bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes
Authors: Wewer Albrechtsen Nicolai J. , Junker Anders E. , Christensen Mette , Hædersdal Sofie , Wibrand Flemming , Lund Allan M. , Galsgaard Katrine D. , Holst Jens J. , Knop Filip K. , Vilsbøll Tina
Published: October 2017

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon’s action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (HbA1c), and cholesterol levels (β = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a “liver-α-cell axis” in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels.

NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.
Activation of the sweet taste receptor, T1R3, by the artificial sweetener sucralose regulates the pulmonary endothelium
Authors: Harrington Elizabeth O. , Vang Alexander , Braza Julie , Shil Aparna , Chichger Havovi
Published: October 2017

A hallmark of acute respiratory distress syndrome (ARDS) is pulmonary vascular permeability. In these settings, loss of barrier integrity is mediated by cell-contact disassembly and actin remodeling. Studies into molecular mechanisms responsible for improving microvascular barrier function are therefore vital in the development of therapeutic targets for reducing vascular permeability in ARDS. The sweet taste receptor T1R3 is a G protein-coupled receptor, activated following exposure to sweet molecules, to trigger a gustducin-dependent signal cascade. In recent years, extraoral locations for T1R3 have been identified; however, no studies have focused on T1R3 within the vasculature. We hypothesize that activation of T1R3, in the pulmonary vasculature, plays a role in regulating endothelial barrier function in settings of ARDS. Our study demonstrated expression of T1R3 within the pulmonary vasculature, with a drop in expression levels following exposure to barrier-disruptive agents. Exposure of lung microvascular endothelial cells to the intensely sweet molecule sucralose attenuated LPS- and thrombin-induced endothelial barrier dysfunction. Likewise, sucralose exposure attenuated bacteria-induced lung edema formation in vivo. Inhibition of sweet taste signaling, through zinc sulfate, T1R3, or G-protein siRNA, blunted the protective effects of sucralose on the endothelium. Sucralose significantly reduced LPS-induced increased expression or phosphorylation of the key signaling molecules Src, p21-activated kinase (PAK), myosin light chain-2 (MLC2), heat shock protein 27 (HSP27), and p110α phosphatidylinositol 3-kinase (p110αPI3K). Activation of T1R3 by sucralose protects the pulmonary endothelium from edemagenic agent-induced barrier disruption, potentially through abrogation of Src/PAK/p110αPI3K-mediated cell-contact disassembly and Src/MLC2/HSP27-mediated actin remodeling. Identification of sweet taste sensing in the pulmonary vasculature may represent a novel therapeutic target to protect the endothelium in settings of ARDS.
Early life stress induces immune priming in kidneys of adult male rats
Authors: De Miguel Carmen , Obi Ijeoma E. , Ho Dao H. , Loria Analia S. , Pollock Jennifer S.
Published: October 2017

Early life stress (ELS) in humans is associated with elevated proinflammatory markers. We hypothesized that ELS induces activation of the immune response in a rat model of ELS, maternal separation (MatSep), in adulthood. MatSep involves separating pups from the dam from postnatal day 2 to postnatal day 14 for 3 h/day. Control rats are nonseparated littermates. We determined circulating and renal immune cell numbers, renal immune cell activation markers, renal cytokine levels, and the renal inflammatory gene expression response to low-dose lipopolysaccharide (LPS) in male MatSep and control rats. We observed that MatSep did not change the percentage of gated events for circulating CD3+, CD4+, CD8+, and CD4+/Foxp3+ cells or absolute numbers of mononuclear and T cells in the circulation and kidneys; however, MatSep led to an increase in activation of renal neutrophils as well as CD44+ cells. Renal toll-like receptor 4 (TLR4) and interleukin 1 beta (IL-1β) was significantly increased in MatSep rats, specifically in the outer and inner medulla and distal nephron, respectively. Evaluation of renal inflammatory genes showed that in response to a low-dose LPS challenge (2 mg/kg iv) a total of 20 genes were significantly altered in kidneys from MatSep rats (17 genes were upregulated and 3 were downregulated), as opposed to no significant differences in gene expression in control vs. control + LPS groups. Taken together, these findings indicate that MatSep induces priming of the immune response in the kidney.
Activation pattern of ACE2/Ang-(1–7) and ACE/Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice
Authors: Tyrankiewicz Urszula , Olkowicz Mariola , Skórka Tomasz , Jablonska Magdalena , Orzylowska Anna , Bar Anna , Gonet Michal , Berkowicz Piotr , Jasinski Krzysztof , Zoladz Jerzy A. , Smolenski Ryszard T. , Chlopicki Stefan
Published: October 2017

Here, we analyzed systemic (plasma) and local (heart/aorta) changes in ACE/ACE-2 balance in Tgαq*44 mice in course of heart failure (HF). Tgαq*44 mice with cardiomyocyte-specific Gαq overexpression and late onset of HF were analyzed at different age for angiotensin pattern in plasma, heart, and aorta using liquid chromatography/mass spectrometry, for progression of HF by in vivo magnetic resonance imaging under isoflurane anesthesia, and for physical activity by voluntary wheel running. Six-month-old Tgαq*44 mice displayed decreased ventricle radial strains and impaired left atrial function. At 8–10 mo, Tgαq*44 mice showed impaired systolic performance and reduced voluntary wheel running but exhibited preserved inotropic reserve. At 12 mo, Tgαq*44 mice demonstrated a severe impairment of basal cardiac performance and modestly compromised inotropic reserve with reduced voluntary wheel running. Angiotensin analysis in plasma revealed an increase in concentration of angiotensin-(1–7) in 6- to 10-mo-old Tgαq*44 mice. However, in 12- to 14-mo-old Tgαq*44 mice, increased angiotensin II was noted with a concomitant increase in Ang III, Ang IV, angiotensin A, and angiotensin-(1–10). The pattern of changes in the heart and aorta was also compatible with activation of ACE2, followed by activation of the ACE pathway. In conclusion, mice with cardiomyocyte Gαq protein overexpression develop HF that is associated with activation of the systemic and the local ACE/Ang II pathway. However, it is counterbalanced by a prominent ACE2/Ang-(1–7) activation, possibly allowing to delay decompensation.

NEW & NOTEWORTHY Changes in ACE/ACE-2 balance were analyzed based on measurements of a panel of nine angiotensins in plasma, heart, and aorta of Tgαq*44 mice in relation to progression of heart failure (HF) characterized by multiparametric MRI and exercise performance. The early stage of HF was associated with upregulation of the ACE2/angiotensin-(1–7) pathway, whereas the end-stage HF was associated with downregulation of ACE2/angiotensin-(1–7) and upregulation of the ACE/Ang II pathway. ACE/ACE-2 balance seems to determine the decompensation of HF in this model.
Impact of Atherosclerosis‐ and Diabetes‐Related Dicarbonyls on Vascular Endothelial Permeability: A Comparative Assessment
Authors: Samsonov Mikhail V. , Khapchaev Asker Y. , Vorotnikov Alexander V. , Vlasik Tatyana N. , Yanushevskaya Elena V. , Sidorova Maria V. , Efremov Evgeniy E. , Lankin Vadim Z. , Shirinsky Vladimir P.
Published: October 2017

Background. Malondialdehyde (MDA), glyoxal (GO), and methylglyoxal (MGO) levels increase in atherosclerosis and diabetes patients. Recent reports demonstrate that GO and MGO cause vascular endothelial barrier dysfunction whereas no evidence is available for MDA. Methods. To compare the effects of MDA, GO, or MGO on endothelial permeability, we used human EA.hy926 endothelial cells as a standard model. To study cortical cytoplasm motility and cytoskeletal organization in endothelial cells, we utilized time‐lapse microscopy and fluorescent microscopy. To compare dicarbonyl‐modified protein band profiles in these cells, we applied Western blotting with antibodies against MDA‐ or MGO‐labelled proteins. Results. MDA (150–250 μM) irreversibly suppressed the endothelial cell barrier, reduced lamellipodial activity, and prevented intercellular contact formation. The motile deficiency of MDA‐challenged cells was accompanied by alterations in microtubule and microfilament organization. These detrimental effects were not observed after GO or MGO (250 μM) administration regardless of confirmed modification of cellular proteins by MGO. Conclusions. Our comparative study demonstrates that MDA is more damaging to the endothelial barrier than GO or MGO. Considering that MDA endogenous levels exceed those of GO or MGO and tend to increase further during lipoperoxidation, it appears important to reduce oxidative stress and, in particular, MDA levels in order to prevent sustained vascular hyperpermeability in atherosclerosis and diabetes patients.
Medical Approach to Right Colon Diverticulitis with Perforation
Authors: Espinosa James , Sharma Rahul , Lucerna Alan , Stranges Doug
Published: October 2017

We report a case of a 71-year-old female who presented with right lower quadrant (RLQ) abdominal pain and was diagnosed on CT scan with right-sided diverticulitis with perforation. She was admitted under the surgical service after consultation and received intravenous fluids, intravenous antibiotics, and pain medications as needed. The patient was discharged 2 days after admission in stable condition with follow-up with gastroenterology. The differential diagnosis of right lower quadrant abdominal pain is vast. Right-sided diverticulitis often presents in a manner similar to appendicitis. In the absence of peritonitis, conservative treatment may be possible. It is predictable that as the population ages, the incidence of right-sided diverticular disease will increase and will result in more presentations of acute right-sided diverticulitis to the emergency department (ED). The aim of this case report is to increase awareness of the incidence, pathophysiology, presentation, work-up (laboratory studies and imaging), and management (medical and surgical) of right-sided diverticulitis among emergency physicians.
12-Item Pruritus Severity Scale: Development and Validation of New Itch Severity Questionnaire
Authors: Reich Adam , Bożek Agnieszka , Janiszewska Katarzyna , Szepietowski Jacek C.
Published: October 2017

Introduction. A validated assessment of pruritus intensity is an important but still difficult clinical problem due to a subjective nature of this sensation. Objective. The aim of this study was the creation and validation of new itch severity questionnaire assessing pruritus intensity. Material and Methods. A total of 148 patients with pruritic dermatoses were asked to assess pruritus intensity using 12-Item Pruritus Severity Score (12-PSS) and Visual Analogue Scale (VAS). Patients were also asked to complete the Dermatology Life Quality Index (DLQI) and Hospitality Anxiety and Depression Scale (HADS). Test-retest comparison of 12-PSS was conducted in 102 subjects who completed the itch questionnaire twice with the 3- to 5-day interval. Results. We have created the 12-PSS assessing pruritus intensity (two questions), pruritus extent (one question) and duration (one question), influence of pruritus on concentration and patient psyche (four questions), and scratching as a response to pruritus stimuli (four questions). A maximum scoring was 22 points. The results showed strong consistency (Cronbach α coefficient 0.81). A significant correlation was observed with VAS (r=0.58, p<0.001) and quality of life level according to DLQI (r=0.53, p<0.001). Test-retest comparison in 102 subjects revealed a satisfactory reproducibility of achieved results (ICC = 0,72). Conclusions. The newly developed pruritus severity questionnaire may be used in daily clinical practice in the future.
Santamarine Inhibits NF-κB Activation and Induces Mitochondrial Apoptosis in A549 Lung Adenocarcinoma Cells via Oxidative Stress
Authors: Wu Xuefeng , Zhu Hua , Yan Jingzhe , Khan Muhammad , Yu Xiuyan
Published: October 2017

Santamarine (STM), a sesquiterpene lactone component of Magnolia grandiflora and Ambrosia confertiflora, has been shown to possess antimicrobial, antifungal, antibacterial, anti-inflammatory, and anticancer activities. However, no study has yet been conducted to investigate the molecular mechanism of STM-mediated anticancer activity. In the present study, we found that STM inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells through induction of oxidative stress. STM induces oxidative stress by promoting reactive oxygen species (ROS) generation, depleting intracellular glutathione (GSH), and inhibiting thioredoxin reductase (TrxR) activity in a dose-dependent manner. Further mechanistic study demonstrated that STM induces apoptosis by modulation of Bax/Bcl-2 expressions, disruption of mitochondrial membrane potential, activation of caspase-3, and cleavage of PARP in a dose-dependent manner. Moreover, STM inhibited the constitutive and inducible translocation of NF-κBp65 into the nucleus. IKK-16 (I-κB kinase inhibitor) augmented the STM-induced apoptosis, indicating that STM induces apoptosis in A549 cells at least in part through NF-κB inhibition. Finally, STM-induced apoptosis and expressions of apoptosis regulators were effectively inhibited by thiol antioxidant N-acetyl-L-cysteine (NAC), indicating that STM exerts its anticancer effects mainly through oxidative stress. To the best of our knowledge, this is the first report providing evidence of anticancer activity and molecular mechanism of STM.
A New Side Effect of Intravitreal Dexamethasone Implant (Ozurdex®)
Authors: Eris Erdem , Erdogan Gurkan , Perente Irfan , Demir Gokhan , Kepez Yildiz Burcin , Aygit Ebru Demet
Published: October 2017

Dexamethasone implant, 0,7 mg (Ozurdex, Allergan, Inc., Irvine, CA, USA), is drug mostly used in the treatment of the diabetic macular edema and edema related to retinal vein occlusion. By reporting this case we aimed to report a new side effect of 0.7 mg intravitreal dexamethasone implant that has not been reported in the literature before.
Exergame Grading Scheme: Concept Development and Preliminary Psychometric Evaluations in Cancer Survivors
Authors: Wang Hsiao-Lan , Liu Chiung-Ju , Kilpatrick Marcus , Jim Heather , McMillan Susan , Vijayakumar Nisha , McDonald Sally , Padhya Tapan , Russell Jeffery , Vondruska Karen , Visovsky Constance
Published: October 2017

The challenge of using exergames to promote physical activity among cancer survivors lies in the selection of the exergames that match their fitness level. There is a need for a standardized grading scheme by which to judge an exergame’s capacity to address specific physical fitness attributes with different levels of physical engagement. The study aimed to develop an Exergame Grading Scheme and preliminarily evaluate its psychometric properties. Fourteen (14) items were created from the human movement and exergame literature. The content validity index (CVI) was rated by content experts with two consecutive rounds (N=5 and N=3 independently). The interrater reliability (IRR) was determined by two raters who used the Exergame Grading Scheme to determine the grading score of the five exergames performed by two cancer survivors (N=10). Each item had a score of 1 for item-level CVI and 1 for k. For IRR, 9 items had rho values of 1, 1 item had 0.93, and 4 items had between 0.80 and 0.89. This valid and reliable Exergame Grading Scheme makes it possible to develop a personalized physical activity program using any type of exergame or fitness mobile application in rehabilitation practice to meet the needs of cancer survivors.
Failure Diagnosis for Distributed Stochastic Discrete Event Systems
Authors: Geng Xuena , Ouyang Dantong , Zhao Xiangfu
Published: October 2017

Because of the complexity of the failure diagnosis for large‐scale discrete event systems (DESs), DESs with decentralized information have received a lot of attention. DESs with communication events are defined as distributed DESs. Stochastic discrete event systems (SDESs) are DESs with a probabilistic structure. A‐diagnosability is an important property in failure diagnosis of SDES. In this paper, we investigate A‐diagnosability in distributed SDESs. We define a local model and global model. Moreover, we construct a synchronized stochastic diagnoser to check A‐diagnosability in distributed SDESs. We also propose a necessary and sufficient condition for a distributed SDES to be A‐diagnosable. Some examples are described to illustrate our algorithms.
Medical First-Trimester Termination of Pregnancy with Massive Fibroid Uterus
Authors: Saad-Naguib Michael , Maguire Karla , Curry Christine , Verma Usha
Published: October 2017

First-trimester termination of pregnancy by medical or surgical route is highly effective with a low complication rate. Uterine abnormalities can complicate a procedure due to distortion of normal anatomy. In this case presentation, medical termination of pregnancy is performed using fetal intracardiac potassium chloride injection and intramuscular methotrexate.
Leptomeningeal Contrast Enhancement Is Associated with Disability Progression and Grey Matter Atrophy in Multiple Sclerosis
Authors: Makshakov Gleb , Magonov Evgeniy , Totolyan Natalia , Nazarov Vladimir , Lapin Sergey , Mazing Alexandra , Verbitskaya Elena , Trofimova Tatiana , Krasnov Vladimir , Shumilina Maria , Skoromets Alexander , Evdoshenko Evgeniy
Published: October 2017

Leptomeningeal contrast enhancement (LMCE) on magnetic resonance imaging (MRI) is a newly recognized possible biomarker in multiple sclerosis (MS), associated with MS progression and cortical atrophy. In this study, we aimed to assess the prevalence of LMCE foci and their impact on neurodegeneration and disability. Materials. 54 patients with MS were included in the study. LMCE were detected with a 3 Tesla scanner on postcontrast fluid-attenuated inversion-recovery (FLAIR) sequence. Expanded Disability Status Scale (EDSS) score, number of relapses during 5 years from MS onset, and number of contrast-enhancing lesions on T1 weighted MRI were counted. Results. LMCE was detected in 41% (22/54) of patients. LMCE-positive patients had longer disease duration (p=0,0098) and higher EDSS score (p=0,039), but not a higher relapse rate (p=0,091). No association of LMCE with higher frequency of contrast-enhancing lesions on T1-weighted images was detected (p=0,3842). Analysis of covariates, adjusted for age, sex, and disease duration, revealed a significant effect of LMCE on the cortex volume (p=0.043, F=2.529), the total grey matter volume (p=0.043, F=2.54), and total ventricular volume (p=0.039, F=2.605). Conclusions. LMCE was shown to be an independent and significant biomarker of grey matter atrophy and disability in MS.
Formation of Condyle-Like Structure after Treatment of Temporomandibular Joint Ankylosis: Literature Review and Long-Term Follow-Up of Two Patients
Authors: Güven Orhan
Published: October 2017

Treatment of ankylosis is one of the greatest challenges in temporomandibular joint (TMJ) surgery. To provide a satisfactory mouth opening, as well as normal jaw function, and to prevent reankylosis in the long term are the most important principles in the treatment of TMJ ankylosis. These functions have been attained in both of the presented patients in the long term. It is known that heterotopic bone formation is rare in the maxillofacial area, but rapid bone regeneration which reconstitutes a new condyle is rarer. The purpose of the presented paper is to reveal the existence of an inherent capability of the mandible, rapid bone growth of the ramus mandible, and reformation of a previously nonexisting condyle after resection of the ramus in patients with TMJ ankylosis. In this paper, two unusual cases of unexpected condyle-like structure formation after treatment of ankylosis were presented.
Cell Signaling Pathway in 12-O-Tetradecanoylphorbol-13-acetate-Induced LCN2 Gene Transcription in Esophageal Squamous Cell Carcinoma
Authors: Meng Lingying , Wang Muting , Du Zepeng , Fang Zhongmin , Wu Bingli , Wu Jianyi , Xie Wenming , Shen Jian , Zhu Tianxiang , Xu XieE , Liao Liandi , Xu Liyan , Li Enmin , Lan Bin
Published: October 2017

LCN2 is involved in various cellular functions, including transport of small hydrophobic molecules, protection of MMP9 from proteolytic degradation, and regulating innate immunity. LCN2 is elevated in multiple human cancers, frequently being associated with tumor size, stage, and invasiveness. Our previous studies have shown that LCN2 expression could be induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in esophageal squamous cell carcinoma (ESCC) by the binding of five nucleoproteins (MISP, KLF10, KLF15, PPP1R18, and RXRβ) at a novel TPA-responsive element (TRE), at −152~−60 bp of the 5′ flanking region of the LCN2 promoter. However, much is unknown about whether these proteins can respond to TPA stimulation to regulate LCN2 transactivation and which cell signaling pathways mediate this process. In this study, expression plasmids encoding these five nucleoproteins were stably transfected into EC109 cells. Then, stable transfectant was characterized by a Dual-Luciferase Reporter Assay System. RT-PCR, real-time PCR, western blotting, specific kinase inhibitor treatment, and bioinformatics analyses were applied in this study. We found that MISP, KLF10, KLF15, PPP1R18, and RXRβ proteins could strongly respond to TPA stimulation and activate LCN2 transcriptional expression. MEK, ERK, JNK, and P38 kinases were involved in the LCN2 transactivation. Furthermore, the MEK-ERK signal pathway plays a major role in this biological process but does not involve PKCα signaling.
Two new species of Ceratophysella (Collembola: Hypogastruridae) from Brazil with a key to South American species of the genus
Authors: Palacios-Vargas J.G. , Cipola N.G. , Bellini B.C.
Published: October 2017

Two new species of the denticulata-group in the genus Ceratophysella
Börner, 1932, C. rogerarlei sp.n. and C. nataliae sp.n., both from Brazil are described and illustrated. Ceratophysella rogerarlei sp.n. is similar to C. engadinensis (Gisin, 1949) in overall chaetotaxy, but it is unique by the combination of Ant. IV with trilobed apical bulb and 5 dorsal sensilla, PAO atypical with antero-lateral lobe clearly shorter than the antero-medial lobe, and the reduction of trunk dorsal chaetotaxy and number of macrosetae. Ceratophysella nataliae sp.n. is similar to C. gibbosa (Bagnall, 1940) and C. tupamara
Palacios-Vargas & Bocanegra, 2012 but differs in dorsal abdominal chaetotaxy, Ant. IV with trilobed apical bulb (simple in C. gibbosa) and dorsal manubrium with 18+18 setae (8+8 in C. tupamara). A key to South American species of the genus is provided. With the descriptions presented, there are now nine species of Ceratophysella recorded from South America and six from Brazil.
A Case Study on Power Outage Impacts from Future Hurricane Sandy Scenarios
Authors: Wanik D. W. , Anagnostou E. N. , Astitha M. , Hartman B. M. , Lackmann G. M. , Yang J. , Cerrai D. , He J. , Frediani M. E. B.
Published: October 2017

Hurricane Sandy (2012, referred to as Current Sandy) was among the most devastating storms to impact Connecticut’s overhead electric distribution network, resulting in over 15 000 outage locations that affected more than 500 000 customers. In this paper, the severity of tree-caused outages in Connecticut is estimated under future-climate Hurricane Sandy simulations, each exhibiting strengthened winds and heavier rain accumulation over the study area from large-scale thermodynamic changes in the atmosphere and track changes in the year ~2100 (referred to as Future Sandy). Three machine-learning models used five weather simulations and the ensemble mean of Current and Future Sandy, along with land-use and overhead utility infrastructure data, to predict the severity and spatial distribution of outages across the Eversource Energy service territory in Connecticut. To assess the influence of increased precipitation from Future Sandy, two approaches were compared: an outage model fit with a full set of variables accounting for both wind and precipitation, and a reduced set with only wind. Future Sandy displayed an outage increase of 42%–64% when using the ensemble of WRF simulations fit with three different outage prediction models. This study is a proof of concept for the assessment of increased outage risk resulting from potential changes in tropical cyclone intensity associated with late-century thermodynamic changes driven by the IPCC AR4 A2 emissions scenario.
Quality Control of Surface Wind Observations in Northeastern North America. Part II: Measurement Errors
Authors: Lucio-Eceiza Etor E. , González-Rouco J. Fidel , Navarro Jorge , Beltrami Hugo , Conte Jorge
Published: October 2017

A quality control (QC) process has been developed and applied to an observational database of surface wind speed and wind direction in northeastern North America. The database combines data from three datasets of different initial quality, including a total of 526 land stations and buoys distributed over the provinces of eastern Canada and five adjacent northeastern U.S. states. The data span from 1953 to 2010. The first part of the QC deals with data management issues and is developed in a companion paper. Part II, presented herein, is focused on the detection of measurement errors and deals with low-variability errors, like the occurrence of unrealistically long calms, and high-variability problems, like rapid changes in wind speed; some types of biases in wind speed and wind direction are also considered. About 0.5% (0.16%) of wind speed (wind direction) records have been flagged. Additionally, 15.87% (1.73%) of wind speed (wind direction) data have been corrected. The most pervasive error type in terms of affected sites and erased data corresponds to unrealistic low wind speeds (89% of sites affected with 0.35% records removed). The amount of detected and corrected/removed records in Part II (~9%) is approximately two orders of magnitude higher than that of Part I. Both management and measurement errors are shown to have a discernible impact on the statistics of the database.
When unbearable suffering incites psychiatric patients to request euthanasia: qualitative study
Authors: Verhofstadt Monica , Thienpont Lieve , Peters Gjalt-Jorn Ygram
Published: October 2017

Background

The concept of ‘unbearable suffering’ is central to legislation governing whether euthanasia requests may be granted, but remains insufficiently understood, especially in relation to psychiatric patients.

Aims

To provide insights into the suffering experiences of psychiatric patients who have made a request for euthanasia.

Method

Testimonials from 26 psychiatric patients who requested euthanasia were analysed using QualiCoder software.

Results

Five domains of suffering were identified: medical, intrapersonal, interpersonal, societal and existential. Hopelessness was confirmed to be an important contributor. The lengthy process of applying for euthanasia was a cause of suffering and added to experienced hopelessness, whereas encountering physicians who took requests seriously could offer new perspectives on treatment.

Conclusions

The development of measurement instruments to assess the nature and extent of suffering as experienced by psychiatric patients could help both patients and physicians to better navigate the complicated and sensitive process of evaluating requests in a humane and competent way. Some correlates of suffering (such as low income) indicate the need for a broad medical, societal and political debate on how to reduce the burden of financial and socioeconomic difficulties and inequalities in order to reduce patients' desire for euthanasia. Euthanasia should never be seen (or used) as a means of resolving societal failures.
Invited commentary on… When unbearable suffering incites psychiatric patients to request euthanasia
Authors: Kelly Brendan D.
Published: October 2017

Euthanasia is available in Belgium and Luxembourg for untreatable and unbearable suffering resulting from ‘physical and/or psychological suffering that cannot be alleviated and results from a serious and incurable disease, caused by accident or illness'. Verhofstadt et al's valuable analysis of testimonials from psychiatric patients requesting euthanasia demonstrates that elements of this suffering might well be alleviated. We should not kill our patients.
Patient safety and quality of care in mental health: a world of its own?
Authors: D'Lima Danielle , Crawford Mike J. , Darzi Ara , Archer Stephanie
Published: October 2017

Quality and safety in healthcare, as an academic discipline, has made significant progress over recent decades, and there is now an active and established community of researchers and practitioners. However, work has predominantly focused on physical health, despite broader controversy regarding the attention paid to, and significance attributed to, mental health. Work from both communities is required in order to ensure that quality and safety is actively embedded within mental health research and practice and that the academic discipline of quality and safety accurately represents the scientific knowledge that has been accumulated within the mental health community.
Randomized Phase III and Extension Studies of Naldemedine in Patients With Opioid-Induced Constipation and Cancer
Authors: Katakami Nobuyuki , Harada Toshiyuki , Murata Toru , Shinozaki Katsunori , Tsutsumi Masakazu , Yokota Takaaki , Arai Masatsugu , Tada Yukio , Narabayashi Masaru , Boku Narikazu
Published: October 2017

Purpose

Opioid-induced constipation (OIC) is a frequent and debilitating adverse effect (AE) of opioids—common analgesics for cancer pain. We investigated the efficacy and safety of a peripherally acting μ-opioid receptor antagonist, naldemedine (S-297995), for OIC, specifically in patients with cancer.

Patients and Methods

This phase III trial consisted of a 2-week, randomized, double-blind, placebo-controlled study (COMPOSE-4) and an open-label, 12-week extension study (COMPOSE-5). In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned on a 1:1 basis to receive once-daily oral naldemedine 0.2 mg or placebo. The primary end point was the proportion of spontaneous bowel movement (SBM) responders (≥ 3 SBMs/week and an increase of ≥ 1 SBM/week from baseline). The primary end point of COMPOSE-5 was safety.

Results

In COMPOSE-4, 193 eligible patients were randomly assigned to naldemedine (n = 97) or placebo (n = 96). The proportion of SBM responders in COMPOSE-4 was significantly greater with naldemedine than with placebo (71.1% [69 of 97 patients] v 34.4% [33 of 96 patients]; P < .0001). A greater change from baseline was observed with naldemedine than with placebo in the frequency of SBMs/week (5.16 v 1.54; P < .0001), SBMs with complete bowel evacuation/week (2.76 v 0.71; P < .0001), and SBMs without straining/week (3.85 v 1.17; P = .0005). In COMPOSE-4, more patients treated with naldemedine than with placebo reported treatment-emergent AEs (TEAEs) (44.3% [43 of 97 patients] v 26.0% [25 of 96 patients]; P = .01); in COMPOSE-5, 105 (80.2%) of 131 of patients reported TEAEs. Diarrhea was the most frequently reported TEAE in COMPOSE-4 (19.6% [19 of 97 patients] v 7.3% [seven of 96 patients] with naldemedine v placebo) and COMPOSE-5 (18.3% [24 of 131 patients] with naldemedine). Naldemedine was not associated with signs or symptoms of opioid withdrawal and had no notable impact on opioid-mediated analgesia.

Conclusion

Once-daily oral naldemedine 0.2 mg effectively treated OIC and was generally well tolerated in patients with OIC and cancer.
Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement
Authors: Kim Edward S. , Bruinooge Suanna S. , Roberts Samantha , Ison Gwynn , Lin Nancy U. , Gore Lia , Uldrick Thomas S. , Lichtman Stuart M. , Roach Nancy , Beaver Julia A. , Sridhara Rajeshwari , Hesketh Paul J. , Denicoff Andrea M. , Garrett-Mayer Elizabeth , Rubin Eric , Multani Pratik , Prowell Tatiana M. , Schenkel Caroline , Kozak Marina , Allen Jeff , Sigal Ellen , Schilsky Richard L.
Published: October 2017

Purpose

The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention’s benefit-risk profile.

Methods

ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community.

Results

Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low.

Conclusion

To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.
MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer
Authors: Goetz Matthew P. , Toi Masakazu , Campone Mario , Sohn Joohyuk , Paluch-Shimon Shani , Huober Jens , Park In Hae , Trédan Olivier , Chen Shin-Cheh , Manso Luis , Freedman Orit C. , Garnica Jaliffe Georgina , Forrester Tammy , Frenzel Martin , Barriga Susana , Smith Ian C. , Bourayou Nawel , Di Leo Angelo
Published: October 2017

Purpose

Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy.

Methods

MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events.

Results

Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%).

Conclusion

Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.
The sedentary (r)evolution: Have we lost our metabolic flexibility?
Authors: Freese Jens , Klement Rainer Johannes , Ruiz-Núñez Begoña , Schwarz Sebastian , Lötzerich Helmut
Published: October 2017

During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans’ primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.
Case Report: Whole exome sequencing identifies variation c.2308G>A p.E770K in RAG1 associated with B- T- NK+ severe combined immunodeficiency
Authors: Govindaraj Geeta Madathil , Karuthedath Vellarikkal Shamsudheen , Jayarajan Rijith , Ravi Rowmika , Verma Ankit , Chakkiyar Krishnan , Jayakrishnan Machinari Puthenpurayil , Arakkal Riyaz , Raj Revathi , Kunnaruvath Rajeevan , Sivasubbu Sridhar , Scaria Vinod
Published: October 2017

Severe combined immunodeficiency is a large clinically heterogeneous group of disorders caused by a defect in the development of humoral or cellular immune responses. At least 13 genes are known to be involved in the pathophysiology of the disease and the mutation spectrum in SCID has been well documented. Mutations of the recombination-activating genes RAG 1 and RAG 2 are associated with a range of clinical presentations including, severe combined immunodeficiency and autoimmunity. Recently, our understanding of the molecular basis of immune dysfunction in RAG deficiency has improved tremendously with newer insights into the ultrastructure of the RAG complex. In this report, we describe the application of whole exome sequencing for arriving at a molecular diagnosis in a child suffering from B- T- NK+ severe combined immunodeficiency. Apart from making the accurate molecular diagnosis, we also add a genetic variation c.2308G>A p.E770K to the compendium of variations associated with the disease.
Surgical Treatment of Annuloaortic Ectasia – Replace or Repair?
Authors: Martino Andrea De , Re Federico , Blasi Stefania , Celiento Michele , Ravenni Giacomo , Pratali Stefano , Milano Aldo , Bortolotti Uberto
Published: October 2017

Background:
Patients with annuloaortic ectasia may be surgically treated with modified Bentall or David I valve-sparing procedures. Here, we compared the long-term results of these procedures.

Methods:
A total of 181 patients with annuloaortic ectasia underwent modified Bentall (102 patients, Group 1) or David I (79 patients, Group 2) procedures from 1994 to 2015. Mean age was 62 ± 11 years in Group 1 and 64 ± 16 years in Group 2. Group 1 patients were in poorer health, with a lower ejection fraction and higher functional class.

Results:
Early mortality was 3% in Group 1 and 2.5% in Group 2. Patients undergoing a modified Bentall procedure had a higher incidence of thromboembolism and hemorrhage, whereas those undergoing a David I procedure had a higher incidence of endocarditis. Actuarial survival was 70 ± 6% at 15 years in Group 1 and 84 ± 7% at 10 years in Group 2. Actuarial freedom from reoperation was 97 ± 2% at 15 years in Group 1 and 84 ± 7% at 10 years in Group 2. In Group 2, freedom from procedure-related reoperations was 98 ± 2% at 10 years. At last follow-up, no cases of moderate or severe aortic regurgitation were observed.

Conclusions:
The modified Bentall and David I procedures showed excellent early and late results. The modified Bentall procedure with a mechanical conduit was associated with thromboembolic and hemorrhagic complications, whereas the David I procedure was associated with unexplained occurrences of endocarditis. Thus, the David I procedure appears to be safe, reproducible, and capable of achieving stable aortic valve repair and is therefore our currently preferred solution for patients with annuloaortic ectasia. However, the much shorter follow-up for David I patients limits the strength of our comparison between the two techniques.
Optimizing an Octane Number of Motor Gasoline (MOGAS) 91 RON with Blending Methods
Authors: Huda A.M. Miftahul , W Subagjo , Sarungu Selvia
Published: October 2017

Motor Gasoline (MOGAS) that serves as modifiers thermal energy into mechanical energy with a Research Octane Number (RON) of 91 was produced by mixing (blending) of two components. RON are high is one of MOGAS specifications needed for good engine performance. To obtain a MOGAS with high RON usually needs additional materials, chemical components. In this work we don’t need any additional materials to increasing the RON. In the field of oil and gas blending method is a method that is widely used to acquire new products that are superior and achieve quality standards. The components used in blending these are products with a value of RON 88 and 92. Examination of specific gravity (ASTMD-1298) was conducted to obtain specific gravity (SG) and temperature observations (T), while the ASTMD-86 distillation examination was conducted to determine the components in materials. The results showed that the product specifications in accordance with the existing products on the market. The acquisition of distillate reached 95% with losses of about 3.9%, and the residue of 1.1%.
Reporters in the age of data journalism
Authors: Veglis Andreas , Bratsas Charalampos
Published: October 2017

In the past, journalists were responsible for reporting the news. But today news stories disseminate as the incidents unfold, from multiple sources. Thus, gathering, filtering and visualizing events has a growing value. Huge amounts of data are available, but exploiting them is not an easy task. Data journalism can be defined as a journalism speciality in which numerical data are used in the production and distribution of information. This article investigates the necessary skills that journalists must have in order to cope with data journalism. More precisely, it defines data journalism, and discusses journalists’ Information and Communication Technology (ICT) skills, as well as the necessary skills for supporting data journalism. Special attention is given to Web 3.0 and open data that can play an important role in data journalism. A survey conducted among professional journalists in Greece concerning data journalism is also presented and discussed.
Applied diversity: A normative approach to improving news representations of ethno-cultural minorities based on the Canadian experience
Authors: Clark Brad
Published: October 2017

Western news organizations have long been accused of either ignoring or misrepresenting ethnic minorities in the media discourse. Proposals for reform have often been tied to hiring ethnically diverse journalists and to broad cultural awareness initiatives. Despite several decades of such efforts, study after study shows ethnic minorities are all too often under- and misrepresented in the news discourse. In Canada, where high rates of immigration and a burgeoning indigenous population are creating unprecedented demographic diversity, news media still struggle to produce consistently inclusive and equitable coverage. This article draws on research from Canada, as well as the United States and other western nations, identifying the major impediments to more accurate representations of ethnic minorities. It challenges reform initiatives of the past and details their failure to address the dominant bias inherent in mainstream news production routines. The author proposes explicit, new approaches to newsgathering practices targeting that dominant bias.
Situational ethics in photojournalism: Moving beyond doing good or doing right
Authors: Kim Yung Soo
Published: October 2017

Readers have different views on a photojournalist’s ethical situation when confronting the dilemma of whether to continue portraying a tragedy or intervening to help those in distress. Using an online experimental design with multiple stimuli, four situational characteristics were tested. Results showed that citizens (N=100) generally adopted a situational ethics rationale rather than an absolutist or utilitarian rationale. These findings substantiate an earlier study showing that readers do not universally condemn photojournalists who perform their professional duty instead of assisting persons in distress. However, readers would not object to photojournalists pursuing different actions according to specific situational circumstances.