bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracting a Biologically Relevant Latent Space from Cancer Transcriptomes with Variational Autoencoders
Authors: Way Gregory P. , Greene Casey S.
Published: August 2017

The Cancer Genome Atlas (TCGA) has profiled over 10,000 tumors across 33 different cancer-types for many genomic features, including gene expression levels. Gene expression measurements capture substantial information about the state of each tumor. Certain classes of deep neural network models are capable of learning a meaningful latent space. Such a latent space could be used to explore and generate hypothetical gene expression profiles under various types of molecular and genetic perturbation. For example, one might wish to use such a model to predict a tumor’s response to specific therapies or to characterize complex gene expression activations existing in differential proportions in different tumors. Variational autoencoders (VAEs) are a deep neural network approach capable of generating meaningful latent spaces for image and text data. In this work, we sought to determine the extent to which a VAE can be trained to model cancer gene expression, and whether or not such a VAE would capture biologically-relevant features. In the following report, we introduce a VAE trained on TCGA pan-cancer RNA-seq data, identify specific patterns in the VAE encoded features, and discuss potential merits of the approach. We name our method “Tybalt” after an instigative, cat-like character who sets a cascading chain of events in motion in Shakespeare’s “Romeo and Juliet”. From a systems biology perspective, Tybalt could one day aid in cancer stratification or predict specific activated expression patterns that would result from genetic changes or treatment effects.
Spring flowering habit in field pennycress (Thlaspi arvense) has arisen multiple independent times
Authors: Dorn Kevin M. , Johnson Evan B. , Daniels Erin , Wyse Donald L. , David Marks M.
Published: August 2017

- Pennycress (Thlaspi arvenseL.) is currently being developed as a new cold-season oilseed crop. Like many Brassicaceae, pennycress can exhibit either a winter or spring annual phenotype. In Arabidopsis, mutations in negative regulators of flowering, including FLOWERING LOCUS C (FLC) and FRIGIDA can cause the transition to a spring annual habit. The genetics underlying the difference between spring and winter annual pennycress are currently unknown.

- Using whole genome sequencing across wild spring annual pennycress accessions, co-segregation analyses, and comparative genomics approaches, we identify new alleles of TaFLC and explore their geographic distribution.

- We report that loss of function mutations in TaFLC confer the spring annual phenotype in pennycress. We have also identified four natural alleles of TaFLC that confer a spring annual growth habit. The two spring annual FLC alleles present in European accessions were only identified in accessions collected in Montana, USA.

- In pennycress, the spring annual habit has arisen several independent times. Accessions harboring the two European alleles were introduced to North America, likely after the species became a widespread on the continent. These findings provide new information on the natural history of the introduction and spread of the spring annual phenotype in pennycress.
Transmission Expression Signature in NascentPlasmodium vivaxBlood Stage Infection
Authors: Adapa Swamy Rakesh , Taylor Rachel A. , Wang Chengqi , Thomson-Luque Richard , Johnson Leah R. , Jiang Rays H.Y.
Published: August 2017

The lack of a continuousin vitroculture system forPlasmodium vivaxseverely limits our knowledge of pathophysiology of the most widespread malaria parasite. To gain direct understanding ofP. vivaxhuman infections, we used Next Generation Sequencing data mining to unravel parasitein vivoexpression profiles forP. vivax,andP. falciparumas comparison. We performed cloud and local computing to extract parasite transcriptomes from publicly available raw data of human blood samples. We developed a Poisson Modelling (PM) method to confidently identify parasite derived transcripts in mixed RNAseq signals of infected host tissues. We successfully retrieved and reconstructed parasite transcriptomes from infected patient blood as early as the first blood stage cycle; and the same methodology did not recover any significant signal from controls. Surprisingly, these first generation blood parasites already show strong signature of transmission, which indicates the commitment from asexual-to-sexual stages. Further, we develop mathematical models forP. vivaxandP. falciparumto assess the epidemiological impact of possible 7-day early stage transmission andP. vivaxcomplex life cycle. The study uncovers the earliest onset ofP. vivaxblood pathogenesis and highlights the challenges ofP. vivaxeradication programs.

Author summary

We discovered thatP. vivax in vivoparasitemia is associated with gametocytogenesis expression signature within the first blood stage cycle, that is, eight days from a mosquito bite. Our results suggest that asexual-to-sexual commitment may happen with first generation merozoite infection. This allows for the possibility of transmission at this early stage, much earlier than forP. falciparum. Our novel mathematical model accounts for multiple unique aspects ofP. vivaxbiology to advance our understanding of expected disease prevalence, and compares the results to those ofP. falciparum. We demonstrate that given the presence of asymptotical carriers and the possibility of relapses, earlier parasite transmission is capable of increasing the spread of disease within human populations. In summary,P. vivaxgametogenesis has the potential to fast track the transmission cycle, which will drive enhanced propagation of the disease during the transmission season and clinical relapses.
A scheme for 3-dimensional morphological reconstruction and force inference in the earlyC. elegansembryo
Authors: Xu Muzhi , Wu Yicong , Shroff Hari , Wu Min , Mani Madhav
Published: August 2017

In this study, we present novel schemes for the reconstruction of cellular morphology and the inference of forces in the earlyC. elegansembryo. We have developed and bench-marked a morphological reconstruction scheme that transforms live-imaging of cellular membranes into a point cloud of smoothed surface patches, which facilitates accurate estimation of membrane curvatures and the angles between membranes.

Assuming an isotropic and homogeneous distribution of tensions along a membrane, we infer a pattern of forces that are 7% deviated from force balance at edges, and 10% deviated from the Young-Laplace relation at membrane faces. We have also demonstrated the stability of our scheme by sensitivity analysis of the coefficient matrices involved and the reproducibility of our image-analysis and force inference pipeline.
Preservation of three-dimensional spatial structure in the gut microbiome
Authors: Hasegawa Yuko , Mark Welch Jessica L. , Rossetti Blair J. , Borisy Gary G.
Published: August 2017

Preservation of three-dimensional structure in the gut is necessary in order to analyze the spatial organization of the gut microbiota and gut luminal contents. In this study, we evaluated preparation methods for mouse gut with the goal of preserving micron-scale spatial structure while performing fluorescence imaging assays. Our evaluation of embedding methods showed that commonly used media such as Tissue-Tek Optimal Cutting Temperature (OCT) compound, paraffin, and polyester waxes resulted in redistribution of luminal contents. By contrast, a hydrophilic methacrylate resin, Technovit H8100, preserved three-dimensional organization. Our mouse intestinal preparation protocol optimized using the Technovit H8100 embedding method was compatible with microbial fluorescencein situhybridization (FISH) and other labeling techniques, including immunostaining and staining with both wheat germ agglutinin (WGA) and 4’,6-diamidino-2-phenylindole (DAPI). Mucus labeling patterns of the samples fixed with paraformaldehyde (PFA) and Carnoy’s fixative were comparable. The protocol optimized in this study enabled simultaneous visualization of micron-scale spatial patterns formed by microbial cells in the mouse intestines along with biogeographical landmarks such as host-derived mucus and food particles.
Bacmeta: simulation for genomic evolution in bacterial metapopulations
Authors: Sipola Aleksi , Marttinen Pekka , Corander Jukka
Published: August 2017

The advent of genomic data from densely sampled bacterial populations has created a need for flexible simulators by which models and hypotheses can be efficiently investigated in the light of empirical observations. Bacmeta provides fast stochastic simulation of neutral evolution within a large collection of interconnected bacterial populations with completely adjustable connectivity network. Stochastic events of mutations, recombinations, insertions/deletions, migrations and microepidemics can be simulated in discrete non-overlapping generations with a Wright-Fisher model that operates on explicit sequence data of any desired genome length. Each model component, including locus, bacterial strain, population, and ultimately the whole metapopulation, is efficiently simulated using C++ objects, and detailed metadata from each level of the simulation can be acquired. The software can be executed in a cluster environment using simple textual input files, enabling, e.g., large-scale simulations and likelihood-free inference. Bacmeta is implemented with C++ for Linux, Mac and Windows. It is available athttps://bitbucket.org/aleksisipola/bacmetaunder the BSD 3-clause license.

Contact

aleksi.sipola@helsinki.fi,

jukka.corander@medisin.uio.no

Supplementary information

Supplementary data are available online at bioRxiv.
Cooperative mechanosensitivity and allostery of focal adhesion clusters
Authors: Foo D. C. W. , Terentjev E. M.
Published: August 2017

We analyse an Ising-like Hamiltonian describing the free energy of cell adhesion on a substrate as a lattice of 3-state mechanosensing sites involving focal adhesion kinase (FAK). We use Monte Carlo stochastic algorithm to find equilibrium configurations of these mechanosensors in two representative geometries: on a 1D ring representing the rim of a cell on flat surface, and a 2D bounded surface representing the whole area of cell contact with flat surface. The level of FAK activation depend on the pulling force applied to the individual FAKintegrin via actin-myosin contractile networks, and the details of the coupling between individual sensors in a cluster. Strong coupling is shown to make the FAK sensors experience a sharp on-off behaviour in their activation, while at low coupling the activation/autoinhibition transition occurs over a broad range of pulling force. We find that the activation/autoinhibition transition of FAK in the 2D system with strong coupling occurs with a hysteresis, the width of which depends on the rate of change of force. The effect of introducing a mediating protein (such as Src) in limited quantity to control FAK activation is explored, and visualizations of clustering in both topologies are presented. In particular the results on the bounded 2D surface indicate that clustering of active FAK occurs preferentially at the boundary, in agreement with experimental observations of focal adhesions in cells.
Network perturbation analysis of gene transcriptional profiles reveals protein targets and mechanism of action of drugs and influenza A viral infection
Authors: Noh Heeju , Shoemaker Jason E. , Gunawan Rudiyanto
Published: August 2017

Genome-wide transcriptional profiling provides a global view of cellular state and how this state changes under different treatments (e.g. drugs) or conditions (e.g. healthy and diseased). Here, we present ProTINA (Protein Target Inference by Network Analysis), a network perturbation analysis method for inferring protein targets of compounds from gene transcriptional profiles. ProTINA uses a dynamic model of the cell-type specific protein-gene transcriptional regulation to infer network perturbations from steady state and time-series differential gene expression profiles. A candidate protein target is scored based on the gene network’s dysregulation, including enhancement and attenuation of transcriptional regulatory activity of the protein on its downstream genes, caused by drug treatments. For benchmark datasets from three drug treatment studies, ProTINA was able to provide highly accurate protein target predictions and to reveal the mechanism of action of compounds with high sensitivity and specificity. Further, an application of ProTINA to gene expression profiles of influenza A viral infection led to new insights of the early events in the infection.
Improving on a modal-based estimation method: model averaging for consistent and efficient estimation in Mendelian randomization when a plurality of candidate instruments are valid
Authors: Burgess Stephen , Zuber Verena , Gkatzionis Apostolos , Rees Jessica MB , Foley Christopher N
Published: August 2017

Background

A robust method for Mendelian randomization does not require all genetic variants to be valid instruments to give consistent estimates of a causal parameter. Several such methods have been developed, including a mode-based estimation method giving consistent estimates if a plurality of genetic variants are valid instruments; that is, there is no larger subset of invalid instruments estimating the same causal parameter than the subset of valid instruments.

Methods

We here develop a model averaging method that gives consistent estimates under the same ‘plurality of valid instruments’ assumption. The method considers a mixture distribution of estimates derived from each subset of genetic variants. The estimates are weighted such that subsets with more genetic variants receive more weight, unless variants in the subset have heterogeneous causal estimates, in which case that subset is severely downweighted. The mode of this mixture distribution is the causal estimate. This heterogeneity-penalized model averaging method has several technical advantages over the previously proposed mode-based estimation method.

Results

The heterogeneity-penalized model averaging method outperformed the mode-based estimation in terms of effciency and outperformed other robust methods in terms of Type 1 error rate in an extensive simulation analysis. The proposed method suggests two distinct mechanisms by which inflammation affects coronary heart disease risk, with subsets of variants suggesting both positive and negative causal effects.

Conclusions

The heterogeneity-penalized model averaging method is an additional robust method for Mendelian randomization with excellent theoretical and practical properties, and can reveal features in the data such as the presence of multiple causal mechanisms. (249 words)

Key messages

We propose a heterogeneity-penalized model averaging method that gives consistent causal estimates if a weighted plurality of the genetic variants are valid instruments.

The method calculates causal estimates based on all subsets of genetic variants, and upweights subsets containing several genetic variants with similar causal estimates.

The method is asymptotically effcient and does not rely on bootstrapping to obtain a confidence interval, nor is the confidence interval constrained to be symmetric.

In particular, the confidence interval can include multiple disjoint intervals, suggesting the presence of multiple causal mechanisms by which the risk factor influences the outcome.

The method can incorporate biological knowledge to upweight the contribution of genetic variants with stronger plausibility of being valid instruments.
Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells
Authors: Pavlaki Ioanna , Docquier France , Chernukhin Igor , Kita Georgia , Gretton Svetlana , Clarkson Christopher T. , Teif Vladimir B. , Klenova Elena
Published: August 2017

CTCF is an evolutionarily conserved and ubiquitously expressed architectural protein regulating a plethora of cellular functions via different molecular mechanisms. CTCF can undergo a number of post-translational modifications which change its properties and functions. One such modifications linked to cancer is poly(ADP-ribosyl)ation (PARylation). The highly PARylated CTCF form has an apparent molecular mass of 180 kDa (referred to as CTCF180), which can be distinguished from hypo- and non-PARylated CTCF with the apparent molecular mass of 130 kDa (referred to as CTCF130). The existing data accumulated so far have been mainly related to CTCF130. However, the properties of CTCF180 are not well understood despite its abundance in a number of primary tissues. In this study we performed ChIP-seq and RNA-seq analyses in human breast cells 226LDM, which display predominantly CTCF130 when proliferating, but CTCF180 upon cell cycle arrest. We observed that in the arrested cells the majority of sites lost CTCF, whereas fewer sites gained CTCF or remain bound (i.e. common sites). The classical CTCF binding motif was found in the lost and common, but not in the gained sites. The changes in CTCF occupancies in the lost and common sites were associated with increased chromatin densities and altered expression from the neighboring genes. Based on these results we propose a model integrating the CTCF130/180 transition with CTCF-DNA binding and gene expression changes. This study also issues an important cautionary note concerning the design and interpretation of any experiments using cells and tissues where CTCF180 may be present.
Common variants ofNRXN1, LRP1BandRORAare associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study
Authors: Alliey-Rodriguez Ney , Grey Tamar A , Shafee Rebecca , Padmanabhan Jaya , Tandon Neeraj , Klinger Madeline , Spring Jonathan , Coppes Lucas , Reis Katherine , Keshavan Matcheri S , Gage Diane , McCarroll Steven , Bishop Jeffrey R , Hill Scot , Reilly James L , Lencer Rebekka , Clementz Brett , Buckley Peter , Meda Shashwath , Narayanan Balaji , Glahn David C , Pearlson Godfrey , Ivleva Elena I , Tamminga Carol , Sweeney John A , Curtis David , Keedy Sarah , Badner Judith A , Liu Chunyu , Gershon Elliot S
Published: August 2017

Schizophrenia, Schizoaffective, and Bipolar Disorders share common illness traits, intermediate phenotypes and a partially overlapping polygenic basis. We performed GWAS on deep phenotyping data, including structural MRI and DTI, clinical, and behavioral scales from 1,115 cases and controls. Significant associations were observed with two cerebrospinal fluid volumes: the temporal horn of left lateral ventricle was associated withNRXN1, and the volume of the cavum septum pellucidum was associated withLRP1BandRORA. Both volumes were associated with illness. Suggestive associations were observed with local gyrification indices, fractional anisotropy and age at onset. The deep phenotyping approach allowed unexpected genetic sharing to be found between phenotypes, including temporal horn of left lateral ventricle and age at onset.
Proofreading-deficient coronaviruses adapt over long-term passage for increased fidelity and fitness without reversion of exoribonuclease-inactivating mutations
Authors: Graepel Kevin W. , Lu Xiaotao , Case James Brett , Sexton Nicole R. , Smith Everett Clinton , Denison Mark R.
Published: August 2017

The coronavirus (CoV) RNA genome is the largest among single-stranded positive sense RNA viruses. CoVs encode a proofreading 3′→5′exoribonuclease within nonstructural protein 14 (nsp14-ExoN) that is responsible for CoV high-fidelity replication. Alanine substitution of ExoN catalytic residues [ExoN(-)] in SARS-CoV and murine hepatitis virus (MHV) disrupts ExoN activity, yielding viable mutant viruses with defective replication, up to 20-fold decreased fidelity, and increased susceptibility to nucleoside analogs. To test the stability of the ExoN(-) genotype and phenotype, we passaged MHV-ExoN(-) 250 times in cultured cells (P250), in parallel with WT-MHV. Compared to MHV-ExoN(-) P3, MHV-ExoN(-) P250 demonstrated enhanced replication, reduced susceptibility to nucleoside analogs, and increased competitive fitness. However, passage did not select for complete or partial reversion at the ExoN-inactivating mutations. We identified novel amino acid changes within the RNA-dependent RNA polymerase (nsp12-RdRp) and nsp14 of MHV-ExoN(-) P250 that partially account for the observed changes in replication, susceptibility to nucleoside analogs, and competitive fitness observed in the passaged virus population, indicating that additional determinants can compensate for the activities of nsp14-ExoN. Our results suggest that while selection favors restoration of replication fidelity in ExoN(-) CoVs, there may be a significant barrier to ExoN(-) reversion. These results also support the hypothesis that high-fidelity replication is linked to CoV fitness and identify additional candidate proteins that may regulate CoV replication fidelity.

IMPORTANCE

Unique among RNA viruses, CoVs encode a proofreading exoribonuclease (ExoN) in nsp14 that mediates high-fidelity RNA genome replication. Proofreading-deficient CoVs with disrupted ExoN activity [ExoN(-)] are either non-viable or have significant defects in replication, RNA synthesis, fidelity, fitness, and virulence. In this study, we show that ExoN(-) murine hepatitis virus can adapt over long-term passage for increased replication and fitness without reverting the ExoN-inactivating mutations. Passage-adapted ExoN(-) mutants also demonstrate increasing resistance to nucleoside analogs that is only partially explained by secondary mutations in nsp12 and nsp14. These data suggest that enhanced resistance to nucleoside analogs is mediated by the interplay of multiple replicase proteins and support the proposed link between CoV fidelity and fitness.
Livestock activity increases exotic plant richness, but wildlife increases native richness, with stronger effects under low productivity
Authors: Eldridge David J. , Delgado‐Baquerizo Manuel , Travers Samantha K. , Val James , Oliver Ian , Dorrough Josh W. , Soliveres Santiago
Published: August 2017

Grazing by domestic livestock is one of the most widespread land uses world‐wide, particularly in rangelands, where it co‐occurs with grazing by wild herbivores. Grazing effects on plant diversity are likely to depend on intensity of grazing, herbivore type, co‐evolution with plants and prevailing environmental conditions.

We collected data on climate, plant productivity, soil properties, grazing intensity and herbivore type, and we measured their effects on plant species richness from 451 sites across 0.4 M km2 of semi‐arid rangelands in eastern Australia. We used structural equation modelling to examine the direct and indirect effects of increasing grazing intensity by different herbivores (cattle, sheep, kangaroos, rabbits) on native and exotic plant species richness across all sites, and in subsets focusing on three woodland communities spanning a gradient in productivity.

Direct effects of grazing by all herbivores were strongest under low productivity but waned with increasing productivity. Increases in the intensity of recent and historic livestock grazing corresponded with greater exotic plant richness under low productivity and less native plant richness under both low and moderate productivity. Rabbit effects were greatest under moderate productivity. Overall, the effects of kangaroos were benign. Grazing indirectly affected native and exotic plant richness by increasing soil phosphorus and reducing soil health (i.e. nutrient cycling).

Synthesis and applications. Our study shows that livestock grazing increases exotic species richness but reduces native richness, while kangaroo grazing increases native richness in environments with low productivity. The results provide clear messages for land managers and policy makers: (1) the coexistence of livestock grazing and plant diversity is only possible within more productive environments and (2) grazing under low or moderate productivity will impact upon native and exotic plant richness.
Structural Changes to the Public Sector and Cultural Incompatibility: The Consequences of Inadequate Cultural Integration
Authors: Buick Fiona , Carey Gemma , Pescud Melanie
Published: August 2017

Structural changes are commonly undertaken to achieve gains, such as enhanced efficiency and performance. In this paper, we explore the cultural issues associated with a structural change in the Australian Public Service. We argue that cultural differences across merged functions were disruptive and challenging to overcome. We posit, however, that these challenges were exacerbated by the lack of systemic effort to integrate cultures, thus impeding synergy realization. Our findings are consistent with the private sector literature that warns mergers and acquisitions undertaken with too much haste and without adequate planning can lead to cultural issues when not managed appropriately.
Tax policy and tax protest in 20 rich democracies, 1980–2010
Authors: William Martin Isaac , Gabay Nadav
Published: August 2017

Why are some policies protested more than others? New data on protest against eight categories of taxation in twenty rich democracies from 1980 to 2010 reveal that economically and socially concentrated taxes are protested most, whereas taxes that confer entitlement to benefits are protested least. Other features of policy design often thought to affect the salience or visibility of costs are unimportant for explaining the frequency of protest. These findings overturn a folk theory that political sociology has inherited from classical political economy; clarify the conditions under which policy threats provoke protest; and shed light on how welfare states persist.
The Worth of Fair Value Accounting: Dissonance between Users and Standard Setters
Authors: Georgiou Omiros
Published: August 2017

Investors and analysts are designated as the primary users of financial reports by standard setters, yet we know very little about their use of accounting information and about their relationship with standard setters. This paper explores how investors and analysts evaluate the usefulness of fair values to their work. Standard setters typically presume that investors and analysts view accounting as a practice of valuation and, therefore, favor the greater use of fair value measurement. However, using interview evidence, it is shown here that investors and analysts expect accounting to provide them with insights into the performance of a business, and are quite cautious about the limits of using fair values in financial reports. Overall, the paper contributes to a better understanding of the relationship between accounting and its users. It adds specifically to research which has analyzed the disconnect between users and standard setters in terms of standard setters ignoring user needs (Young ), and in terms of users being indifferent about, or uncritical of, outcomes of standard‐setting processes (Durocher, Fortin, and Cote ; Durocher and Gendron ). The paper suggests a re‐theorization of the disconnect between the two groups that involves thinking away from tension, or blame. Drawing on the work of David Stark (), the situation observed is conceptualized as one of “dissonance,” where the different ways of evaluating fair values coexist without being involved in a fierce contest. That is, even though the principles of valuation and performance differ, this difference does not lead to open disagreement and political lobbying from investors and analysts. Consequences of this dissonance to our understandings of the (absence of) worth of fair values in capital markets are discussed.
Acacia saligna's soil legacy effects persist up to 10 years after clearing: Implications for ecological restoration
Authors: Nsikani Mlungele M. , Novoa Ana , van Wilgen Brian W. , Keet Jan‐Hendrik , Gaertner Mirijam
Published: August 2017

To reduce the negative impacts of invasive plants, management interventions such as control or eradication are usually necessary. It is often assumed that the impacts of invasive plants will diminish immediately after such interventions. However, in some cases the invader can have legacy effects in the soil that might persist for long periods, preventing the natural restoration of the areas managed. Therefore, to achieve the re‐establishment of a functional native ecosystem it is important to understand for how long such legacies can persist in the soil. This paper explores this issue, using Acacia saligna in South Africa as case study. We collected soil samples in invaded, non‐invaded and previously invaded sites (representing 2, 6 and 10 years after clearing) and analysed the levels of pH, carbon, nitrogen, available phosphorus, ammonium, nitrate and electrical conductivity. We also analysed enzyme activities (β‐1,4‐glucosidase, urease and acid phosphatase). Acacia saligna invasion alters overall soil characteristics but specifically raises pH by 0.6–1.8. Moreover, soil characteristics (e.g. pH) are not restored to natural conditions after control (soil legacy effects persist up to 10 years after clearing). Furthermore, A. saligna control elevates soil levels and these can remain higher than in invaded (1.55–6.67 mg kg−1) and non‐invaded (2.16–4.35 mg kg−1) sites up to 10 years after clearing. Elevated often facilitates secondary invasion and/or weedy native species dominance which may hinder the restoration of functional native ecosystems. Therefore, strategies to manage areas previously invaded by A. saligna should take into account the removal of litter from the target invader, secondary invaders and weedy native species.
Body weight status and health‐care expenditure among university retirees in Beijing, China
Authors: Jiang Ning , Yu Hongjun , An Ruopeng
Published: August 2017

Objective

This study examined the impact of overweight and obesity on health‐care expenditure among university retirees in Beijing, China.

Methods

Annual health surveys of retirees were conducted at Tsinghua University during 2011–2016. Individual random‐effect regressions were performed to estimate incremental health‐care expenditures attributable to overweight/obesity, adjusting for various individual characteristics.

Results

Compared to their normal‐weight counterparts, obesity was associated with an increase in annual out‐of‐pocket expenditure on outpatient care by 27%, inpatient care 19% and medication 15%, and an increase in annual total out‐of‐pocket health‐care expenditure by 33%. Overweight was associated with an increase in annual out‐of‐pocket expenditure on inpatient care by 13%, and an increase in annual total out‐of‐pocket health‐care expenditure by 13%. The impact of obesity on health‐care expenditure was statistically significant among men but not women.

Conclusion

Overweight, and obesity in particular, was associated with substantial increases in out‐of‐pocket health‐care expenditures among Chinese older adults.
Clinical Aspects of Opium Adulterated with Lead in Iran: A Review
Authors: Alinejad Samira , Aaseth Jan , Abdollahi Mohammad , Hassanian‐Moghaddam Hossein , Mehrpour Omid
Published: August 2017

Adulteration of drugs with poisonous substances during production or consumption has caused numerous health problems. Among contaminants that have the potential of producing poisonous effects are the heavy metals lead, arsenic and thallium that make up an important group of toxic substances. The emergence of these new health problems related to opioid abuse has precipitated this MiniReview on the status of the most hazardous and common opioid adulterants. In fact, adulterated opium is a major public health problem and can threaten the health of users. In this study, we searched for information on opium, opiates, lead poisoning, toxicity, intoxication, Iran and heavy metals in the TUMS Digital Library, PubMed, Scopus, EMBASE and Google Scholar bibliographical databases. This MiniReview primarily included articles on lead poisoning, signs and symptoms, and management in opioid‐dependent individuals. Exclusion criteria were articles dealing with animal studies, specific paediatric studies, adulterants other than heavy metals and substances other than opioids. Adulterated opium is one of the new sources of exposure to lead and has precipitated an increase in lead‐poisoned cases owing to the widespread use of opium. The toxicology of lead and general guidelines on diagnosis and treatment of lead poisoning is briefly reviewed. The symptoms of lead toxicity mimic several diseases often leading to unnecessary diagnostic methods, misdiagnoses and even surgery. Finally, owing to the fact that lead toxicity shows non‐specific signs and symptoms, screening for this disease, by taking blood samples and assessing blood lead levels in high‐risk people, should be given an utmost priority. It is recommended that screening tests are adopted and applied for any drug‐abusing patient with non‐specific subacute signs and symptoms like abdominal pain, constipation and anaemia.
Monitoring and depth of strategy use in computer‐based learning environments for science and history
Authors: Deekens Victor M. , Greene Jeffrey A. , Lobczowski Nikki G.
Published: August 2017

Background

Self‐regulated learning (SRL) models position metacognitive monitoring as central to SRL processing and predictive of student learning outcomes (Winne & Hadwin, 2008; Zimmerman, 2000). A body of research evidence also indicates that depth of strategy use, ranging from surface to deep processing, is predictive of learning performance.

Aims

In this study, we investigated the relationships among the frequency of metacognitive monitoring and the utilization of deep and surface‐level strategies, and the connections between these SRL processes and learning outcomes across two academic domains, science and history.

Sample

This was a secondary data analysis of two studies. The first study sample was 170 undergraduate students from a University in the south‐eastern United States. The second study sample consisted of 40 US high school students in the same area.

Methods

We collected think‐aloud protocol SRL and knowledge measure data and conducted both structural equation modelling and path analysis to investigate our research questions.

Results

Findings showed across both studies and two distinct academic domains, students who enacted more frequent monitoring also enacted more frequent deep strategies resulting in better performance on academic evaluations.

Conclusions

These findings suggest the importance of measuring not only what depth of strategies learners use, but also the degree to which they monitor their learning. Attention to both is needed in research and practice.
Positioning, telling, and performing a male illness: Chronic prostatitis/chronic pelvic pain syndrome
Authors: Wood Nicholas , Qureshi Annum , Mughal Fahim
Published: August 2017

Objectives

There is a paucity of illness accounts of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), despite a significant level of prevalence and burden of disease. This qualitative study thus elicited twelve accounts from men suffering with CP/CPPS.

Methods

Narrative analysis was employed, focusing primarily on narrative content.

Results

Three major narrative themes were identified: (1) Medical stories: Blame and shame; (2) The Erratic nature of CP/CPPS; and (3) Ongoing struggles for coping and cures and the Search for meaning.

Conclusions

Recommendations were made for health care providers and increasing the internal agency, support and activism of men with this debilitating condition.

Statement of contribution

What is already known on this subject?

One qualitative account of this male illness (CP/CPPS) exists: an IPA study.

Five cross‐sectional themes: (1) Need for repeated confirmation – disease not life‐threatening nor leading inexorably towards cancer; (2) Disturbed sleep and fatigue; (3) Concealing pain and problems – ‘normalizing’; (4) Enduring pain by performing activities; and (5) Abrupt mood swings and limited sociality.

What does this study add?

Narrative analysis adds information as to how this illness is managed and survived over time.

It challenges the findings (above) by providing an insider perspective.

Novel narrative themes include meaning‐making amongst others.

Masculine performance and experiences are also crucial to this stigmatized illness.
Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy
Authors: Kyburz A. , Urban S. , Altobelli A. , Floess S. , Huehn J. , Cover T. L. , Müller A.
Published: August 2017

Background

Food allergy is an increasingly common health problem in Western populations. Epidemiological studies have suggested both positive and negative associations between food allergy and infection with the gastric bacterium Helicobacter pylori.

Objective

The objective of this work was to investigate whether experimental infection with H. pylori, or prophylactic treatment with H. pylori‐derived immunomodulatory molecules, affects the onset and severity of food allergy, either positively or negatively.

Methods

We infected neonatal C57BL/6 or C3H mice with H. pylori or treated animals with H. pylori components (bacterial lysate or the immunomodulator VacA) and subsequently subjected them to four different protocols for food allergy induction, using either ovalbumin or peanut extract as allergens for sensitization and challenge. Readouts included anaphylaxis scoring, quantification of allergen‐specific serum IgE and IgG1 and of the mast cell protease MCPT1, as well as splenic T‐helper‐2 cell‐derived cytokine production. Mesenteric lymph node CD4+FoxP3+ regulatory T cells were subjected to flow cytometric quantification and sorting followed by qRT‐PCR, and to DNA methylation analyses of the Treg‐specific demethylated region (TSDR) within the FOXP3 locus.

Results

Mice that had been infected with H. pylori or treated with H. pylori‐derived immunomodulators showed reduced anaphylaxis upon allergen sensitization and challenge, irrespective of the allergen used. Most of the immunologic assays confirmed a protective effect of H. pylori. CD4+FoxP3+ T cells were more abundant in protected mice and exhibited a stable Treg phenotype characterized by FOXP3 TSDR demethylation.

Conclusions and Clinical Relevance

Helicobacter pylori confers protection against the anaphylaxis associated with ovalbumin and peanut allergy and affects the epigenome of T cells, thereby promoting stable Treg differentiation and functionality. Prophylactic treatment with H. pylori‐derived immunomodulators appears to be a promising strategy for food allergy prevention.
Overcoming severe adverse reactions to venom immunotherapy using anti‐IgE antibodies in combination with a high maintenance dose
Authors: Stretz E. , Oppel E. M. , Räwer H.‐C. , Chatelain R. , Mastnik S. , Przybilla B. , Ruëff F.
Published: August 2017

Background

An omalizumab treatment and a high maintenance venom dose may both help to prevent recurrent systemic allergic reactions (SAR) to venom immunotherapy (VIT). The effectiveness of this combination therapy, however, is unclear.

Objective

We wanted to explore the possibility whether a temporary treatment with the anti‐IgE antibody omalizumab combined with a VIT using an elevated maintenance dose of >100 μg venom may establish a permanent tolerance of maintenance VIT.

Methods

For this retrospective case series, we scoured our institutional data base for patients who had had an insect venom allergy, and in whom it had not been possible to continue VIT because of repeated unstoppable SAR during maintenance VIT. Patients were divided into those who had received the combination therapy (omalizumab group) and those who had not received omalizumab because its costs could not be covered (controls). Guided by the total IgE level and by body weight, omalizumab had been given subcutaneously 5, 3 and 1 weeks before VIT had been restarted. Three to 6 months after an elevated maintenance dose (200‐300 μg venom) had been reached, omalizumab had been stopped.

Results

Between 2006 and 2011, 15 patients had qualified for an off‐label use of omalizumab: 10 patients had received the combination therapy, and 5 patients had remained without such a therapy. The combination therapy leads to a durable tolerance of VIT in all patients even after omalizumab had been discontinued (median of follow‐up time 5.8 years, IQR 2.7‐8.6 years). Sting challenge tests were tolerated by all of the re‐stung omalizumab patients (n = 8). In all controls, VIT had to be stopped permanently due to repeated SARs (P < .001 vs omalizumab group).

Conclusions and Clinical Relevance

Combining a temporary omalizumab therapy with an elevated maintenance dose seems a promising approach to achieve a tolerance of treatment in patients with a recurrent SAR to VIT.
Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men
Authors: Skorupskaite Karolina , George Jyothis T. , Veldhuis Johannes D. , Millar Robert P. , Anderson Richard A.
Published: August 2017

Objective

Patients with mutations of neurokinin B (NKB) and its receptor show hypogonadotrophic hypogonadism, but there is little evidence for the importance of this pathway in reproductive function in normal men, or its functional hierarchy with kisspeptin.

Design

An open label study wherein men (n = 6) were administered the NK3R antagonist MLE4901 40 mg orally twice a day for 7 days. Kisspeptin‐10 (0.3 μg/kg iv bolus) was given before and on day 7 of NK3R antagonist treatment.

Patients

Subjects were healthy men.

Measurements

Reproductive hormones were measured before and during the NK3R antagonist administration, including frequent sampling on two occasions for analysis of pulsatile LH secretion.

Results

LH, FSH and testosterone secretion were decreased during NK3R antagonist administration. LH showed a biphasic response, being reduced after 24 hours of treatment (4.5 ± 0.6 IU/L pretreatment to 1.7 ± 0.2 IU/L, P < .05), with partial recovery thereafter, but it was again decreased on day 7 (2.5 ± 0.6 IU/L, P < .05 vs pretreatment). FSH secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone secretion was decreased from 24 hours (18.4 ± 1.6 pretreatment vs 5.6 ± 1.5 nmol/L, P < .01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility showed that both basal and pulsatile LH secretion were markedly suppressed but there was no detected change in LH pulse frequency. Kisspeptin‐10 stimulated LH secretion, with similar responses before and during NK3R antagonist administration.

Conclusions

These data demonstrate a central role for NKB/NK3R in the physiological regulation of reproductive function in men, and that this is functionally upstream of kisspeptin‐mediated GnRH secretion.
Gene‐panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication
Authors: Pelttari L.M. , Shimelis H. , Toiminen H. , Kvist A. , Törngren T. , Borg Å. , Blomqvist C. , Bützow R. , Couch F. , Aittomäki K. , Nevanlinna H.
Published: August 2017

Gene‐panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high‐risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene‐panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein‐truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n = 1149), in unselected breast (n = 1729) and ovarian cancer cohorts (n = 553), and in population controls (n = 1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P = .032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.
Examining the association between depression and obesity during a weight management programme
Authors: Fuller N. R. , Burns J. , Sainsbury A. , Horsfield S. , da Luz F. , Zhang S. , Denyer G. , Markovic T. P. , Caterson I. D.
Published: August 2017

The prevalence of depression in those with obesity is reported to be as high as double that in individuals of normal weight. There is potentially a bi‐directional relationship between obesity and depression. Some research has suggested that depression results in weight gain and obesity, and other studies have suggested that those with obesity are more likely to develop depression at a later stage. The aim of this study was to investigate the association of depression symptoms with weight change over a 12‐month study. Seventy participants undertook a 3‐month lifestyle (diet and exercise) weight loss intervention, and were followed up as part of a 12‐month study. Participants completed the Beck Depression Inventory‐II (BDI‐II) and had their body weight measured throughout the study. Baseline body mass index (BMI) of participants (mean ± standard deviation [SD]) was 31.1 ± 3.9 kg m−2, body weight was 89.4 ± 16.1 kg, and age was 45.4 ± 11.1 years; 63% of the cohort were female. The mean weight change from baseline to 3 months was −5.2% (±SD 4.3%), and from baseline to 12 months was −4.2% (±SD 6.1%). There was a significant decrease in BDI‐II scores over the 12‐month study, and a 1‐unit decrease in BDI‐II score was associated with a further decrease in body weight of −0.4%. The current study indicated that weight loss was associated with improvements in mood for non‐clinically depressed individuals with obesity, and these improvements persisted during a period of 3–12 months of follow‐up.
A preliminary study of static and dynamic balance in sedentary obese young adults: the relationship between BMI, posture and postural balance
Authors: do Nascimento J. A. , Silva C. C. , dos Santos H. H. , de Almeida Ferreira J. J. , de Andrade P. R.
Published: August 2017

The aim of this study was to evaluate the postural control of obese young adults with normal body mass index during different static (bipedic and unipedic support) and dynamic postural conditions (gait velocity and limits of stability) in order to compare the static and dynamic balance of these individuals.

A cross‐sectional quantitative study was carried out to evaluate static and dynamic balance in 25 sedentary individuals. The sample was divided into two groups, 10 in the normal‐weight group (24.70 ± 3.89 years and 21.5 ± 1.66 kg m−2) and 15 in the obese group (26.80 ± 5.16 years and 35.66 ± 4.29 kg m−2). Postural evaluation was performed through visual inspection, and balance analyses were performed using the Timed Up & Go test (TUGT) and Balance System (Biodex). Descriptive analyses, Fisher's exact test and Mann Whitney U‐tests were performed using the Statistical Package for Social Sciences (SPSS – 20.0, Armonk, NY) software.

Most of the obese volunteers presented postural alterations, such as head protrusion (47.6%), hyperkyphosis (46.7%) and hyperlordosis (26.7%). Medial–lateral dynamic displacement, risk of falls and mean time to perform the limits of stability test and TUGT were higher for obese subjects (P < 0.05), while there were no significant differences between the groups (P > 0.05) for static balance tests for either bipedal or unipedal tasks.

The disadvantage presented by the young obese subjects occurs in dynamic activities, representing worse balance and an increase in time needed to accomplish these activities.