bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review: adrenal insufficiency secondary to swallowed topical corticosteroids in eosinophilic oesophagitis
Authors: Philpott H. , Dougherty M. K. , Reed C. C. , Caldwell M. , Kirk D. , Torpy D. J. , Dellon E. S.
Published: March 2018

Background

Swallowed topical corticosteroids are prescribed for eosinophilic oesophagitis (EoE), but there is a theoretical risk of adrenal insufficiency from their use.

Aims

To determine if the use of topical corticosteroids to treat EoE is associated with the development of adrenal insufficiency.

Method

We conducted a systematic review of the published literature from January 1, 1950 to April 1, 2017 using Pubmed, Embase, Web of Science and Cochrane Central. Studies and meeting abstracts were included that described patients with EoE who received swallowed topical corticosteroids and any investigation for adrenal insufficiency.

Results

The search revealed 1610 unique publications, and 17 met inclusion criteria. There were 7 randomised controlled trials (RCTs), 6 prospective observational studies, 3 retrospective observational studies, and 1 case report. Cortisol measurements were performed on 596 individuals with EoE who received topical corticosteroids. Adrenal testing was abnormal, as defined by each study, in 94/596 patients (crude rate of 15.8%). Only 2 studies were considered to have a low risk of bias, being randomised controlled trials that estimated adrenal insufficiency in the active treatment and placebo groups, before and after treatment. None of the seven randomised controlled trials demonstrated statistically significantly different rates of adrenal insufficiency between topical corticosteroid and placebo over treatment intervals of 2‐12 weeks.

Conclusion

Topical corticosteroids were associated with adrenal insufficiency in a minority of patients. Most cases came from uncontrolled observational studies, with widely varying definitions of adrenal insufficiency. Longer follow‐up and larger controlled studies are needed to quantify the risk of adrenal insufficiency with maintenance topical corticosteroid therapy in EoE.
Genetic evaluation of reproductive potential in the Zatorska goose under a conservation program
Authors: Graczyk Magdalena , Andres Krzysztof , Kapkowska Ewa , Szwaczkowski Tomasz
Published: March 2018

The aim of this study was to estimate the genetic parameters and inbreeding effect on the fertility, embryo mortality and hatchability traits in the Zatorska goose covered by the animal genetic resources conservation program. The material for this study contains information about results of hatching of 18 863 eggs from 721 dams and 168 sires, laid between 1998–2015. Genetic parameters were estimated based on the threshold animal model by the use of Restricted Maximum Likelihood and Gibbs sampling. The percentage of fertilized eggs ranged yearly between 37–80%. The percentage of embryo mortality was very low, ranging between 4.63–23.73%. The percentage of the hatched goslings from the total number of analyzed eggs was on average 33.18%, and 53.72% from fertilized eggs. On average based on both methods, the heritability estimates of the fertility, embryo mortality and hatchability reached 0.36, 0.07, 0.24 for males and 0.44, 0.11, 0.32 for females. The genetic trend had increasing tendency for fertility and hatchability and was stable for embryo mortality for both sexes. The obtained result shows that the Zatorska goose can be still maintained in the reserves of the local gene pool according to current rules and use in the local market as a breed with good reproductive potential.
Pharmacokinetics of Tildrakizumab (MK‐3222), an Anti‐IL‐23 Monoclonal Antibody, After Intravenous or Subcutaneous Administration in Healthy Subjects
Authors: Khalilieh Sauzanne , Hodsman Peter , Xu Christine , Tzontcheva Anjela , Glasgow Shirley , Montgomery Diana
Published: March 2018

Tildrakizumab, a high‐affinity humanized IgG1k antibody that selectively binds interleukin (IL)‐23 p19 subunit of cytokine IL‐23 and neutralizes its function, is under investigation for treatment of moderate‐to‐severe chronic plaque psoriasis. The objective of this analysis was to assess the pharmacokinetics, bioavailability and safety/tolerability of single ascending doses of tildrakizumab after intravenous (IV) and subcutaneous (SC) dosing in healthy subjects. P05661 was a phase 1, single‐dose, randomized, placebo‐controlled study of tildrakizumab IV doses of 0.1, 0.5, 3 and 10 mg/kg, or placebo. P05776 was a phase 1, single‐dose, randomized, placebo‐controlled study of tildrakizumab SC doses of 50 or 200 mg, or placebo. After either single IV or SC dosing, tildrakizumab exhibited slow systemic clearance (CL), limited volume of distribution and a long t1/2. Both the Cmax and the area under the curve (AUC) increased proportionally with doses from 0.1 to 10 mg/kg, or 50–200 mg. The bioavailability of SC dosing was ~80% (90% CI: 62–103%) for 50 mg and ~73% (90% CI: 46–115%) for 200 mg, respectively, versus 0.5 and 3 mg/kg IV. Across both studies, six of 43 evaluable subjects were positive for post‐dose antidrug antibodies; two of these were positive for neutralizing antibodies. Most adverse events (AEs) were mild; the most frequent AEs included upper respiratory tract infection and headache. Single doses of tildrakizumab 0.1, 0.5, 3 and 10 mg/kg administered IV or single doses of 50 and 200 mg administered SC were safe and well tolerated in healthy adult subjects.
Desperately seeking a cure: Treatment seeking and appraisal in irritable bowel syndrome
Authors: Harvey J. Matthew , Sibelli Alice , Chalder Trudie , Everitt Hazel , Moss‐Morris Rona , Bishop Felicity L.
Published: March 2018

Objectives

Irritable bowel syndrome (IBS) is common and adversely affects patients' quality of life. Multiple potential treatment options exist for patients (and clinicians) to choose from, with limited evidence to inform treatment selection. The aim was to explore how patients with IBS go about seeking and appraising different treatment modalities, with a view to elucidating the psychological processes involved and identifying opportunities to improve clinical practice.

Design

Qualitative study nested within a randomized controlled trial of therapist‐delivered and web‐based cognitive behavioural therapy versus treatment‐as‐usual for IBS.

Methods

A total of 52 people participated in semi‐structured interviews about their prior experiences of treatments for IBS. Transcripts were analysed using inductive thematic analysis.

Results

Key themes (desperation for a cure, disappointment at lack of cure, appraising the effects of diverse treatments, and hope for positive effects) clustered around an overarching theme of being trapped within a vicious cycle of hope and despair on treatment seeking. A desperation and willingness drove interviewees to try any treatment modality available that might potentially offer relief. Coming to accept there is no cure for IBS helped interviewees escape the vicious cycle. Treatments were appraised for their effects on symptoms and quality of life while also considering, but rarely prioritizing, other aspects including convenience of the regimen itself, whether it addressed the perceived root causes of IBS, perceived side‐effects, and cost.

Conclusion

Treatment seeking in IBS can be challenging for patients. Supportive discussions with health care professionals about illness perceptions, treatment beliefs, and goals could improve patients' experiences.

Statement of contribution

What is already known on this subject?

Irritable bowel syndrome (IBS) is a highly prevalent chronic relapsing functional gastrointestinal disorder.

Studies show few treatment modalities provide complete symptom relief.

IBS is associated with emotional and physical distress, and negatively impacts personal, social, and professional aspects of quality of life.

What does this study add?

Patients appraise IBS treatments for impact on quality of life and treatment characteristics.

Developing acceptance and coping strategies helps escape treatment‐seeking vicious cycles of hope and despair.

Clinicians could better support patients by discussing their illness perceptions, treatment goals, and values.
Abnormal development of the inferior temporal region in fetuses with Down syndrome
Authors: Guidi Sandra , Giacomini Andrea , Stagni Fiorenza , Emili Marco , Uguagliati Beatrice , Bonasoni Maria Paola , Bartesaghi Renata
Published: March 2018

Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17–21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR‐positive vs. CR‐negative cells was greater than in euploid fetuses, both in the FG (177%) and ITG (161%). An increased ratio of CR‐positive vs. CR‐negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS.
Tumour growth rate of follicular thyroid carcinoma is not different from that of follicular adenoma
Authors: Kim Mijin , Han Minkyu , Lee Jeong Hyun , Song Dong Eun , Kim Kyunggon , Baek Jung Hwan , Shong Young Kee , Kim Won Gu
Published: March 2018

Objective

Distinguishing malignancy from benign thyroid nodule has always been challenging, especially in follicular lesions. Thyroid nodules with small size and indeterminate cytology do not lead to immediate surgery. We tried to evaluate whether tumour size and tumour growth rate can distinguish follicular thyroid carcinoma (FTC) from follicular adenoma (FA).

Design and Patients

This retrospective study included patients with pathologically proven FTCs (n = 50) and FAs (n = 110) who underwent preoperative serial neck ultrasonography (US) at least 3 times: it comprises 30% of all follicular tumours (32% FAs and 25% FTCs). The growth rates of follicular tumours on serial US were measured using at least 3 consecutive examinations during a median follow‐up of 4.1 years (range, 0.7‐13.3 years) by experienced radiologists.

Results

The FA and FTC groups showed no significant difference in clinicopathological characteristics, including age, proportion of large nodules (>4 cm) and preoperative cytology. The maximum diameter of thyroid nodule was gradually increased in both groups with statistical significance (P < .001 and P < .001, respectively). No significant differences in change of maximum diameter of thyroid nodule (P = .132) and tumour volume (P = .208) were found between the FA and FTC groups during the follow‐up. The median time to a significant tumour growth from baseline was not different between the FA and FTC groups (1.4 years and 1.7 years, respectively, P = .556). When we divided the patients into four groups (rapid, moderate, slow and no growth) according to the growth velocity of the thyroid tumours, no significant difference in growth velocity was found among the groups.

Conclusions

The tumour size and growth rate of the thyroid nodule itself could not predict malignancy. Diagnostic approaches that use molecular markers would be more important than clinical features for the decision of diagnostic surgery for patients with follicular tumours.
Direct Position‐Based Solver for Stiff Rods
Authors: Deul Crispin , Kugelstadt Tassilo , Weiler Marcel , Bender Jan
Published: March 2018

In this paper, we present a novel direct solver for the efficient simulation of stiff, inextensible elastic rods within the position‐based dynamics (PBD) framework. It is based on the XPBD algorithm, which extends PBD to simulate elastic objects with physically meaningful material parameters. XPBD approximates an implicit Euler integration and solves the system of non‐linear equations using a non‐linear Gauss–Seidel solver. However, this solver requires many iterations to converge for complex models and if convergence is not reached, the material becomes too soft. In contrast, we use Newton iterations in combination with our direct solver to solve the non‐linear equations which significantly improves convergence by solving all constraints of an acyclic structure (tree), simultaneously. Our solver only requires a few Newton iterations to achieve high stiffness and inextensibility. We model inextensible rods and trees using rigid segments connected by constraints. Bending and twisting constraints are derived from the well‐established Cosserat model. The high performance of our solver is demonstrated in highly realistic simulations of rods consisting of multiple 10 000 segments. In summary, our method allows the efficient simulation of stiff rods in the PBD framework with a speedup of two orders of magnitude compared to the original XPBD approach.
Biocompatibility and osteoconductivity of PLCL coated and noncoated xenografts: An in vitro and preclinical trial
Authors: Mayer Yaniv , Ginesin Ofir , Khutaba Alaa , Machtei Eli E. , Zigdon Giladi Hadar
Published: March 2018

Background

Cells, scaffolds, and growth factors are the key components in bone tissue engineering. Scaffold composition, topography, and architecture influence the amount of regenerated bone in the implantation site. The aims of the study were to compare viability and proliferation of mesenchymal stem cells (MSCs) seeded onto two commercial xenografts: Bio‐Oss (BO) and bioactive bone bovine (BB). Next, these materials were compared for histomorphometric bone formation in a socket preservation model in rats.

Materials and Methods

MSCs were seeded onto monolayers of BO or BB granules. Cell viability and proliferation were evaluated after incubation of 0, 2, 20, and 48 h. A total of 24 Sprague Dawley rats underwent unilateral extraction of maxillary molars. Rats were randomly divided into three groups: natural healing (nongrafted socket) or socket preservation with either BO or BB. Rats were sacrificed after 8 weeks, and histomorphometric analysis was done to evaluate bone formation and residual scaffold at the extraction site.

Results

Differences in the metabolic activity of MSCs that were seeded onto BO or BB was observed at 2 h after seeding: the metabolic activity was elevated compared to baseline in the BB (P = .046) and not changed in the BO wells (P = .84). After 20 h, the metabolic activity of MSCs seeded onto BO was decreasing (P = .005), while cell viability was not changed in the BB group (P = .356). Intergroup comparison revealed higher metabolic activity of MSCs seeded on BB after 48 h compared with BO (P = .016). The in vivo results demonstrated differences in socket healing between the groups: percentage of new bone was higher in the BB compared to BO group (39.1 ± 14.3 vs. 23.7 ± 10.8%, respectively, P = .096). Connective tissue portion was higher in the BO group compared with BB (73.7 ± 11.1 vs. 49.6 ± 13.7%, respectively, P = .018). Residual grafting martial was higher in the BB (11.34 ± 4.18 vs. 2.62 ± 1.23%, P = .011).

Conclusions

The results of this study demonstrating higher vitality and proliferation of MSCs seeded onto BB. Furthermore, following ridge preservation, higher percentage of new bone and lower residual scaffold were found in the BB compared with BO. This enhanced regenerative response might be the result of an enhancement of metabolic activity in cells attached to it. Further research will be needed to understand the precise mechanism.
Brain structure alterations in depression: Psychoradiological evidence
Authors: Zhang Fei‐Fei , Peng Wei , Sweeney John A. , Jia Zhi‐Yun , Gong Qi‐Yong
Published: March 2018

Depression is the leading cause of disability around the world, but little is known about its pathology. Currently, the diagnosis of depression is made based on clinical manifestations, with little objective evidence. Magnetic resonance imaging (MRI) has been used to investigate the pathological changes in brain anatomy associated with this disorder. MRI can identify structural alterations in depressive patients in vivo, which could make considerable contributions to clinical diagnosis and treatment. Numerous studies that focused on gray and white matter have found significant brain region alterations in major depressive disorder patients, such as in the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. The results are inconsistent and controversial because of the different demographic and clinical characteristics. However, some regions overlapped; thus, we think that there may be a “hub” in MDD and that an impairment in these regions contributes to disease severity. Brain connections contain both structural connections and functional connections, which reflect disease from a different view and support that MDD may be caused by the interaction of multiple brain regions. According to previous reports, significant circuits include the frontal‐subcortical circuit, the suicide circuit, and the reward circuit. As has been recognized, the pathophysiology of major depressive disorder is complex and changeable. The current review focuses on the significant alterations in the gray and white matter of patients with the depressive disorder to generate a better understanding of the circuits. Moreover, identifying the nuances of depressive disorder and finding a biomarker will make a significant contribution to the guidance of clinical diagnosis and treatment.
Hand eczema and wet work: dose–response relationship and effect of leaving the profession
Authors: Carøe Tanja K. , Ebbehøj Niels E. , Bonde Jens P. E. , Flachs Esben M. , Agner Tove
Published: March 2018

Background

Wet work is an important risk factor for occupational hand eczema.

Objectives

To examine the effect of job change in workers with occupational hand eczema caused by wet work, and to evaluate the dose–response relationship between intensity of wet work and eczema.

Method

The study is based on a subgroup (n = 954) from a descriptive, registry‐based study including all participants with occupational hand eczema caused by wet work recognized by the Danish Labour Market Insurance Authority in 2010 and 2011. A follow‐up questionnaire was sent out 4–5 years later (response 58%).

Results

Change of profession and being outside the labour market had a positive effect on healing and improvement of hand eczema. Inverse dose–response relationships were found between the amount of time spent with wet hands at work and healing (p = 0.001) and improvement (p < 0.001), and between the frequency of hand washing at work and healing (p = 0.013) and improvement (p < 0.001).

Conclusions

Leaving the profession has a positive effect on eczema; however, even minor changes in exposure to wet work were associated with healing and improvement. This information has implications with respect to advice given to patients with occupational hand eczema caused by wet work.
Cytomorphology of proximal epithelioid sarcoma in the paratesticular location
Authors: Stephen N. S. , Gochhait D. , Dehuri P. , Subramanian H. , Goldar R. S.
Published: March 2018

Cytology of epithelioid sarcoma is rare and the tumor has not been described in the paratesticular location. The cytomorphology of epithelioid sarcoma can be confused with many other sarcomas with epithelioid morphology and epithelial malignancy. These tumors express nuclear Cyclin D1 and Loss of INI 1 which can be proved on immunohistochemistry.
Identification of metastatic papillary thyroid carcinoma in FNA specimens using thyroid peroxidase immunohistochemistry
Authors: Shield P. W. , Crouch S. J. , Papadimos D. J. , Walsh M. D.
Published: March 2018

Introduction

We evaluated immunohistochemical staining for thyroid peroxidase (TPO), a glycoprotein found in the apical plasma membrane of thyroid follicular cells, as a marker for metastatic PTC in FNA samples and compared results with thyroglobulin (Tg) and thyroid transcription factor 1 (TTF1) staining.

Methods

Cell block sections prepared from 100 FNA specimens were stained with a rabbit monoclonal antibody to TPO (EP159). The FNAs included 64 metastatic malignancies from non‐thyroid primary sites, including 18 lung, and 36 cases of thyroid tumours (29 PTC, six cases of medullary thyroid carcinoma and one thyroid anaplastic carcinoma). Thyroid tumours were stained with TTF1 and Tg in addition to TPO. All cases of metastatic lung carcinoma also had TTF‐1 staining results.

Results

TPO staining was negative in all non‐thyroid malignancies. Ninety percent (26/29) of PTC were positive. All positive cases showed strong cytoplasmic staining, although 54% (14/26) showed positivity in less than half of the cells. By comparison, Tg staining of TPC cases was present in 62% and TTF‐1 in 100%. In addition to showing higher sensitivity, interpretation of staining results with TPO was generally easier with than Tg. All metastatic lung adenocarcinomas were positive for TTF‐1 and TPO negative. The six medullary cancers showed positivity in 17%, 0% and 83% with TPO, Tg and TTF‐1, respectively.

Conclusions

TPO (mAb EP159) may be a useful addition to immunohistochemical panels for FNA specimens where metastatic PTC is a consideration, particularly in cases where metastatic lung carcinoma features in the differential diagnosis.
Pastor as friend: Reinterpreting Christian leadership
Authors: Adiprasetya Joas
Published: March 2018

Christian leadership has long enjoyed the idea of servant‐leadership or doularchy that has been seen as standing against any form of kyriarchy. This article is an attempt to solve the problems left by doularchy and construct a model of philiarchic leadership based on the identity of pastors as friends. Several texts in the Gospel of John will be reinterpreted using the philiarchic lens. The article concludes with three applied ideas that today's Christian leaders should take into consideration.
The Dream of the Red Chamber and Christian theology: Seeking a new philosophy of love from the Christian perspective
Authors: Yuan Gao
Published: March 2018

The Dream of the Red Chamber (Honglou meng or The Story of the Stone), composed by Cao Xueqin in the middle of the eighteenth century during the Qing dynasty, is celebrated as the greatest of all classical Chinese novels. However, little effort has been made to explore its theological dimension, as well as the theological interaction with Chinese classical philosophy in the field of Redology (the name for research around this text). This article aims to fill this gap to explore the theological influences upon the thematic ideas of this novel. Attending to the newly discovered theological materials in recent studies, I argue that the author of Honglou meng is not ignorant of Christianity, and in fact, used a triadic image to refer to the trinitarian persons.
Safety of intranasal human insulin: A review
Authors: Schmid Vera , Kullmann Stephanie , Gfrörer Wieland , Hund Verena , Hallschmid Manfred , Lipp Hans‐Peter , Häring Hans‐Ulrich , Preissl Hubert , Fritsche Andreas , Heni Martin
Published: March 2018

Aims

To conduct a review in order to assess the safety of intranasal human insulin in clinical studies as well as the temporal stability of nasal insulin sprays.

Material and methods

An electronic search was performed using MEDLINE. We selected original research on intranasal human insulin without further additives in humans. The studies included could be of any design as long as they used human intranasal insulin as their study product. All outcomes and adverse side effects were extracted.

Results

A total of 38 studies in 1092 individuals receiving acute human intranasal insulin treatment and 18 studies in 832 individuals receiving human intranasal insulin treatment lasting between 21 days and 9.7 years were identified. No cases of symptomatic hypoglycaemia or severe adverse events (AEs) were reported. Transient local side effects in the nasal area were frequently experienced after intranasal insulin and placebo spray, while other AEs were less commonly reported. There were no reports of participants being excluded as a result of AEs. No instances of temporal stability of nasal insulin were reported in the literature. Tests on insulin that had been repacked into spray flasks showed that it had a chemical stability of up to 57 days.

Conclusions

Our retrospective review of published studies on intranasal insulin did not reveal any safety concerns; however, there were insufficient data to ensure the long‐term safety of this method of chronic insulin administration. Improved insulin preparations that cause less nasal irritation would be desirable for future treatment.
Left ventricular structural alterations are accompanied by subclinical systolic dysfunction in type 2 diabetes mellitus patients with concomitant hyperlipidemia: An analysis based on 3D speckle tracking echocardiography
Authors: Wang Qingqing , Tan Kaibin , Xia Hongmei , Gao Yunhua
Published: March 2018

Aims

The aims of the current study were to analyze and compare the left ventricular (LV) structure and function in type 2 diabetes mellitus (T2DM) patients with or without hyperlipidemia using conventional echocardiography and real‐time three‐dimensional speckle tracking echocardiography (3DSTE) and to determine the variables that could affect LV strain values in these patients.

Methods

Eighty‐one T2DM patients with normal LVEF (≥55%) were included, 41 of whom had hyperlipidemia as comorbidity. Forty age‐ and gender‐matched healthy volunteers were recruited as the control group. Conventional echocardiography and 3DSTE were performed, and LV global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS) were measured.

Results

Significant differences in two‐dimensional LV geometry were found among three groups (P = .015). Compared with the control group, LV remodeling was more prevalent in the patients with T2DM, and LV hypertrophy was most prevalent in the T2DM patients with hyperlipidemia. GLS and GCS values decreased significantly in the T2DM patients without hyperlipidemia relative to the control group (P < .01 andP < .05). The GLS, GCS, GAS, and GRS values in the T2DM patients with hyperlipidemia were all significantly lower than those in the control group (allP < .001) and were also significantly lower than those in the T2DM patients without hyperlipidemia (P < .01 orP < .05). Both fasting plasma glucose (FPG) and hyperlipidemia were independently associated with all strain values in patients with T2DM.

Conclusions

The combination of conventional echocardiography and 3DSTE could detect subclinical LV abnormalities in T2DM patients with or without hyperlipidemia.
Agitated saline contrast echocardiography reveals a systemic‐to‐pulmonary venous shunt
Authors: Masoero Giovanni , Papachristidis Alexandros , Theodoropoulos Konstantinos C. , Harries Derek , Monaghan Mark J. , Sado Daniel M.
Published: March 2018

Contrast echocardiography with agitated saline is used to assess mainly the existence of interatrial communication. We report a case of a 26‐year‐old woman, with a “port‐a‐cath” central venous line, who had an unusual finding in agitated saline contrast echocardiography. Multimodality imaging revealed occlusion of superior vena cava and a systemic‐to‐pulmonary venous shunt.
Insect adaptations toward plant toxins in milkweed–herbivores systems – a review
Authors: Birnbaum S.S.L. , Abbot P.
Published: March 2018

Studies of plant defenses and insect herbivores have been important in the development of our understanding of coevolution and specialization. Milkweed–herbivore systems have been a model for studying plant secondary chemistry defense evolution, insect adaptations to that chemistry, and coevolution between toxic plants and their herbivores for over a century. Yet, we are only beginning to unravel the multitude of adaptations required for insect specialization on milkweed plants. We review the empirical evidence for specialist insect adaptations toward milkweed toxins, coevolution between insects and milkweed plants, and canonical paradigms for sequestration and highlight the areas for further research. By comparing research performed with diverse milkweed insects, we discuss the need to comprehensively study adaptations and specialization in divergent insect taxa.
Hegel on the value of the market economy
Authors: Heisenberg Thimo
Published: March 2018

It is widely known that Hegel is a proponent and defender of the market economy. But why exactly does Hegel think that the market economy is superior to other economic systems? In this paper, I argue that Hegel's answer to this question has not been sufficiently understood. Commentators, or so I want to claim, have only identified one part of Hegel's argument—but have left out the most original and surprising dimension of his view: namely, Hegel's conviction that we should embrace the market economy for its educational impact. Indeed, Hegel thinks that the market, by creating a sphere of life apart from traditional norms and expectations, teaches us something about ourselves, about others, and about the world we inhabit together—something that we could not learn anywhere else, but that we inevitably need to live well as individuals.
Declining trend in valproate use in Finland among females of childbearing age in 2012–2016 – a nationwide registry‐based outpatient study
Authors: Virta L. J. , Kälviäinen R. , Villikka K. , Keränen T.
Published: March 2018

Background and purpose

Documented teratogenic effects of valproate (VPA) prompted restrictions of its use in females of childbearing age in 2014. We investigated possible annual changes in the outpatient use of VPA in Finland during 2008–2016 with a special focus on women.

Methods

We identified all outpatients with VPA purchases between 2008 and 2016 categorizing users due to epilepsy, bipolar disorder or miscellaneous indications. Temporal trends in the annual prevalence rates of VPA use were estimated using Poisson regression analyses.

Results

Between 2012 and 2016, the prevalence of VPA use among women aged 15–44 years decreased by 19%, from 50/10 000 to 40/10 000 (prevalence rate ratio, 0.81; 95% confidence intervals, 0.77–0.91; P < 0.001). The use of VPA due to epilepsy decreased significantly in females aged 15–24 and 25–34 years and that due to bipolar disorders decreased significantly in females aged 25–34 and 35–44 years. The use of VPA in the miscellaneous indication group decreased by 32% after 2014 in females aged 15–44 years and, most strikingly, by 56% among those aged 15–25 years. In women with epilepsy, the use of VPA increased among those over the age of 44 years.

Conclusions

The rates of female VPA users with childbearing potential have decreased in all three major indication groups in Finland during recent years, especially after the European Medicines Agency restrictions were published in 2014. However, it still remains open to question as to whether the practice of VPA use follows current guidelines. A special concern is the relatively high prevalence of off‐label use of VPA in fertile‐aged females.
Partial loss of function of colony‐stimulating factor 1 receptor in a patient with white matter abnormalities
Authors: Konno T. , Miura T. , Harriott A. M. , Mezaki N. , Edwards E. S. , Rademakers R. , Ross O. A. , Meschia J. F. , Ikeuchi T. , Wszolek Z. K.
Published: March 2018

Background and purpose

Mutations in colony‐stimulating factor 1 receptor (CSF1R) cause adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Patients with ALSP can be misdiagnosed as having acute ischemic stroke due to hyperintensity lesions on diffusion‐weighted magnetic resonance imaging. Mutant CSF1R proteins identified in ALSP show a complete loss of autophosphorylation of CSF1R.

Methods

We conducted mutation screening of CSF1R in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke. The pathogenicity of identified variants was evaluated using functional analyses. The levels of autophosphorylation of CSF1R in response to treatment with ligands of CSF1R were examined in cells transfected with wild‐type and mutant CSF1R.

Results

We identified eight CSF1R variants, six were known non‐pathogenic polymorphisms, whereas the other two were missense variants inducing substitution of amino acid residues (p.Glu573Lys and p.Gly747Arg). Functional assay showed that the levels of autophosphorylation of p.Gly747Arg were similar to those of wild‐type when treated with ligands. The autophosphorylation of p.Glu573Lys was detectable, but significantly decreased compared with those of wild‐type CSF1R (P < 0.001, two‐way anova with Bonferroni). The clinical presentation of the patient with p.Glu573Lys was consistent with cerebral embolism. The patient did not have typical clinical findings of ALSP. However, periventricular white matter abnormalities, unrelated to the recent infarct, were evident on brain magnetic resonance imaging.

Conclusions

In contrast to ALSP‐associated missense mutations, CSF1R p.Glu573Lys variant in a patient with acute ischemic cerebrovascular syndrome showed a partial loss of autophosphorylation of CSF1R; its clinical significance warrants further investigation.
The relationship between mucosal damage in celiac disease and the risk of neurological and psychiatric conditions is much more complex than previously thought
Authors: Parisi P.
Published: March 2018

Click here to view the accompanying paper in this volume.
Myosin 10 is involved in murine pigmentation
Authors: Liakath‐Ali Kifayathullah , Vancollie Valerie E. , Sequeira Inês , Lelliott Christopher J. , Watt Fiona M.
Published: March 2018

Myosins are molecular motors that are well known for their role in cell movement and contractile functions. Although extensively studied in muscle physiology, little is known about the function of myosins in mammalian skin. As part of the Sanger Institute Mouse Genetics Project, we have identified a role for Myo10 in pigmentation, with a phenotype unlike those of Myo5a or Myo7a. Adult mice homozygous for a disrupted Myo10 allele on a C57BL/6N background displayed a high degree of penetrance for white patches on their abdomen and dorsal surface. Forepaw syndactyly and hind paw syndactyly were also observed in these mice. Tail epidermal wholemounts showed a complete lack of melanocytes in the hair follicles and interfollicular epidermis. Myo10 has previously been implicated in human pigmentation. Our current study reveals involvement of Myo10 in murine skin pigmentation.
Grand challenges and great potential in foreign language teaching and learning
Authors: Hlas Anne Cummings
Published: March 2018

This article argues for the field of foreign languages to begin to identify and define our Grand Challenges, which are difficult yet solvable problems facing our field. Seeking answers to these challenges can provide new opportunities for collaboration and can spur new directions and innovation within language learning and teaching. Researchable questions that emerge from these Grand Challenges can form a research trajectory, build community support, and contribute to changing public opinion about the role of languages in greater society.
Phosphorylation of N‐terminal regions of REV‐ERBs regulates their intracellular localization
Authors: Ohba Yuki , Tei Hajime
Published: March 2018

Circadian rhythms are generated by the cyclic expression of several clock genes in mammals. The rhythmic expression of these genes is maintained by multiple transcriptional–translational feedback loops in addition to the posttranslational regulation of the clock proteins. Transcription of one of the key clock genes, Bmal1, which exhibits a nocturnal transcriptional rhythm in the suprachiasmatic nucleus of the mouse brain, is induced and repressed by RORs and REV‐ERBs, respectively. Thus, the dynamics of the RORs and REV‐ERBs expression, modification, subcellular localization and degradation of these transcriptional factors are critical for the transcriptional regulation of Bmal1. In this study, we found that the highly homologous N‐terminal regions of REV‐ERBα and REV‐ERBβ determined both their own CK1‐catalyzed phosphorylation and the cytoplasmic accumulation of each hyperphosphorylated form. Of the homologous N‐terminal regions, three serine‐rich clusters in REV‐ERBβ are required for the phosphorylation and cytoplasmic localization. Our results indicate that the REV‐ERBs phosphorylation by CK1 plays a key role in their subcellular localization, thereby controlling the timings of the transcriptional activation and inhibition of Bmal1.
A comparative review of the isotretinoin pregnancy risk management programs across four continents
Authors: Kovitwanichkanont Tom , Driscoll Tim
Published: March 2018

Isotretinoin has revolutionized the treatment of severe acne vulgaris, a condition which if left untreated may result in significant socio‐psychological implications for those affected. Timely access to isotretinoin therapy is important to avoid the risks of potential physical and emotional scarring. However, due to its high risks of teratogenicity, isotretinoin must be used with care in females of childbearing potential. Since isotretinoin's introduction, numerous risk management programs have been implemented across the world in an attempt to prevent isotretinoin use in pregnancy. This paper aims to provide an evidence‐based review of the risk management programs for isotretinoin in Australia, Europe, Singapore, New Zealand, and the United States of America. The effectiveness of these programs and the factors leading to isotretinoin exposure in pregnancy are critically analyzed in an effort to inform the future direction with respect to designing the ideal regulatory program. Stringent risk management programs, such as the iPLEDGE in the US and Pregnancy Prevention Program (PPP) in Europe, may not be effective in reducing the risks of fetal exposure to isotretinoin when used alone. There is evidence that such strenuous regulation results in increased fear of teratogenic risks but does not translate into a reduced rate of pregnancies exposed to isotretinoin. A successful program must prioritize education about effective contraception, while minimizing any extraneous requirements, to ensure that women are not inadvertently undertreated for acne.
Le partenariat social, une voie d'avenir pour les syndicats indiens? Illustration par le cas de la fonction publique
Authors: BADIGANNAVAR Vidu
Published: March 2018

En Inde, depuis les réformes économiques de 1991, les syndicats ont toujours moins d'influence sur les politiques adoptées et l'issue de la négociation collective. En se fondant sur des données recueillies dans l'État du Maharashtra, auprès de délégués de deux centrales syndicales, l'auteur cherche à vérifier si le «partenariat social», au sens de coopération avec l'employeur, pourrait permettre aux syndicats d'inverser la tendance et de servir plus efficacement les intérêts des travailleurs. Si la législation protectrice du Maharashtra semble propice à la concertation, les pratiques sur le terrain, l'indifférence des autorités et une jurisprudence défavorable réduisent les possibilités de bâtir un véritable partenariat social.
Developing a Quality of Experience (QoE) model for Web Applications
Authors: Lycett Mark , Radwan Omar
Published: March 2018

Web‐based service providers have long been required to deliver high quality services in accordance with standards and customer requirements. Increasingly, however, providers are required to think beyond service quality and develop a deeper understanding of their customers' Quality of Experience (QoE). Although models exist that assess the QoE of Web Application, significant challenges remain in: (1) Defining QoE factors from a Web engineering perspective, (2) quantifying the relationship between so‐called “objective” and “subjective” factors of relevance, and (3) dealing with limited data available in relation to subjective factors. In response, the work here presents a novel model (and associated software instantiation) that integrates factors through Key Performance Indicators and Key Quality Indicators. The mapping is incorporated into a correlation model that assesses the QoE of Web Applications, with a consideration of defining the factors in term of quality requirements derived from web architecture. The data resulting from the mapping is used as input of the proposed model to develop artefacts that quantify and predict QoE using Machine Learning. The development of proposed model is framed and guided by Design Science Research approach with the purpose of enabling providers to more informed decisions regarding QoE and/or to optimise resources accordingly. Although the work is oriented at developing an artefact that has clear utility for practice, the nascent design theory underpinning the work is developed and discussed.
The contribution of neutral evolution and adaptive processes in driving phenotypic divergence in a model mammalian species, the Andean fox Lycalopex culpaeus
Authors: Martinez Pablo A. , Pia Monica V. , Bahechar Ilham A. , Molina Wagner F. , Bidau Claudio J. , Montoya‐Burgos Juan I.
Published: March 2018

Aim

Understanding the mechanisms that drive phenotypic divergence along climatic gradients is a long‐standing goal of biogeography. To fulfil this objective, we tested if neutral and/or adaptive effects drive phenotypic diversification. We quantified the effects of neutral evolution and natural selection on morphological variability of a well‐suited mammalian species, the fox, Lycalopex culpaeus.

Location

South America.

Methods

We analysed variations in skull shape, jaw shape and skull size in L. culpaeus. The processes underlying our models were: local adaptation, and short‐ or long‐term neutral evolution. We inferred genetic population structure using mitochondrial and nuclear markers, we quantified morphological differences among populations by performing geometric morphometric analyses, and we inferred an ecological niche model for calculating environmental resistance between populations.

Results

We identified six genetically differentiated populations of the Andean fox, which correspond well to the described subspecies. We showed that skull shape variation is explained by population structure. Skull size showed a clear Bergmannian pattern with larger animals in higher latitudes (in absolute values). Skull size divergence is driven by the combined effects of environmental factors and population structure. Intriguingly, none of the models explains the variation observed in jaw shape.

Main Conclusion

Population phenotypic variation in the Andean fox L. culpaeus is driven by deterministic and neutral processes. The methodological framework presented here opens up new opportunities to study phenotypic evolution; it allowed us to demonstrate that the processes explaining trait variation can differ among traits and to show empirically for the first time that a trait can diverge among populations due to simultaneous adaptation and neutral evolution.
“Strangers in the ER”: Quality indicators and third party interference in Dutch emergency care
Authors: Moes Floortje B. , Houwaart Eddy S. , Delnoij Diana M. J. , Horstman Klasien
Published: March 2018

Rationale, aims, and objectives

This paper examines a remarkable dispute between Dutch insurers, hospitals, doctors, and patients about a set of quality indicators. In 2013, private insurers planned to drastically reform Dutch emergency care using quality indicators they had formulated drawing from clinical guidelines, RCTs, and systematic reviews. Insurers' plans caused much debate in the field of emergency care. As quality indicators have come to play a more central role in health care governance, the questions what constitutes good evidence for them, how they ought to be used, and who controls them have become politically and morally charged. This paper is a case study of how a Dutch public knowledge institution, the National Health Care Institute, intervened in this dispute and how they addressed these questions.

Method

We conducted ethnographic research into the knowledge work of the National Health Care Institute. Research entailed document analysis, participant observation, in‐depth conversations, and formal interviews with 5 key‐informants.

Results

The National Health Care Institute problematized not only the evidence supporting insurers' indicators, but also—and especially—the scope, purpose, and use of the indicators. Our analysis shows the institute's struggle to reconcile the technical rationality of quality indicators with their social and political implications in practice. The institute deconstructed quality indicators as national standards and, instead, promoted the use of indicators in dialogue with stakeholders and their local and contextual knowledge.

Conclusions

Even if quality indicators are based on scientific evidence, they are not axiomatically good or useful. Both proponents and critics of Evidence‐based Medicine always feared uncritical use of evidence by third parties. For non‐medical parties who have no access to primary care processes, the type of standardized knowledge professed by Evidence‐based Medicine provides the easiest way to gain insights into “what works” in clinical practice. This case study reminds us that using standardized knowledge for the management of health care quality requires the involvement of stakeholders for the development and implementation of indicators, and for the interpretation of their results.
Assessment of knowledge and applications of hygiene practices in the food service sector
Authors: Schirone Maria , Visciano Pierina , Di Serafino Gabriella , Tofalo Rosanna , Ciccarelli Andrea , Suzzi Giovanna
Published: March 2018

Forty food service establishments were investigated in the Abruzzo region (central Italy) by two physical inspections and in the second one the managers were asked to fill a detailed checklist aiming at verifying the application of good hygiene practices and other regulatory requirements intended to all member states of the European Union. The results showed that training and personal hygiene were observed by most establishments (92.5 and 60%, respectively), as well as sanitation and update of supplier list (from 75 to 100% the first item and 87.5% the last). On the contrary, the major nonconformances regarded the registration documents, above all food traceability (90%), and storage for incoming raw materials (77.5%). The compliance to the investigated requirements did not depend on the size of food service establishment but it was strictly affected by the manager capacity or sensitivity. The specific points of the checklist (personnel, foodstuffs supplier, storage, temperature control, sanitation, personal hygiene, pest control, and registration documents) proposed in this study could facilitate and promote a good management of the food distribution system also to avoid the potential occurrence of health hazards for consumers.

Practical applications

The study deals with the application of good hygiene practices in forty food service establishments located in the Abruzzo region, central Italy. The investigation was achieved with the support of a detailed checklist prepared by the authors and the responses were analyzed by a multiple correspondence analysis and then a cluster analysis. This article can assist the food business operators by providing some suggestions to deliver and ameliorate the potential nonconformances observed in the investigated establishments.