bluuebunny/crossref_metadata_2025 huggingface dataset:
Labour market regulation and subjective well‐being in low‐income countries
Authors: FLAVIN PATRICK , PACEK ALEXANDER C. , RADCLIFF BENJAMIN
Published: February 2019

A growing literature suggests social democratic policies, as exemplified by the welfare state and active labour market policies, promote higher levels of life satisfaction compared to the neoliberal agenda of austerity, smaller government and more ‘flexible’ labour markets. In this article, this inquiry is extended to low‐income countries. A theoretical argument is developed for why labour market regulation (LMR) (rather than social welfare spending or the general size of government) is a more appropriate locus of attention outside of the industrial democracies. The relationship between LMR and several measures of well‐being is then empirically evaluated, finding robust evidence that people live more satisfying lives in countries that more stringently regulate their labour market. Moreover, it is found that positive benefits of LMR on well‐being are the largest among individuals with lower incomes. The implications for public policy and the study of human well‐being are discussed.
Fraud Allegations and Government Contracting
Authors: HEESE JONAS , PÉREZ‐CAVAZOS GERARDO
Published: February 2019

This paper examines whether fraud allegations affect firms’ contracting with the government. Using a data set of whistleblower allegations brought under the False Claims Act against firms accused of defrauding the government, we find that federal agencies do not reduce the total dollar volume of contracts with accused firms; however, they substitute approximately 14% of the harder‐to‐monitor cost‐plus contracts for fixed‐price contracts. This effect is concentrated in the procurement of services and explained by contract and service substitution. Finally, we find that after the conclusion of the investigation, the government reduces the contract dollar volume by approximately 15% for cases that resulted in a settlement. Our findings indicate that contract‐design changes are used to mitigate uncertainty in suppliers’ reputation.
Bystanders in workplace bullying: working university students’ perspectives on action versus inaction
Authors: Paull Megan , Omari Maryam , D'Cruz Premilla , Güneri Çangarli Burcu
Published: February 2019

There is increasing interest in bystanders to workplace bullying, including from human resource management (HRM) perspectives. This paper draws on literature from the fields of sexual harassment and helping behaviour to develop understanding of bystander action and inaction. Part of a project on workplace bullying, this study used online story‐based responses from university students in Australia, India and Turkey with workplace experience to elicit bystander and target interpretations of the behaviour. Findings suggest that even when bystanders are aware of bullying, they do not always intervene for reasons ranging from powerlessness and fear to avoidance and ignorance. Helping behaviours, including private support or making a report, were described by some respondents, with contextual factors linked to the perpetrator or the organisation influencing responses. The importance of the HRM role in facilitating bystander action, drawing on the helping behaviour and sexual harassment literature, is a focus of the findings and implications.
Lung cancer imaging methods in China from 2005 to 2014: A national, multicenter study
Authors: Hou Dong‐Hui , Zhao Shi‐Jun , Shi Ju‐Fang , Wang Le , Wang De‐Bin , Huang Yun‐Chao , Liao Xian‐Zhen , Xing Xiao‐Jing , Du Ling‐Bin , Yang Li , Liu Yu‐Qin , Zhang Yong‐Zhen , Wei Dong‐Hua , Liu Yun‐Yong , Zhang Kai , Li Ni , Chen Wan‐Qing , Qiao You‐Lin , He Jie , Dai Min , Wu Ning ,   LuCCRES Group
Published: February 2019

Background

The study was conducted to examine changes in diagnostic and staging imaging methods for lung cancer in China over a 10‐year period and to determine the relationships between such changes and socioeconomic development.

Methods

This was a hospital‐based, nationwide, multicenter retrospective study of primary lung cancer cases. The data were extracted from the 10‐year primary lung cancer databases at eight tertiary hospitals from various geographic areas in China. The chi‐squared test was used to assess the differences and the Cochran–Armitage trend test was used to estimate the trends of changes.

Results

A total of 7184 lung cancer cases were analyzed. Over the 10‐year period, the utilization ratio of diagnostic imaging methods, such as chest computed tomography (CT) and chest magnetic resonance imaging (MRI), increased from 65.79% to 81.42% and from 0.73% to 1.96%, respectively, while the utilization ratio of chest X‐ray declined from 50.15% to 30.93%. Staging imaging methods, such as positron emission tomography‐CT, neck ultrasound, brain MRI, bone scintigraphy, and bone MRI increased from 0.73% to 9.29%, 22.95% to 47.92%, 8.77% to 40.71%, 42.40% to 62.22%, and 0.88% to 4.65%, respectively; abdominal ultrasound declined from 83.33% to 59.9%. These trends were more notable in less developed areas than in areas with substantial economic development.

Conclusion

Overall, chest CT was the most common radiological diagnostic method for lung cancer in China. Imaging methods for lung cancer tend to be used in a diverse, rational, and regionally balanced manner.
When and how do endodontic specialists use cone‐beam computed tomography?
Authors: Krug Ralf , Connert Thomas , Beinicke Andrea , Soliman Sebastian , Schubert Alexander , Kiefner Peter , Sonntag David , Weiger Roland , Krastl Gabriel
Published: February 2019

This study investigated the use of cone‐beam computed tomography (CBCT) by endodontists in Germany and Switzerland. Sixty‐eight German endodontic specialists (G‐ES), 22 Swiss endodontic specialists (CH‐ES) and 95 dentists with a German Master of Science in endodontics (MSc) were invited to participate. Data on the timing of diagnostic assessments, endodontic case difficulty and indications forCBCTuse were collected by questionnaire. The frequencies of pre‐, intra‐ and postoperative use of periapical radiography andCBCTwere analysed by case difficulty level. In high difficulty cases, access to aCBCTdevice was significantly associated with the frequency of both pre‐ and intraoperativeCBCTuse. The type of endodontic qualification had a significant impact on the rate of preoperativeCBCTuse in high difficulty cases. German endodontic specialists used preoperativeCBCTmore frequently thanCH‐ESandMSc. Our findings show thatCBCTis a valuable imaging tool for endodontists, particularly in high difficulty cases.
Winter survival of Ceramica pisi (Lepidoptera: Noctuidae) in Iceland
Authors: Hrafnkelsdottir Brynja , Sigurdsson Bjarni D. , Oddsdottir Edda S. , Sverrisson Halldor , Halldorsson Gudmundur
Published: February 2019

The broom moth Ceramica pisi, a native species in Iceland, has shown a marked expansion from south Iceland towards the north, concurrent with increasing temperatures.

Winter temperatures have increased more than summer temperatures in Iceland and, in the present study, the hypothesis was that the winter warming has facilitated the range shift of C. pisi.

Winter survival of pupae in Iceland was studied in the laboratory. Pupae were collected in the autumn of 2012 at five separate locations, then weighed and placed at temperatures from −6 to −18 °C. One month after the sub‐zero treatments, the pupae were placed at room temperature and pupal emergence was recorded.

No significant effect of sub‐zero treatments on the survival of C. pisi pupae was found. The primary hypothesis of the present study was therefore rejected.

The major factor affecting low temperature survival of C. pisi pupae, however, was their autumn weight. The response was sigmoid and the 5%, 50% and 95% likelihoods for winter survival were at 157, 274 and 393 mg autumn pupal mass, respectively.

This finding indicates that factors other than winter temperature, such as summer available thermal budget for larval growth, may be a limiting factor to the spread of C. pisi in Iceland.
A strategy for high‐dimensional multivariable analysis classifies childhood asthma phenotypes from genetic, immunological, and environmental factors
Authors: Krautenbacher Norbert , Flach Nicolai , Böck Andreas , Laubhahn Kristina , Laimighofer Michael , Theis Fabian J. , Ankerst Donna P. , Fuchs Christiane , Schaub Bianca
Published: February 2019

Background

Associations between childhood asthma phenotypes and genetic, immunological, and environmental factors have been previously established. Yet, strategies to integrate high‐dimensional risk factors from multiple distinct data sets, and thereby increase the statistical power of analyses, have been hampered by a preponderance of missing data and lack of methods to accommodate them.

Methods

We assembled questionnaire, diagnostic, genotype, microarray, RT‐qPCR, flow cytometry, and cytokine data (referred to as data modalities) to use as input factors for a classifier that could distinguish healthy children, mild‐to‐moderate allergic asthmatics, and nonallergic asthmatics. Based on data from 260 German children aged 4‐14 from our university outpatient clinic, we built a novel multilevel prediction approach for asthma outcome which could deal with a present complex missing data structure.

Results

The optimal learning method was boosting based on all data sets, achieving an area underneath the receiver operating characteristic curve (AUC) for three classes of phenotypes of 0.81 (95%‐confidence interval (CI): 0.65‐0.94) using leave‐one‐out cross‐validation. Besides improving the AUC, our integrative multilevel learning approach led to tighter CIs than using smaller complete predictor data sets (AUC = 0.82 [0.66‐0.94] for boosting). The most important variables for classifying childhood asthma phenotypes comprised novel identified genes, namely PKN2 (protein kinase N2), PTK2 (protein tyrosine kinase 2), and ALPP (alkaline phosphatase, placental).

Conclusion

Our combination of several data modalities using a novel strategy improved classification of childhood asthma phenotypes but requires validation in external populations. The generic approach is applicable to other multilevel data‐based risk prediction settings, which typically suffer from incomplete data.
Electrocardiographic measures of ventricular repolarization dispersion and arrhythmic outcomes among ST elevation myocardial infarction patients with pre‐infarction angina undergoing primary percutaneous coronary intervention
Authors: Ahmed Tarek A. N. , Abdel‐Nazeer Amr A. , Hassan Ayman K. M. , Hasan‐Ali Hosam , Youssef Amr A.
Published: February 2019

Background

Arrhythmias are considered one of the major causes of death in ST elevation myocardial infarction (STEMI), particularly in the early in‐hospital phase. Pre‐infarction angina (PIA) has been suggested to have a protective role.

Objectives

To study the difference in acute electrocardiographic findings between STEMI patients with and without PIA and to assess the in‐hospital arrhythmias in both groups.

Material and Methods

We prospectively enrolled 238 consecutive patients with STEMI. Patients were divided into two groups: those with or without PIA. ECG data recorded and analyzed included ST‐segment resolution (STR) at 90 min, corrected QT interval (QTc) and dispersion (QTD), T‐peak‐to‐T‐end interval (Tp‐Te), and dispersion and Tp‐Te/QT ratio. In‐hospital ventricular arrhythmias encountered in both groups were recorded. Predictors of in‐hospital arrhythmias were assessed among different clinical and electrocardiographic parameters.

Results

Of the 238 patients included, 42 (17%) had PIA and 196 (83%) had no PIA. Patients with PIA had higher rates of STR (p < 0.0001), while patients with no PIA had higher values of QTc (p = 0.006), QTD (p = 0.001), Tp‐Te interval (p = 0.001), Tp‐Te dispersion (p < 0.0001), and Tp‐Te/QT ratio (p = 0.01) compared to those with angina preceding their incident infarction (PIA). This was reflected into significantly higher rates of in‐hospital arrhythmias among patients with no PIA (20% vs. 7%, p = 0.04). Furthermore, longer Tp‐Te interval and higher Tp‐Te/QT ratio independently predicted in‐hospital ventricular arrhythmias.

Conclusion

Pre‐infarction angina patients had better electrocardiographic measures of repolarization dispersion and encountered significantly less arrhythmic events compared to patients who did not experience PIA.
Levonorgestrel intrauterine contraceptive systems (13.5 mg and 52 mg) and risk of ectopic pregnancy
Authors: Graner Sofie , Mc Taggart Julia , Nordström Fanny , Melander Emma , Widenberg Johan , Kopp Kallner Helena
Published: February 2019

Introduction

The objective was to investigate the Pearl index for ectopic pregnancy in women using the levonorgestrel intrauterine system (LNG‐IUS) at the time of conception.

Material and methods

This was a substudy of a hospital‐based historical cohort including women with an ectopic pregnancy diagnosed in 4 referral hospitals in Stockholm, Sweden between December 2013 and April 2017. Study participants and type of contraception at time of conception were identified through the electronic medical chart system. Cases were defined as women with LNG‐IUS 13.5 or 52 mg in situ at the time of diagnosis of ectopic pregnancy who had their LNG‐IUS inserted 1 January 2014 or later. Outcome was defined as the incidence rate for ectopic pregnancy during use per 100 woman‐years (Pearl index) with 95% confidence interval (95% CI).

Results

The study includes 35 cases with LNG‐IUS 13.5 mg and 13 cases with LNG‐IUS 52 mg, which occurred in 18 488 (13.5 mg) and 50 246 (52 mg) exposed woman‐years. Pearl index for ectopic pregnancy was estimated at 0.19 (95% CI 0.15‐0.28) for LNG‐IUS 13.5 mg and to 0.006 (95% CI 0.00‐0.01) for LNG‐IUS 52 mg. The most cases for the LNG‐IUS 13.5 mg (n = 26; 74%) occurred during the first year of use with a corresponding Pearl index at 0.23 (95% CI 0.14‐0.35).

Conclusions

The absolute risk of ectopic pregnancy during the use of LNG‐IUS remains low. Our method may underestimate as well as overestimate the Pearl index for ectopic pregnancy. The findings underline the importance of identifying risk factors for ectopic pregnancy at insertion, and to rule out ectopic pregnancy for all women presenting with abdominal discomfort during the use of LNG‐IUS. Longer observation periods and prospective studies in a general population are a priority for further research.
Trial of labor after cesarean section in risk pregnancies: A population‐based cohort study
Authors: Lehmann Sjur , Baghestan Elham , Børdahl Per Engebret , Muller Irgens Lorentz , Rasmussen Svein Arvid
Published: February 2019

Introduction

In most pregnancies after a cesarean section, a trial of labor is an option. The objective of the study was to explore trial of labor and its failure in pregnancies with medical risk conditions, in a population with a high trial of labor rate.

Material and methods

In a cohort study (n = 57 109), using data from the Medical Birth Registry of Norway 1989‐2014, women with a second delivery after a first pregnancy cesarean section were included. Preterm, multiple, and non‐cephalic deliveries were excluded. The outcomes were trial of labor and failed trial of labor, assessed as rates and relative risk, using deliveries without risk conditions as reference. Temporal trends were assessed by 3‐year periods. The exposures were selected medical risk conditions, ie previous offspring death, labor dystocia, diabetes, heart conditions, chronic hypertension, chronic kidney disease, rheumatoid arthritis, thyroid disease, asthma, prepregnancy psychiatric conditions, epilepsy, obesity, gestational diabetes, eclampsia and preeclampsia, gestational hypertension, major malformations, second‐pregnancy psychiatric conditions, assisted reproduction, macrosomia, and small‐for‐gestational‐age neonates. Induced onset of labor was compared with spontaneous onset of labor for each condition studied.

Results

In risk pregnancies (n = 31 994) the trial of labor rate was 64.9% and failure rate was 27.6%, compared with 74.6% and 16.4% in pregnancies without any of the risk conditions studied (n = 25 115). The lowest trial of labor rates were observed in diabetes type 1 (49.5%), diabetes type 2 (46.7%), maternal heart conditions (54.5%), and pregnancy‐related psychiatric conditions (19.7%). The highest failure rates were observed in diabetes type 1 (43.1%), diabetes type 2 (40.3%), maternal obesity (36.9%), gestational diabetes (36.0%), and offspring macrosomia (43.0%). Induced labor was associated with failed trial of labor (P < .05), whereas after spontaneous labor, failure rates were less than 40% in all conditions studied.

Conclusions

In conditions with high rates of failed trial of labor, eg diabetes, macrosomia, and obesity, a planned cesarean section might be a better option than a trial of labor, particularly if induction of delivery might be needed.
Immunohistochemical localization of a proto‐cadherin fat tumour‐suppressor homolog in the regenerating tail of lizard suggests a role in apical growth control
Authors: Alibardi Lorenzo
Published: February 2019

The present immunohistochemical and western blotting study evaluates the localization of a proto‐cadherin which gene is overexpressed in the regenerating blastema of the lizard Podarcis muralis. Bioinformatic analysis suggests that the antibody recognizes FAT1/2 proteins. Western blot indicates a main band around 50 kDa, a likely fragment derived from the original membrane‐bound large protein. Immunofluorescence shows main labelling in differentiating wound keratinocytes, lower in ependyma, mesenchyme and extracellular matrix of the blastema. The apical epidermal peg contains keratinocytes with labelled peripheral cytoplasm, as confirmed using ultrastructural immunogold that also reveals most labelling located along the cell surface of mesenchymal cells. Myoblasts and differentiating myotubes of regenerating muscles are less intensely labelled. The regenerating cartilaginous tube contains sparse labelled chondroblasts, especially in external and internal perichondria. In regenerating scales, differentiating beta‐cells appear immunofluorescent mainly along the cell perimeter. In more differentiated muscle, cartilage and connective tissues of the new tail, the labelling lowers or disappears. The observations indicate that FAT1/2 proto‐cadherins are present in the apical blastema where an intense remodelling takes place for the growth of the new tail but where also a tight control of cell division and migration is active and may regulate potential tumorigenic process.
Cuticular microstructure of Australian ant mandibles confirms common appendage construction
Authors: Barlow Molly M. , Bicknell Russell D. C. , Andrew Nigel R.
Published: February 2019

Exoskeletons characterise Arthropoda and have allowed the morphological and taxonomic diversity of the phylum. Exoskeletal sclerotisation occurs in genetically designated regions, and mandibles represent one such area of high sclerotisation. Mandible morphology reflects dietary preferences and niche partitioning and has therefore been well documented. However, mandibular cuticular microstructure has been under‐documented. Here we use scanning electron microscopy to explore mandible microstructure in four disparate Australian Formicidae taxa (ants) with different life modes and diets: Camponotus nigriceps, Iridomyrmex purpureus, Odontomachus simillimus and Rhytidoponera aciculata. We test the hypothesis that mandible construction is highly conserved across these species, as would be expected for arthropod cuticle. We show broadly similar mandible microstructure but report that pore canals and cuticular indentations are not ubiquitous among all studied taxa. Our preliminary results demonstrate that ant taxa have morphologically plastic mandibles with a highly conserved construction, potentially reflecting an interesting record of evolutionary stasis.
Patterns of gabapentin and pregabalin use and misuse: Results of a population‐based cohort study in France
Authors: Driot Damien , Jouanjus Emilie , Oustric Stéphane , Dupouy Julie , Lapeyre‐Mestre Maryse
Published: February 2019

Aims

The aim of this study was to assess the use and factors associated with the misuse of gabapentin and pregabalin in the general French population, through a cohort study in the EGB (General Sample of Beneficiaries), a national representative sample of the French general population.

Methods

New users of gabapentin and pregabalin were identified from June 2006 to December 2014, and new users of duloxetine served as control group. Misuse was defined as a use of higher daily doses than recommended. Cox proportional hazard regression models were performed to identify associated factors of misuse.

Results

Misuse was more frequent in the 8692 new users of pregabalin (12.8%) than in the 1963 gabapentin (6.6%) or the 3214 duloxetine new users (9.7%) (P < 0.001). Factors associated with misuse were pregabalin (hazard ratio [HR] 1.48; 95% confidence interval [CI] [1.29–1.69]), age (HR[18–45] versus > 70 years 1.98 [1.70–2.31] and HR[58–70] versus > 70 years 1.25 [1.06–1.47]), multiple prescribers (HR2 or 3 versus 1 prescriber 1.29 [1.15–1.45]; HR4 or more versus 1 prescriber 1.54 [1.30–1.83]), cancer (1.28 [1.11–1.47]), multiple sclerosis (1.53 [1.07–2.18]), neuropathy (1.85 [1.19–2.89]), depression (1.26 [1.07–1.49]) and methadone (2.61 [1.16–5.84]). After this first episode of drug misuse, 11.6% of gabapentin and 10.7% of pregabalin misusers developed a primary addiction.

Conclusion

In a cohort of new users, misuse is more likely to occur in new users of pregabalin, with different associated factors of misuse compared to gabapentin and duloxetine. Health professionals and prescribers must be aware of this misuse potential, which could lead to abuse and dependence.
The motivations of external whistleblowers and their impact on the intention to blow the whistle again
Authors: Park Heungsik , Lewis David
Published: February 2019

The purpose of this study was to inquire into the relative importance of morality, cost‐benefit, and emotion as motivations for the decision to blow the whistle externally, and the effects of such factors as motivations, perceived negative consequences, and preferences for reform on the intention to blow the whistle again. Based on a literature review, we formulated some hypotheses and, to test them, we used the data collected from a survey of 127 external whistleblowers in South Korea. The results revealed that morality was the most important motivation, followed by emotion, and then cost‐benefit, which thus, seemed to be the least important for the whistleblowers. Morality as a motivation and the perceived negative consequences of whistleblowing had a significant effect on the intention to blow the whistle again. This study helps advance the understanding of the motivations behind whistleblowing and the factors that influence the intention to blow the whistle again.
Do employees value strategic CSR? A tale of affective organizational commitment and its underlying mechanisms
Authors: Rodrigo Pablo , Aqueveque Claudio , Duran Ignacio J.
Published: February 2019

Virtually all studies that focus on the relationship between CSR perceptions and employees’ organizational commitment have not taken into consideration the fit between social and environmental activities and a firm’s business‐unit strategy. This is essential to inquire because scholars have argued that when companies ingrain CSR activities into their strategy‐making process (i.e., in their vision, mission, and overall business model), this might send a more compelling message that resonates closer to workers’ personal standards, and actually enhance employee‐level outcomes. Nevertheless, there is no certainty “if” and “how” these evaluations could affect employees’ organizational commitment. To address this issue, we use cue consistency theory and social identity theory as overarching frameworks to develop a model where we conceptually link perceptions of strategy‐CSR fit with a particular type of organizational commitment: affective. In addition, we posit and test three mediators to understand the underlying psychological mechanisms of this relationship: perceived external prestige, organizational identification, and work meaningfulness. Through structural equation modeling, and using a heterogeneous final sample of 579 employees, we find compelling evidence to support the fact that strategy‐CSR fit enhances employees’ affective organizational commitment through the proposed mediators. Academic contributions and practical implications are then discussed.
Current directions in visual working memory research: An introduction and emerging insights
Authors: Liesefeld Heinrich René , Müller Hermann J.
Published: February 2019

Visual working memory (VWM) is a core construct in the cognitive (neuro‐)sciences, assumed to serve as a hub for information exchange and thus supporting a multitude of cognitive functions related to processing visual information. Here, we give an introduction into key terms and paradigms and an overview of ongoing debates in the field, to which the articles collected in this Special Issue on ‘Current Directions in Visual Working Memory Research’ contribute. Our aim is to extract, from this overview, some ‘emerging’ theoretical insights concerning questions such as the optimal way to examine VWM, which types of mental representations contribute to performance on VWM tasks, and how VWM keeps features from the same object together and apart from features of concurrently maintained objects (the binding problem).
The psychometrics of psychosis – assessing and rating perceptual and ideational disturbance in adolescents
Authors: Tiffin Paul A. , Paton Lewis W.
Published: February 2019

Background

The early recognition and management of psychosis spectrum disorders is associated with superior outcomes in affected individuals. However, this can be challenging for numerous reasons. This article provides perspectives on the effective evaluation and rating of potentially psychotic phenomena young people. We compare and contrast two widely used instruments that can support this process.

Findings

The Comprehensive Assessment for At‐Risk Mental States (CAARMS) is used to explore potentially psychotic experiences in young people perceived to be at risk of an emerging or imminent psychosis. There is evidence to support its reliability and, to some extent, the predictive validity of the resultant scores. However, relatively low short–medium transition rates to psychosis in ‘positive’ cases suggest that its use as a screening instrument should be restricted to groups who show some indication of impending risk (e.g. help‐seeking, distress, declining functioning, perceptual disturbance, etc.). In contrast, the Positive and Negative Syndrome Scale (PANSS) is calibrated to rate symptoms in those with an established psychosis, especially those with a diagnosis related to the schizophrenia spectrum. Consequently, the PANSS is useful for evaluating the clinical course and outcomes of psychotic illness.

Conclusions

Although neither instrument is designed specifically for use in those under 18, with care they can be used to effectively support the management of adolescents reporting perceptual and ideational disturbance. However, it is important that any instrument ratings are placed meaningfully in the context of the overall clinical picture and all available information.
Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin‐fixed paraffin‐embedded specimens
Authors: Kohsaka Shinji , Tatsuno Kenji , Ueno Toshihide , Nagano Masaaki , Shinozaki‐Ushiku Aya , Ushiku Tetsuo , Takai Daiya , Ikegami Masachika , Kobayashi Hiroshi , Kage Hidenori , Ando Mizuo , Hata Keisuke , Ueda Hiroki , Yamamoto Shogo , Kojima Shinya , Oseto Kumiko , Akaike Keisuke , Suehara Yoshiyuki , Hayashi Takuo , Saito Tsuyoshi , Takahashi Fumiyuki , Takahashi Kazuhisa , Takamochi Kazuya , Suzuki Kenji , Nagayama Satoshi , Oda Yoshinao , Mimori Koshi , Ishihara Soichiro , Yatomi Yutaka , Nagase Takahide , Nakajima Jun , Tanaka Sakae , Fukayama Masashi , Oda Katsutoshi , Nangaku Masaomi , Miyazono Kohei , Miyagawa Kiyoshi , Aburatani Hiroyuki , Mano Hiroyuki
Published: February 2019

Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture‐based next‐generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost‐effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.
Home‐based cow's milk reintroduction using a milk ladder in children less than 3 years old with IgE‐mediated cow's milk allergy
Authors: Ball Heidi Britt , Luyt David
Published: February 2019

Background

The development of tolerance to cow's milk in allergic children is best determined by supervised baked milk exposure. Widely recommended hospital‐based challenges can potentially delay contact because of resource limitations.

Objective

We sought to determine the efficacy and safety of our low‐dose home‐based reintroduction programme.

Methods

In our allergy service, children with IgE‐mediated cow's milk allergy who met set criteria (presenting with skin and/or gastrointestinal symptoms only and skin prick test < 8 mm) are considered for home‐based milk reintroduction (HMR). Early contact is low‐dose ingestion of a commercial baked milk biscuit with slow gradual further exposure followed by increasing milk contact using a milk ladder. We retrospectively reviewed 4‐6 monthly attendance records assessing allergic symptoms, evolving milk tolerance, and compliance. Tolerance was determined using a 7 scale scoring system based on the milk ladder.

Results

The clinic attendance and dietetic contact records of 86 children (49 girls) who underwent HMR were reviewed. HMR was started at a median of 13 months with 49% 8‐12 months, 40% 13‐18 months and 11% 19‐33 months. Allergic symptoms were reported in 81 (43%) of 189 dietetic reviews, 65 (80%) of which were from the milk ladder; no patient experienced anaphylaxis requiring treatment with intramuscular adrenaline. After four reviews, only eight patients were not tolerating almost all dairy products, and there was a high rate of completion with only a further seven patients lost to the programme.

Conclusion and Clinical Relevance

Cow's milk can be successfully and safely reintroduced in a cautious low‐dose exclusively home‐based programme in the appropriate clinical and family setting.
Endothelin‐1 mediates Aspergillus fumigatus‐induced airway inflammation and remodelling
Authors: Labram Briony , Namvar Sara , Hussell Tracy , Herrick Sarah E.
Published: February 2019

Background

Asthma is a chronic inflammatory condition of the airways and patients sensitized to airborne fungi such as Aspergillus fumigatus have more severe asthma. Thickening of the bronchial subepithelial layer is a contributing factor to asthma severity for which no current treatment exists. Airway epithelium acts as an initial defence barrier to inhaled spores, orchestrating an inflammatory response and contributing to subepithelial fibrosis.

Objective

We aimed to analyse the production of pro‐fibrogenic factors by airway epithelium in response to A fumigatus, in order to propose novel anti‐fibrotic strategies for fungal‐induced asthma.

Methods

We assessed the induction of key pro‐fibrogenic factors, TGF‐β1, TGF‐β2, periostin and endothelin‐1, by human airway epithelial cells and in mice exposed to A fumigatus spores or secreted fungal factors.

Results

Aspergillus fumigatus specifically caused production of endothelin‐1 by epithelial cells in vitro but not any of the other pro‐fibrogenic factors assessed. A fumigatus also induced endothelin‐1 in murine lungs, associated with extensive inflammation and airway remodelling. Using a selective endothelin‐1 receptor antagonist, we demonstrated for the first time that endothelin‐1 drives many features of airway remodelling and inflammation elicited by A fumigatus.

Conclusion

Our findings are consistent with the hypothesis that elevated endothelin‐1 levels contribute to subepithelial thickening and highlight this factor as a possible therapeutic target for difficult‐to‐treat fungal‐induced asthma.
Evaluation of the Ability of Immune Humanized Mice to Demonstrate CD20‐Specific Cytotoxicity Induced by Ofatumumab
Authors: Semple Kenrick M. , Gonzaléz Carlos M. , Zarr Melissa , Austin José R. , Patel Vikram , Howard Kristina E.
Published: February 2019

CD20 monoclonal antibodies are well‐established therapeutics for the treatment of B‐cell malignancies. Several mechanisms of target cell killing occur from anti‐CD20 therapy, including complement‐dependent cytotoxicity (CDC) cell lysis and antibody‐dependent cell‐mediated cytotoxicity. Human Fc receptors (FcRs) are required to mediate these functions and are either not present or not cross‐reactive in mice and most animal species. In contrast, some nonhuman primates have cross‐reactive FcR; however, their cellular expression and function may differ from humans. Therefore, we tested bone marrow‐liver‐thymus (BLT) humanized mice to determine if they could recapitulate the pharmacokinetics (PKs), pharmacodynamics, and potential toxicities of ofatumumab, for which CDC is the predominant mechanism of action. Ofatumumab‐treated BLT mice depleted B cells in a dose‐dependent manner in all tissues sampled and recapitulated the PKs observed in humans, suggesting that BLT mice can mediate the CDC effector mechanism associated with biological drug products.
Plaque‐like myofibroblastic tumor, a rare entity of childhood: Possible pitfalls in differential diagnosis
Authors: Virdi Annalucia , Baraldi Carlotta , Barisani Alessia , Corti Barbara , Savoia Francesco , Patrizi Annalisa , Neri Iria
Published: February 2019

Plaque‐like myofibroblastic tumor is a rare and benign pediatric soft tissue tumor. It presents as a slowly growing plaque reaching several centimeters in diameter, made up of multiple nodules. The clinical and histological features of this benign entity are similar to other fibrohistiocytic or myofibroblastic tumors occurring in childhood, so the diagnosis can be difficult. The correlation between clinical data, histopathology, and immunohistochemistry is necessary for the correct diagnosis.
Clinical factors associated with cutaneous histopathologic findings in dermatomyositis
Authors: Wolstencroft Paige W. , Rieger Kerri E. , Leatham Hayley W. , Fiorentino David F.
Published: February 2019

Background

Common histopathologic findings in cutaneous dermatomyositis include vacuolar interface with dyskeratosis, mucin, and perivascular inflammation. Data examining the relationships between these and other histologic abnormalities, or their dependence on biopsy site, and medications are limited.

Methods

Using 228 dermatomyositis skin biopsies and statistical analyses including Chi‐squared analyses, calculations of relative risk, and adjusted generalized estimating equation regressions, we investigated relationships between 14 histopathologic findings and the impact of clinical factors on these findings.

Results

In biopsies taken from sites of visible rash, interface dermatitis was seen in 91%, and 95% had at least one of perivascular inflammation, mucin, or basal vacuolization. Vascular abnormalities were not closely associated with epidermal or inflammatory findings. Concomitant prednisone significantly decreased the odds of basal vacuolization (odds ratio [OR] = 0.34, 95% confidence interval [CI]: 0.12‐0.98,P‐value = 0.05), perivascular inflammation (OR = 0.19, 95% CI: 0.07‐0.53,P‐value = 0.002), and vessel damage (OR = 0.81, 95% CI: 0.68‐0.96,P‐value = 0.02).

Conclusion

Vasculopathy and classic findings of interface dermatitis may be driven by unique pathways in dermatomyositis. Corticosteroid use may impact skin biopsy findings. There is a need for clinicopathologic correlation when diagnosing dermatomyositis.
Direct medical costs in the preceding, event and subsequent years of a first severe hypoglycaemia episode requiring hospitalization: A population‐based cohort study
Authors: Wong Carlos K. H. , Tong Thaison , Cheng Garvin H. L. , Tang Eric H. M. , Thokala Praveen , Tse Emily T. Y. , Lam Cindy L. K.
Published: February 2019

Aims

We aimed to estimate the use of healthcare services and the direct medical costs accrued by patients with diabetes mellitus (DM) during the year of the first severe hypoglycaemia (SH) event, as well as during the years before and after the event year.

Materials and Methods

We analysed a population‐based, retrospective cohort including all adults with DM managed in the primary care setting from the Hong Kong Hospital Authority between 2006 and 2013. DM patients for whom SH was first recorded during the designated period were identified and matched to a control group of patients who had not experienced an SH event using the propensity score method. Direct medical costs in the years before, during and after the first SH event were determined by totalling the costs of health services utilized within respective years.

Results

After matching, a total of 22 694 DM patients were divided into the first recorded‐SH group (n = 11 347) and the non‐SH control group (n = 11 347). Patients for whom SH was first recorded, on average, made 7.85 outpatient clinic visits, made 1.89 emergency visits and spent 17.75 nights hospitalized during the event year. Mean direct medical costs during the event year were 11 751 US$, more than 2‐fold that during the preceding year (4846 US$; P < 0.001) and subsequent years (4198–4700 US$; P < 0.001) and was 4.5 times that 2 years before the event (2481 US$; P < 0.001). Incremental costs of SH patients vs matched controls during the event year and the preceding year were 10 873 US$ (P < 0.001) and 3974 US$ (P < 0.001), respectively.

Conclusions

SH is associated with excessive hospital admission rates and direct medical costs during the event year and, in particular, during the year before as compared to patients who had not experienced an SH event.
Weight loss in patients with type 2 diabetes receiving once‐weekly dulaglutide plus insulin lispro or insulin glargine plus insulin lispro: A post‐hoc analysis of the AWARD‐4 study across baseline body mass index subgroups
Authors: Fuechtenbusch Martin , Aberle Jens , Heitmann Elke , Nicolay Claudia , Jung Heike
Published: February 2019

Aims

Insulin‐treated patients with type 2 diabetes (T2D) and obesity are challenged in achieving body weight stability or reduction, in addition to glycaemic control. Post‐hoc analyses of body weight and insulin dose data from the AWARD‐4 trial involved comparison of treatment with once‐weekly dulaglutide 1.5 mg (N = 295) or 0.75 mg (N = 293) and treatment with daily insulin glargine (N = 296), each with prandial insulin lispro (± metformin).

Materials and methods

Changes in weight and in the proportion of patients without weight gain or with weight loss of at least 3%, 5% or 10% or composites of HbA1c less than 7% without weight gain and weight loss of at least 3% after 52 weeks were compared between the dulaglutide (either dose) groups and the insulin glargine group, overall and by baseline BMI (<30, 30‐<35, ≥35 kg/m2), using analysis of covariance and logistic regression, including interaction terms.

Results

The following parameters were statistically significant (P < 0.01) in favour of the dulaglutide‐treated groups, at lower mean total daily insulin doses, vs the insulin glargine group. The achieved targets were more pronounced with dulaglutide 1.5 mg than with insulin glargine: LSM weight change difference, −3.23 kg; proportion of patients without weight gain, 49.0% vs 19.0%; proportion of patients with weight loss ≥3%, 21.7% vs 5.7% or with weight loss ≥5%, 10.5% vs 2.4%; proportion of patients with HbA1c <7% without weight gain, 26.2% vs 7.9%; proportion of patients with HbA1c <7% and weight loss ≥3%, 11.9% vs 1.4%, respectively. Treatment effect for these parameters was not significantly different across BMI categories.

Conclusions

Larger proportions of patients in late‐stage T2D needing treatment intensification achieved glycemic control without weight gain or with weight loss at lower insulin doses with once‐weekly dulaglutide plus daily prandial insulin than with a basal‐bolus insulin regimen, overall and across all three BMI subgroups.
Labour productivity in African manufacturing: Does the level of skills development matter?
Authors: Mike Okumu Ibrahim , Mawejje Joseph
Published: February 2019

Motivation

This article provides the first comprehensive evidence on the relationship between skills and labour productivity among manufacturing firms across Africa. It makes two contributions. First, we re‐examine the relationship between skills and labour productivity using nuanced firm‐level data. Second, we examine whether the relationship between employee skills and firm productivity varies by size and age of the firm.

Purpose

This paper poses two questions. What is the relationship between skills and labour productivity using nuanced firm‐level data? Is the relationship between employee skills and firm productivity mediated by firm size and age?

Approach and Methods

We used the World Bank’s Enterprise Survey data and employed the pooled Ordinary Least Squares estimation. Owing to endogeneity concerns, we used Instrumental Variables, where country‐sector‐size averages instrument for high school and university education. Propensity Score Matching was used to estimate the effects of training.

Findings

We find that the effects of high school and university education are higher among small and young firms respectively. Training is positively associated with labour productivity, particularly among older and large firms.

Policy implications

Overall this article highlights the importance of skills development in Africa’s aspiration to boost manufacturing. Key to this is encouraging schoolchildren to complete the education cycle. It helps too if employers can identify the level of education that suits their needs for skills, given firm size and age. They need to identify skill gaps, then match training to the skills employees require.
A case of unguarded tricuspid valve orifice diagnosed accidentally in an adult
Authors: Abdelnabi Mahmoud Hassan , Shehata Hoda , Saleh Yehia , Elgowelly Mohamed , Almaghraby Abdallah
Published: February 2019

Unguarded tricuspid orifice is the most extreme of tricuspid valve dysplasia with a very variable natural history. They can tolerate tricuspid regurgitation well, and they become symptomatic only if significant right ventricular dysfunction or atrial fibrillation occurs. Patients with a mild degree of right ventricular dysfunction can survive to adulthood and even reach old age. Surgical treatment is a difficult option due to variable natural history, and surgical results are not too encouraging.
Stratification by MYC expression has prognostic impact in MYC translocated B‐cell lymphoma—Identifies a subgroup of patients with poor outcome
Authors: Pedersen Mette Ølgod , Gang Anne Ortved , Clasen‐Linde Erik , Breinholt Marie Fredslund , Knudsen Helle , Nielsen Signe Ledou , Poulsen Tim Svenstrup , Klausen Tobias Wirenfeldt , Høgdall Estrid , Nørgaard Peter
Published: February 2019

Objective

In patients with large B‐cell lymphoma (LBCL) according to WHO, the prognostic significance of MYC translocation is still not sufficiently clarified. We therefore aimed to investigate whether prognostication could be improved in patients with MYC translocation positive LBCL by additional stratification according to MYC and BCL2 protein expression levels or MYC translocation partner gene as well as concurrent BCL2 and/or BCL6 translocation (DH).

Methods

From an unselected consecutive cohort of >600 patients with LBCL investigated with fluorescent in situ hybridization (FISH), 64 patients were diagnosed with MYC translocation positive LBCL and included in the study. They were further investigated for supplemental translocations with FISH and MYC and BCL2 protein expression with immunohistochemistry (IHC).

Results

MYC expression >75% was associated with both reduced progression‐free survival (PFS) and overall survival (OS) (PFS: HR 6.8 (95% CI 1.5‐31), P = 0.004. OS: HR 4.3 (95% CI 0.9‐21), P = 0.05). Immunoglobulin (IG) MYC translocation partner gene was related to high MYC protein expression (P = 0.047) but was not prognostic for PFS (P = 0.8) or OS (P = 0.6). DH did not confer a worse outcome compared to MYC single hit (SH). These findings were confirmed in a comparable, independent validation cohort of 28 patients with MYC translocation positive LBCL. All patients included in the survival analyses were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R‐CHOEP (R‐CHOP + etoposide).

Conclusion

These findings suggest that in patients with LBCL stratification by MYC protein expression level significantly improves the prognostic impact associated with MYC translocation.
Parents of early‐maturing girls die younger
Authors: Hõrak Peeter , Valge Markus , Fischer Krista , Mägi Reedik , Kaart Tanel
Published: February 2019

According to the life‐history theory, rates of sexual maturation have coevolved with mortality rates so that individuals who mature faster tend to die younger. We used two data sets, providing different markers for the speed of pubertal development to test whether rates of sexual maturation of women predict the age at death of their parents. In the data set of Estonian schoolgirls born between 1936 and 1961, the rate of breast development predicted lifespan of both mothers and fathers (irrespectively of their socio‐economic position), so that parents of rapidly maturing girls died at younger age. This finding supports the view that fast maturation rates in humans have coevolved with short lifespans and that such trade‐offs can be detected as intergenerational phenotypic correlations in modern populations. Menarcheal age of participants of Estonian Biobank (born between 1925 and 1996) did not predict the age of death of their mothers; however, it did predict survival of their fathers, but only in environment where the genetic variation is exposed (families where at least one parent had tertiary education). In such families (where girls also matured 0.2–0.4 years earlier than in poorly educated families), 1‐year delay in daughter's menarche corresponded to 9% lower hazard of father's death. Heritability of menarcheal age was also highest in well‐educated families. The latter findings are consistent with the idea that genetic differences in the rate of pubertal maturation may be expressed most clearly in well‐off families because in such families, the contribution of environmental variance to total phenotypic variance in menarcheal age is smallest. Our findings suggest that with global improvement and equalization of growth conditions, reductions of environmental variation in the rate of maturation increasingly expose the genetic differences in menarcheal age to selection. Under such conditions, selection on menarcheal age has a potential to affect the evolution of lifespan.