bluuebunny/crossref_metadata_2025 huggingface dataset:
Chiron: Translating nanopore raw signal directly into nucleotide sequence using deep learning
Authors: Teng Haotian , Cao Minh Duc , Hall Michael B. , Duarte Tania , Wang Sheng , Coin Lachlan J.M.
Published: August 2017

Sequencing by translocating DNA fragments through an array of nanopores is a rapidly maturing technology which offers faster and cheaper sequencing than other approaches. However, accurately deciphering the DNA sequence from the noisy and complex electrical signal is challenging. Here, we report Chiron, the first deep learning model to achieve end-to-end basecalling: directly translating the raw signal to DNA sequence without the error-prone segmentation step. Trained with only a small set of 4000 reads, we show that our model provides state-of-the-art basecalling accuracy even on previously unseen species. Chiron achieves basecalling speeds of over 2000 bases per second using desktop computer graphics processing units.
Meta-analysis and Commentary: Preemptive Correction of Arteriovenous Access Stenosis
Authors: Raimann Jochen G. , Waldron Levi , Koh Elsie , Miller Gregg A. , Sor Murat H. , Gray Richard J. , Kotanko Peter
Published: August 2017

Background

A recent meta-analysis by Ravani and colleagues (Ravani, P., et al., Am J Kidney Dis, 2016. 67(3): p. 446-60.) studied the effect of pre-emptive correction of arterio-venous dialysis vascular access versus deferred care, based on data from 11 trials. The authors reported a non-significant protective treatment effect of pre-emptive correction on access loss, while showing a significant protective effect on thrombosis rates conferred by pre-emptive correction. We revisit this analysis, including data extraction and effects of a heterogenous study population.

Methods

We repeated data extraction from all referenced publications in the meta-analysis by Ravani et al. and corrected event counts where applicable. We repeated the meta-analyses with access loss as the outcome for studies that recruited patients with arterio-venous fistulae (AVF) and grafts (AVG), respectively, using a random effects model with relative risk (RR) and risk difference (RD) of access loss as the outcomes of interest. We repeated data extraction from all referenced publications, and corrected event counts where applicable.

Results

Our conclusions differ from the original findings in two ways. First, after some amendment of the event counts extracted from Mayer et al. (Vascular and Endovascular Surgery 1993), we find a significant overall positive effect of pre-emptive correction on arterio-venous access loss in the overall study population [RR 0.80 (95% CI 0.64 to 0.99), RD −0.07 (95% CI −0.12 to −0.02); Figure 1]. Secondly, we highlight the impact of heterogeneous study populations on the meta-analysis. Whereas the data do not conclusively show a benefit of pre-emptive correction for arteriovenous grafts (AVG; RR = 0.87, 95% CI: 0.69 – 1.11), they show a strong protective effect for arteriovenous fistulae (AVF; RR = 0.5, 95% CI: 0.29 to 0.86).

Figure 1:

Meta-analysis of access loss, overall and by access type using risk ratio (RR) as the measure of association.

Discussion and Conclusion

These findings corroborate clinical arguments such as superior long-term patency of AVF and the nature of AVG failure that often involve infectious causes. The available data indicate mild or no benefit of pre-emptive correction for AVG, but strongly support tight monitoring of dialysis accesses and preemptive intervention and correction upon the slightest suspicion of access stenosis for AVF.
Medical relevance of protein-truncating variants across 337,208 individuals in the UK Biobank study
Authors: DeBoever Christopher , Tanigawa Yosuke , McInnes Greg , Lavertu Adam , Chang Chris , Bustamante Carlos D. , Daly Mark J. , Rivas Manuel A.
Published: August 2017

Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. We characterized the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and found 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We performed phenome-wide analyses and directly measured the effect of homozygous carriers, commonly referred to as “human knockouts,” across medical phenotypes for genes implicated to be protective against disease or associated with at least one phenotype in our study and found several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.
A risk stratification model for lung cancer based on gene coexpression network
Authors: Choi Hongyoon , Na Kwon Joong
Published: August 2017

Risk stratification model for lung cancer with gene expression profile is of great interest. Instead of the previously reported models based on individual prognostic genes, we aimed to develop a novel system-level risk stratification model for lung adenocarcinoma based on gene coexpression network. Using multiple microarray datasets obtained from lung adenocarcinoma, gene coexpression network analysis was performed to identify survival-related network modules. Representative genes of these network modules were selected and then, risk stratification model was constructed exploiting deep learning algorithm. The model was validated in two independent test cohorts. Survival analysis using univariate and multivariate Cox regression was performed using the output of the model to evaluate whether the model could predict patients’ overall survival independent of clinicopathological variables. Five network modules were significantly associated with patients’ survival. Considering prognostic significance and representativeness, genes of the two survival-related modules were selected for input data of the risk stratification model. The output of the model was significantly associated with patients’ overall survival in the two independent test sets as well as training set (p < 0.00001, p < 0.0001 and p = 0.02 for training set, test set 1 and 2, respectively). In multivariate analyses, the model was associated with patients’ prognosis independent of other clinical and pathological features. Our study presents a new perspective on incorporating gene coexpression networks into the gene expression signature, and the clinical application of deep learning in genomic data science for prognosis prediction.
A Mathematical model to predict Trichodesmiunspp. bloom during a sewage burst
Authors: Rosales Guido Santos
Published: August 2017

A modified version of the Monod equation is proposed to understand the bloom emergence ofTrichodesmiun spp. in presence of sewage outburst. The mathematical model predicts that the bacterial population does not affect the bloom growth. Also, the quotient between the bacteria during the sewage outburst and before is proposed to be equal to the quotient between the influx of limiting resources during burst and the influx before the burst.
Financial constraints and optimal working capital – evidence from an emerging market
Authors: Chauhan Gaurav S. , Banerjee Pradip
Published: August 2017

Purpose

The purpose of this paper is to investigate the existence of an optimal or target level of working capital for the Indian manufacturing firms, and whether firms intensely follow the target or not.

Design/methodology/approach

The paper uses cash conversion cycle as a measure of net working capital and employs partial-adjustment dynamic panel models to test its target-following behavior.

Findings

The empirical results show that there is no evidence of systematic target-following behavior of working capital for the Indian manufacturing firms. The results hold true even after dividing the sample into four groups depending on the sign and magnitude of deviation. The results further show that lack of target-following tendency is not quite influenced by varying firm-specific characteristics and, therefore, seems to be a systematic feature across firms in India.

Research limitations/implications

Scarcity of such working capital management studies across emerging economies, facing several financial constraints, limits the comparison of findings. Future studies should be conducted to confirm the results.

Practical implications

The findings imply that even though an optimal working capital might exist, emerging market firms may not be able to actively pursue it on account of several financial constraints and managerial considerations.

Originality/value

The study contributes to the scant existing literature on the target-following behavior of working capital management in the Indian manufacturing firms, representing a typical emerging market facing several financial constraints.
Rhetorical strategies in Indian commercial microfinance
Authors: Sarma Sushanta Kumar
Published: August 2017

Purpose

This paper examines the rhetorical strategies of two Indian microfinance organizations as they transformed from non-profit to commercial format. They shifted forms at a time (year 2010), when commercialization had been criticized severely. The purpose of this paper is to understand “How does a microfinance organization justify its action of transformation to retain legitimacy?”

Design/methodology/approach

The paper adopts a qualitative case study method to understand the phenomena. Interview, archival documents, and field observations are the major source of data for the study. Data analysis is carried out through coding method.

Findings

Drawing from Suddaby and Greenwood’s (2005) work on rhetorical strategies, the paper suggests that these organizations have used two types of rhetorical strategies – cosmological and teleological. These strategies operate in a performative role and link deviant practices with routines. It focuses on institutional maintenance rather than change.

Research limitations/implications

The paper acknowledges two important limitations. First, the rhetorical focus may be influenced by the history of organization. So depending on organization selected, the focus may vary. Second, the paper is constricted by the low-documentation practices prevailing in many civil society organizations.

Originality/value

The paper contributes to the literature on hybrid organization by unpacking the process of sense making in a hybrid form. The paper also reinforces the argument that language operates in a performative role. The paper provides a new context (India) to understand the process of rhetorical strategies.
Physical activity promotion in care homes
Authors: Turpie Lindsay , Whitelaw Sandy , Topping Christopher
Published: August 2017

Purpose

The purpose of this paper is to report on the implementation of a physical activity (PA) scheme – Let’s Motivate (LM) – within private care homes (CHs) in Dumfries and Galloway (D&G), Scotland; aiming to provide an insight into the different factors which might contribute to its success and further sustainability.

Design/methodology/approach

A qualitative study is described in which one-to-one semi-structured interviews were carried out with eight key staff involved in implementing the project within two purposively sampled CHs; in order to explore their views and experiences of implementation.

Findings

The paper provides an insight into the different factors which stand to both promote and impede the successful implementation of LM, within the two CHs involved.

Originality/value

This paper explores a new and innovative PA initiative in CHs in D&G, Scotland. Studies exploring the factors which can both promote and impede implementation are important as they can help to usefully inform the implementation and sustainability of initiatives.
Disseminated cutaneous Mycobacterium kansasii infection presenting with Rosai–Dorfman disease‐like histological features in a patient carrying anti‐interferon‐γ autoantibodies
Authors: King Yih‐An , Hu Chung‐Hong , Lee Yuarn‐Jang , Lin Chiou‐Feng , Liu Donald , Wang Kuo‐Hsien
Published: August 2017

Typical cutaneous non‐tuberculous mycobacteria (NTM) infections show a histopathology pattern of granulomas with admixed Langhans giant cells, and abscesses may be observed in acute lesions. Herein, we describe a patient carrying a high titer of autoantibodies to interferon (IFN)‐γ with disseminated Mycobacterium kansasii infection presenting with emperipolesis and Rosai–Dorfman disease (RDD)‐like histopathological features characterized by remarkable, large, pale‐staining “RD cells”, which were CD68 and S100 positive and CD1a negative. The patient was misdiagnosed with RDD initially, but exhibited a poor response to all interventions. A re‐biopsy revealed Langhans‐type multinucleated giant cells; multiple definite acid‐fast bacilli were also found. M. kansasii was isolated from cultured tissues. Anti‐NTM treatment was initiated. After treatment, all lesions resolved almost completely within the following month. High‐titer anti‐IFN‐γ autoantibodies were detected during follow up, leading to the diagnosis of adult‐onset immunodeficiency syndrome. In conclusion, patients carrying high‐titer autoantibodies to IFN‐γ who also have a disseminated cutaneous M. kansasii infection may present with RDD‐like histopathological features, which may be a pitfall in the diagnosis of disseminated cutaneous NTM infections.
Simulated moult reduces flight performance but overlap with breeding does not affect breeding success in a long‐distance migrant
Authors: Tomotani Barbara M. , Muijres Florian T. , Koelman Julia , Casagrande Stefania , Visser Marcel E.
Published: August 2017

Long‐distance migrants are time‐constrained as they need to incorporate many annual cycle stages within a year. Migratory passerines moult in the short interval between breeding and migration. To widen this interval, moult may start while still breeding, but this results in flying with moulting wings when food provisioning.

We experimentally simulated wing gaps in breeding male pied flycatchers by plucking two primary feathers from both wings. We quantified the nest visitations of both parents, proportion of high‐quality food brought to the nestlings and adults and nestlings condition. Differences in oxidative damage caused by a possible reduction in flight efficiency were measured in amounts of ROMs and OXY in the blood. We also measured how flight performance was affected with recordings of the male`s escape flight using high‐speed cameras. Finally, we collected data on adult survival, clutch size and laying date in the following year.

“Plucked” males travelled a 5% shorter distance per wingbeat, showing that our treatment reduced flight performance. In line with this, “plucked” males visited their nests less often. Females of “plucked” males, however, visited the nest more often than controls, and fully compensated their partner's reduced visitation rate. As a result, there were no differences between treatments in food quality brought to the nest, adult or chick mass or number of successfully fledged chicks. Males did not differ in their oxidative damage or local survival to the following year. In contrast, females paired with plucked males tended to return less often to breed in the next year in comparison to controls, but this difference was not significant. For the birds that did return, there were no effects on breeding.

Our results reveal that wing gaps in male pied flycatchers reduce their flight performance, but when it occurs during breeding they prioritise their future reproduction by reducing parental care. As a result, there is no apparent detriment to their condition during breeding. Because non‐moulting females are able to compensate their partner's reduced care, there is also no immediate cost to the offspring, but females may pay the cost suffering from a reduced survival.

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Transient exposure to oxygen or nitrate reveals ecophysiology of fermentative and sulfate‐reducing benthic microbial populations
Authors: Saad Sainab , Bhatnagar Srijak , Tegetmeyer Halina E. , Geelhoed Jeanine S. , Strous Marc , Ruff S. Emil
Published: August 2017

For the anaerobic remineralization of organic matter in marine sediments, sulfate reduction coupled to fermentation plays a key role. Here, we enriched sulfate‐reducing/fermentative communities from intertidal sediments under defined conditions in continuous culture. We transiently exposed the cultures to oxygen or nitrate twice daily and investigated the community response. Chemical measurements, provisional genomes and transcriptomic profiles revealed trophic networks of microbial populations. Sulfate reducers coexisted with facultative nitrate reducers or aerobes enabling the community to adjust to nitrate or oxygen pulses. Exposure to oxygen and nitrate impacted the community structure, but did not suppress fermentation or sulfate reduction as community functions, highlighting their stability under dynamic conditions. The most abundant sulfate reducer in all cultures, related to Desulfotignum balticum, appeared to have coupled both acetate‐ and hydrogen oxidation to sulfate reduction. We describe a novel representative of the widespread uncultured candidate phylum Fermentibacteria (formerly candidate division Hyd24‐12). For this strictly anaerobic, obligate fermentative bacterium, we propose the name ‘USabulitectum silens’ and identify it as a partner of sulfate reducers in marine sediments. Overall, we provide insights into the function of fermentative, as well as sulfate‐reducing microbial communities and their adaptation to a dynamic environment.
House price to income ratio and fundamentals: Evidence on long‐horizon forecastability
Authors: Chen Nan‐Kuang , Cheng Han‐Liang
Published: August 2017

This paper studies the relationship between the house price‐to‐income ratio (PIR) and economic fundamentals, and investigates the long‐horizon forecastability of the PIR. We first construct a small DSGE model to derive a dynamic expression of PIR, linking PIR to macroeconomic fundamentals and the stance of monetary policy. Based on the theoretically derived PIR, variance decomposition suggests that interest rate and real income growth appear to be the main sources for the deviations of PIR. Using the difference between actual PIR and the estimated fundamental PIR as the predictor, we find that both in‐sample and out‐of‐sample forecastability of the PIR over the future dynamics of PIR are significant.
Effects of capital flow on the equity and housing markets in Hong Kong
Authors: Cheung Yin‐Wong , Chow Kenneth K. , Yiu Matthew S.
Published: August 2017

The revival of strong capital flows to emerging economies following the global financial crisis in 2008–2009 has rekindled the debate on effects of excessive capital inflows. We study the effects of official and illicit capital flows on Hong Kong, which is a small and open economy with minimal restrictions on cross‐border fund movements. It is found that the official and illicit capital flow measures display a low level of comovement and exhibit differential effects on Hong Kong's equity and residential housing markets. The results highlight the complexity of managing capital flows, and the relevance of sector‐specific capital management policies.
Listeria monocytogenes survival during production and storage of water buffalo Mozzarella cheese
Authors: Murru Nicoletta , Peruzy Maria Francesca , De Carlo Esterina , Mercogliano Raffaelina , Aponte Maria , Morena Carmelo , Serluca Giovanna , Fraulo Pasquale
Published: August 2017

The ability of Listeria monocytogenes to survive during the manufacture of water buffalo Mozzarella and to grow during its shelf life was evaluated. A wild‐type and a reference strain were used to contaminate raw milk. The viable count of the reference strain ATCC 9525 dropped after the stretching process, and in the cheese, it fell to below 100 cfu/g. When the wild‐type strain was used, however, stretching did not appear to have any effect on the pathogen. The artificially contaminated cheeses were stored, for eleven days, at 4, 20 and 30 °C. Pathogen populations increased at 20 (≈2.60 log cfu/g) and 30 °C (≈1.95 log cfu/g).
Hydrography shapes community composition and diversity of amoA‐containing Thaumarchaeota in the coastal waters off central Chile
Authors: Bertagnolli Anthony D. , Ulloa Osvaldo
Published: August 2017

Thaumarchaea are often abundant in low oxygen marine environments, and recent kinetic studies indicate a capacity for aerobic ammonia oxidation at vanishingly low oxygen levels (nM). However, molecular diversity surveys targeting this group to high sequencing coverage are limited, and how these populations are coupled to changes in dissolved oxygen remains unknown. In this study, the ammonia monooxygenase subunit A (amoA) gene was sequenced from samples collected in the Chilean coast (36.5 °S), a system prone to recurrent seasonal hypoxia and anoxia, at several depths over one year, to read depths that saturated coverage statistics. Temperature, salinity and depth displayed a stronger impact on community composition than chemical and biological variables, such as dissolved oxygen. The Nitrosopumilus water‐column A clade (WCA) displayed high proportional representation in all samples (42%–100% of all amoA OTUs). The two dominant WCA OTUs displayed differences in their distributions that were inversely correlated with one another, providing the first evidence for intra‐subgroup specific differences in the distributions among closely related WCA Thaumarcheota. Nitrosopumilus water‐column B (WCB) representatives displayed increased proportional abundances (42%) at deeper depths during the spring and summer, were highly coupled to decreased dissolved oxygen conditions and were non‐detectable during the austral winter. The depth of sequencing also enabled observation of lower abundance taxa that are typically not observed in marine environments, such as members of the genus Nitrosotalea amid austral winter surface waters. This study highlights a strong coupling between Thaumarchaeal community diversity and hydrographic variables, is the first to highlight intra‐subclade depth specific shifts in community diversity amongst members of the WCA clade, and links the WCB clade to upwelling conditions associated with seasonal oxygen depletion.
Why Do Overconfident REIT CEOs Issue More Debt? Mechanisms and Value Implications
Authors: Tan Kelvin Jui Keng
Published: August 2017

This paper examines why overconfident CEOs issue more debt than equity within US Real Estate Investment Trusts (REITs) and the value implications of this debt preference. Consistent with a demand‐side story, the paper finds that overconfident CEOs choose to issue more debt than equity than their non‐overconfident counterparts. The findings also rule out the supply‐side story that overconfident CEOs are screened out of the equity market. CEO preference for debt is associated with a decline in shareholder wealth. Specifically, using an event study, the paper finds that overconfident CEOs suffer an approximately $67 million loss associated with debt issues in market capitalization. Further analysis suggests that the loss stems from the higher default risk induced by overconfident REIT CEOs’ debt preference. The demand‐side explanation remains robust even after considering several CEO demographics, estimation methods, and the following five possible alternative drivers of the main results: (1) insider information; (2) risk tolerance; (3) past performance; (4) dividends; and (5) board pressure.
Prospective Validation of Clinical Score for Males Presenting With an Acute Scrotum
Authors: Frohlich Lillian C. , Paydar‐Darian Niloufar , Cilento Bartley G. , Lee Lois K.
Published: August 2017

Objective

The objective was to validate the Testicular Workup for Ischemia and Suspected Torsion (TWIST) score among pediatric emergency medicine providers for the evaluation of pediatric males presenting with testicular pain and swelling (acute scrotum).

Methods

We conducted a prospective cohort study of males 3 months to 18 years old presenting with an acute scrotum. History and physical examination findings, including components of the TWIST score (hard testicle, absent cremasteric reflex, nausea/vomiting, and high riding testicle) as well as diagnostic results (ultrasound, urine, sexually transmitted infection testing) were recorded. Testicular torsion was confirmed by surgical exploration. Frequencies of patient characteristics, TWIST components, and tests were calculated. We performed the kappa statistic for inter‐rater reliability and calculated the test characteristics and receiver operator characteristics curves for the TWIST score (range = 0–7).

Results

During the study period 258 males were enrolled in the study; 19 (7.4%) had testicular torsion. The mean (±SD) age was 9.8 (±0.3) years. The high‐risk TWIST score of 7 had 100% specificity (95% confidence interval [CI] = 98%–100%) with 100% positive predictive value (95% CI = 40%–100%) for testicular torsion. The area under the curve was 0.82. The kappa statistic for the overall TWIST score was fair at 0.39.

Conclusions

In this prospective validation of the TWIST score among pediatric emergency providers, the high‐risk score demonstrated strong test characteristics for testicular torsion. The TWIST score could be used as part of a standardized approach for evaluation of the pediatric acute scrotum to provide more efficient and effective care.
Water depletion drives plant succession in farm ponds and overrides a legacy of continuous anthropogenic disturbance
Authors: Toyama Fumiya , Akasaka Munemitsu
Published: August 2017

Questions

Abandonment of anthropogenic ecosystems threatens biodiversity in rural areas globally. Successional responses in anthropogenic ecosystems have been shown to differ from those in natural ecosystems because of the legacy of continuous management activities. However, few studies have focused on successional changes in anthropogenic freshwater ecosystems following abandonment. Focusing on two drivers (water depletion and cessation of anthropogenic disturbance), we tested whether water depletion plays a larger role than years since abandonment in determining the both plant functional diversity and composition in farm ponds.

Location

Awaji Island, western Japan.

Methods

We investigated flora at 200 farm ponds, which had experienced long‐term continuous anthropogenic disturbance. We interviewed 100 managers of the surveyed ponds and local farmers to identify the ponds’ management status. To capture community processes during succession, we focused on functional richness and functional trait composition. We assessed the relative contribution of the two successional drivers in determining functional richness by adopting a linear model. We classified the survey ponds into five groups based on the two successional drivers and performed PERMANOVA to test differences in functional composition among the groups.

Results

Water depletion played a larger role than elapsed time since cessation of anthropogenic disturbance in determining functional richness. Functional composition of water‐depleted ponds significantly differed from that of managed ponds, regardless of years since abandonment.

Conclusions

Our results indicate that water depletion has a larger effect on successional changes in ponds than cessation of anthropogenic disturbance; that is, water depletion drives succession and overrides the legacy of continuous anthropogenic disturbance. The results suggest that, in freshwater ecosystems, the functional change in a community is greater in the transition from macrophytes to terrestrial plants than it is in the transition from stress‐tolerant species to competitive species.
Phenotypic differentiation analysis: A case study in hybridizing Çoruh trout (Salmo coruhensis), Rize trout (Salmo rizeensis) and brown trout (Salmo trutta fario)
Authors: Kocabaş Mehmet , Kutluyer Filiz , Başçinar Nadir
Published: August 2017

The aim of this study was to determine and compare the phenotypic variation in Çoruh trout (Salmo coruhensis), Rize trout (Salmo rizeensis), brown trout (Salmo trutta fario) and their native hybrids (S. rizeensis × S. t. fario;S. t. fario × S. coruhensis;S. rizeensis × S. coruhensis). The numbers and diameters of red and black spots were determined on operculum, fins and above and below the lateral line. The results from this study indicate that there were differences in spotting pattern, colour pattern or fin pigmentation traits betweenS. rizeensis,S. t. fario,S. coruhensisand their hybrids. Consequently, nativeS. rizeensis,S. t. farioandS. coruhensiswere affected by interaction and phenotypic plastic aspects of traits inS. rizeensiswere dominant in their hybrids (S. rizeensis × S. t. fario;S. rizeensis × S. coruhensis).
Assessment of Appropriateness of an Initial Dosing Regimen of Vancomycin and Development of a New Dosing Nomogram
Authors: Yoon Seonghae , Park Kyoung Ryun , Lee SeungHwan , Song Sang‐Hoon , Park Wan Beom , Jang In‐Jin , Yu Kyung‐Sang
Published: August 2017

Vancomycin is a glycopeptide antibiotic used to treat Gram‐positive infections including methicillin‐resistant Staphylococcus aureus (MRSA). The objectives of this study were to evaluate the appropriateness of the initial dosing regimen of vancomycin, identify factors to be considered in regimen selection and develop a new dosing nomogram. Therapeutic drug monitoring (TDM) data of vancomycin obtained from Seoul National University Hospital from 2011 to 2013 were included in this analysis. The vancomycin trough concentrations at steady‐state were estimated using Abbott's PKS software program and then categorized into three levels: subtherapeutic, therapeutic and toxic. The newly developed nomograms were evaluated by analysing the percentage of patients with target vancomycin trough concentration using the data of 2,570 patients of the first TDM cases. Therapeutic level was achieved only in approximately one‐fifth of the cases, while 56.0% and 23.8% of the TDMs were considered subtherapeutic and toxic, respectively. As body‐weight and creatinine clearance (CrCL) increased, the proportion of patients with a subtherapeutic level increased. Using the newly developed nomogram increased the proportion of patients who achieved therapeutic levels from 23.1% to 45.0% or 13.8% to 36.2% (target, 10–15 and 15–20 mg/L, respectively). These results suggest that the vancomycin concentrations fail to reach the therapeutic level or exceed the safe upper margin of the therapeutic level depending on age, body‐weight and CrCL. Considering these factors, the new nomograms provide a strategy to achieve target concentrations of vancomycin more rapidly than existing regimens.
Evaluation of Post‐Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation
Authors: Sjöholm Louise K. , Ransome Yusuf , Ekström Tomas J. , Karlsson Oskar
Published: August 2017

The number of epigenetic studies on brain functions and diseases are dramatically increasing, but little is known about the impact of post‐mortem intervals and post‐sampling effects on DNA modifications such as 5‐methylcytosine (5mC) and 5‐hydroxymethylcytosine (5hmC). Here, we examined post‐mortem‐induced changes in global brain 5mC and 5hmC levels at post‐mortem intervals up to 540 min., and studied effects of tissue heat stabilization, using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post‐mortem interval reaching a significantly lower level in cerebellum tissue at the post‐mortem interval 540 min. (2.9 ± 0.7%; mean ± S.E.M.) compared to control (3.7 ± 0.6%). The global 5hmC levels increased with post‐mortem interval reaching a significantly higher level at 540 min. (0.29 ± 0.06%) compared to control (0.19 ± 0.03%). This suggests that the post‐mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post‐mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post‐mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post‐mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms.
Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial
Authors: Tunbridge EM , Attenburrow MJ , Gardiner A , Rendell JM , Hinds C , Goodwin GM , Harrison PJ , Geddes JR
Published: August 2017

Objectives

CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double‐blind, randomized, placebo‐controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction.

Methods

The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms—self report version 16 (QIDS‐SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one‐carbon metabolism and functional polymorphisms in catechol‐O‐methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1).

Results

Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect.

Conclusions

Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine−FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow‐on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.
An 810‐year history of cold season temperature variability for northern Poland
Authors: Balanzategui Daniel , Knorr Antje , Heussner Karl‐Uwe , Wazny Tomasz , Beck Wolfgang , Słowiński Michał , Helle Gerhard , Buras Allan , Wilmking Martin , Van Der Maaten Ernst , Scharnweber Tobias , Dorado‐Liñán Isabel , Heinrich Ingo
Published: August 2017

Scots pine (Pinus sylvestris L.) is a widely used tree species in European dendroclimatology studies due to its common distribution across much of the continent. Almost all studies find radial growth strongly related to summer temperature, a result reflecting site selection at high elevation/latitude environments where trees grow at their ecophysiological limits. Due to the amount of attention spent on these sites there is a geographical and seasonal bias in temperature reconstructions based upon tree‐ring proxies in Europe. To overcome the limited availability of tree‐ring data in temperate lowlands, we present a northern Poland ring‐width chronology developed from living and historic Scots pine material with a strong common growth signal going back to AD 1200. Investigations into climate‐growth relationships found year‐to‐year ring‐width variability to be more strongly correlated to cold season temperature (November to April) prior to the growing season than summer temperatures during tree‐ring formation. Based on this relationship it was possible to reconstruct cold season temperature conditions for the last 810 years. Spatial field correlations with gridded instrumental records indicated that the reconstruction provides relevant cold season temperature information across the land regions bordering the North Atlantic Ocean and Baltic Sea, lowlands and uplands of western and central Europe, and the eastern and central interior of Russia. Despite an unsuccessful attempt to find a stationary relationship with the North Atlantic Oscillation, comparisons with several cold season temperature reconstructions confirmed the long‐term connection between our reconstructed temperature series for northern Poland and the wider area.
Late Quaternary glaciation of the northern Urals: a review and new observations
Authors: Astakhov Valery I.
Published: August 2017

This is a synthesis of the glacial history of the northern Urals undertaken using published works and the results of geological surveys as well as recent geochronometric and remote sensing data. The conclusions differ from the classical model that considers the Urals as an important source of glacial ice and partly from the modern reconstructions. The principal supporting evidence for the conventional model – Uralian erratics found on the adjacent plains – is ambiguous because Uralian clasts were also delivered by a thick external ice sheet overriding the mountains during the Middle Pleistocene. Alternative evidence presented in this paper indicates that in the late Quaternary the Ural mountains produced only valley glaciers that partly coalesced in the western piedmont to form large piedmont lobes. The last maximum glaciation occurred in the Early Valdaian time at c. 70–90 ka when glacial ice from the Kara shelf invaded the lowlands and some montane valleys but an icecap over the mountains was not formed. The moraines of the alpine glaciation are preserved only beyond the limits of the Kara ice sheet and therefore cannot be younger than MIS 4. More limited glaciation during MIS 2 generated small alpine moraines around the cirques of the western Urals (Mangerud et al. 2008: Quaternary Science Reviews 27, 1047). The largest moraines of Transuralia were probably produced by the outlet glaciers of a Middle Pleistocene ice sheet that formed on the western plains and discharged across the Polar Urals. The resultant scheme of limited mountain glaciation is possibly also applicable as a model for older glacial cycles.
Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets
Authors: Fu Yi , Wang Xian , Kong Wei
Published: August 2017

Homocysteine is a sulphur‐containing non‐proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy‐induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up‐regulates pathogenic genes and down‐regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy‐induced vascular injury leads to neuronal damage and disease. Also, an HHcy‐activated sympathetic system and HHcy‐injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy‐induced vascular injury, which are further considered as potential therapeutic targets in this condition.

Linked Articles

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
Exploring the feasibility and acceptability of a school‐based self‐referral intervention for emotional difficulties in older adolescents: qualitative perspectives from students and school staff
Authors: McKeague Lynn , Morant Nicola , Blackshaw Emily , Brown June S. L.
Published: August 2017

Background

Adolescents with emotional difficulties need accessible, acceptable and evidence‐based mental health interventions. Self‐referral workshops (DISCOVER workshops) were offered to stressed 16‐ to 19‐year olds in 10 Inner London schools.

Method

Semistructured interviews were conducted with three groups of participants: students who attended a 1‐day workshop (n = 15); students who initially showed interest in the DISCOVER workshop programme, but decided not to take part (n = 9); and school staff who helped organise the programme in their schools (n = 10). Students were purposively sampled to ensure that those from Black and minority ethnic (BME) backgrounds were represented. Data were analysed using thematic analysis.

Results

The accounts generally indicate that the delivery and evaluation of this intervention is perceived as feasible and acceptable. Students, including those from BME backgrounds, described the setting as suitable and reported that the workshop helped them develop new understandings of stress and how to handle it. They expressed a preference for engaging and interactive activities, and valued a personalised approach to workshop provision. School staff felt that the workshop was in line with school values. They described some logistical barriers to providing the workshops in school settings, and expressed a desire for more information about the workshop in order to provide follow‐up support. The main reason students gave for nonparticipation was limited time.

Conclusions

Findings are discussed in relation to increasing the feasibility of implementing school‐based psychological interventions and the value of providing access to mental health support in schools.
Young Children's Self‐Concepts Include Representations of Abstract Traits and the Global Self
Authors: Cimpian Andrei , Hammond Matthew D. , Mazza Giulia , Corry Grace
Published: August 2017

There is debate about the abstractness of young children's self‐concepts—specifically, whether they include representations of (a) general traits and abilities and (b) the global self. Four studies (N = 176 children aged 4–7) suggested these representations are indeed part of early self‐concepts. Studies 1 and 2 reexamined prior evidence that young children cannot represent traits and abilities. The results suggested that children's seemingly immature judgments in previous studies were due to peculiarities of the task context not the inadequacy of children's self‐concepts. Similarly, Studies 3 and 4 revealed that, contrary to claims of immaturity in reasoning about the global self, young children update their global self‐evaluations in flexible, context‐sensitive ways. This evidence suggests continuity in the structure of self‐concepts across childhood.
Active form of vitamin D directly protects the blood–brain barrier in multiple sclerosis
Authors: Takahashi Shiori , Maeda Toshihiko , Sano Yasuteru , Nishihara Hideaki , Takeshita Yukio , Shimizu Fumitaka , Kanda Takashi
Published: August 2017

Objectives

The active form of vitamin D, 1α,25‐dihydroxyvitamin D3 (1α,25‐[OH]2D3), is reported to have protective effects for multiple sclerosis (MS), but the precise mechanisms of this effect on MS remain unclear. We hypothesized that 1α,25‐(OH)2D3 has protective effects on the blood–brain barrier (BBB) in MS.

Methods

The expression of vitamin D receptor in a human brain microvascular endothelial cell line (HBMEC) was examined. The effects of 1α,25‐(OH)2D3 on HBMEC after stimulation with tumor necrosis factor‐α were observed. In addition, we assessed the effects of sera from MS patients, including those in the acute and stable phase of relapse–remitting MS or secondary progressive MS, on the BBB property in the presence or absence of 1α,25‐(OH)2D3.

Results

HBMEC were found to express the vitamin D receptor at both the mRNA and protein level. Pretreatment of HBMEC with 1α,25‐(OH)2D3 attenuated the decrease of zonula occludens‐1 and claudin‐5, and the increase of intercellular adhesion molecule‐1 (ICAM‐1) induced by tumor necrosis factor‐α. In addition, nuclear factor kappa B activation mediated by tumor necrosis factor‐α was decreased after incubation with the activated vitamin D. Furthermore, incubation with 1α,25‐(OH)2D3 attenuated the increase of vascular cell adhesion molecule‐1 and anti‐phospho‐nuclear factor kappa B in HBMEC after exposure to sera from patients with relapse‐remitting MS and secondary progressive MS, and restored the decrease of zonula occludens‐1 and claudin‐5 in HBMEC after incubation with sera from the acute phase of relapse–remitting MS patients.

Conclusions

Treatment with 1α,25‐(OH)2D3 prevents BBB disruption caused by both relapse–remitting MS and secondary progressive MS sera through upregulation of tight junction proteins and downregulation of cell adhesion molecules in HBMEC, suggesting that 1α,25‐(OH)2D3 might have the direct protective effects on the fragile BBB in MS patients.
Ethyl pyruvate does not require microglia for mediating neuroprotection after excitotoxic injury
Authors: Pieroh Philipp , Wagner Daniel‐Christoph , Ghadban Chalid , Birkenmeier Gerd , Dehghani Faramarz
Published: August 2017

Aims

Ethyl pyruvate (EP) mediates protective effects after neuronal injury. Besides a direct conservation of damaged neurons, the modulation of indigenous glial cells has been suggested as one important mechanism for EP‐related neuroprotection. However, the specific contribution of glial cells is still unknown.

Methods

Organotypic hippocampal slice cultures (OHSC) were excitotoxically lesioned by 50 μmol/L N‐methyl‐D‐aspartate (NMDA, for 4 hours) or left untreated. In an additional OHSC subset, microglia was depleted using the bisphosphonate clodronate (100 μg/mL) before lesion. After removal of NMDA, EP containing culture medium (0.84 μmol/L, 8.4 μmol/L, 42 μmol/L, 84 μmol/L, 168 μmol/L) was added and incubated for 72 hours. OHSC were stained with propidium iodide to visualize degenerating neurons and isolectin IB4‐FITC to identify microglia. Effects of EP at concentrations of 0.84, 8.4, and 84 μmol/L (0‐48 hours) were analyzed in the astrocytic scratch wound assay.

Results

EP significantly reduced neurodegeneration following induced excitotoxicity except for 168 μmol/L. For 84 μmol/L, a reduction in the microglia cells was observed. Microglia depletion did not affect neuronal survival after EP treatment. EP decelerated astrocytic wound closure at 48 hours after injury.

Conclusion

EP‐mediated neuroprotection seems to be mediated by astrocytes and/or neurons.