bluuebunny/crossref_metadata_2025 huggingface dataset:
How perceptions of immigrants trigger feelings of economic and cultural threats in two welfare states
Authors: Fietkau Sebastian , Hansen Kasper M
Published: October 2017

Better understanding of attitudes toward immigration is crucial to avoid misperception of immigration in the public debate. Through two identical online survey experiments applying morphed faces of non-Western immigrants and textual vignettes, the authors manipulate complexion, education, family background, and gender in Denmark and Germany. For women, an additional split in which half of the women wore a headscarf is performed. In both countries, highly skilled immigrants are preferred to low-skilled immigrants. Danes are more skeptical toward non-Western immigration than Germans. Essentially, less educated Danes are very critical of accepting non-Western immigrants in their country. It is suggested that this difference is driven by a large welfare state in Denmark compared to Germany, suggesting a stronger fear in welfare societies that immigrants will exploit welfare benefits.
Pink, Brown, and Read All Over: Representation at the 2017 Women’s March on Washington
Authors: Presley Rachel E. , Presswood Alane L.
Published: October 2017

In this dual-autoethnographic narrative, we examine the Women’s March on Washington in relation to critical approaches to activism. We draw upon our own unique experiences at the March, coupled with a chronology of the event’s origins, its approaches to diversity and inclusion, and media coverage of the movement. We contend that despite initial critiques of whitewashing feminism, the Women’s March thoughtfully addresses issues of solidarity and intersectionality from a point of transnational resistance and encourages demonstrators to unite in new formations of protest. Tracing the lineage of feminist scholarship from Gloria Anzaldúa and Audre Lorde to Leela Fernandes and Sara Ahmed, we fold theory into praxis and advocate for reimagined understandings of collective resistance efforts that attend to the postmodern, global contexts of Trumpian politics. We rely on Hardt and Negri’s conception of “commoning” within the multitude to explore how the March enters into a larger conversation of intersectional justice, both within and beyond academia.
Perceptions of Equipoise, Risk–Benefit Ratios, and “Otherwise Healthy Volunteers” in the Context of Early-Phase HIV Cure Research in the United States: A Qualitative Inquiry
Authors: Dubé Karine , Dee Lynda , Evans David , Sylla Laurie , Taylor Jeff , Brown Brandon , Miller Veronica , Corneli Amy , Skinner Asheley , Greene Sandra B. , Tucker Joseph D. , Rennie Stuart
Published: October 2017

Early-phase HIV cure research is conducted against a background of highly effective antiretroviral therapy, and involves risky interventions in individuals who enjoy an almost normal life expectancy. To explore perceptions of three ethical topics in the context of HIV cure research—(a) equipoise, (b) risk–benefit ratios, and (c) “otherwise healthy volunteers”—we conducted 36 in-depth interviews (IDIs) with three groups of purposively selected key informants: clinician-researchers ( n = 11), policy-makers and bioethicists ( n = 13), and people living with HIV (PLWHIV; n = 12). Our analysis revealed variability in perceptions of equipoise. Second, most key informants believed there was no clear measure of risk–benefit ratios in HIV cure research, due in part to the complexity of weighing (sometimes unknown) risks to participants and (sometimes speculative) benefits to science and society. Third, most clinician-researchers and policy-makers/bioethicists viewed potential HIV cure study participants as “otherwise healthy volunteers,” but this perception was not shared among PLWHIV in our study.
Dynamic Functional Assessment of Hand Motion Using an Animation Glove: The Effect of Stenosing Tenosynovitis
Authors: Schreck Michael J. , Kelly Meghan , Lander Sarah , Kaushik Anjan , Smith Heather , Bell Scott , Raman Vishwanath , Olles Deana , Geigel Joe , Olles Mark , Elfar John C.
Published: October 2017

Background: The aim of the present study is to determine whether an animation glove can be utilized to provide a reliable and reproducible assessment of dynamic hand function and whether this assessment is altered in the setting of hand pathology. Methods: Ten subjects without known hand pathology and 11 subjects with known stenosing tenosynovitis were assessed on tasks involving hand function at varied speeds, including forceful and gradual making of a fist and the quick and slow grip of a baseball using an animation glove to record range of motion and measures of velocity (CyberGlove II). Results: In normal subjects, peak extension and flexion velocity of the index and middle finger was highest in the metacarpophalangeal and lowest in the distal interphalangeal; however, the converse was true in the ring finger. In those subjects with stenosing tenosynovitis, the animation glove was able to detect a triggering event during assessment. Furthermore, there was a significant decrease in the maximum velocity of the proximal interphalangeal joint observed with the slow fist task in both flexion and extension (55%, P < .01) in the affected hand when compared with the unaffected hand. Conclusions: The CyberGlove II can be utilized in the dynamic functional analysis of the hand and is able to detect a triggering event in subjects with known stenosing tenosynovitis. Those subjects demonstrate a significant decrease in maximum velocity in slow fist tasks, highlighting the need for comprehensive assessment to ascertain the full extent of functional limitations that can occur in the setting of hand pathology.
Identifying Strategies for Effective Telemedicine Use in Intensive Care Units
Authors: Rak Kimberly J. , Kuza Courtney C. , Ashcraft Laura Ellen , Morrison Penelope K. , Angus Derek C. , Barnato Amber E. , Hravnak Marilyn , Hershey Tina B. , Kahn Jeremy M.
Published: October 2017

Telemedicine, the use of audiovisual technology to provide health care from a remote location, is increasingly used in intensive care units (ICUs). However, studies evaluating the impact of ICU telemedicine show mixed results, with some studies demonstrating improved patient outcomes, while others show limited benefit or even harm. Little is known about the mechanisms that influence variation in ICU telemedicine effectiveness, leaving providers without guidance on how to best use this potentially transformative technology. The Contributors to Effective Critical Care Telemedicine (ConnECCT) study aims to fill this knowledge gap by identifying the clinical and organizational factors associated with variation in ICU telemedicine effectiveness, as well as exploring the clinical contexts and provider perceptions of ICU telemedicine use and its impact on patient outcomes, using a range of qualitative methods. In this report, we describe the study protocol, data collection methods, and planned future analyses of the ConnECCT study. Over the course of 1 year, the study team visited purposefully sampled health systems across the United States that have adopted telemedicine. Data collection methods included direct observations, interviews, focus groups, and artifact collection. Data were collected at the ICUs that provide in-person critical care as well as at the supporting telemedicine units. Iterative thematic content analysis will be used to identify and define key constructs related to telemedicine effectiveness and describe the relationship between them. Ultimately, the study results will provide a framework for more effective implementation of ICU telemedicine, leading to improved clinical outcomes for critically ill patients.
Motivations, enrollment decisions, and socio-demographic characteristics of healthy volunteers in phase 1 research
Authors: Grady Christine , Bedarida Gabriella , Sinaii Ninet , Gregorio Mark Anthony , Emanuel Ezekiel J
Published: October 2017

Background/aim:

Phase 1 trials with healthy volunteers are an integral step in drug development. Commentators worry about the possible exploitation of healthy volunteers because they are assumed to be disadvantaged, marginalized, and inappropriately influenced by the offer of money for research for which they do not appreciate the inherent risks. Yet there are limited data to support or refute these concerns. This study aims to describe the socio-demographic characteristics, motivations, and enrollment decision-making of a large cohort of healthy volunteers.

Methods:

We used a cross-sectional anonymous survey of 1194 healthy volunteers considering enrollment in phase 1 studies at Pfizer Clinical Research Units in New Haven, CT; Brussels, Belgium; and Singapore. Descriptive statistics describe motivations and socio-demographic characteristics. Comparisons between groups were examined.

Results:

The majority rated consideration of risks as more important to their enrollment decision than the amount of money, despite reporting that their primary motivation was financial. Risk, time, money, the competence and friendliness of research staff, and contributing to medical research were important factors influencing enrollment decisions for most participants. The majority of healthy volunteers in this cohort were male, single, reported higher than high school education, and 70% had previous research experience. Many reported low annual incomes (50% below USD$25,000) and high rates of unemployment (33% overall). Nonetheless, risk as an important consideration, money, and other reported considerations and motivations, except for time, did not vary by income, employment, education, or previous experience. There were regional differences in both socio-demographic characteristics and factors important to participation decisions.

Conclusion:

Healthy volunteers in phase 1 studies consider risks as more important to their enrollment decisions than the amount of money offered, although most are motivated to participate by the offer of money. Healthy volunteers are indeed low income, disproportionately unemployed, and have significant prior research experience. Yet these factors do not appear to affect either their motivations for participation or factors important to their research enrollment decisions.
Does perioperative ketamine have a role in the prevention of chronic postsurgical pain: the ROCKet trial
Authors: Schug Stephan A , Peyton Philip
Published: October 2017

Identifying operations and individuals with an increased risk of chronic postsurgical pain (CPSP) has led to significant interest in interventions with the potential to achieve primary prevention of this condition. Pharmacological prevention remains controversial with a Cochrane review identifying perioperative ketamine administration as the only intervention with possible benefit although, with only small, heterogeneous studies, the authors called for a large randomised controlled trial (RCT) to confirm the validity of this result. In response to these data, a group of researchers from Australia and Hong Kong designed the ROCKet trial – Reduction Of Chronic Post-surgical Pain with Ketamine, endorsed by the Australian and New Zealand College of Anaesthetists (ANZCA) Clinical Trials Network (CTN).
Acceptability of targeting social embarrassment in a digital intervention to reduce student alcohol consumption: A qualitative think aloud study
Authors: Davies Emma L , Law Cara , Hennelly Sarah E , Winstock Adam R
Published: October 2017

Objective

Increasing knowledge about alcohol-related harms, changing social norms, or encouraging drinking within safe unit levels often fails to change behaviour in young people. A novel intervention called ‘OneTooMany’ was developed, which targets the short-term social, and potentially, embarrassing consequences of drinking alcohol. The aim of this paper was to explore its acceptability, and to determine any features that might influence its effectiveness as a means of reducing alcohol consumption.

Methods

Participants were 23 young adults (aged 18–30) currently studying at university ( n = 18) or in the first six months following graduation ( n = 5). A think aloud interview approach was employed. Three main themes were identified in a deductive thematic analysis.

Results

Embarrassing experiences were a normalised part of drinking occasions, while some were actively avoided, others were celebrated. Humour served as a device to engage and interest participants, but could also diminish intervention messages. OneTooMany prompted reflections on many regrettable drinking experiences, but the participants did not see themselves as the target audience for this intervention.

Conclusions

Interventions may benefit from focusing on some of the short term, embarrassing consequences of excessive alcohol consumption. Further research is needed to ensure that reflections on past behaviour are helpful in addressing future behaviour.
An exploratory study of mobile messaging preferences by age: Middle-aged and older adults compared to younger adults
Authors: Kuerbis Alexis , van Stolk-Cooke Katherine , Muench Frederick
Published: October 2017

Introduction

Mobile technologies, such as short message service or text messaging, can be an important way to reach individuals with medical and behavioral health problems who are homebound or geographically isolated. Optimally tailoring messages in short message service interventions according to preferences can enhance engagement and positive health outcomes; however, little is known about the messaging preferences of middle-aged and older adults.

Methods

Utilizing secondary data, global messaging preferences were examined to inform the development of short message service interventions for adults of all ages. Two hundred and seventy-seven adults were recruited through an online labor market. They completed an online survey by evaluating message dyads in 22 content groupings. Dyads were identical in subject matter but structurally or linguistically varied. Participants selected the message in each dyad they would prefer to receive when attempting to meet a self-selected personal goal. Preferences were tested for two age groups ≤50 and 51 and older.

Results

Findings reveal adults 51 and older have clear messaging preferences that differ significantly from the younger group for only two content groupings; specifically, they prefer no emoticon to a smiley face emoticon and “you” statements rather than “we” statements.

Conclusion

Recommendations for optimizing messaging for older adults are reviewed.
Concussion in motor sport: A medical literature review and engineering perspective
Authors: Deakin Naomi D , Cronin Thomas , Trafford Paul , Olvey Stephen , Roberts Ian , Mellor Andrew , Hutchinson Peter J
Published: October 2017

‘WARNING: motor sport can be dangerous’. The spectrum of head injuries in motor sport has shifted dramatically in recent decades, fuelled by advances in medicine and engineering. Despite these successes, there are growing public and professional concerns regarding concussion in motor sport. This review appraises the published literature concerning concussion in motor sport, with particular focus on the current medical and technical challenges in the field. The incidence and assessment of concussion in motor sport is discussed, in addition to modifiable risk factors within and outside the automobile environment. Lastly, areas for further research and development are outlined.
Risk Factors for Continued Opioid Use in Conservative Versus Surgical Management of Low Back Pain Originating From the Sacroiliac Joint
Authors: Dengler Julius , Sturesson Bengt , Kools Djaya , Prestamburgo Domenico , Cher Daniel , van Eeckhoven Eddie , Erk Emanuel , Gasbarrini Alessandro , Pflugmacher Robert , Vajkoczy Peter
Published: October 2017

Study Design:

Secondary analysis of data from a randomized controlled trial.

Objectives:

To identify risk factors for continued opioid use after conservative management (CM) or minimally invasive surgical management (MISM) of low back pain (LBP) originating from the sacroiliac joint.

Methods:

Patients were randomized either to CM (n = 49) or MISM (n = 52). We documented opioid use, pain intensity (visual analogue scale [VAS]), Oswestry Disability Index (ODI), and the Zung depression score (Zung Self-Rating Depression Scale) at baseline and at months 3 and 6 after treatment initiation.

Results:

Compared with opioid nonusers, opioid users at baseline had higher mean levels of disability (ODI 61.5, standard deviation [SD] 13.3 vs ODI 51.5, SD 12.8; P < .01) and higher depression scores (Zung 48.5, SD 8.5, vs Zung 42.2, SD 7.2; P < .01). At 6 months, opioid users had higher 6-month pain levels (VAS 60.4, SD 24.0, vs VAS 42.4, SD 28.2; P < .01), higher disability scores (ODI 50.5, SD 16.2, vs ODI 32.7, SD 19.3; P < .01) and higher depression scores (Zung 47.6, SD 8.0, vs Zung 38.8, SD 8.9; P < .01). Risk factors for continued opioid use at 6 months were patient age (odds ratio [OR] for age = 0.91; P = .02) and an increase in LBP (OR 1.08; P = .02) in the CM group and a lack of improvement in depression scores (OR 1.12; P = .03) in the MISM group.

Conclusions:

In our patient cohort, the risk of continued opioid use in the treatment of LBP increased not only with pain intensity but also with levels of depression during the course of treatment.
The Anterolateral Complex of the Knee
Authors: Herbst Elmar , Albers Marcio , Burnham Jeremy M. , Fu Freddie H. , Musahl Volker
Published: October 2017

Background:

Significant controversy exists regarding the anterolateral structures of the knee.

Purpose:

To determine the layer-by-layer anatomic structure of the anterolateral complex of the knee.

Study Design:

Descriptive laboratory study.

Methods:

Twenty fresh-frozen cadaveric knees (age range, 38-56 years) underwent a layer-by-layer dissection to systematically expose and identify the various structures of the anterolateral complex. Quantitative measurements were performed, and each layer was documented with high-resolution digital imaging.

Results:

The anterolateral complex of the knee consisted of different distinct layers, with the superficial and deep iliotibial band (ITB) representing layer 1. The superficial ITB had a distinct connection to the distal femoral metaphysis and femoral condyle (Kaplan fibers), and the deep layers of the ITB were identified originating at the level of the Kaplan fibers proximally. This functional unit, consisting of the superficial and deep ITB, was reinforced by the capsulo-osseous layer of the ITB, which was continuous with the fascia of the lateral gastrocnemius and biceps femoris muscles. These 3 components of the ITB became confluent distally, and the insertion spanned from the Gerdy tubercle anteriorly to the lateral tibia posteriorly on a small tubercle (lateral tibial tuberosity). Layer 3 consisted of the anterolateral capsule, in which 35% (7/20) of specimens had a discreet mid-third capsular ligament.

Conclusion:

The anterolateral complex consists of the superficial and deep ITB, the capsulo-osseous layer of the ITB, and the anterolateral capsule. The anterolateral complex is defined by the part of the ITB between the Kaplan fibers proximally and its tibial insertion, which forms a functional unit. A discrete anterolateral ligament was not observed; however, the anterolateral ligament described in recent studies likely refers to the capsulo-osseous layer or the mid-third capsular ligament.

Clinical Relevance:

The anterolateral knee structures form a complex functional unit. Surgeons should use caution when attempting to restore this intricate structure with extra-articular procedures designed to re-create a single discreet ligament.
A Lifesaving View of Vascularized Composite Allotransplantation
Authors: Bramstedt Katrina A
Published: October 2017

Introduction:

Most solid organ transplantation is viewed as lifesaving, whereas vascularized composite allotransplantation (VCA) has been viewed as life enhancing. This article challenges the latter and argues that “social death” evident in severe face, hand, and larynx disfigurement can be potentially treated via VCA. Social death (from a social science perspective) consists of a combination of 7 components: social isolation, loneliness, ostracism, loss of personhood, change of role and identity, harm, and disfigurement.

Methods:

In February 2016, PubMed and Google were searched for case reports of human face, hand, and larynx transplantation. Patient and team narratives were then coded for components of social death using social science and medical model criteria.

Results:

Eleven narratives were identified among 9 articles. The social science model (but not the medical model) described pretransplant social death and the resolution of social death by receiving VCA. Notably, the medical model of social death was deemed unsuitable for application to VCA. This is because case narratives consistently contradict elements of the medical model.

Conclusions:

By including social death as a patient inclusion criterion for face, hand, and larynx VCA, these transplants can be considered lifesaving. Additionally, because VCA requires lifelong immunosuppressant medication, considering VCA as a lifesaving intervention improves the technology’s risk–benefit analysis. Guidance for assessing social death is provided.
NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications
Authors: Russo Antonio , Oliveira Giacomo , Berglund Sofia , Greco Raffaella , Gambacorta Valentina , Cieri Nicoletta , Toffalori Cristina , Zito Laura , Lorentino Francesca , Piemontese Simona , Morelli Mara , Giglio Fabio , Assanelli Andrea , Stanghellini Maria Teresa Lupo , Bonini Chiara , Peccatori Jacopo , Ciceri Fabio , Luznik Leo , Vago Luca
Published: October 2017

Key Points

Posttransplantation cyclophosphamide eliminates most mature donor NK cells infused with the graft, including alloreactive NK cells. High levels of serum interleukin-15 early after HSCT provide a favorable environment for adoptive infusion of mature donor NK cells.
Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease
Authors: DeFilipp Zachariah , Nazarian Rosalynn M. , El-Jawahri Areej , Li Shuli , Brown Jami , Del Rio Candice , Smith Melissa , Valles Betsy , Ballen Karen K. , McAfee Steven L. , Rosenblatt Jacalyn , Antin Joseph H. , Cutler Corey S. , Chen Yi-Bin
Published: October 2017

Key Points

Physician-assessed clinical responses and immunohistochemical changes were seen in association with sonidegib therapy for cGVHD. Sonidegib therapy was limited by ongoing cGVHD symptoms and adverse events not attributed to treatment.
Long-term effects of inhaled corticosteroids on sputum bacterial and viral loads in COPD
Authors: Contoli Marco , Pauletti Alessia , Rossi Maria Rita , Spanevello Antonio , Casolari Paolo , Marcellini Andrea , Forini Giacomo , Gnesini Giulia , Marku Brunilda , Barnes Neil , Rizzi Andrea , Curradi Giacomo , Caramori Gaetano , Morelli Paolo , Papi Alberto
Published: October 2017

Inhaled corticosteroid-containing medications reduce the frequency of COPD exacerbations (mainly infectious in origin) while paradoxically increasing the risk of other respiratory infections.The aim was to determine the effects of inhaled corticosteroids on airway microbial load in COPD patients and evaluate the influence of the underlying inflammatory profile on airway colonisation and microbiome.

This is a proof-of-concept prospective, randomised, open-label, blinded endpoint study. Sixty patients with stable moderate COPD were randomised to receive one inhalation twice daily of either a combination of salmeterol 50 μg plus fluticasone propionate 500 μg or salmeterol 50 μg for 12 months. The primary outcome was the change of sputum bacterial loads over the course of treatment.

Compared with salmeterol, 1-year treatment with salmeterol plus fluticasone was associated with a significant increase in sputum bacterial load (p=0.005), modification of sputum microbial composition and increased airway load of potentially pathogenic bacteria. The increased bacterial load was observed only in inhaled corticosteroid-treated patients with lower baseline sputum or blood eosinophil (≤2%) levels but not in patients with higher baseline eosinophils.

Long-term inhaled corticosteroid treatment affects bacterial load in stable COPD. Lower eosinophil counts are associated with increased airway bacterial load.
A virtual asthma clinic for children: fewer routine outpatient visits, same asthma control
Authors: van den Wijngaart Lara S. , Roukema Jolt , Boehmer Annemie L.M. , Brouwer Marianne L. , Hugen Cindy A.C. , Niers Laetitia E.M. , Sprij Arwen J. , Rikkers-Mutsaerts Eleonora R.V.M. , Rottier Bart L. , Donders A. Rogier T. , Verhaak Chris M. , Pijnenburg Mariëlle W. , Merkus Peter J.F.M.
Published: October 2017

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.

In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6–16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.

We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42–2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09–2.25; p=0.03). No differences were found for other outcome measures.

Routine outpatient visits can partly be replaced by monitoring asthmatic childrenviaeHealth.
A complete project environment simulation to improve six sigma training class engagement
Authors: NG Chee Kai
Published: October 2017

Most of the learners view statistical-related training, such as Six Sigma training as a “monotonous” area despite the group discussions, case studies, active summaries, Q&A sessions, and role-playing being included as part of Six Sigma training today. The learners will be less enthusiastic when similar training manner is repeatedly adopted and becomes predictable. An uninteresting training approach could cause the learners to be disengaged and demotivated to learn and thus cause the training to be ineffective and could potentially hinder the organization strategies. Therefore, to keep the learner more attentive and involved during the Six Sigma training, a fun Six Sigma training approach with a properly designed class game is desirable. The game aims to provide a complete Six Sigma project experience by simulating a real-life competitive atmosphere of commercial industry, which can help the learners to internalize the Six Sigma knowledge and its applications. The Six Sigma game embraces the form of team competition, where it covers two major aspects, namely, (i) Six Sigma expertise on how to formulate a meaningful y = f(x) and (ii) basic element of project management as a coherent approach to Six Sigma training. In this paper, the author adopted the Kirkpatrick learning evaluation model to evaluate how the learners react to the newly implemented Six Sigma game and to gauge how much their know-how improved after the training. The post-training feedback, pre-training, and post-training evaluation suggest that the Six Sigma game can engage and motivate the learners.
Behavioural activation for depression in older people: systematic review and meta-analysis
Authors: Orgeta Vasiliki , Brede Janina , Livingston Gill
Published: October 2017

Background

Behavioural activation is an effective treatment for depression in the general adult population but it is unclear whether it is effective for older people.

Aims

To systematically review randomised controlled trials (RCTs) of behavioural activation for depression in older people.

Method

We searched Medline, EMBASE, PsycINFO, CINAHL and online trial registers for RCTs of behavioural activation for depression in older people.

Results

Eighteen trials were included in the meta-analyses. Behavioural activation reduced mean depression scores for older people living in the community as a stand-alone treatment: standardised mean difference (SMD) −0.72, 95% Cl −1.04 to −0.41. It was also effective as part of a multicomponent intervention (SMD −0.44, 95% CI −0.56 to −0.32).

Conclusions

Behavioural activation significantly reduces depressive symptoms in older people in the community; however, given that most studies are small and with significant bias results should be interpreted with caution. Further high-quality trials of behavioural activation for this age group are needed.
DNA Methylation–Based Classifier for Accurate Molecular Diagnosis of Bone Sarcomas
Authors: Wu S. Peter , Cooper Benjamin T. , Bu Fang , Bowman Christopher J. , Killian J. Keith , Serrano Jonathan , Wang Shiyang , Jackson Twana M. , Gorovets Daniel , Shukla Neerav , Meyers Paul A. , Pisapia David J. , Gorlick Richard , Ladanyi Marc , Thomas Kristen , Snuderl Matija , Karajannis Matthias A.
Published: October 2017

Purpose

Pediatric sarcomas provide a unique diagnostic challenge. There is considerable morphologic overlap between entities, increasing the importance of molecular studies in the diagnosis, treatment, and identification of therapeutic targets. We developed and validated a genome-wide DNA methylation–based classifier to differentiate between osteosarcoma, Ewing sarcoma, and synovial sarcoma.

Methods

DNA methylation status of 482,421 CpG sites in 10 Ewing sarcoma, 11 synovial sarcoma, and 15 osteosarcoma samples were determined using the Illumina Infinium HumanMethylation450 array. We developed a random forest classifier trained from the 400 most differentially methylated CpG sites within the training set of 36 sarcoma samples. This classifier was validated on data drawn from The Cancer Genome Atlas synovial sarcoma, TARGET-Osteosarcoma, and a recently published series of Ewing sarcoma.

Results

Methylation profiling revealed three distinct patterns, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from The Cancer Genome Atlas were accurately classified as synovial sarcoma (10 of 10; sensitivity and specificity, 100%), all but one sample from TARGET-Osteosarcoma were classified as osteosarcoma (85 of 86; sensitivity, 98%; specificity, 100%), and 14 of 15 Ewing sarcoma samples were classified correctly (sensitivity, 93%; specificity, 100%). The single misclassified osteosarcoma sample demonstrated high EWSR1 and ETV1 expression on RNA sequencing, although no fusion was found on manual curation of the transcript sequence. Two additional clinical samples that were difficult to classify by morphology and molecular methods were classified as osteosarcoma; one had been suspected of being a synovial sarcoma and the other of being Ewing sarcoma on initial diagnosis.

Conclusion

Osteosarcoma, synovial sarcoma, and Ewing sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide diagnostic assistance when histologic and standard techniques are inconclusive.
“Passing Everybody and Never Halting”:Dromosand Speed in Jack Kerouac'sOn the Road
Authors: Mikelli Eftychia
Published: October 2017

My article explores the implications of rapid movement in Jack Kerouac's On the Road both on a literary and a political level, while drawing on Paul Virilio's work on speed and acceleration. The article examines the nature of the main characters' impetus for perpetual motion and discusses the ambiguity of their desire for speedy driving. Considering the significance of mobility within the cultural context of Cold War America, I investigate the influence of speed on identity formation in the novel. I subsequently look at the impact of both accelerated and decelerated movement on plot and narrative structure, and I explore the political implications of speed as reflected in the protagonists' interactions with agents of civilian power.
Phosphatase-regulated recruitment of the spindle- and Kinetochore-Associated (Ska) Complex to kinetochores
Authors: Sivakumar Sushama , Gorbsky Gary J.
Published: October 2017

Kinetochores move chromosomes on dynamic spindle microtubules and regulate signaling of the spindle checkpoint. The Spindle and Kinetochore-Associated (Ska) Complex, a hexamer composed of two copies of Ska1, Ska2 and Ska3, has been implicated in both roles. Phosphorylation of kinetochore components by the well-studied mitotic kinases, Cdk1, Aurora B, Plk1, Mps1, and Bub1 regulate chromosome movement and checkpoint signaling. Roles for the opposing phosphatases are more poorly defined. Recently, we showed that the C terminus of Ska1 recruits protein phosphatase 1 (PP1) to kinetochores. Here we show that PP1 and protein phosphatase 2A (PP2A) both promote accumulation of Ska at kinetochores. Depletion of PP1 or PP2A by siRNA reduces Ska binding at kinetochores, impairs alignment of chromosomes to the spindle midplane, and causes metaphase delay or arrest, phenotypes that are also seen after depletion of Ska. Artificial tethering of PP1 to the outer kinetochore protein Nuf2 promotes Ska recruitment to kinetochores, and it reduces but does not fully rescue chromosome alignment and metaphase arrest defects seen after Ska depletion. We propose that Ska has multiple functions in promoting mitotic progression and that kinetochore-associated phosphatases function in a positive feedback cycle to reinforce Ska complex accumulation at kinetochores.
Light regimes differentially affect baseline transcript abundance of stress-axis and (neuro)development related genes in zebrafish (Danio rerio, Hamilton 1822) AB and TL larvae
Authors: van den Bos Ruud , Zethof Jan , Flik Gert , Gorissen Marnix
Published: October 2017

Many strains of zebrafish (Danio rerio) are readily available. Earlier we observed differences between AB and Tupfel long-fin (TL) larvae regarding baseline hypothalamus-pituitary-interrenal (HPI) axis activity and (neuro)development. Light regimes, i.e. 14 h light:10 h dark and 24 h continuous dark or light, affect hatching rate and larval growth. Here, we assessed baseline transcript abundance of HPI-axis-related genes and (neuro)development-related genes of AB and TL larvae (5 days post fertilisation) using these light regimes. A Principal Component Analysis revealed that in AB larvae the baseline expression of HPI-axis-related genes was higher the more hours of light, while the expression of (neuro)development-related genes was higher under 14L:10D than under both continuous light or dark. In TL larvae, a complex pattern emerged regarding baseline expression of HPI-axis-related and (neuro)development-related genes. These data extend data of earlier studies by showing that light regimes affect gene-expression in larvae, and more importantly so, strengthen the notion of differences between larvae of the AB and TL strain. The latter finding adds to the growing database of phenotypical differences between zebrafish of the AB and TL strain.
Re-evaluating functional landscape of the cardiovascular system during development
Authors: Takada Norio , Omae Madoka , Sagawa Fumihiko , Chi Neil C. , Endo Satsuki , Kozawa Satoshi , Sato Thomas N.
Published: October 2017

The cardiovascular system facilitates body-wide distribution of oxygen, a vital process for development and survival of virtually all vertebrates. However, zebrafish, a vertebrate model organism, appears to form organs and survive mid-larval periods without the functional cardiovascular system. Despite such dispensability, it is the first organ to develop. Such enigma prompted us to hypothesize yet other cardiovascular functions that are important for developmental and/or physiological processes. Hence, systematic cellular ablations and functional perturbations are performed on zebrafish cardiovascular system to gain comprehensive and body-wide understanding of such functions and to elucidate underlying mechanisms. This approach identifies a set of organ-specific genes, each implicated for important functions. The study also unveils distinct cardiovascular mechanisms, each differentially regulating their expressions in organ-specific and oxygen-independent manners. Such mechanisms are mediated by organ-vessel interactions, circulation-dependent signals, and circulation-independent beating-heart-derived signals. Hence, a comprehensive and body-wide functional landscape of the cardiovascular system reported herein may provide a clue as to why it is the first organ to develop. Furthermore, the dataset herein could serve as a resource for the study of organ development and function.
Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling
Authors: Nagy Péter , Szatmári Zsuzsanna , Sándor Gyöngyvér O. , Lippai Mónika , Hegedűs Krisztina , Juhász Gábor
Published: October 2017

Genetic variations of Atg16L1, Slit and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship of these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine cells (pre-EEs) accumulate that fail to differentiate into properly functioning secretory EEs. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling trigger an intestinal inflammatory response. Surprisingly, analysis of Rab19 and domain-specific Atg16 mutants indicates that their stem cell niche regulatory function is independent of autophagy. Our study reveals how mutations in these different genes may contribute to IBD.
Direct and efficient transfection of mouse neural stem cells and mature neurons by in vivo mRNA electroporation
Authors: Bugeon Stéphane , de Chevigny Antoine , Boutin Camille , Coré Natalie , Wild Stefan , Bosio Andreas , Cremer Harold , Beclin Christophe
Published: October 2017

In vivo brain electroporation of DNA expression vectors is a widely used method for lineage and gene function studies in the developing and postnatal brain. However, transfection efficiency of DNA is limited and adult brain tissue is refractory to electroporation. Here we present a systematic study of mRNA as a vector for acute genetic manipulation in the developing and adult brain. We demonstrate that mRNA electroporation is far more efficient than DNA and leads to faster and more homogeneous protein expression in vivo. Importantly, mRNA electroporation allows the manipulation of neural stem cells and postmitotic neurons in the adult brain with minimal invasive procedures. Finally, we show that this approach can be efficiently used for functional studies as exemplified by transient overexpression of the neurogenic factor Myt1l and by stably inactivating Dicer nuclease in vivo in adult born olfactory bulb interneurons and in fully integrated cortical projection neurons.
Phyllotactic regularity requires the Paf1 complex in Arabidopsis
Authors: Fal Kateryna , Liu Mengying , Duisembekova Assem , Refahi Yassin , Haswell Elizabeth S. , Hamant Olivier
Published: October 2017

In plants, aerial organs are initiated at stereotyped intervals, both spatially (every 137 degrees in a pattern called phyllotaxis) and temporally (at prescribed time intervals called plastochron). To investigate the molecular basis of such regularity, mutants with altered architecture have been isolated. However, most of them only exhibit defects in plastochron and/or produce a new, albeit equally reproducible, phyllotactic pattern. This leaves open the question of a molecular control of phyllotaxis regularity. Here we show that phyllotaxis regularity depends on the function of VIP proteins, components of the PolII-associating factor 1 (Paf1) complex. Divergence angles between successive organs along the stem exhibited increased variance in vip3-1 and vip3-2 than in the WT, in two different growth conditions. Similar results were obtained with the weak vip3-6 allele and in vip6, a mutant for another Paf1c subunit. Mathematical analysis confirmed that these defects could not be explained solely by plastochron defects. Instead, increased variance in phyllotaxis in vip3 was observed at the meristem and related to defects in spatial patterns of auxin activity. Thus the regularity of spatial, auxin-dependent, patterning at the meristem requires Paf1c.
Regulation of mitosis-meiosis transition by the ubiquitin ligase β-TrCP in male germ cells
Authors: Nakagawa Tadashi , Zhang Teng , Kushi Ryo , Nakano Seiji , Endo Takahiro , Nakagawa Makiko , Yanagihara Noriko , Zarkower David , Nakayama Keiko
Published: October 2017

The mitosis-meiosis transition is essential for spermatogenesis. Specific and timely down-regulation of the transcription factor DMRT1, and consequent induction of Stra8 expression, is required for this process in mammals, but the molecular mechanism has remained unclear. Here we show that β-TrCP, the substrate recognition component of an E3 ubiquitin ligase complex, targets DMRT1 for degradation and thereby controls the mitosis-meiosis transition in mouse male germ cells. Conditional inactivation of β-TrCP2 in male germ cells of β-TrCP1 knockout mice resulted in sterility due to a lack of mature sperm. The β-TrCP–deficient male germ cells did not enter meiosis, but instead underwent apoptosis. The induction of Stra8 expression was also attenuated in association with the accumulation of DMRT1 at the Stra8 promoter in β-TrCP–deficient testes. DMRT1 contains a consensus β-TrCP degron sequence that was found to bind β-TrCP. Overexpression of β-TrCP induced the ubiquitylation and degradation of DMRT1. Heterozygous deletion of Dmrt1 in β-TrCP–deficient spermatogonia increased meiotic cells with a concomitant reduction of apoptosis. Collectively, our data indicate that β-TrCP regulates the transition from mitosis to meiosis in male germ cells by targeting DMRT1 for degradation.
Functional assays for the assessment of the pathogenicity of variants in GOSR2, an ER-to-Golgi SNARE involved in progressive myoclonus epilepsies
Authors: Völker Jörn M. , Dergai Mykola , Abriata Luciano A. , Mingard Yves , Ysselstein Daniel , Krainc Dimitri , Dal Peraro Matteo , von Mollard Gabriele Fischer , Fasshauer Dirk , Koliwer Judith , Schwake Michael
Published: October 2017

Progressive myoclonus epilepsies (PME) are inherited disorders characterized by myoclonus, generalized tonic-clonic seizures, and ataxia. One of the genes that are associated with PME is the ER-to-Golgi Qb-SNARE GOSR2, which forms a SNARE complex with Syntaxin5, Bet1 and Sec22b. Most PME patients are homo­zygous for a p.Gly144Trp mutation and develop similar clinical presentations. Recently, a patient who was compound heterozygous for the p.Gly144Trp and a novel p.Lys164del mutation was identified. Since this patient presented with a milder disease phenotype, we hypothesized that the p.Lys164del mutation may be less severe compared to p.Gly144Trp. To characterize the effect of the p.Gly144Trp and p.Lys164del mutations, both of which are present in the SNARE motif of GOSR2, we examined the corresponding mutations in the yeast orthologue Bos1. Yeasts expressing the orthologous mutants in Bos1 showed impaired growth, suggesting a partial loss of function, which was more severe for the Bos1 p.Gly176Trp mutation. Using anisotropy and gel filtration, we report that Bos1 p.Gly176Trp and p.Arg196del are capable of complex formation, however with partly reduced activity. Molecular dynamics simulations showed that the hydrophobic core, which triggers SNARE complex formation, is compromised due to the glycine to tryptophan substitution in both GOSR2 and Bos1. In contrast, the deletion of residue p.Lys164 (or p.Arg196del in Bos1) interferes with the formation of hydrogen bonds between GOSR2 and Syntaxin5. Despite these perturbations, all SNARE complexes stayed intact during longer simulations. Thus, our data suggest that the milder course of disease in compound heterozygous PME is due to less severe impairment of the SNARE function.
Evaluation of human dermal fibroblasts directly reprogrammed to adipocyte-like cells as a metabolic disease model
Authors: Chen Jian-Hua , Goh Kim Jee , Rocha Nuno , Groeneveld Matthijs P. , Minic Marina , Barrett Timothy G. , Savage David , Semple Robert K.
Published: October 2017

Adipose tissue is the primary tissue affected in most single gene forms of severe insulin resistance, and growing evidence has implicated it as a site where many risk alleles for insulin resistance identified in population-wide studies may exert their effect. There is thus increasing need for human adipocyte models in which to interrogate the function of known and emerging genetic risk variants, yet primary adipocyte cultures, existing immortalised cell lines, and stem-cell based models all have significant biological or practical limitations. In an attempt to widen the repertoire of human cell models in which to study adipocyte-autonomous effects of relevant human genetic variants, we have undertaken direct reprogramming of skin fibroblasts to adipocyte-like cells by employing an inducible recombinant lentivirus overexpressing the master adipogenic transcription factor PPARγ2. Doxycycline-driven expression of PPARγ2 and adipogenic culture conditions converted dermal fibroblasts into triglyceride-laden cells within days. The resulting cells recapitulated most of the critical aspects of adipocyte biology in vivo, including the expression of mature adipocyte markers, secreted high levels of the adipokine adiponectin, and underwent lipolysis when treated with isoproterenol/IBMX. They did not, however, exhibit insulin-inducible glucose uptake, and withdrawal of doxycycline produced rapid de-lipidation and loss of adipogenic markers. This protocol was applied successfully to a panel of skin cells from individuals with monogenic severe insulin resistance, however, surprisingly, even cell lines harbouring mutations causing severe, generalised lipodystrophy accumulated large lipid droplets and induced adipocyte-specific genes. The direct reprogramming protocol of human dermal fibroblasts to adipocyte-like cells we established is simple, fast and efficient, and has the potential to generate cells which can serve as a tool to address some, though not all, aspects of adipocyte function in the presence of endogenous disease-causing mutations.
Pharmacological analysis of the transmembrane action potential configuration in myoepithelial cells of the spontaneously beating heart of the ascidianStyela rustica in vitro
Authors: Golovko Vladimir A. , Kosevich Igor A. , Gonotkov Mikhail A.
Published: October 2017

The mechanisms of action potential (AP) generation in the myoepithelial cells of the Tunicata heart are not yet well understood. Here, an attempt was made to elucidate these mechanisms by analyzing the effects of specific blockers of K+, Na+ and Ca2+ currents on the configuration of transmembrane APs and their frequency in the spontaneously beating ascidian heart. In addition, an immunocytochemical analysis of heart myoepithelial cells was performed. Staining with anti-FMRF-amide and anti-tubulin antibodies did not reveal any nerve elements within the heart tube. Treatment with 1 mM TEA (IK blocker) resulted in depolarization of heart cell sarcolemma by 10 mV, and inhibition of APs generation was recorded after 3-three min exposure. Prior to this moment, the frequency of APs generation in a burst decreased from 16–18 to 2 beats per min due to prolongation of the diastole. After application of ivabradine (3 or 10 µM), the spontaneous APs generation frequency decreased by 24%. Based on these results and published data, it is concluded that the key role in the automaticity of the ascidian heart is played by the outward K+ currents, Na+ currents, activated hyperpolarization current If, and a current of unknown nature IX.