bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripartum cardiomyopathy and hypertensive disorders of pregnancy and cardiovascular events among 1.6 million California pregnancies
Authors: Arnaout Rima , Nah Gregory , Marcus Gregory M. , Tseng Zian H. , Foster Elyse , Harris Ian , Divanji Punag , Klein Liviu , Gonzalez Juan M. , Parikh Nisha I.
Published: August 2018

Background

Cardiovascular complications during and soon after pregnancy present an opportunity to assess risk for subsequent cardiovascular disease. We sought to determine whether peripartum cardiomyopathy and hypertensive disorder of pregnancy subtypes predict future myocardial infarction, heart failure, or stroke independent of one another and independent of other risks like gestational diabetes, preterm birth, and intrauterine growth restriction.

Methods and Results

The California Healthcare Cost and Utilization Project database was used to identify all hospitalized pregnancies from 2005-2009, with follow-up through 2011, for a retrospective cohort study. Pregnancies, exposures, covariates and outcomes were defined by ICD-9 codes. Among 1.6 million pregnancies (mean age 28y; median follow-up time to event 2.7y), 558 cases of peripartum cardiomyopathy, 123,603 cases of hypertensive disorders of pregnancy, 107,636 cases of gestational diabetes, 116,768 preterm births, and 23,504 cases of intrauterine growth restriction were observed. Using multivariable Cox proportional hazards models, peripartum cardiomyopathy was independently associated with a 13.0-fold increase in myocardial infarction [95%CI, 4.1-40.9], a 39.2-fold increase in heart failure [95%CI, 30.0-51.9], and a 7.7-fold increase in stroke [95%CI, 2.4-24.0]. Hypertensive disorders of pregnancy were associated with a 1.4 [95%CI, 1.0-2.0] to 7.6 [95%CI, 5.4-10.7] fold higher risk of myocardial infarction, heart failure, and stroke. Gestational diabetes, preterm birth, and intrauterine growth restriction had more modest associations with CVD.

Conclusions

These findings support close monitoring of women with cardiovascular pregnancy complications for prevention of early subsequent cardiovascular events and further study of mechanisms underlying their development.
The Role of Toll-like receptor 4 in respiratory syncytial virus replication, interferon lambda 1 induction, and chemokine responses
Authors: Broadbent Lindsay , Coey Jonathon D. , Shields Michael D. , Power Ultan F.
Published: August 2018

Respiratory syncytial virus (RSV) infection is the leading cause of severe lower respiratory tract infections (LRTI) in infants worldwide. The immune responses to RSV infection are implicated in RSV pathogenesis but RSV immunopathogenesis in humans remains poorly understood. We previously demonstrated that IFN-λ1 is the principle interferon induced following RSV infection of infants and well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). Interestingly, RSV F interacts with the TLR4/CD14/MD2 complex to initiate secretion of pro-inflammatory cytokines, while TLR4 stimulation with house dust mite induces IFN-λ1 production. However, the role of TLR4 in RSV infection and concomitant IFN-λ1 induction remains unclear. Using our RSV/WD-PBEC infection model, we found that CLI-095 inhibition of TLR4 resulted in significantly reduced viral growth kinetics, and secretion of IFN-λ1 and pro-inflammatory chemokines. To elucidate specific TLR4 signalling intermediates implicated in virus replication and innate immune responses we selected 4 inhibitors, including LY294002, U0126, SB203580 and JSH-23. SB203580, a p38 MAPK inhibitor, reduced both viral growth kinetics and IFN-λ1 secretion, while JSH-23, an NF-κB inhibitor, reduced IFN-λ1 secretion without affecting virus growth kinetics. Our data indicate that TLR4 plays a role in RSV entry and/or replication and IFN-λ1 induction following RSV infection is mediated, in part, by TLR4 signalling through NF- κB and/or p38 MAPK. Therefore, targeting TLR4 or downstream effector proteins could present novel treatment strategies against RSV.

Importance

The role of TLR4 in RSV infection and IFN-λ1 induction is controversial. Using our WD-PBEC model, which replicates many hallmarks of RSV infection in vivo, we demonstrated that the TLR4 pathway is involved in both RSV infection and/or replication and the concomitant induction of IFN-λ1 and other pro-inflammatory cytokines. Increasing our understanding of the role of TLR4 in RSV immunopathogenesis may lead to the development of novel RSV therapeutics.
Benchmark Problems for Dynamic Modeling of Intracellular Processes
Authors: Hass Helge , Loos Carolin , Alvarez Elba Raimundez , Timmer Jens , Hasenauer Jan , Kreutz Clemens
Published: August 2018

Motivation

Dynamic models are used in systems biology to study and understand cellular processes like gene regulation or signal transduction. Frequently, ordinary differential equation (ODE) models are used to model the time and dose dependency of the abundances of molecular compounds as well as interactions and translocations. A multitude of computational approaches have been developed within recent years. However, many of these approaches lack proper testing in application settings because a comprehensive set of benchmark problems is yet missing.

Results

We present a collection of 20 ODE models developed given experimental data as benchmark problems in order to evaluate new and existing methodologies, e.g. for parameter estimation or uncertainty analysis. In addition to the equations of the dynamical system, the benchmark collection provides experimental measurements as well as observation functions and assumptions about measurement noise distributions and parameters. The presented benchmark models comprise problems of different size, complexity and numerical demands. Important characteristics of the models and methodological requirements are summarized, estimated parameters are provided, and some example studies were performed for illustrating the capabilities of the presented benchmark collection.

Availability

The models are provided in several standardized formats, including an easy-to-use human readable form and machine-readable SBML files. The data is provided as Excel sheets. All files are available athttps://github.com/Benchmarking-Initiative/Benchmark-Models, with MATLAB code to process and simulate the models.

Contact

jan.hasenauer@helmholtz-muenchen.de,ckreutz@fdm.uni-freiburg.de
Efficacy and safety of fosravuconazole L‐lysine ethanolate, a novel oral triazole antifungal agent, for the treatment of onychomycosis: A multicenter, double‐blind, randomized phase III study
Authors: Watanabe Shinichi , Tsubouchi Ichiro , Okubo Akihiro
Published: August 2018

Fosravuconazole L‐lysine ethanolate (F‐RVCZ) is a prodrug of ravuconazole, a novel triazole antifungal agent, exerting broad and potent antifungal activity. The efficacy and safety of F‐RVCZ, compared with a placebo, were investigated in a multicenter, double‐blind, randomized study of Japanese onychomycosis patients with 25% or more clinical involvement of the target toenail. Subjects (n = 153) were randomly assigned to receive F‐RVCZ (100 mg RVCZ, n = 101) or placebo (n = 52) p.o. once daily for 12 weeks. The primary end‐point was the rate of complete cure (clinical cure [0% clinical involvement of the target toenail] plus mycological cure [negative potassium hydroxide examination]) at week 48 (36‐week post‐treatment visit). Secondary end‐points were changes over time in the efficacy and mycological effect of F‐RVCZ. Safety was also evaluated. The complete cure rate at week 48 was significantly higher with F‐RVCZ (59.4%, 60/101) than the placebo (5.8%, 3/52) in the full analysis set (P < 0.001). The mycological cure rate at week 48 was also significantly higher with F‐RVCZ (82.0%, 73/89) than the placebo (20.0%, 10/50, P < 0.001). Regarding safety, adverse events were observed in 83.2% (84/101) and 80.8% (42/52), and adverse drug reactions (ADR) in 23.8% (24/101) and 3.8% (2/52) of F‐RVCZ and placebo subjects, respectively. ADR were mild to moderate in severity, with none being serious. F‐RVCZ (equivalent to 100 mg ravuconazole) administrated once daily for 12 weeks was more effective than placebo and tolerable in patients with onychomycosis, suggesting it to be a promising drug for onychomycosis treatment.
Open‐label pilot study to evaluate the effectiveness of topical bimatoprost on rhododendrol‐induced refractory leukoderma
Authors: Fukaya Saki , Kamata Masahiro , Kasanuki Tomoko , Yokobori Makoto , Takeoka Shintaro , Hayashi Kotaro , Tanaka Takamitsu , Fukuyasu Atsuko , Ishikawa Takeko , Ohnishi Takamitsu , Iimuro Satoshi , Tada Yayoi , Watanabe Shinichi
Published: August 2018

Rhododendrol (RD), 4‐(4‐hydroxyphenyl)‐2‐butanol, inhibits melanin synthesis and had been used in skin‐whitening cosmetic products until 2013. However, some individuals developed leukoderma on the skin where RD had been applied and have suffered from refractory depigmentation even after discontinuing RD application. Bimatoprost is a prostaglandin F2α analog and is often used for eyelash growth for cosmetic reasons as well as in the treatment of glaucoma. It was reported that bimatoprost induced skin pigmentation in addition to iris pigmentation as adverse effects. Therefore, we conducted an open‐label single‐center pilot study to evaluate the effectiveness of bimatoprost on refractory RD‐induced leukoderma. Eleven Japanese female patients with skin type III who developed leukoderma on the exact or slightly extended area of skin where RD had been applied and gained a halt of enlargement of leukoderma or repigmentation on a part of the affected skin after discontinuation of RD were enrolled. Bimatoprost 0.03% solution was applied on the leukoderma once daily for 3 months, and then the frequency of application was increased to twice daily for the subsequent 3 months. Ten patients completed the 6‐month course of bimatoprost application. In four patients, bimatoprost application brought slight improvement in RD‐induced refractory leukoderma by dermatologists’ evaluation. Because the number of enrolled patients was limited, further larger studies are necessary to better assess the effectiveness of bimatoprost in inducing repigmentation in patients with RD‐induced refractory leukoderma.
Phenazines in plant‐beneficial Pseudomonas spp.: biosynthesis, regulation, function and genomics
Authors: Biessy Adrien , Filion Martin
Published: August 2018

Plant‐beneficial phenazine‐producing Pseudomonas spp. are proficient biocontrol agents of soil‐dwelling plant pathogens. Phenazines are redox‐active molecules that display broad‐spectrum antibiotic activity toward many fungal, bacterial and oomycete plant pathogens. Phenazine compounds also play a role in the persistence and survival of Pseudomonas spp. in the rhizosphere. This mini‐review focuses on plant‐beneficial phenazine‐producing Pseudomonas spp. from the P. fluorescens species complex, which includes numerous well‐known phenazine‐producing strains of biocontrol interest. In this review the current knowledge on phenazine biosynthesis and regulation, the role played by phenazines in biocontrol and rhizosphere colonization, as well as exciting new advances in the genomics of plant‐beneficial phenazine‐producing Pseudomonas spp. will be discussed.
A Participatory Personality? Examining the Influence of Personality Traits on Political Participation
Authors: Lindell Marina , Strandberg Kim
Published: August 2018

The aim of this article is to examine whether core personality traits are associated with opinions on and engagement in political participation of either participatory or deliberative nature. The Finish National Election Survey 2015 is used to explore the link between the Big Five personality dimensions and a wide array of political opinions and behaviour. The results suggest that variations in personality to some extent affect what kind of activities one prefers and engages in. Personality traits seem to better predict actual engagement in participatory and deliberative activities rather than having favorable opinions about them. This suggests that there is a difference between being positive about an activity in principle and actually engaging in it. Extraversion and Openness are positively linked to engagement in both participatory and deliberative activities, while Agreeableness and Emotional stability are negatively related. There are stronger effects of personality traits in predicting opinions on and engagement in deliberative activities than for participatory activities. The traits associated with deliberation differ from traits associated with preferring more traditional forms of politics. Thus, the results clearly suggest that the impact of personality on participation should not be neglected.
Is Ethnic Diversity Bad for Any Dimension of Social Capital? Trust, Networks and Voluntarism in Norwegian Communities
Authors: Fladmoe Audun , Steen‐Johnsen Kari
Published: August 2018

Ethnic diversity has been posed as a threat to social capital, but results from existing research are inconclusive. This study takes as its starting point that different aspects of social capital may be influenced differently by ethnic diversity and uses one specific welfare state context – Norway – to explore such variations. Analysing an original dataset, nine different measures are used to explore three dimensions of social capital in 61 communities in Norway, amongst the majority population and residents with immigrant background. The results suggest, first, a differentiated impact of ethnic heterogeneity on trust. Ethnic diversity is negatively associated with spatially bounded forms of trust, but not with generalized trust. Second, a negative association with traditional forms of voluntarism is found – albeit this latter relationship is much weaker than the former. Third, the results suggest that these relationships are fairly similar across different (immigrant) groups. Although residents with immigrant background typically express lower levels of generalized trust than the majority population, the relative differences between residents living in diverse or homogeneous communities are limited. Given its strong institutions Norway could be seen as a least likely case for studying the impact of ethnic diversity on social capital. On the one hand, effects are more limited than what has been found in studies from the United States. On the other hand, the fact that effects are found on community trust and volunteering indicates that this type of societal model can indeed be affected by ethnic diversification.
Does memory contribute to reading comprehension in adults who struggle with reading?
Authors: Talwar Amani , Greenberg Daphne , Li Hongli
Published: August 2018

This study explored the relations between reading comprehension and two memory capacities, short‐term memory (STM) and working memory (WM), for adults who read between the third and eighth grade levels. With a sample of 407 adults from two countries, we computed correlations among measures and conducted hierarchical regression and commonality analyses for reading comprehension. Reading comprehension had moderate positive correlations with STM and WM. Additionally, STM and WM jointly accounted for approximately 19% of the reading comprehension variance and uniquely contributed approximately 4% and 7% of the variance, respectively. The predictive utility of memory to reading comprehension was greatly reduced after controlling for age, word reading, fluency and oral vocabulary. WM appears to be a slightly stronger predictor of reading comprehension than STM for struggling adult readers. However, the overall contributions of memory capacities to reading comprehension are much smaller than those of reading‐related skills.
Knowledge of Metropolitan Governance in the South
Authors: Tomlinson Richard , Harrison Philip
Published: August 2018

The practices of metropolitan governance in the South are normalized and legitimized through the workings of a ‘knowledge market’ that has evolved at an extraordinary juncture between geopolitical and technological transformations. This essay describes the packaging and management of knowledge since the early 1990s, a period which has seen increasing references to concepts such as ‘public–private partnerships’, ‘new public management’ (NPM), ‘metropolitan governance' and ‘best practice’. It explains the shift in terms of the coinciding dissolution of the Soviet Union in 1991, which removed the brakes on ‘neoliberal policy programmes’, and the practicability of using the web for knowledge management. Accompanying the ‘metropolitan renaissance’ since the early 1990s, NPM theory provided support for private sector‐style management of formerly public services and the claimed ‘global trend’ of decentralization of those services. The essay subsequently explains how, since the early 2000s, knowledge exchange relevant to metros in the South has also arisen from participation in transnational municipal networks (TMNs). Knowledge exchange has become more geographically complex, including learning across sites in the South. A policy discourse once dominated by global agencies and national governments now primarily takes the form of global agency knowledge transfer via the web and participation in TMNs.
Cloning and characterization of Methoprene‐tolerant (Met) and Krüppel homolog 1 (Kr‐h1) genes in the wheat blossom midge, Sitodiplosis mosellana
Authors: Cheng Wei‐Ning , Li Xue‐Jiao , Zhao Jia‐Jia , Zhu‐Salzman Keyan
Published: August 2018

Juvenile hormone (JH), a growth regulator, inhibits ecdysteroid‐induced metamorphosis and controls insect development and diapause. Methoprene‐tolerant (Met) and Krüppel homolog 1 (Kr‐h1) are two proteins involved in JH action. To gain some insight into their function in development of Sitodiplosis mosellana, an insect pest undergoing obligatory larval diapause at the mature 3rd instar stage, we cloned full‐length complementary DNAs of Met and Kr‐h1 from this species. SmMet encoded a putative protein, which contained three domains typical of the bHLH‐PAS family and eight conserved amino acid residues important for JH binding. SmKr‐h1 encoded a protein showing high sequence homology to its counterparts in other species, and contained all eight highly conserved Zn‐finger motifs for DNA‐binding. Expression patterns of SmMet and SmKr‐h1 were developmentally regulated and JH III responsive as well. Their mRNA abundance increased as larvae entered early 3rd instar, pre‐diapause and maintenance stages, and peaked during post‐diapause quiescence, a pattern correlated with JH titers in this species. Different from reduced expression of SmMet, SmKr‐h1 mRNA increased at mid‐to‐late period of post‐diapause development. Topical application of JH III on diapausing larvae also induced the two genes in a dose‐dependent manner. Expression of SmMet and SmKr‐h1 clearly declined in the pre‐pupal phase, and was significantly higher in female adults than male adults. These results suggest that JH‐responsive SmMet and SmKr‐h1 might play key roles in diapause induction and maintenance as well as in post‐diapause quiescence and adult reproduction, whereas metamorphosis from larvae to pupae might be correlated with their reduced expression.
Prospective application of an implementation framework to improve postoperative nutrition care processes: Evaluation of a mixed methods implementation study
Authors: Byrnes Angela , Young Adrienne , Mudge Alison , Banks Merrilyn , Clark David , Bauer Judy
Published: August 2018

Aim

To describe prospective application of an implementation framework to guide and evaluate a quality improvement (QI) project to improve adherence to evidence‐based postoperative diet guidelines (consistent with Enhanced Recovery After Surgery, ERAS) in older surgical patients.

Methods

A hybrid mixed methods study guided by the integrated Promoting Action on Research Implementation in Health Services (i‐PARIHS) framework was used. A pre‐implementation audit identified gaps in nutrition‐related care practices against ERAS guidelines for older surgical patients. Qualitative interviews explored barriers to practice change, informing development of the facilitated implementation strategy. Iterative facilitation interventions were identified by field notes and classified using i‐PARIHS facilitator's tool‐kit. Post‐implementation audit measured implementation outcomes, and clinical processes and outcomes using controlled before–after comparative study.

Results

Implementation involved 17 discrete facilitation activities. Early postoperative diet upgrade was acceptable, well adopted (79%) and appropriate for 89% of patients. Fidelity (i.e. protocol delivered as intended) was 59%, with loss of fidelity primarily because of incorrect diet codes. Clinical processes and outcome evaluation (n = 155) compared data pre‐implementation (intervention: n = 45, control: n = 27; mean age 73 (SD 6) years, 60% male) and post‐implementation (intervention: n = 47, control: n = 36; mean age 74 (SD 6) years, 57% male). Patients on the intervention ward had higher odds of receiving early nutrition post‐implementation (adjusted odds ratio [95% CI]: 6.5 [1.9–22.4], P = 0.01).

Conclusions

Prospective application of an implementation framework supported planning and successful implementation in this QI project. Multi‐level evaluation of facilitation strategies, implementation outcomes, and clinical processes and outcomes helps to understand areas of success and continuing challenges.
Sediment Fingerprinting to Delineate Sources of Sediment in the Agricultural and Forested Smith Creek Watershed, Virginia, USA
Authors: Gellis A.C. , Gorman Sanisaca L.
Published: August 2018

The sediment fingerprinting approach was used to apportion fine‐grained sediment to cropland, pasture, forests, and streambanks in the agricultural and forested Smith Creek, watershed, Virginia. Smith Creek is a showcase study area in the Chesapeake Bay watershed, where management actions to reduce nutrients and sediment are being monitored. Analyses of suspended sediment at the downstream and upstream sampling sites indicated streambanks were the major source of sediment (76% downstream and 70% upstream). Current management strategies proposed to reduce sediment loadings for Smith Creek do not target streambanks as a source of sediment, whereas the results of this study indicate that management strategies to reduce sediment loads in Smith Creek may be effective if directed toward managing streambank erosion. The results of this study also highlight the utility of sediment fingerprinting as a management tool to identify sediment sources.
Accuracy, limitations and cost efficiency of eDNA‐based community survey in tropical frogs
Authors: Bálint Miklós , Nowak Carsten , Márton Orsolya , Pauls Steffen U. , Wittwer Claudia , Aramayo José Luis , Schulze Arne , Chambert Thierry , Cocchiararo Berardino , Jansen Martin
Published: August 2018

Rapid environmental change in highly biodiverse tropical regions demands efficient biomonitoring programmes. While existing metrics of species diversity and community composition rely on encounter‐based survey data, eDNA recently emerged as alternative approach. Costs and ecological value of eDNA‐based methods have rarely been evaluated in tropical regions, where high species richness is accompanied by high functional diversity (e.g., the use of different microhabitats by different species and life stages). We first tested whether estimation of tropical frogs' community structure derived from eDNA data is compatible with expert field assessments. Next, we evaluated whether eDNA is a financially viable solution for biodiversity monitoring in tropical regions. We applied eDNA metabarcoding to investigate frog species occurrence in five ponds in the Chiquitano dry forest region in Bolivia and compared our data with a simultaneous visual and audio encounter survey (VAES). We found that taxon lists and community structure generated with eDNA and VAES correspond closely, and most deviations are attributable to different species' life histories. Cost efficiency of eDNA surveys was mostly influenced by the richness of local fauna and the number of surveyed sites: VAES may be less costly in low‐diversity regions, but eDNA quickly becomes more cost‐efficient in high‐diversity regions with many sites sampled. The results highlight that eDNA is suitable for large‐scale biodiversity surveys in high‐diversity areas if life history is considered, and certain precautions in sampling, genetic analyses and data interpretation are taken. We anticipate that spatially extensive, standardized eDNA biodiversity surveys will quickly emerge in the future.
Re‐examining RAMRY/94‐az‐Zālif 1 no. 1: probable finding of a previously unknown name for a temple of S1yn amid a plurality of scribal errors
Authors: Weimar Jason Everett
Published: August 2018

RAMRY/94‐az‐Zālif 1 no. 1 (first century BCE to second century CE) is a Hadramitic inscription from ancient az‐Zālif that has eluded a full interpretation because of scribal errors and lacunae. I survey and critique Frantsouzoff’s and the Digital Archive for the Study of pre‐Islamic Arabian Inscriptions’ previous treatments of the text. After proposing an emendation of an incompletely engraved letter and noting the presence of construction text formulary phrases, I reconstruct the lacunae and suggest that the inscription records the erection of a sanctuary for S1yn Bql, a previously unknown epithet for the god S1yn. This new reading will show that the text contains more errors than previously known and implies that Bql is the hitherto unknown name of the temple in which the inscription was found.
Distinctions in Alcohol‐Induced Memory Impairment: A Mixed Methods Study of En Bloc Versus Fragmentary Blackouts
Authors: Miller Mary Beth , Merrill Jennifer E. , DiBello Angelo M. , Carey Kate B.
Published: August 2018

Background

Blackouts—or memory loss for all or part of a drinking event—are reliable predictors of alcohol‐related consequences. Studies suggest a distinction between en bloc (complete memory loss) and fragmentary (off‐and‐on memory loss) blackouts; however, research has not consistently differentiated between these 2 forms of blackout. This study aimed to validate the distinction between en bloc and fragmentary blackouts among young adults.

Methods

Data were collected using qualitative (Study 1) and quantitative (Study 2) research methods. Participants in both studies were college students with a history of alcohol‐induced memory impairment. They were recruited using community advertisement (Study 1, N = 50, 56% female) and Qualtrics survey panels (Study 2, N = 350, 56% female). Study 1 participants engaged in 8 focus groups. Discussions were audio‐recorded, transcribed verbatim, and coded using applied thematic analysis. Findings guided assessment of en bloc and fragmentary blackout in Study 2. In Study 2, a separate sample of participants completed an online survey assessing drinking behavior, alcohol‐induced memory impairment, and theoretical correlates of en bloc and fragmentary blackouts.

Results

Study 1 participants differentiated between en bloc and fragmentary blackouts (which they referred to as “blackouts” and “brownouts,” respectively) based on duration and extent of memory loss. They indicated that blackouts occur along a continuum, with en bloc “blackouts” at the extreme. They also stated that the term “blackout drinking” does not always imply memory loss. Study 2 participants reported higher rates of “brownouts” (81%) than “blackouts” (54%). They reported less negative outcome expectancies and attitudes, greater personal approval, higher prevalence estimates, lower self‐efficacy, and stronger intentions for “brownouts” than “blackouts” (p < 0.001). Women perceived “blackouts/brownouts” as more prevalent than men and reported lower intentions to experience “blackouts” (p < 0.005).

Conclusions

Young adults are more permissive of fragmentary than en bloc blackout. En bloc blackouts may be a target for future interventions.
Deletion at 12q12 increases the risk of developmental delay and intellectual disability
Authors: Weng Ying , Luo Xiaoping , Hou Ling
Published: August 2018

Single‐nucleotide polymorphism (SNP) arrays have been widely used to identify novel genomic imbalances. Many of these genomic imbalances have been confirmed to interact with developmental delays, intellectual disabilities (IDs), and congenital defects. Here, we identify a Chinese girl with a 3.18‐Mb deletion at 12q12 (human genome build 19: 43,418,911‐46,601,627) who showed postnatal growth delay, low‐set ears, small hands and feet, widely spaced nipples, and blue sclerae. Deletions at 12q12 are extremely rare chromosomal imbalances; only four cases involving a deletion of this type have previously been reported. In these five sporadic cases, all of the patients exhibited developmental issues accompanied by different degrees of ID. A review of DECIPHER patient data revealed an additional six cases involving genomic deletion at 12q12. Many of the patients in these cases exhibited developmental delay and ID. When these patients were included, 91% and 73% of individuals with a deletion in this chromosomal region presented with developmental retardation and ID, respectively. Database searches indicated that this copy number variant (CNV) has not been found in normal humans. Therefore, we suggest that a CNV in this region is a risk factor for developmental retardation and ID.
Does a Comprehensive Inpatient Rehabilitation Program Improve Patients’ and Caregivers’ Emotional State in LVAD Patients?
Authors: Rossi Ferrario Silvia , Bacich Daniela , Beltrame Laura , Balestroni Gianluigi , Pistono Massimo
Published: August 2018

Few studies evaluated the effect of cardiac rehabilitation programs on perceived emotional and health status of left ventricular assist device (LVAD) patients, and none explored their effect on caregivers’ strain. We enrolled 119 adult LVAD patients, together with their caregivers (n = 91), in two Rehabilitation Institutes that provided inpatient multidisciplinary activities. At admittance and prior to discharge they completed questionnaires evaluating patient emotional state and subjective perception of health status, caregiver strain, and patient and caregiver perception of the VAD. Six months after discharge, patients and caregivers were contacted again and asked specific questions about their quality of life. Patients’ state anxiety and depression symptoms significantly diminished at discharge (0.000), whereas their perception of general health status rose (0.000). Caregivers’ perceived strain also significantly decreased (0.001) and the perceived device management skill grew both for patients and caregivers (0.000). A substantial amount (36%) of psychologically frail patients and caregivers, although improving their emotional condition, never reached that of the less frail subjects. At the 6‐month follow‐up, both patients and caregivers appeared stable in evaluating respectively their general health and their caregiving‐related strain, compared to discharge. Our data show that a comprehensive inpatient rehabilitation program improves the emotional state of LVAD patients and of their caregivers, even in psychologically frailer subjects. Team approach makes patients and caregivers self‐confident about device management, increasing their knowledge, clarifying their doubts, and encouraging them to handle the difficulties met during the rehabilitation period, suggesting strategies to cope with daily life at home.
Longitudinal bleb morphology in anterior segment OCT after minimally invasive transscleral ab interno Glaucoma Gel Microstent implantation
Authors: Lenzhofer Markus , Strohmaier Clemens , Hohensinn Melchior , Hitzl Wolfgang , Sperl Philipp , Gerner Matthias , Steiner Veit , Moussa Sarah , Krall Eva , Reitsamer Herbert A.
Published: August 2018

Purpose

Like the classic trabeculectomy, the minimally invasive, ab interno XEN Glaucoma Gel Microstent (XEN‐GGM) creates a filtration bleb in the conjunctiva. The goal of this study was to investigate internal bleb morphology over time with anterior segment optical coherence tomography (AS‐OCT) after XEN‐GGM implantation.

Methods

In a prospective, single‐centre, single‐armed cohort study, blebs were characterized using AS‐OCT in 78 eyes of 60 patients at day 1, at weeks 1 and 2 and at months 1, 3, 6, 9 and 12 after XEN‐GGM implantation in patients with open‐angle glaucoma. Morphological bleb characteristics were correlated with IOP and surgical success.

Results

Anterior segment optical coherence tomography data indicate early and late bleb changes in the course of 12 months. Uniform blebs in AS‐OCTs showed higher IOPs at all examinations between week 1 (17.7 ± 4.8 mmHg versus 11.3 ± 7.1 mmHg, p = 0.001) and month 3 (16.4 ± 6.1 versus 13.4 ± 6.1, p = 0.04). Subconjunctival tissue separation bleb morphology was associated with lower mean IOPs during the course of 12 months (r = −0.75, p = 0.031). Predictors for surgical failure at month 12 were microcystic multiform bleb morphology in AS‐OCT at month 3 (60% versus 15%, relative risk 4.0, p = 0.043) and uniform bleb morphology at month 9 (33% versus 23%, relative risk 1.4, p = 0.015).

Conclusion

Bleb appearance after XEN surgery seems to be different to classic trabeculectomy literature. The present data suggest correlation of IOP and surgical long‐term success with bleb morphology in AS‐OCT. Prevalence of small diffuse cysts is directly associated with lower IOPs, while cystic encapsulation at 3 months predicts higher surgical failure.
Transient receptor potential vanilloid‐4 channels are involved in diminished myogenic tone in brain parenchymal arterioles in response to chronic hypoperfusion in mice
Authors: Chan Siu‐Lung , Nelson Mark T. , Cipolla Marilyn J.
Published: August 2018

Aim

Adaptive responses of brain parenchymal arterioles (PAs), a target for cerebral small vessel disease, to chronic cerebral hypoperfusion are largely unknown. Previous evidence suggested that transient receptor potential vanilloid 4 channels may be involved in the regulation of cerebrovascular tone. Therefore, we investigated the role of TRPV4 in adaptations of PAs in a mouse model of chronic hypoperfusion.

Methods

TRPV4 knockout (−/−) and wild‐type (WT) mice were subjected to unilateral common carotid artery occlusion (UCCAo) for 28 days. Function and structure of PAs ipsilateral to UCCAo were studied isolated and pressurized in an arteriograph.

Results

Basal tone of PAs was similar between WT and TRPV4−/− mice (22 ± 3 vs 23 ± 5%). After UCCAo, active inner diameters of PAs from WT mice were larger than control (41 ± 2 vs 26 ± 5 μm, P < 0.05) that was due to decreased tone (8 ± 2 vs 23 ± 5%, P < 0.05), increased passive inner diameters (46 ± 3 vs 34 ± 2 μm, P < 0.05), and decreased wall‐to‐lumen ratio (0.104 ± 0.01 vs 0.137 ± 0.01, P < 0.05). However, UCCAo did not affect vasodilation to a small‐ and intermediate‐conductance calcium‐activated potassium channel agonist NS309, the nitric oxide (NO) donor sodium nitroprusside, or constriction to a NO synthase inhibitor L‐NNA. Wall thickness and distensibility in PAs from WT mice were unaffected. In TRPV4−/− mice, UCCAo had no effect on active inner diameters or tone and only increased passive inner diameters (53 ± 2 vs 43 ± 3 μm, P < 0.05).

Conclusion

Adaptive response of PAs to chronic cerebral hypoperfusion includes myogenic tone reduction and outward remodelling. TRPV4 channels were involved in tone reduction but not outward remodelling in response to UCCAo.
Stability of oestrogen and progesterone receptor antigenicity in formalin‐fixed paraffin‐embedded breast cancer tissue over time
Authors: Ehinger Anna , Bendahl Pär‐ola , Rydén Lisa , Fernö Mårten , Alkner Sara
Published: August 2018

Use of archived formalin‐fixed paraffin‐embedded (FFPE) tissue is a standard method for evaluation of proposed prognostic and predictive tumour markers. However, little is known of the preservation of biomarker expression in old FFPE tumour blocks. We investigate the quality of immunohistochemical (IHC) oestrogen (ER) and progesterone receptor (PR) evaluation in FFPE tissue over time (1978–2000) using a large breast cancer tissue microarray (N = 573) with access to receptor analyses in cytosol (CYT) at diagnosis, coexpression of other biomarkers and follow‐up data. We found a good correlation between ER analysed with CYT at diagnosis and ER analysed with IHC in archived FFPE tissue from the same tumour. ER evaluation did not seem to be affected by tissue storage time. Nor was there any time‐dependent difference in ERIHC correlation with other biomarkers (HER2, Ki67) or survival. Discordant cases were more often classified as ER‐positive with IHC than with CYT. For PR, however, we found an increased correlation between methods in more recent time periods. This may possibly be explained by more reliable PRIHC results in newer samples, although other explanations may also contribute. Our results indicate stable ER expression in FFPE tissue archived for up to 40 years.
Vascular adhesion protein‐1 as indicator of breast cancer tumor aggressiveness and invasiveness
Authors: Lai Yen‐Chang Clark , Chang Shu‐Jyuan , Kostoro Joanna , Kwan Aij‐Lie , Chai Chee‐Yin
Published: August 2018

Recent studies suggest that vascular adhesion protein‐1 (VAP‐1), a 180‐KDa homodimeric glycoprotein, may be associated with cancer‐related events including tumor cell migration, motility, invasion, or metastasis. Therefore, this study applies VAP‐1 immunohistochemical staining to demonstrate the invasiveness component of the breast cancer. The VAP‐1 staining results were compared in 148 breast cancer cases to identify possible correlations with clinical status, including age, tumor size, tumor grade, TNM stage, lymphatic invasion, metastasis, recurrence, and survival rate. Immunohistochemical staining results showed VAP‐1 negative or weak staining in normal ducts and ductal carcinoma in situ (DCIS), but these phenotypes were positively associated with a stiffened VAP‐1 that presented at the invasive front of the lesion. Our data demonstrated that VAP‐1 expression was positively associated with lymphatic invasion, distant metastasis, and patient survival in breast carcinoma. Notably, VAP‐1 expression was found to be significantly correlated with the overall survival (p < 0.0001). Multivariate Cox analysis indicated that VAP‐1 expression was a significant independent prognostic indicator of overall survival in breast carcinoma (p < 0.0001). In conclusion, this study suggests that VAP‐1 is linked to progression of tumor invasion and metastasis in breast carcinoma. VAP‐1 is shown to be a biomarker that can be predict invasive potential and clinical outcome in breast cancer.
Soft tissue sarcoma in a short‐beaked echidna (Tachyglossus aculeatus)
Authors: Robey RL , Sangster C , Gabor M , Lindsay SA
Published: August 2018

Case report

An adult male short‐beaked echidna in poor body condition was found with a 25 × 12 mm round, ulcerated and bleeding mass on the left side of the face at the base of the beak. The animal responded well to initial supportive care and was referred to a specialist wildlife centre for further assessment and treatment. Clinical pathology showed moderate neutrophilia, mild anaemia, mild elevation in liver enzymes (ALT, AST and ALP) and mild azotaemia. Initial clinical differential diagnoses for the facial mass favoured an inflammatory rather than a neoplastic lesion, based on previous reports. Examination of an incisional biopsy identified a malignant spindle cell proliferation (sarcoma) not amenable to complete surgical excision. The animal was euthanased on humane grounds. Immunohistochemical assessment of the mass showed it to be negative for cytokeratin, desmin, smooth muscle actin, periaxin and MAC387 antibody labelling. Definitive histogenesis was undetermined and a final diagnosis of poorly differentiated sarcoma, unlikely to be of muscle, Schwann cell or histiocytic origin, was made.

Conclusion

Reports of neoplasia in prototherian mammals (monotremes) are rare. To the authors’ knowledge this is the first report of such a tumour in a monotreme species and the first immunohistochemical characterisation of a stromal tumour in these animals. The malignant nature of this tumour contrasts with a previous report of benign neoplasia (fibroma) associated with the beak. Although rare, malignant neoplasia should be included in the differential diagnoses of mass lesions in monotremes, despite inflammatory or traumatic mass lesions being more commonly reported.
Automated identification of intensive animal production locations from aerial photography
Authors: Sheffield KJ , Hunnam JC , Cuzner TN , Morse‐McNabb EM , Sloan SM , Nunan J , Smith J , Harvey W , Lewis H
Published: August 2018

Objective

Successful control of an emergency animal disease outbreak requires the timely and accurate identification of properties of interest. The identification of commercial piggeries within study areas in the Goulburn–Murray Irrigation District in Victoria, Australia, is used to demonstrate the innovative application of object‐based image analysis (OBIA) techniques for the identification of intensive animal production land uses, to improve the accuracy of existing datasets.

Methods

Characteristics of infrastructure and landscape features were combined to form a commercial piggery identification algorithm. These criteria were applied to recent aerial photography that had been classified using OBIA techniques. The results were then compared with three datasets containing known commercial piggery locations and visually checked by roadside surveys.

Results

The OBIA technique identified 21 potential piggery locations across three study areas, 14 of which were identified in existing databases. Of the 7 additional sites, 4 were dairy properties, 1 was a cropping and sheep property and 2 were previously undocumented piggery locations.

Conclusions

The OBIA approach has potential of OBIA for identifying the locations of commercial piggeries. Further development and testing will determine how generic this approach is in terms of industry type and operation size. The method described is cost‐effective, automated and repeatable, and could be used to regularly update existing databases by analysing newly acquired aerial imagery to identify possible land use changes. This would improve the reliability of currently available data and increase the effectiveness of a biosecurity response during an emergency animal disease outbreak.
Anti‐IL‐7 receptor α monoclonal antibody (GSK2618960) in healthy subjects – a randomized, double‐blind, placebo‐controlled study
Authors: Ellis Joanne , van Maurik Andre , Fortunato Lea , Gisbert Sophie , Chen Keguan , Schwartz Ann , McHugh Simon , Want Andrew , Santos Franco Sara , Oliveira Joao‐Joaquim , Price Jeffrey , Coles Alasdair , Brown Kim , Su Donggang , Craigen Jenny L. , Yang Jiansong , Brett Sara , Davis Bill , Cheriyan Joseph , Kousin‐Ezewu Onajite , Gray Frank , Thompson Paul W. , Fernando Disala
Published: August 2018

Aim

Interleukin (IL)‐7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL‐7 receptor‐α subunit (CD127) monoclonal antibody.

Methods

A double‐blind (sponsor‐unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg–1 or 2.0 mg kg–1) or placebo was carried out in 18 healthy subjects over 24 weeks.

Results

GSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half‐life was 5 (±1) days (2.0 mg kg–1), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg–1) and day 22 (2.0 mg kg–1). Maximal inhibition of IL‐7‐mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg–1). Mean circulating IL‐7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg–1) and days 2 and 22 (2.0 mg kg–1). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL‐6, tumour necrosis factor‐α, interferon‐γ, IL‐2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg–1 (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg–1 (neutralizing in 5/6).

Conclusion

GSK2618960 was well tolerated and blocked IL‐7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half‐life is likely the result of target‐mediated rather than ADA‐mediated clearance.
Lysophosphatidic acid acts on LPA1receptor to increase H2O2during flow‐induced dilation in human adipose arterioles
Authors: Chabowski Dawid S , Kadlec Andrew O , Ait‐Aissa Karima , Hockenberry Joseph C , Pearson Paul J , Beyer Andreas M , Gutterman David D
Published: August 2018

Background and Purpose

NO produces arteriolar flow‐induced dilation (FID) in healthy subjects but is replaced by mitochondria‐derived hydrogen peroxide (mtH2O2) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH2O2in human visceral and subcutaneous adipose arterioles.

Experimental Approach

Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L‐NAME) or H2O2scavenging (Peg‐Cat) ± LPA (10 μM, 30 min), ±LPA1/LPA3receptor antagonist (Ki16425) or LPA2receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells.

Key Results

FID was inhibited by L‐NAME but not Peg‐Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg‐Cat while L‐NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA1and LPA2but not LPA3receptors were detected in arterioles. LPA1but not LPA3receptor protein was detected by Western blot. Pretreatment of vessels with an LPA1/LPA3, but not LPA2, receptor antagonist prior to LPA preserved NO‐mediated dilation.

Conclusions and Implications

These findings suggest an LPA1receptor‐dependent pathway by which LPA increases arteriolar release of mtH2O2as a mediator of FMD.
Knowledge‐intensive entrepreneurship in manufacturing and creative industries: Same, same, but different
Authors: Heidemann Lassen Astrid , McKelvey Maureen , Ljungberg Daniel
Published: August 2018

To date, there is little empirical evidence on the specificities and commonalities of entrepreneurship in the creative industries relative to other sectors. This paper explores this issue by comparing knowledge‐intensive entrepreneurship (KIE) in the manufacturing and creative industries by examining their differences and similarities. Given the lack of prior studies, our comparison is exploratory and based on descriptive statistics. We use survey data that comes from a large‐scale Eurupean Union research project (AEGIS) which studied KIE firms across 10 countries and a diverse set of industries. Our analysis shows that KIE firms in creative industries resemble those in manufacturing in several dimensions, but also that there are some pronounced differences, such as (i) a higher level of knowledge intensity of KIE firms in creative industries, with higher educational attainment of both founders and employees; (ii) that personal financing plays a much larger role in creative industries; (iii) KIE in creative industries focuses more on service innovations, but introduces radical innovations to a lesser extent; and (iv) they remain smaller in terms of number of employees and turnover, but are more profitable than KIE in manufacturing relative to their size. We end the paper by pointing out directions for future research, based on our exploratory results.