bluuebunny/crossref_metadata_2025 huggingface dataset:
Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives
Authors: Costa N , Marques O , Godinho S I , Carvalho C , Leal B , Figueiredo A M , Vasconcelos C , Marinho A , Moraes-Fontes M F , Gomes da Costa A , Ponte C , Campanilho-Marques R , Cóias T , Martins A R , Viana J F , Lima M , Martins B , Fesel C
Published: May 2017

Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+FoxP3+CD45RO–CD31+ recent thymic emigrant Tregs. This first component effect influenced the proportions of circulating CD4+FoxP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs, but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg-directed therapies can be monitored more effectively when taking this distinction into account.
Tanshinone IIA ameliorates chronic arthritis in mice by modulating neutrophil activities
Authors: Zhang S , Huang G , Yuan K , Zhu Q , Sheng H , Yu R , Luo G , Xu A
Published: May 2017

Rheumatoid arthritis (RA) is a chronic immune inflammatory disease mediated by the influx of immune cells into the synovial joint space. As Tanshinone IIA (TIIA) has potent anti-oxidant and anti-inflammatory activities, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TIIA on RA and immune cell activation. The anti-arthritic activity of TIIA was investigated in an adjuvant-induced arthritis model of RA in mice. Myeloperoxidase and neutrophil elastase expression levels were assessed in ankle joints by immunohistochemistry analysis. Immune cell infiltration was evaluated in air pouch experiments. Proinflammatory cytokines expression levels were determined by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. Neutrophil extracellular traps (NETs) were assessed by immunostaining and confocal microscopy. Treatment with TIIA alleviated cartilage erosion and neutrophil infiltration in the ankle joints of AA mice and reduced proinflammatory cytokine expression levels in sera. TIIA suppressed interleukin-6 and tumour necrosis factor-α expression and release in neutrophils and promoted neutrophil apoptosis. TIIA also inhibited the NET formation of neutrophils. Our findings demonstrated that TIIA can ameliorate RA effectively by targeting neutrophils, indicating that TIIA may act as a potential therapeutic for RA.
Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities
Authors: Noor A. , Bogatan S. , Watkins N. , Meschino W.S. , Stavropoulos D.J.
Published: May 2017

There is a broad phenotypic spectrum of patients with 17p13.3 deletions. One of the most prominent feature is lissencephaly caused by haploinsufficiency of the gene PAFAH1B1. The deletion of this gene and those distal to it, results in Miller‐Dieker syndrome, however there have been many reports of patients with haploinsufficiency of the distal genes alone. The deletions of these genes including YWHAE CRK and TUSC5 have been studied extensively and YWHAE has been postulated to be the cause of neurological abnormalities. The patients with deletions of the Miller‐Dieker syndrome distal region present with variable clinical features including brain abnormalities, growth retardation, developmental delay, facial dysmorphisms and seizures. While there have been many patients reported to have deletions involving the YWHAE gene along with other genes, here we present the first detailed clinical description of a patient with deletion of YWHAE alone, allowing a more accurate characterization of the pathogenicity of YWHAE haploinsufficiency. The patient reported here demonstrated brain abnormalities, learning disabilities, and seizures supporting the role of YWHAE in these features. We review the literature and use this case report to better characterize and further confirm the genotype‐phenotype relationship of the genes within the critical region of Miller‐Dieker Syndrome.
On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation
Authors: Tello C. , Darling A. , Lupo V. , Pérez‐Dueñas B. , Espinós C.
Published: May 2017

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next‐generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.
Level of vascular tie and its effect on functional outcome 2 years after anterior resection for rectal cancer
Authors: Kverneng Hultberg D. , Afshar A. A. , Rutegård J. , Lange M. , Haapamäki M. M. , Matthiessen P. , Rutegård M.
Published: May 2017

Aim

Previous research indicates that high tie of the inferior mesenteric artery during anterior resection for rectal cancer might be associated with an increased risk of postoperative functional disturbances. The goal of this population‐based retrospective cohort study was to further investigate that association.

Method

Patients who underwent anterior resection for rectal cancer from April 2011 to September 2012 were identified through the Swedish Colorectal Cancer Registry. Bowel and urogenital function were assessed by a postal questionnaire 2 years after surgery. Information on the level of mesenteric tie and clinical variables was retrieved from the registry. The outcome was defined as any defaecatory, urinary or sexual dysfunction as reported by the patient. The association between high tie and the outcome was evaluated with multivariable logistic and linear regression with adjustment for confounders, such as sex, body mass index, comorbidity and preoperative radiation.

Results

With a response rate of 86%, 805 patients were included in the study. Of these, 46% were operated with high tie. After adjustment for confounders, high tie did not affect the risk of faecal incontinence (OR 0.85; 95% CI 0.59–1.22), urinary incontinence (OR 0.94; 95% CI 0.63–1.41) or various aspects of sexual dysfunction (erectile dysfunction, anejaculation, dyspareunia and coital vaginal dryness). However, an association between high tie and defaecation at night was detected (OR 1.44; 95% CI 1.02–2.03).

Conclusion

This study does not support that the level of vascular tie influences the risk of major defaecatory, urinary or sexual disturbances 2 years after anterior resection for rectal cancer.
Crop wild relatives range shifts and conservation in Europe under climate change
Authors: Aguirre‐Gutiérrez Jesús , van Treuren Rob , Hoekstra Roel , van Hintum Theo J.L.
Published: May 2017

Aim

Climate change is expected to have a great impact on the distribution of wild flora around the world. Wild plant species are an important component of the genetic resources for crop improvement, which is especially important in face of climate change impacts. Still, many crop wild relatives (CWRs) are currently threatened in their natural habitat and are poorly represented in gene bank collections. To guide in situ conservation measures and to prioritize species for ex situ conservation, predictions are needed about future species distributions as a result of climate change.

Location

Europe.

Methods

Using species occurrence data and present and future climatic information, we investigated the possible impacts of future climate change on the European distribution of a selection of CWRs red‐listed in the Netherlands using a species distribution modelling framework. The representation of the CWRs in European protected areas was investigated for the current and future climatic conditions. The models were created based on an optimistic (RCP 2.6) and pessimistic (RCP 8.5) climate change scenario.

Results

A shift in distribution range, mostly towards northern locations, was observed for all investigated species. A loss of distribution area of up to 61.10% (full dispersal assumption) and 68.91% (no dispersal) according to RCP 2.6 was observed for some species. A distribution area loss of up to 90.92% (full dispersal) and 98.36% (no dispersal) was predicted for the most affected species under the RCP 8.5. Based on the predicted distribution in protected areas, present occupation in nature reserves appeared to be no guarantee for the species’ future protection and persistence.

Main conclusions

We conclude that in situ conservation measures, ignoring the effects of climate change, will not be effective for many CWRs and that large‐scale ex situ conservation actions are needed to safeguard CWRs.
The mid‐distance dispersal optimum, evidence from a mixed‐model climate vulnerability analysis of an edaphic endemic shrub
Authors: Pérez‐García Nora , Thorne James H. , Domínguez‐Lozano Felipe
Published: May 2017

Aim

Predicting accurate species responses to climate change in fragmented landscapes is challenging in conservation biogeography. We assessed the role of dispersal, including long‐distance dispersal (LDD), for the long‐term persistence of a rare plant species (Vella pseudocytisus subsp. paui) under current climate conditions and four future climate scenarios; and analysed the effect of competition for its regional survival.

Location

Ester Iberian system, Aragón, Spain.

Methods

We used BioMove, a linked modelling platform that integrates demographic, dispersal and competition features with biogeographic predictions of range dynamics, and whose results can inform risk assessments and conservation planning. We linked Vella's population dynamics and habitat suitability models with its well‐documented life history traits and ecological characteristics to enhance our understanding of its inherent vulnerability to dispersal, competitive interactions and climate change.

Results

We found thresholds in the effect of long dispersal distances on population persistence, suggesting a mid‐distance optimum, which reduces mortality risk associated with the increasing proportion of LDD seeds. Moreover, increasing the proportion of LDD propagules reduces Vella's ability to compete in currently occupied and nearby unoccupied habitats by reducing the number of local recruitments.

Main conclusions

Whereas LDD ability is generally assumed to be beneficial for the long‐term persistence of plant species in fragmented landscapes, our results suggest that moderate to high distances between new colonization increase the species’ dispersal‐related mortality. Higher numbers of LDD events reduce the number of local propagules in established populations, reducing regional survival for Vella. Moreover, associated range shifts of potentially better climate‐adapted competitors could prevent Vella individuals from colonizing new climatically suitable habitats. These findings can support development of more efficient conservation management strategies for establishing new population patches to mitigate population losses due to climate change. Our findings may also apply as a framework for other narrowly distributed endemic shrub species, particularly edaphic endemics.
Overseas Expansion and Domestic Business Restructuring in Japanese Firms
Authors: Ito Keiko , Ikeuchi Kenta
Published: May 2017

In this paper, we examine domestic business restructuring by Japanese multinational enterprises by using establishment‐level panel data for the years 2001, 2006, 2009, and 2012. Focusing on the routine‐task intensity of establishments, we examine the impact of restructuring in terms of: (1) what type of establishments are closed or newly established; and (2) what type of establishments increase or reduce their employment when a firm becomes multinational. We measure the skill level of each establishment using occupation‐level routine‐task intensity and occupation composition for each industry. We find that more routine‐task intensive establishments have a greater likelihood of exiting the domestic market when the firm becomes multinational. In the case of continuing establishments, less routine‐task intensive establishments tend to have a higher employment growth rate when a firm becomes multinational. Our results imply that overseas expansion accelerates domestic business restructuring within multinational enterprises and shifts domestic activities toward less routine‐task intensive ones.
Do we know the true mechanism of action of the DPP‐4 inhibitors?
Authors: Andersen Emilie S. , Deacon Carolyn F. , Holst Jens J.
Published: May 2017

The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti‐diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a recent addition to the anti‐diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side‐effect profile and their low hypoglycaemia risk. The actions of DPP‐4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide, are known substrates, but other incretin‐independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP‐4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.
Ghrelin receptor inverse agonists as a novel therapeutic approach against obesity‐related metabolic disease
Authors: Abegg Kathrin , Bernasconi Lara , Hutter Melanie , Whiting Lynda , Pietra Claudio , Giuliano Claudio , Lutz Thomas A. , Riediger Thomas
Published: May 2017

Aims

Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand‐independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR‐IA) might be effective for the treatment of obesity‐related metabolic disease, we tested 2 novel synthetic compounds GHSR‐IA1 and GHSR‐IA2.

Materials and Methods

In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR‐IA1 and GHSR‐IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet‐induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids.

Results

Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR‐IA1 increased metabolic rate in chow‐fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR‐IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair‐fed and vehicle‐treated mice. GHSR‐IA2‐treated DIO mice showed decreased blood lipids. GHSR‐IA1 treatment markedly decreased HS in DIO mice.

Conclusions

Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity‐related metabolic disorders including diabetes mellitus.
Deregulated expression of long non‐coding RNA UCA1 in multiple myeloma
Authors: Sedlarikova Lenka , Gromesova Barbora , Kubaczkova Veronika , Radova Lenka , Filipova Jana , Jarkovsky Jiri , Brozova Lucie , Velichova Roberta , Almasi Martina , Penka Miroslav , Bezdekova Renata , Stork Martin , Adam Zdenek , Pour Ludek , Krejci Marta , Kuglík Petr , Hajek Roman , Sevcikova Sabina
Published: May 2017

Objectives

Long non‐coding RNAs (lncRNAs) are RNA transcripts longer than 200 nucleotides that are not translated into proteins. They are involved in pathogenesis of many diseases including cancer and have a potential to serve as diagnostic and prognostic markers. We aimed to investigate lncRNA expression profiles in bone marrow plasma cells (BMPCs) of newly diagnosed multiple myeloma (MM) patients in comparison to normal BMPCs of healthy donors (HD) in a three‐phase biomarker study.

Methods

Expression profile of 83 lncRNA was performed by RT2 lncRNA PCR Array (Qiagen), followed by quantitative real‐time PCR using specific TaqMan non‐coding RNA assays analyzing 84 newly diagnosed MM patients and 25 HD.

Results

Our analysis revealed dysregulation of two lncRNAs; NEAT1 (sensitivity of 55.0% and specificity of 79.0%) and UCA1 (sensitivity of 85.0% and specificity of 94.7%). UCA1 levels correlated with albumin and monoclonal immunoglobulin serum levels, cytogenetic aberrations, and survival of MM patients.

Conclusion

Our study suggests a possible prognostic impact of UCA1 expression levels on MM patients.
Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations
Authors: Patsalos Philip N. , Zugman Miguel , Lake Charlotte , James Anthony , Ratnaraj Neville , Sander Josemir W.
Published: May 2017

Objective

Given that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide and N‐desmethyl clobazam), using standardized methodology and under set conditions.

Methods

The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.

Results

Gabapentin and pregabalin are non–protein‐bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7–74.8%).

Significance

These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine‐epoxide and N‐desmethyl‐clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment.
QTLand systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field
Authors: Delprato A. , Algéo M.‐P. , Bonheur B. , Bubier J. A. , Lu L. , Williams R. W. , Chesler E. J. , Crusio W. E.
Published: May 2017

The open field is a classic test used to assess exploratory behavior, anxiety and locomotor activity in rodents. Here, we mapped quantitative trait loci (QTLs) underlying behaviors displayed in an open field, using a panel of 53BXDrecombinant inbred mouse strains with deep replication (10 per strain and sex). The use of these strains permits the integration and comparison of data obtained in different laboratories, and also offers the possibility to study trait covariance by exploiting powerful bioinformatics tools and resources. We quantified behavioral traits during 20‐min test sessions including (1) percent time spent and distance traveled near the wall (thigmotaxis), (2) leaning against the wall, (3) rearing, (4) jumping, (5) grooming duration, (6) grooming frequency, (7) locomotion and (8) defecation. All traits exhibit moderate heritability making them amenable to genetic analysis. We identified a significantQTLon chromosomeM.m.4 at approximately 104 Mb that modulates grooming duration in both males and females (likelihood ratio statistic values of approximately 18, explaining 25% and 14% of the variance, respectively) and a suggestiveQTLmodulating locomotion that maps to the same locus. Bioinformatic analysis indicatesDisabled 1(Dab1, a key protein in the reelin signaling pathway) as a particularly strong candidate gene modulating these behaviors. We also found 2 highly suggestiveQTLsfor a sex by strain interaction for grooming duration on chromosomes 13 and 17. In addition, we identified a pairwise epistatic interaction between loci on chromosomes 12 at 36–37 Mb and 14 at 34–36 Mb that influences rearing frequency in males.
Predicting dose sparing benefit and bleeding risk of pharmacokinetic‐based personalized prophylactic dosing of factor VIII products
Authors: Tegenge M. A. , Yang H. , Forshee R. A.
Published: May 2017

Background

Previously published factor VIII (FVIII) pharmacokinetic (PK)‐based dosing approaches employ fixed infusion interval with a wide dose range that may lead to increased risk of bleeding, excessive doses or decreased health‐related quality of life.

Aim

The objectives of the study includes (i) personalizing infusion interval in lieu of fixed infusion, (ii) constraining dose within the range of 10‐50 IU/kg and (iii) characterizing bleeding risk of PK‐based dosing in comparison with empiric standard doses.

Methods

Patient demographics and PK parameters for conventional FVIII products were obtained from published literatures. Subject‐specific PK parameters were derived from FVIII activities vs time data generated through simulation.

Results

Our data indicated approximately 4%, 38%, 37% and 20% of the subjects can be dosed with infusion interval of every 24, 48, 72 and 96 hours, respectively, for maintaining a target 1 IU/dL FVIII level within the dose range of 10‐50 IU/kg. Maintaining an alternative trough value of 3 or 5 IU/dL requires more frequent infusion. The predicted median probability of bleeding risk per year was 35.7% (range, 11%‐49%) for PK‐based dosing maintaining 1 IU/dL. Predicted median bleeding risk was 37.9% (0%‐74%), 32.8% (0%‐72%) and 26.7% (0%‐70%) for standard dosing of 20, 30 and 50 IU/kg, respectively. PK‐based dosing resulted in a dose sparing benefit compared to standard dose of 30 or 50 IU/kg three times per week.

Conclusion

The results of the study demonstrate the feasibility of individualizing infusion interval, restricting FVIII dose, trough and peak concentration within an acceptable range.
Effectiveness of shared goal setting and decision making to achieve treatment targets in type 2 diabetes patients: A cluster‐randomized trial (OPTIMAL)
Authors: Den Ouden Henk , Vos Rimke C. , Rutten Guy E. H. M.
Published: May 2017

Objective

About 20% of patients with type 2 diabetes achieve all their treatment targets. Shared decision making (SDM) using a support aid based on the 5‐years results of the ADDITION study on multifactorial treatment, could increase this proportion.

Research design and methods

Cluster‐randomized trial in 35 former ADDITION primary care practices. Practices were randomized to SDM or care as usual (1:1). Both ADDITION and non‐ADDITION type 2 diabetes patients, 60‐80 years, known with diabetes for 8‐12 years, were included. In the intervention group, patients were presented evidence about the relationship between treatment intensity and cardiovascular events. They chose intensive or less intensive treatment and prioritized their targets. After 1 year priorities could be rearranged. Follow‐up: 24 months. Intention‐to‐treat analysis. Main outcome measure: proportion of patients that achieved all three treatment targets.

Results

At baseline 26.4% in the SDM group (n=72) had already achieved all three treatment goals (CG: 23.5%, n=81). In the SDM group 44 patients chose intensive treatment, 25 continued their former less intensive treatment and three people switched from the more to the less intensive protocol. After 24 months 31.8% of the patients in the SDM group achieved all three treatment targets (CG: 25.3%), RR 1.26 (95% CI 0.81‐1.95). Mean systolic blood pressure decreased in the SDM group (−5.4 mm Hg, P<.01), mean HbA1c and total cholesterol did not change.

Conclusions

Despite an already high baseline level of diabetes care, we found strong indications that SDM on both intensity of treatment and prioritizing treatment goals further improved outcomes.
Comprehensive characterization of RSPO fusions in colorectal traditional serrated adenomas
Authors: Sekine Shigeki , Ogawa Reiko , Hashimoto Taiki , Motohiro Kojima , Yoshida Hiroshi , Taniguchi Hirokazu , Saito Yutaka , Yasuhiro Ohno , Ochiai Atsushi , Hiraoka Nobuyoshi
Published: May 2017

Aims

Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK–RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to characterize comprehensively the prevalence and variability of RSPO fusions in colorectal TSAs.

Methods and results

We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions analysed previously for WNT pathway gene mutations. Quantitative polymerase chain reaction (qPCR) analyses identified three and 43 TSAs overexpressing RSPO2 and RSPO3, respectively, whereas the expression of RSPO1 and RSPO4 was marginal or undetectable in all cases. RSPO overexpression was always mutually exclusive with other WNT pathway gene mutations. Known PTPRK–RSPO3 fusions were detected in 37 TSAs, all but one of which overexpressed RSPO3. In addition, rapid amplification of cDNA ends revealed three novel RSPO fusion transcripts, an NRIP1–RSPO2 fusion and two PTPRK–RSPO3 fusion isoforms, in six TSAs. Overall, 43 TSAs had RSPO fusions (33%), whereas four TSAs (3%) overexpressed RSPO in the absence of RSPO fusions. TSAs with RSPO fusions showed several clinicopathological features, including distal localization (P = 0.0063), larger size (P = 0.0055), prominent ectopic crypt foci (P = 8.4 × 10−4), association of a high‐grade component (P = 1.1 × 10−4), and the presence of KRAS mutations (P = 4.5 × 10−5).

Conclusions

The present study identified RSPO fusion transcripts, including three novel transcripts, in one‐third of colorectal TSAs and showed that PTPRK–RSPO3 fusions were the predominant cause of RSPO overexpression in colorectal TSA.
Improvement of hydration and epidermal barrier function in human skin by a novel compound isosorbide dicaprylate
Authors: Chaudhuri R. K. , Bojanowski K.
Published: May 2017

Objective

The study involved the synthesis of a novel derivative of caprylic acid – isosorbide dicaprylate (IDC) – and the evaluation of its potential in improving water homoeostasis and epidermal barrier function in human skin.

Methods

The effect of IDC on gene expression was assayed in skin organotypic cultures by DNA microarrays. The results were then confirmed for a few key genes by quantitative PCR, immuno‐ and cytochemistry. Final validation of skin hydration properties was obtained by four separate clinical studies. Level of hydration was measured by corneometer either by using 2% IDC lotion alone vs placebo or in combination with 2% glycerol lotion vs 2% glycerol only. A direct comparison in skin hydration between 2% IDC and 2% glycerol lotions was also carried out. The epidermal barrier function improvement was assessed by determining changes in transepidermal water loss (TEWL) on the arms before and after treatment with 2% IDC lotion versus placebo.

Results

IDC was found to upregulate the expression of AQP3, CD44 and proteins involved in keratinocyte differentiation as well as the formation and function of stratum corneum. A direct comparison between 2% IDC versus 2% glycerol lotions revealed a three‐fold advantage of IDC in providing skin hydration. Severely dry skin treated with 2% IDC in combination with 2% glycerol showed 133% improvement, whereas 35% improvement was observed with moderately dry human skin.

Conclusion

Topical isosorbide dicaprylate favourably modulates genes involved in the maintenance of skin structure and function, resulting in superior clinical outcomes. By improving skin hydration and epidermal permeability barrier, it offers therapeutic applications in skin ageing.
Survival difference according to mutation status in a prospective cohort study of Australian patients with metastatic non‐small‐cell lung carcinoma
Authors: Tan Lavinia , Alexander Marliese , Officer Ann , MacManus Michael , Mileshkin Linda , Jennens Ross , Herath Dishan , de Boer Richard , Fox Stephen B , Ball David , Solomon Benjamin
Published: May 2017

Background

Non‐small‐cell lung cancer (NSCLC) is a heterogeneous disease comprising not only different histological subtypes but also different molecular subtypes.

Aim

To describe the frequency of oncogenic drivers in patients with metastatic NSCLC, the proportion of patients tested and survival difference according to mutation status in a single‐institution study.

Methods

Metastatic NSCLC patients enrolled in a prospective Thoracic Malignancies Cohort Study between July 2012 and August 2016 were selected. Patients underwent molecular testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangements, Kirsten rat sarcoma (KRAS), B‐Raf proto‐oncogene (BRAF) mutations and ROS1 gene rearrangements. Survival was calculated using the Kaplan‐Meier method for groups of interest, and comparisons were made using the log‐rank test.

Results

A total of 392 patients were included, 43% of whom were female with median age of 64 years (28–92). Of 296 patients tested, 172 patients (58%) were positive for an oncogenic driver: 81 patients (27%) were EGFR positive, 25 patients (9%) were ALK positive, 57 patients (19%) had KRAS mutation and 9 patients (3%) were ROS1 or BRAF positive. Patients with an actionable mutation (EGFR/ALK) had a survival advantage when compared with patients who were mutation negative (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.33–0.71; P < 0.01). Survival difference between mutation negative and mutation status unknown was not statistically significant when adjusted for confounding factors in a multivariate analysis (HR 1.29; 95% CI 0.97–1.78, P = 0.08).

Conclusion

In this prospective cohort, the presence of an actionable mutation was the strongest predictor of overall survival. These results confirm the importance of molecular testing and suggest likely survival benefit of identification and treatment of actionable oncogenes.
Pregnancy outcomes among Syrian refugee and Jordanian women: a comparative study
Authors: Alnuaimi K. , Kassab M. , Ali R. , Mohammad K. , Shattnawi K.
Published: May 2017

Aim

To compare pregnancy outcomes of Syrian refugee women and Jordanian women.

Background and introduction

In the past few years, thousands of Syrians fled Syria to neighbouring countries such as Jordan as a result of the continuing conflict in their country. Pregnant refugee women are facing many difficulties that increase the prevalence of antenatal complications. However, there is limited awareness of whether Syrian refugee women have different risks of pregnancy outcomes than Jordanian women.

Methods

Using a retrospective cohort design, we examined pregnancy outcomes for Syrian refugee (N = 616) and Jordanian women (N = 644) giving birth at two governmental hospital in northern Jordan, between 1 January 2014 and 31 December 2014. A checklist of 13 variables was utilized. The primary outcome measures were delivery by Caesarean section, maternal complications, low birthweight (<2500 g), APGAR score and preterm delivery (<37 weeks’ gestational age).

Results

Statistical analysis revealed that refugee mothers had a significant increase in the rate of Caesarean section and higher rate of anaemia, a lower neonates’ weight and APGAR scores when compared to their Jordanian counterparts.

Discussion

Results were congruent with findings from other studies in the region and worldwide.

Conclusion and implications for nursing and health policy

Minimizing inequalities in pregnancy outcomes between Syrian refugees and Jordan women is a healthcare priority. The findings could guide the planning and development of health policies in Jordan that would help to alleviate the situation regarding refugee populations. Action is required by policy makers, specifically targeting public and primary healthcare services, to address the problem of adequately meeting the needs for antenatal care of this vulnerable population.
Treatments for people living with schizophrenia in Sub‐Saharan Africa: an adapted realist review
Authors: Chidarikire S. , Cross M. , Skinner I. , Cleary M.
Published: May 2017

Aim

To identify the treatments and interventions available and their impact on people living with schizophrenia in Sub‐Saharan Africa.

Background

Help‐seeking behaviour and the choice of treatment are largely influenced by socio‐cultural factors and beliefs about the causes of mental illness. This review addresses the gap in knowledge regarding the treatment options available to people living with schizophrenia in Sub‐Saharan Africa.

Design

Adapted realist literature review.

Data sources

Electronic databases searched in June 2016 included PubMed, EMBASE, PsycINFO, ProQuest and CINAHL.

Review methods

The adapted realist review approach used to synthesize the published research involved identifying the review aim, searching and selecting relevant studies, extracting, iteratively analysing and synthesizing relevant data and reporting results.

Results

Forty studies from eight countries were reviewed. Most people were treated by both faith/traditional healers and modern psychiatry. Common treatments included antipsychotics, electroconvulsive therapy and psychosocial interventions. Few treatment options were available outside major centres, there was poor adherence to medication and families reported a high level of burden associated with caring for a relative.

Limitations

Major limitations of this review were the lack of studies, variable quality and low level of evidence available from most countries from Sub‐Saharan Africa and lack of generalizability.

Conclusion

People living with schizophrenia in Sub‐Saharan Africa were treated by faith, traditional healers and modern psychiatry, if at all. Further research is needed to better understand the local situation and the implications for caring for people from this region.

Implications for nursing and health policy

Mental health services in Sub‐Saharan Africa are limited by fiscal shortages, lack of mental health services and qualified mental health professionals. This review provides evidence to inform nursing and healthcare policy, including recruiting and training mental health professionals and ensuring access to evidence‐based, person‐centred and culturally relevant mental health services within the primary care context.
A Two‐Step Procedure to Measure Representativeness of Internet Data Sources
Authors: Beręsewicz Maciej
Published: May 2017

So far, statistics has mainly relied on information collected from censuses and sample surveys, which are used to produce statistics about selected characteristics of the population. However, because of cost cuts and increasing non‐response in sample surveys, statisticians have started to search for new sources of information, such as registers, Internet data sources (IDSs, i.e. web portals) or big data. Administrative sources are already used for purposes of official statistics, while the suitability of the latter two sources is currently being discussed in the literature. Unfortunately, only a few papers devoted to statistical theory point out methodological problems related to the use of IDSs, particularly in the context of survey methodology. The unknown generation mechanism and the complexity of such data are often neglected in view of their size. Hence, before IDSs can be used for statistical purposes, especially for official statistics, they need to be assessed in terms of such fundamental issues as representativeness, non‐sampling errors or bias. The paper attempts to fill the first gap by proposing a two‐step procedure to measure representativeness of IDSs. The procedure will be exemplified using data about the secondary real estate market in Poland.
Foliage‐applied sodium nitroprusside and hydrogen peroxide improves resistance against terminal drought in bread wheat
Authors: Farooq M. , Nawaz A. , Chaudhary M. A. M. , Rehman A.
Published: May 2017

Terminal drought is threatening the wheat productivity worldwide, which is consumed as a staple food by millions across the globe. This study was conducted to examine the influence of foliage‐applied stress signalling molecules hydrogen peroxide (H2O2; 50, 100, 150 μm) and nitric oxide donor sodium nitroprusside (SNP; 50, 100, 150 μm) on resistance against terminal drought in two bread wheat cultivars Mairaj‐2008 and BARS‐2009. These stress signalling molecules were applied at anthesis stage (BBCH 61); drought was then imposed by maintaining pots at 35% water holding capacity. Terminal drought caused significant reduction in grain yield of both tested bread wheat cultivars; however, foliage application of both stress signalling molecules at either concentration improved the performance of both bread wheat cultivars. Maximum improvement in 100‐grain weight (12.2%), grains per spike (19.7%), water‐use efficiency (WUE; 19.8%), chlorophyll content index (10.7%), total soluble phenolics (21.6%) and free leaf proline (34.3%), and highest reduction in leaf malondialdehyde contents (20.4%) was recorded when H2O2 was foliage‐applied at 100 μm. Foliage application of SNP enhanced the grains per spike, 100‐grain weight and grain yield by 14.9%, 11.3% and 20.1%, respectively, than control. The foliage‐applied stress signalling molecules improved the accumulation of soluble phenolics, proline and glycine betaine with simultaneous reduction in malondialdehyde contents, which enabled wheat plants to sustain the biological membranes under stress resulting in better stay green (high chlorophyll contents) under drought. This helped improving the grain number, grain weight, grain yield, WUE and transpiration efficiency. In crux, foliage‐applied H2O2 and SNP, at pre‐optimized rate, may be opted to lessen the drought‐induced yield losses in bread wheat in climate change conditions.
Conservation of resources theory in nurse burnout and patient safety
Authors: Prapanjaroensin Aoyjai , Patrician Patricia A. , Vance David E.
Published: May 2017

Aims

To examine how the Conservation of Resources theory explains burnout in the nursing profession.

Background

Burnout, which is an accumulation of work‐related mental stress in people‐oriented occupations, has been an issue of concern for decades for healthcare workers, especially nurses. Yet, few studies have examined a unified theory that explains the aetiology, progression and consequences of nurse burnout.

Design

This discussion article integrates current knowledge on nurse burnout using Conservation of Resources theory, which focuses on four resources (i.e., objects, conditions, personal characteristics and energy).

Data sources

The databases that were used in this study included CINAHL, PubMed and PsycINFO. All reviewed articles were published between January 2006 ‐ June 2016.

Findings

The Conservation of Resources theory explains that burnout will occur as a result of perceived or actual loss of these four resources. Furthermore, nurse burnout could affect work performance, leading to lower alertness and overall quality of care.

Implications for nursing

Healthcare organizations and nursing administration should develop strategies to protect nurses from the threat of resource loss to decrease nurse burnout, which may improve nurse and patient safety. The Conservation of Resources theory can guide interventions to decrease burnout and future research that examines the relationship between professional nurse burnout and patient safety.

Conclusion

The Conservation of Resources theory explains the aetiology, progression and consequences of nurse burnout. Future studies must explore whether nurse performance is a mediating factor between nurse burnout and patient safety.
On the Strength of Children's Right to Bodily Integrity: The Case of Circumcision
Authors: Mazor Joseph
Published: May 2017

This article considers the question of how much weight the infringement of children's right to bodily integrity should be given compared with competing considerations. It utilises the example of circumcision to explore this question, taking as given this practice's opponents' view of circumcision's harmfulness. The article argues that the child's claim against being subjected to (presumably harmful) circumcision is neither a mere interest nor a right so strong that it trumps all competing interests. Instead, it is a right of moderate strength. Indeed, even the aggregate strength of children's rights against the practice of (presumably harmful) circumcision as a whole is not so weighty so as to always trump competing interests. The harms are not sufficiently serious to justify such a status. And the expressive wrongs associated with non‐negligently benevolent harming are much less serious than those associated with intentional harming. The debate over banning circumcision thus cannot be conducted only in terms of competing rights. Competing interests, such as those that would be set back by the departure of religious citizens, should be considered as well and might plausibly justify allowing even a rights‐infringing practice to continue.
Reducing perceived social loafing in virtual teams: The effect of team feedback with guided reflexivity
Authors: Peñarroja Vicente , Orengo Virginia , Zornoza Ana
Published: May 2017

The aim of this study was twofold. The first aim was to study the effect of an intervention combining team feedback and guided reflexivity on virtual teams' affective outcomes. The second was to examine the mediating role of perceived social loafing in this relationship. An experimental laboratory study was carried out with 54 teams randomly assigned to an experimental condition or a control condition. Results showed that this intervention had an effect on satisfaction with the result, but not on group cohesion and satisfaction with the team. Moreover, perceived social loafing fully mediated the effect of this intervention on group cohesion and partially mediated its effect on satisfaction with the team and the result.
Diverse delivery methods and strong psychological benefits: A review of online formative assessment
Authors: McLaughlin T. , Yan Z.
Published: May 2017

This article is a review of literature on online formative assessment (OFA). It includes a narrative summary that synthesizes the research on the diverse delivery methods of OFA, as well as the empirical literature regarding the strong psychological benefits and limitations. Online formative assessment can be delivered using many traditional assessment methods. These assessments can be delivered using a variety of programs and software. The benefits of using OFAs include both gains in achievement scores and the development of essential complex cognitive processes, such as self‐regulation. While attention is paid to both K–12 and higher education settings, this article highlights how OFA has been used distinctly in each. This paper has high utility for both academics and practitioners.
Self and identity in borderline personality disorder: Agency and mental time travel
Authors: Gold Natalie , Kyratsous Michalis
Published: May 2017

We consider how conceptions of the self and identity from the philosophical literature can help us to understand identity disturbance in borderline personality disorder (BPD). We present 3 philosophical approaches: connectedness, narrative, and agency. We show how these map on to 3 different ways in which the self can be temporally extended. The connectedness approach is dominant in philosophy, and the narrative approach has been used by psychiatry, but we argue that the lesser‐known agency approach provides a promising way to theorize some aspects of identity disturbance in BPD. It relates the 2 diagnostic criteria of identity disturbance and disinhibition and is consistent with evidence of memory deficits and altered self‐processing in BPD patients.