bluuebunny/crossref_metadata_2025 huggingface dataset:
Autopsy interrogation of emergency medicine dispute cases: how often are clinical diagnoses incorrect?
Authors: Liu Danyang , Gan Rongchang , Zhang Weidi , Wang Wei , Saiyin Hexige , Zeng Wenjiao , Liu Guoyuan
Published: September 2017

Aims

Emergency medicine is a ‘high risk’ specialty. Some diseases develop suddenly and progress rapidly, and sudden unexpected deaths in the emergency department (ED) may cause medical disputes. We aimed to assess discrepancies between antemortem clinical diagnoses and postmortem autopsy findings concerning emergency medicine dispute cases and to figure out the most common major missed diagnoses.

Methods

Clinical files and autopsy reports were retrospectively analysed and interpreted. Discrepancies between clinical diagnoses and autopsy diagnoses were evaluated using modified Goldman classification as major and minor discrepancy. The difference between diagnosis groups was compared with Pearson χ2test.

Results

Of the 117 cases included in this study, 71 of cases (58 class I and 13 class II diagnostic errors) were revealed as major discrepancies (60.7%). The most common major diagnoses were cardiovascular diseases (54 cases), followed by pulmonary diseases, infectious diseases and so on. The difference of major discrepancy between the diagnoses groups was significant (p<0.001). Aortic dissection and myocardial infarction were the most common cause of death (15 cases for each disease) and the most common missed class I diagnoses (80% and 66.7% for each), higher than the average 49.6% of all class I errors of the study patients.

Conclusions

High major disparities between clinical diagnoses and postmortem examinations exist in emergency medical disputes cases; acute aortic dissection and myocardial infarction are the most frequently major missed diagnoses that ED clinicians should pay special attention to in practice. This study reaffirmed the necessity and usefulness of autopsy in auditing death in EDs.
Clinical performance evaluation of the Idylla NRAS-BRAF mutation test on retrospectively collected formalin-fixed paraffin-embedded colorectal cancer tissue
Authors: Johnston Louise , Power Michael , Sloan Philip , Long Anna , Silmon Angela , Chaffey Ben , Lisgo Andrea Jane , Little Liam , Vercauteren Ellen , Steiniche Torben , Meyer Tine , Simpson John
Published: September 2017

Aims

Understanding the molecular mechanisms of underlying disease has led to a movement away from the one-drug-fits-all paradigm towards treatment tailored to the genetic profile of the patient. The Biocartis Idylla platform is a novel fully automated, real-time PCR–basedin vitrodiagnostic system. The Idylla NRAS-BRAF mutation test has been developed for the qualitative detection of mutations inNRASandBRAFoncogenes, facilitating genetic profiling of patients with cancer. The aim of this study was to carry out a formal clinical performance evaluation.

Methods

Two-hundred and forty-two formalin-fixed paraffin-embedded (FFPE) human malignant colorectal cancer (CRC) tissue samples were identified in departmental archives and tested with both the Idylla NRAS-BRAF mutation test and the Agena Bioscience MassARRAY test.

Results

The overall concordance between the Idylla NRAS-BRAF mutation test and the MassARRAY comparator reference test result was 241/242 (99.59%, lower bound of one-sided 95% CI=98.1%) forNRASand 242/242 (lower bound of 95% one-sided 95% CI=98.89%) forBRAF. The Idylla NRAS-BRAF test detected oneNRASmutation that had not been reported by the MassARRAY comparator reference test. Reanalysis of this sample by droplet digital PCR confirmed that the mutation was present, but at an allelic frequency below the stated sensitivity level of the MassARRAY system.

Conclusion

These results confirm that the Idylla NRAS-BRAF mutation test has high concordance with a widely usedNRAS-BRAFtest, and is therefore suitable for use as anin vitrodiagnostic device for this application.
A data-driven approach for identifying project manager competency weights
Authors: Hanna Awad S. , Iskandar Karim A. , Lotfallah Wafik , Ibrahim Michael W. , Russell Jeffrey S.
Published: September 2017

Competent project managers (PMs) are the backbone of any construction project. It is extremely important to constantly develop and enhance their competencies. However, to establish effective training and development plans for PMs, the relative importance of the key competencies that define a PM’s performance should be first understood. Instead of subjectively weighting the relative importance of differing competencies, this paper aims at developing an automated model that uses real-life data to compute the PM competency weights. The rationale behind the model is to maximize the distance in a higher dimensional space between average and exceptional PM performances. The model solves an eigenvalue problem, and identifies a single data-based weight for each competency. The model is generic and can be applied to various research settings to alleviate the problems associated with opinion-based assessment and reduce individuals’ subjectivity. Findings within this paper reveal the most critical competencies that enable PMs to perform their roles in construction projects exceptionally.
Wanted dead or alive: a state-space mark–recapture–recovery model incorporating multiple recovery types and state uncertainty
Authors: Hostetter Nathan J. , Gardner Beth , Evans Allen F. , Cramer Bradley M. , Payton Quinn , Collis Ken , Roby Daniel D.
Published: September 2017

We developed a state-space mark–recapture–recovery model that incorporates multiple recovery types and state uncertainty to estimate survival of an anadromous fish species. We apply the model to a dataset of outmigrating juvenile steelhead trout (Oncorhynchus mykiss (Walbaum, 1792)) tagged with passive integrated transponders, recaptured during outmigration, and recovered on bird colonies in the Columbia River basin (2008–2014). Recoveries on bird colonies are often ignored in survival studies because the river reach of mortality is often unknown, which we model as a form of state uncertainty. Median outmigration survival from release to the lower river (river kilometre 729 to 75) ranged from 0.27 to 0.35, depending on year. Recovery probabilities were frequently ≥0.20 in the first river reach following tagging, indicating that one out of five fish that died in that reach was recovered on a bird colony. Integrating dead recovery data provided increased parameter precision, estimation of where birds consumed fish, and survival estimates across larger spatial scales. More generally, these modeling approaches provide a flexible framework to integrate multiple sources of tag recovery data into mark–recapture studies.
Symmetric bound states of Josephson vortices in BEC
Authors: Qadir Muhammad Irfan , Zoma Tehseen
Published: September 2017

A system of two parallel coupled cigar-shaped Bose–Einstein condensates is considered in an effectively one-dimensional limit. The dynamics of the system is characterized by a pair of coupled nonlinear Gross–Pitaevskii equations. In particular, the existence and stability of symmetric bound states of Josephson vortices are investigated. It is realized that the symmetric bound state Josephson vortices solution persists stably in its whole domain of existence for the coupling strength. Nevertheless, the bound states solution converts into a dark soliton at a critical value of coupling parameter.
Large third-order optical nonlinearity in PdO thin films
Authors: Brodyn M. S. , Volkov V. I. , Rudenko V. I. , Liakhovetskyi V. R. , Borshch A. O.
Published: September 2017

We report on a study of the absorption spectra and third-order nonlinear optical properties of crystalline PdO thin films, grown by oxidation of thin palladium films deposited on a substrate. The spectra reveal an absorption peak at [Formula: see text][Formula: see text]nm, which grows and narrows significantly as the temperature is lowered to [Formula: see text][Formula: see text]K. This behavior suggests an exciton nature of the peak. According to the position of the long wavelength absorption edge in the spectra, the bandgap of the material is [Formula: see text][Formula: see text]eV. Utilizing the techniques of degenerate four-wave mixing and Z-scan, using a pulsed laser radiation with a wavelength [Formula: see text][Formula: see text]nm and a pulse duration of [Formula: see text][Formula: see text]ns, we determined the real part of the third-order nonlinear susceptibility of Re[Formula: see text][Formula: see text]esu. Possible nature of this high refractive nonlinearity is discussed.
Secure IoT-Based, Incentive-Aware Emergency Personnel Dispatching Scheme with Weighted Fine-Grained Access Control
Authors: Yeh Lo-Yao , Tsaur Woei-Jiunn , Huang Hsin-Han
Published: September 2017

Emergency response times following a traffic accident are extremely crucial in reducing the number of traffic-related deaths. Existing emergency vehicle dispatching systems rely heavily on manual assignments. Although some technology-assisted emergency systems engage in emergency message dissemination and path planning, efficient emergency response is one of the main factors that can decrease traffic-related deaths. Obviously, effective emergency response often plays a far more important role in a successful rescue. In this article, we propose a secure IoT-based and incentive-aware emergency personnel dispatching scheme (EPDS) with weighted fine-grained access control. Our EPDS can recruit available medical personnel on-the-fly, such as physicians driving in the vicinity of the accident scene. An appropriate incentive, such as paid leave, can be offered to encourage medical personnel to join rescue missions. Furthermore, IoT-based devices are installed in vehicles or wearable on drivers to gather biometric signals from the driver, which can be used to decide precisely which divisions or physicians are needed to administer the appropriate remedy. Additionally, our scheme can cryptographically authorize the assigned rescue vehicle to control traffic to increase rescue efficacy. Our scheme also takes advantage of adjacent roadside units to organize the appropriate rescue personnel without requiring long-distance communication with a trusted traffic authority. Proof of security is provided and extensive analyses, including qualitative and quantitative analyses and simulations, show that the proposed scheme can significantly improve rescue response time and effectiveness. To the best of our knowledge, this is the first work to make use of medical personnel that are close by in emergency rescue missions.
High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine
Authors: Panasevich M. R. , Meers G. M. , Linden M. A. , Booth F. W. , Perfield J. W. , Fritsche K. L. , Wankhade Umesh D. , Chintapalli Sree V. , Shankar K. , Ibdah J. A. , Rector R. S.
Published: September 2017

Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high-cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.
Methodological considerations for a chronic neural interface with the cuneate nucleus of macaques
Authors: Suresh Aneesha K. , Winberry Jeremy E. , Versteeg Christopher , Chowdhury Raeed , Tomlinson Tucker , Rosenow Joshua M. , Miller Lee E. , Bensmaia Sliman J.
Published: September 2017

While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult-to-access brain stem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top-down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implanting arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brain stem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates.

NEW & NOTEWORTHY In primates, the neural basis of touch and of our sense of limb posture and movements has been studied in the peripheral nerves and in somatosensory cortex, but coding in the cuneate and external cuneate nuclei, the first processing stage for these signals in the central nervous system, remains an enigma. We have developed a method to record from these nuclei, thereby paving the way to studying how sensory information from the limb is encoded there.
Surface electrodes record and label brain neurons in insects
Authors: Kostarakos Konstantinos , Hedwig Berthold
Published: September 2017

We used suction electrodes to reliably record the activity of identified ascending auditory interneurons from the anterior surface of the brain in crickets. Electrodes were gently attached to the sheath covering the projection area of the ascending interneurons and the ringlike auditory neuropil in the protocerebrum. The specificity and selectivity of the recordings were determined by the precise electrode location, which could easily be changed without causing damage to the tissue. Different nonauditory fibers were recorded at other spots of the brain surface; stable recordings lasted for several hours. The same electrodes were used to deliver fluorescent tracers into the nervous system by means of electrophoresis. This allowed us to retrograde label the recorded auditory neurons and to reveal their cell body and dendritic structure in the first thoracic ganglion. By adjusting the amount of dye injected, we specifically stained the ringlike auditory neuropil in the brain, demonstrating the clusters of cell bodies contributing to it. Our data provide a proof that surface electrodes are a versatile tool to analyze neural processing in small brains of invertebrates.

NEW & NOTEWORTHY We show that surface suction electrodes can be used to monitor the activity of auditory neurons in the cricket brain. They also allow delivering electrophoretically a fluorescent tracer to label the structure of the recorded neurons and the local neuropil to which the electrode was attached. This new extracellular recording and labeling technique is a versatile and useful method to explore neural processing in invertebrate sensory and motor systems.
The superior colliculus and the steering of saccades toward a moving visual target
Authors: Goffart Laurent , Cecala Aaron L. , Gandhi Neeraj J.
Published: September 2017

Following the suggestion that a command encoding current target location feeds the oculomotor system during interceptive saccades, we tested the involvement of the deep superior colliculus (dSC). Extracellular activity of 52 saccade-related neurons was recorded in three monkeys while they generated saccades to targets that were static or moving along the preferred axis, away from (outward) or toward (inward) a fixated target with a constant speed (20°/s). Vertical and horizontal motions were tested when possible. Movement field (MF) parameters (boundaries, preferred vector, and firing rate) were estimated after spline fitting of the relation between the average firing rate during the motor burst and saccade amplitude. During radial target motions, the inner MF boundary shifted in the motion direction for some, but not all, neurons. Likewise, for some neurons, the lower boundaries were shifted upward during upward motions and the upper boundaries downward during downward motions. No consistent change was observed during horizontal motions. For some neurons, the preferred vectors were also shifted in the motion direction for outward, upward, and “toward the midline” target motions. The shifts of boundary and preferred vector were not correlated. The burst firing rate was consistently reduced during interceptive saccades. Our study demonstrates an involvement of dSC neurons in steering the interceptive saccade. When observed, the shifts of boundary in the direction of target motion correspond to commands related to past target locations. The absence of shift in the opposite direction implies that dSC activity does not issue predictive commands related to future target location.

NEW & NOTEWORTHY The deep superior colliculus is involved in steering the saccade toward the current location of a moving target. During interceptive saccades, the active population consists of a continuum of cells ranging from neurons issuing commands related to past locations of the target to neurons issuing commands related to its current location. The motor burst of collicular neurons does not contain commands related to the future location of a moving target.
Factors Associated with Types and Intensity of Postoperative Pain following Gynecological Laparoscopic Surgery: A Cross-Sectional Study
Authors: Hsien Chia-Fen , Wang Chiu-Lin , Long Cheng-Yu , Chen Yung-Hung , Lee Winter Yu-Ning , Chen Shih-Chin , Lin Kun-Ling , Jeng Cherng-Jye , Tsai Eing-Mei , Tang Feng-Hsiang
Published: September 2017

Objective. To evaluate influences of various factors on the types and intensity of postoperative pain following gynecologic laparoscopic surgery. Study Design. Cross-sectional questionnaire and chart review. Results. A total of 84 questionnaires were distributed and returned. The types of postlaparoscopic pain are different in multiparous women and nulliparous ones (71.43% surgical wound pain versus 63.64% nonsurgical wound pain, p=0.0033) and those with striae gravidarum and without striae gravidarum (93.94% surgical wound pain versus 52.94% nonsurgical wound pain, p<0.0001). On postoperative day 1, the average VAS score is higher in nonsurgical wound pain than in surgical wound pain (5.62 ± 1.50 versus 3.51 ± 1.68, p<0.0001). The CO2 removal procedure has a significant negative correlation with the VAS of nonsurgical wound pain (coefficient: -0.4339, p=0.0187). Conclusion. Our study suggests that women with abdominal rigidity (nulliparous, no striae gravidarum) experience mainly nonsurgical wound pain, while women with abdominal wall laxity mostly experience surgical wound pain. The VAS score of nonsurgical wound pain is greater than surgical wound pain on postoperative day 1. The CO2 removal procedure has negative correlation to the VAS score of nonsurgical wound pain on postoperative day 1.
Pricing Zero-Coupon Catastrophe Bonds Using EVT with Doubly Stochastic Poisson Arrivals
Authors: Ma Zonggang , Ma Chaoqun , Xiao Shisong
Published: September 2017

The frequency and severity of climate abnormal change displays an irregular upward cycle as global warming intensifies. Therefore, this paper employs a doubly stochastic Poisson process with Black Derman Toy (BDT) intensity to describe the catastrophic characteristics. By using the Property Claim Services (PCS) loss index data from 2001 to 2010 provided by the US Insurance Services Office (ISO), the empirical result reveals that the BDT arrival rate process is superior to the nonhomogeneous Poisson and lognormal intensity process due to its smaller RMSE, MAE, MRPE, and U and larger E and d. Secondly, to depict extreme features of catastrophic risks, this paper adopts the Peak Over Threshold (POT) in extreme value theory (EVT) to characterize the tail characteristics of catastrophic loss distribution. And then the loss distribution is analyzed and assessed using a quantile-quantile (QQ) plot to visually check whether the PCS index observations meet the generalized Pareto distribution (GPD) assumption. Furthermore, this paper derives a pricing formula for zero-coupon catastrophe bonds with a stochastic interest rate environment and aggregate losses generated by a compound doubly stochastic Poisson process under the forward measure. Finally, simulation results verify pricing model predictions and show how catastrophic risks and interest rate risk affect the prices of zero-coupon catastrophe bonds.
The Rising Phoenix-Progesterone as the Main Target of the Medical Therapy for Leiomyoma
Authors: Chill H. H. , Safrai M. , Reuveni Salzman A. , Shushan A.
Published: September 2017

Leiomyomas, also known as uterine fibroids, are a common benign tumor in women of reproductive age. These lesions disrupt the function of the uterus causing menorrhagia and pelvic pressure as well as reproductive disorders. These women pose a true challenge for clinicians in the attempt of choosing the suitable treatment for each patient. Patient’s age, interest in fertility preservation, and leiomyoma location and size are all factors to be taken into account when deciding upon the preferable therapeutic option. For the past few decades, surgical treatment was the only reliable long-term treatment available. A variety of surgical approaches have been developed over the years but these developments have come at the expense of other treatment options. The classical medical treatment includes gonadotropin-releasing hormone (GnRH) agonists and antagonists. These agents are well known for their limited clinical effect as well as their broad spectrum of side effects, inspiring a need for new pharmacological treatments. In recent years, promising results have been reported with the use of selective progesterone receptor modulators (SPRM). Long-term clinical trials have shown a reduction in bleeding and shrinkage of leiomyoma mass. These results instill hope for women suffering from symptomatic leiomyomas seeking an effective, long-term medical option for their condition.
Surface Plasmon Resonance Enhanced Spontaneous Upconversion and Stimulated Emissions in Glass Ceramics Containing Ba2LaF7 Nanocrystals
Authors: Li Sai , Lu Wei , Yang Qihua , Zhou Dacheng , Qiu Jianbei , Xu Xuhui , Yu Xue
Published: September 2017

Glass ceramics containing Yb3+, Er3+ codoped Ba2LaF7 nanocrystals were fabricated via melt quenching method and the subsequent heating treatment. The formation of Ba2LaF7 nanocrystals in the glass ceramics was confirmed by X-ray diffraction (XRD) and transmission electron microscope (TEM). The spontaneous upconversion (UC) emission and the stimulated counterpart as a random lasing action of Er3+, which were related to the characteristic transitions of Er3+ ions, were achieved in the Yb3+, Er3+-doped Ba2LaF7 nanocrystals embedded glass ceramic hybrid. Furthermore, the absorption spectra verified the surface plasmon resonance (SPR) band of Ag, which precipitated from the matrix glasses as Ag nanoparticles (NPs). By incorporating Ag NPs in the glass ceramic hybrid, spontaneous UC emission intensity of Er3+ in visible region was significantly enhanced, while the threshold of the random lasing was decreased from 480 to 350 nJ/cm2.
Clinical Characteristics and Laboratory Identification of Aerococcus Infections: An Australian Tertiary Centre Perspective
Authors: Narayanasamy Shanti , King Katherine , Dennison Amanda , Spelman Denis W. , Aung Ar Kar
Published: September 2017

Aerococci uncommonly cause urinary tract (UTI) and bloodstream infections (BSI). The clinical characteristics and laboratory identification rates of Aerococcus in the Australian context are unknown. A retrospective observational cohort study of patients with positive Aerococcus cultures between 2010 and 2015 was performed. Patients were analysed according to predefined “asymptomatic bacteriuria,” “UTI,” and “BSI” groups. Forty-seven [40 (85%) for urine and 7 (15%) for blood] isolates were identified [38% male, median age of 79 (IQR 62–85) years], with corresponding identification rates of 24.2/100,000/year for urine (0.02%) and 7.3/100,000/year for blood cultures (0.007%). Since the use of matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) identification rate in urine has increased from 14.7/100,000/year to 32/100,000/year (p=0.02). For urine isolates, 14 (35%) met the definition for UTI whilst 26 (65%) were “asymptomatic bacteriuria.” Underlying urological abnormalities, catheterisation, and polymicrobial growth were common. Seventy percent of bacteriuria was treated regardless of colonisation or active infection status. Symptomatic patients were more likely to receive treatment (OR 7.2, 95% CI 1.4–35.3). In patients with BSI, 1 (14.2%) had endocarditis and 1 (14.2%) died. The majority of isolates were susceptible to penicillin (11/12 tested, 92%).
Heat Stroke: A Medical Emergency Appearing in New Regions
Authors: Mørch Sofie Søndergaard , Andersen Johnny Dohn Holmgren , Bestle Morten Heiberg
Published: September 2017

Heat stroke is an acute, life-threatening emergency characterized clinically by elevated body temperature and central nervous system dysfunction. Early recognition and treatment including aggressive cooling and management of life-threatening systemic complications are essential to reduce morbidity and mortality. This case report describes two Danish patients diagnosed with heat stroke syndrome during a heat wave in the summer of 2014. Both patients were morbidly obese and had several predisposing illnesses. However since heat stroke is a rare condition in areas with temperate climate, they were not diagnosed until several days after admittance; hence treatment with cooling was delayed. Both patients were admitted to the intensive care unit, where they were treated with an external cooling device and received treatment for complications. Both cases ended fatally. As global warming continues, more heat waves will occur in previously cooler regions. Therefore it is important to raise awareness of heat stroke since outcome depends on early recognition and rapid cooling.
Nevus Lipomatosus Superficialis on the Left Proximal Arm
Authors: Leung Alexander K. C. , Barankin Benjamin
Published: September 2017

We report a 58-year-old woman with a solitary type of nevus lipomatosus superficialis on the left proximal arm. To our knowledge, the occurrence of a solitary type of nevus lipomatosus superficialis on the arm has very rarely been reported. A perusal of the literature revealed but one case, to which we are going to add another one. Recognition of this clinical manifestation is important so that a proper diagnosis can be made.
Polydatin Prevents Methylglyoxal‐Induced Apoptosis through Reducing Oxidative Stress and Improving Mitochondrial Function in Human Umbilical Vein Endothelial Cells
Authors: Pang Ningbo , Chen Tangting , Deng Xin , Chen Ni , Li Rong , Ren Meiping , Li Yongjie , Luo Mao , Hao Haiyan , Wu Jianbo , Wang Liqun
Published: September 2017

Methylglyoxal (MGO), an active metabolite of glucose, has been reported to induce vascular cell apoptosis in diabetic complication. Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions, such as antioxidative, anti‐inflammatory, and nephroprotective properties. However, the protective effects of PD on MGO‐induced apoptosis in endothelial cells remain to be elucidated. In this study, human umbilical vein endothelial cells (HUVECs) were used to explore the effects of PD on MGO‐induced cell apoptosis and the possible mechanism involved. HUVECs were pretreated with PD for 2 h, followed by stimulation with MGO. Then cell apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) impairment, mitochondrial morphology alterations, and Akt phosphorylation were assessed. The results demonstrated that PD significantly prevented MGO‐induced HUVEC apoptosis. PD pretreatment also significantly inhibited MGO‐induced ROS production, MMP impairment, mitochondrial morphology changes, and Akt dephosphorylation. These results and the experiments involving N‐acetyl cysteine (antioxidant), Cyclosporin A (mitochondrial protector), and LY294002 (Akt inhibitor) suggest that PD prevents MGO‐induced HUVEC apoptosis, at least in part, through inhibiting oxidative stress, maintaining mitochondrial function, and activating Akt pathway. All of these data indicate the potential application of PD for the treatment of diabetic vascular complication.
Determinants of Acute Malnutrition among Children Aged 6–59 Months in Public Health Facilities of Pastoralist Community, Afar Region, Northeast Ethiopia: A Case Control Study
Authors: Seid Anwar , Seyoum Berhanu , Mesfin Firehiwot
Published: September 2017

Background. In low income countries, acute malnutrition continues to be the most important risk factor for illnesses and deaths. The aim of this study was to assess the determinants of acute malnutrition among children aged 6–59 months.Methods. A facility based unmatched case control study was employed on 420 (140 cases and 280 controls) children aged 6–59 months with their caregivers between January 20 and February 20, 2014. Data was analyzed using SPSS version 20.0. APvalue < 0.05 was considered statistically significant.Results. Children aged 12–23 months [AOR = 10.51, 95% CI = 4.93, 22.34], rural residence [AOR = 2.42, 95% CI = 1.22, 4.79], illiterate father [AOR = 2.47, 95% CI = 1.32, 4.61], Monthly income of less than 1000 birr [AOR = 3.98, 95% CI 2.05, 7.69], and food served together with family [AOR = 2.18, 95% CI = 1.10, 4.30] were associated with acute malnutrition.Conclusion. Rural residence, illiterate father, monthly income of less than 1000 birr, and food served together with family are statistically associated with acute malnutrition. Improving practices of parents on appropriate child feeding and creating awareness related to key risk factors of acute malnutrition should be further strengthened.
Latent Class Analysis of Noninvasive Methods and Liver Biopsy in Chronic Hepatitis C: An Approach without a Gold Standard
Authors: Fernandes Flavia F. , Perazzo Hugo , Andrade Luiz E. , Dellavance Alessandra , Terra Carlos , Pereira Gustavo , Pereira João L. , Campos Frederico , Ferraz Maria L. , Perez Renata M.
Published: September 2017

Aims.To evaluate the applicability of the Latent Class Analysis (LCA) and accuracy of transient elastography (TE), aspartate-to-platelet-ratio-index (APRI), enhanced liver fibrosis (ELF), and liver biopsy (LB) for liver fibrosis assessment in a model without a gold standard.Methods.Significant fibrosis was defined asTE≥7.1 kPa,APRI≥1.5,ELF≥9.37, or LB METAVIRF≥2. Cirrhosis was defined asTE≥12.5 kPa,APRI≥2.0,ELF≥10.31, or LB as METAVIRF=4.Results.117 patients with chronic hepatitis C were included. In the LCA, for significant fibrosis the sensitivities and specificities (95% CI) were 0.92 (0.86–0.98) and 0.79 (0.72–0.86) for TE; 0.47 (0.40–0.54) and 0.99 (0.95–1.00) for APRI; 0.81 (0.74–0.88) and 0.78 (0.71–0.85) for ELF; and 0.86 (0.68–1.00) and 0.91 (0.79–1.00) for LB. For cirrhosis, the sensitivities and specificities were 0.92 (0.76–1.00) and 0.94 (0.91–0.97) for TE; 0.57 (0.37–0.77) and 0.97 (0.93–1.00) for APRI; 0.94 (0.84–1.00) and 0.88 (0.82–0.94) for ELF; and 0.30 (0.12–0.48) and 1.00 for LB.Conclusion.LCA was useful to evaluate accuracy of methods for liver fibrosis staging. Sensitivities and specificities of noninvasive methods were increased in LCA compared to the use of LB as the gold standard.
Combining Upper Limb Robotic Rehabilitation with Other Therapeutic Approaches after Stroke: Current Status, Rationale, and Challenges
Authors: Mazzoleni Stefano , Duret Christophe , Grosmaire Anne Gaëlle , Battini Elena
Published: September 2017

A better understanding of the neural substrates that underlie motor recovery after stroke has led to the development of innovative rehabilitation strategies and tools that incorporate key elements of motor skill relearning, that is, intensive motor training involving goal-oriented repeated movements. Robotic devices for the upper limb are increasingly used in rehabilitation. Studies have demonstrated the effectiveness of these devices in reducing motor impairments, but less so for the improvement of upper limb function. Other studies have begun to investigate the benefits of combined approaches that target muscle function (functional electrical stimulation and botulinum toxin injections), modulate neural activity (noninvasive brain stimulation), and enhance motivation (virtual reality) in an attempt to potentialize the benefits of robot-mediated training. The aim of this paper is to overview the current status of such combined treatments and to analyze the rationale behind them.
Overexpression of MicroRNA-145 Ameliorates Astrocyte Injury by Targeting Aquaporin 4 in Cerebral Ischemic Stroke
Authors: Zheng Lifang , Cheng Wei , Wang Xijia , Yang Zhigang , Zhou Xiangling , Pan Chunlian
Published: September 2017

Cerebral ischemic stroke, which affects the global population, is a major disease with high incidence, mortality, and disability. Accumulating evidence has indicated that abnormal microRNA (miRNA) expression plays essential roles in the pathologies of ischemic stroke. Yet, the underlying regulatory mechanism of miRNAs in cerebral ischemic stroke remains unclear. We investigated the role of miR-145 in cerebral ischemic stroke and its potential mechanism in a model using primary cultured astrocytes. We detected the expression levels of miR-145 and its target gene AQP4 and assessed the role of miR-145 in cell death and apoptosis caused by oxygen-glucose deprivation (OGD). Bioinformatics analysis was used to explore the targets of miR-145. miR-145 expression levels were significantly decreased in primary astrocytes subjected to OGD. miR-145 overexpression promoted astrocyte health and inhibited OGD-induced apoptosis. AQP4 was a direct target of miR-145, and miR-145 suppressed AQP4 expression. Moreover, AQP4 enhanced astrocyte injury in ischemic stroke, and AQP4 knockdown diminished the miR-145-mediated protective effect on ischemic injury. Taken together, our results show that miR-145 plays an important role in protecting astrocytes from ischemic injury by downregulating AQP4 expression. These findings may highlight a novel therapeutic target in cerebral ischemic stroke.
Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo
Authors: Traboulsi Wael , Sergent Frédéric , Boufettal Houssine , Brouillet Sophie , Slim Rima , Hoffmann Pascale , Benlahfid Mohammed , Zhou Qun Y. , Balboni Gianfranco , Onnis Valentina , Bolze Pierre A. , Salomon Aude , Sauthier Philippe , Mallet François , Aboussaouira Touria , Feige Jean J. , Benharouga Mohamed , Alfaidy Nadia
Published: September 2017

Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland–derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy.

Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control (n = 20) and in distinctive CHM (n = 38) and CC (n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice.

Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions.

Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130–40. ©2017 AACR.
Targeting Prostate Cancer Subtype 1 by Forkhead Box M1 Pathway Inhibition
Authors: Ketola Kirsi , Munuganti Ravi S.N. , Davies Alastair , Nip Ka Mun , Bishop Jennifer L. , Zoubeidi Amina
Published: September 2017

Purpose: Prostate cancer was recently classified to three clinically relevant subtypes (PCS) demarcated by unique pathway activation and clinical aggressiveness. In this preclinical study, we investigated molecular targets and therapeutics for PCS1, the most aggressive and lethal subtype, with no treatment options available in the clinic.

Experimental Design: We utilized the PCS1 gene set and our model of enzalutamide (ENZR) castration-resistant prostate cancer (CRPC) to identify targetable pathways and inhibitors for PCS1. The findings were evaluated in vitro and in the ENZR CRPC xenograft model in vivo.

Results: The results revealed that ENZR CRPC cells are enriched with PCS1 signature and that Forkhead box M1 (FOXM1) pathway is the central driver of this subtype. Notably, we identified Monensin as a novel FOXM1-binding agent that selectively targets FOXM1 to reverse the PCS1 signature and its associated stem-like features and reduces the growth of ENZR CRPC cells and xenograft tumors.

Conclusions: Our preclinical data indicate FOXM1 pathway as a master regulator of PCS1 tumors, namely in ENZR CRPC, and targeting FOXM1 reduces cell growth and stemness in ENZR CRPC in vitro and in vivo. These preclinical results may guide clinical evaluation of targeting FOXM1 to eradicate highly aggressive and lethal PCS1 prostate cancer tumors. Clin Cancer Res; 23(22); 6923–33. ©2017 AACR.
Matrix Screen Identifies Synergistic Combination of PARP Inhibitors and Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors in Ewing Sarcoma
Authors: Heske Christine M. , Davis Mindy I. , Baumgart Joshua T. , Wilson Kelli , Gormally Michael V. , Chen Lu , Zhang Xiaohu , Ceribelli Michele , Duveau Damien Y. , Guha Rajarshi , Ferrer Marc , Arnaldez Fernanda I. , Ji Jiuping , Tran Huong-Lan , Zhang Yiping , Mendoza Arnulfo , Helman Lee J. , Thomas Craig J.
Published: September 2017

Purpose: Although many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations.

Experimental Design: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class. Comprehensive metabolomic and proteomic profiling was performed to better understand the mechanism underlying the synergy. Xenograft experiments were performed to determine efficacy and in vivo mechanism.

Results: Several promising candidates emerged, including the combination of small-molecule PARP and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, a rational combination as NAMPTis block the rate-limiting enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a necessary substrate of PARP. Mechanistic drivers of the synergistic cell killing phenotype of these combined drugs included depletion of NMN and NAD+, diminished PAR activity, increased DNA damage, and apoptosis. Combination PARPis and NAMPTis in vivo resulted in tumor regression, delayed disease progression, and increased survival.

Conclusions: These studies highlight the potential of these drugs as a possible therapeutic option in treating patients with Ewing sarcoma. Clin Cancer Res; 23(23); 7301–11. ©2017 AACR.
Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping, and Monitoring
Authors: Kang Zhigang , Stevanović Sanja , Hinrichs Christian S. , Cao Liang
Published: September 2017

Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making.

Experimental Design: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet PCR (ddPCR). Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome.

Results: In blinded tests, HPV ccfDNA was detected in 19 of 19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87 of 87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2–3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy.

Conclusions: HPV ccfDNA represents a promising tumor marker for noninvasive HPV genotyping and may be used in selecting patients for HPV type–specific T-cell-based immunotherapies. It may also have value in detecting antitumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Clin Cancer Res; 23(22); 6856–62. ©2017 AACR.
Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis
Authors: Hartmann Jessica A. , McGorry Patrick D. , Schmidt Stefanie J. , Amminger G. Paul , Yuen Hok Pan , Markulev Connie , Berger Gregor E. , Chen Eric Y.H. , de Haan Lieuwe , Hickie Ian B. , Lavoie Suzie , McHugh Meredith J. , Mossaheb Nilufar , Nieman Dorien H. , Nordentoft Merete , Riecher-Rössler Anita , Schäfer Miriam R. , Schlögelhofer Monika , Smesny Stefan , Thompson Andrew , Verma Swapna Kamal , Yung Alison R. , Nelson Barnaby
Published: September 2017

Background: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. Methods: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. Results: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. Conclusions: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.
Dose Escalation of Antidepressants in Unipolar Depression: A Meta-Analysis of Double-Blind, Randomized Controlled Trials
Authors: Dold Markus , Bartova Lucie , Rupprecht Rainer , Kasper Siegfried
Published: September 2017

Background: As many patients with unipolar depression do not respond sufficiently to initial antidepressant monotherapy, a dose increase of the current administered antidepressant (dose escalation, high-dose treatment) is frequently carried out as next treatment measure. Methods: We conducted a meta-analysis which included all double-blind randomized controlled trials (RCTs) comparing a dose increase of antidepressants directly to continuation of standard-dose treatment in unipolar depressive patients who were non- responders to standard-dose pharmacotherapy. A mean change in the Hamilton Rating Scale for Depression (HAM-D) total score was the primary outcome. Secondary outcomes were response rates and discontinuation rates due to any reason, inefficacy, and adverse effects. Hedges g and risk ratios were calculated as effect sizes. Results: Seven double-blind RCTs (8 study arms) representing 1,208 participants were included. Fluoxetine (N [number of studies] = 2, n [number of patients] = 448), sertraline (N = 2, n = 272), paroxetine (N = 2, n = 146), duloxetine (N = 1, n = 255), and maprotiline (N = 1, n = 87) were investigated. Dose escalation was not more efficacious in HAM-D total score reduction than maintaining standard-dose treatment, neither for the pooled antidepressant group (N = 7, n = 999; Hedges g = -0.04, 95% CI: -0.20 to 0.12; p = 0.63) nor the individual antidepressants. No differences could be determined for response rates, all-cause discontinuation, and drop-outs due to inefficacy. Significantly more patients in the dose escalation group dropped out due to adverse effects than in the standard-dose continuation group. The metaregressions indicate no influence of baseline symptom severity or amounts of dose increments on effect sizes. Conclusions: According to our meta-analytic findings, dose escalation after initial non-response to standard-dose pharmacotherapy cannot be regarded as general evidence-based treatment option in unipolar depression.