bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide uniformity of human ‘open’ pre-initiation complexes
Authors: Lai William K.M. , Pugh B. Franklin
Published: November 2016

Transcription of protein-coding and noncoding DNA occurs pervasively throughout the mammalian genome. Their sites of initiation are generally inferred from transcript 5′ ends and are thought to be either locally dispersed or focused. How these two modes of initiation relate is unclear. Here, we apply permanganate treatment and chromatin immunoprecipitation (PIP-seq) of initiation factors to identify the precise location of melted DNA separately associated with the preinitiation complex (PIC) and the adjacent paused complex (PC). This approach revealed the two known modes of transcription initiation. However, in contrast to prevailing views, they co-occurred within the same promoter region: initiation originating from a focused PIC, and broad nucleosome-linked initiation. PIP-seq allowed transcriptional orientation of Pol II to be determined, which may be useful near promoters where sufficient sense/anti-sense transcript mapping information is lacking. PIP-seq detected divergently oriented Pol II at both coding and noncoding promoters, as well as at enhancers. Their occupancy levels were not necessarily coupled in the two orientations. DNA sequence and shape analysis of initiation complex sites suggest that both sequence and shape contribute to specificity, but in a context-restricted manner. That is, initiation sites have the locally “best” initiator (INR) sequence and/or shape. These findings reveal a common core to pervasive Pol II initiation throughout the human genome.
Sexual selection can both increase and decrease extinction probability: reconciling demographic and evolutionary factors
Authors: Martínez‐Ruiz Carlos , Knell Robert J.
Published: November 2016

Previous theoretical models of the effect of sexual selection on average individual fitness in a population have mostly predicted that sexually selected populations should adapt faster and clear deleterious mutations more quickly than populations where sexual selection is not operating.

While some laboratory studies have supported these predictions, others have not and studies of field systems have tended to find negative effects of sexual selection, or no effect. The negative effects of sexual selection found in field and other studies are usually ascribed to the costs associated with strong sexual selection acting on the population.

Here, using an individual‐based model that allows feedback between demographic and evolutionary processes, we find that sexual selection can lead to both increases and decreases in population‐level fitness measures such as extinction probability and adaptation rate. Whether fitness increases or decreases depends on a variety of environmental and demographic factors including the nature of environmental change, the carrying capacity of the environment, the average fecundity of the population in question and the strength of condition dependence.

In many cases, our model predicts that sexual selection leads to higher extinction probability in small populations because of an increased risk of demographic stochasticity, but lower extinction probability in larger populations because of faster adaptation rates. This is consistent with field studies that have mostly focussed on very small populations such as recently introduced birds, and tend to find negative effects, and also with laboratory studies that tend to use larger populations and have tended to find positive effects.

These findings go at least some way towards an understanding of the apparent contradictions between theoretical predictions, laboratory studies and field data.
Technologies of Translocality: Vegetables, Meat and Dresses in Arab Muslim Detroit
Authors: Kinder Kimberley
Published: November 2016

The diversification of US suburbs in terms of race, ethnicity and immigration has created invaluable opportunities for scholars to study technologies of translocality‐in‐the‐making. Translocal landscapes are described as spaces of ‘here' studded with ‘parts of elsewhere' (Allen and Cochrane, )—but which pieces of the landscape count as meaningfully ‘of elsewhere', how do those parts get there, and what range of meanings can they signify? This article is based on qualitative, in‐depth interviews and explores these questions in the context of an Arab Muslim ethnic enclave and retail district in an inner‐ring suburb of Detroit. The findings indicate that ‘parts of elsewhere' are more internally pluralized, multifunctional, multidirectional and aesthetically diverse than commonly recognized. The implications of these findings challenge scholars to develop more robust frameworks to explain how translocal geographies are produced, why they matter, and how they can be recognized.
Organizational Factors Affect Safety‐Net Hospitals’ Breast Cancer Treatment Rates
Authors: Bickell Nina A. , Moss Alexandra DeNardis , Castaldi Maria , Shah Ajay , Sickles Alan , Pappas Peter , Lewis Theophilus , Kemeny Margaret , Arora Shalini , Schleicher Lori , Fei Kezhen , Franco Rebeca , McAlearney Ann Scheck
Published: November 2016

Objective

To identify key organizational approaches associated with underuse of breast cancer care.

Setting

Nine New York City area safety‐net hospitals.

Study Design

Mixed qualitative–quantitative, cross‐sectional cohort.

Methods

We used qualitative comparative analysis (QCA) of key stakeholder interviews, defined organizational “conditions,” calibrated conditions, and identified solution pathways. We defined underuse as no radiation after lumpectomy in women <75 years or mastectomy in women with ≥4 positive nodes, or no systemic therapy in women with tumors ≥1 cm. We used hierarchical models to assess organizational and patient factors’ impact on underuse.

Principal Findings

Underuse varied by hospital (8–29 percent). QCA found lower underuse sites designated individuals to track and follow‐up no‐shows; shared clinical information during handoffs; had fully integrated electronic medical records enabling transfer of responsibility across specialties; had strong system support; allocated resources to cancer clinics; had a patient‐centered culture paying close organizational attention to clinic patients. High underuse sites lacked these characteristics. Multivariate modeling found that hospitals with strong approaches to follow‐up had low underuse rates (RR = 0.28; 0.08–0.95); individual patient characteristics were not significant.

Conclusions

At safety‐net hospitals, underuse of needed cancer therapies is associated with organizational approaches to track and follow‐up treatment. Findings provide varying approaches to safety nets to improve cancer care delivery.
Sibship Analysis Based on Parental Genotype Reconstruction from Any Number of Reference Siblings
Authors: Huang Jian , Huang YuSong
Published: November 2016

Previous analyses of alleged siblings have calculated the conditional probability of a test sibling's genotype given a reference sibling's genotype; however, more genetic information is available when two or more reference siblings are tested. Based on the root concept of identity by descent (IBD), we present a sibship method of parental genotype reconstruction (PGR) that can use any number of reference sibs. Nine PGR patterns, along with their respective IBD proportions of full‐sibs and half‐sibs, were identified and used to calculate joint sibship probabilities and likelihood ratio formulas. In addition, a correction PGR was developed for situations involving the same genotype repeating in the reference sibs. The method is simple and can be applied to any number of alleged full or half‐siblings.
Computational Study of Fracture Characteristics in Infant Skulls Using a Simplified Finite Element Model
Authors: Jiang Binhui , Zhu Feng , Cao Libo , Presley Barbara R. , Shen Ming , Yang King H.
Published: November 2016

Skull fracture characteristics are associated with loading conditions (such as the impact point and impact velocity) and could provide indication of abuse or accident‐induced head injuries. However, correlations between fracture characteristics and loading conditions in infant and toddler are ill‐understood. A simplified computational model representing an infant head was built to simulate skull responses to blunt impacts. The fractures were decided through a first principal strain‐based element elimination strategy. Simulation results were qualitatively compared with test data from porcine heads. This simplified model well captured the fracture pattern, initial fracture position, and direction of fracture propagation. The model also very well described fracture characteristics found in studies with human infant cadaveric specimens. A series of parametric studies was conducted, and results indicated that the parameters studied had substantial effects on fracture patterns. Additionally, the jagged shapes of sutures were associated with strain concentrations in the skull.
Characterization of hangover following intravenous alcohol exposure in social drinkers: methodological and clinical implications
Authors: Vatsalya Vatsalya , Stangl Bethany L. , Schmidt Veronica Y. , Ramchandani Vijay A.
Published: November 2016

Hangover refers to the cluster of physiological and behavioral symptoms that occur following the end of a drinking episode. While hangover has been studied after the typical oral consumption of alcohol, the occurrence of hangover following intravenous (IV) alcohol administration in human laboratory studies has not been previously reported. This study characterizes hangover symptoms and post‐infusion drinking behavior following acute IV alcohol administration in social drinkers. Twenty‐one to thirty‐year‐old healthy social drinkers (n = 24) underwent an alcohol clamp session at breath alcohol concentration of 0.06 percent. Hangover symptoms as well as any post‐infusion drinking that occurred between the end of the session and the following morning were assessed using the Acute Hangover Scale, and examined for influences of recent drinking history, family history of alcoholism and Sex. Results indicated a 79 percent prevalence of hangover symptoms, with the most common symptoms being ‘tired’, ‘thirsty’ and ‘headache’. Recent drinking measures showed significant effects on Average Hangover Scale scores, with heavier drinkers showing greater hangover symptoms. There was a significant sex difference in average hangover scores, with females reporting higher scores than males. Subjective measures of stimulation and intoxication were also associated with Average Hangover Scale scores. The probability of post‐infusion drinking was not predicted by hangover scores, but was related to recent drinking history; subjective response to alcohol was a significant mediator of this relationship. These findings demonstrate that hangover symptoms are experienced following IV alcohol administration, and extend previous studies of influences of risk factors for alcohol use disorders including recent drinking on hangover.
PPARγ agonism attenuates cocaine cue reactivity
Authors: Miller William R , Fox Robert G , Stutz Sonja J , Lane Scott D , Denner Larry , Cunningham Kathryn A , Dineley Kelly T
Published: November 2016

Cocaine use disorder is a chronic relapsing condition characterized by compulsive drug seeking and taking even after prolonged abstinence periods. Subsequent exposure to drug‐associated cues can promote intense craving and lead to relapse in abstinent humans and rodent models. The responsiveness to these cocaine‐related cues, or ‘cue reactivity’, can trigger relapse and cocaine‐seeking behaviors; cue reactivity is measurable in cocaine‐dependent humans as well as rodent models. Cue reactivity is thought to be predictive of cocaine craving and relapse. Here we report that PPARγ agonism during abstinence from cocaine self‐administration reduced previously active lever pressing in Sprague Dawley rats during cue‐reactivity tests, while administration of the PPARγ antagonist, GW9662, reversed this effect. PPARγ agonism also normalized nuclear ERK activity in the medial prefrontal cortex and hippocampus which was reversed with GW9662. Our results support the utility of PPARγ agonism as a relapse prevention strategy to maintain abstinence in the presence of cocaine‐associated cues.
Mixed‐amphetamine salts increase abstinence from marijuana in patients with co‐occurring attention‐deficit/hyperactivity disorder and cocaine dependence
Authors: Notzon Daniel P. , Mariani John J. , Pavlicova Martina , Glass Andrew , Mahony Amy L. , Brooks Daniel J. , Grabowski John , Levin Frances R.
Published: November 2016

Background and Objectives

The prevalence of ADHD is greater in substance use disorders than the general population, and ADHD and substance use disorders share neurobiological features such as dysregulation of reward circuitry. We tested the hypothesis that stimulants would decrease marijuana use in a randomized controlled trial of extended release mixed amphetamine salts (MAS‐XR) for treatment of co‐occurring ADHD and cocaine use disorders.

Methods

Marijuana users were defined as participants reporting use in the 30 days before study initiation, collected with timeline follow‐back. The original 14‐week trial utilized a 3‐arm randomized design, comparing placebo, MAS‐XR 60 mg, and MAS‐XR 80 mg. For this analysis, both MAS‐XR groups were combined, leaving n = 20 in the placebo group and n = 37 in the MAS‐XR group. The primary outcome was proportion of subjects reporting any marijuana use per study week. Comparisons between groups were made using a logistic mixed effects model incorporating multiple predictors and modeling time‐by‐treatment interactions.

Results

There were no significant baseline differences in marijuana use frequency and quantity. There was a significant decrease in the proportion of participants using marijuana over time in the MAS‐XR group, but no difference in the proportion of marijuana‐use days over time.

Discussion and Conclusions

Treatment of ADHD and comorbid cocaine use disorders with MAS‐XR is associated with increased weekly abstinence from marijuana but not with a decrease in the proportion of marijuana using days per week.

Scientific Significance

Stimulant treatment of ADHD and cocaine use disorders may diminish co‐occurring cannabis use. (Am J Addict 2016;25:666–672)
Development of Australia's first older adult‐specific early intervention for alcohol‐related harm: Feasibility and proof of concept
Authors: Bright Stephen J , Williams Cylie M
Published: November 2016

Objectives

The rate of older Australians at risk of experiencing alcohol‐related harm increased by 31% over the past 10 years, yet there are no Australian age‐specific early interventions. We describe the development of Australia's first age‐specific early intervention protocol.

Methods

Through examining effective overseas older adult‐specific interventions, in addition to other relevant literature, an early intervention protocol was developed.

Results

The Older Wiser Lifestyles (OWL) early intervention protocol extends protocols that have been developed overseas through providing: (i) interventions that are tailored to the person's readiness to change, including the provision of harm reduction strategies for people who are precontemplative; and (ii) individualised psychoeducational materials regarding medical conditions and medications.

Conclusion

The OWL protocol has been successfully implemented in a service, and preliminary data warrant a clinical trial of the intervention. Australian health‐care providers should consider the OWL protocol as a simple method to reduce the risk from alcohol consumption among older adults.
Systemic treatment in advanced biliary cancers: A multicenter Australian analysis and review
Authors: Brungs Daniel , Aghmesheh Morteza , Sjoquist Katrin , Goldstein David
Published: November 2016

Aim

While first‐line palliative chemotherapy (CT1) improves survival and quality of life in advanced biliary cancer (ABC), there is no randomized evidence to support second‐line chemotherapy (CT2) in ABC. We aim to explore to role of CT2 in ABC.

Methods

We performed a retrospective review of all patients who received one or more lines of chemotherapy for ABC at four Australian cancer centers between 2008 and 2011. A Cox proportional hazard model was developed to determine the impact of clinicopathologic variables on overall survival (OS) from time of progression on CT1.

Results

We identified 73 patients who received palliative chemotherapy for ABC. Twenty‐five patients (34%) received two or more lines of chemotherapy. Patients with a preserved performance status on progression on first‐line chemotherapy (CT1) were more likely to receive second‐line chemotherapy (CT2) (P < 0.001). Disease control rate with CT2 was 36%, and mean progression‐free survival was 3.2 months (95% confidence interval 1.5–4.9 months). The following variables were significant in the univariate analysis of OS from time of progression on CT1: lines of chemotherapy (P = 0.0001), Eastern Cooperative Oncology Group performance status at progression on CT1 (P < 0.0001) and disease control with CT1 (P = 0.027). Lines of chemotherapy received and performance status remained significant in the multivariate analysis for OS from progression on CT1.

Conclusion

Second‐line chemotherapy is feasible in a subset of patients with ABC. Even after accounting for confounding variables, CT2 appears to increase OS in ABC, although we are unable to exclude other unmeasured factors such as tumor biology. These findings warrant further evaluation with prospective trials.
Systematic review and meta‐analysis of studies of biliary reconstruction in adult living donor liver transplantation
Authors: Chok Kenneth S. H. , Lo Chung Mau
Published: November 2016

Background

The chance of biliary complication after living donor liver transplantation (LDLT) is considerable. The objective of this study was to investigate the impact of biliary reconstruction method on post‐LDLT biliary complications. Data sources are from PubMed and Web of Science.

Methods

A systematic search was conducted using the search term ‘[biliary complications] OR [biliary complication] OR [biliary stricture] OR [bile leak] AND [living donor liver transplantation]’. Cross‐referencing was allowed so as to encompass more potentially relevant studies. All English papers on adult LDLT published between 1990 and 2014 were considered for review. Papers focusing on biliary reconstruction method in relation to post‐LDLT biliary complications were included.

Results

The meta‐analysis recruited six retrospective studies but no randomized trial or prospective study. The six studies covered 1286 patients with 260 cases (20.2%) of biliary anastomotic stricture (BAS) and 118 cases (9.2%) of biliary leakage (BL). For biliary reconstruction, 365 patients (28.4%) underwent hepaticojejunostomy (HJ) and 909 (70.7%) underwent duct‐to‐duct anastomosis (DDA), while 12 (0.9%) underwent both and were thus excluded from the analysis. A lower rate of BAS was found in patients with HJ compared with patients with DDA (Mantel–Haenszel odds ratio 0.448, 95% confidence interval 0.311–0.643; P = 0.000). Rates of BL were similar in the two groups (Mantel–Haenszel odds ratio 1.27, 95% confidence interval 0.821–1.966; P = 0.283).

Conclusion

In the comparison of HJ and DDA in adult LDLT, the latter was found to be associated with a bigger chance of BAS but not BL.
Contraceptive use in the Nordic countries
Authors: Lindh Ingela , Skjeldestad Finn E. , Gemzell‐Danielsson Kristina , Heikinheimo Oskari , Hognert Helena , Milsom Ian , Lidegaard Øjvind
Published: November 2016

Introduction

The aim was to compare contraceptive use in the Nordic countries and to assess compliance with recommendations from the European Medicines Agency regarding the use of combined oral contraception containing low‐dose estrogen and levonorgestrel, norethisterone or norgestimate.

Material and methods

Data on hormonal contraceptive prescriptions and sales figures for copper intrauterine devices were obtained from national databases and manufacturers in Denmark, Finland, Iceland, Norway and Sweden in 2010–2013.

Results

Contraceptive use was highest in Denmark (42%) and Sweden (41%), followed by Finland (40%). Combined oral contraception was the most used method in all countries, with the highest use in Denmark (26%). The second most used method was the levonorgestrel‐releasing intrauterine system, with the highest use in Finland (15%) and ≈10% in the other countries. Copper intrauterine devices (7%) and the progestin‐only pill (7%) were most often used in Sweden. Combined oral contraception use decreased with increasing age and levonorgestrel‐releasing intrauterine system and progestin‐only pills use increased. The use of long‐acting reversible methods of contraception (=levonorgestrel‐releasing intrauterine system, copper intrauterine devices, and implants) increased with time and was highest in Sweden (20%) and Finland (18%). The highest use of European Medicines Agency recommended combined oral contraception was in Denmark, increasing from 13 to 50% between 2010 and 2013. In Finland, recommended combined oral contraception remained below 1%.

Conclusions

Contraceptive use was highest in Denmark and Sweden, levonorgestrel‐releasing intrauterine system use was highest in Finland and all long‐acting methods were most common in Sweden. The use of combined oral contraception recommended by the European Medicines Agency was highest in Denmark.
Sleep quality during pregnancy: associations with depressive and anxiety symptoms
Authors: Polo‐Kantola Päivi , Aukia Linda , Karlsson Hasse , Karlsson Linnea , Paavonen E. Juulia
Published: November 2016

Introduction

Sleep disturbances are common during pregnancy, yet underdiagnosed and under‐investigated. We evaluated sleep quality during pregnancy and assessed associated factors, especially depressive and anxiety symptoms.

Material and methods

A total of 78 healthy pregnant women from the FinnBrain Birth Cohort Study were studied twice prospectively during pregnancy (in mid‐pregnancy and late pregnancy). Sleep quality was evaluated by the Basic Nordic Sleep Questionnaire, depressive symptoms by the Edinburgh Postnatal Depression Scale, and anxiety symptoms by the State‐Trait Anxiety Inventory.

Results

Poor general sleep quality, difficulty falling asleep, the number of nocturnal awakenings per night, and too‐early morning awakenings increased in late pregnancy compared with mid‐pregnancy (all p‐values < 0.020). The total insomnia score (p < 0.001) and sleep latency increased (p = 0.005), but sleep duration and preferred sleep duration did not change. Women tended to snore more often in late pregnancy, but apneas remained rare. Almost one‐fourth of the women reported both morning and daytime sleepiness, but the frequencies did not increase during the follow up. In late pregnancy, depressive and anxiety symptoms were cross‐sectionally related to sleep disturbances, but depressive or anxiety symptoms in mid‐pregnancy were not associated with sleep disturbances in late pregnancy.

Conclusions

We found deterioration in sleep quality across pregnancy. However, no increase in negative daytime consequences was found, presumably indicating a compensatory capacity against sleep impairment. Additionally, depressive and anxiety symptoms and sleep disturbances were only cross‐sectionally associated. Our study calls for further research on the factors that influence sleep disturbances during pregnancy.
Irritable bowel syndrome and active inflammatory bowel disease diagnosed by faecal gas analysis
Authors: Aggio R. B. M. , White P. , Jayasena H. , de Lacy Costello B. , Ratcliffe N. M. , Probert C. S. J.
Published: November 2016

Background

Inflammatory bowel disease and irritable bowel syndrome may present in a similar manner. Measuring faecal calprotectin concentration is often recommended to rule out inflammatory bowel disease, however, there are no tests to positively diagnose irritable bowel syndrome and invasive tests are still used to rule out other pathologies.

Aim

To investigate a platform technology for diagnosing inflammatory bowel disease and irritable bowel syndrome based on faecal gas.

Methods

The platform technology is composed of a gas chromatography column coupled to a metal oxide gas sensor (OdoReader) and a computer algorithm. The OdoReader separates the volatile compounds from faecal gas and the computer algorithm identifies resistance patterns associated with specific medical conditions and builds classification models. This platform was applied to faecal samples from 152 patients: 33 patients with active inflammatory bowel disease; 50 patients with inactive inflammatory bowel disease; 28 patients with irritable bowel syndrome and 41 healthy donors (Control).

Results

The platform classified samples with accuracies from 75% to 100% using rigorous validation schemes: namely leave‐one‐out cross‐validation, 10‐fold cross‐validation, double cross‐validation and their Monte Carlo variations. The most clinically important findings, after double cross‐validation, were the accuracy of active Crohn's disease vs. irritable bowel syndrome (87%; CI 84–89%) and irritable bowel syndrome vs. controls (78%; CI 76–80%). These schemes provide an estimate of out‐of‐sample predictive accuracy for similar populations.

Conclusions

This is the first description of an investigation for the positive diagnosis of irritable bowel syndrome, and for diagnosing inflammatory bowel disease.
First‐in‐human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL‐17A and IL‐17F, in mild psoriasis
Authors: Glatt Sophie , Helmer Eric , Haier Birgit , Strimenopoulou Foteini , Price Graham , Vajjah Pavan , Harari Olivier A. , Lambert John , Shaw Stevan
Published: November 2016

Aims

To assess safety, pharmacokinetics (PK) and clinical efficacy of bimekizumab (formerly UCB4940), a novel humanized monoclonal antibody and dual inhibitor of interleukin (IL)‐17A and IL‐17F, in subjects with mild plaque psoriasis.

Methods

Randomized, double‐blind, first‐in‐human study of bimekizumab in 39 subjects who received single‐dose intravenous bimekizumab (8–640 mg) or placebo (NCT02529956).

Results

Bimekizumab demonstrated dose‐proportional linear PK and was tolerated across the dose range assessed. No subject discontinued due to treatment‐emergent adverse events and no severe adverse events were reported. Bimekizumab demonstrated fast onset of clinically‐meaningful effects on skin of patients with mild psoriasis as early as Week 2. Maximal improvements (100% or near 100% reductions from baseline) in all measures of disease activity were observed between Weeks 8–12 in subjects receiving 160–640 mg bimekizumab. The duration of effect at doses ≥160 mg was evident up to Weeks 12–20 after a single intravenous dose, dependent on endpoint.

Conclusions

This is the first study to demonstrate the safety, tolerability and clinical efficacy of a dual IL‐17A and IL‐17F inhibitor, in subjects with mild psoriasis. Bimekizumab showed fast onset of clinically‐meaningful efficacy by Week 2, with a maximal or near‐maximal magnitude of response that was maintained up to study Weeks 12–20. These findings support the continued clinical development of bimekizumab for diseases mediated by both IL‐17A and IL‐17F, including psoriasis.
Colchicine Increases Ventricular Vulnerability in an Experimental Whole‐Heart Model
Authors: Frommeyer Gerrit , Krawczyk Julius , Dechering Dirk G. , Kochhäuser Simon , Leitz Patrick , Fehr Michael , Eckardt Lars
Published: November 2016

The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole‐heart model. Ten rabbit hearts were isolated and Langendorff‐perfused. Thereafter, colchicine was administered in two concentrations (1 and 3 μM). Eight endo‐ and epicardial monophasic action potentials and a 12‐lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose‐dependent significant decrease of effective refractory period (ERP; 1 μM: −19 ms, 3 μM: −22 ms; p < 0.05). In the present study, acute infusion of colchicine in isolated rabbit hearts resulted in a reduction of ERP in the presence of a stable myocardial repolarization. This led to a significantly elevated inducibility of ventricular fibrillation. In 4 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a pro‐arrhythmic or toxic effect of colchicine and underline that further clinical studies on potential adverse effects should be conducted before the drug can be recommended for routine use after atrial fibrillation ablation.
Work and freedom? Working self‐objectification and belief in personal free will
Authors: Baldissarri Cristina , Andrighetto Luca , Gabbiadini Alessandro , Volpato Chiara
Published: November 2016

The current work aimed to extend the burgeoning literature on working objectification by investigating the effects of particular job activities on self‐perception. By integrating relevant theoretical reflections with recent empirical evidence, we expected that performing objectifying (i.e., repetitive, fragmented, and other‐directed) tasks would affect participants' self‐objectification and, in turn, their belief in personal free will. In three studies, we consistently found that performing a manual (Study 1 and Study 2) or a computer (Study 3) objectifying task (vs. a non‐objectifying task and vs. the baseline condition) led participants to objectify themselves in terms of both decreased self‐attribution of human mental states (Study 1 and Study 3) and increased self‐perception of being instrument‐like (Study 2 and Study 3). Crucially, this increased self‐objectification mediated the relationship between performing an objectifying activity and the participants' decreased belief in personal free will. The theoretical and practical implications of these findings are considered.
Forkhead box P3 regulates ARHGAP15 expression and affects migration of glioma cells through the Rac1 signaling pathway
Authors: Sun Zhen , Zhang Biao , Wang Chen , Fu Tao , Li Lianling , Wu Qiaoli , Cai Ying , Wang Jinhuan
Published: November 2016

Forkhead box P3 (FOXP3) plays a crucial role in the development and function of regulatory T cells and was recently identified as a tumor suppressor in different cancer types. Forkhead box P3 is expressed in normal brain tissues, but is strongly downregulated or absent in glioblastomas. In order to understand the FOXP3 adjustment mechanisms in glioma cells, we performed a DNA microarray in U87 cells overexpressing FOXP3 and validated the differences using quantitative real‐time PCR, Western blot analysis, and immunohistochemistry in vitro and in vivo. We found that FOXP3 can regulate the expression of ARHGAP15. Expression of FOXP3 was also correlated with ARHGAP15 in glioma samples. Overexpression of FOXP3 inhibited glioma cell migration through ARHGAP15 upregulation and Rac1 inactivation. Silencing of FOXP3 promoted migration through ARHGAP15 downregulation and Rac1 activation. ARHGAP15, a GTPase‐activating protein for Rac1, inhibits small GTPase signaling in a dual negative manner. We found that there is a correlation between expression of ARHGAP15 and glioma level. The small GTPase Rac1 plays an important role in cell migration. In addition, we found that FOXP3 regulates expression of epithelial–mesenchymal transition markers E‐cadherin and N‐cadherin, which is important given that epithelial–mesenchymal transition is critically involved in tumor spreading and dissemination. Thus, FOXP3 or ARHGAP15 may serve as a new molecular target for antimetastatic therapies in treating glioma.
To Copy or To Innovate? The Role of Personality and Social Networks in Children's Learning Strategies
Authors: Rawlings Bruce , Flynn Emma , Kendal Rachel
Published: November 2016

In our technologically complex world, children frequently have problems to solve and skills to learn. They can develop solutions through learning strategies involving social learning or asocial endeavors. While evidence is emerging that children may differ individually in their propensity to adopt different learning strategies, little is known about what underlies these differences. In this article, we reflect on recent research with children, adults, and nonhuman animals regarding individual differences in learning strategies. We suggest that characteristics of children's personalities and children's positions in their social networks are pertinent to individual differences in their learning strategies. These are likely pivotal factors in the learning strategies children adopt, and thus can help us understand who copies and who innovates, an important question for cultural evolution. We also discuss how methodological issues constrain developmental researchers in this field and provide suggestions for ongoing work.
Comparison of anti‐interleukin‐5 therapies in patients with severe asthma: global and indirect meta‐analyses of randomized placebo‐controlled trials
Authors: Cabon Y. , Molinari N. , Marin G. , Vachier I. , Gamez A. S. , Chanez P. , Bourdin A.
Published: November 2016

Inconsistent results have been reported regarding IL‐5 blockade treatment in asthma. There were no direct between‐treatment comparisons. Only differences between each drug and placebo were studied. We identified all RCTs with anti‐IL5 treatments for patients with asthma over the 1990‐September 2015 period. RCTs were searched on Medline, Cochrane and Embase. At least 50 patients were enrolled in each study. Outcomes considered were exacerbation rate reduction, FEV1 changes, ACQ‐5 improvement, adverse events and serious adverse events. A global meta‐analysis was first conducted followed by an indirect comparison of each IL‐5‐targeting drug: benralizumab, reslizumab and mepolizumab. Further eosinophilic subgroup analysis and sensitivity analysis were also conducted in case of heterogeneity. Ten trials involving 3421 patients were eligible for meta‐analysis. IL‐5 blockade significantly reduced annual exacerbation rates vs. placebo by 40% [29–50] (P < 0.01, I2 = 0.61). ACQ‐5 was significantly improved vs. placebo but below the recognized MCID level (−0.31 [−0.41, −0.21], P < 0.01, I2 = 0.11). FEV1 changes from baseline were improved vs. placebo by 0.09 L [0.05–0.12] (P < 0.01, I2 = 0.28). The subgroup analysis identified a slight additional improvement in mean treatment effects in eosinophilic (> 300 mm3/L) patients with severe asthma. Similar patterns and rates of adverse events and severe adverse events were reported with the three drugs. The data interpretations were not affected by the sensitivity analysis. IL‐5 blockade appears to be a relevant treatment strategy to improve severe asthma management, particularly for eosinophilic patients. No clear superiority appeared between the drugs when appropriate doses were compared.
The effect of inhaled corticosteroids on bone mineral density measured by quantitative ultrasonography in an older population
Authors: Sarwar Ghulam , Bisquera Alessandra , Peel Roseanne , Hancock Stephen , Grainge Christopher , Attia John
Published: November 2016

Introduction

Prolonged use of systemic corticosteroids leads to reduced bone mineral density and osteoporosis, in turn increasing the risk of minimal trauma fractures with their associated morbidity and mortality in elderly populations. However, the effect of inhaled corticosteroids on bone mineral density has been debated in the medical literature.

Objectives

We aimed to determine the effect of inhaled corticosteroids on bone mineral density measured using calcaneal quantitative ultrasonography in a cohort of older Australians.

Methods

Data was collected from the Hunter Community Study, a longitudinal cohort of Australians aged 55‐85. Simple and multiple linear regression methods were used to test the cross‐sectional association between inhaled corticosteroids and calcaneal bone mineral density measured with quantitative ultrasound at baseline. A causal diagram was used to determine the minimally sufficient number of co‐variates necessary to determine the unconfounded effect of inhaled corticosteroids on bone mineral density; these included gender, body mass index, smoking, asthma, alcohol use, age, physical activity, and diet.

Results

There were 152 (6.8%) patients on inhaled corticosteroids and 2098 (93%) controls. Simple and multiple linear regression methods showed a non‐significant effect of inhaled steroids on BMD with slight decrease of BMD −0.010 g/cm2 (95% CI −0.042 to 0.022, P = .55) and −0.013 g/cm2 (95% CI −0.062 to 0.036, P = .61) respectively. Age, gender, body mass index, and smoking were stronger predictors of BMD.

Conclusions

No statistically significant relationship was detected between the use of inhaled corticosteroids and reduced bone mineral density in this observational study of a cohort of older Australians.
Long‐term effects of high‐intensity interval training in heart transplant recipients: A 5‐year follow‐up study of a randomized controlled trial
Authors: Yardley Marianne , Gullestad Lars , Bendz Bjørn , Bjørkelund Elisabeth , Rolid Katrine , Arora Satish , Nytrøen Kari
Published: November 2016

Background

Previous studies have demonstrated that high‐intensity interval training (HIT) is superior to moderate‐continuous exercise in general and in cardiovascular diseases. Recently, we also found HIT safe and efficient after heart transplantation (HTx). This study reports the 5‐year long‐term effects.

Design and Methods

Forty‐one HTx patients who had completed the previous 12‐month randomized controlled trial, comparing HIT intervention with usual care, were eligible. In particular, we measured VO2peak, muscular capacity, intravascular ultrasound, and questionnaires measuring physical and mental health.

Results

The baseline mean±SD values were as follows: age; 49.1±16.5 years, men; 68%, time since HTx: 4.1±2.2 years. Within the HIT group, initial VO2peak increased significantly from 27.7±5.7 to 31.2±5.3 mL/kg/min. However, during the next 4 years, VO2peak decreased to 26.0±6.2 mL/kg/min. The control group showed slightly decreasing VO2peak values during the entire 5‐year period. The HIT group reported significantly less anxiety symptoms, but there were no long‐term differences in VO2peak, muscular capacity, or cardiac allograft vasculopathy between the groups. The similar VO2peak values correspond to our findings of similar everyday activity.

Conclusion

Our findings suggest that intermittent periods of HIT may be necessary to maintain the initial benefits gained from the intervention. However, HIT probably reduces the burden of anxiety, which is a frequent health issue following HTx.
Serum sickness‐like drug reaction: two cases with a neutrophilic urticarial pattern
Authors: Nguyen Cuong V. , Miller Daniel D.
Published: November 2016

The diagnosis of serum sickness‐like reaction (SSLR) is typically based on clinical findings. Histopathologic examination is often deferred, as these eruptions commonly present in young children, and often to primary care providers. A PubMed literature search revealed only five existing cases of SSLR which describe cutaneous histopathologic features. We report two cases of SSLR, one each to bupropion and cefazolin. Skin biopsy findings in both cases showed a neutrophil‐predominant urticarial pattern resembling neutrophilic urticaria or neutrophilic urticarial dermatosis. We also provide a summary of the histopathologic findings that can help support a diagnosis of SSLR.
Erythema multiforme‐like cutaneous lesions in monomorphic epitheliotropic intestinal T‐cell lymphoma: a rare case report
Authors: Aiempanakit Kumpol , Amatawet Chitiarpa , Chiratikarnwong Kanokphorn , Auepemkiate Sauvarat , Kayasut Kanita , Suwiwat Supaporn , Apinantriyo Benjawan
Published: November 2016

Monomorphic epitheliotropic intestinal T‐cell lymphoma (MEITL), also known as Type II enteropathy‐associated T‐cell lymphoma (EATL), is an aggressive peripheral T‐cell lymphoma. EATL generally presents in adults with gastrointestinal symptoms. Skin involvement is very rare, found only in approximately five percent of patients. The authors report a 67‐year‐old Asian male who presented with chronic diarrhea and developed erythema multiforme‐like cutaneous lesions. A skin biopsy revealed extensive pagetoid spread of atypical lymphocytes in the epidermis. The results of an immunohistochemistry test led to a diagnosis of MEITL. This report points to the need for dermatologists and dermatopathologists to consider a possible diagnosis of MEITL when encountering similar cases.
The Darwin cure for apiculture? Natural selection and managed honeybee health
Authors: Neumann Peter , Blacquière Tjeerd
Published: November 2016

Recent major losses of managed honeybee, Apis mellifera, colonies at a global scale have resulted in a multitude of research efforts to identify the underlying mechanisms. Numerous factors acting singly and/or in combination have been identified, ranging from pathogens, over nutrition to pesticides. However, the role of apiculture in limiting natural selection has largely been ignored. This is unfortunate, because honeybees are more exposed to environmental stressors compared to other livestock and management can severely compromise bee health. Here, we briefly review apicultural factors that influence bee health and focus on those most likely interfering with natural selection, which offers a broad range of evolutionary applications for field practice. Despite intense breeding over centuries, natural selection appears to be much more relevant for the health of managed A. mellifera colonies than previously thought. We conclude that sustainable solutions for the apicultural sector can only be achieved by taking advantage of natural selection and not by attempting to limit it.
Collateral ligament reconstruction in two horses following traumatic avulsion fracture using a knotless suture anchor construct
Authors: Bell C. , Torske K. , Lobb B.
Published: November 2016

This case report describes a technique for repair of medial collateral ligament avulsions in two horses. Both horses sustained traumatic injuries resulting in avulsion fractures at the origin of their medial tarsal and carpal collateral ligaments. This report describes the use of a knotless suture anchor to mechanically reconstruct medial collateral ligament avulsion injuries in two horses. The first horse, a 9‐year‐old Hannovarian Warmblood gelding presented for an acute nonweightbearing lameness in the right hindlimb. The injury was localised to the medial malleolus of the tibia and an avulsion fracture of the origin of the short medial collateral ligament of the tibiotarsal joint with disruption of the ligament was found on radiographs and ultrasound. The horse was taken to surgery and a reconstruction of the short medial collateral ligament was performed with a modified single row construct using a biocompatible, multistrand, long chain ultra‐high molecular weight polyethylene braided composite suture tape (2 mm Fibertape) and a single knotless suture anchor (5.5 × 19.1 mm PEEK SwivelLock C). The second horse, a 5‐year‐old Thoroughbred gelding presented for an acute nonweightbearing lameness in the left forelimb. The injury was localised to the medial styloid process of the radius and an avulsion fracture of the origin of the medial collateral ligament of the antebrachial carpal joint was found on radiographs and ultrasound. The horse was taken to surgery and a similar reconstruction procedure was performed to the collateral ligament. Both horses were recovered in a Robert Jones bandage without the use of casts or splints and recovered without incident. Both horses are sound and returned to previous level of athletic performance at 18 months and 8 months, respectively.
Allogeneic major histocompatibility complex‐mismatched equine bone marrow‐derived mesenchymal stem cells are targeted for death by cytotoxic anti‐major histocompatibility complex antibodies
Authors: Berglund A.K. , Schnabel L.V.
Published: November 2016

Background

Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)‐mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response.

Objectives

To determine if cytotoxic anti‐MHC antibodies generated in vivo following MHC‐mismatched MSC injections are capable of initiating complement‐dependent cytotoxicity of MSCs.

Study design

Experimental controlled study.

Methods

Antisera previously collected at Days 0, 7, 14 and 21 post‐injection from 4 horses injected with donor MHC‐mismatched equine leucocyte antigen (ELA)‐A2 haplotype MSCs and one control horse injected with donor MHC‐matched ELA‐A2 MSCs were utilised in this study. Antisera were incubated with ELA‐A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA‐A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control.

Results

Antisera from all 4 horses injected with MHC‐mismatched MSCs contained antibodies that caused the death of ELA‐A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post‐injection. MSC death was consistently equivalent to that of ELA‐A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC‐matched MSCs did not contain cytotoxic ELA‐A2 antibodies at any of the time points examined.

Main limitations

This study examined MSC death in vitro only and utilized antisera from a small number of horses.

Conclusions

The cytotoxic antibody response induced in recipient horses following injection with donor MHC‐mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC‐mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death.