bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular and Biophysical Pipeline for the Screening of Peroxisome Proliferator-Activated Receptor Beta/Delta Agonists: Avoiding False Positives
Authors: Videira Natália Bernardi , Batista Fernanda Aparecida Heleno , Torres Cordeiro Artur , Figueira Ana Carolina Migliorini
Published: April 2018

Peroxisome proliferator-activated receptor beta/delta (PPARß/δ) is considered a therapeutic target for metabolic disorders, cancer, and cardiovascular diseases. Here, we developed one pipeline for the screening of PPARß/δ agonists, which reduces the cost, time, and false-positive hits. The first step is an optimized 3-day long cellular transactivation assay based on reporter-gene technology, which is supported by automated liquid-handlers. This primary screening is followed by a confirmatory transactivation assay and by two biophysical validation methods (thermal shift assay (TSA) and (ANS) fluorescence quenching), which allow the calculation of the affinity constant, giving more information about the selected hits. All of the assays were validated using well-known commercial agonists providing trustworthy data. Furthermore, to validate and test this pipeline, we screened a natural extract library (560 extracts), and we found one plant extract that might be interesting for PPARß/δ modulation. In conclusion, our results suggested that we developed a cheaper and more robust pipeline that goes beyond the single activation screening, as it also evaluates PPARß/δ tertiary structure stabilization and the ligand affinity constant, selecting only molecules that directly bind to the receptor. Moreover, this approach might improve the effectiveness of the screening for agonists that target PPARß/δ for drug development.
CRISPR/Cas9 Genome Editing of Epidermal Growth Factor Receptor Sufficiently Abolished Oncogenicity in Anaplastic Thyroid Cancer
Authors: Huang Li-Chi , Tam Ka-Wai , Liu Wei-Ni , Lin Chun-Yu , Hsu Kai-Wen , Hsieh Wen-Shyang , Chi Wei-Ming , Lee Ai-Wei , Yang Jinn-Moon , Lin Ching-Ling , Lee Chia-Hwa
Published: April 2018

Anaplastic carcinoma of the thyroid (ATC), also called undifferentiated thyroid cancer, is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers. The aim of this study is to explore essential biomarker and use CRISPR/Cas9 with lentivirus delivery to establish a gene-target therapeutic platform in ATC cells. At the beginning, the gene expression datasets from 1036 cancers from CCLE and 8215 tumors from TCGA were collected and analyzed, showing EGFR is predominantly overexpressed in thyroid cancers than other type of cancers (P=0.017 in CCLE and P=0.001 in TCGA). Using CRISPR/Cas9 genomic edit system, ATC cells with EGFR sgRNA lentivirus transfection obtained great disruptions on gene and protein expression, resulting in cell cycle arrest, cell growth inhibition, and most importantly metastasis turn-off ability. In addition, the FDA-approved TKI of afatinib for EGFR targeting also illustrates great anticancer activity on cancer cell death occurrence, cell growth inhibition, and cell cycle arrest in SW579 cells, an EGFR expressing human ATC cell line. Furthermore, off-target effect of using EGFR sgRNAs was measured and found no genomic editing can be detected in off-target candidate gene. To conclude, this study provides potential ATC therapeutic strategies for current and future clinical needs, which may be possible in increasing the survival rate of ATC patients by translational medicine.
Extranodal Rosai–Dorfman Disease Presenting as a Mediastinal Mass with Pulmonary Artery Invasion
Authors: Orr Andrew R. , Lefler Daniel , Deshpande C. , Kumar Pallavi
Published: April 2018

Rosai–Dorfman disease (RDD) is a rare, nonmalignant disorder of histiocyte proliferation typically involving the cervical lymph nodes. However, a subset of patients with RDD will display extranodal manifestations that are highly variable in presentation, more challenging to diagnose, and less likely to spontaneously regress compared to nodal disease. While case reports of extranodal involvement in nearly every organ system exist, documented instances of mediastinal and pulmonary artery involvement are particularly rare. This study describes the case of a middle-aged woman presenting with new onset right heart failure who was found to have extranodal RDD in the form of a large mediastinal mass with invasion and occlusion of the main pulmonary arteries.
Long-Term Management of Recurrent Cholecystitis after Initial Conservative Treatment: Endoscopic Transpapillary Gallbladder Stenting
Authors: Kamada Hideki , Kobara Hideki , Uchida Naohito , Kato Kiyohito , Fujimori Takayuki , Kobayashi Kiyoyuki , Yamashita Takuma , Ono Masahiro , Aritomo Yuichi , Tsutsui Kunihiko , Okano Keiichi , Suzuki Yasuyuki , Masaki Tsutomu
Published: April 2018

Background. Endoscopic transpapillary gallbladder stenting (ETGBS) is an effective procedure for treating high-risk patients with acute cholecystitis and severe comorbidities. However, the efficacy of ETGBS for recurrent cholecystitis (RC) remains unclear. This study aimed to explore its efficacy in patients with RC for whom cholecystectomy is contraindicated because of its high surgical risk.Methods. Data on 19 high-risk patients who had undergone ETGBS for RC after initial conservative therapy in our institution between June 2006 and May 2012 were retrospectively examined. The primary outcome was the clinical success rate, which was defined as no recurrences of acute cholecystitis after ETGBS until death or the end of the follow-up period. Secondary outcomes were technical success rate and adverse events (AEs).Results. The clinical success rate of ETGBS was 100%, the technical success rate 94.7%, and AE rate 5%: one patient developed procedure-related mild acute pancreatitis. The clinical courses of all patients were as follows: four died of nonbiliary disease, and the remaining 15 were subsequently treated conservatively. The median duration of follow-up was 14.95 months (range 3–42 months).Conclusions. ETGBS is an effective alternative for managing RC in high-risk patients with severe comorbidities.
Weak Fault Signal Detection of Rotating Machinery Based on Multistable Stochastic Resonance and VMD‐AMD
Authors: Han Dongying , Su Xiao , Shi Peiming
Published: April 2018

For solving detection problems of multifrequency weak signals in noisy background, a novel weak signal detection method based on variational mode decomposition (VMD) and rescaling frequency‐shifted multistable stochastic resonance (RFMSR) with analytical mode decomposition (AMD) is proposed. In this method, different signal frequency bands are processed by rescaling subsampling compression to make each frequency band meet the conditions of stochastic resonance. Before the enhanced signal components are synthesized, they are processed to achieve the enhanced signal by means of AMD, leaving only the enhanced sections of the signal. The processed signal is decomposed into intrinsic mode functions (IMF) by VMD, in order to require the detection of weak multifrequency signals. The experimental analysis of the rolling bearing inner ring fault and gear fault diagnosis demonstrate that the proposed method can not only enhance signal amplitude, reduce false components, and improve the VMD algorithm’s accuracy, but also effectively detect weak multifrequency signals submerged by noise.
Low‐Temperature Brazing of Titanium Using Al‐Based Filler Alloys
Authors: Muhrat A. , Puga H. , Barbosa J.
Published: April 2018

Brazing of titanium using low melting temperature filler alloys is a preferred choice regarding cost and preserving its mechanical properties. However, brazing titanium at low temperature is still a challenge, especially regarding aluminum‐based filler alloys. During the last years, several brazing methods and Al‐based fillers were developed to meet industrial requirements; some of them might achieve some of those requirements. The use of ultrasound in brazing has gained increased attention recently, which helps to reduce the time and the necessity for a special brazing environment, subsequently, reducing cost and increasing applicability. Brazing titanium below the α↔β transformation temperature, using commercial and experimental Al‐based fillers of different compositions, is presented in this review; including the procedures of traditional and ultrasound‐assisted brazing methods. Correspondingly, the effects of brazing conditions and alloying elements on the mechanical properties and the intermetallic compounds formation are examined.
Legendre Cooperative PSO Strategies for Trajectory Optimization
Authors: Liu Lei , Wang Yongji , Xie Fuqiang , Gao Jiashi
Published: April 2018

Particle swarm optimization (PSO) is a population‐based stochastic optimization technique in a smooth search space. However, in a category of trajectory optimization problem with arbitrary final time and multiple control variables, the smoothness of variables cannot be satisfied since the linear interpolation is widely used. In the paper, a novel Legendre cooperative PSO (LCPSO) is proposed by introducing Legendre orthogonal polynomials instead of the linear interpolation. An additional control variable is introduced to transcribe the original optimal problem with arbitrary final time to the fixed one. Then, a practical fast one‐dimensional interval search algorithm is designed to optimize the additional control variable. Furthermore, to improve the convergence and prevent explosion of the LCPSO, a theorem on how to determine the boundaries of the coefficient of polynomials is given and proven. Finally, in the numeral simulations, compared with the ordinary PSO and other typical intelligent optimization algorithms GA and DE, the proposed LCPSO has traits of lower dimension, faster speed of convergence, and higher accuracy, while providing smoother control variables.
miR-144-5p Enhances the Radiosensitivity of Non-Small-Cell Lung Cancer Cells via Targeting ATF2
Authors: Song Lei , Peng Liping , Hua Shucheng , Li Xiaoping , Ma Lianjun , Jie Jing , Chen Dong , Wang Ying , Li Dan
Published: April 2018

MicroRNAs (miRNAs or miRs) regulate gene expression at the posttranscriptional level and are involved in many biological processes such as cell proliferation and migration, stem cell differentiation, inflammation, and apoptosis. In particular, miR-144-3p is downregulated in various cancers, and its overexpression inhibits the proliferation and metastasis of cancer cells. However, the role of miR-144-5p in non-small-cell lung cancer (NSCLC), especially radiosensitivity, is unknown. In this study, we found that miR-144-5p was downregulated in NSCLC clinical specimens as well as NSCLC cell lines exposed to radiation. Enhanced expression of miR-144-5p promoted the radiosensitivity of NSCLC cells in vitro and A549 cell mouse xenografts in vivo. Furthermore, we identified activating transcription factor 2 (ATF2) as the direct and functional target of miR-144-5p using integrated bioinformatics analysis and a luciferase reporter assay. In addition, restoration of ATF2 expression inhibited miR-144-5p-induced NSCLC cell sensitivity to radiation in vitro and in vivo. Our findings suggest that deregulation of the miR-144-5p/ATF2 axis plays an important role in NSCLC cell radiosensitivity, thus representing a new potential therapeutic target for NSCLC.
Comparison of Machine Learning Techniques for the Prediction of Compressive Strength of Concrete
Authors: Chopra Palika , Sharma Rajendra Kumar , Kumar Maneek , Chopra Tanuj
Published: April 2018

A comparative analysis for the prediction of compressive strength of concrete at the ages of 28, 56, and 91 days has been carried out using machine learning techniques via “R” software environment. R is digging out a strong foothold in the statistical realm and is becoming an indispensable tool for researchers. The dataset has been generated under controlled laboratory conditions. Using R miner, the most widely used data mining techniques decision tree (DT) model, random forest (RF) model, and neural network (NN) model have been used and compared with the help of coefficient of determination (R2) and root‐mean‐square error (RMSE), and it is inferred that the NN model predicts with high accuracy for compressive strength of concrete.
An Operation Control Strategy for the Connected Maglev Trains Based on Vehicle‐Borne Battery Condition Monitoring
Authors: Zhang Wenjing , Wei Wenjun , Yang Yifan , Nan Nan
Published: April 2018

Vehicle‐borne battery condition is an important factor affecting the efficiency of the maglev train operation and other connected ones. To effectively eliminate the influence of the battery condition and improve the operation efficiency of the connected maglev trains, an operation control strategy is proposed to guarantee train operation safety. First, based on Internet of Things, a sensor network is designed to monitor vehicle‐borne battery condition in each vehicle of the train. Second, the train Operation Control System collects battery data of all vehicles in a maglev train by Train Communication Network. Third, all connected maglev trains share the battery data via a 38 GHz directional Radio Communication System and adjust operation control strategy accordingly. Simulation results indicate that the proposed strategy can guarantee the operation safety of the connected maglev trains.
Rapid and Visual Detection ofCoxiella burnetiiUsing Recombinase Polymerase Amplification Combined with Lateral Flow Strips
Authors: Qi Yong , Yin Qiong , Shao Yinxiu , Li Suqin , Chen Hongxia , Shen Wanpeng , Rao Jixian , Li Jiameng , Li Xiaoling , Sun Yu , Lin Yu , Deng Yi , Zeng Wenwen , Zheng Shulong , Liu Suyun , Li Yuexi
Published: April 2018

Coxiella burnetii, a global-distributed biological warfare agent, is the causative agent of Q fever. Correct diagnosis of Q fever is challenging and developing a fast, simple, and reliable detection method is necessary. In this study, recombinase polymerase amplification (RPA) assay combined with lateral flow (LF) test was developed targeting 23S rRNA gene ofC. burnetiiXinqiao strain. Primers and probe were designed and synthesized, with one set with high amplification efficiency screened for establishment of the method. Reaction conditions were optimized. Sensitivity, specificity, and accuracy were evaluated. The established RPA-LF reaction could be completed in 30 minutes by combining RPA at 37°C with LF at room temperature, with visually judged results. The method showed good specificity without recognizing other bacteria evaluated. It detected positive plasmid and genomic DNA at levels of 10 copies/reaction and 7 copies/reaction, respectively, levels comparable to that of real-time quantitative PCR (RT-qPCR) targeting 23S rRNA gene established previously. Both RPA-LF and RT-qPCR were used to detectC. burnetii-infected mouse samples and the results were fully consistent. The method showed superior detection performance and will provide technical support againstC. burnetiiin resources-limited areas.
Novel Biomarker Candidates for Febrile Neutropenia in Hematological Patients Using Nontargeted Metabolomics
Authors: Lappalainen Marika , Jokkala Jenna , Juutilainen Auni , Hämäläinen Sari , Koivula Irma , Jantunen Esa , Hanhineva Kati , Pulkki Kari
Published: April 2018

Background. Novel potential small molecular biomarkers for sepsis were analyzed with nontargeted metabolite profiling to find biomarkers for febrile neutropenia after intensive chemotherapy for hematological malignancies.Methods. Altogether, 85 patients were included into this prospective study at the start of febrile neutropenia after intensive chemotherapy for acute myeloid leukemia or after autologous stem cell transplantation. The plasma samples for the nontargeted metabolite profiling analysis by liquid chromatography-mass spectrometry were taken when fever rose over 38° and on the next morning.Results. Altogether, 90 differential molecular features were shown to explain the differences between patients with complicated (bacteremia, severe sepsis, or fatal outcome) and noncomplicated courses of febrile neutropenia. The most differential compounds were an androgen hormone, citrulline, and phosphatidylethanolamine PE(18:0/20:4). The clinical relevance of the findings was evaluated by comparing them with conventional biomarkers like C-reactive protein and procalcitonin.Conclusion. These results hold promise to find out novel biomarkers for febrile neutropenia, including citrulline. Furthermore, androgen metabolism merits further studies.
Renoprotective Effect of a Chinese Herbal Formula, Qidan Dihuang Decoction, on Streptozotocin‐Induced Diabetes in Rat
Authors: Chen Z. J. , Ma F. , Sun X. M. , Zhao X. S. , Luo R.
Published: April 2018

Qidan Dihuang decoction (QDD) is the latest development of Chinese medicine compound and mainly provides renal protection. The study presented was designed to evaluate the renoprotective effects of QDD on streptozotocin‐induced diabetes and to explore the possible mechanisms of this action. We established a diabetes rat model. The condition of the rats was observed. The biochemistry indexes for diabetic rats were examined. Renal tissues were stained with HE, PAS, and Masson and we performed immunohistochemical staining for α‐SMA and TGF‐β. The proteins expressions of α‐SMA, TGF‐β, renin, and AT1 were detected by western blot. After treatment for 8 weeks, serum creatinine and 24 h proteinuria were significantly reduced in the rats which received losartan and Qidan Dihuang decoction while blood glucose, urine volume, blood urea nitrogen, and KW/BW did not improve. The pathology of renal tissue of rats treated with losartan and Qidan Dihuang decoction was inhibited. In addition, western blot showed that the expression of α‐SMA, TGF‐β, renin, and AT1 proteins was significantly decreased after receiving Qidan Dihuang decoction and losartan. Taken together, the results indicate that Qidan Dihuang decoction can improve the renal function and inhibit renal fibrosis of DN rat via modulating RAS system.
Bone Morphogenetic Proteins 2/4 Are Upregulated during the Early Development of Vascular Calcification in Chronic Kidney Disease
Authors: Wei Xiao , Wu Weihua , Li Li , Lin Jiaru , Liu Qi , Gan Linwang , Ou Santao
Published: April 2018

Vascular calcification is a main cause of increased cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study aimed to investigate the role of the bone morphogenetic protein (BMP) signaling pathway in the early development of vascular calcification in CKD. A CKD vascular calcification rat model was established by providing rats with a 1.8% high-phosphorus diet and an intragastric administration of 2.5% adenine suspension. The kidney and aortic pathologies were analyzed. Blood biochemical indicators, serum BMP-2 and BMP-4 levels, and aortic calcium content were determined. The expression levels of BMP-2, BMP-4, bone morphogenetic protein receptor-IA (BMPR-IA), and matrix Gla protein (MGP) in aorta were examined by quantitative real-time polymerase chain reaction and immunohistochemistry. Compared with the normal control (Nor) rats, the CKD rats exhibited a significantly decreased body weight and an increased kidney weight as well as abnormal renal function and calcium-phosphorus metabolism. Aortic von Kossa and Alizarin red staining showed massive granular deposition and formation of calcified nodules in aorta at 8 weeks. The aortic calcium content was significantly increased, which was positively correlated with the serum BMP-2 (r=0.929; P<0.01) and serum BMP-4 (r=0.702; P<0.01) levels in CKD rats. The rat aortic BMP-2 mRNA level in the CKD rats was persistently increased, and the BMP-4 mRNA level was prominently increased at the 4th week, declining thereafter. Strong staining of BMP-2, BMP-4, BMPR-IA, and MGP proteins was observed in the tunica media of the aorta from the 4th week after model induction. In conclusion, activation of the BMP signaling pathway is involved in the early development of vascular calcification in CKD. Therefore, elevated serum BMP-2 and BMP-4 levels may serve as serum markers for CKD vascular calcification.
Aflibercept Treatment Leads to Vascular Abnormalization of the Choroidal Neovascularization
Authors: Wylęgała Adam , Wylęgała Filip , Wylęgała Edward
Published: April 2018

Recent studies do not support the hypothesis of vascular normalization in the eyes receiving various types of intravitreous antivascular endothelial growth factor (VEGF). This retrospective study considered 57 eyes of 32 patients with vascular age-related macular degeneration (AMD) undergoing aflibercept treatment. In this study, we measured the vessel density, Horton-Strahler (HS) ramification ratio (complexity), and the length ratio in 14 eyes with choroidal neovascularization treated with 3–5 Eylea injections, 17 eyes receiving 1-2 injections, and 14 treatment-naïve eyes to the use of swept source optical coherence tomography angiography (OCTA). Macular 6 × 6 mm scans were acquired using the DRI OCT Triton by a single trained technician. OCTA images were standardized, binarized, and skeletonized using ImageJ. Then, the HS analysis of the CNV was performed. Our data suggest that the vascular density significantly decreases after an anti-VEGF injection 36 and 93 versus 41 and 87 in treatment-naïve patients. Moreover, CNV before the treatment and in a group with 3–5 injections was more complex than after receiving 1-2 injections. The branch length was not changed. Repeated anti-VEGF can lead to vascular abnormalization and further research is needed to confirm the results of this study.
Prophylactic Use of Troxerutin Can Delay the Development of Diabetic Cognitive Dysfunction and Improve the Expression of Nrf2 in the Hippocampus on STZ Diabetic Rats
Authors: Zhang Songyun , Yuan Lingling , Zhang Lihui , Li Caige , Li Jie
Published: April 2018

Background. With the change in lifestyle and the aging population, the incidence of cognitive dysfunction in diabetes mellitus is rising sharply. Oxidative stress is an important mechanism in the development of diabetic cognitive dysfunction. Nuclear factor E2-related factor 2 (Nrf2) is the core transcription factor of antioxidative stress. Early prevention and treatment of diabetic cognitive dysfunction can reduce the incidence of dementia and improve the quality of life of diabetic patients.Aim. This study was aimed at determining effect of troxerutin on the development of cognitive dysfunction and the expression level of Nrf2 in the hippocampus of streptozotocin (STZ) diabetic rats, when used in the early preventive stage.Methods. An STZ-induced diabetic rat model was established (n=30), and the animals were randomly divided into 2 groups: diabetic control group (DC,n=15) and diabetic troxerutin intervention group (DT,n=15). Another 10 normoglycemic rats were put into a normal control group (NC,n=10). While the DT group was injected with troxerutin (60 mg/kg), the DC group and the NC group were injected with physiological saline for 12 weeks daily. Learning and memory behaviors were tested using the Morris water maze test. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, mRNA level, and protein level of Nrf2 were measured. Data were collected and analyzed by the statistical software package SPSS 19.0, which included one-way analysis of variance with completely randomized design.Results. Learning and memory levels were significantly improved in the DT group compared with the DC group. Moreover, in the DT group, the expression level of Nrf2 in the hippocampus was increased, activity of SOD was elevated, and MDA content was decreased.Conclusion. Prophylactic use of troxerutin delays the development of diabetic cognitive dysfunction and increases the expression level of Nrf2 in the hippocampus of STZ diabetic rats.
Quality of Life in Transitioned Trans Persons: A Retrospective Cross-Sectional Cohort Study
Authors: Jellestad Lena , Jäggi Tiziana , Corbisiero Salvatore , Schaefer Dirk J. , Jenewein Josef , Schneeberger Andres , Kuhn Annette , Garcia Nuñez David
Published: April 2018

Background. Medical gender-affirming interventions (GAI) are important in the transition process of many trans persons. The aim of this study was to examine the associations between GAI and quality of life (QoL) of transitioned trans individuals. Methods. 143 trans persons were recruited from a multicenter outpatient Swiss population as well as a web-based survey. The QoL was assessed using the Short Form (36) Health Survey questionnaire (SF-36). Depressive symptoms were examined using the Short Form of the Center for Epidemiologic Studies-Depression Scale (ADS-K). Multiple interferential analyses and a regression analysis were performed. Results. Both transfeminine and transmasculine individuals reported a lower QoL compared to the general population. Within the trans group, nonbinary individuals showed the lowest QoL scores and significantly more depressive symptoms. A detailed analysis identified sociodemographic and transition-specific influencing factors. Conclusions. Medical GAI are associated with better mental wellbeing but even after successful medical transition, trans people remain a population at risk for low QoL and mental health, and the nonbinary group shows the greatest vulnerability.
AC-CUTE: An Open-Label Study to Evaluate Progression of Structural Joint Damage and Inflammation in Subjects with Moderate to Severe Rheumatoid Arthritis
Authors: Bird Paul , Peterfy Charles , Countryman Peter , Griffiths Hedley , Barrett Rina , Youssef Peter , Joshua Fredrick , Hall Stephen
Published: April 2018

Aim. Examine the efficacy of once-weekly subcutaneous tocilizumab (SC-TCZ) on joint damage at 24 weeks based on radiography of the hands and feet and magnetic resonance imaging (MRI) of the hand in subjects with moderate to severe rheumatoid arthritis (RA). Methods. In this Australian open-label, multicentre, prospective, single-arm study, subjects received 162 mg SC-TCZ weekly. Primary endpoint was change in radiographic Genant-modified Total Sharp Score (TSS) between baseline and Week 24. Secondary endpoints included change from baseline to Week 24 in RA MRI scoring (RAMRIS) of erosions, synovitis, and osteitis and Cartilage Loss Score (CARLOS) in the dominant hand and disease activity score 28 (DAS28). Results. 52 subjects were enrolled (80% female, mean (SD) age 57  (12) years). Radiography showed mild but not significant progression of joint damage (mean (SD) change in TSS 0.46 (1.29)). Synovitis reduced significantly on MRI; however, osteitis, erosion, and cartilage loss did not change significantly. DAS28 improved significantly by Week 24; 78% of subjects achieved DAS28 remission. SC-TCZ was generally well tolerated. Conclusion. Synovitis and DAS28 decreased significantly; however, no significant change in osteitis or joint damage was observed at Week 24. Trial registration. This trial is registered with Clinicaltrials.gov registration number NCT01951170 (ML28703).
Debugging Nondeterministic Failures in Linux Programs through Replay Analysis
Authors: Majeed Shakaiba , Ryu Minsoo
Published: April 2018

Reproducing a failure is the first and most important step in debugging because it enables us to understand the failure and track down its source. However, many programs are susceptible to nondeterministic failures that are hard to reproduce, which makes debugging extremely difficult. We first address the reproducibility problem by proposing an OS-level replay system for a uniprocessor environment that can capture and replay nondeterministic events needed to reproduce a failure in Linux interactive and event-based programs. We then present an analysis method, called replay analysis, based on the proposed record and replay system to diagnose concurrency bugs in such programs. The replay analysis method uses a combination of static analysis, dynamic tracing during replay, and delta debugging to identify failure-inducing memory access patterns that lead to concurrency failure. The experimental results show that the presented record and replay system has low-recording overhead and hence can be safely used in production systems to catch rarely occurring bugs. We also present few concurrency bug case studies from real-world applications to prove the effectiveness of the proposed bug diagnosis framework.
Comparative Analysis of the Effects of Olive Oil Hydroxytyrosol and Its 5‐S‐Lipoyl Conjugate in Protecting Human Erythrocytes from Mercury Toxicity
Authors: Officioso Arbace , Panzella Lucia , Tortora Fabiana , Alfieri Maria Laura , Napolitano Alessandra , Manna Caterina
Published: April 2018

Oxidative stress is one of the underlying mechanisms of the toxic effects exerted by mercury (Hg) on human health. Several antioxidant compounds, including the olive oil phenol hydroxytyrosol (HT), were investigated for their protective action. Recently, we have reported that 5‐S‐lipoylhydroxytyrosol (Lipo‐HT) has shown increased antioxidant activities compared to HT and exerted potent protective effects against reactive oxygen species (ROS) generation and oxidative damage in human hepatocellular carcinoma HepG2 cell lines. In this study, the effects of Lipo‐HT and HT on oxidative alterations of human erythrocytes induced by exposure to 40 μM HgCl2 were comparatively evaluated. When administered to the cells, Lipo‐HT (5–20 μM) proved nontoxic and it decreased the Hg‐induced generation of ROS, the hemolysis, and the depletion of intracellular GSH levels. At all tested concentrations, Lipo‐HT exhibited higher ability to counteract Hg‐induced cytotoxicity compared to HT. Model studies indicated the formation of a mercury complex at the SH group of Lipo‐HT followed by a redox reaction that would spare intracellular GSH. Thus, the enhanced erythrocyte protective action of Lipo‐HT from Hg‐induced damage with respect to HT is likely due to an effective chelating and reducing ability toward mercury ions. These findings encourage the use of Lipo‐HT in nutraceutical strategies to contrast heavy metal toxicity in humans.
High-Intensity Statin Therapy Is “Too Much,” Thus Not Indicated for Very Elderly Patients
Authors: Lee Ok Sang , Zhang Jinlong , Jung Sun-Hoi , Kim Hyang-Sook , Lee Myung-Koo , Lee Hae-Young
Published: April 2018

Purpose: Although moderate- to high-intensity statin therapy is increasingly recommended in cardiovascular disease patients, the efficacy and safety in elderly patients have not been proven clearly. Here, we compare the effect of various-intensity statins between elderly and very elderly patients. Methods: 43,870 patients over 65 years old who were treated with statins were screened using electronic medical record data. Results: We evaluated 451 patients in the elderly group aged 65–74 years and 159 patients in the very elderly group over 75 years old. Baseline cholesterol profiles were similar between the 2 groups, but the 10-year atherosclerotic cardiovascular disease (ASCVD) risk was significantly higher in the very elderly (20.9 ± 11.5% vs. 37.2 ± 13.6%, p < 0.001). The reduction rate of low-density lipoprotein (LDL) (–40.2 ± 21.3% vs. –39.3 ± 21.0%, p = 0.634) and the ratio of target LDL attainment (74.2 vs. 79.2%, p = 0.252) were similar between the 2 groups. Low-intensity statins showed comparable LDL cholesterol reduction with moderate-intensity statins both in the elderly and the very elderly groups. The 10-year ASCVD risk reduction was similar between the 2 groups (–3.5 ± 4.9% vs. –3.0 ± 8.4%, p = 0.480), but in the very elderly group, no different ASCVD reduction rate was shown in low- to high-intensity statins (p = 0.784). Only the elderly group showed a significant correlation (r = 0.112, p = 0.017) with LDL reduction and 10-year ASCVD risk. Interestingly, the incidence of adverse drug reaction (ADR) was higher in the very elderly group (4.4%) than in the elderly group (2.7%) and was more frequent in high-intensity statin therapy. Conclusion: The efficacy of statins in LDL reduction was similar between the elderly and very elderly population. However, the benefit of moderate- to high-intensity statins is limited considering potential ADR. Therefore, the stepwise intensification of statin therapy might be necessary for the very elderly in spite of the higher cardiovascular risk.
Factors Associated with Functional Performance among Patients on Hemodialysis in Taiwan
Authors: Lai Yu-Cheng , Wang Chun-Yeh , Moi Sin-Hua , Wu Chien-Hsing , Yang Cheng-Hong , Chen Jin-Bor
Published: April 2018

Background/Aims: We investigated factors associated with functional performance in hemodialysis (HD) patients as well as their relationships with mortality. Methods: We enrolled 790 HD patients who were followed up from 2009 to 2013. Functional performance was evaluated by Karnofsky Performance Status Scale (KPSS) scores. We examined the associations of clinical variables and all-cause mortality with KPSS scores. Results: Of the participants, 460 had high KPSS scores (range 90–100) and 330 had low KPSS scores (below 80). On multivariate analysis, age and weekly HD sessions were associated with significantly increased odds of a lower KPSS score (age: OR 1.05, 95% CI 1.04–1.07, p < 0.001; weekly HD: OR 2.10, 95% CI 1.37–3.21, p = 0.001). A low KPSS score was a significant predictor of increased all-cause mortality (hazard ratio 1.49; 95% CI 1.02–2.16, p = 0.037), as determined using Cox regression analysis. Conclusion: Functional performance was associated with clinical variables and all-cause mortality in HD patients.
Lebensverlängerung um jeden Preis?
Authors: Lübbe Andreas Stephan
Published: April 2018

Extrapulmonary small-cell neuroendocrine cancers are rare in clinical practice. They are frequently metastatic at the time of diagnosis with survival in months even with the most intensive treatment. So far, treatment recommendations for this group rely on data from the similar but more common small-cell carcinoma of the lungs. Immune checkpoint inhibitors are being investigated for the treatment of metastatic small-cell lung cancer with positive outcome. We applied the experience from these studies to a case of metastatic small-cell neuro-endocrine cancer of the pancreas using nivolumab as a treatment of last resort. We noted a favorable and durable response suggesting that this may be superior to all currently available options for palliative treatment in a similar scenario.
Effects of Volume Overload and Current Techniques for the Assessment of Fluid Status in Patients with Renal Disease
Authors: Ekinci Can , Karabork Merve , Siriopol Dimitrie , Dincer Neris , Covic Adrian , Kanbay Mehmet
Published: April 2018

Volume overload is an important, may be the foremost, independent prognostic factor determining the outcome of hemodialysis patients. Therefore, it is crucial to measure fluid status of these patients and avoid volume overload. This review aims to evaluate volume overload, its effects on patients with renal diseases and current methodologies measuring volume status in the body. These techniques will be first classified as clinical evaluation and non-clinical and/or instrumental techniques, which includes biomarkers, ultrasonography, relative blood volume monitoring, bioimpedance, echocardiography, pulmonary artery catheterization, esophageal and/or suprasternal Doppler, and blood viscosity. Advantages and limitations of these different techniques will be reviewed extensively by comparing each other. At last, insights gained from this review can highlight the future prospects in this active area of research.
Relation of Retinopathy of Prematurity to Brain Volumes at Term Equivalent Age and Developmental Outcome at 2 Years of Corrected Age in Very Preterm Infants
Authors: Sveinsdóttir Kristbjörg , Ley David , Hövel Holger , Fellman Vineta , Hüppi Petra S. , Smith Lois E.H. , Hellström Ann , Hansen Pupp Ingrid
Published: April 2018

Background: Retinopathy of prematurity (ROP) is a major complication of preterm birth and has been associated with later visual and nonvisual impairments. Objectives: To evaluate relationships between any stage of ROP, brain volumes, and developmental outcomes. Methods: This study included 52 very preterm infants (gestational age [mean ± SD]: 26.4 ± 1.9 weeks). Total brain, gray matter, unmyelinated white matter (UWMV), and cerebellar volumes were estimated in 51 out of 52 infants by magnetic resonance imaging at term-equivalent age. Bayley Scales of Infant Development were used to assess developmental outcomes in 49 out of 52 infants at a mean corrected age of 24.6 months. Results: Nineteen out of 52 infants developed any stage of ROP. Infants with ROP had a lower median (IQR) UWMV (173 [156–181] vs. 204 [186–216] mL, p < 0.001) and cerebellar volume (18.3 [16.5–20] vs. 22.3 [20.3–24.7] mL, p < 0.001) than infants without ROP. They also had a lower median (IQR) mental developmental index (72 [56–83] vs. 100 [88–104], p < 0.001) and a lower psychomotor developmental index (80 [60–85] vs. 92 [81–103], p = 0.002). Brain volumes and developmental outcomes did not differ among infants with different stages of ROP. Conclusion: Any stage of ROP in preterm infants was associated with a reduced brain volume and an impaired developmental outcome. These results suggest that common pathways may lead to impaired neural and neurovascular development in the brain and retina and that all stages of ROP may be considered in future studies on ROP and development.
Is There Enough Evidence to Prove That Hemodiafiltration Is Superior?
Authors: Kawanishi Hideki
Published: April 2018

The evidence concerning online hemodiafiltration (HDF) includes the following: (1) the increase of removal of uremic toxin, (2) the prevention of dialysis rerated hypotension, (3) the recovery of survival, and (4) the recovery of dialysis related uncertain symptoms. Although clinical evidence has been noted, the hypothesis of the efficacy of HDF are still indefinite and require further precise research.
Genetic Background of a Recurrent Unusual Combined Form of Retinal Vein Occlusion: A Case Report
Authors: Bucan Kajo , Plestina Borjan Ivna , Bucan Ivona , Paradzik Simunovic Martina , Borjan Ivan
Published: April 2018

The authors report a rare case of nonischemic branch retinal vein occlusion and nonischemic hemiretinal vein occlusion in a patient with impaired fibrinolysis. A 61-year-old woman presented to the Department of Ophthalmology, Clinical Hospital Center Split, Croatia, with acute blurring of vision in the right eye (RE) due to branch retinal vein occlusion. Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 0.02 in the RE and of 1.0 in the left eye. Ophthalmoscopy and fluorescein angiography of the RE demonstrated signs of nonischemic branch retinal vein occlusion. She was otherwise healthy and had no other ocular and systemic diseases. She was treated with 3 consecutive intravitreal applications of anti-vascular endothelial growth factor (anti-VEGF; bevacizumab) due to cystoid macular edema with full resolution of the intraretinal fluid and improvement of the BCVA to 0.9. After 8 months, she presented again with acute blurring of vision in the same (right) eye with a BCVA of 0.5. Ophthalmoscopy and fluorescein angiography of the RE indicated nonischemic hemiretinal vein occlusion. She was treated with a single intravitreal application of anti-VEGF (ranibizumab) due to macular edema. Full resolution of the intraretinal fluid and improvement of the BCVA to 0.9 were achieved. A laboratory workup was performed to rule out all known causes of retinal venous occlusive disease, which showed negative results. A molecular analysis showed the gen of thrombophilia – plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism genotype – as the only risk factor for retinal venous occlusive disease in our patient.
Hereditary Leukonychia Totalis: A Case Report and Review of the Literature
Authors: Pakornphadungsit Kallapan , Suchonwanit Poonkiat , Sriphojanart Tueboon , Chayavichitsilp Pamela
Published: April 2018

Leukonychia is defined as white discoloration of the nails caused by an abnormal keratinization of the nail matrix. Congenital leukonychia totalis is a rare nail disorder, which is typically inherited in an autosomal dominant pattern. This condition can be presented as an isolated condition or in association with systemic diseases. We report a case of a 7-year-old Thai boy who developed asymptomatic white discoloration of all the nails since birth, with an absence of any predisposing factors or associated conditions.
Mechanisms of Cardiac Repair and Regeneration
Authors: Broughton Kathleen M. , Wang Bingyan J. , Firouzi Fareheh , Khalafalla Farid , Dimmeler Stefanie , Fernandez-Aviles Francisco , Sussman Mark A.
Published: April 2018

Cardiovascular regenerative therapies are pursued on both basic and translational levels. Although efficacy and value of cell therapy for myocardial regeneration can be debated, there is a consensus that profound deficits in mechanistic understanding limit advances, optimization, and implementation. In collaboration with the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes), this review overviews several pivotal aspects of biological processes impinging on cardiac maintenance, repair, and regeneration. The goal of summarizing current mechanistic understanding is to prompt innovative directions for fundamental studies delineating cellular reparative and regenerative processes. Empowering myocardial regenerative interventions, whether dependent on endogenous processes or exogenously delivered repair agents, ultimately depends on mastering mechanisms and novel strategies that take advantage of rather than being limited by inherent myocardial biology.
Outcomes of Peripheral Vascular Interventions in Select Patients With Lower Extremity Acute Limb Ischemia
Authors: Inagaki Elica , Farber Alik , Kalish Jeffrey A. , Eslami Mohammad H. , Siracuse Jeffrey J. , Eberhardt Robert T. , Rybin Denis V. , Doros Gheorghe , Hamburg Naomi M. ,   the Vascular Study Group of New England
Published: April 2018

Background

Contemporary data on patients presenting with acute limb ischemia (
ALI
), who are selected for treatment with endovascular peripheral vascular interventions (
PVI
), are limited. Our study examined outcomes following endovascular
PVI
in patients with
ALI
by comparing with patients treated for chronic critical limb ischemia using a regional quality improvement registry.

Methods and Results

Of the 11 035 patients in the Vascular Study Group of New England
PVI
database (2010–2014), we identified 365 patients treated for lower extremity
ALI
who were 5:1 frequency matched (by procedure year and arterial segments treated) to 1808 patients treated for critical limb ischemia.
ALI
patients treated with
PVI
had high burden of atherosclerotic risk factors and were more likely to have had prior ipsilateral revascularizations.
ALI
patients were less likely to be treated with self‐expanding stents and more likely to undergo thrombolysis than patients with critical limb ischemia. In multivariable analysis,
ALI
was associated with higher technical failure (odds ratio 1.7, 95% confidence interval, 1.1%–2.5%), increased rate of distal embolization (odds ratio 2.7, 95% confidence interval, 1.5%–4.9%), longer length of stay (means ratio 1.6, 95% confidence interval, 1.4%–1.8%), and higher in‐hospital mortality (odds ratio 2.8, 95% confidence interval, 1.3%–5.9%).
ALI
was not associated with risk of major amputation or mortality at 1 year.

Conclusions

In a multicenter cohort of patients treated with
PVI
, we found that
ALI
patients selected for treatment with endovascular techniques experienced greater short‐term adverse events but similar long‐term outcomes as their critical limb ischemia counterparts. Further studies are needed to refine the selection of
ALI
patients who are best served by
PVI
.
Pro‐Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction
Authors: Abernethy Abraham , Raza Sadi , Sun Jie‐Lena , Anstrom Kevin J. , Tracy Russell , Steiner Johannes , VanBuren Peter , LeWinter Martin M.
Published: April 2018

Background

Underlying inflammation has been increasingly recognized in heart failure with a preserved ejection fraction (
HF
p
EF
). In this study we tested the hypothesis that pro‐inflammatory biomarkers are elevated in patients with acutely decompensated
HF
p
EF
(
AD
‐
HF
p
EF
) compared with patients with stable
HF
p
EF
(S‐
HF
p
EF
).

Methods and Results

Using a post hoc analysis the serum biomarkers tumor necrosis factor‐alpha, high‐sensitivity C‐reactive protein interleukin 6 and pentraxin 3 (
PTX
3) and clinical, demographic, echocardiographic‐Doppler and clinical outcomes data were analyzed in
HF
p
EF
patients enrolled in
NHLBI
Heart Failure Research Network clinical trials which enrolled patients with either
AD
‐
HF
p
EF
or S‐
HF
p
EF
. Compared to S‐
HF
p
EF
,
AD
‐
HF
p
EF
patients had higher levels of
PTX
3 (3.08 ng/
mL
versus 1.27 ng/
mL
,
P
<0.0001),
interleukin
‐6 (4.14 pg/
mL
versus 1.71 pg/
mL
,
P
<0.0001),
tumor necrosis factor‐alpha
(11.54 pg/
mL
versus 8.62 pg/
mL
,
P
=0.0015), and high‐sensitivity C‐reactive protein (11.90 mg/
dL
versus 3.42 mg/
dL
,
P
<0.0001). Moreover, high‐sensitivity C‐reactive protein,
interleukin
‐6 and
PTX
3 levels were significantly higher in
AD
‐
HF
p
EF
compared with S‐
HF
p
EF
patients admitted for decompensated
HF
within the previous year.
PTX
3 was positively correlated with left atrial volume index (
r
=0.41,
P
=0.0017) and left ventricular mass (
r
=0.26,
P
=0.0415), while tumor necrosis factor‐alpha was inversely correlated with E/A ratio (
r
=−0.31,
P
=0.0395).

Conclusions

Levels of pro‐inflammatory biomarkers are strikingly higher in
AD
‐
HF
p
EF
compared with S‐
HF
p
EF
patients.
PTX
3 and tumor necrosis factor‐alpha are correlated with echocardiographic‐Doppler evidence of diastolic dysfunction. Taken together these data support the concept that a heightened pro‐inflammatory state has a pathophysiologic role in the development of
AD
‐
HF
p
EF
.
Outcomes in Asymptomatic Severe Aortic Stenosis With Preserved Ejection Fraction Undergoing Rest and Treadmill Stress Echocardiography
Authors: Huded Chetan P. , Masri Ahmad , Kusunose Kenya , Goodman Andrew L. , Grimm Richard A. , Gillinov A. Marc , Johnston Douglas R. , Rodriguez L. Leonardo , Popovic Zoran B. , Svensson Lars G. , Griffin Brian P. , Desai Milind Y.
Published: April 2018

Background

In asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction, we sought to assess the incremental prognostic value of resting valvuloarterial impedence (Zva) and left ventricular global longitudinal strain (
LV
‐
GLS
) to treadmill stress echocardiography.

Methods and Results

We studied 504 such patients (66±12 years, 78% men, 32% with coronary artery disease who underwent treadmill stress echocardiography between 2001 and 2012. Clinical and exercise variables (% of age‐sex predicted metabolic equivalents [%
AGP
‐
MET
s]) were recorded. Resting Zva ([systolic arterial pressure+mean aortic valve gradient]/[
LV
‐stroke volume index]) and
LV
‐
GLS
(measured offline using Velocity Vector Imaging, Siemens) were obtained from the baseline resting echocardiogram. Death was the primary outcome. There were no major adverse cardiac events during treadmill stress echocardiography. Indexed aortic valve area, Zva, and
LV
‐
GLS
were 0.46±0.1 cm
2
/m
2
, 4.5±0.9 mm Hg/mL per m
2
and −16±4%, respectively; only 50% achieved >100%
AGP
‐
MET
s. Sixty‐four percent underwent aortic valve replacement. Death occurred in 164 (33%) patients over 8.9±3.6 years (2 within 30 days of aortic valve replacement). On multivariable Cox survival analysis, higher Society of Thoracic Surgeons score (hazard ratio or
HR
1.06), lower %
AGP
‐
METS
(
HR
1.16), higher Zva (
HR
1.25) and lower
LV
‐
GLS
(
HR
1.12) were associated with higher longer‐term mortality, while aortic valve replacement (
HR
0.45) was associated with improved survival (all
P
<0.01). Sequential addition of
ZV
a and
LV
‐
GLS
to clinical model (Society of Thoracic Surgeons score and %
AGP
‐
MET
s) increased the c‐statistic from 0.65 to 0.69 and 0.75, respectively, both
P
<0.001); findings were similar in the subgroup of patients who underwent aortic valve replacement.

Conclusions

In asymptomatic patients with severe aortic stenosis undergoing treadmill stress echocardiography,
LV
‐
GLS
and
ZV
a offer incremental prognostic value.