such as checklists, bundles, and standard operating procedures. Data and process is important, but we also need to be strategic. For a process to be effective, it needs to be part of a coherent strategy. And once we have data, process, and strategic thinking, we come to the third essential element, which is culture. Are there some dangers in embracing these new approaches? In a word, yes. We cannot abandon the traditional role of surgeons as leaders. We need to think about training the next generation of surgeons and the risk that this over-systemization of care begets. Surgeons have always led change, so though these new challenges seem profoundly disruptive, I am sure that we will again rise to the task.
The hyperfibrinolytic phenotype is the most lethal and resource intense presentation of fibrinolysis in massive transfusion patients
Authors: Taylor John R. , Fox Erin E. , Holcomb John B. , Rizoli Sandro , Inaba Kenji , Schreiber Martin A. , Brasel Karen , Scalea Thomas M. , Wade Charles E. , Bulger Eileen , Cotton Bryan A.
Published: September 2017

BACKGROUND

Among bleeding patients, we hypothesized that the hyperfibrinolytic (HF) phenotype would be associated with the highest mortality, whereas shutdown (SD) patients would have the greatest complication burden.

METHODS

Severely injured patients predicted to receive a massive transfusion at 12 Level I trauma centers were randomized to one of two transfusion ratios as described in the Pragmatic, Randomized, Optimal Platelet and Plasma Ratio trial. Fibrinolysis phenotypes were determined based on admission clot lysis at 30 minutes (LY30): SD ≤0.8%, physiologic (PHYS) 0.9–2.9%, and HF ≥3%. Univariate and multivariate analysis was performed. Logistic regression was used to adjust for age, gender, arrival physiology, shock, injury severity, center effect, and treatment arm.

RESULTS

Among the 680 patients randomized, 547(80%) had admission thrombelastography (TEG) values available to determine fibrinolytic phenotypes. Compared to SD and PHYS, HF patients had higher Injury Severity Score (25 vs. 25 vs. 34), greater base deficit (−8 vs. −6 vs. −12) and were more uniformly hypocoagulable on admission by PT, PTT, and TEG values; all p <0.001. HF patients also received more red blood cells, plasma, and platelets (at 3, 6, and 24 hours); had fewer ICU-, ventilator-, and hospital-free days; and had higher 24-hour and 30-day mortality. There were no differences in complications between the three phenotypes. Multivariate logistic regression demonstrated that HF on admission was associated with a threefold higher mortality (OR 3.06, 95% CI 1.57–5.95, p = 0.001).

CONCLUSIONS

Previous data have shown that both the SD and HF phenotypes are associated with increased mortality and complications in the general trauma population. However, in a large cohort of bleeding patients, HF was confirmed to be a much more lethal and resource-intense phenotype. These data suggest that further research into the understanding of SD and HF is warranted to improve outcomes in this patient population.

LEVEL OF EVIDENCE

Prognostic, level II.
The coefficient of determinationR2and intra-class correlation coefficient from generalized linear mixed-effects models revisited and expanded
Authors: Nakagawa Shinichi , Johnson Paul C. D. , Schielzeth Holger
Published: September 2017

The coefficient of determinationR2quantifies the proportion of variance explained by a statistical model and is an important summary statistic of biological interest. However, estimatingR2for generalized linear mixed models (GLMMs) remains challenging. We have previously introduced a version ofR2that we calledfor Poisson and binomial GLMMs, but not for other distributional families. Similarly, we earlier discussed how to estimate intra-class correlation coefficients (ICCs) using Poisson and binomial GLMMs. In this paper, we generalize our methods to all other non-Gaussian distributions, in particular to negative binomial and gamma distributions that are commonly used for modelling biological data. While expanding our approach, we highlight two useful concepts for biologists, Jensen's inequality and the delta method, both of which help us in understanding the properties of GLMMs. Jensen's inequality has important implications for biologically meaningful interpretation of GLMMs, whereas the delta method allows a general derivation of variance associated with non-Gaussian distributions. We also discuss some special considerations for binomial GLMMs with binary or proportion data. We illustrate the implementation of our extension by worked examples from the field of ecology and evolution in theRenvironment. However, our method can be used across disciplines and regardless of statistical environments.
Mitotic post-translational modifications of histones promote chromatin compaction
in vitro
Authors: Zhiteneva Alisa , Bonfiglio Juan Jose , Makarov Alexandr , Colby Thomas , Vagnarelli Paola , Schirmer Eric C. , Matic Ivan , Earnshaw William C.
Published: September 2017

How eukaryotic chromosomes are compacted during mitosis has been a leading question in cell biology since the nineteenth century. Non-histone proteins such as condensin complexes contribute to chromosome shaping, but appear not to be necessary for mitotic chromatin compaction. Histone modifications are known to affect chromatin structure. As histones undergo major changes in their post-translational modifications during mitotic entry, we speculated that the spectrum of cell-cycle-specific histone modifications might contribute to chromosome compaction during mitosis. To test this hypothesis, we isolated core histones from interphase and mitotic cells and reconstituted chromatin with them. We used mass spectrometry to show that key post-translational modifications remained intact during our isolation procedure. Light, atomic force and transmission electron microscopy analysis showed that chromatin assembled from mitotic histones has a much greater tendency to aggregate than chromatin assembled from interphase histones, even under low magnesium conditions where interphase chromatin remains as separate beads-on-a-string structures. These observations are consistent with the hypothesis that mitotic chromosome formation is a two-stage process with changes in the spectrum of histone post-translational modifications driving mitotic chromatin compaction, while the action of non-histone proteins such as condensin may then shape the condensed chromosomes into their classic mitotic morphology.
An ant–plant mutualism through the lens of cGMP-dependent kinase genes
Authors: Malé Pierre-Jean G. , Turner Kyle M. , Doha Manjima , Anreiter Ina , Allen Aaron M. , Sokolowski Marla B. , Frederickson Megan E.
Published: September 2017

In plant–animal mutualisms, how an animal forages often determines how much benefit its plant partner receives. In many animals, foraging behaviour changes in response toforaginggene expression or activation of the cGMP-dependent protein kinase (PKG) thatforagingencodes. Here, we show that this highly conserved molecular mechanism affects the outcome of a plant–animal mutualism. We studied the two PKG genes ofAllomerus octoarticulatus,an Amazonian ant that defends the ant–plantCordia nodosaagainst herbivores. Some ant colonies are better ‘bodyguards’ than others. Working in the field in Peru, we found that colonies fed with a PKG activator recruited more workers to attack herbivores than control colonies. This resulted in less herbivore damage. PKG gene expression in ant workers correlated with whether an ant colony discovered an herbivore and how much damage herbivores inflicted on leaves in a complex way; natural variation in expression levels of the two genes had significant interaction effects on ant behaviour and herbivory. Our results suggest a molecular basis for ant protection of plants in this mutualism.
Neural evidence supports a dual sensory-motor role for insect wings
Authors: Pratt Brandon , Deora Tanvi , Mohren Thomas , Daniel Thomas
Published: September 2017

Flying insects use feedback from various sensory modalities including vision and mechanosensation to navigate through their environment. The rapid speed of mechanosensory information acquisition and processing compensates for the slower processing times associated with vision, particularly under low light conditions. While halteres in dipteran species are well known to provide such information for flight control, less is understood about the mechanosensory roles of their evolutionary antecedent, wings. The features that wing mechanosensory neurons (campaniform sensilla) encode remains relatively unexplored. We hypothesized that the wing campaniform sensilla of the hawkmoth,Manduca sexta,rapidly and selectively extract mechanical stimulus features in a manner similar to halteres. We used electrophysiological and computational techniques to characterize the encoding properties of wing campaniform sensilla. To accomplish this, we developed a novel technique for localizing receptive fields using a focused IR laser that elicits changes in the neural activity of mechanoreceptors. We found that (i) most wing mechanosensors encoded mechanical stimulus features rapidly and precisely, (ii) they are selective for specific stimulus features, and (iii) there is diversity in the encoding properties of wing campaniform sensilla. We found that the encoding properties of wing campaniform sensilla are similar to those for haltere neurons. Therefore, it appears that the neural architecture that underlies the haltere sensory function is present in wings, which lends credence to the notion that wings themselves may serve a similar sensory function. Thus, wings may not only function as the primary actuator of the organism but also as sensors of the inertial dynamics of the animal.
Older fathers' children have lower evolutionary fitness across four centuries and in four populations
Authors: Arslan Ruben C. , Willführ Kai P. , Frans Emma M. , Verweij Karin J. H. , Bürkner Paul-Christian , Myrskylä Mikko , Voland Eckart , Almqvist Catarina , Zietsch Brendan P. , Penke Lars
Published: September 2017

Higher paternal age at offspring conception increases de novo genetic mutations. Based on evolutionary genetic theory we predicted older fathers' children, all else equal, would be less likely to survive and reproduce, i.e. have lower fitness. In sibling control studies, we find support for negative paternal age effects on offspring survival and reproductive success across four large populations with an aggregate
N
> 1.4 million. Three populations were pre-industrial (1670–1850) Western populations and showed negative paternal age effects on infant survival and offspring reproductive success. In twentieth-century Sweden, we found minuscule paternal age effects on survival, but found negative effects on reproductive success. Effects survived tests for key competing explanations, including maternal age and parental loss, but effects varied widely over different plausible model specifications and some competing explanations such as diminishing paternal investment and epigenetic mutations could not be tested. We can use our findings to aid in predicting the effect increasingly older parents in today's society will have on their children's survival and reproductive success. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time periods.
Long-legged bees make adaptive leaps: linking adaptation to coevolution in a plant–pollinator network
Authors: Pauw Anton , Kahnt Belinda , Kuhlmann Michael , Michez Denis , Montgomery Graham A. , Murray Elizabeth , Danforth Bryan N.
Published: September 2017

Adaptation is evolution in response to natural selection. Hence, an adaptation is expected to originate simultaneously with the acquisition of a particular selective environment. Here we test whether long legs evolve in oil-collecting
Rediviva
bees when they come under selection by long-spurred, oil-secreting flowers. To quantify the selective environment, we drew a large network of the interactions between
Rediviva
species and oil-secreting plant species. The selective environment of each bee species was summarized as the average spur length of the interacting plant species weighted by interaction frequency. Using phylogenetically independent contrasts, we calculated divergence in selective environment and evolutionary divergence in leg length between sister species (and sister clades) of
Rediviva
. We found that change in the selective environment explained 80% of evolutionary change in leg length, with change in body size contributing an additional 6% of uniquely explained variance. The result is one of four proposed steps in testing for plant–pollinator coevolution.
Gordonia sternal wound infection treated with ceftaroline: case report and literature review
Authors: Akrami Kevan , Coletta Joelle , Mehta Sanjay , Fierer Joshua
Published: September 2017

Introduction. Case reports have emerged with identification of Gordonia bronchialis infections including sternal wound infections and foreign bodies such as central lines and shunts.

Case presentation. We present a case that demonstrates the need to consider Gordonia infection as a cause of sternal wound infection and highlights the utility of novel diagnostics to aid in the identification of unusual pathogens that can cause post-operative infections. We report here the first successful use of ceftaroline for treatment of a G. bronchialis sternal wound infection.

Conclusion. There are only case reports and in vitro assays to date to guide treatment of this infection, and we now add ceftaroline as a new drug to consider, though adequate surgical debridement is paramount.
In vivo relevance of intercellular calcium signaling inDrosophilawing development
Authors: Wu Qinfeng , Brodskiy Pavel A. , Huizar Francisco , Jangula Jamison J. , Narciso Cody , Levis Megan , Brito-Robinson Teresa , Zartman Jeremiah J.
Published: September 2017

Recently, organ-scale intercellular Ca2+transients (ICTs) were reported in the Drosophila wing disc. However, the functional in vivo significance of ICTs remains largely unknown. Here we demonstrate the in vivo relevance of intercellular Ca2+signaling and its impact on wing development. We report that Ca2+signaling in vivo decreases as wing discs mature. Ca2+signaling ex vivo responds to fly extract in a dose-dependent manner. This suggests ICTs occur in vivo due to chemical stimulus that varies in concentration during development. RNAi mediated inhibition of genes required for ICTs results in defects in the size, shape, and vein patterning of adult wings. It also leads to reduction or elimination of in vivo Ca2+transients. Further, perturbations to the extracellular matrix along the basal side of the wing disc stimulates intercellular Ca2+waves. This is the first identified chemically defined, non-wounding stimulus of ICTs. Together, these results point toward specific in vivo functions of intercellular Ca2+signaling to mediate mechanical stress dissipation and ensure robust patterning during development.
Motility-gradient induced elongation of the vertebrate embryo
Authors: Regev Ido , Guevorkian Karine , Pourquie Olivier , Mahadevan L
Published: September 2017

The body of vertebrate embryos forms by posterior elongation from a terminal growth zone called the Tail Bud (TB). The TB produces highly motile cells forming the presomitic mesoderm (PSM), a tissue playing an important role in elongation movements. PSM cells establish an anterior-posterior cell motility gradient which parallels the degradation of a specific cellular signal (Fgf8) known to be implicated in cell motility. Here, we combine electroporation of fluorescent reporters in the PSM to time-lapse imaging in the chicken embryo to quantify cell diffusive movements along the motility gradient. We show that simple microscopic and macroscopic mechano-chemical models for tissue extension that couple Fgf activity, cell motility and tissue rheology at both the cellular and continuum levels suffice to capture the speed and extent of elongation. These observations explain how the continuous addition of cells that exhibit a gradual reduction in motility combined with lateral confinement can be converted into an oriented movement that drives body elongation. The results of the models compare well with our experimental results, with implications for other elongation processes in the embryo.
Methylation-To-Expression Feature Models of Breast Cancer Accurately Predict Overall Survival, Distant-Recurrence Free Survival, And Pathologic Complete Response in Multiple Cohorts
Authors: Thompson Jeffrey A. , Christensen Brock C. , Marsit Carmen J.
Published: September 2017

Background:

Approaches that capitalize on the benefits of multi-omic data integration in invasive breast carcinoma to define prognostic biomarkers for precision medicine have been slow to emerge. In this work, we examined the efficacy of our methylation-to-expression feature model (M2EFM) approach to combining molecular and clinical predictors as part of a single analysis to create prognostic risk scores for overall survival, distant metastasis, and chemosensitivity.

Methods:

Gene expression and DNA methylation values as well as clinical variables were integrated via M2EFM to build prognostic models of overall survival using 1028 breast tumor samples and further applied to external validation cohorts of 61 and 327 samples. Data-integrated prognostic models of distant recurrence-free survival and pathologic complete response were built using 306 samples and validated on 182 samples of external validation data. Additionally, we compared the discrimination and calibration of M2EFM models to other approaches.

Results:

Despite different populations and assays, M2EFM models validated with good accuracy (C-index or AUC ≥ .7) for all outcomes in all validation data. M2EFM models had the most consistent performance overall and superior calibration, suggesting a greater likelihood of clinical utility. Finally, we demonstrated that M2EFM identifies functionally relevant genes, which could be useful in translating an M2EFM biomarker to the clinic.

Conclusion:

M2EFM uses multiple levels of genomic data to infer disrupted regulatory patterns, thus providing a gene signature that connects loss of regulatory control with cancer prognosis.

Funding:

The analyses described in this report were supported by NIH grants R01ES022222, P30CA138292, P30ES019776, and R01DE022772.

Conflicts of Interest:

The authors declare no potential conflicts of interest.
Impacts of Recurrent Hitchhiking on Divergence and Demographic Inference inDrosophila
Authors: Lange Jeremy D. , Pool John E.
Published: September 2017

In species with large population sizes such asDrosophila, natural selection may have substantial effects on genetic diversity and divergence. However, the implications of this widespread nonneutrality for standard population genetic assumptions and practices remain poorly resolved. Here, we assess the consequences of recurrent hitchhiking (RHH), in which selective sweeps occur at a given rate randomly across the genome. We use forward simulations to examine two published RHH models forD. melanogaster, reflecting relatively common/weak and rare/strong selection. We find that unlike the rare/strong RHH model, the common/weak model entails a slight degree of Hill-Robertson interference in high recombination regions. We also find that the common/weak RHH model is more consistent with our genome-wide estimate of the proportion of substitutions fixed by natural selection betweenD. melanogasterandD. simulans(19%). Finally, we examine how these models of RHH might bias demographic inference. We find that these RHH scenarios can bias demographic parameter estimation, but such biases are weaker for parameters relating recently-diverged populations, and for the common/weak RHH model in general. Thus, even for species with important genome-wide impacts of selective sweeps, neutralist demographic inference can have some utility in understanding the histories of recently-diverged populations.
Crossing enhanced and high fidelity SpCas9 nucleases to optimize specificity and cleavage
Authors: Kulcsér Péter István , Tálas András , Huszár Krisztina , Ligeti Zoltán , Tóth Eszter , Weinhardt Nóra , Fodor Elfrieda , Welker Ervin
Published: September 2017

Background

The propensity for off-target activity of Streptococcus pyogenes Cas9 (SpCas9) has been considerably decreased by rationally engineered variants with increased fidelity (eSpCas9; SpCas9-HF1). However, a subset of targets still generate considerable off-target effects. To deal specifically with these targets, we generated new "Highly enhanced Fidelity" nuclease variants (HeFSpCas9s) containing mutations from both eSpCas9 and SpCas9-HF1 and examined these improved nuclease variants side-by-side, to decipher the factors that affect their specificities and to determine the optimal nuclease for applications sensitive to off-target effects.

Results

These three increased-fidelity nucleases can routinely be used only with perfectly matching 20 nucleotide-long spacers; a matching 5' G extension being more detrimental to their activities than a mismatching one. HeFSpCas9s exhibit substantially improved specificity specifically for those targets for which eSpCas9 and SpCas9-HF1 have higher off-target propensity. There is also a ranking among the targets by their cleavability and off-target effects manifested by the increased fidelity nucleases. Furthermore, we show that the mutations in these variants may diminish the cleavage, but not the DNA-binding, of SpCas9s.

Conclusions

No single nuclease variant shows generally superior fidelity; instead, for highest specificity cleavage, each target needs to be matched with an appropriate high fidelity nuclease. We provide here a framework for generating new nuclease variants for targets that currently have no matching optimal nuclease, and offer a simple mean for identifying the optimal nuclease for targets in the absence of accurate target-ranking prediction tools.
Microcircuitry of Performance Monitoring
Authors: Sajad Amir , Godlove David C. , Schall Jeffrey D.
Published: September 2017

Cortical circuit mechanisms in medial frontal cortex enabling executive control are unknown. Hence, in monkeys performing a saccade countermanding task to earn larger or smaller fluid rewards, we sampled spiking and synaptic activity simultaneously across all layers of the supplementary eye field (SEF), an agranular cortical area contributing to performance monitoring in nonhuman primate and human studies. Laminar-specific synaptic currents with associated spike rate facilitation and suppression represented error production, reward gain or loss feedback, and reward delivery. The latency, polarity and magnitude of current and spike rate modulation were not predicted by the canonical cortical microcircuit. Pronounced synaptic currents in layer 2/3, which are modulated by loss magnitude, will contribute to the error-related negativity (ERN) and feedback-related negativity (FRN). These unprecedented findings reveal critical features of the cortical microcircuitry supporting performance monitoring and demonstrate that SEF can contribute to the error- and feedback-related negativity.
The Rome de Lisle problem
Authors: Voytekhovsky Yury L. , Stepenshchikov Dmitry G.
Published: September 2017

The `Rome de Lisle problem' on the vertex and edge truncations has been formulated and solved for all crystal closed simple forms (two, eight, five and 15 for orthorhombic, trigonal + hexagonal, tetragonal and cubic syngonies, respectively). The collections of simple forms obtained are enumerated and considered as special combinations of simple forms in symmetry classes.
Strategic organizational discourse and framing in hypermodal spaces
Authors: Ravazzani Silvia , Maier Carmen Daniela
Published: September 2017

Purpose

The purpose of this paper is to explore how organizations can strategically frame their legitimate perspective on a specific issue in order to gain salience and public support in a social media context.

Design/methodology/approach

By means of framing theory and a critical perspective on strategic discourse in hypermodal spaces, the study examines in detail the discursive strategies and framing processes employed by a non-profit organization that faces local and global contestation of its corporate operations.

Findings

Through a critical discourse analysis of the organization’s 385 Facebook posts during two periods of time, the results not only show how the corporate perspective is strategically framed and legitimized, but also challenged and consequently adapted in this hypermodal issue sub-arena. In addition to legitimizing the organizational perspective by providing evidence-based facts and external expert views as reliable and neutral sources, and echoing supporters’ voices and actions as further endorsements, the organization also strategically manages the Facebook dialogue by delegitimizing counterarguments.

Originality/value

This study contributes to the corporate communication field by revealing how framing can be materialized in specific discursive strategies aimed to legitimize and delegitimize. It shows how such strategies are interrelated in hypermodal clusters in ways that sustain the organizational discourse, and can evolve across time and within the same actor’s strategy. Methodologically, this study expands the research toolkit by introducing hypermodality in exploring framing and strategic organizational discourse.
Secrecy and communication: towards a research agenda
Authors: Fan Ziyun , Costas Jana , Grey Chris
Published: September 2017

Purpose

The purpose of this paper is to identify possible lines of research relating to communication and secrecy.

Design/methodology/approach

This paper is a conceptual essay drawing on recent research on secrecy.

Findings

The findings suggest that secrecy entails the communication of rules about communication, and that secrecy can play a role in the communicative constitution of organizations.

Originality/value

The paper is innovative in configuring secrecy as a form of communication rather than being the opposite of communication, and in showing the linkages between what are normally two separate domains of research.
You can lead a horse to water but you can’t make it drink: how effective is staff training in the prevention of abuse of adults?
Authors: Moore Steve
Published: September 2017

Purpose

The purpose of this paper is to present findings from a research project designed to determine the qualifications held by those staff who had perpetrated abuse in private sector care and nursing homes for older people during a 12-month period.

Design/methodology/approach

A self-completion, postal questionnaire was issued to the safeguarding teams of all local authorities in England with adult social care responsibilities to determine the qualifications held by staff who were proven to have perpetrated abuse in these facilities.

Findings

Though findings with respect to qualified nurses who had perpetrated abuse when considered in isolation were inconclusive in numerical terms, the proportion of all nursing and care staff who had perpetrated abuse, and who held either a professional or vocational qualification was high.

Research limitations/implications

Responses to the postal questionnaire represented 21.8 per cent of local authorities with social services responsibilities, yet the data secured suggests that care providing staff who have received recognised training are disproportionately represented among those proven to have perpetrated abuse.

Originality/value

Findings indicate that recognised training for those who provide care in care and nursing homes is of limited efficacy in the prevention of abuse.
Alamandine reverses hyperhomocysteinemia‐induced vascular dysfunction via PKA‐dependent mechanisms
Authors: Qaradakhi Tawar , Matsoukas Minos Timotheos , Hayes Alan , Rybalka Emma , Caprnda Martin , Rimarova Kvetoslava , Sepsi Milan , Büsselberg Dietrich , Kruzliak Peter , Matsoukas John , Apostolopoulos Vasso , Zulli Anthony
Published: September 2017

Introduction

Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium‐dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary.

Aim

We tested the hypothesis that alamandine, a vasoactive peptide of the renin‐angiotensin system (RAS), could reverse HHcy‐induced vascular dysfunction through the MrgD receptor and that this is mediated by the protein kinase A (PKA) pathway. Furthermore, we sought to determine a putative binding model of alamandine to the MrgD receptor through docking and molecular dynamics simulations.

Method

The abdominal aorta was excised from New Zealand white rabbits (n = 15) and incubated with 3 mmol/L Hcy (to mimic HHcy) to induce vascular dysfunction in vitro. Vascular function was assessed by vasodilatory responses to cumulative doses of acetylcholine.

Result

Vasodilation was significantly impaired in HHcy‐incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0%; Hcy, 30.3 ± 9.8%; alamandine + Hcy, 59.7 ± 4.8%, P < .0001). KT5720 (PKA inhibitor) significantly inhibited the ability of alamandine to attenuate the impaired vasodilation caused by HHcy (KT5720 + Hcy + alamandine, 27.1 ± 24.1, P < .01). Following immunohistochemistry analysis, the MrgD receptor was highly expressed within the media and endothelial layer of aortic rings in HHcy compared to control (media: 0.23 ± 0.003 vs control 0.16 ± 0.01, P < .05 and endothelium: 0.68 ± 0.07 vs control 0.13 ± 0.02, P < .01, in PA/I (A.U) units). Computational studies also propose certain interactions of alamandine within the MrgD transmembrane domain.

Conclusion

This study shows that alamandine is effective in reversing HHcy‐induced vascular dysfunction, possibly through the PKA signaling pathway via MrgD. Our results indicate a therapeutic potential of alamandine in reversing the detrimental effects of HHcy.
Effects of red blood cell storage time on transfused patients in the ICU—protocol for a systematic review
Authors: Rygård S. L. , Jonsson A. B. , Madsen M. B. , Perner A. , Holst L. B. , Johansson P. I. , Wetterslev J.
Published: September 2017

Background

Patients in the intensive care unit (ICU) are often anaemic due to blood loss, impaired red blood cell (RBC) production and increased RBC destruction. In some studies, more than half of the patients were treated with RBC transfusion. During storage, the RBC and the storage medium undergo changes, which lead to impaired transportation and delivery of oxygen and may also promote an inflammatory response. Divergent results on the clinical consequences of storage have been reported in both observational studies and randomised trials. Therefore, we aim to gather and review the present evidence to assess the effects of shorter vs. longer storage time of transfused RBCs for ICU patients.

Methods

We will conduct a systematic review with meta‐analyses and trial sequential analyses of randomised clinical trials, and also include results of severe adverse events from large observational studies. Participants will be adult patients admitted to an ICU and treated with shorter vs. longer stored RBC units. We will systematically search the Cochrane Library, MEDLINE, Embase, BIOSIS, CINAHL and Science Citation Index for relevant literature, and we will follow the recommendation by the Cochrane Collaboration and the Preferred Reporting Items for Systemtic Review and Meta‐Analysis (PRISMA)‐statement. We will assess the risk of bias and random errors, and we will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the overall quality of evidence.

Conclusion

We need a high‐quality systematic review to summarise the clinical consequences of RBC storage time among ICU patients.
Return of spontaneous circulation and long‐term survival according to feedback provided by automated external defibrillators
Authors: Agerskov M. , Hansen M. B. , Nielsen A. M. , Møller T. P. , Wissenberg M. , Rasmussen L. S.
Published: September 2017

Background

We aimed to investigate the effect of automated external defibrillator (AED) feedback mechanisms on survival in out‐of‐hospital cardiac arrest (OHCA) victims. In addition, we investigated converting rates in patients with shockable rhythms according to AED shock waveforms and energy levels.

Methods

We collected data on OHCA occurring between 2011 and 2014 in the Capital Region of Denmark where an AED was applied prior to ambulance arrival. Patient data were obtained from the Danish Cardiac Arrest Registry and medical records. AED data were retrieved from the Emergency Medical Dispatch Centre (EMDC) and information on feedback mechanisms, energy waveform and energy level was downloaded from the applied AEDs.

Results

A total of 196 OHCAs had an AED applied prior to ambulance arrival; 62 of these (32%) provided audio visual (AV) feedback while no feedback was provided in 134 (68%). We found no difference in return of spontaneous circulation (ROSC) at hospital arrival according to AV‐feedback; 34 (55%, 95% confidence interval (CI) [13–67]) vs. 72 (54%, 95% CI [45–62]), P = 1 (odds ratio (OR) 1.1, 95% CI [0.6–1.9]) or 30‐day survival; 24 (39%, 95% CI [28–51]) vs. 53 (40%, 95% CI [32–49]), P = 0.88 (OR 1.1 (95% CI [0.6–2.0])). Moreover, we found no difference in converting rates among patients with initial shockable rhythm receiving one or more shocks according to AED energy waveform and energy level.

Conclusions

No difference in survival after OHCA according to AED feedback mechanisms, nor any difference in converting rates according to AED waveform or energy levels was detected.
Sudden cardiac death in isolated right ventricular hypertrabeculation/noncompaction cardiomyopathy
Authors: Bekheit Soad , Karam Boutros , Daneshvar Farshid , Zaidan Julie , Tabet Rabih , Spagnola Jonathan , Lafferty James
Published: September 2017

Hypertrabeculation/noncompaction of the myocardium is a rare disorder that involves most commonly the left ventricle of the heart and it has been recognized as a distinct cardiomyopathy by the World Health Organization. However, it is extremely rare for this condition to involve exclusively the right ventricle. We report the cases of three patients who presented with ventricular tachyarrhythmia and sudden cardiac death. They were found to have isolated right ventricular hypertrabeculation/noncompaction on echocardiography. This supports the hypothesis that this condition is highly arrhythmogenic and is associated with high mortality similarly to the left ventricular hypertrabeculation/noncompaction cardiomyopathy.
Specificity of wide QRS complex tachycardia criteria and algorithms in patients with ventricular preexcitation
Authors: Jastrzębski Marek , Moskal Paweł , Kukla Piotr , Fijorek Kamil , Kisiel Roksana , Czarnecka Danuta
Published: September 2017

Background

Despite substantial progress in the field of differentiation between ventricular tachycardia (VT) and supraventricular tachycardia (SVT) with wide QRS complexes, differentiation between VT and preexcited SVT remains largely unresolved due to significant overlap in QRS morphology. Our aim was to assess the specificities of various single ECG criteria and sets of criteria (Brugada algorithm, aVR algorithm, Steurer algorithm, and the VT score) for diagnosis of VT in a sizable cohort of patients with preexcitation.

Methods

We performed a retrospective study of consecutive accessory pathway ablation procedures to identify preexcited tachycardias. Among 670 accessory pathway ablation procedures, 329 cases with good quality ECG with either bona fide preexcited SVT (n = 30) or a surrogate preexcited SVT (fast paced atrial rhythm with full preexcitation, n = 299) were identified. ECGs were analyzed with the use of wide QRS complex algorithms/criteria to determine specificities of these methods.

Results

The Steurer algorithm and VT score (≥3 points), with specificities of 97.6% and 96.1%, respectively, were significantly (p < .01) more specific for the diagnosis of VT than Brugada algorithm, aVR algorithm, and Pava criterion with specificities of 31%, 11.6%, and 57.1%, respectively. The first step of the Brugada algorithm and the first step of the aVR algorithm had also high specificities of 93.3% and 96.0%, respectively.

Conclusion

There are sufficient electrocardiographical differences between VT and preexcited SVT to allow electrocardiographic differentiation. VT score, Steurer algorithm, and some single criteria do not overdiagnose VT in patients with preexcitation.
Total cosine R‐to‐T for predicting ventricular arrhythmic and mortality outcomes: A systematic review and meta‐analysis
Authors: Tse Gary , Gong Mengqi , Wong Cheuk Wai , Chan Cynthia , Georgopoulos Stamatis , Chan Yat Sun , Yan Bryan P. , Li Guangping , Whittaker Paula , Ciobanu Ana , Ali‐Hasan‐Al‐Saegh Sadeq , Wong Sunny H. , Wu William K. K. , Bazoukis George , Lampropoulos Konstantinos , Wong Wing Tak , Tse Lap Ah , Baranchuk Adrian M. , Letsas Konstantinos P. , Liu Tong ,   International Health Informatics Study (IHIS) Network
Published: September 2017

Background

The total cosine R‐to‐T (TCRT), a vectorcardiographic marker reflecting the spatial difference between the depolarization and repolarization wavefronts, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in different clinical settings. However, its prognostic value has been controversial.

Objective

This systematic review and meta‐analysis evaluated the significance of TRCT in predicting arrhythmic and/or mortality endpoints.

Methods

PubMed and Embase databases were searched through December 31, 2016.

Results

Of the 890 studies identified initially, 13 observational studies were included in our meta‐analysis. A total of 11,528 patients, mean age 47 years old, 72% male, were followed for 43 ± 6 months. Data from five studies demonstrated lower TCRT values in myocardial infarction patients with adverse events (syncope, ventricular arrhythmias, or sudden cardiac death) compared to those without these events (mean difference = −0.36 ± 0.05, p < .001; I2 = 48%). By contrast, only two studies analyzed outcomes in heart failure, and pooled meta‐analysis did not demonstrate significant difference in TCRT between event‐positive and event‐negative patients (mean difference = −0.01 ± 0.10, p > .05; I2 = 80%).

Conclusion

TCRT is lower in MI patients at high risk of adverse events when compared to those free from such events. It can provide additional risk stratification beyond the use of clinical parameters and traditional electrocardiogram markers. Its value in other diseases such as heart failure requires further studies.