bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Intuitionistic Fuzzy TOPSIS in Site Selection of Wind Power Plants in Turkey
Authors: Daneshvar Rouyendegh Babak , Yildizbasi Abdullah , Arikan Ümmühan Z. B.
Published: August 2018

The reduction of energy resources and the increase in environmental consciousness have recently increased the interest in renewable energy sources. Wind energy is from renewable energy sources, which are used in many countries. Turkey has a lot alternative wind energy plants thanks to its favorable geographical location. Where the wind power plant is to be established is a complex and important decisive factor. It is very important to select the appropriate wind power plant site to take advantage of wind energy and reduce costs. In this study, we aimed to reach the solution of wind energy plant site selection. For this purpose 4 alternative wind power plant locations have been identified. To evaluate the alternatives, 10 criteria in four dimensions including wind potential, location, cost, and social benefits are selected. Since the Multicriterion Decision Making (MCDM) methods are often used in problem of location selection from past to present, TOPSIS method combined with intuitionistic fuzzy set (IFS) has been used to achieve this goal. The main purpose of the TOPSIS method is to rank the alternatives in the worst way. The IFS are used to reflect approval, rejection, and hesitation of decision makers by dealing with real life uncertainty, imprecision, vagueness, and linguistic human decisions. Finally, a numerical example is applied for wind power plant site selection. In order to demonstrate the effectiveness of IFS, the problem is solved by the Fuzzy TOPSIS method using the same data. Then, the obtained results are compared with the IFS method to show the effectiveness of the proposed method.
Risk and Outcome after Simultaneous Carotid Surgery and Cardiac Surgery: Single Centre Experience
Authors: Tirilomis Theodor , Zenker Dieter , Stojanovic Tomislav , Malliarou Stella , Schoendube Friedrich A.
Published: August 2018

Objective. Carotid artery stenosis in patients undergoing open-heart surgery may increase risk and deteriorate outcome. The aim of the study was the analysis of risks and outcome after simultaneous carotid and cardiac surgery. Methods. We retrospectively reviewed the medical records of 100 consecutive patients who underwent simultaneous carotid surgery and open-heart surgery during a 5-year period (from 2006 to 2010). Seventy patients were male and 30 female; the mean age was 70.9±7.9 years (median: 71.8 years). Seventy-three patients underwent coronary bypass grafting (CABG), 18 patients combined CABG and valve procedures, 7 patients CABG combined with other procedures, and 3 patients isolated valve surgery. More than half of patients had had bilateral carotid artery pathology (n=51) including contralateral carotid artery occlusion in 12 cases. Results. Carotid artery patch plasty was performed in 71 patients and eversion technique in 29. In 75 cases an intraluminal shunt was used. Thirty-day mortality rate was 7% due to cardiac complications (n=5), metabolic disturbance (n=1), and diffuse cerebral embolism (n=1). There were no carotid surgery-related deaths. Postoperatively, transient cerebral ischemia occurred in one patient and stroke with mild permanent neurological deficit (Rankin level 2) in another patient. Conclusion. Simultaneous carotid artery surgery and open-heart surgery have low risk. The underlying cardiac disease influences outcome.
Novel Learning Algorithms for Efficient Mobile Sink Data Collection Using Reinforcement Learning in Wireless Sensor Network
Authors: Soni Santosh , Shrivastava Manish
Published: August 2018

Generally, wireless sensor network is a group of sensor nodes which is used to continuously monitor and record the various physical, environmental, and critical real time application data. Data traffic received by sink in WSN decreases the energy of nearby sensor nodes as compared to other sensor nodes. This problem is known as hot spot problem in wireless sensor network. In this research study, two novel algorithms are proposed based upon reinforcement learning to solve hot spot problem in wireless sensor network. The first proposed algorithm RLBCA, created cluster heads to reduce the energy consumption and save about 40% of battery power. In the second proposed algorithm ODMST, mobile sink is used to collect the data from cluster heads as per the demand/request generated from cluster heads. Here mobile sink is used to keep record of incoming request from cluster heads in a routing table and visits accordingly. These algorithms did not create the extra overhead on mobile sink and save the energy as well. Finally, the proposed algorithms are compared with existing algorithms like CLIQUE, TTDD, DBRkM, EPMS, RLLO, and RL‐CRC to better prove this research study.
An Interactive Consensus Model for Group Decision-Making with Incomplete Multi-Granular 2-Tuple Fuzzy Linguistic Preference Relations
Authors: Song Yongming , Yuan Feng
Published: August 2018

As a result of the heterogeneity of decision-makers, it is more suitable to use multi-granular linguistic information to express assessing information over alternatives for decision-makers. Decision-makers may only provide partial preference information as the limitation of knowledge over the alternatives. Thus, the incomplete multi-granular 2-tuple fuzzy linguistic preference relations (IMGFLPRs) can be applied to manage the GDM problems in complex environments. In this paper, we propose a novel group decision-making (GDM) model based on mathematical programming with IMGFLPRs. It is more important that the proposed mathematical programming can directly deal with IMGFLPRs and does not need to be converted into a uniform form. By this means, we construct a consensus reaching process based on IMGFLPRs, considering simultaneously dynamic adjustment of experts’ weight. Finally, an emergency plan selection problem is solved by the proposed model, which shows the result of GDM is effectiveness.
Driving Risk Assessment in Work Zones Using Cloud Model
Authors: Zhang Chi , Zhang Hong , Ma Xiongying , Zhang Min , Wang Shiwei
Published: August 2018

Work zones are prone to traffic accidents. They are considered as dangerous parts of expressways not only for drivers but also for highway construction workers, as they face a higher risk of traffic accidents in work zones. In order to identify the driving risks and to provide guidance to detect traffic risks in work zone, a comprehensive risk assessment method based on cloud model is developed to examine the driving risks in work zones. The proposed model relies on three parameters to determine the driving risks in work zones, namely, coefficient of variation of speed, deceleration, and minimum safety distance. VISSIM simulation software is used as a tool to construct the work zone driving conditions and the reverse cloud model is used to divide the concept and concept jump. The maximum activation intensity is considered as the base factor to determine the core risk level. Other activation intensities are used as a basis to optimize the edge level effect and generate a comprehensive function. The reconstruction area in Anhui Province is used as a case study to assess the driving risks in three expressway work zones. The results revealed that the risk scores of the three work zones 1, 2, and 3 are 48.48, 62.49, and 34.33, respectively. The results obtained by the developed driving risk assessment model are in good agreement with the experimental results. Hence, the model proposed in this paper can accurately assess the driving risks in work zones using a more scientific and intuitive approach, which provides an excellent tool to design safe expressway work zones.
Neuroprotective Effects of dl‐3‐n‐Butylphthalide against Doxorubicin‐Induced Neuroinflammation, Oxidative Stress, Endoplasmic Reticulum Stress, and Behavioral Changes
Authors: Liao Dehua , Xiang Daxiong , Dang Ruili , Xu Pengfei , Wang Jiemin , Han Wenxiu , Fu Yingzhou , Yao Dunwu , Cao Lizhi , Jiang Pei
Published: August 2018

Doxorubicin (DOX) is a broad‐spectrum antitumor drug while its use is limited due to its neurobiological side effects associated with depression. We investigated the neuroprotective efficacy of dl‐3‐n‐butylphthalide (dl‐NBP) against DOX‐induced anxiety‐ and depression‐like behaviors in rats. dl‐NBP was given (30 mg/kg) daily by gavage over three weeks starting seven days before DOX administration. Elevated plus maze (EPM) test, forced swimming test (FST), and sucrose preference test (SPT) were performed to assess anxiety‐ and depression‐like behaviors. Our study showed that the supplementation of dl‐NBP significantly mitigated the behavioral changes induced by DOX. To further explore the mechanism of neuroprotection induced by dl‐NBP, several biomarkers including oxidative stress markers, endoplasmic reticulum (ER) stress markers, and neuroinflammatory cytokines in the hippocampus were quantified. The results showed that dl‐NBP treatment alleviated DOX‐induced neural apoptosis. Meanwhile, DOX‐induced oxidative stress and ER stress in the hippocampus were significantly ameliorated in dl‐NBP pretreatment group. Our study found that dl‐NBP alleviated the upregulation of malondialdehyde (MDA), nitric oxide (NO), CHOP, glucose‐regulated protein 78 kD (GRP‐78), and caspase‐12 and increased the levels of reduced glutathione (GSH) and activities of catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) in the hippocampus of rats exposed to DOX. Additionally, the gene expression of interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and tumor necrosis factor‐alpha (TNF‐α) and protein levels of inducible nitric oxide synthase (iNOS) were significantly increased in DOX‐treated group, whereas DOX‐induced neuroinflammation was significantly attenuated in dl‐NBP supplementation group. In conclusion, dl‐NBP could alleviate DOX‐induced anxiety‐ and depression‐like behaviors via attenuating oxidative stress, ER stress, inflammatory reaction, and neural apoptosis, providing a basis as a therapeutic potential against DOX‐induced neurotoxicity.
Adult Granulosa Cell Tumors of the Ovary: A Retrospective Study of 36 FIGO Stage I Cases with Emphasis on Prognostic Pathohistological Features
Authors: Babarović Emina , Franin Ivan , Klarić Marko , Ferrari Ani Mihaljević , Karnjuš-Begonja Ružica , Eminović Senija , Ostojić Damjana Verša , Vrdoljak-Mozetič Danijela
Published: August 2018

Objective. Adult granulosa cell tumors (AGCTs) represent 2%–5% of all ovarian malignancies. The aim of this study was to analyze clinical and pathohistological parameters and their impact on recurrence, overall, and disease-free survival in FIGO stage I AGCT patients. Methods. The tumor specimens analyzed in this retrospective study were obtained from a total of 36 patients with diagnosis of ovarian AGCT surgically treated at the Department of Gynecology, Rijeka University Hospital Centre, between 1994 and 2012. Clinical, pathological, and follow-up data were collected. Results. The mean age at diagnosis was 54.5 years with a range of 24–84. The majority of the patients, 30 (83%), were in FIGO stage IA, 3 (8%) in stage IC1, 1 (3%) in stage IC2, and 2 (6%) in stage IC3. During follow-up period (median 117.5 months, range 26–276), recurrence occurred in 4 patients (12%) with 2 deaths of the disease recorded. In univariate analysis, the 5-year survival rates were significantly shorter in patients with FIGO substage IC (p=0.019), with positive LVSI (p=0.022), with presence of necrosis (p=0.040), and with hemorrhage (p=0.017). In univariate analysis, the 5-year disease-free survival rates were significantly shorter in patients treated with fertility surgery (p=0.004), with diffuse growth pattern (p=0.012), with moderate and severe nuclear atypia (p=0.032), and with presence of hemorrhage (p=0.022). FIGO substage IC proved to be independent predictor for recurrence (OR = 16.87, p=0.015, and OR = 23.49, p=0.023, resp.) and disease-free survival (p=0.0002; HR 20.84, p=0.02) at the uni- and multivariate analyses. Conclusions. FIGO substage IC is predictive of recurrence and disease-free survival in patients with early-stage AGCTs. LVSI, presence of necrosis and hemorrhage, diffuse growth pattern, and nuclear atypia in AGCTs seem to be associated with overall and disease-free survival, so these pathological features should be taken into consideration when managing patients with AGCT.
Numerical Studies on the Failure Process of Heterogeneous Rock Material with Preexisting Fracture under Uniaxial Compression
Authors: Zhang Qi , Ma Dan , Liu Jiangfeng , Zhang Kai , Fan Zhiqiang
Published: August 2018

It is of vital importance to understand the failure processes of the heterogeneous rock material with different kinds of preexisting fractures in underground engineering. A damage model was introduced to describe the initiation and propagation behaviors of the fractures in rock. Reduced parameters were applied in this work because the microcracks in the rock were neglected. Then, the numerical model was validated through comparing the simulation results with the laboratory observations. Finally, a number of numerical uniaxial compressive tests were performed on heterogeneous rock specimens with preexisting fracture, and the influence of the heterogeneity of the rock and the angle and length of the preexisting fractures was fully discussed. The results showed that the brittleness of the rock increased with the increase of the homogeneity index, and tensile failure was the main failure form for relatively heterogeneous rock, whilst shear failure was the main failure form for relatively homogeneous rock. The uniaxial compressive strengths of the specimens with the angles of 0, 30, 45, and 60 of the preexisting fracture dropped 62.7%, 54.7%, 46.6%, and 38.2% compared with that of the intact specimen; the tensile cracks were more difficult to form, and the required load was increasing with the increase of the angle of the preexisting fracture; besides, antiwing cracks were difficult to form than wing cracks because the tensile stress in wing cracks’ area was greater than that in antiwing cracks’ area. The uniaxial compressive strengths of the specimens with the lengths of 20 mm, 25 mm, 30 mm, and 35 mm of preexisting fracture dropped 38.6%, 46.6%, 53.4%, and 56.6% compared with that of the intact specimen, and the damage conditions of the samples with different lengths of preexisting fracture were similar.
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Authors: Wei Spencer C. , Duffy Colm R. , Allison James P.
Published: August 2018

Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge.

Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.
Agranulocytosis Associated with Waldenström Macroglobulinemia
Authors: Vaxman Iuliana , Shepshelovich Daniel , Hayman Lucille , Raanani Pia , Lahav Meir
Published: August 2018

Currently, there are only 2 case reports of Waldenström macroglobulinemia (WM) associated with severe neutropenia. This is a case report of a woman with a past medical history of WM who presented with neutropenic fever. The patient’s febrile neutropenia resolved after RCD chemotherapy (cyclophosphamide 750 mg/m2, dexamethasone 20 mg, and rituximab 375 mg/m2). Fourteen days after administration, the neutrophil level had started to rise and normalized after 6 days. To the best of our knowledge, this is the 3rd reported case of agranulocytosis due to WM.
Extracorporeal Membrane Oxygenation in Predominantly Leuco- and Thrombocytopenic Haematologic/Oncologic Patients with Acute Respiratory Distress Syndrome - a Single-Centre Experience
Authors: Stecher Stephanie-Susanne , Beyer Georg , Goni Elisabetta , Tischer Johanna , Herold Tobias , Schulz Christoph , op den Winkel Mark , Stemmler H. Joachim , Lippl Stephanie
Published: August 2018

Aims: The acute respiratory distress syndrome (ARDS) is a frequent condition following pneumonia in immunocompromised cancer patients. Extracorporeal membrane oxygenation (ECMO) may serve as a rescue therapy in refractory ARDS but has still not been studied in predominantly leuco- and thrombocytopenic cancer patients. Patients and Methods: In this monocentric, retrospective, observational study, we assessed all cancer patients treated with ECMO for ARDS between 2013 and 2017. Results: 25 patients, 11 of whom underwent haematopoietic stem cell transplantation (SCT), were analysed. The main reason for ARDS was pneumonia in 72%. All patients were under invasive ventilation at ECMO. All but 9/3 patients suffered from leuco-/thrombocytopenia due to anti-cancer treatment or underlying disease. Overall, 17 patients (68%) died on ECMO, whereas 5 patients survived to hospital discharge (20%). All patients after recent allogeneic (allo-)SCT have died. 4 patients experienced severe bleeding events. Conclusions: Discouraging survival rates in patients treated after allo-SCT do not support the use of ECMO for ARDS in this patient subgroup. On the contrary, cancer patients in at least stable disease otherwise eligible for full-code intensive care unit management, even those with severe thrombocytopenia, may be potential candidates for ECMO in case of severe ARDS failing conventional measures.
Assessment of Placental Cortisol Pathway Gene Expression in Term Pregnant Women with Anxiety
Authors: Sheehan Penelope M. , Bousman Chad , Komiti Angela , Judd Fiona , Newman Louise , Tonge Bruce , Castle David , Everall Ian
Published: August 2018

Introduction: The aim of this study was to expand on this field of work by examining, within a cohort of pregnant women with diagnosed clinical anxiety, the mRNA expression of a panel of genes associated with the cortisol pathway and comparing them to controls. Methods: Placental samples were obtained from 24 pregnant women, 12 with a diagnosed anxiety disorder and 12 with no psychiatric history, within 30 min of delivery. Differential expression analysis of 85 genes known to be involved in glucocorticoid synthesis, metabolism or signalling was conducted for the: (1) full sample, (2) those at term without labour (5 cases, 7 controls) and (3) those at term with labour (7 cases, 5 controls). Correlation analyses between gene expression and measures of anxiety and depressive symptom severity were also conducted. Results: No robust difference in placental gene expression between pregnant women with and without anxiety disorder was found nor did we detect robust differences by labour status. However, correlational analyses putatively showed a decrease in PER1 expression was associated with an increase in anxiety symptom severity, explaining up to 32% of the variance in anxiety symptom severity. Discussion: Overall, the strongest correlation was found between a decrease in placental PER1 expression and increased anxiety scores. Labour status was found to have a profound effect on mRNA expression. The placental samples obtained from women following labour produced greater numbers of significant differences in mRNA species expression suggesting that in long-standing anxiety the placenta may respond differently under conditions of chronic stress.
Identifying Barriers to Idiopathic Pulmonary Fibrosis Treatment: A Survey of Patient and Physician Views
Authors: Maher Toby M. , Swigris Jeffrey J. , Kreuter Michael , Wijsenbeek Marlies , Cassidy Nicola , Ireland Lucy , Axmann Judit , Nathan Steven D.
Published: August 2018

Background: Antifibrotics are recommended for the treatment of individuals with idiopathic pulmonary fibrosis (IPF), but treatment use remains at ∼60%. Objective: To investigate the views of individuals with IPF and pulmonologists on the diagnosis and management of IPF to understand treatment patterns. Methods: Interviews and/or online surveys were completed by patients and pulmonologists from Canada, France, Germany, Italy, Spain, and the UK. Responses from physicians were analyzed by time between diagnosis and treatment initiation in the majority of patients with IPF (group A, > 4 months; group B, ≤4 months). Statistical comparisons between physicians were undertaken using z tests, with p < 0.05 considered statistically significant. Results: The physicians in group A saw fewer patients, were less comfortable discussing the IPF prognosis with patients, and had less belief in the benefits of antifibrotic treatments than the physicians in group B. These physicians’ attitudes contrasted with those of the patients, who wanted more information about the IPF prognosis and pharmacological treatment options at diagnosis and were more concerned about preventing disease progression than avoiding medication side effects. Differences between countries were found regarding physicians’ comfort in discussing the prognosis at diagnosis and access to care. Conclusions: Several barriers to antifibrotic treatment, principally reflecting the differing views and values of patients and physicians, were identified in this study, suggesting a need for better patient-physician communication about pharmacological therapy for IPF.
Chartis Measurement of Collateral Ventilation: Conscious Sedation versus General Anesthesia – A Retrospective Comparison
Authors: Welling Jorrit B.A. , Hartman Jorine E. , ten Hacken Nick H.T. , Franz Ina , Charbonnier Jean-Paul , van Rikxoort Eva M. , Kerstjens Huib A.M. , Klooster Karin , Slebos Dirk-Jan
Published: August 2018

Background: Absence of interlobar collateral ventilation using the Chartis measurement is the key predictor for successful endobronchial valve treatment in severe emphysema. Chartis was originally validated in spontaneous breathing patients under conscious sedation (CS); however, this can be challenging due to cough, mucus secretion, mucosal swelling, and bronchoconstriction. Performing Chartis under general anesthesia (GA) avoids these problems and may result in an easier procedure with a higher success rate. However, using Chartis under GA with positive pressure ventilation has not been validated. Objectives: In this study we investigated the impact of anesthesia technique, CS versus GA, on the feasibility and outcomes of Chartis measurement. Methods: We retrospectively analyzed all Chartis measurements performed at our hospital from October 2010 until December 2017. Results: We analyzed 250 emphysema patients (median forced expiratory volume in 1 s 26%, range 12–52% predicted). In 121 patients (48%) the measurement was performed using CS, in 124 (50%) using GA, and in 5 (2%) both anesthesia techniques were used. In total, 746 Chartis readings were analyzed (432 CS, 277 GA, and 37 combination). Testing under CS took significantly longer than GA (median 19 min [range 5—65] vs. 11 min [3–35], p < 0.001) and required more measurements (3 [1–13] vs. 2 [1–6], p < 0.001). There was no significant difference in target lobe volume reduction after treatment (–1,123 mL [–3,604 to 332] in CS vs. –1,251 mL [–3,333 to –1] in GA, p = 0.35). Conclusions: In conclusion, Chartis measurement under CS took significantly longer and required more measurements than under GA, without a difference in treatment outcome. We recommend a prospective trial comparing both techniques within the same patients to validate this approach.
Definition of Late Onset Alzheimer’s Disease and Anticipation Effect of Genome-Wide Significant Risk Variants: Pilot Study of the APOE e4 Allele
Authors: De Luca Vincenzo , Spalletta Gianfranco , Souza Renan P. , Graff Ariel , Bastos-Rodrigues Luciana , Camargos Bicalho Maria Aparecida
Published: August 2018

Background/Objectives: This study aims to investigate the role of apolipoprotein E (APOE) e4 influencing the age at onset (AAO) of Alzheimer’s disease (AD). In AD, the AAO of dementia varies from 40 to 90 years. Usually, AD patients who develop symptoms before the age of 65 are considered as early-onset AD (EOAD). However, considering the heterogeneity of the AD onset, the definition of late-onset AD (LOAD) cannot rely on an arbitrary cut-off. Thus, we aim to validate the anticipation effect of the APOE e4 allele in LOAD. Methods/Overview: Firstly, the optimal number of AAO subgroups was determined using MCLUST for 3 AD samples from Italy, Brazil, and from the ADNI consortium. MCLUST selects the best-fitting model based on the Bayesian information criterion (BIC), and the ideal cut-off for separating early onset from late onset in each sample. Then, when the AAO was modeled for each sample, the finite mixture model (FMM) analysis was used to analyze the effect of the APOE e4 in determining the risk for anticipated onset in LOAD. For the Brazilian sample, the ancestry was incorporated as a covariate. The FMM results from the 3 samples were meta-analyzed using METAL. Results: We performed the AAO analysis on the APOE e4 in 474 Italian patients enrolled at the IRCCS Santa Lucia Foundation in Italy, 135 AD from the Outpatients Reference Center for Geriatrics from the Federal University of Minas Gerais in Brazil, and 376 from the ADNI consortium. Using this distribution model, we found that the specific LOAD cut-off was ≥64 for the Italian sample, ≥67 for the ADNI sample, and ≥74 for the Brazilian sample. The APOE e4 showed a significant anticipatory effect specific for LOAD in all 3 samples. The METAL analysis for the anticipatory e4 effect was genome-wide significant when analyzing the LOAD effect size under the fixed model (beta = –8.1; p < 0.0001). However, when analyzing EOAD there was no genome-wide significant anticipation effect (beta = 1.9244; p = 0.0219). Conclusions: This study showed that the mixture analysis can refine the ideal cut-off for defining LOAD as a homogeneous genetic entity. We also validated the e4 allele anticipatory effect only in LOAD. In summary, the tool developed in this study is a sophisticated statistical pipeline to analyze the AAO in genome-wide association studies of AD, to find new molecular targets as a new line of translational research to foster drug discovery.
Long-Term Outcomes of Full-Fluence and Half-Fluence Photodynamic Therapy for Chronic Central Serous Chorioretinopathy
Authors: Son Bo Kwon , Kim Kiyoung , Kim Eung Suk , Yu Seung-Young
Published: August 2018

Purpose: To evaluate the efficacy and safety of full-fluence photodynamic therapy (PDT) and half-fluence PDT in chronic central serous chorioretinopathy (CSC). Procedures: A retrospective review of CSC patients treated with full-fluence or half-fluence PDT for 12 months was performed. Best-corrected visual acuity (BCVA), central macular thickness (CMT), neural retinal thickness, subfoveal choroidal thickness (SFCT), resolution of subretinal fluid (SRF), and incidence of retinal pigment epithelium (RPE) atrophy at 12, 24, and 36 months were assessed. Results: Thirty-seven and 30 eyes received full-fluence and half-fluence PDT, respectively. The BCVA and CMT improved significantly in both the full-fluence and half-fluence groups at 36 months, without a significant difference between the groups. Both groups showed significant reductions in SFCT with full-fluence (416.8–316.8 µm) being better overall than half-fluence (409.7–349.1 µm, p = 0.002). All patients achieved complete resolution without recurrence after one PDT treatment per eye. A few cases of RPE atrophy occurred, which could be correlated to PDT in both groups during the follow-up. Conclusion: Both treatments were effective and safe in chronic CSC, with significant improvements in anatomic and visual parameters, without recurrence of SRF.
Characterization and Outcomes of Disease Progression in 52 Patients Treated with BRAF-V600 + MEK Inhibitors for Advanced Melanoma
Authors: Lucas Philippine , Boulinguez Serge , Sibaud Vincent , Mourey Loïc , Lamant Laurence , Paul Carle , Meyer Nicolas
Published: August 2018

Background: Combined treatment with BRAF-V600 and MEK inhibitors has significantly improved progression-free and overall survival of patients with BRAF-mutated melanoma. Pattern of disease progression and outcomes in patients have not been fully characterized. Methods: We conducted a single-center, retrospective, descriptive analysis of a cohort of 52 patients treated with BRAF-V600 + MEK inhibitors for advanced melanoma over a 12-month period. The aim of this study was to characterize disease progression, defined as metastatic pattern, disease kinetics, and response to subsequent therapies, in melanoma patients treated with BRAF-V600 + MEK inhibitors. Results: Disease progression was observed in 31/52 (59.6%) patients treated with BRAF-V600 + MEK inhibitors. Relapse of melanoma involved the CNS for 22/31 (70.9%) patients with disease progression, including 18/31 (58%) patients who had exclusive intracranial metastases. Sixteen patients died from disease progression. Among the 31 patients who had disease progression, the median time until a relapse was 8 months, and the median survival time after disease progression was 2 months. Conclusion: Our study shows that, for patients treated with BRAF-V600 + MEK inhibitors who lose response, disease progression was aggressive and had poor outcomes. Most patients had CNS metastases and low rates of therapeutic response to any subsequent therapy.
Molecular Genetics of the Human Neutrophil Antigens
Authors: Flesch Brigitte Katharina , Reil Angelika
Published: August 2018

Background and Objective: Antibodies to human neutrophil antigens (HNAs) have been implicated in transfusion-related acute lung injury and allo- and autoimmune neutropenia. To date, five HNA systems are assigned, and during the last decades enormous efforts have been undertaken to identify the underlying genes and to characterize the antigens. This review of the literature will provide the current genetic, molecular and functional information on HNAs. Recent Findings: New information on alleles and antigens has been added to nearly each of the five HNA systems. HNA-1d has been added as the antithetical epitope to HNA-1c that is located on the glycoprotein encoded by FCGR3B*02 but not by FCGR3B. FCGR3B*04 and *05 now are included as new alleles. A CD177*787A>T substitution was demonstrated as the main reason for the HNA-2-negative phenotype on neutrophils. The target glycoprotein of HNA-3 antibodies could be identified as choline transporter-like protein 2 (CTL2) encoded by SLC44A2. The conformation sensitive epitope discriminates between arginine and glutamine at position 152 resulting in HNA-3a and HNA-3b. An additional Leu151Phe substitution can impair HNA-3a antibody binding. Recently an alloantibody against HNA-4b which discriminates from HNA-4a by an Arg61His exchange of the glycoprotein encoded by the ITGAM gene was reported in neonatal alloimmune neutropenia. An update of the current HNA nomenclature based on the new findings was provided in 2016 by the ISBT Granulocyte Immunobiology Working Party nomenclature subcommittee. Conclusions: The molecular basis of each of the five HNA antigen systems has been decoded during the past decades. This enables reliable molecular typing strategies, antibody detection and specification as well as development of new assays based on recombinant antigens. However, research on HNA alleles, antigens, and antibodies is not finally terminated and also in the future will add new findings.
Associated Pulmonary Hypertension Is an Independent Contributor to Exercise Intolerance in Chronic Fibrosing Interstitial Pneumonias
Authors: Yoo David K. , Zompatori Maurizio , Barrile Annapina , Rossi Giorgia , D’Amato Dejanira , Sergiacomi Gianluigi , Rogliani Paola , Mura Marco
Published: August 2018

Background: Associated pulmonary hypertension (APH) is frequently observed in fibrosing interstitial pneumonias (FIP), such as idiopathic pulmonary fibrosis (IPF). APH is associated with worse prognosis, but it remains unclear whether it is associated with greater functional impairment. Six-minute walk distance (6MWD) is widely used to assess functional capacity in pulmonary hypertension and FIP. Objectives: To investigate if APH independently contributes to exercise intolerance in FIP, irrespective of the extent of underlying fibrosis. Methods: Patients diagnosed with FIP (September 2009 to June 2017) were included in the study if they underwent right heart catheterization, high-resolution chest computed tomography (HRCT), and 6MWD within 3 months. Recruitment was not limited only to patients undergoing lung transplant assessment. APH was defined as mean pulmonary artery pressure (mPAP) ≥25 mm Hg. The extent of fibrosis was quantified on HRCT using a visual fibrosis score by 2 separate observers. Results: Seventy-two patients (60 with IPF) were identified. Fifty-five patients had APH. mPAP was not significantly different in subgroups stratified according to the extent of fibrosis on HRCT. Pulmonary vascular resistance (PVR) was the strongest predictor of 6MWD on both univariate and stepwise regression analyses, and remained so considering only patients with normal wedge pressure (< 15 mm Hg) (n = 61). HRCT fibrosis score and pulmonary function tests did not significantly correlate with 6MWD. Conclusions: In patients with FIP, PVR is a significant contributor of 6MWD, independently from the extent of fibrosis on HRCT. These results strengthen both the rationale to use 6MWD as endpoint in FIP and to target APH with specific therapies.
Whole-Body Plethysmography and Blood Gas Analysis in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention
Authors: Dreher Michael , Daher Ayham , Keszei András , Marx Nikolaus , Müller Tobias , Cornelissen Christian , Brandenburg Vincent
Published: August 2018

Background: Chronic obstructive pulmonary disease (COPD) and coronary heart disease (CHD) often occur together. However, COPD is underdiagnosed among CHD patients. Objectives: This study investigated the prevalence of COPD and relevant pulmonary function test (PFT) impairments in patients with acute myocardial infarction (AMI). Methods: Patients undergoing coronary angiography for AMI were prospectively included. Body plethysmography, lung diffusing capacity, blood gas analysis, and echocardiography were performed. The following patient subgroups were compared: with versus without COPD, ST elevation myocardial infarction (STEMI) versus non-STEMI (NSTEMI). The prevalence of PFT impairments was also recorded. Results: A total of 100 patients (51 with NSTEMI, 49 with STEMI) were included. Twenty patients had diagnosed COPD, of whom 15 were diagnosed for the first time; 80% of all COPD patients were not receiving COPD therapy. Patients with COPD had higher maximum creatine kinase (p = 0.008) and troponin T (p = 0.054) levels than those without COPD. Hypoxaemia was more common in COPD patients (lower oxygen saturation [p = 0.008] and partial pressure of oxygen [PaO2] [p = 0.005]). PaO2 was significantly lower in STEMI compared with NSTEMI (p = 0.017). Independent of a COPD diagnosis, 65 patients had relevant PFT impairments. Conclusions: The high prevalence of undiagnosed COPD and relevant pulmonary function impairments in this cohort of patients with AMI, and the fact that pulmonary disease was untreated in the majority of COPD patients, highlight the importance of a general pulmonary workup of patients with AMI. Furthermore, patients with CHD should undergo screening for COPD, given the fact that COPD patients had larger infarction size.
The Use of a Long-Acting Somatostatin Analogue (Lanreotide) in Three Children with Focal Forms of Congenital Hyperinsulinaemic Hypoglycaemia
Authors: Dastamani Antonia , Güemes Maria , Pitfield Catherine , Morgan Kate , Rajab Mansoor , Rottenburger Christof , Bomanji Jamshed  , De Coppi Paolo , Dattani Mehul , Shah Pratik
Published: August 2018

Background: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. Conclusion: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.
The Positive Effect of Sialendoscopy with Irrigation Lavage for Sialadenitis without Sialolithiasis or Stenosis
Authors: Schwarz David , Stuermer Konrad Johannes , Luers Jan Christoffer
Published: August 2018

Aims: The aim of the study was to evaluate different irrigation solutions during sialendoscopy to reduce complaints caused by sialodochitis. Methods: The investigators designed and implemented a retrospective study composed of 94 patients with sialodochitis but no sialolithiasis or relevant stenosis of the salivary duct system. Three different irrigations (normal saline, cortisone single-shot, and cortisone) were used. After the sialendoscopy, the patients were asked about the current status of the affected salivary gland, and the quantity and quality of the gland swelling/inflammation over a follow-up period of 11.6 months (6–24 months). Results: At the time of follow-up, 41 patients (43.6%) no longer had any complaints with the salivary gland in question. In 75.5% of the patients, a satisfying result was achieved. In total, only 3 patients needed submandibulectomy in the course of the study due to persistent complaints. The outcome showed no statistical differences between the mean of the 3 groups (p = 0.149). Conclusion: Sialendoscopy with flushing/lavage seems to be a good treatment option for patients with sialodochitis lacking sialolithiasis. The results of this study suggest that the type of irrigation used during sialendoscopy seems to be secondary.
Association of the Aquaporin 3 Gene Polymorphism (rs2231231) with Epstein-Barr Virus-Associated Cancers in China
Authors: Wang Jiayi , Liu Wen , Zhao Zhenzhen , Zhang Yan , Luo Bing
Published: August 2018

Background/Aims: Aquaporins are widely expressed in a variety of cancers and were found to play an important role in cell migration, angiogenesis, tumor formation, and tumor development. Thus, they have been proposed as a potential biomarker for some cancers. Accordingly, we analyzed the association between a single-nucleotide polymorphism locus of aquaporin 3 (rs2231231) and Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (EBVaNPC), lymphoma (EBVaL), and gastric carcinoma in China. Methods: Sequenom MassARRAY technique and polymerase chain reaction sequencing were used to test the genotype of 393 cases of patients with cancer and 148 normal control (NC) samples. A χ2 test or correction for continuity or the likelihood ratio was used for statistical analysis, and two-sided p values < 0.05 were considered a statistically significant difference. Results: We found that the genotype distributions were significantly different between either the EBVaNPC group and the NC group or the EBVaL case group and the NC group. However, no statistical associations between rs2231231 and gastric carcinoma was observed in the current study. Conclusions: The AQP3 gene polymorphism is associated with a susceptibility to EBVaNPC and EBVaL, and the homozygous AA genotype is more frequently observed in individuals who develop EBVaNPC and EBVaL.
ANTXR1 Intronic Variants Are Associated with Fetal Hemoglobin in the Arab-Indian Haplotype of Sickle Cell Disease
Authors: Al-Ali Zhara A. , Fallatah Rana K. , Aljaffer Esra A. , Albukhari Eman R. , Sadek Al-Ali Neriman , Al-Ghannam Ziyad T. , Sayeb Al-Atrash Reem , Alsuliman Ahmed , Vatte Chittibabu
Published: August 2018

Disease severity of sickle cell anemia is highly variable, and it is commonly accepted that fetal hemoglobin (HbF) levels play a major role as an ameliorating factor. Investigation of genetic variants have identified several genes to be the principal influencers of HbF regulation. Here, we further elucidated the association of rs4527238 and rs35685045 of ANTXR1 genes in the context of HbF level variance in sickle cell anemia patients of the Arab-Indian haplotype. Samples from 630 sickle cell anemia patients were analyzed for the mutations at 2 specific locations of the ANTXR1 gene by TaqMan®-based real-time PCR. The CC genotype (p = 0.018) of rs4527238 and the TT genotype (p = 0.048) of rs35685045 of ANTXR1 were found to be significantly associated with low HbF expression. The frequency of the CC genotype of rs4527238 was observed to be high in the low HbF patient group compared to the high HbF group (p = 0.009). Likewise, the frequency of the TT genotype of rs35685045 was also high among the low HbF group (p = 0.017). The ANTXR1 genetic mutations and the association with HbF expression in the Arab-Indian haplotype sickle cell patients revealed that the ANTXR1 gene may be a major HbF modulator leading to potential therapeutic options that should be further explored.
Prepubertal Children Exposed to Maternal Gestational Diabetes Have Latent Low-Grade Inflammation
Authors: Antikainen Leena , Jääskeläinen Jarmo , Nordman Henrikki , Voutilainen Raimo , Huopio Hanna
Published: August 2018

Background: Maternal gestational diabetes mellitus (GDM) and overweight are associated with an increased risk of obesity and the metabolic syndrome in the adult offspring. We studied the influence of maternal GDM on prepubertal children’s height, weight, body mass index (BMI), lipid and glucose metabolism, and low-grade inflammation. Methods: A cohort of 135 prepubertal Caucasian children (age range 4.4–9.7 years) was studied in a controlled cross-sectional study. Seventy-seven children had been exposed to maternal GDM, and 58 children born after a normal pregnancy served as controls. The outcomes were height, weight, BMI, blood pressure, and biochemical markers of glucose and lipid metabolism and inflammation. Results: There were no differences in height, weight, BMI, fasting serum insulin, plasma glucose, lipids, or blood pressure between the study groups. However, high-sensitivity C-reactive protein (hs-CRP) was significantly higher in the GDM group than in the controls (p = 0.001). Conclusions: Higher hs-CRP as a marker of low-grade inflammation was detected in prepubertal children exposed to maternal GDM, but no differences were seen in height, weight, BMI, or markers of glucose and lipid metabolism compared to control children. This finding may reflect an ongoing process of metabolic changes in children born after a GDM pregnancy.
Anti-Cancer Effects of Radix Angelica Sinensis (Danggui) and N-Butylidenephthalide on Gastric Cancer: Implications for REDD1 Activation and mTOR Inhibition
Authors: Liao Kuan-Fu , Chiu Tsung-Lang , Huang Sung-Ying , Hsieh Teng-Fu , Chang Shu-Fang , Ruan Jhen-Wei , Chen Shee-Ping , Pang Cheng-Yoong , Chiu Sheng-Chun
Published: August 2018

Background/Aims: Radix Angelica Sinensis (danggui in Chinese) is widely used in traditional chinese medicine (TCM). N-butylidenephthalide (BP), a bioactive compound in danggui, is a potential antitumor agent for various cancer types. However, its clinical effect and mechanism in the treatment of gastric cancer remain undetermined. Methods: The in vivo protective effect of danggui in patients with gastric cancer were validated using data from Taiwan’s National Health Insurance Research Database (NHIRD). The genes induced by BP-treatment were analyzed by whole transcriptome RNA sequencing (RNA-seq) and validated by real-time PCR, western blot and siRNA transfection. The effect of BP on AGS cell migration and invasion was evaluated in transwell assays. The antitumor effects of BP were evaluated in vivo in an AGS xenograft animal model. Results: Danggui users were found to have an increased survival rate when compared with danggui nonusers (log-rank test p = 0.002) . The use of danggui highly associated with decreased mortality (the adjusted hazard ratio (HR) of danggui user was 0.72 [95 % CI, 0.57-0.92] (p = 0.009). The in vitro results showed that BP inhibited gastric cancer cell proliferation, and triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Using RNA-seq analysis we found that REDD1 was the highest transcript induced by BP in gastric cancer cells. BP induce an increase of REDD1 expression that inhibits mTOR signaling, thus inhibiting gastric cancer growth. We used RNA interference to demonstrate that the knock-down of REDD1 attenuated the BP-induced mTORC1 activation and growth inhibition. BP suppressed the growth of AGS xenografts tumor in vivo. Conclusion: Danggui can prolong the survival rate of gastric cancer patients in Taiwan. BP caused gastric cancer cell death through the activation of mitochondria-intrinsic pathway and induced the REDD1 expression leading to mTOR signal pathway inhibition in gastric cancer cells. BP inhibited the in vivo growth of AGS xenograft tumors. These results may provide the basis for a new therapeutic approach toward the treatment of gastric cancer progression.