bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of The Psychiatric Risk Gene Ankyrin 3 Enhances Microtubule Dynamics Through GSK3/CRMP2 Signaling
Authors: Garza Jacob C , Qi Xiaoli , Gjeluci Klaudio , Leussis Melanie P , Basu Himanish , Reis Surya A , Zhao Wen Ning , Piguel Nicolas H , Penzes Peter , Haggarty Stephen J , Martens Gerard J , Poelmans Geert , Petryshen Tracey L
Published: April 2018

The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specificAnk3isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus fromAnk3+/-andAnk3+/+mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, inAnk3+/-mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons fromAnk3+/-mice revealed impaired elongation of microtubules. Using a CRISPR-dCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specificAnk3increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specificAnk3repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization inAnk3repressed cells by lithium or CHIR99021, suggesting microtubule instability induced byAnk3repression is dependent on CRMP2 activity. Taken together, our data indicate that aNK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.
SpeciFlex: A Protocol for Mining Binding Site Conformational Selectivity in Structure-Based Inhibitor Discovery
Authors: Tonero Matthew E. , Kuhn Leslie A.
Published: April 2018

Selectivity for a target site is challenging when the site is conserved in homologous proteins. A novel protocol is presented for attaining selectivity by taking advantage of conformational population differences between homologs. Conformational ensembles of the targeted protein and the homolog are compared to identify pockets significantly populated in the target, but rarely or never sampled in the homolog. SLIDE screening then identifies molecules that fit the unique pocket and also interact well with an adjacent substrate pocket. The SpeciFlex protocol, demonstrated for a pair of pyrophosphokinases, yields ligand candidates with good interactions in both the substrate and unique pockets of the targetYersinia pestisprotein, while selecting against interactions with the homologous site inEscherichia coli.
Instantaneous midbrain control of saccade kinematics
Authors: Smalianchuk Ivan , Jagadisan Uday , Gandhi Neeraj J.
Published: April 2018

The ability to interact with our environment requires the brain to transform spatially-represented sensory signals into temporally-encoded motor commands for appropriate control of the relevant effectors. For visually-guided eye movements, or saccades, the superior colliculus (SC) is assumed to be the final stage of spatial representation, and instantaneous control of the movement is achieved through a rate code representation in the lower brain stem. We questioned this dogma and investigated whether SC activity also employs a dynamic rate code, in addition to the spatial representation. Noting that the kinematics of repeated movements exhibits trial-to-trial variability, we regressed instantaneous SC activity with instantaneous eye velocity and found a robust correlation throughout saccade duration. Peak correlation was tightly linked to time of peak velocity, and SC neurons with higher firing rates exhibited stronger correlations. Moreover, the strong correlative relationship was preserved when eye movement profiles were substantially altered by a blink-induced perturbation. These results indicate that the rate code of individual SC neurons can control instantaneous eye velocity, similar to how primary motor cortex controls hand movements, and argue against a serial process for transforming spatially encoded information into a rate code.
Free energy calculations of protein-water complexes with Gromacs
Authors: Shahzad M. A.
Published: April 2018

We used GFP(Green Fluorescent Protein) to understand its basic structure, adding solvent water around the GFP, minimize and equilibrating it using molecular dynamics simulation with Gromacs. Gromacs is an open source software and widely used in molecular dynamics simulation of biological molecules such as proteins, and nucleic acids (DNA AND RNA-molecules). We employ the CHARMM (Chemistry at HARvard Molecular Mechanics) program for the force fields which enable the potential energy of a molecular system to be calculated rapidly. In this particular simple molecular mechanics interaction fields (CHARMM), the force fields consists of stretching energy, bending energy and torsion energy. The non-bond interaction energy is modeled by Lennard-Jones potential. The pdb2gmx gromacs command is implemented to obtained the basic coordinate file and topology for the particular system from the GFP PDB file (1gfl.pdb). We enclosed water molecule in a rhombic dodecahedron box having size 0.5nm, and protein are embedded in solvent water. The steepest descent method (first-order minimization) are implemented to calculate the local energy minimum with 104-steps. The stability of protein with solvent water molecule are analyzed by measuring the root-mean square displacement (RMSD) of all atoms. It was shown with help of figure that RMSD initially increases rapidly in the first part of simulation, but become stable around 0.14nm, roughly the resolution of the X-ray structure. The difference is partly due to the moving and vibration of atoms around an equilibrium structure. Secondary structure of GFP protein is presented with the help of DSSP-program.
DivNet: Estimating diversity in networked communities
Authors: Willis Amy D , Martin Bryan D
Published: April 2018

Diversity is a marker of ecosystem health in ecology, microbiology and immunology, with implications for disease diagnosis and infection resistance. However, accurately comparing diversity across environmental gradients is challenging, especially when number of different taxonomic groups in the community is large. Furthermore, existing approaches to estimating diversity do not perform well when the taxonomic groups in the community interact via an ecological network, such as by competing within their niche, or with mutualistic relationships. To address this, we propose DivNet, a method for estimating within- and between-community diversity in ecosystems where taxa interact via an ecological network. In particular, accounting for network structure permits more accurate estimates of alpha- and beta-diversity, even in settings with a large number of taxa and a small number of samples. DivNet is fast, accurate, precise, performs well with large numbers of taxa, and is robust to both weakly and strongly networked communities. We show that the advantages of incorporating taxon interactions into diversity estimation are especially clear in analyzing microbiomes and other high-diversity, strongly networked ecosystems. Therefore, to illustrate the method, we analyze the microbiome of seafloor basalts based on a 16S amplicon sequencing dataset with 1490 taxa and 13 samples.
Regulatory B cells contribute to the alleviation of colitis induced by Dextran Sulphate Sodium afterH.pyloriinfection
Authors: Li Xia , Tan Jiang , Zhang Feng , Xue Qian , Wang Ning , Cong Xu , Wang Jingtong
Published: April 2018

Background

Epidemiological studies showed that there was an inverse relationship betweenHelicobacter pyloriinfection and the incidence of inflammatory bowel disease. Our previous research indicated that the regulatory immune responses induced byH.pyloriinfection were not limited to gastric mucosa, and the balance of intestinal mucosal immunity was influenced. In this study, we investigated the role of the regulatory B cells in the effects of theH.pyloriinfection on acute and chronic colitis induced by dextran sulphate sodium.

Methods

Mice were infected withH.pyloriand then colitis was induced by 3% DSS, the CD19+IL-10+Breg cells and CD4+CD25+Foxp3+Treg cells in blood、 spleen、 mesenteric lymph nodes (MLN)、 Peyer’s Patches (PP) and gastrointestinal mucosa were measured and examined. The anti– and pro-inflammatory cytokines were also detected at mRNA level.

Results

In the acute and chronic colitis groups, DAI and colonic histological scores reduced significantly and colon length shorted less; the anti-inflammatory cytokines mRNA expression upregulated while the pro-inflammatory cytokines mRNA expression downregulated in colonic mucosa; and the percentages of CD19+IL-10+Breg cells in blood spleen MLN、 PP were higher in theH.pylori/DSS co-treated group compared with the DSS treated group.

Conclusion

H.pyloriinfection can alleviate the acute and chronic colitis induced by DSS. CD19+IL-10+Breg cells may play a critical role in the alleviation of acute and chronic colitis followingH.pyloriinfection.
CD161 mediates prenatal immune suppression of IFNγ-producing PLZF+T cells
Authors: Halkias Joanna , Rackaityte Elze , Aran Dvir , Mendoza Ventura F. , Eckalbar Walter L. , Burt Trevor
Published: April 2018

While the fetal immune system defaults to a program of tolerance, there is concurrent need for protective immunity to meet the antigenic challenges after birth. Activation of fetal T cells is associated with fetal inflammation and the termination of pregnancy, yet which fetal T cells contribute to this process is poorly understood. Here we show a transcriptionally distinct population of pro-inflammatory T cells that predominates in the human fetal intestine. Activation of PLZF+T cells results in rapid production of Th1 cytokines and is inhibited upon ligation of surface CD161. This mechanism of fetal immune suppression may inform how immune dysregulation could result in fetal and neonatal inflammatory pathologies such as preterm birth. Our data support that human development of protective adaptive immunity originatesin uterowithin the specialized microenvironment of the fetal intestine.
Intrinsic timescales of sensory integration for motion perception
Authors: Choi Woochul , Paik Se-Bum
Published: April 2018

A subject-specific process of accumulation of information may be responsible for variations in decision time following visual perceptions in humans. A detailed profile of this perceptual decision making, however, has not yet been verified. Using a coherence-varying motion discrimination task, we precisely measured the perceptual decision kernel of subjects. We observed that the kernel size (decision time) is consistent within subjects, independent of stimulus dynamics, and the observed kernel could accurately predict each subject’s performance. Interestingly, the performance of most subjects was optimized when stimulus duration was matched to their kernel size. We also found that the observed kernel size was strongly correlated with the perceptual alternation in bistable conditions. Our result suggests that the observed decision kernel reveals a subject-specific feature of sensory integration.
A Freeloader?: The Highly Eroded Yet large Genome of theSerratia symbioticasymbiont ofCinara strobi
Authors: Manzano-Marín Alejandro , d’acier Armelle Coeur , Clamens Anne-Laure , Orvain Céline , Cruaud Corinne , Barbe Valérie , Jousselin Emmanuelle
Published: April 2018

Genome reduction is pervasive among maternally-inherited bacterial endosymbionts. This genome reduction can eventually lead to serious deterioration of essential metabolic pathways, thus rendering an obligate endosymbiont unable to provide essential nutrients to its host. This loss of essential pathways can lead to either symbiont complementation (sharing of the nutrient production with a novel co-obligate symbiont) or symbiont replacement (complete takeover of nutrient production by the novel symbiont). However, the process by which these two evolutionary events happen remains somewhat enigmatic by the lack of examples of intermediate stages of this process.Cinaraaphids (Hemiptera: Aphididae) typically harbour two obligate bacterial symbionts:BuchneraandSerratia symbiotica.However, the latter has been replaced by different bacterial taxa in specific lineages, and thus species within this aphid lineage could provide important clues into the process of symbiont replacement. In the present study, using 16S rRNA high-throughput amplicon sequencing, we determined that the aphidCinara strobiharbours not two, but three fixed bacterial symbionts:Buchnera aphidicola,aSodalissp., andS. symbiotica.Through genome assembly and genome-based metabolic inference, we have found that only the first two symbionts (BuchneraandSodalis) actually contribute to the hosts’ supply of essential nutrients whileS. symbioticahas become unable to contribute towards this task. We found thatS. symbioticahas a rather large and highly eroded genome which codes only for a few proteins and displays extensive pseudogenisation. Thus, we propose an ongoing symbiont replacement withinC. strobi,in which a once ‘‘competent”S. symbioticadoes no longer contribute towards the beneficial association. These results suggest that in dual symbiotic systems, when a substitute co-symbiont is available, genome deterioration can precede genome reduction and a symbiont can be maintained despite the apparent lack of benefit to its host.
Directional coupling of slow and fast hippocampal gamma with neocortical alpha/beta oscillations in human episodic memory
Authors: Griffiths Benjamin J. , Parish George , Roux Frederic , Michelmann Sebastian , van der Plas Mircea , Kolibius Luca D. , Chelvarajah Ramesh , Rollings David T. , Sawlani Vijay , Hamer Hajo , Gollwitzer Stephanie , Kreiselmeyer Gernot , Staresina Bernhard , Wimber Maria , Hanslmayr Simon
Published: April 2018

Episodic memories hinge upon our ability to process a wide range of multisensory information and bind this information into a coherent, memorable representation. On a neural level, these two processes are thought to be supported by neocortical alpha/beta desynchronisation and hippocampal theta/gamma synchronisation, respectively. Intuitively, these two processes should couple to successfully create and retrieve episodic memories, yet this hypothesis has not been tested empirically. We address this by analysing human intracranial EEG data recorded during two associative memory tasks. We find that neocortical alpha/beta (8-20Hz) power decreases reliably precede and predict hippocampal “fast” gamma (60-80Hz) power increases during episodic memory formation; during episodic memory retrieval however, hippocampal “slow” gamma (40-50Hz) power increases reliably precede and predict later neocortical alpha/beta power decreases. We speculate that this coupling reflects the flow of information from neocortex to hippocampus during memory formation, and hippocampal pattern completion inducing information reinstatement in the neocortex during memory retrieval.

Significance Statement

Episodic memories detail our personally-experienced past. The formation and retrieval of these memories has long been thought to be supported by a division of labour between the neocortex and the hippocampus, where the former processes event-related information and the latter binds this information together. However, it remains unclear how the two regions interact. We uncover directional coupling between these regions, with power decreases in the neocortex that precede and predict power increases in the hippocampus during memory formation. Fascinatingly, this process reverses during memory retrieval, with hippocampal power increases preceding and predicting neocortical power decreases. These results suggest a bidirectional flow of information between the neocortex and hippocampus is fundamental to the formation and retrieval of episodic memories.
The closed form of Mad2 is bound to Mad1 and Cdc20 at unattached kinetochores
Authors: Zhang Gang , Nilsson Jakob
Published: April 2018

The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation by delaying anaphase onset in response to unattached kinetochores. Anaphase is delayed by the generation of the mitotic checkpoint complex (MCC) composed of the checkpoint proteins Mad2 and BubR1/Bub3 bound to the protein Cdc20. Current models assume that MCC production is catalyzed at unattached kinetochores and that the Mad1/Mad2 complex is instrumental in the conversion of Mad2 from an open form (O-Mad2) to a closed form (C-Mad2) that can bind to Cdc20. Importantly the levels of Mad2 at kinetochores correlate with SAC activity but whether C-Mad2 at kinetochores exclusively represents its complex with Mad1 is not fully established. Here we use a recently established C-Mad2 specific monoclonal antibody to show that Cdc20 and C-Mad2 levels correlate at kinetochores and that depletion of Cdc20 reduces Mad2 but not Mad1 kinetochore levels. Importantly reintroducing wild type Cdc20 but not Cdc20 R132A, a mutant form that cannot bind Mad2, restores Mad2 levels. In agreement with this live cell imaging of fluorescent tagged Mad2 reveals that Cdc20 depletion strongly reduces Mad2 localization to kinetochores. These results support the presence of Mad2-Cdc20 complexes at kinetochores in agreement with current models of the SAC but also argue that Mad2 levels at kinetochores cannot be used as a direct readout of Mad1 levels.
Comparison of two commercial ELISA kits for detection of rubella specific IgM and IgG antibodies
Authors: Viswanathan Rajlakshmi , George Suji , Murhekar Manoj V , Abraham Asha Mary , Singh Mini P , Jadhav Santoshkumar M , Nag Vijayalakshmi , Naik Sadanand , Raut Chandrashekhar , Ashok M , Gupta Minakshi , Jagtap Vishal , Kaduskar Ojas , Gupta Nivedita , Sapkal Gajanan N
Published: April 2018

Enzyme linked immunosorbent assay (ELISA) plays an important role in laboratory confirmation of congenital rubella syndrome (CRS), postnatal rubella and seroprevalence studies in different populations. Variation of results are documented for samples tested by different commercial kits. The Enzygnost rubella ELISA, widely used in the WHO network, is expensive and not readily available. In the present study, performance of the Euroimmun ELISA was compared to the Enzygnost ELISA for detection of rubella specific IgM and IgG antibodies.

Two hundred and eighty five serum samples collected from suspected CRS patients identified through a recently initiated surveillance for CRS at six sentinel hospitals and 435 serum samples from a serosurvey of pregnant women from these sites, were available for testing of rubella specific IgM and IgG antibodies respectively. Qualitative agreement (concordance percentage and Cohen’s Kappa coefficient -κ) was evaluated for both IgM and IgG assays. Bland – Altman plots were used to assess the difference in quantitative agreement for IgG titers.

Good qualitative agreement between the two ELISA kits was observed for detection of both anti rubella IgM (94.7% agreement and k of 0.86) and IgG (96.3% agreement and k of 0.84). Sensitivity and specificity of Euroimmun assays compared to Enzygnost was 100% and 93.1% for IgM and 95.9% and 100% for IgG respectively. Bland – Altman analysis for paired quantitative results of rubella specific IgG yielded a mean difference of 0.781 IU/ml with majority of values (97.1%) within ± 2 SD of the mean difference. Euroimmun ELISA provided on an average, higher titers as compared to Enzygnost.

Our study findings suggest that Euroimmun ELISA may be considered for detection of rubella specific IgM in suspected CRS cases and rubella specific IgG in surveillance studies.
Rbfox1 mediates cell-type-specific splicing in cortical interneurons
Authors: Jaglin Xavier Hubert , Wamsley Brie , Favuzzi Emilia , Quattracolo Giulia , Nigro Maximiliano José , Yusef Nusrath , Khodadadi-Jamayran Alireza , Rudy Bernardo , Fishell Gordon
Published: April 2018

Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.
KAMO: towards automated data processing for microcrystals
Authors: Yamashita Keitaro , Hirata Kunio , Yamamoto Masaki
Published: April 2018

In protein microcrystallography, radiation damage often hampers complete and high-resolution data collection from a single crystal, even under cryogenic conditions. One promising solution is to collect small wedges of data (5–10°) separately from multiple crystals. The data from these crystals can then be merged into a complete reflection-intensity set. However, data processing of multiple small-wedge data sets is challenging. Here, a new open-source data-processing pipeline, KAMO, which utilizes existing programs, including the XDS and CCP4 packages, has been developed to automate whole data-processing tasks in the case of multiple small-wedge data sets. Firstly, KAMO processes individual data sets and collates those indexed with equivalent unit-cell parameters. The space group is then chosen and any indexing ambiguity is resolved. Finally, clustering is performed, followed by merging with outlier rejections, and a report is subsequently created. Using synthetic and several real-world data sets collected from hundreds of crystals, it was demonstrated that merged structure-factor amplitudes can be obtained in a largely automated manner using KAMO, which greatly facilitated the structure analyses of challenging targets that only produced microcrystals.
Researching the multinational corporation: contributions of critical realist ethnography
Authors: Sharpe Diana Rosemary
Published: April 2018

Purpose

The purpose of this paper is to discuss the contributions that critical realist ethnographies can make to an understanding of the multinational corporation.

Design/methodology/approach

This paper draws on a discussion of methodological challenges in researching the multinational corporation and the ways in which critical realist ethnographies can respond to these challenges. The example of research on the transfer of management practices is used to illustrate this.

Findings

Taking the example of researching the transfer of management practices within the multinational, the paper argues that the potential of critical realist ethnography including critical realist global ethnography to contribute to the field of International Business and International Management remains relatively untapped.

Research limitations/implications

Adopting the sociological imagination of the critical realist ethnographer has implications for the kinds of questions that are asked by the researcher and the ways in which we seek to address these methodologically. Researching from a critical standpoint fruitful empirical themes for further research relate to the experience of change for example in business systems, internationalization of organizations and “globalization”.

Practical implications

The critical realist ethnographer can contribute insights into the complex social and political processes within the multinational and provide insights into how social structures are both impacting on and impacted by individuals and groups. Ethnographic research located within a critical realist framework has the potential to address questions of how stability and change take place within specific structural, cultural and power relations.

Originality/value

At the methodological level, this paper highlights the potential of critical realist ethnography in researching the multinational, in addressing significant questions facing the critical researcher and in gaining a privileged insight into the lived experience of globalization.
The Belgian Cannabis Social Club landscape
Authors: Pardal Mafalda
Published: April 2018

Purpose

The purpose of this paper is to map the presence of the Cannabis Social Club (CSC) model in Belgium since its emergence in the country and to analyze the inter-organizational relations among CSCs and between the CSCs and other supportive actors engaged in the wider cannabis movement.

Design/methodology/approach

This analysis draws on qualitative interviews (n=42) with directors of seven currently active and one former Belgian CSC(s), as well as with organizations or individuals reportedly collaborating with the Belgian CSCs. That data are complemented by fieldwork observations and a review of CSC internal documents.

Findings

Despite an uninterrupted presence in the country over the last decade, CSC presence in Belgium remains rather volatile and vulnerable to external control pressure. The CSC landscape is a somewhat segmented field as cooperation among CSCs remains limited. At the same time, the support base for the movement is diverse, encompassing different types of secondary organizations ranging from national and international advocacy groups, to cannabis industry entrepreneurs and other consultants.

Originality/value

This paper contributes to the yet limited body of knowledge on CSCs, by providing a first comprehensive overview of the presence of CSCs in one of the key settings associated with the model, by shedding light into the interplay between CSCs, and between other organizations supportive of the cannabis movement.
Genetic characterization of hemagglutinin protein of measles viruses in Hokkaido district, Japan, 2006–2015
Authors: Miyoshi Masahiro , Komagome Rika , Yamaguchi Hiroki , Ishida Setsuko , Nagano Hideki , Okano Motohiko
Published: April 2018

Strains of measles virus of genotypes D5, H1, D4, D8, and B3 were detected among epidemic, endemic, imported and import–associated cases in Hokkaido district, Japan, during 2006–2015. In the present study, their antigenic features were evaluated by determining the complete nucleotide sequences of their hemagglutinin proteins, which are a major target for neutralizing antibodies, and their amino acid sequences deduced. It was found that the hemagglutinin proteins of these strains had several novel amino acid changes in some functional regions. Although these strains have not caused further infections thus far, these antigenic changes should continue to be monitored to maintain their elimination status.
Cardiovascular effects of sitagliptin – An anti‐diabetes medicine
Authors: Zhou Yi , Guo Zhiying , Yan Wenjing , Wang Wen
Published: April 2018

Dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors, as the most recent available anti‐diabetic agents, were generally used in clinical treatment of type 2 diabetes (T2DM). In addition to anti‐diabetic effects, the five most widely used DPP‐4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) also exert cardiovascular protective effects. In recent years, increasing studies suggest that sitagliptin shows pleiotropic impacts towards the cardiovascular system either with or without diabetes. In this review, we summarized the recent reports to provide an update discussion about cardiovascular protective effects of sitagliptin and the corresponding mechanisms. Sitagliptin has positive effects towards ischaemic cardiovascular diseases, atherosclerosis and hypertension. These effects are mainly conducted through DPP‐4 inhibitions. In addition, sitagliptin exerts anti‐inflammation, anti‐oxidative stress, anti‐apoptosis, mediation on lipid accumulation and so on, which also contribute to its cardiovascular effects.
Placental adaptations to micronutrient dysregulation in the programming of chronic disease
Authors: Hofstee Pierre , McKeating Daniel R , Perkins Anthony V , Cuffe James SM
Published: April 2018

Poor nutrition during pregnancy is known to impair foetal development and increase the risk of chronic disease in offspring. Both macronutrients and micronutrients are required for a healthy pregnancy although significantly less is understood about the role of micronutrients in the programming of chronic disease. This is despite the fact that modern calorie rich diets are often also deficient in key micronutrients. The importance of micronutrients in gestational disorders is clearly understood but how they impact long term disease in humans requires further investigation. In contrast, animal studies have demonstrated how diets high or low in specific micronutrients influence offspring physiology. Many of these studies highlight the importance of the placenta in determining disease risk. This review will explore the effects of individual vitamins, minerals and trace elements on offspring disease outcomes and discuss several key placental adaptations that are affected by multiple micronutrients. These placental adaptations include micronutrient induced dysregulation of oxidative stress, altered methyl donor availability and its impact on epigenetic mechanisms as well as endocrine dysfunction. Critical gaps in our current knowledge and the relative importance of different micronutrients at different gestational ages will also be highlighted. Finally, this review will discuss the need for further studies to characterise the micronutrient status of Australian women of reproductive age and correlate micronutrient status to placental adaptations, pregnancy complications and offspring disease.
Giving up sugar and the inequalities of abstinence
Authors: Throsby Karen
Published: April 2018

Sugar is increasingly supplanting fat as public enemy number one in public health campaigns, and calls for significant reductions in consumption have provided fertile ground for the proliferation of popular texts and services advocating sugar abstention. This article explores three modes of popular sugar abstention (evangelical, experimental and charitable). These vary in chronology, philosophy and the intensity of abstention, but all serve as sites of identity production and self‐entrepreneurship for those able to advocate for, and engage with, them. The article argues that these abstention narratives are not only premised on the exercise of social privilege, but that they also necessarily reproduce and sediment those social hierarchies. This is achieved through a combination of nutritionism and healthism, dislocating sugar and its consumption from the vast social, economic and environmental inequalities within which both the consumption of sugar, and the act of giving it up, is made meaningful. (A virtual abstract of this paper can be found at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA)
Do young female candidates face double barriers or an outgroup advantage? The case of the European Parliament
Authors: STOCKEMER DANIEL , SUNDSTRÖM AKSEL
Published: April 2018

While intersectionality is a recurrent theme in the literature on women's political representation, few studies empirically disentangle who are the women who get elected to parliaments. An argument on biases in recruitment practices suggests that those who are members of more than one outgroup, such as young women, benefit from an ‘outgroup advantage’. In elections, a candidate with two outgroup features might attract more voter support than a candidate with just one outgroup feature. Hence, nominating a candidate that is both young and female could be a rational move by (male) elites in political parties that allows them to open fewer seats to newcomers. These expectations are tested on data for all members of the European Parliament since 1979. Not only is it found that women's presence increased steadily throughout the parliament's history, but also that women's representation is consistently highest among the group of young representatives, lower among middle‐aged Members of the European Parliament and lowest among older representatives.
Primary lymphoepthelial carcinoma of the parotid gland, pictorial review of a rare entity
Authors: Halder Arani , Sommerville Jennifer , Gandhi Mitesh
Published: April 2018

Lymphoepithelial carcinoma (LEC) is a rare malignancy of the salivary gland arising from the parotid in 80% of cases. LEC is indistinguishable histologically from more common non‐keratinising undifferentiated nasopharyngeal carcinoma (NPC). Up to 40% of patients with primary LEC present with a cervical metastasis and histological assessment of the primary lesion or nodal metastasis may be reported as NPC. The absence of a nasopharyngeal lesion on imaging and endoscopic assessment together with a parotid mass strengthens the case for a LEC. A retrospective review of three cases of primary parotid LEC presenting to a tertiary head and neck clinic was performed. Clinical information, imaging and histopathology findings are presented in the form of a pictorial review. Two female and one male patient with an average age of 42 years presented with a neck lump. Initial pathology results were poorly differentiated carcinoma (2/3) and possible NPC (1/3). MR neck revealed unilateral parotid masses with ipsilateral cervical lymphadenopathy and assessment of the nasopharynx was negative (3/3). Resection occurred in all patients and consensus was metastatic LEC with parotid primary in all cases (3/3). 2 patients are disease free, and 1 patient is deceased (as a result of disease) at the time of this report. Lymphoepithelial carcinoma is identical histologically to NPC, this pictorial review highlights the need for clinical and radiological correlation to establish the diagnosis.
A 20‐year Review: The Use of Exception From Informed Consent and Waiver of Informed Consent in Emergency Research
Authors: Klein Lauren , Moore Johanna , Biros Michelle
Published: April 2018

Background

Due to the acuity and time‐sensitive needs of their clinical condition, patients presenting with certain emergent pathologies may lack capacity to provide meaningful prospective informed consent to participate in clinical research. For these reasons, these populations have often been excluded from research investigations. To mitigate this, regulations allowing exception from informed consent (EFIC; 21 CFR 50.24) or waiver of informed consent (WIC; 45 CFR 46.101) were developed in 1996. The purpose of this study was to identify trends in the utilization of EFIC and WIC in emergency research. We also sought to describe the disclosure of necessary prestudy regulatory requirements and justification for the use of EFIC/WIC as reported in completed EFIC/WIC clinical trials.

Methods

This study is a review of 20 years of published trials using EFIC or WIC as the primary method of patient consent. Studies were identified using a MEDLINE search; ClinicalTrials.gov; queries to emergency and resuscitation researchers, research directors, department chairs, and principal investigators of acute care research networks; clinical review papers; and a query of the Federal Drug Administration (FDA) docket. All eligible studies were reviewed by three investigators and study data of interest were abstracted. Data are presented descriptively.

Results

We identified 45 potentially eligible studies; 11 were ongoing (with no data yet available), four were completed (with no publications or data available), and two did not use EFIC or WIC. Of the remaining 28 studies, 24 (86%) used EFIC and four used WIC. The most common pathologies under study were cardiac arrest (10), hemorrhagic shock (six), and traumatic brain injury (five). Completion of the prestudy regulatory requirements was reported as follows: FDA investigational new drug/investigational device exemption application (for FDA regulated studies; 14, 50%), community consultation (13, 46%), public disclosure (10, 36%), and opt‐out procedures if requested by the institutional review board (seven, 25%). The justification of the need for the use of EFIC or WIC in the reported clinical trial, as defined as mention of at least one of the eight established criteria, was described in the text of 13 (46%) publications.

Conclusions

Since their implementation in 1996, the EFIC/WIC regulations have allowed progress in research aimed at determining optimal care for devastating life‐threatening conditions. However, consistent and rigorous report of regulatory prestudy requirements and justification of the use of EFIC/WIC is lacking in clinical trial publications or on websites such as ClinicalTrials.gov. Since research without consent is an ethically sensitive issue and not widely understood, better justification of its needs within the presentation of the research itself may educate the general medical community and also reduce concerns about whether or not the regulations are being properly applied.
Are changes in drinking related to changes in cannabis use among Swedish adolescents? A time–series analysis for the period 1989–2016
Authors: Gripe Isabella , Danielsson Anna‐Karin , Ramstedt Mats
Published: April 2018

Aims

To examine if changes in alcohol consumption are associated with changes in cannabis use among Swedish adolescents in a period of diverging trends, and to investigate if cannabis and alcohol act as complements or substitutes.

Design, setting, participants and measurements

Data comprise a nationally representative annual school survey of alcohol and drug habits among Swedish 9th‐grade students (aged 15−16 years) covering years 1989–2016 (n = 149 603). Alcohol and cannabis use were measured concurrently and alcohol consumption was measured in litres of 100% alcohol per year. Frequency of cannabis use was transformed into a mean using category mid‐points. Autoregressive integrated moving average (ARIMA) time–series analysis was used to estimate the association between cannabis and alcohol use. To elucidate changes in the association during the study period, two subperiods (2000−16 and 1989−99) were analysed.

Findings

There was a positive and statistically significant association between changes in alcohol consumption and changes in frequency of cannabis use among cannabis users for the period 1989−2016. A 1‐litre increase in mean alcohol consumption was associated with a 0.28 increase in frequency of cannabis use (P = 0.010). The corresponding increase for the period 1989–99 was 0.52 (P = 0.003). When restricting the analysis to 2000−16, the association was not statistically significant (P = 0.735). When analysing all adolescents we found no statistically significant association between changes in alcohol consumption and changes in frequency of cannabis use.

Conclusions

From 1989 to 2016 there appears to be a positive association between alcohol and cannabis consumption among Swedish adolescents who use cannabis. This association seems to have become weaker over time, suggesting that alcohol and cannabis are neither substitutes nor complements among Swedish adolescents and that the recent decline in youth drinking is not associated with the increase in frequency of cannabis use.
Effects of a prior authorization policy for extended‐release/long‐acting opioids on utilization and outcomes in a state Medicaid program
Authors: Keast Shellie L. , Kim Hyunjee , Deyo Richard A. , Middleton Luke , McConnell K. John , Zhang Kun , Ahmed Sharia M. , Nesser Nancy , Hartung Daniel M.
Published: April 2018

Background and aims

In response to the opioid overdose epidemic, US state Medicaid programs have adopted restrictive policies for opioid analgesics, yet effects on prescribing patterns and health outcomes are uncertain. This study aimed to examine effects of a prior authorization policy for extended‐release/long‐acting (ER/LA) opioids on opioid use in the Oklahoma, USA state Medicaid program.

Design

Retrospective difference‐in‐differences design study comparing changes in opioid use in Oklahoma Medicaid to control (Oregon Medicaid).

Setting

Oklahoma and Oregon, USA.

Participants

Medicaid beneficiaries in the Oklahoma and Oregon fee‐for‐service Medicaid programs between July 2007 and June 2009 (33 724 in Oklahoma and 13 520 in Oregon)

Measurements

The primary outcome was incident opioid‐naive ER/LA opioid use. Secondary outcomes included other opioid and non‐opioid pain medication use. We also examined indicators of high‐risk prescribing (e.g. high‐dosage opioid use) and opioid‐related hospitalizations or emergency department (ED) visits.

Findings

The prior authorization policy was associated with a 0.7 percentage point reduction in the likelihood of incident opioid‐naive ER/LA opioid use [95% confidence interval (CI) = −1.16 to −0.33 percentage points; 70% pre‐policy mean reduction, a 1.4 percentage point decrease in likelihood of any new ER/LA opioid prescriptions (95% CI = –2.1 to −0.7 percentage points; 33% pre‐policy mean reduction) and a decline of 0.16 in total ER/LA opioid prescriptions per enrollee (PPE) (95% CI = –0.29 to −0.04 PPE)]. There was a significant increase in the number of short‐acting opioids filled after the policy (0.36; 95% CI = 0.22–0.50 PPE), increases in likelihood of having overlapping opioids and benzodiazepines, but significant reductions in likelihood of having overlapping opioids. No significant changes in opioid‐related hospitalizations or ED visits were observed.

Conclusions

In Oklahoma, USA's July 2008 prior authorization policy for extended‐release/long‐acting opioids appears to have reduced the number of opioid‐naive patients initiating extended‐release/long‐acting opioid use by more than half, but may also have increased short‐acting opioid prescriptions by 7%.
An RCT with the combination of varenicline and bupropion for smoking cessation: clinical implications for front line use
Authors: Cinciripini Paul M. , Minnix Jennifer A. , Green Charles E. , Robinson Jason D. , Engelmann Jeffrey M. , Versace Francesco , Wetter David W. , Shete Sanjay , Karam‐Hage Maher
Published: April 2018

Background and Aims

Despite the availability of several efficacious smoking cessation treatments, fewer than 25% of smokers who quit remain abstinent 1 year post‐treatment. This study aimed to determine if varenicline and bupropion combination treatment would result in higher abstinence rates than varenicline alone.

Design

A double‐blind, randomized, parallel‐group smoking cessation clinical trial in which participants were exposed to 12 weeks of treatment and followed for 12 months.

Setting

Hospital‐based out‐patient clinic in Texas, USA specializing in cancer prevention.

Participants

A total of 385 community smokers (58.44% male) who smoked 1 pack of cigarettes/day [mean = 19.66 cigarettes/day, standard deviation (SD) = 9.45]; had average carbon monoxide (CO) of 26.43 parts per million (SD = 13.74); and were moderately dependent (Fagerström Test for Cigarette Dependence = 4.79; SD = 2.07).

Interventions and comparator

Smokers were randomized in a 3 : 1 (active: Placebo) ratio to 12 weeks of treatment as follows: placebo (n = 56), varenicline (Var; n = 166), and varenicline + bupropion (Combo; n = 163).

Measurements

A priori primary outcome: prolonged abstinence at 12 months. Secondary outcomes: 7‐day point prevalence abstinence and continuous abstinence; all abstinence measures at end of treatment and 6‐month follow‐ups.

Findings

Intention‐to‐treat analysis: the Combo group (n = 163) failed to demonstrate superiority to the Var group (n = 166) for prolonged abstinence at 12 months [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.50–1.64], supported by Bayes factor = 0.06. Both the Var (OR = 6.66, 95% CI = 1.61–59.27) and Combo groups (OR = 6.06, 95% CI = 1.45–54.09) demonstrated superiority to the Placebo group (n = 56; score = 8.38, P < 0.016).

Conclusions

The addition of bupropion to varenicline treatment does not appear to increase smoking abstinence rates above that of varenicline alone. The findings support previous research showing a consistently favorable effect of both varenicline and the combination of varenicline and bupropion on smoking cessation compared with placebo.
Sexual‐orientation differences in alcohol use trajectories and disorders in emerging adulthood: results from a longitudinal cohort study in the United States
Authors: Coulter Robert W. S. , Jun Hee‐Jin , Calzo Jerel P. , Truong Nhan L. , Mair Christina , Markovic Nina , Charlton Brittany M. , Silvestre Anthony J. , Stall Ron , Corliss Heather L.
Published: April 2018

Aims

We estimated sexual‐orientation differences in alcohol use trajectories during emerging adulthood, and tested whether alcohol use trajectories mediated sexual‐orientation differences in alcohol use disorders (AUDs).

Design

Longitudinal self‐reported survey data from the Growing Up Today Study.

Setting

United States.

Participants

A total of 12 493 participants aged 18–25 during the 2003, 2005, 2007 or 2010 surveys.

Measurements

Stratified by gender, longitudinal latent class analyses estimated alcohol use trajectories (using past‐year frequency, quantity and binge drinking from 2003 to 2010). Multinomial logistic regression tested differences in trajectory class memberships by sexual orientation [comparing completely heterosexual (CH) participants with sexual‐minority subgroups: mainly heterosexual (MH), bisexual (BI) and gay/lesbian (GL) participants]. Modified Poisson regression and mediation analyses tested whether trajectories explained sexual‐orientation differences in AUDs (past‐year DSM‐IV abuse/dependence in 2010).

Findings

Six alcohol use trajectory classes emerged for women and five for men: these included heavy (23.5/36.9% of women/men), moderate (31.8/26.4% of women/men), escalation to moderately heavy (9.7/12.0% of women/men), light (17.0% for women only), legal (drinking onset at age 21; 11.1/15.7% of women/men) and non‐drinkers (7.0/9.1% of women/men). Compared with CH women, MH and BI women had higher odds of being heavy, moderate, escalation to moderately heavy and light drinkers versus non‐drinkers (odds ratios = 2.02–3.42; P‐values < 0.01–0.04). Compared with CH men, MH men had higher odds of being heavy, moderate and legal drinkers versus non‐drinkers (odds ratios = 2.24–3.34; P‐values < 0.01–0.01). MH men and women, BI women and GLs had higher risk of AUDs in 2010 than their same‐gender CH counterparts (risk ratios = 1.34–2.17; P‐values < 0.01). Alcohol use trajectories mediated sexual‐orientation differences in AUDs for MH and GL women (proportion of effect mediated = 30.8–31.1%; P‐values < 0.01–0.02), but not for men.

Conclusions

In the United States, throughout emerging adulthood, several sexual‐minority subgroups appear to have higher odds of belonging to heavier alcohol use trajectories than completely heterosexuals. These differences partially explained the higher risk of alcohol use disorders among mainly heterosexual and gay/lesbian women but not among sexual‐minority men.