bluuebunny/crossref_metadata_2025 huggingface dataset:
GenomeChronicler: The Personal Genome Project UK Genomic Report Generator Pipeline
Authors: Guerra-Assunção José Afonso , Conde Lucia , Moghul Ismail , Webster Amy P. , Ecker Simone , Chervova Olga , Chatzipantsiou Christina , Prieto Pablo P. , Beck Stephan , Herrero Javier
Published: January 2020

In recent years, there has been a significant increase in whole genome sequencing data of individual genomes produced by research projects as well as direct to consumer service providers. While many of these sources provide their users with an interpretation of the data, there is a lack of free, open tools for generating reports exploring the data in an easy to understand manner.

GenomeChronicler was developed as part of the Personal Genome Project UK (PGP-UK) to address this need. PGP-UK provides genomic, transcriptomic, epigenomic and self-reported phenotypic data under an open-access model with full ethical approval. As a result, the reports generated by GenomeChronicler are intended for research purposes only and include information relating to potentially beneficial and potentially harmful variants, but without clinical curation.

GenomeChronicler can be used with data from whole genome or whole exome sequencing, producing a genome report containing information on variant statistics, ancestry and known associated phenotypic traits. Example reports are available from the PGP-UK data page (personalgenomes.org.uk/data).

The objective of this method is to leverage existing resources to find known phenotypes associated with the genotypes detected in each sample. The provided trait data is based primarily upon information available in SNPedia, but also collates data from ClinVar, GETevidence and gnomAD to provide additional details on potential health implications, presence of genotype in other PGP participants and population frequency of each genotype.

The analysis can be run in a self-contained environment without requiring internet access, making it a good choice for cases where privacy is essential or desired: any third party project can embed GenomeChronicler within their off-line safe-haven environments. GenomeChronicler can be run for one sample at a time, or in parallel making use of the Nextflow workflow manager.

The source code is available from GitHub (https://github.com/PGP-UK/GenomeChronicler), container recipes are available for Docker and Singularity, as well as a pre-built container from SingularityHub (https://singularity-hub.org/collections/3664) enabling easy deployment in a variety of settings. Users without access to computational resources to run GenomeChronicler can access the software from the Lifebit CloudOS platform (https://lifebit.ai/cloudos) enabling the production of reports and variant calls from raw sequencing data in a scalable fashion.
Spatial accumulation of salicylic acid is regulated by RBOHD in potato immunity against viruses
Authors: Lukan Tjaša , Pompe-Novak Maruša , Baebler Špela , Tušek-Žnidarič Magda , Kladnik Aleš , Križnik Maja , Blejec Andrej , Zagorščak Maja , Stare Katja , Dušak Barbara , Coll Anna , Pollmann Stephan , Morgiewicz Karolina , Hennig Jacek , Gruden Kristina
Published: January 2020

While activation of resistance (R) proteins has been intensively studied, the downstream signaling mechanisms leading to restriction of pathogen remain mostly unknown. We studied the immunity network response conditioned by the potatoNy-1gene against potato virus Y. We analyzed the processes in the cell death zone and surrounding tissue on the biochemical and gene expression levels to reveal spatiotemporal regulation of immune response. We show that the transcriptional response in the cell death zone and surrounding tissue is dependent on salicylic acid (SA). For some genes, spatiotemporal regulation is completely lost in SA-deficient line, while the others show different response, indicating multiple connections between hormonal signaling modules. The induction of NADPH oxidase RBOHD expression occurs specifically on the lesion border during resistance response. In plants with silenced RBOHD, the functionality of resistance response is perturbed and virus spread is not arrested at the site of infection. RBOHD is required for spatial accumulation of SA, and conversely RBOHD is under transcriptional regulation of SA signaling. Using spatially resolved RNA-Seq, we also identified spatial regulation of an UDP-glucosyltransferase, another component in feedback activation of SA biosynthesis, thus deciphering a novel aspect of resistance signaling.
Identifying Sequence Perturbations to an Intrinsically Disordered Protein that Determine Its Phase Separation Behavior
Authors: Schuster Benjamin S. , Dignon Gregory L. , Tang Wai Shing , Kelley Fleurie M. , Ranganath Aishwarya Kanchi , Jahnke Craig N. , Simpkins Alison G. , Regy Roshan Mammen , Hammer Daniel A. , Good Matthew C. , Mittal Jeetain
Published: January 2020

Phase separation of intrinsically disordered proteins (IDPs) commonly underlies the formation of membraneless organelles, which compartmentalize molecules intracellularly in the absence of a lipid membrane. Identifying the protein sequence features responsible for IDP phase separation is critical for understanding physiological roles and pathological consequences of biomolecular condensation, as well as for harnessing phase separation for applications in bio-inspired materials design. To expand our knowledge of sequence determinants of IDP phase separation, we characterized variants of the intrinsically disordered RGG domain from LAF-1, a model protein involved in phase separation and a key component of P granules. Based on a predictive coarse-grained IDP model, we identified a region of the RGG domain that has high contact probability and is highly conserved between species; deletion of this region significantly disrupts phase separation in vitro and in vivo. We determined the effects of charge patterning on phase behavior through sequence shuffling. By altering the wild-type sequence, which contains well-mixed charged residues, to increase charge segregation, we designed sequences with significantly increased phase separation propensity. This result indicates the natural sequence is under negative selection to moderate this mode of interaction. We measured the contributions of tyrosine and arginine residues to phase separation experimentally through mutagenesis studies and computationally through direct interrogation of different modes of interaction using all-atom simulations. Finally, we show that in spite of these sequence perturbations, the RGG-derived condensates remain liquid-like. Together, these studies advance a predictive framework and identify key biophysical principles of sequence features important to phase separation.

Significance Statement

Membraneless organelles are assemblies of highly concentrated biomolecules that form through a liquid-liquid phase separation process. These assemblies are often enriched in intrinsically disordered proteins, which play an important role in driving phase separation. Understanding the sequence-to-phase behavior relationship of these disordered proteins is important for understanding the biochemistry of membraneless organelles, as well as for designing synthetic organelles and biomaterials. In this work, we explore a model protein, the disordered N-terminal domain of LAF-1, and highlight how three key features of the sequence control the protein’s propensity to phase separate. Combining predictive simulations with experiments, we find that phase behavior of this model IDP is dictated by the presence of a short conserved domain, charge patterning, and arginine-tyrosine interactions.
Anti-tumor effects of an Id antagonist with no acquired resistance
Authors: Wojnarowicz Paulina M. , Escolano Marta Garcia , Huang Yun-Han , Desai Bina , Chin Yvette , Shah Riddhi , Xu Sijia , Ouerfelli Ouathek , Soni Rajesh Kumar , Philip John , Montrose David C. , Healey John H. , Rajasekhar Vinagolu K. , Garland William A. , Norton Larry , Rosen Neal , Hendrickson Ronald C. , Zhou Xi Kathy , Iavarone Antonio , Massague Joan , Dannenberg Andrew J. , Lasorella Anna , Benezra Robert
Published: January 2020

Id proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket and efficient degradation of the Id proteins. Thus, AGX51 is a first-in-class compound that antagonizes Id proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
Functions of olfactory receptors are decoded from their sequence
Authors: Cong Xiaojing , Ren Wenwen , Pacalon Jody , de March Claire A. , Xu Lun , Matsunami Hiroaki , Yu Yiqun , Golebiowski Jérôme
Published: January 2020

G protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diversified. This work investigated how the functional variations in olfactory GPCRs (ORs)-the largest GPCR family-are encoded in the primary sequence. With the aid of site-directed mutagenesis and molecular simulations, we built machine learning models to predict OR-ligand pairs as well as basal activity of ORs. In vitro functional assay confirmed 20 new OR-odorant pairs, including 9 orphan ORs. Residues around the odorant-binding pocket dictate the odorant selectivity/specificity of the ORs. Residues that encode the varied basal activities of the ORs were found to mostly surround the conserved motifs as well as the binding pocket. The machine learning approach, which is readily applicable to mammalian OR families, will accelerate OR-odorant mapping and the decoding of combinatorial OR codes for odors.
Modeling gene expression evolution with EvoGeneX uncovers differences in
evolution of species, organs and sexes
Authors: Pal Soumitra , Oliver Brian , Przytycka Teresa M.
Published: January 2020

While DNA sequence evolution has been well studied, the expression of genes
is also subject to evolution, yet the evolution of gene expression is currently
not well understood. Recently, new tissue/organ-specific gene expression
datasets spanning several organisms across the tree of life, have become
available, providing the opportunity to study gene expression evolution in more
detail. While a theoretical model to study the evolution of continuous traits
exists, in practice computational methods often cannot confidently distinguish
between alternative evolutionary scenarios. This lack of power has been
attributed to modest numbers of species considered in these studies.

We hypothesised that biological replicates can be used to increase
predictive power of these models. With this in mind, we introduce EvoGeneX, a
computationally efficient method to uncover the mode of gene expression
evolution based on the Ornstein-Uhlenbeck process. Importantly, in addition to
modelling expression variations between species, EvoGeneX models within-species
variation.

Furthermore, to facilitate comparative analysis of gene expression
evolution, we introduce a formal approach, based on Michaelis-Menten equation,
to measure the dynamics of evolutionary divergence of a group of genes in terms
of group’s asymptotic divergence level and rate.

Finally, we used these tools to preform the first analysis the evolution of
gene expression across different body parts, species, and sexes of the
Drosophila genus. Our analysis revealed that
neutral expression evolution can be confidently rejected in favor of purifying
selection in nearly half of the genes. In addition, we quantified differences in
the evolutionary dynamics of male and female gonads and uncovered interesting
examples of adaptive gene expression evolution.
Synthesis and crystal structures of a bis(3-hydroxy-cyclohex-2-en-1-one) and two hexahydroquinoline derivatives
Authors: Steiger Scott A. , Li Chun , Gates Christina , Natale Nicholas R.
Published: January 2020

The title compound I, 2,2′-[(2-nitrophenyl)methylene]bis(3-hydroxy-5,5-dimethylcyclohex-2-enone), C23H27NO6, features a 1,3-ketone–enol conformation which is stabilized by two intramolecular hydrogen bonds. The most prominent intermolecular interactions in compound I are C—H...O hydrogen bonds, which link molecules into a two-dimensional network parallel to the (001) plane and a chain perpendicular to (1\overline{1}1). Both title compounds II, ethyl 4-(4-hydroxy-3,5-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C23H29NO6, and III, ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C29H29NO3, share the same structural features, such as a shallow boat conformation of the dihydropyridine group and an orthogonal aryl group attached to the dihydropyridine. Intermolecular N—H...O bonding is present in the crystal packing of both compound II and III.
Understanding the diversity of alliance governance in OECD healthcare settings
Authors: Cousins Kimberly , Gauld Robin , Greatbanks Richard
Published: January 2020

Purpose

Healthcare alliances are a mechanism for developing collaborative and integrated care governance and service delivery arrangements. Yet is not known how widespread alliance arrangements are in Organisation for Economic Co-operation and Development (OECD) countries, how alliances function or how effective they are. The purpose of this paper is to provide an overview of alliances in OECD countries, including key areas covered and how performance is measured.

Design/methodology/approach

A structured narrative review of literature published between 2010 and 2018 was undertaken, focussed on OECD countries. The literature included peer-reviewed articles as well as publications from key policy analysis organisations.

Findings

Many OECD countries have implemented integrated care models but only a small number had explicitly adopted health alliances that link primary and secondary providers under joint governance arrangements. Most alliances are pilot initiatives and not broadly adopted. Most had not adopted a unified performance measurement framework.

Practical implications

Policy makers and service providers interested in joint governance arrangements that support integration must consider the range of potential options overviewed in this paper, as well as how to create supportive performance measurement frameworks.

Originality/value

This is the first narrative review of alliance arrangements in OECD countries. It provides an overview of arrangements, while illustrating that there is considerable scope for further alliance development.
Household demand for basic foodstuffs in a recessed economy: a case study of Southwest Nigeria
Authors: Sowunmi Fatai Abiola , Daramola Oladunni Akinwande , Tijani Ishaq Adewale
Published: January 2020

Purpose

The economic recession that Nigeria recently passed through caused distortions in economic and well-being of Nigerians. The purpose of this paper is to examine the effects of the economic recession on households’ demand for basic foodstuffs in Southwest Nigeria.

Design/methodology/approach

Data were collected from 380 respondents drawn from urban areas of Lagos, Osun and Oyo states using multistage sampling technique. Descriptive statistics and Quadratic Almost Ideal Demand System were employed to analyze data collected.

Findings

The study showed sharp increase in the prices of basic foodstuffs during recession. Households were compelled to spend higher percentage of their monthly income on basic foodstuffs. Also, 51.1 percent of the respondents were government workers who experienced inconsistent or modulated monthly salary during the period. The percentage of households that were food insecure was 36.4 percent. Osun State had the highest monthly per capita expenditure (₦5,147.13) on foodstuffs, followed by Lagos and Oyo states while rice had the highest expenditure share (0.26), followed by yam (0.18), beans (0.106), vegetable oil (0.104) and garri (0.101). The breakdown also showed that 11.7, 18.1 and 17.7 percent of the total household monthly expenditures in Lagos, Osun and Oyo states, respectively, were spent on basic foodstuffs.

Research limitations/implications

There purchasing power of naira reduced significantly during recession, thus compelled households to spend more on basic foodstuffs compared to similar purchases before economic recession.

Practical implications

The reduction in purchasing power of naira affected the formal and informal sector. Irregular salary for civil servants reduced their expenditure on goods and services.

Originality/value

The study is original and topical, serving as literature of accounts that transpired among the households as far as demand for basic foodstuffs is concerned during the economic recession.
Impact of big data analytics capabilities on supply chain sustainability
Authors: Shokouhyar Sajjad , Seddigh Mohammad Reza , Panahifar Farhad
Published: January 2020

Purpose

The purpose of this paper is to develop a theoretical model to explain the impact of big data analytics capabilities (BDAC) on company’s supply chain sustainability (CSCS). The secondary objective of the study is to assess the relationship between different dimensions of supply chain sustainability and companies’ BDAC.

Design/methodology/approach

This research was carried out by conducting a survey among 234 pharmaceutical companies in Iran (a case study of Iran), using a standard questionnaire of BDAC and United Nations (UN) online self-assessment on supply chain sustainability. However, the respond of managers of 188 companies were usable in this research. Smart PLS3 was used to employ partial least squares method to examine the validity and reliability of the measurement and structural model.

Findings

The results of this study demonstrate that BDAC have a strong impact on both pharmaceutical supply chain sustainability, and the dimensions including vision, engage and internal. It is found that the relationships between BDAC and the other dimensions of supply chain sustainability including expect, scope and goals are not significant but positive.

Research limitations/implications

Research on the relationship between BDAC and CSCS, especially in the pharmaceutical supply chain, is scanty, and this gap is highlighted in developing countries and the pharmaceutical supply chain that plays a prominent role in public health. This paper discusses several important barriers to forming a sustainable supply chain and strong BDA capabilities.

Practical implications

This paper could be a guide to managers and consultants who are involved in big data analytics and sustainable development. Since UN urges companies do the online self-assessment, the results of this paper would be attractive and useful for UN global compact specialists.

Originality/value

No study has directly measured the relation between BDAC and CSCS and different dimensions of CSCS, using a comprehensive survey throughout all pharmaceutical companies in Iran. Moreover, this research assesses the different dimensions of BDA capabilities and supply chain sustainability. This paper represents the facts about situation of sustainability of pharmaceutical supply chain and BDAC in these companies, and discloses several related issues that are serious barriers to forming a sustainable supply chain and strong BDAC. In addition, this paper provided academic support for UN questionnaire about CSCS and used it in the survey.
Disentangling fire intensity and species’ susceptibility to fire in a species‐rich seasonal tropical forest
Authors: Trouvé Raphaël , Bunyavejchewin Sarayudh , Baker Patrick J.
Published: January 2020

Increasing temperatures and human activity are likely to reduce fire return intervals in the seasonal tropics. Anticipating how more frequent fires may alter forest community structure and composition requires understanding how fire intensity and species‐specific responses to fires interact to drive fire‐induced mortality for large numbers of species. We developed an analytical framework to estimate unobserved fire intensities and species‐ and size‐specific susceptibility to fire using observed mortality data.

We used census data from a 50‐ha forest dynamics plot in western Thailand to better understand species and community responses to a fire that burned ∼60% of the plot in 2005. Trees species, size and status (live, dead) were censused just before the fire (2004) and again 5 years later (2009). We jointly estimated a map of relative fire intensity and species‐specific size‐dependent background and fire‐induced mortality. We then calculated the time required for individuals of each species to reach a fire‐safe size threshold (the age at which the fire‐induced mortality probability was <50%). To better understand community‐level responses to fire, we compared results among different species groups (canopy status, forest‐type association).

Our model‐derived map of fire intensity closely matched the field survey taken in the days after the fire. On average, individuals growing at the 95th percentile growth rate for most species groups required ∼5 years to reach their species’ fire‐safe size threshold, while individuals growing at the median growth rate required ∼17 years (assuming growth <1 cm diameter at breast height was similar to growth >1 cm). However, understorey species associated with the seasonal evergreen forest took 1.8 times longer than average to reach their fire‐safe size threshold, with one species requiring up to 190 years.

Synthesis. Our approach provided insights into spatial patterning of fire intensity in a seasonal tropical forest and species‐ and size‐specific susceptibility to fire‐induced mortality. Our results suggest increasing fire frequency will have the greatest impact on slow‐growing understorey species of the evergreen forest. In addition, our model accurately predicts the growing dominance of a fast‐growing understorey species, Croton roxburghii; Euphorbiaceae, common to evergreen and deciduous forests that can reach its fire‐safe size threshold in 1.3 years.
Artificial Intelligence, Neom and Saudi Arabia's Economic Diversification from Oil and Gas
Authors: Hassan Oz
Published: January 2020

Saudi Arabia is diversifying its economy by becoming a global technological hub. Driven by its ‘Vision 2030' initiative, it has embarked on the most ambitious and far‐reaching transformation plan in the Kingdom's history. At the core of this transformation are the investment and development of artificial intelligence (AI) and its integration into a new mega‐city, Neom. Currently under construction, Neom is seeking to integrate robotics and AI seamlessly into every aspect of citizens' lives in a bid to generate revenues from key economic sectors for the future. This transition from an economy based on hydrocarbons to AI is, however, more than economic. It is a bid to secure the survival of the House of Saud and meet the growing challenges of constructing a state around oil. Nevertheless, what happens in Neom may provide insights into how AI will impact the world beyond a cross‐roads built on sand.
Arsonists Suffering From Schizophrenia—A Description in Comparison with Other Offenders with a Similar Diagnosis
Authors: Günther Moritz Philipp , Kirchebner Johannes , Lau Steffen
Published: January 2020

This study aims to describe the small and distinct subgroup of arsonists diagnosed with schizophrenia, their motives, personal, and crime scene characteristics. While prior research identified significant differences to other criminals, firesetters in general, or mentally disordered offenders, there are no comparisons with other offender patients with schizophrenia so far. In a forensic institution in Switzerland, a group of 30 arsonists with schizophrenia spectrum disorder (SSD) was compared to 340 other offender patients with SSD using retrograde file analysis and multiple adapted Fisher´s exact tests. While symptoms of SSD were most defining of both groups, arsonists with SSD were more often single, unemployed, prescribed psychiatric medication at index offense, had a smaller variety of criminal motives, and acted out of anger or revenge in the context of a relationship. In conclusion, symptoms of SSD may be more defining and useful in guiding clinical practice than aspects specific to arsonists.
Intensity of renal replacement therapy and outcomes in critically ill patients with acute kidney injury: Critical appraisal of the dosing recommendations
Authors: Schiffl Helmut
Published: January 2020

The current care of critically ill patients with severe acute kidney injury requiring dialysis (AKI‐D) is limited to supportive management in which renal replacement therapy (RRT) plays a central role. Renal replacement techniques are invasive bioincompatible procedures and are therefore associated with complications that may prove harmful to fragile patients. Inexperience with the standards and lacking or misinterpreted recommendations for the delivery of the RRT dose increases the risk of serious complications. Neither the optimal doses of intermittent or continuous RRTs nor the minimal or maximal effective doses are known. The Kidney Disease Improving Global outcomes (KDIGO) AKI guidelines for RRT dosing recommendations are inflexible, based on limited research, and may be at least partially outdated. High‐intensity therapy may be associated with clinically relevant alterations in systemic and renal hemodynamics, profound electrolyte imbalances, the loss of nutrients or thermal energy, and underdosing of antimicrobial agents. However, higher doses of continuous renal replacement therapy (CRRT) may confer a survival benefit for certain subgroups of intensive care patients with severe AKI. Lower CRRT doses than the recommended adequate dosage may not lead to negative health outcomes, at least in Asian patients. Future research should evaluate the demand‐capacity concept, recognizing that the delivery of the RRT dose is dynamic and should be modified in response to patient‐related factors. There is a need for large‐scale studies evaluating whether precision RRT dose modifications may improve patient‐centered outcomes in subgroups of critically ill patients.
Feedback survey on the Royal Australian and New Zealand College of Radiologists Faculty of Radiation Oncology trainee research requirement
Authors: Foley Elizabeth F , Roos Daniel E
Published: January 2020

Introduction

The Royal Australian and New Zealand College of Radiologists Faculty of Radiation Oncology (FRO) requires trainees to complete a research project prior to the exit (phase II) examinations. We report results of a survey of current FRO trainees and Fellows graduating since 2013, regarding their experience of the overall requirement, supervision, barriers to project completion and subsequent publication.

Methods

A 32‐question online survey was sent via email to 285 FRO members in July 2019. Responses were anonymous.

Results

The overall response rate was 32% (trainees 41%, Fellows 21%); 70% of respondents were trainees. About three‐quarters of projects were retrospective reviews (64%) or surveys (13%), 94% met College requirements at first submission, 71% were published, and 81% were presented at a scientific meeting. Most assistance was provided by the project supervisor (57%), statistician (47%), another consultant (36%) or the Director of Training (28%). Finding time amongst other clinical/curriculum commitments, rotating to another training site and availability of a suitable supervisor were notable obstacles. Over half (52%) of respondents were satisfied/very satisfied with the process overall and 20% dissatisfied/very dissatisfied; 19% and 30%, respectively, thought requiring acceptance for peer review and completion prior to the phase II examination unreasonable/very unreasonable. Four per cent reported being less likely to be involved in future research as a result of this experience.

Conclusion

While the majority of respondents perceive the FRO research requirements as reasonable, a significant minority are not satisfied with aspects of the programme. Amendment of the pre‐phase II stipulation may be worthy of consideration.
The direct and indirect costs of axial spondyloarthritis (axSpA) in Singapore
Authors: Kwan Yu Heng , Kwoh Shi Yun , Phang Jie Kie , Cheen Mcvin Hua Heng , Lim Ka Keat , Wang Charmaine Tze May , Leung Ying Ying , Koh Hwee‐Ling , Ostbye Truls , Thumboo Julian , Fong Warren
Published: January 2020

Objective

To estimate the economic annual direct and indirect costs of axial spondyloarthritis (axSpA) in Singapore, and to identify factors associated with these costs.

Methods

A retrospective, cross‐sectional, Institutional Review Board‐approved study was conducted. A questionnaire was administered to the patients between 2013 and 2016 from the Singapore General Hospital (SGH) spondyloarthritis registry. Direct medical costs and indirect costs were estimated using the SGH database and the human capital approach respectively. Multivariate analyses using generalized linear model with gamma distribution and a log‐linked function was conducted to identify factors associated with these total, direct and indirect costs. All costs were adjusted to 2017 using the Singapore Consumer Price Index and converted to 2017 US dollars (USD) by purchasing power parity.

Results

A total of 135 consecutive patients were included in the study, with a mean age of 40.4 ± 13.2 years. The overall annual total economic cost to society was around USD 74 790 820, with annual direct cost being the main component of total cost (90.8%). Annual direct cost was around USD 67 931 457, while annual indirect cost was around USD 6 855 951. Presence of extra‐spinal symptoms (ever) was associated with an increase in total and direct costs. Higher education level and Patient Global Assessment were associated with an increase in indirect costs. Lack of employment was associated with a decrease in indirect costs.

Conclusion

The disease burden of axSpA in Singapore is not trivial given that the disease is relatively common. This highlights the need for measures to accommodate patients with axSpA economically in Singapore.
Acarbose improved survival for Apc+/Min mice
Authors: Dodds Sherry G. , Parihar Manish , Javors Martin , Nie Jia , Musi Nicolas , Dave Sharp Zelton , Hasty Paul
Published: January 2020

Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice. The ITP found rapamycin, an inhibitor to the pro‐growth mTORC1 (mechanistic target of rapamycin complex 1) pathway, improved survival and it suppressed tumors in Apc+/Min mice providing a plausible rationale to ask if acarbose had a similar effect. Apc+/Min is a mouse model prone to intestinal polyposis and a mimic of familial adenomatous polyposis in people. Polyp‐associated anemia contributed to their death. To address this knowledge gap, we fed two doses of acarbose to Apc+/Min mice. Acarbose improved median survival at both doses. A cross‐sectional analysis was performed next. At both doses, ACA fed mice exhibited reduced intestinal crypt depth, weight loss despite increased food consumption and reduced postprandial blood glucose and plasma insulin, indicative of improved insulin sensitivity. Dose‐independent and dose‐dependent compensatory liver responses were observed for AMPK and mTORC1 activities, respectively. Only mice fed the high dose diet exhibited reductions in tumor number with higher hematocrits. Because low‐dose acarbose improved lifespan but failed to reduced tumors, its effects seem to be independent of cancer. These data implicate the importance of improved carbohydrate metabolism on survival.
Increasing incidence of endometrial carcinoma in a high‐risk New Zealand community
Authors: Bigby Susan M. , Tin Tin Sandar , Eva Lois J. , Shirley Phillipa , Dempster‐Rivett Kieran , Elwood Mark
Published: January 2020

Background

Endometrial carcinoma (EC) is increasing in incidence, attributed largely to the obesity epidemic. Ethnic differences in New Zealand have long been recognised, with Pacific women bearing the greater burden of disease. We hypothesise that the pooled national incidence rates underestimate the true burden of EC in our high‐risk community.

Aims

We aimed to: (1) determine the incidence, trends and outcome of EC in the high‐risk community served by our hospital, relative to national data; and (2) examine associated demographic, and clinicopathological features with reference to risk factors, to identify potential clinical and population intervention points.

Materials and Methods

All area‐resident women treated for EC at Middlemore Hospital from 2000 to 2014 were identified from records, and clinicopathological data obtained. Incidence and time trend analyses were performed with reference to tumour type, age and ethnicity.

Results

The study included 588 women. Pacific, followed by Māori, women had the highest incidence of EC (relative risk = 5.11 and 2.47, respectively, relative to ‘Other’ women). The incidence increased for all ethnicities (annual percentage change (APC) of 7.3; 95% CI 3.6–11.1), most marked in women aged below 50 years (APC of 12.2; 95% CI 5.2–19.7). This occurred predominantly in Pacific women, who had a high prevalence of potentially reversible risk factors. Disease‐specific survival was worse in Pacific, and to a lesser extent, Māori women.

Conclusions

Prompt investigation of symptomatic, high‐risk women regardless of age may detect endometrial abnormalities at an early, potentially reversible stage. The prevention and management of identifiable high‐risk factors would help mitigate the risk of EC and associated diseases.
Unprincipled Principals: Co‐opted Bureaucrats and Corruption in Ghana
Authors: Brierley Sarah
Published: January 2020

In theory, granting politicians tools to oversee bureaucrats can reduce administrative malfeasance. In contrast, I argue that the political control of bureaucrats can increase corruption when politicians need money to fund election campaigns and face limited institutional constraints. In such contexts, politicians can leverage their discretionary powers to incentivize bureaucrats to extract rents from the state on politicians' behalf. Using data from an original survey of bureaucrats (N = 864) across 80 randomly sampled local governments in Ghana, I show that bureaucrats are more likely to facilitate politicians' corrupt behavior when politicians are perceived to be empowered with higher levels of discretionary control. Using qualitative data and a list experiment to demonstrate the mechanism, I show that politicians enact corruption by threatening to transfer noncompliant officers. My findings provide new evidence on the sources of public administrative deficiencies in developing countries and qualify the presumption that greater political oversight improves governance.
When Descriptive Norms Backfire: Attitudes Induce Undesirable Consequences during Disaster Preparation
Authors: Ozaki Taku , Nakayachi Kazuya
Published: January 2020

This study aimed to examine the adverse effects of descriptive norms in the context of disaster preparation, although the cumulative evidence has demonstrated that descriptive norms desirably promote social behavior. Descriptive norms inevitably inform that some people do not prepare; therefore, the secondary meaning can be utilized to confirm the receiver's already possessed attitudes, and it results in a backfire. We conducted two preregistered experiments examining preparation behaviors for natural disasters while manipulating descriptive norms. In Study 1 (N = 262), the only promotive effect of descriptive norms was obtained among U.S. participants. In Study 2 (N = 329), when replicated with a sample of Japanese participants, participants’ attitudes moderated the effects of descriptive norms. The patterns of moderation were consistent with our prediction and suggested that descriptive norms suppressed the desirable behavior when participants held negative attitudes. The pitfalls of descriptive normative approaches are also practically important.
Ensemble cluster pruning via convex‐concave programming
Authors: Özöğür‐Akyüz Süreyya , Otar Buse Çisil , Atas Pınar Karadayı
Published: January 2020

Ensemble learning is the process of aggregating the decisions of different learners/models. Fundamentally, the performance of the ensemble relies on the degree of accuracy in individual learner predictions and the degree of diversity among the learners. The trade‐off between accuracy and diversity within the ensemble needs to be optimized to provide the best grouping of learners as it relates to their performance. In this optimization theory article, we propose a novel ensemble selection algorithm which, focusing specifically on clustering problems, selects the optimal subset of the ensemble that has both accurate and diverse models. Those ensemble selection algorithms work for a given number of the best learners within the subset prior to their selection. The cardinality of a subset of the ensemble changes the prediction accuracy. The proposed algorithm in this study determines both the number of best learners and also the best ones. We compared our prediction results to recent ensemble clustering selection algorithms by the number of cardinalities and best predictions, finding better and approximated results to the optimum solutions.
Vitamin D deficiency is common in kidney transplant recipients, but is not associated with infections after transplantation
Authors: Schreiber Peter W. , Kusejko Katharina , Bischoff‐Ferrari Heike A. , Boggian Katia , Bonani Marco , van Delden Christian , Enriquez Natalia , Fehr Thomas , Garzoni Christian , Hirsch Hans H. , Hirzel Cédric , Manuel Oriol , Meylan Pascal , Saleh Lanja , Weisser Maja , Mueller Nicolas J. ,   the Swiss Transplant Cohort Study (STCS)
Published: January 2020

The relevance of vitamin D for infections after kidney transplantation is poorly defined. 25‐OH vitamin D (25‐OHD) levels of 135 kidney transplant recipients, enrolled in the Swiss Transplant Cohort Study, were determined peri‐transplant and 6 months post‐transplant. Logistic regression was used to address the associations of 25‐OHD and overall infections and bacterial infections, respectively. For the first 6 months post‐transplant, 25‐OHD peri‐transplant, and for the second period (after 6 to 30 months post‐transplant), 25‐OHD at 6 months post‐transplant was considered. Vitamin D deficiency was common peri‐transplant and remained highly prevalent 6 months after transplantation despite frequent supplementation. Median 25‐OHD levels increased from 12.0 ng/mL (IQR 5.3‐19.5) peri‐transplant to 16.5 ng/mL (IQR 10.6‐22.6) 6 months post‐transplant (P = .005). We did not detect a significant association between 25‐OHD and overall infections (adjusted odds ratio (aOR) 1.05, 95% confidence interval (95%CI) 0.44‐2.51; aOR 0.67, 95%CI 0.31‐1.43) or bacterial infections (aOR 0.79, 95%CI 0.32‐1.96; aOR 0.79, 95%CI 0.35‐1.75) for the first and second period. To conclude, at both time points, vitamin D deficiency was observed in more than 50% of kidney recipients, albeit an increase in 25‐OHD in the longitudinal course was observed. No significant association between 25‐OHD and infections was detected.
Efficacy of 10‐20‐30 training versus moderate‐intensity continuous training on HbA1c, body composition and maximum oxygen uptake in male patients with type 2 diabetes: A randomized controlled trial
Authors: Baasch‐Skytte Thomas , Lemgart Charlotte T. , Oehlenschläger Mads H. , Petersen Pernille E. , Hostrup Morten , Bangsbo Jens , Gunnarsson Thomas P.
Published: January 2020

Aim

To compare the efficacy of 10‐20‐30 training versus moderate‐intensity continuous training (MICT) on HbA1c, body composition and maximum oxygen uptake (V˙O2max) in male patients with type 2 diabetes (T2D).

Materials and Methods

Fifty‐one male participants with T2D were randomly assigned (1:1) to a 10‐20‐30 (N = 26) and a MICT (N = 25) training group. Interventions consisted of supervised cycling three times weekly for 10 weeks, lasting 29 minutes (10‐20‐30) and 50 minutes (MICT) in a local non‐clinical setting. The primary outcome was change in HbA1c from baseline to 10‐week follow‐up.

Results

Of 51 participants enrolled, 44 (mean age 61.0 ± 6.8 [mean ± SD] years, diagnosed 7.5 ± 5.8 years, baseline HbA1c 7.4% ± 1.3%) were included in the analysis. Training compliance was 84% and 86% in 10‐20‐30 and MICT, respectively. No adverse events occurred during the intervention. HbA1c decreased (P <0.001) by 0.5 (95% CI −0.72 to −0.21) percentage points with training in 10‐20‐30, with no change in MICT. The change in 10‐20‐30 was greater (P <0.05) than in MICT. Visceral fat mass decreased (P <0.05) only with 10‐20‐30 training, whereas total fat mass decreased (P <0.01) and V˙O2max increased (P <0.01) with training in both groups.

Conclusions

Ten weeks of 10‐20‐30 training was superior to MICT in lowering HbA1c, and only 10‐20‐30 training decreased visceral fat mass in patients with T2D. Furthermore, 10‐20‐30 training was as effective as MICT in reducing total fat mass and increasing V˙O2max, despite a 42% lower training time commitment.
SCN1A/NaV1.1 channelopathies: Mechanisms in expression systems, animal models, and human iPSC models
Authors: Mantegazza Massimo , Broccoli Vania
Published: January 2020

Pathogenic SCN1A/NaV1.1 mutations cause well‐defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, SCN1A/NaV1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/NaV1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene‐targeted animal models, and the induced pluripotent stem cell (iPSC) technology, highlighting advantages, limits, and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathologic mechanism of epileptogenic SCN1A/NaV1.1 mutations is loss‐of‐function of NaV1.1 leading to hypoexcitability of at least some types of γ‐aminobutyric acid (GABA)ergic neurons (including cortical and hippocampal parvalbumin‐positive and somatostatin‐positive ones). Conversely, more limited results point to NaV1.1 gain‐of‐function for familial hemiplegic migraine (FHM) mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled.
SCN2A channelopathies: Mechanisms and models
Authors: Hedrich Ulrike B. S. , Lauxmann Stephan , Lerche Holger
Published: January 2020

Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders.
Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults
Authors: Darra Francesca , Battaglia Domenica , Dravet Charlotte , Patrini Mara , Offredi Francesca , Chieffo Daniela , Piazza Elena , Fontana Elena , Olivieri Giorgia , Turrini Ida , Dalla Bernardina Bernardo , Granata Tiziana , Ragona Francesca
Published: January 2020

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age. Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy.
USP15 potentiates NF‐κB activation by differentially stabilizing TAB2 and TAB3
Authors: Zhou Qiaoqiao , Cheng Cheng , Wei Yujuan , Yang Jing , Zhou Wanzhu , Song Qiuyi , Ke Mengxiang , Yan Wanyao , Zheng Ling , Zhang Yu , Huang Kun
Published: January 2020

Tumor necrosis factor α (TNFα)‐ and interleukin 1β (IL‐1β)‐induced nuclear factor‐κB (NF‐κB) activation play key roles in inflammation, immunity, and cancer development. Here, we identified one of the deubiquitinating enzymes (DUBs), ubiquitin‐specific protease 15 (USP15), as a positive regulator in both TNFα‐ and IL‐1β‐induced NF‐κB activation. Overexpression of USP15 potentiated TNFα‐ or IL‐1β‐triggered NF‐κB activation and downstream gene transcription, whereas knockdown of USP15 had opposite effects. Mechanistically, upon TNFα stimulation, USP15 showed an enhanced interaction with transforming growth factor‐β activated kinase‐1 (TAK1)‐TAK1 binding protein (TAB) complex to inhibit the proteolysis of TAB2/3 by different pathways. Apart from deubiquitination dependently inducing cleavage of lysine 48‐linked TAB2 ubiquitination, USP15 also DUB independently inhibited lysosome‐associated TAB2 degradation, thus enhanced TAB2 stabilization. For TAB3, USP15 inhibited NBR1‐mediated selective autophagic TAB3 degradation independent of its deubiquitinating activity. Together, our results reveal a novel USP15‐mediated mechanism through which efficient NF‐κB activation is achieved by differentially maintaining the TAB2/3 stability.