bluuebunny/crossref_metadata_2025 huggingface dataset:
Tackling clinical inertia: Use of coproduction to improve patient engagement
Authors: Soto Carmen , Strain William David
Published: June 2018

Clinical inertia is common in all chronic diseases, including diabetes. Despite the advent of newer agents for the management of hyperglycemia, hypertension, and dyslipidemia, the number of people with diabetes hitting all three targets remains small. The causes of clinical inertia are multifactorial, with contributory elements from people with diabetes, physicians, and the system within which they work. Every health care provider should have the best interest of their patients at heart; most people with diabetes want to maintain their health for as long as possible, and the maintenance of good health is not only the purpose of the system, but also the most cost‐effective strategy. It is the thesis of this article that a potential reversible contributor to clinical inertia is the communication among these individual elements, which can be called “coproduction.” The coproduction model of open communication encourages discourse, allowing the person with diabetes to understand their diagnosis and therefore better engage in treatment options. Improving engagement allows the healthcare team, including the physician and the person with diabetes, to establish shared goals that are important to all team members and to agree to acceptable side effects or risks of interventions in order to achieve these goals. Everyone needs to acknowledge that non‐adherence exists and can be an issue, thereby allowing reasons to be explored. Only once the person with diabetes is allowed to take full ownership of their disease and actively participate in decision making can they take control of their disease, thereby improving outcomes.
hsa_circ_0000729, a potential prognostic biomarker in lung adenocarcinoma
Authors: Li Shicheng , Sun Xiao , Miao Shuncheng , Lu Tong , Wang Yuanyong , Liu Jia , Jiao Wenjie
Published: June 2018

Background

Increasing evidence has demonstrated that circular RNAs (circRNAs) may play an important role in oncogenesis and tumor development; however, their role in lung adenocarcinoma (LUAD) remains unclear. We identified the differentially expressed circRNAs in LUAD and investigated the potential mechanisms for cancer progression.

Methods

We examined differentially expressed circRNAs in LUAD and paired normal tissues using downloaded circRNA microarrays from the Gene Expression Omnibus. We constructed gene co‐expression networks based on the degree of Pearson correlation to predict the critical circRNA in LUAD. Gene Ontology analysis was performed on the genes in the network. We observed one novel circRNA upregulated in LUAD, hsa_circ_0000792, as well as its potential sponged microRNA, miR‐375. Subsequent real‐time quantitative PCR was used to verify the bioinformatics analysis.

Results

Several circRNAs showed significantly different expression levels in LUAD tissues. Real‐time quantitative PCR and further co‐expression network analysis of 42 matched tissue samples showed a significant difference in expression between LUAD and normal tissues in hsa_circ_0000792 (P < 0.001). We built a network of hsa_circ_0000792‐targeted miRNA gene interactions, including miR‐375 and the corresponding messenger RNAs. Gene Ontology analysis revealed that hsa_circ_0000792 could participate in signal transduction and cell communication during LUAD development. Larger area under the curve by receiver operating characteristic curve analysis of hsa_circ_0000792 and miR‐375 (0.815 and 0.772, respectively) in LUAD indicated greater potential as biomarkers.

Conclusions

We identified hsa_circ_0000792 as a potential LUAD biomarker; however, further studies are required to determine the mechanism of this circRNA in LUAD development.
Mandatory IFRS Adoption and the Role of Accounting Earnings in CEO Turnover
Authors: Wu Joanna Shuang , Zhang Ivy Xiying
Published: June 2018

We study whether mandatory adoption of International Financial Reporting Standards (IFRS) is associated with changes in the sensitivity of CEO turnover to accounting earnings and how the impact of IFRS adoption varies with country‐level institutions and firm‐level incentives. We find that CEO turnover responds more to a firm's accounting performance after adoption. This increase in turnover‐to‐earnings sensitivity is concentrated in countries with stronger enforcement of financial reporting and is more prominent for mandatory adopters that have strong firm‐level compliance incentives. In addition, we link the change in turnover‐to‐earnings sensitivity directly to accounting changes due to IFRS adoption and find a stronger adoption effect when firms report large overall accounting changes and large de‐recognition of loss provisions upon adoption. Some of the above findings are sensitive to the exclusion of UK firms, which account for more than half of our sample.
The Impact of Maryland's Global Budget Payment Reform on Emergency Department Admission Rates in a Single Health System
Authors: Galarraga Jessica E. , Frohna William J. , Pines Jesse M.
Published: June 2018

Background

In 2014, the state of Maryland (MD) moved away from fee‐for‐service payments and into a global budget revenue (GBR) structure where hospitals have a fixed revenue target, independent of patient volume or services provided. We assess the effects of GBR adoption on emergency department (ED) admission decisions among adult encounters.

Methods

We used hospital medical record and billing data from adult ED encounters from January 1, 2011, through December 31, 2015, with four MD hospitals and two District of Columbia (DC) hospitals within the same health system. We performed difference‐in‐differences analysis and calculated the effects of the GBR model on ED admission rates (inpatient and observation) using hospital fixed‐effect regression adjusted for patient, hospital, and community factors. We also examined changes in the distribution of acuity among ED admissions with GBR adoption.

Results

The study sample included 1,492,953 ED encounters with a mean ED admission rate of 20.5%. The ED admission rate difference pre‐ and post‐GBR was –1.14% (95% confidence interval [CI] = –0.89 to –1.40) for MD hospitals and –0.04% (95% CI = –0.24 to 0.32) for DC hospitals with a difference‐in‐differences result of –1.10% (95% CI = –1.34 to –0.86). This change was attributable to a –3.3% (95% CI = –3.54 to –3.08) decline in inpatient admissions and 2.7% (95% CI = 2.53 to 2.79) increase in observation admissions. Declines in admissions were observed primarily among mild‐to‐moderate severity of illness encounters with a low risk of mortality.

Conclusions

Within the same health system, implementation of global budgeting in MD hospitals was associated with a decline in ED admissions—particularly lower‐acuity admissions—compared to DC hospitals that remained under fee‐for‐service payments.
Executive stock option vesting conditions, corporate governance and CEO attributes: evidence from Australia
Authors: Qu Xin , Percy Majella , Stewart Jenny , Hu Fang
Published: June 2018

We investigate the association between executive stock option (ESO) vesting conditions, corporate governance and CEO attributes. Using observations from the 250 largest Australian firms, we find that stronger corporate governance is positively associated with the length of the vesting period and the use of performance hurdles. We also find that when CEOs approach retirement, firms are more likely to grant longer time‐vesting options but are less likely to impose performance hurdles. Further, more powerful CEOs appear to influence the granting of ESOs with less restrictive vesting conditions. Our findings suggest that both corporate governance and CEO attributes significantly shape the design of ESOs.
Association between COMT SNP variation and timidity in Golden and Labrador Retrievers
Authors: Luo D. , Ma X. , Bai J. , Zhou Z. , Wang F. , Wang A. , Wang J.
Published: June 2018

Timidity in dogs is a trait with high heritability. However, the relevant genetic factors and markers associated with this condition are largely unknown. The function of the catechol‐O‐methyl transferase (COMT) gene has been found to be associated with human fearful or anxious emotions, and the COMT:p.Val158Met polymorphism locus is significantly related to anxious behavior. In the present study, the correlation between timidity and four single nucleotide polymorphism (SNP) variations (C.‐1666C>G c.39A>G, c.216G>A, c.482G>A) of the COMT gene was investigated in dogs. The evaluation was based on the dog courage assessment assay and a genotype and haplotype analysis in Labrador Retrievers (LR) and Golden Retrievers (GR). The principal components analysis factor structure of the courage phenotype was invariant between LR and GR. Sex, breed and age had no statistically significant effect on the timidity of the dogs. All SNP loci detected were in Hardy–Weinberg equilibrium. The c.39A>G locus was removed in the subsequent association analysis due to the significant difference between LR and GR in genotype distributions. Intriguingly, the genotypes and haplotypes of the COMT gene were significantly and highly correlated with the timidity of LR and GR. The A alleles of the COMT:c.216G>A and c.482G>A loci appeared to play a dominant role in the timid behavior of the dogs. This result supports and broadens the warrior/worrier hypothesis and will have important implications for the understanding of the evolution of temperament in dogs. Additionally, the results provide predictive genetic markers for temperament in dogs.
Observation of “complete clinical response” in rectal cancer after neoadjuvant chemoradiation: The Flinders experience
Authors: Sposato Luigi A. , Lam Yick , Karapetis Chris , Vatandoust Sina , Roy Amitesh , Hakendorf Paul , Dwyer Andrew , de Fontgalland Dayan , Hollington Paul , Wattchow David
Published: June 2018

Aim

Observation with close follow‐up (“watch and wait”) is a recognized treatment option in patients who achieve a complete clinical response to long course chemoradiotherapy. This review of a prospective database aims to evaluate the clinical outcomes among patients with a complete clinical response managed with observation.

Methods

A prospective study of 32 patients who achieved a complete clinical response was undertaken. The primary outcomes measured were overall and recurrence‐free survival, and rate of organ preservation in patients who deferred immediate surgery.

Results

Seven patients developed local regrowth over a median follow‐up period of 38 months (range, 9–91 months). Median time to detection was 12 months. All seven underwent salvage surgery with complete surgical clearance. One patient developed combined local and systemic recurrence following a low anterior resection. Organ preservation was possible in 25 (78%) patients who sustained a complete clinical response with no evidence of local regrowth or disease recurrence. Among the patients who sustained a complete response, two developed isolated systemic disease. Overall and recurrence‐free survival was 95.7% and 87.0%, respectively.

Conclusion

The majority of patients with rectal cancer who achieved a complete clinical response after chemoradiotherapy and managed with a “watch and wait” approach preserved their rectum and did not develop cancer relapse. Salvage surgery was achieved in all patients who developed local regrowth. The study supports a period of observation in rectal cancer patients who achieve a complete clinical response.
The changing paradigm of management in melanoma brain metastases
Authors: Ladwa Rahul , Atkinson Victoria
Published: June 2018

Aim

Improved systemic treatment has improved the prognosis of metastatic melanoma (MM). However, brain metastases (BMs) are a frequent complication. We aimed to explore the outcome of these patients with modern therapeutic options.

Method

We retrospectively analyzed 142 patients diagnosed with BM from MM at two institutions in Brisbane, Queensland, Australia during 2009–2016. Basic clinico‐pathological parameters, treatments used and mortality data were collected.

Results

With a median follow‐up of 8 months, 115 patients had died, 112 from MM and 99 from neurologic death. Management included ablative therapy (n = 8), ablative therapy with targeted/immunotherapy (n = 54), targeted/immunotherapy (n = 55) and whole‐brain radiotherapy/best supportive care (n = 25). The median overall survival (OS) was 8 (6.9–9.1) months. Statistically improved OS was found with the use of ablative techniques and BRAF/MEK tyrosine kinase inhibitor (TKI) post diagnosis of BM. In BRAF mutant patients (n = 117) who were TKI naïve at diagnosis of BM (n = 60), the median OS was 9 (6.2–11.8) months versus 5 (1.1–8.9) months in patients who developed BM on TKI treatment (P = 0.001). A complete intracranial response rate occurred in 12% of patients who had immunotherapy (n = 65) with all but two patients receiving stereotactic radiosurgery and no deaths have occurred in this group.

Conclusions

The outcomes of those with BM remain poor, particularly of those with BRAF mutant MM who fail TKI therapy with new BM. Most patients present with multiple BM and death is frequently due to neurological progressive disease. The use of ablative techniques and TKI use confers a longer OS in selected patients.
UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan‐induced toxicity: A meta‐analysis
Authors: Yang Yuwei , Zhou MengMeng , Hu Mingjun , Cui Yanjie , Zhong Qi , Liang Ling , Huang Fen
Published: June 2018

Background

Previous articles explored the role of UGT1A1 polymorphism on predicting irinotecan‐induced toxicity, but the conclusions were still inconsistent and not comprehensive. We performed this meta‐analysis to investigate the association between UGT1A1 polymorphism and irinotecan‐induced toxicity.

Methods

PubMed and Web of Science were searched for articles before July 2017. Inclusion and exclusion criteria were set to select eligible articles, and corresponding data were extracted from those articles. Subgroup analyses based on different cancer categories, doses and races were carried out to achieve comprehensive results. Statistical analyses were conducted using STATA 11.0.

Results

A total of 38 studies with 6742 cases were included after reading full text. Both UGT1A1*6 and UGT1A1*28 polymorphism are significantly associated with severe irinotecan‐induced toxicity. Both Asian and Caucasian cancer patients with UGT1A1*28 variant had an increased risk. Compared with heterozygous variant, patients with homozygous variant suffered from a higher risk of toxicity. The effect of UGT1A1*28 polymorphism on diarrhea was less than on neutropenia. Subgroup analysis exhibited that for UGT1A1*6 polymorphism, patients treated with low‐dose irinotecan were at a notable risk of toxicity. Moreover, the association between UGT1A1*6 polymorphism and irinotecan‐induced toxicity was found in patients suffering from respiratory system cancers.

Conclusions

Both UGT1A1*6 and UGT1A1*28 polymorphisms can be considered as predictors of irinotecan‐induced toxicity, with effect varying by race, cancer type and irinotecan dose.
Long‐term effect of exemestane therapy on bone mineral density supported by bisphosphonates: Results of 5‐year adjuvant treatment in postmenopausal women with early‐stage breast cancer
Authors: Hirano Akira , Inoue Hiroaki , Ogura Kaoru , Hattori Akinori , Yukawa Hiroko , Sakaguchi Shiho , Matsuoka Aya , Tanaka Natsuko , Kodera Asaka , Kamimura Mari , Naritaka Yoshihiko , Shimizu Tadao
Published: June 2018

Purpose

Unlike anastrozole, the effect of long‐term exemestane (EXE) therapy on bone mineral density (BMD) is still unknown. We assessed changes in BMD from baseline to 5 years of EXE treatment.

Methods

Postmenopausal women with endocrine‐responsive breast cancer receiving EXE as adjuvant therapy were enrolled in this study. EXE was administered for 5 years. The BMD of the lumbar spine (LS) and femoral neck (FN) was assessed by dual‐energy X‐ray absorptiometry at baseline and after 6 months and 1, 2, 3, 4, 5 and 6 years. Oral bisphosphonate (Bis) treatment was initiated when patients were diagnosed with osteoporosis with a T‐score of −2.5 or lower.

Results

Eighty‐one patients were enrolled in the study between 2005 and 2010. The median follow‐up period was 54.9 months. Forty‐two patients were administered Bis. Overall, the BMD of the LS increased by 7.3% from baseline and that of the FN increased by 3.4% with 5 years of EXE treatment. At the sixth year (i.e. 1 year after the treatment), BMD of the LS increased by 7.2% and that of the FN increased by 5.7%. Furthermore, the BMD of the FN increased by 12.0% in patients treated upfront with Bis and by 1.2% in those not treated with Bis (P = 0.0262). Fractures developed in nine patients (11.1%) and seven (8.6%) had fragility fractures.

Conclusion

Oral Bis improves BMD of the FN in patients with osteoporosis. Five‐year EXE treatment with proper addition of Bis helps maintain the BMD of the LS and FN at the sixth year.
Hypoxia regulates placental angiogenesis via alternatively activated macrophages
Authors: Zhao Hui , Kalish Flora S. , Wong Ronald J. , Stevenson David K.
Published: June 2018

Problem

Uterine and placental macrophages play critical roles in maintaining a normal pregnancy. The majority of these macrophages are believed to be alternatively activated macrophages (M2).

Method of Study

Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with IL‐4 [M2a] or IL‐10 [M2c] and M1 with LPS/IFN‐γ as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles.

Results

Compared to M1, M2 showed strong pro‐angiogenic activity by expressing higher mRNA for angiogenic‐associated factors (Cxcl12, Vegfa, PlGF, Mmp2). M2c produced the highest levels of PlGF, Mmp2, and Cxcr4. To mimic the normal placental microenvironment, M2 were exposed to hypoxia and sex hormones (progesterone, estrogen). In both M2c and M2a, severe hypoxic (1%‐3% O2) exposure significantly suppressed PlGF, Cxcl12, and Mmp2 mRNA, but not Vegfa, compared to normoxia (21% O2) or physiological hypoxia (5% O2). mRNA expression returned to normal when hypoxic cells were returned to normoxia. Hypoxia (1%) reduced antioxidant levels in M2 and re‐exposure to normoxia significantly increased superoxide dismutase (Sod1, Sod2) and heme oxygenase‐1 (HO‐1) levels in M2a, and only glutathione peroxidase (Gpx1, Gpx3, Gpx4) in M2c. However, progesterone and estrogen treatment had minimal effects on angiogenic factor expression in M2.

Conclusion

M2, particularly M2c, displayed strong pro‐angiogenic potential, which decreased under severe hypoxia such as in early pregnancy. Thus, conditions that alter the placental oxygen microenvironment or macrophage response in early pregnancy might cause aberrant angiogenesis and vascular remodeling, and lead to abnormal placental vascular development.
Left bundle branch block: Epidemiology, etiology, anatomic features, electrovectorcardiography, and classification proposal
Authors: Pérez‐Riera Andrés R. , Barbosa‐Barros Raimundo , de Rezende Barbosa Marianne P. C. , Daminello‐Raimundo Rodrigo , de Abreu Luiz C. , Nikus Kjell
Published: June 2018

In left bundle branch block (LBBB), the ventricles are activated in a sequential manner with alterations in left ventricular mechanics, perfusion, and workload resulting in cardiac remodeling. Underlying molecular, cellular, and interstitial changes manifest clinically as changes in size, mass, geometry, and function of the heart. Cardiac remodeling is associated with progressive ventricular dysfunction, arrhythmias, and impaired prognosis. Clinical and diagnostic notions about LBBB have evolved from a simple electrocardiographic alteration to a critically important finding affecting diagnostic and clinical management of many patients. Advances in cardiac magnetic resonance imaging have significantly improved the assessment of patients with LBBB and provided additional insights into pathophysiological mechanisms of left ventricular remodeling. In this review, we will discuss the epidemiology, etiologies, and electrovectorcardiographic features of LBBB and propose a classification of the conduction disturbance.
Use of prescription drugs among women diagnosed with epithelial ovarian cancer in Denmark
Authors: Pottegård Anton , Friis Søren , Verdoodt Freija , Dehlendorff Christian , Hallas Jesper , Kjær Susanne K.
Published: June 2018

Introduction

Epithelial ovarian cancer patients often suffer from chronic diseases requiring drug treatment. We assessed temporal patterns of drug use among women with ovarian cancer.

Material and methods

We identified all postmenopausal women with epithelial ovarian cancer in Denmark 2005‐2012 and a comparison cohort of age‐matched women without cancer. We calculated rates of new drug treatment and total drug use and examined use of new and prevalent drugs before and after diagnosis. Analyses were stratified by histological type and stage of epithelial ovarian cancer.

Results

We identified 2742 patients. The rate of new drug treatment increased from 3 to 5 months before diagnosis and peaked in the first month after diagnosis at 99 new types of drug therapy per 100 individuals (mainly antiemetics, proton‐pump inhibitors, hypnotics, and opioids). Although declining, the rate of new drug use remained substantially higher among epithelial ovarian cancer patients than among controls throughout the 3‐year postdiagnosis follow‐up period. The number of prevalent drugs increased slightly from a median of 4 drugs (interquartile range 2‐7) before diagnosis to 5 drugs (interquartile range 2‐8) shortly after the diagnosis. The use of preventive drugs decreased only slightly after diagnosis. In stratified analyses, we found limited variation according to histological type, whereas patterns were slightly more pronounced among women with nonlocalized disease compared with localized disease.

Conclusions

Drug use among postmenopausal women with epithelial ovarian cancer was substantial and varied considerably in relation to the time of cancer diagnosis, although only limited changes were seen in the use of preventive medicines.
Relational spaces and relational care: Campus sexual violence, intimate geopolitics and topological polis
Authors: Bartos Ann E.
Published: June 2018

Critical care ethics argues that care's political potential lies in its relationality. Geographic scholarship on relationality can provide an avenue for unpacking the politics of care. This paper explores how a spatial relational care approach illuminates how caring agencies occurring in particular places have political reach to people and places well beyond those initial sites. A spatial relational care approach seeks to bring visibility to the diversity of caring and non‐caring relationalities that occur between multiple people, places, events, times and structural underpinnings. Such geographic relational scholarship on care brings attention to the ways that people and places are non‐autonomous through caring relations. This paper suggests that the frameworks of topological polis and intimate geopolitics can extend our relational understandings of care and offer insights into aspects of social life that care research has yet to explore. Empirically, this paper draws on a high‐profile campus sexual assault case to argue that the spaces of care need to be understood beyond where the initial care act took place, that responding to care creates relational poleis and that the site of the body is relationally bound with care and violence.
Threshold Regression to Accommodate a Censored Covariate
Authors: Qian Jing , Chiou Sy Han , Maye Jacqueline E. , Atem Folefac , Johnson Keith A. , Betensky Rebecca A.
Published: June 2018

In several common study designs, regression modeling is complicated by the presence of censored covariates. Examples of such covariates include maternal age of onset of dementia that may be right censored in an Alzheimer's amyloid imaging study of healthy subjects, metabolite measurements that are subject to limit of detection censoring in a case-control study of cardiovascular disease, and progressive biomarkers whose baseline values are of interest, but are measured post-baseline in longitudinal neuropsychological studies of Alzheimer's disease. We propose threshold regression approaches for linear regression models with a covariate that is subject to random censoring. Threshold regression methods allow for immediate testing of the significance of the effect of a censored covariate. In addition, they provide for unbiased estimation of the regression coefficient of the censored covariate. We derive the asymptotic properties of the resulting estimators under mild regularity conditions. Simulations demonstrate that the proposed estimators have good finite-sample performance, and often offer improved efficiency over existing methods. We also derive a principled method for selection of the threshold. We illustrate the approach in application to an Alzheimer's disease study that investigated brain amyloid levels in older individuals, as measured through positron emission tomography scans, as a function of maternal age of dementia onset, with adjustment for other covariates. We have developed an R package, censCov, for implementation of our method, available at CRAN.
Soluble syndecans: biomarkers for diseases and therapeutic options
Authors: Bertrand Jessica , Bollmann Miriam
Published: June 2018

Syndecans are important mediators of signalling by transmitting external stimuli into the cells. This role in signal transduction has been attributed mainly to the membrane‐bound syndecans. In the last years, however, the soluble ectodomain of syndecans generated by shedding has come into the focus of research as this process has been show to modulate the syndecan‐dependent signalling pathways, as well as other pathways. This review summarizes the current knowledge about the induction of syndecan shedding and the different pathways modulated by shed syndecan proteins. This review summarizes the known and putative sheddases for each syndecan and describes the exemplary conditions of sheddase activity for some syndecans. This review summarizes the proposed use of shed syndecans as biomarkers for various diseases, as the shedding process of syndecans depends crucially on tissue‐ and disease‐specific activation of the sheddases. Furthermore, the potential use of soluble syndecans as a therapeutic option is discussed, on the basis of the current literature.

Linked Articles

This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc
Connexin 43 C‐terminus directly inhibits the hyperphosphorylation of Akt/ERK through protein–protein interactions in glioblastoma
Authors: Kuang Jing‐Ya , Guo Yu‐Feng , Chen Ying , Wang Jun , Duan Jiang‐Jie , He Xiao‐Li , Li Lin , Yu Shi‐Cang , Bian Xiu‐Wu
Published: June 2018

Although the deregulation of epidermal growth factor receptor (EGFR) is one of the most common molecular mechanisms of glioblastoma (GBM) pathogenesis, the efficacy of anti‐EGFR therapy is limited. Additionally, response to anti‐EGFR therapy is not solely dependent on EGFR expression and is more promising in patients with reduced activity of EGFR downstream signaling pathways. Thus, there is considerable interest in identifying the compensatory regulatory factors of the EGFR signaling pathway to improve the efficacy of anti‐EGFR therapies for GBM. In this study, we confirmed the low efficacy of EGFR inhibitors in GBM patients by meta‐analysis. We then identified a negative correlation between connexin 43 (Cx43) expression and Akt/ERK activation, which was caused by the direct interactions between Akt/ERK and Cx43. By comparing the interactions between Akt/ERK and Cx43 using a series of truncated and mutated Cx43 variants, we revealed that the residues T286/A305/Q308/Y313 and S272/S273 at the carboxy terminus of Cx43 are critical for its binding with Akt and ERK, respectively. In addition, Kaplan–Meier survival analysis using data from The Cancer Genome Atlas datasets indicated that the expression of Cx43 significantly improved the prognosis of GBM patients who express EGFR. Together, our results suggested that Cx43 acts as an inhibitory regulator of the activation of growth factor receptor downstream signaling pathways, indicating the potential of Cx43 as a marker for predicting the efficacy of EGFR inhibitor treatments for GBM. Targeting the interaction between the carboxy terminus of Cx43 and Akt/ERK could be an effective therapeutic strategy against GBM.
Identification of a new pyruvate kinase M2 isoform (PKM2) activator for the treatment of non‐small‐cell lung cancer (NSCLC)
Authors: Li Run‐Ze , Fan Xing‐Xing , Shi Dan‐Feng , Zhu Guo‐Yuan , Wang Yu‐Wei , Luo Lian‐Xiang , Pan Hu‐Dan , Yao Xiao‐Jun , Leung Elaine Lai‐Han , Liu Liang
Published: June 2018

Lung cancer is the number one cancer in terms of both mortality and incidence. Cancer cells differ from normal cells in that they can reprogram their metabolism to support a rapid proliferation rate and alter oxidative phosphorylation processes toward lactic acid fermentation, even under aerobic conditions. Therefore, we aimed to identify new compounds that might act as pyruvate kinase M2 isoform (PKM2) activators and to investigate their anti‐cancer efficacy in non‐small‐cell lung cancer (NSCLC) cells. The molecular docking method was applied to screen PKM2 activators from our virtual natural products library. Then, compounds with promising docking scores were examined for cytotoxic effects in a panel of NSCLC cells using the MTT assay. Functional effects and therapeutic mechanisms were investigated by in vitro enzyme assays, western blotting (WB), and flow cytometry. Molecular docking showed that 0089‐0022 acts as a potential PKM2 activator by binding to the kinase pocket. An in vitro enzyme activity assay showed that 0089‐0022 is a direct PKM2 activator and that it effectively induces apoptosis in A549 and H1975 cells through inhibition of AKT phosphorylation. Our results suggest that 0089‐0022 activates PKM2 and thus is a promising anti‐cancer therapeutic candidate in NSCLC.
Post‐surgical versus post‐intravitreal injection endophthalmitis: changing patterns in causative flora
Authors: Ong Aaron PC , Angbue Te Nikki , Zagora Sophia L , Symes Richard J , Yates William , Chang Andrew A , McCluskey Peter J , Simunovic Matthew P
Published: June 2018

Importance

Endophthalmitis is a serious complication of intraocular procedures: knowledge of its causative organisms and outcomes may guide prevention and treatment.

Background

To determine the outcomes and spectrum of causative organisms in acute post‐procedural endophthalmitis.

Design

A retrospective observational case series performed at a tertiary referral hospital during the period 1 July 2012 to 31 July 2017.

Participants

Two hundred and forty‐eight patients diagnosed with acute (≤ 6 weeks post‐inciting event) endophthalmitis.

Methods

Chart review of microbiological and clinical data.

Main Outcome Measures

The main outcome measure was odds of any improvement in visual acuity (3 months versus presentation). Secondary outcomes included causative organism, likelihood of vitrectomy and likelihood of evisceration.

Results

One hundred and ninty cases were post‐cataract surgery or post‐intravitreal injection (49 and 141, respectively). Causative organisms were identified in 45% of post‐cataract surgery and 54% of post‐injection cases (OR = 0.69; P = 0.61). Staphylococcus epidermidis was the most frequent causative organism. Streptococcus species accounted for 32% of post‐surgical and 7% of culture‐positive post‐injection cases (OR = 6.63; P = 0.02). At 3 months, 81% of post‐surgical and 84% of post‐injection cases had improved BCVA over presentation (OR 0.59; P = 0.61).

Conclusions and Relevance

S. epidermidis is the most common causative organism. In contrast to other studies, we did not find evidence for an increased odds of Streptococcus spp. endophthalmitis following intravitreal injection. This may in turn reflect guideline‐driven changes in practice.
Epidemiology of fungal keratitis in Queensland, Australia
Authors: Chew Rusheng , Woods Marion L
Published: June 2018

Importance

Fungal keratitis is a rare but sight‐threatening ocular infection. The epidemiology varies with geography, in particular climate and demography.

Background

We present descriptive epidemiology of fungal keratitis in Queensland, a large, geographically heterogenous Australian state.

Design

Descriptive ecological study.

Participants

Queensland residents in the period 1996 to January 2016.

Methods

We searched the state‐wide pathology database for positive fungal cultures from corneal scrapings, aqueous humour, vitreous humour or contact lens specimens. Data were analysed by age, sex, climate and location. Cumulative incidence rates were estimated.

Main Outcome Measures

Episodes of fungal keratitis, from which the abovementioned positive fungal cultures were assumed to originate.

Results

Two hundred and twenty‐one episodes of fungal keratitis in 215 Queensland residents were identified (140 males and 75 females). The median age was 48 years and the modal age range was 25–50 years. Seasonal variation was seen in tropical Queensland. Fusarium (33%) and Aspergillus (13%) were the commonest pathogens. The cumulative incidence per 100 000 population was 4.7, but was significantly higher in rural/regional (5.4) and tropical Queensland (7.9).

Conclusions and Relevance

In Queensland, fungal keratitis occurs most frequently in males under 50 with increased case identification associated with the hot dry season in tropical Queensland. The sex and age distribution may reflect increased environmental exposure to fungi related to occupation. The higher cumulative incidence in tropical Queensland is in keeping with the rates observed in other tropical regions of the world. Knowledge of the epidemiology of the condition is essential in formulating empirical antifungal regimens in suspected fungal keratitis.
A brain network model for depression: From symptom understanding to disease intervention
Authors: Li Bao‐Juan , Friston Karl , Mody Maria , Wang Hua‐Ning , Lu Hong‐Bing , Hu De‐Wen
Published: June 2018

Understanding the neural substrates of depression is crucial for diagnosis and treatment. Here, we review recent studies of functional and effective connectivity in depression, in terms of functional integration in the brain. Findings from these studies, including our own, point to the involvement of at least four networks in patients with depression. Elevated connectivity of a ventral limbic affective network appears to be associated with excessive negative mood (dysphoria) in the patients; decreased connectivity of a frontal‐striatal reward network has been suggested to account for loss of interest, motivation, and pleasure (anhedonia); enhanced default mode network connectivity seems to be associated with depressive rumination; and diminished connectivity of a dorsal cognitive control network is thought to underlie cognitive deficits especially ineffective top‐down control of negative thoughts and emotions in depressed patients. Moreover, the restoration of connectivity of these networks—and corresponding symptom improvement—following antidepressant treatment (including medication, psychotherapy, and brain stimulation techniques) serves as evidence for the crucial role of these networks in the pathophysiology of depression.
Weak environmental controls on the composition and diversity of medium and large‐sized vertebrate assemblages in neotropical rain forests of the Guiana Shield
Authors: Denis Thomas , Hérault Bruno , Brunaux Olivier , Guitet Stéphane , Richard‐Hansen Cécile
Published: June 2018

Aim

Despite their often high‐trophic position and their contribution to many ecosystem functions, little is known about the factors affecting assemblage structure of medium‐ and large‐sized neotropical vertebrates. We examined the relative roles played by the physical and biological environment, and by purely spatial processes, in shaping the composition and diversities of these vertebrate assemblages. Then, based on the theory that the Guianan forest cover shrank to isolated pockets during the late Pleistocene–Holocene, we tested if the past forest refugia may have shaped current vertebrate assemblages.

Location

French Guiana, Guiana Shield, South America.

Methods

Abundances of 19 medium‐ and large‐sized vertebrates were estimated at 21 locations in undisturbed Guianan rain forests. Using taxonomic, functional and phylogenetic metrics, we partitioned the effects of a range of physical and biological environmental conditions and purely spatial predictors in shaping both assemblage composition and (alpha and beta) diversities.

Results

We identified a significant, but weak relationship between taxonomic, functional and phylogenetic assemblage composition and environmental conditions. Assemblage diversity patterns were mainly explained by spatial predictors irrespective of the metrics. Current assemblage diversities are correlated with Pleistocene–Holocene forest history, with the highest alpha diversities outside of putative forest refugia, and the highest beta diversities inside these areas.

Main conclusions

Current vertebrate assemblage composition is not strongly marked by common environmental factors. Our main conclusion is that assemblage composition results from individual species responses to the environment. Our findings also suggest that dispersal‐related processes or more probably historical processes shape (alpha and beta) diversity patterns. In fact, forest fragmentation during Pleistocene–Holocene climate changes could have led to isolated vertebrate assemblages evolving into unique species assemblages creating the current high beta diversity inside refugia, whereas the lower habitat stability outside of refugia could have led to mixed assemblages in areas recolonized by forest vertebrates (current high alpha diversity outside of refugia).
Cannulation method for intradiverticular papilla with long oral protrusion using biopsy forceps for axis alignment
Authors: Takenaka Mamoru , Minaga Kosuke , Kudo Masatoshi
Published: June 2018

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Consent for participating in clinical trials ‐ Is it really informed?
Authors: Alexa‐Stratulat Teodora , Neagu Marius , Neagu Anca‐Iulia , Alexa Ioana Dana , Ioan Beatrice Gabriela
Published: June 2018

The article explores the challenges of ensuring voluntary and informed consent which is obtained from potential research subjects in the north‐eastern part of Romania. This study is one of the first empirical papers of this nature in Romania. The study used a quantitative survey design using the adapted Quality of Informed Consent (QuIC) questionnaire. The target population consisted of 100 adult persons who voluntarily enrolled in clinical trials. The informed consent form must contain details regarding the potential risks and benefits, the aim of the clinical trial, study design, confidentiality, insurance and contact details in case of additional questions. Our study confirmed that although all required information was included in the ICF, few clinical trial participants truly understood it. We also found that the most important predictive factor for a good subjective and objective understanding of the clinical trial was the level of education. Our study suggests that researchers should consider putting more effort in order to help clinical trials participants achieve a better understanding of the informed consent. In this way they will ensure that participants’ decision‐making is meaningful and that their interests are protected.
Partiality, impartiality and the ethics of triage
Authors: Okorie Ndukaku
Published: June 2018

In this paper, I discuss the question of partiality and impartiality in the application of triage. Triage is a process in medical research which recommends that patients should be sorted for treatment according to the degree or severity of their injury. In employing the triage protocol, however, the question of partiality arises because socially vulnerable groups will be neglected since there is the likelihood that the social determinants of a patient's health may diminish her chance of survival. As a process that is based on the severity of a patient's injury, triage will be unfair, and hence negatively partial, to socially vulnerable people. Thus, I aim in this paper to show that the triage protocol fails as an impartial evaluative process because its only aim is to maximize survivability. I contend that: (i) triage would lead to the neglect of the social condition of patients or victims, and (ii) it will only serve the utilitarian purpose of maximization of outcomes which may not be justified in some cases.
Effect of the anteroposterior position of the model on fabricated mouthguard thickness: Part 2 Influence of sheet thickness and material
Authors: Takahashi Mutsumi , Bando Yogetsu
Published: June 2018

Aim

Mouthguards can reduce the risk of sports‐related injuries, but the sheet material and thickness have a large effect on their efficacy and safety. The aim of this study was to investigate the thickness of molded mouthguards when the model position on the forming table was changed stepwise in the anteroposterior direction for different sheet thicknesses and materials.

Materials and Methods

Ethylene vinyl acetate sheets and olefin copolymer sheets with 4.0 or 2.0 mm thick were used for thermoforming by a pressure‐forming machine. The working model was trimmed to the height of 25 mm at the maxillary central incisor and 20 mm at first molar. The model was placed with its anterior rim positioned 40, 30, 25, 20, or 10 mm from the front of the sheet frame. Sheet thickness after fabrication was determined for the incisal edge, labial surface, and buccal surface using a specialized caliper. The differences of the model position on the thickness reduction were analyzed by two‐way analysis of variance and Bonferroni's multiple comparison tests.

Results

Thickness reductions at the incisal edge, labial surface, and buccal surface were about −60%, −50%, and −40%, respectively; for a distance of 25 mm up to the height of the anterior part of the model and the frame from the model rim, the 4.0 and 2.0 mm sheets showed similar thickness reduction. When the model was moved forward, the anterior thickness reduction of the 2.0‐mm‐thick sheet increased to larger than that of the 4.0‐mm‐thick sheet.

Conclusion

The thickness reduction of the mouthguard was not affected by the sheet material and thickness when the distance from the model to the frame was the same. However, when the distance between the model and the frame decreased, the thickness reduction of the adjacent portion of the model increased, such that the influence was larger in thin sheets.
Müllerian mimetic radiation of Delias butterflies (Lepidoptera: Pieridae) in Bali and Timor
Authors: Morinaka Sadaharu , Erniwati Erni , Minaka Nobuhiro , Miyata Tadashi
Published: June 2018

Mimicry rings are present among Delias butterflies, and those butterflies are also considered to be mimetic models of other lepidopteran insects; however, experimental evidence for their unpalatability to predators is limited. In Bali and Timor, a total of three mimicry rings of Delias species are present; particularly, male and female D. lemoulti join different rings in Timor. The present study examined the unpalatability of Delias in Bali and Timor to the caged avian predator Pycnonotus aurigaster. The birds ate eight Delias species in similar numbers, and ate the palatable butterfly Mycalesis horsfieldii much more frequently than Delias butterflies. The result suggests that the three mimicry rings of Delias species in Bali and Timor are Müllerian rather than Batesian. Based on previous findings on their phylogenetic relationships, the Müllerian mimicry rings of Delias in Bali and Timor are suggested to have emerged through the convergent evolution and phylogenetic constraints of wing color patterns. In the D. hyparete species group, mimetic radiation may have occurred between Bali and Timor.
A pilot study on the use of ultra‐deformable liposomes containing bleomycin in the treatment of equine sarcoid
Authors: Knottenbelt D. C. , Watson A. H. , Hotchkiss J. W. , Chopra S. , Higgins A. J.
Published: June 2018

The efficacy of a novel topical liposome‐encapsulated preparation of bleomycin (Bleosome) was studied in 118 clinical cases of equine sarcoid and efficacy was compared with two other standard conventional treatments, tazarotene and 5‐fluorouracil (5‐FU) as well as with the Bleosome in combination with each of these two conventional treatments. Treatments were arbitrarily assigned. Fifty‐two of the 118 sarcoids (44%) were resolved after 12 months but there were significant differences between treatment groups with the combinations of either 5‐FUand bleomycin, or tazarotene and bleomycin resulting in significantly superior resolution of 77 and 78% of the lesions, respectively. The preliminary results suggest that bleomycin in a liposomal carrier may be a useful treatment modality for superficial, diffuse and verrucose sarcoids. The treatment process was simple, and outcomes were functionally and cosmetically excellent. Liposome‐encapsulated bleomycin is economic compared to radiation and other treatment options and can be applied effectively by the owner under guidance. Further studies with different administration protocols and higher concentrations of bleomycin are warranted.
Early colonisation and temporal dynamics of the gut microbial ecosystem in Standardbred foals
Authors: Quercia S. , Freccero F. , Castagnetti C. , Soverini M. , Turroni S. , Biagi E. , Rampelli S. , Lanci A. , Mariella J. , Chinellato E. , Brigidi P. , Candela M.
Published: June 2018

Background

Even if horses strictly depend on the gut microbiota for energy homeostasis, only a few molecular studies have focused on its characterisation and none on the perinatal gut microbial colonisation process.

Objectives

To explore the perinatal colonisation process of the foal gut microbial ecosystem and the temporal dynamics of the ecosystem assembly during the first days of life.

Study design

Longitudinal study.

Methods

Thirteen Standardbred mare‐foal pairs were included in the study. For each pair, at delivery we collected the mare amniotic fluid, faeces and colostrum, and the foal meconium. Milk samples and faeces of both mare and foal were also taken longitudinally, until day 10 post‐partum. Samples were analysed by means of next‐generation sequencing of the 16S rRNA gene on Illumina MiSeq.

Results

Our findings suggest that microbial components derived from the mare symbiont communities establishes in the foal gut since fetal life. After birth, an external transmission route of mare microorganisms takes place. This involves a rapid and dynamic process of assembling the mature foal gut microbiome, in which the founder microbial species are derived from both the milk and the gut microbial ecosystems of the mare.

Main limitations

The inability to discriminate between live and dead cells, the possible presence of contaminating bacteria in low biomass samples (e.g. meconium and amniotic fluid), the limits of the phylogenetic assignment down to species level, and the presence of unassigned operational taxonomic units.

Conclusions

Our data highlight the importance of mare microbiomes as a key factor for the establishment of the gut microbial ecosystem of the foal.