bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning
Authors: Rice Nathaniel C. , Rauscher Noah A. , Wilkins William L. , Lippner Dennean S. , Rockwood Gary A. , Myers Todd M.
Published: March 2019

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional‐poisoning hazard. Effective antidotes to cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective cyanide antidote that can be administered intramuscularly in pre‐hospital and/or mass‐casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25‐200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25‐100 mg/kg) increased survival after oral cyanide poisoning, and the lower DMTS doses (6.25‐25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50‐200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24‐72 hour. Thus, DMTS shows promise as an intramuscularly administered cyanide antidote useful for prompt pre‐hospital or mass‐casualty emergency medical treatment.
Heat shock factor 1 in cancer‐associated fibroblasts is a potential prognostic factor and drives progression of oral squamous cell carcinoma
Authors: Wang Qiong , Zhang Yu‐Chao , Zhu Li‐Fang , Pan Lu , Yu Miao , Shen Wei‐Li , Li Bang , Zhang Wei , Liu Lai‐Kui
Published: March 2019

Heat shock factor 1 (HSF1) is highly expressed in various malignancies and is a potential modulator of tumor progression. Emerging evidence suggests that HSF1 activation in stromal cells is closely related to poor patient prognosis. However, the role of HSF1 in oral squamous cell carcinoma (OSCC) remains elusive. We aimed to investigate the function of HSF1 in cancer‐associated fibroblasts (CAFs) of the tumor microenvironment (TME) and in tumor development. In the present study, we found that HSF1 was highly expressed in both CAFs and tumor cells, and was significantly correlated with poor prognosis and overall survival. Moreover, HSF1 overexpression in CAFs resulted in a fibroblast‐like phenotype of Cal27 cells, induced epithelial‐mesenchymal transition (EMT), and promoted proliferation, migration and invasion in Cal27 cells. HSF1 knockdown attenuated features of CAFs and reduced EMT, proliferation, migration and invasion in Cal27 cells. Furthermore, HSF1 in CAFs promoted tumor growth in nude mice. Taken together, these data suggest that HSF1 expression in CAFs drive OSCC progression, and could serve as an independent prognostic marker of patients with OSCC. Thus, HSF1 is a potent mediator of OSCC malignancy.
Targeting HOX/PBX dimer formation as a potential therapeutic option in esophageal squamous cell carcinoma
Authors: Shen Lu‐Yan , Zhou Ting , Du Ya‐Bing , Shi Qi , Chen Ke‐Neng
Published: March 2019

Homeobox genes are known to be classic examples of the intimate relationship between embryogenesis and tumorigenesis, which are a family of transcriptional factors involved in determining cell identity during early development, and also dysregulated in many malignancies. Previously, HOXB7, HOXC6 and HOXC8 were found abnormally upregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with normal mucosa and seen as poor prognostic predictors for ESCC patients, and were shown to promote cell proliferation and anti‐apoptosis in ESCC cells. These three HOX members have a high level of functional redundancy, making it difficult to target a single HOX gene. The aim of the present study was to explore whether ESCC cells are sensitive to HXR9 disrupting the interaction between multiple HOX proteins and their cofactor PBX, which is required for HOX functions. ESCC cell lines (KYSE70, KYSE150, KYSE450) were treated with HXR9 or CXR9, and coimmunoprecipitation and immunofluorescent colocalization were carried out to observe HOX/PBX dimer formation. To further investigate whether HXR9 disrupts the HOX pro‐oncogenic function, CCK‐8 assay and colony formation assay were carried out. Apoptosis was assessed by flow cytometry, and tumor growth in vivo was investigated in a xenograft model. RNA‐seq was used to study the transcriptome of HXR9‐treated cells. Results showed that HXR9 blocked HOX/PBX interaction, leading to subsequent transcription alteration of their potential target genes, which are involved in JAK‐signal transducer and activator of transcription (STAT) activation and apoptosis inducement. Meanwhile, HXR9 showed an antitumor phenotype, such as inhibiting cell proliferation, inducing cell apoptosis and significantly retarding tumor growth. Therefore, it is suggested that targeting HOX/PBX may be a novel effective treatment for ESCC.
Transanal total mesorectal excision: how are we doing so far?
Authors: Sparreboom C. L. , Komen N. , Rizopoulos D. , van Westreenen H. L. , Doornebosch P. G. , Dekker J. W. T. , Menon A. G. , Tuynman J. B. , Daams F. , Lips D. , van Grevenstein W. M. U. , Karsten T. M. , Lange J. F. , D'Hoore A. , Wolthuis A. M.
Published: March 2019

Aim

This subgroup analysis of a prospective multicentre cohort study aims to compare postoperative morbidity between transanal total mesorectal excision (TaTME) and laparoscopic total mesorectal excision (LaTME).

Method

The study was designed as a subgroup analysis of a prospective multicentre cohort study. Patients undergoing TaTME or LaTME for rectal cancer were selected. All patients were followed up until the first visit to the outpatient clinic after hospital discharge. Postoperative complications were classified according to the Clavien–Dindo classification and the comprehensive complication index (CCI). Propensity score matching was performed.

Results

In total, 220 patients were selected from the overall prospective multicentre cohort study. After propensity score matching, 48 patients from each group were compared. The median tumour height for TaTME was 10.0 cm (6.0–10.8) and for LaTME was 9.5 cm (7.0–12.0) (P = 0.459). The duration of surgery and anaesthesia were both significantly longer for TaTME (221 vs 180 min, P < 0.001, and 264 vs 217 min, P < 0.001). TaTME was not converted to laparotomy whilst surgery in five patients undergoing LaTME was converted to laparotomy (0.0% vs 10.4%, P = 0.056). No statistically significant differences were observed for Clavien–Dindo classification, CCI, readmissions, reoperations and mortality.

Conclusion

The study showed that TaTME is a safe and feasible approach for rectal cancer resection. This new technique obtained similar postoperative morbidity to LaTME.
Mental models for conservation research and practice
Authors: Moon Katie , Guerrero Angela M. , Adams Vanessa. M. , Biggs Duan , Blackman Deborah A. , Craven Luke , Dickinson Helen , Ross Helen
Published: March 2019

Conservation practice requires an understanding of complex social‐ecological processes of a system and the different meanings and values that people attach to them. Mental models research offers a suite of methods that can be used to reveal these understandings and how they might affect conservation outcomes. Mental models are representations in people's minds of how parts of the world work. We seek to demonstrate their value to conservation and assist practitioners and researchers in navigating the choices of methods available to elicit them. We begin by explaining some of the dominant applications of mental models in conservation: revealing individual assumptions about a system, developing a stakeholder‐based model of the system, and creating a shared pathway to conservation. We then provide a framework to “walk through” the stepwise decisions in mental models research, with a focus on diagram‐based methods. Finally, we discuss some of the limitations of mental models research and application that are important to consider. This work extends the use of mental models research in improving our ability to understand social‐ecological systems, creating a powerful set of tools to inform and shape conservation initiatives.
Randomized controlled study of the prediction of diminutive/small colorectal polyp histology using didactic versus computer‐based self‐learning module in gastroenterology trainees
Authors: Smith Samuel C. L. , Saltzman John , Shivaji Uday N. , Lethebe Brendan C. , Cannatelli Rosanna ,   The Birmingham Colonic Polyp Characterisation Group, Ghosh Subrata , Iacucci Marietta
Published: March 2019

Background and Aim

The aim of this randomized trial was to evaluate the performance of self‐training versus didactic training in order to increase the diagnostic accuracy of diminutive/small colonic polyp histological prediction by trainees.

Methods

Sixteen trainees reviewed 78 videos (48 iSCAN‐OE and 30 NBI) of diminutive/small polyps in a pretraining assessment. Trainees were randomized to receive computer‐based self‐learning (n = 8) or didactic training (n = 8) using identical teaching materials and videos. The same 78 videos, in a different randomized order, were assessed. The NICE (NBI International Colorectal Endoscopic) and SIMPLE (Simplified Identification Method for Polyp Labeling during Endoscopy) classification systems were used to classify diminutive/small polyps.

Results

A higher proportion of high‐confidence predictions of polyps was made by the self‐training group versus the didactic group using both the SIMPLE classification (77.1% [95% CI 73.4–80.3] vs 69.9% [95% CI 66.1–73.5%] [P = 0.005]) and the NICE classification (77% [95% CI 73.2–80.4%] vs 69.8% [95% CI 66–73.4%] [P = 0.006]). When using NICE, sensitivity of the self‐training group compared with the didactic group was 72% versus 83% (P = 0.0005), and the accuracy was 66.1% versus 69.1%. The training improved the confidence of participants and SIMPLE was preferred over NICE.

Conclusion

Self‐learning for the prediction of diminutive/small polyp histology is a method of training that can achieve results similar to didactic training. Availability of adequate self‐learning teaching modules could enable widespread implementation of optical diagnosis in clinical practice.
The AppVox mobile application, a tool for speech and language training sessions
Authors: Rocha Tânia , Gonçalves Cirano , Fernandes Hugo , Reis Arsénio , Barroso João
Published: March 2019

AppVox is a mobile application that provides support for children with speech and language impairments in their speech therapy sessions, while also allowing autonomous training at home. The application simulates a vocalizer with an audio stimulus feature, which can be used to train and amend the pronunciation of specific words through repetition. In this paper, we aim to present the development of the application as an assistive technology option, by adding new features to the vocalizer as well as assessing it as a usable option for daily training interaction for children with speech and language impairments. In this regard, we invited 15 children with speech and language impairments and 20 with no impairments to perform training activities with the application. Likewise, we asked three speech therapists and three usability experts to interact, assess, and give their feedback. In this assessment, we include the following parameters: successful conclusion of the training tasks (effectiveness); number of errors made, as well as number and type of difficulties found (efficiency); and the acceptance and level of comfort in completing the requested tasks (satisfaction). Overall, the results showed that children conclude the training tasks successfully and helped to improve their language and speech capabilities. Therapists and children gave positive feedback to the AppVox interface.
Psychological Well‐Being and Parent‐Child Relationship Quality in Relation to Child Autism: An Actor‐Partner Modeling Approach
Authors: Hickey Emily J. , Hartley Sigan L. , Papp Lauren
Published: March 2019

Parents of children with autism spectrum disorder (ASD) often report poor psychological well‐being, including a high level of parenting stress and depressive symptoms. Little is known about the extent to which poor parent psychological well‐being alters the emotional quality of the parent‐child relationship in a context of child ASD. This study examined the association between actor (one's own) and partner (one's partner's) level of parenting stress and depressive symptoms and the emotional quality of the parent‐child relationship using a Five Minute Speech Sample (FMSS) in 150 families of children with ASD, aged 5–12 years (85.7% male). Mothers and fathers were aged 38.69 (SD = 5.62) and 40.76 (SD = 6.19), respectively; 76% of mothers and 68% of fathers had a college degree. Structural equation modeling, using Analysis of Moment Structures software, was used to test Actor‐Partner Interdependence Models. Results indicated that mother's level of parenting stress and depressive symptoms were associated with her own FMSS Warmth and Criticism toward the child with ASD 12 months later in negative and positive directions. Mother's level of parenting stress was also negatively associated with father's FMSS Warmth toward the child with ASD 12 months later. Finally, father's level of parenting stress was positively associated with his FMSS Criticism toward the child with ASD. Overall, findings indicate that the mother‐child and father‐child relationship are both impacted by parent psychological well‐being in families of children with ASD; however, actor effects are stronger for mothers and partner effects were only found for fathers. Implications for interventions are discussed.
Biochar application as a tool to decrease soil nitrogen losses (NH3 volatilization, N2O emissions, and N leaching) from croplands: Options and mitigation strength in a global perspective
Authors: Liu Qi , Liu Benjuan , Zhang Yanhui , Hu Tianlong , Lin Zhibin , Liu Gang , Wang Xiaojie , Ma Jing , Wang Hui , Jin Haiyang , Ambus Per , Amonette James E. , Xie Zubin
Published: March 2019

Biochar application to croplands has been proposed as a potential strategy to decrease losses of soil‐reactive nitrogen (N) to the air and water. However, the extent and spatial variability of biochar function at the global level are still unclear. Using Random Forest regression modelling of machine learning based on data compiled from the literature, we mapped the impacts of different biochar types (derived from wood, straw, or manure), and their interactions with biochar application rates, soil properties, and environmental factors, on soil N losses (NH3 volatilization, N2O emissions, and N leaching) and crop productivity. The results show that a suitable distribution of biochar across global croplands (i.e., one application of <40 t ha−1 wood biochar for poorly buffered soils, such as those characterized by soil pH<5, organic carbon<1%, or clay>30%; and one application of <80 t ha−1 wood biochar, <40 t ha−1 straw biochar, or <10 t ha−1 manure biochar for other soils) could achieve an increase in global crop yields by 222–766 Tg yr−1 (4%–16% increase), a mitigation of cropland N2O emissions by 0.19–0.88 Tg N yr−1 (6%–30% decrease), a decline of cropland N leaching by 3.9–9.2 Tg N yr−1 (12%–29% decrease), but also a fluctuation of cropland NH3 volatilization by −1.9–4.7 Tg N yr−1 (−12%–31% change). The decreased sum of the three major reactive N losses amount to 1.7–9.4 Tg N yr−1, which corresponds to 3%–14% of the global cropland total N loss. Biochar generally has a larger potential for decreasing soil N losses but with less benefits to crop production in temperate regions than in tropical regions.
Diverse diversities—Open innovation in small towns and rural areas
Authors: Meili Rahel , Shearmur Richard
Published: March 2019

It is generally accepted that cities and other forms of geographic agglomerations are conducive to innovation because their density and variety of firms, sectors and individuals create a diverse environment. However, a growing body of work shows that innovation also occurs in peripheral regions and small towns. Furthermore, work on rural social networks shows that diversity is multidimensional, and that along certain dimensions networks developed in rural areas are more diverse than those observed in cities. In this paper, we develop these arguments, then report our observations of seven successful firms in Swiss small towns. These firms benefit from at least three types of diversity: internal diversity; multiplexed interactions between workers at different hierarchical levels; and external diversity as firms reach beyond the region. We conclude that diversity conducive to firm‐level innovation is not a specifically urban attribute: at least some of its dimensions are present in small towns and more peripheral areas.
Subjectivation processes and gender in a neoliberal model of science in three Spanish research centres
Authors: Vayreda Agnès , Conesa Ester , Revelles‐Benavente Beatriz , González Ramos Ana M.
Published: March 2019

From a Foucauldian approach, neoliberal rationality in science can be understood as a form of governance of the self that produces mechanisms through which the subject is constructed and subordinated at the same time. In this study we examine subjectivation processes and gender in centres of research created under neoliberal scientific rationality. We analyse 19 semi‐structured interviews of men and women researchers conducted in three highly competitive centres of excellence — a context rarely addressed in the literature of academic subjectivities. Following a critical discourse analysis, we show how subjectivation processes of neoliberal rationality result in two main discursive mechanisms of subjection that prevent or hinder alternative subjectivities and collective resistance, especially for women, presenting a double turn that we call: a ‘turn on oneself’ and a ‘gendered turn on oneself’. We conclude that these centres are spaces which provide the conditions of possibility to develop a scientific entrepreneurial self, excluding ‘other’ scientific subjectivities and preventing possible resistances that could emerge from them.
Structural accommodations of patriarchy: Women and workplace gender segregation in Qatar
Authors: Salem Rania , Yount Kathryn M.
Published: March 2019

As the institutions of classic patriarchy erode in Qatar, women are entering the labour force in growing numbers. It is argued that women's need to work in societies historically characterized by classic patriarchy causes them to enact strategic accommodations that signal their feminine respectability and conformity to male domination. We find the Qatari context to be characterized by structural rather than individual accommodations of patriarchy. State institutions and several employers have made available gender‐segregated workplaces that facilitate women's employment while maintaining many elements of patriarchy. Using semi‐structured interview data with university‐aged Qatari women, we examine attitudes towards employment, specifically those related to gender mixing in the workplace. Young women's narratives reveal complex schemas regarding the acceptability of gender mixing, which depends on characteristics of the working woman, characteristics of the men with whom she must interact in the workplace and the spatial organization of the workplace itself. Women's protection of their reputations, critical to maintaining their families’ support and their own marriageability, emerged as a key motivation for limiting interactions with men. The preference for gender‐segregated workplaces reveals Qatari women's continued subscription to the patriarchal bargain — they constrain their behaviour in return for protection from male kin.
Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma
Authors: Pareja Fresia , Selenica Pier , Brown David N , Sebastiao Ana P M , da Silva Edaise M , Da Cruz Paula Arnaud , Del Angela , Fu Li , Weigelt Britta , Brogi Edi , Reis‐Filho Jorge S , Wen Hannah Y
Published: March 2019

Aims

Micropapillary variant of mucinous carcinoma of the breast (MPMC) is a rare histological form of oestrogen receptor (ER)‐positive invasive carcinoma that is characterised by micropapillary clusters of tumour cells in lakes of extracellular mucin. The aims of this study were to determine the genetic alterations underpinning MPMCs, and to determine whether they overlap with those of mucinous carcinomas and/or invasive micropapillary carcinomas.

Methods and results

DNA from five MPMCs was subjected to whole‐exome sequencing. Somatic mutations, copy number alterations and mutational signatures were determined with state‐of‐the‐art bioinformatics methods. No mutations in genes significantly mutated in breast cancer, including TP53, PIK3CA, GATA3, and MAP3K1, were detected. We identified copy number alterations that have been reported in invasive micropapillary carcinomas, such as recurrent gains in 1q, 6p, 8q, and 10q, and recurrent losses in 16q, 11q, and 13q, as well as a recurrent 8p12–8p11.2 amplification encompassing FGFR1. Like mucinous carcinomas, three of the five MPMCs analysed lacked PIK3CA mutations, 1q gains, and 16q losses, which are the hallmark genetic alterations of ER‐positive breast cancers, whereas two MPMCs harboured 16q losses and/or a complex pattern of copy number alterations similar to those found in breast‐invasive micropapillary carcinomas.

Conclusions

MPMCs are heterogeneous at the genetic level; some tumours show a pattern of somatic genetic alterations similar to those of mucinous carcinomas, whereas others resemble invasive micropapillary carcinomas at the genetic level. These findings suggest that MPMCs may not constitute one histological subtype, but rather a convergent phenotype that can stem from mucinous carcinomas or invasive micropapillary carcinomas.
Female Immigrant Entrepreneurs: More Than a Family Strategy
Authors: De Luca Deborah , Ambrosini Maurizio
Published: March 2019

This article explores the issue of immigrant women entrepreneurship. It focuses on the emergence of new points of view on self‐employed migrant women and in particular their search for independence. With the support of qualitative research carried on in Italy, it will set out a typology of motivations and strategies to become self‐employed in which, besides a “family strategy” and an “independency strategy”, a “mixed network strategy” also emerges. This last focuses on the role of mixed networks (with other foreigners and/or natives) not only in business management but also in the promotion of transnational social activities. Policies that support associations, creating opportunities for gathering and exchanging with local residents and improving the presence of immigrant women in local institutions, could have the side‐effect of increasing participation by immigrant women in self‐employment, not for lack of alternatives but as a path towards self‐fulfilment and empowerment.
HPCAL1 promotes glioblastoma proliferation via activation of Wnt/β‐catenin signalling pathway
Authors: Zhang Dongming , Liu Xidong , Xu Xuebin , Xu Jianmeng , Yi Zhongjun , Shan Baochang , Liu Bing
Published: March 2019

Glioblastoma (GBM) is the most prevalent primary malignancy of the central nervous system with obvious aggressiveness, and is associated with poor clinical outcome. Studies have indicated that calcium ion (Ca2+) can positively regulate the initiation of malignancy with regard to GBM by modulating quiescence, proliferation, migration and maintenance. Hippocalcin like‐1 protein (HPCAL1) serves as a sensor of Ca2+. However, the understanding of HPCAL1 activity in GBM is limited. The present study revealed that the gene HPCAL1 was up‐regulated by Ca2+ in the tissues and cells of GBM. Ectopic expression of HPCAL1 promoted proliferation of cells. Exhaustion of HPCAL1 inhibited cell growth not only in vivo, but also in vitro. In addition, HPCAL1 enhanced the Wnt pathway by stimulating β‐catenin accumulation and nuclear translocation in GBM cells, while β‐catenin silencing significantly inhibited the proliferation and growth of the GBM cells. Our results showed that Ser9 phosphorylation of GSK3β was significantly decreased after HPCAL1 knockdown in GBM cells, and knockdown of the gene GSK3β in GBM cells enhanced cell proliferation and promoted transcription of the genes CCND1 and c‐Myc. Furthermore, the phosphorylation of ERK was decreased in the cells with HPCAL1 knockdown, while it was promoted via overexpression of HPCAL1. The suppression or depletion of the gene ERK decreased proliferation triggered by overexpression of HPCAL1 and impaired transcription of the genes c‐Myc and CCND1. These studies elucidate the tumour‐promoting activity of HPCAL1. They also offer an innovative therapeutic strategy focusing on the HPCAL1‐Wnt/β‐catenin axis to regulate proliferation and development of GBM.
Annual Research Review: Does late‐onset attention‐deficit/hyperactivity disorder exist?
Authors: Asherson Philip , Agnew‐Blais Jessica
Published: March 2019

Attention‐deficit/hyperactivity disorder (ADHD) is conceptualized as an early onset childhood neurodevelopmental disorder. Prevalence in adults is around two‐thirds that in childhood, yet longitudinal outcome studies of children with ADHD found a minority continue to meet full criteria in adulthood. This suggests that not all adult cases meet ADHD criteria as children, a conclusion supported by earlier studies relying on retrospective recall in adolescent and adult samples. More recently prospective follow‐up of population and control samples suggest that adolescent and young adult ADHD is not always a continuation of childhood ADHD. Here, we review the literature on age of onset, to explore whether late‐onset ADHD exists, and if so, examine the evidence for whether this should be considered the same or a different disorder as childhood onset ADHD. We conclude that current evidence supports the view that a significant proportion of young adults meeting criteria for ADHD would not have met full diagnostic criteria for ADHD as children. However, many in the late‐onset group show some ADHD symptoms in childhood, or an externalizing disorder such as oppositional defiant disorder. Furthermore, the current studies suggest that most (but not all) cases of late‐onset ADHD develop the disorder between the ages of 12–16 and can therefore be considered adolescent or early adult onset ADHD. There is a relative lack of data spanning young to older adulthood to address the question of adult‐onset. Currently, there is insufficient data to clarify the extent to which early and late onset ADHD reflect a different balance of genetic and environmental risks or share the same underlying neural mechanisms. Clinicians should be aware that significantly impairing forms of ADHD can emerge beyond the age of 12 years, although perhaps rarely in the context of a complete absence of precursors. The current evidence on treatment responses is limited.
Implementing accurate identification and measurement of dyskinesia in cerebral palsy into clinical practice: A knowledge translation study
Authors: Stewart Kirsty , de Vries Tessa , Harvey Adrienne
Published: March 2019

Aim

The application of current, best evidence into clinical practice is problematic. This article describes a knowledge translation (KT) project aimed at improving clinician identification, classification and measurement of dyskinesia in children with cerebral palsy (CP).

Method

A 2‐year KT fellowship investigated clinicians' understanding of dyskinetic CP, identified knowledge gaps, determined educational needs and implemented a multifaceted KT strategy and dissemination framework to address those needs.

Results

Australian and New Zealand medical and allied health clinicians identified significant gaps in their clinical knowledge regarding dyskinetic CP, particularly confidence in identifying and measuring dyskinesia and poor knowledge of available identification and measurement tools. Following a targeted implementation strategy, there was a definite shift towards increased awareness of dyskinetic CP, a significant improvement in identification and measurement confidence (mean change from 47 to 66% confidence, P < 0.0001), and the embedding of the knowledge and skills into everyday clinical practice.

Conclusions

This targeted and well‐resourced KT project in dyskinetic CP improved clinician knowledge and led to meaningful change in clinical practice. The strategy utilised would be appropriate across a range of health‐care settings.
Revolution and Intervention
Authors: Renzo Massimo
Published: March 2019

Provided that traditional jus ad bellum principles are fulfilled, military humanitarian intervention to stop large scale violations of human rights (such as genocide, crimes against humanity or war crimes) is widely regarded as morally permissible. In cases of “supreme humanitarian emergency”, not only are the victims morally permitted to rebel, but other states are also permitted to militarily intervene. Things are different if the human rights violations in question fall short of supreme humanitarian emergency. Because of the importance of respecting political self‐determination, in cases of “ordinary oppression”, we normally think that rebellion might be permissible, but not military humanitarian intervention. Thus, according to the received view, the conditions for the permissibility of intervention coincide with the conditions for the permissibility of revolution in cases of supreme humanitarian emergency, but not in cases of ordinary oppression. In cases of ordinary oppression there is an asymmetry between the conditions for the permissibility of revolution and intervention (call this the Asymmetry View). Should we accept the Asymmetry View? I answer this question by outlining an account of political self‐determination and by illustrating the complex role that this notion should play in discussing the morality of revolution and intervention.
Multitrait genome‐wide association analysis of Populus trichocarpa identifies key polymorphisms controlling morphological and physiological traits
Authors: Chhetri Hari B. , Macaya‐Sanz David , Kainer David , Biswal Ajaya K. , Evans Luke M. , Chen Jin‐Gui , Collins Cassandra , Hunt Kimberly , Mohanty Sushree S. , Rosenstiel Todd , Ryno David , Winkeler Kim , Yang Xiaohan , Jacobson Daniel , Mohnen Debra , Muchero Wellington , Strauss Steven H. , Tschaplinski Timothy J. , Tuskan Gerald A. , DiFazio Stephen P.
Published: March 2019

Genome‐wide association studies (GWAS) have great promise for identifying the loci that contribute to adaptive variation, but the complex genetic architecture of many quantitative traits presents a substantial challenge.

We measured 14 morphological and physiological traits and identified single nucleotide polymorphism (SNP)‐phenotype associations in a Populus trichocarpa population distributed from California, USA to British Columbia, Canada. We used whole‐genome resequencing data of 882 trees with more than 6.78 million SNPs, coupled with multitrait association to detect polymorphisms with potentially pleiotropic effects. Candidate genes were validated with functional data.

Broad‐sense heritability (H2) ranged from 0.30 to 0.56 for morphological traits and 0.08 to 0.36 for physiological traits. In total, 4 and 20 gene models were detected using the single‐trait and multitrait association methods, respectively. Several of these associations were corroborated by additional lines of evidence, including co‐expression networks, metabolite analyses, and direct confirmation of gene function through RNAi.

Multitrait association identified many more significant associations than single‐trait association, potentially revealing pleiotropic effects of individual genes. This approach can be particularly useful for challenging physiological traits such as water‐use efficiency or complex traits such as leaf morphology, for which we were able to identify credible candidate genes by combining multitrait association with gene co‐expression and co‐methylation data.
Promiscuous terpene synthases from Prunella vulgaris highlight the importance of substrate and compartment switching in terpene synthase evolution
Authors: Johnson Sean R. , Bhat Wajid Waheed , Sadre Radin , Miller Garret P. , Garcia Alekzander Sky , Hamberger Björn
Published: March 2019

The mint family (Lamiaceae) is well documented as a rich source of terpene natural products. More than 200 diterpene skeletons have been reported from mints, but biosynthetic pathways are known for just a few of these.

We crossreferenced chemotaxonomic data with publicly available transcriptomes to select common selfheal (Prunella vulgaris) and its highly unusual vulgarisin diterpenoids as a case study for exploring the origins of diterpene skeletal diversity in Lamiaceae. Four terpene synthases (TPS) from the TPS‐a subfamily, including two localised to the plastid, were cloned and functionally characterised. Previous examples of TPS‐a enzymes from Lamiaceae were cytosolic and reported to act on the 15‐carbon farnesyl diphosphate. Plastidial TPS‐a enzymes using the 20‐carbon geranylgeranyl diphosphate are known from other plant families, having apparently arisen independently in each family.

All four new enzymes were found to be active on multiple prenyl‐diphosphate substrates with different chain lengths and stereochemistries. One of the new enzymes catalysed the cyclisation of geranylgeranyl diphosphate into 11‐hydroxy vulgarisane, the likely biosynthetic precursor of the vulgarisins.

We uncovered the pathway to a rare diterpene skeleton. Our results support an emerging paradigm of substrate and compartment switching as important aspects of TPS evolution and diversification.
Terrestrial insects and climate change: adaptive responses in key traits
Authors: Kellermann Vanessa , van Heerwaarden Belinda
Published: March 2019

Understanding and predicting how adaptation will contribute to species' resilience to climate change will be paramount to successfully managing biodiversity for conservation, agriculture, and human health‐related purposes. Making predictions that capture how species will respond to climate change requires an understanding of how key traits and environmental drivers interact to shape fitness in a changing world. Current trait‐based models suggest that low‐ to mid‐latitude populations will be most at risk, although these models focus on upper thermal limits, which may not be the most important trait driving species' distributions and fitness under climate change. In this review, we discuss how different traits (stress, fitness and phenology) might contribute and interact to shape insect responses to climate change. We examine the potential for adaptive genetic and plastic responses in these key traits and show that, although there is evidence of range shifts and trait changes, explicit consideration of what underpins these changes, be that genetic or plastic responses, is largely missing. Despite little empirical evidence for adaptive shifts, incorporating adaptation into models of climate change resilience is essential for predicting how species will respond under climate change. We are making some headway, although more data are needed, especially from taxonomic groups outside of Drosophila, and across diverse geographical regions. Climate change responses are likely to be complex, and such complexity will be difficult to capture in laboratory experiments. Moving towards well designed field experiments would allow us to not only capture this complexity, but also study more diverse species.
Renal medullary carcinoma in a young mixed‐race man in Japan
Authors: Toriyama Akane , Izumi Hiroshi , Tomita Shigeki , Nagashima Yoji , Ueda Yoshihiko , Aoki Yusuke , Tsujimura Akira , Yao Takashi , Hino Okio
Published: March 2019

Renal medullary carcinoma (RMC) is a rare and aggressive cancer associated with the sickle cell trait. The diagnosis of RMC depends on recognition of its histologic features and immunohistochemical deficiency of INI1, but correct diagnosis is sometimes difficult, especially if a patient's information on race, past, and family medical history is unclear. At present, this is the first report on RMC in Japan.
Detecting Imbalances in House Prices: What Goes Up Must Come Down?*
Authors: Anundsen André K.
Published: March 2019

I suggest a toolkit of four bubble‐detection methods that can be used to monitor developments in house prices. These methods are applied to US, Finnish, and Norwegian data. For the United States, all measures unanimously suggest a bubble in the early to mid‐2000s, whereas current US house prices are found to be aligned with economic fundamentals. One of the measures indicates imbalances in Finland, while there are no signs of a bubble in Norway. I find that large parts of the US house price bubble can be explained by the sharp increase in capital inflows and the extension of loans to the subprime mortgage market.
Effect of pH and temperature on calcium carbonate precipitation by CO2 removal from iron‐rich water
Authors: Korchef Atef , Touaibi Meriam
Published: March 2019

In the present work, the effect of temperature and solution pH on calcium carbonate precipitation from iron‐rich waters was investigated. Calcium carbonate was precipitated by CO2 removal. The increase in the temperature or the solution pH leads to the acceleration of calcium carbonate nucleation and crystal growth. Iron addition retards the formation of calcium carbonate crystals and enhanced the precipitation in the bulk solution. At high supersaturations, the inhibition effectiveness of iron is small and it could be improved by lowering the solution pH. The results of the present work show that it is possible to reduce or completely prevent scale formation in different water treatment processes by controlling the operating parameters which favourably affects the water treatment costs, increases the equipment life and allows increased product water recovery.
Modeling muscle
Authors: Raman Ritu
Published: March 2019

A biohybrid machine offers insight into muscle growth, adaptation, and repair
Activin type II receptor signaling in cardiac aging and heart failure
Authors: Roh Jason D. , Hobson Ryan , Chaudhari Vinita , Quintero Pablo , Yeri Ashish , Benson Mark , Xiao Chunyang , Zlotoff Daniel , Bezzerides Vassilios , Houstis Nicholas , Platt Colin , Damilano Federico , Lindman Brian R. , Elmariah Sammy , Biersmith Michael , Lee Se-Jin , Seidman Christine E. , Seidman Jonathan G. , Gerszten Robert E. , Lach-Trifilieff Estelle , Glass David J. , Rosenzweig Anthony
Published: March 2019

Activin type II receptor signaling regulates cardiac function in aging and heart failure by modulating proteasome-dependent SERCA2a degradation.
Humanized Mouse Model of HIV-1 Latency with Enrichment of Latent Virus in PD-1
+
and TIGIT
+
CD4 T Cells
Authors: Llewellyn George N. , Seclén Eduardo , Wietgrefe Stephen , Liu Siyu , Chateau Morgan , Pei Hua , Perkey Katherine , Marsden Matthew D. , Hinkley Sarah J. , Paschon David E. , Holmes Michael C. , Zack Jerome A. , Louie Stan G. , Haase Ashley T. , Cannon Paula M.
Published: March 2019

HIV-1 can establish latent infections that are not cleared by current antiretroviral drugs or the body’s immune responses and therefore represent a major barrier to curing HIV-infected individuals. However, the lack of expression of viral antigens on latently infected cells makes them difficult to identify or study. Here, we describe a humanized mouse model that can be used to detect latent but reactivatable HIV-1 in both untreated mice and those on ART and therefore provides a simple system with which to study the latent HIV-1 reservoir and the impact of interventions aimed at reducing it.
Paediatric neurodisability and sleep disorders: clinical pathways and management strategies
Authors: McDonald Aoife , Joseph Desaline
Published: March 2019

Sleep disorders are common in children with neurodisability. Their presentation is often complex. This complexity of presentation can make sleep disorders in children with neurodisability daunting to diagnose and manage. Both parents and healthcare professionals have identified sleep disorders as a healthcare outcome that they prioritise in children with neurodisability. We aim to explore the challenges of diagnosing sleep problems, discuss common difficulties with sleep in children with neurodisability and will touch on how to set up a service to support and manage sleep, working through case examples.
Development and performance evaluation of the Medicines Optimisation Assessment Tool (MOAT): a prognostic model to target hospital pharmacists’ input to prevent medication-related problems
Authors: Geeson Cathy , Wei Li , Franklin Bryony Dean
Published: March 2019

Background

Medicines optimisation is a key role for hospital pharmacists, but with ever-increasing demands on services, there is a need to increase efficiency while maintaining patient safety.

Objective

To develop a prediction tool, the Medicines Optimisation Assessment Tool (MOAT), to target patients most in need of pharmacists’ input in hospital.

Methods

Patients from adult medical wards at two UK hospitals were prospectively included into this cohort study. Data on medication-related problems (MRPs) were collected by pharmacists at the study sites as part of their routine daily clinical assessments. Data on potential risk factors, such as number of comorbidities and use of ‘high-risk’ medicines, were collected retrospectively. Multivariable logistic regression modelling was used to determine the relationship between risk factors and the study outcome: preventable MRPs that were at least moderate in severity. The model was internally validated and a simplified electronic scoring system developed.

Results

Among 1503 eligible admissions, 610 (40.6%) experienced the study outcome. Eighteen risk factors were preselected for MOAT development, with 11 variables retained in the final model. The MOAT demonstrated fair predictive performance (concordance index 0.66) and good calibration. Two clinically relevant decision thresholds (ie, the minimum predicted risk probabilities to justify pharmacists’ input) were selected, with sensitivities of 90% and 66% (specificity 30% and 61%); these equate to positive predictive values of 47% and 54%, respectively. Decision curve analysis suggests that the MOAT has potential value in clinical practice in guiding decision-making.

Conclusion

The MOAT has potential to predict those patients most at risk of moderate or severe preventable MRPs, experienced by 41% of admissions. External validation is now required to establish predictive accuracy in a new group of patients.
Iron-containing micronutrient powders modify the effect of oral antibiotics on the infant gut microbiome and increase post-antibiotic diarrhoea risk: a controlled study in Kenya
Authors: Paganini Daniela , Uyoga Mary A , Kortman Guus A M , Cercamondi Colin I , Winkler Hans C , Boekhorst Jos , Moretti Diego , Lacroix Christophe , Karanja Simon , Zimmermann Michael B
Published: March 2019

Objective

Many African infants receiving iron fortificants also receive antibiotics. Antibiotic efficacy against enteropathogens may be modified by high colonic iron concentrations. In this study, we evaluated the effect of antibiotics on the infant gut microbiome and diarrhoea when given with or without iron-containing micronutrient powders (MNPs).

Design

In a controlled intervention trial, four groups of community-dwelling infants (n=28; aged 8–10 months) received either: (A) antibiotics for 5 days and iron-MNPs for 40 days (Fe+Ab+); (B) antibiotics and no-iron-MNPs (Fe−Ab+); (C) no antibiotics and iron-MNPs (Fe+Ab−); or (D) no antibiotics and no-iron-MNPs (Fe−Ab−). We collected a faecal sample before the first antibiotic dose (D0) and after 5, 10, 20 and 40 days (D5–D40) to assess the gut microbiome composition by 16S profiling, enteropathogens by quantitative PCR, faecal calprotectin and pH and assessed morbidity over the 40-day study period.

Results

In Fe+Ab+, there was a decrease in Bifidobacterium abundances (p<0.05), but no decrease in Fe−Ab+. In Fe−Ab+, there was a decrease in abundances of pathogenic Escherichia coli (p<0.05), but no decrease in Fe+Ab+. In Fe−Ab+, there was a decrease in pH (p<0.05), but no decrease in Fe+Ab+. Longitudinal prevalence of diarrhoea was higher in Fe+Ab+ (19.6%) compared with Fe−Ab+ (12.4%) (p=0.04) and compared with Fe+Ab− (5.2%) (p=0.00).

Conclusion

Our findings need confirmation in a larger study but suggest that, in African infants, iron fortification modifies the response to broad-spectrum antibiotics: iron may reduce their efficacy against potential enteropathogens, particularly pathogenic E. coli, and may increase risk for diarrhoea.

Trial registration number

NCT02118402; Pre-results.
Clinical trials of transcatheter aortic valve replacement
Authors: Al-Azizi Karim , Hamandi Mohanad , Mack Michael
Published: March 2019

Transcatheter aortic valve replacement(TAVR) has emerged as an effective treatment option in patients with severe aortic stenosis, in large part due to a robust evidence base generated by a series of randomised controlled trials (RCTs). During the past decade more than 15 000 patients have been randomised worldwide in nine clinical trials, mostly for regulatory approval in the USA, making it one of the most carefully scrutinised medical devices at the time of introduction into clinical practice. Initial trials were performed in inoperable or extreme risk patients compared to medical therapy and demonstrated superiority. Subsequent RCTs compared TAVR to surgical aortic valve replacement in high and intermediate surgical risk patients and TAVR was found to be non-inferior in all studies. RCTs of low surgical risk patients have completed enrolment and 1 year outcomes will be available in early 2019. The details of the trials, trial results, outcomes and remaining clinical questions are summarised in this article.
Differential payment to research participants in the same study: an ethical analysis
Authors: Persad Govind , Fernandez Lynch Holly , Largent Emily
Published: March 2019

Recognising that offers of payment to research participants can serve various purposes—reimbursement, compensation and incentive—helps uncover differences between participants, which can justify differential payment of participants within the same study. Participants with different study-related expenses will need different amounts of reimbursement to be restored to their preparticipation financial baseline. Differential compensation can be acceptable when some research participants commit more time or assume greater burdens than others, or if inter-site differences affect the value of compensation. Finally, it may be permissible to offer differential incentive payments if necessary to advance the goals of a study. We encourage investigators and Institutional Review Boards to think about whether to offer payment, in what amounts and for what purpose, and also to consider whether differential payment can help promote the scientific and ethical goals of clinical research.