bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on silk fibroin nanofibers with long length
Authors: Lu Shenzhou , Wen Zhuangzhuang , Yin Zhuping , Kuang Dajiang , Xing Tieling
Published: May 2019

Aqueous silk fibroin (SF) sol is a colloidal solution. With the colloidal hydration layer and electrostatic repulsion, the SF sol can hardly make the efficient collision/assembly among micelles and perform like a following sol for a long time. In this paper, hydrophilic silk-based sequences (HSF) derived from SF molecules were obtained by immersing the dried SF condensates with water and extracting the dissolving fraction. The HSF was obtained by immersing the SF condensate dried at the temperature of [Formula: see text]–[Formula: see text] and relative humid of 55–60% in water and collected the lixivium. The dissolving ratio was about 30%. The HSF sol (0.5%, w/v) self-assembled into the mesoscopic 3D nanofibrous network within 8 h. The obtained HSF nanofibers were 10–100 [Formula: see text] in length and 50–100 nm in diameter. The HSF nanofiber possesses similar hierarchical structure consisting of nanofibrils bundles to the native silk fiber. There were significant aggregation structure transitions from random coil to [Formula: see text]-sheet and amorphous chains to Silk II crystal aggregation during the formation of HSF nanofibers. The HSF nanofiber holds the potential to give further insight into the reconstruction of native silk in vitro and the fabrication of tough silk-based biomaterials.
Formal Interoperability Models of Sensor Networks Based on Logical Workflow Nets
Authors: Liu Wei , Lin Mao , Yan Chun
Published: May 2019

With the advent of Internet of things and cyber physical system, sensor networks become more and more important. To better accomplish a task, multiple sensors or even multiple sensor networks need to interoperate. Logical workflow nets and cooperative logical workflow nets are introduced to formally model and analyze interoperability of sensor networks. Independent feasibility and Interoperable feasibility are important properties for ensuring correct execution and interoperability of sensor networks. Complete path nets, possible path nets, cooperative complete path nets and cooperative possible path nets are presented to decide independent feasibility and interoperable feasibility of logical workflow nets and cooperative logical workflow nets denoting interoperability of sensor networks.
PROBABILISTIC MODELING AND ANALYSIS OF DNA FRAGMENTATION
Authors: POURMOHAMMADI REZA , ABOUEI JAMSHID , ANPALAGAN ALAGAN
Published: May 2019

Deoxyribonucleic Acid (DNA) sequencing has become indispensable to the modern biological and medicine sciences. DNA fragmentation is a preliminary step in a dominant technique called shotgun sequencing that provides a time and cost effective strategy for the DNA sequencing. In this paper, we propose a probabilistic model for the random DNA fragmentation and derive an average number of fragments with the suitable length along with the probability of covering the entire DNA strand through the de novo assembly or the referenced-based mapping assembly. We formulate the coverage problem in terms of the probability of bond breaking between nucleotides and the number of DNA molecules participating in the fragmentation process, and provide insights into the optimal DNA fragmentation. We obtain the lower bound for the minimum number of suitable fragments required to reconstruct the DNA strand with the specified reliability. We evaluate the derived results with our DNA Fragmentation Tool which demonstrate, the validity of these results based on our model. Finally, we update our model with respect to the fragments’ size distribution of real data.
A NOVEL GAIT-INSPIRED FOUR-BAR LOWER LIMB EXOSKELETON TO GUIDE THE WALKING MOVEMENT
Authors: SINGH RAMANPREET , CHAUDHARY HIMANSHU , SINGH AMIT KUMAR
Published: May 2019

Background: Walking is a complex process that involves rhythmic movement of lower limb along with the coordination of brain, nerves and muscles. If the coordination is disturbed, gait may be effected or disordered. Therefore, it should be treated effectively and efficiently using assistive devices/exoskeletons. The exoskeletons and assistive devices may be embedded with the linkage and other mechanisms to imitate the behavior of human lower limb. However, these mechanisms are synthesized using the complex conventional procedures. Thus, a new gait-inspired algorithm is proposed in this study for synthesizing a four-bar mechanism for exoskeletons.

Methods: This paper presents a design of four-bar linkage for lower limb exoskeleton to support walking. A new gait-inspired algorithm to synthesize four-bar linkage is also proposed which uses two phases of gait, namely, the swing phase and the stance phase, for lower limb exoskeleton. The trajectory is derived for each phase of the gait and is combined with the optimization techniques. The trajectory passes through 10 precision points in each phase giving a total of 20 precision points for one gait cycle. The optimization is performed in two stages. The first stage deals with the minimization of error between the desired and the generated foot trajectories; whereas, the second stage deals with the minimization of error between the desired and generated hip trajectories of the linkage. Besides the gait-inspired four-bar linkage synthesis, a hybrid teaching-learning-particle-swarm-optimization (HTLPSO) technique is also used to solve the problem.

Results: A well-established genetic algorithm (GA) and a new hybrid (HTLPSO) algorithm are used to compare the results of the tracking error of the linkage. It is found that the HTLPSO optimization algorithm performs better in comparison to GA for the problem considered here. Finally, a solid model of the proposed design for lower limb exoskeleton is presented. Moreover, the obtained linkage tracks all the prescribed points accurately and the simulation of designed linkage has been demonstrated using stick diagram for one gait cycle.

Conclusion: The proposed method has simplified the synthesis procedure to a great extent, and a feasible design is obtained using the optimization algorithm. The mechanism obtained using the proposed method can walk smoothly which is validated through stick diagram. The proposed mechanism can be used for exoskeleton, assistive devices, bipeds etc. Moreover, the proposed method may be extended to six- and eight-bar mechanisms.
EFFECTS OF DIABETES MELLITUS ON VISCOELASTICITY OF ULTRASTRUCTURES OF PERIPHERAL NERVES: THREE-DIMENSIONAL FINITE ELEMENT ANALYSES
Authors: TSENG GUAN-HAO , CHANG CHENG-TAO , LIN CHOU-CHING K. , CHEN TERRY YUAN-FANG , JU MING-SHAUNG
Published: May 2019

Diabetes mellitus induces a variety of neuropathies and causes various symptoms. Understanding how diabetes affects mechanical properties of nerves is useful for preventing complications of diabetes mellitus such as the carpal tunnel syndrome. In a previous study, a two-dimensional hyper-viscoelastic finite element model (FEM) of the ultra-structures of normal rat sciatic nerves was developed using an optical coherence tomography (OCT) microscope and in vitro parallel compression tests. The main goal of this study was to extend the FEM from two to three dimensions and use it to explore hyper-viscoelasticity of ultra-structures of sciatic nerves of diabetic rats. A modification of the compression testing system to enhance OCT cross-sectional images of the nerve samples was also conducted. The results showed that the instantaneous shear moduli of the perineurium, epineurium, and endoneurium of the diabetic rat were all greater than those of the normal rats. Due to high instantaneous shear moduli and low percentage of relaxation, the diabetic nerve is prone to damage when subjected to prolonged mechanical loads.
Event detection and visualization of ocean eddies simulated by ocean general circulation model
Authors: Matsuoka Daisuke , Araki Fumiaki , Sasaki Hideharu
Published: May 2019

Numerical study of ocean eddies has been carried out by using high-resolution ocean general circulation models. In order to understand ocean eddies from the large volume data produced by simulations, visualizing only eddy distribution at each time step is insufficient; time-variations in eddy events and phenomena must also be considered. However, existing methods cannot precisely find and track eddy events such as amalgamation and bifurcation. In this study, we propose an original approach for eddy detection, tracking, and event visualization based on an eddy classification system. The proposed method detects streams and currents as well as eddies, and it classifies discovered eddies into several categories using the additional stream and current information. By tracking how the classified eddies vary over time, detecting events such as eddy amalgamation and bifurcation as well as the interaction between eddies and ocean currents becomes achievable. We adopt the proposed method for two ocean areas in which strong ocean currents exist as case studies. We visualize the detected eddies and events in a time series of images, allowing us to acquire an intuitive understanding of a region of interest concealed in a high-resolution data set. Furthermore, our proposed method succeeded in clarifying the occurrence place and seasonality of each type of eddy event.
Engineering trustworthy systems
Authors: Saydjari O. Sami
Published: May 2019

Cybersecurity design reduces the risk of system failure from cyberattack, aiming to maximize mission effectiveness.
Personalized Travel Time Prediction Using a Small Number of Probe Vehicles
Authors: Li Yang , Gunopulos Dimitrios , Lu Cewu , Guibas Leonidas J.
Published: May 2019

Predicting the travel time of a path is an important task in route planning and navigation applications. As more GPS probe data has been collected to monitor urban traffic, GPS trajectories of the probe vehicles have been frequently used to predict path travel time. However, most trajectory-based methods rely on deploying GPS devices and collect real-time data on a large taxi fleet, which can be expensive and unreliable in smaller cities. This work deals with the problem of predicting path travel time when only a small number of cars are available. We propose an algorithm that learns local congestion patterns of a compact set of frequently shared paths from historical data. Given a travel time prediction query, we identify the current congestion patterns around the query path from recent trajectories, then infer its travel time in the near future. Driver identities are also used in predicting personalized travel time. Experimental results using 10--25 taxis in urban areas of Shenzhen, China, show that personal prediction has on average 3.4mins of error on trips of duration 10--75mins. This result improves the baseline approach of using purely historical trajectories by 16.8% on average, over four regions with various degrees of path regularity. It also outperforms a state-of-the-art travel time prediction method that uses both historical trajectories and real-time trajectories.
An interview with David Brin on resiliency
Authors: Denning Peter J. , Brin David
Published: May 2019

Many risks of catastrophic failures of critical infrastructures can be significantly reduced by relatively simple measures to increase resiliency.
The Anthropology of Death Revisited
Authors: Engelke Matthew
Published: May 2019

This article brings together classic work in the anthropology of death, much of which focused on funerary rites, with more recent studies, some of which continue with the classic focus and some of which introduce distinct views and problematics. The anthropology of death has become a capacious field, linking to broader debates on violence, suffering, medicine, subjectivity, race, gender, faith, modernity, and secularity (among others). In much of this work, though, we find common concerns with, and recurrent considerations of, certain themes. This review focuses on two of the most important: the symbolic imaginaries of how life conquers death; and, even more centrally, the materiality of death. A range of topics are addressed, including putrescence, burial, bones, commemorations, debts, care, sovereignty, and personal loss.
Effects of combined glucocorticoid/mineralocorticoid receptor modulation (CORT118335) on energy balance, adiposity, and lipid metabolism in male rats
Authors: Nguyen Elizabeth T. , Berman Sarah , Streicher Joshua , Estrada Christina M. , Caldwell Jody L. , Ghisays Valentina , Ulrich-Lai Yvonne , Solomon Matia B.
Published: May 2019

Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids act primarily through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high-fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3, 10, or 30 mg/kg) or vehicle once daily. A 5-day treatment with CORT118335 at 30 mg/kg induced weight loss in rats fed a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily because of decreased calorific efficiency, as there were no significant differences in food intake compared with vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-wk treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18 days) treatment of CORT118335 (10 mg/kg) reversed body weight gain and adiposity in animals fed a high-fat diet for 13 wk. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue-specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.
The Effect of Triptolide-Loaded Exosomes on the Proliferation and Apoptosis of Human Ovarian Cancer SKOV3 Cells
Authors: Liu Huan , Shen Ming , Zhao De , Ru Dan , Duan Yourong , Ding Chenhuan , Li He
Published: May 2019

Triptolide has been proven to possess anticancer efficacy; however, its application in the clinical practice was limited by poor water solubility, hepatotoxicity, and nephrotoxicity. In this study, a triptolide-loaded exosomes delivery system (TP-Exos) was constructed and its effects on the proliferation and apoptosis of SKOV3 cells in vitro and in vivo were observed. SKOV3-exosomes (SK-Exos) were collected by ultracentrifugation and ultrafiltration centrifugation. TP-Exos was constructed by sonication and ultrafiltration centrifugation. SK-Exos and TP-Exos were characterized by transmission electron microscopy, western blotting, nanoparticle-tracking analysis, and high-performance liquid chromatography. Cellular uptake of exosomes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, bromodeoxyuridine (BrdU) cell proliferation assay, and cell apoptosis experiment were used to study the effect of TP-Exos on ovarian cancer in vitro. Tumor-targeting study of exosomes, monitoring the tumor volume of mice, and TdT-mediated dUTP Nick-End labeling (TUNEL) assay were used to evaluate the effect of TP-Exos on ovarian cancer in vivo. The toxicity of TP-Exos in vivo was evaluated by liver and kidney function and histopathology of major organs (heart, liver, spleen, lung, kidney, and ovary). The results revealed that TP-Exos not only have the general characteristics of exosomes but also have high drug encapsulation efficiency. Besides, PKH26 labeled exosomes (PKH26-Exos) could be uptaken by SKOV3 cells, and Dir labeled exosomes (Dir-Exos) could be enriched to the tumor site of tumor bearing mice. Furthermore, the cytotoxic and apoptotic effects on SKOV3 cells of TP-Exos were weaker than those of free TP, and tumor cell proliferation inhibition and tumor growth inhibition were stronger than that of free TP. Moreover, TP-Exos have toxic effect on liver and spleen. In conclusion, the TP-Exos could be a promising strategy for ovarian cancer, but they need to be further optimized to attenuate the damage to liver and spleen.
Analysis of the Antiproliferative Effect of Ankaferd Hemostat on Caco-2 Colon Cancer Cells via LC/MS Shotgun Proteomics Approach
Authors: Koçak Engin , Çelebier Mustafa , Haznedaroglu Ibrahim C. , Altınöz Sacide
Published: May 2019

Ankaferd hemostat (ABS), a traditional herbal extract, is a hemostatic agent used for wound healing and bleeding treatment. A standardized form of plants contains many biomolecules. In recent years, previous studies have demonstrated the antineoplastic effect of ABS. In the present work, we focused on the mechanism of its antineoplastic effect over Caco-2 colon cancer cells. The LC/MS-based proteomics method was used to understand the effect of ABS at the protein level. The results were evaluated with gene ontology, protein interaction, and pathway analysis. As shown by our results, ABS altered glucose, fatty acids, and protein metabolism. Moreover, ABS affects the cell cycle machinery. Moreover, we found that ABS induced critical cancer target and suppressor proteins such as carboxyl-terminal hydrolase 1, 60S ribosomal protein L5, Tumor protein D52-like2, karyopherin alpha 2, and protein deglycase DJ-1. In conclusion, the proteomics results indicated that ABS affects various cancer targets and suppressor proteins. Moreover ABS has systematical effect on cell metabolism and cell cycle in Caco-2 cells, suggesting that it could be used as an antineoplastic agent.
Bacterial Isolates and Drug Susceptibility Pattern of Sterile Body Fluids from Tertiary Hospital, Northern Ethiopia: A Four-Year Retrospective Study
Authors: Tsegay Ephrem , Hailesilassie Aregawi , Hailekiros Haftamu , Niguse Selam , Saravanan Muthupandian , Abdulkader Mahmud
Published: May 2019

This study was conducted in Ayder comprehensive specialized Hospital, Mekelle, Northern Ethiopia, to determine the bacterial profiles and drug susceptibility pattern from body fluids. A total of 218 patients were investigated, of which 146 (67%) were males. The age of the study subjects ranged from 2 days to 80 years with 96(44%) in the age group of 15 years and above. The overall bacterial infection was 44 (20.2 %) of which gram positive bacteria were prevalent, 23 (52.3%) than gram negative bacteria 21 (47.7%). The predominantly isolated bacteria wereS. pneumonia,followed byK.pneumoniae, S. aureus, andE coli.Multidrug resistance was observed in 12 (100%) of the isolated gram positive bacteria and in 6 (75%) of the isolated gram negative bacteria.
Triglyceride Levels Greater Than 10,000 mg/dL in a 49-Year-Old Female without Evidence of Pancreatitis
Authors: Toor Anika , Toor Amit , Khalighi Koroush , Krishnamurthy Mahesh
Published: May 2019

We present a rare case of a 49-year-old female with very severe hypertriglyceridemia (HTG) having a total triglyceride (TG) count of > 10,000 mg/dL in the absence of pancreatitis. Based on literature review, this is one of the highest recorded TG counts in an adult without evidence of pancreatitis. HTG is a common occurrence in clinical practice, but rarely do numbers exceed 2000 mg/dl. It is crucial to evaluate and rapidly lower TG levels to prevent potentially life-threatening complications such as severe pancreatitis. Removal of potential predisposing medications, control of underlying diseases known to cause HTG, and maintenance therapies are essential to prevent reoccurrence.
Stochastic Optimal Control for Buffer-Aided Cooperative Relaying Systems Using Nonorthogonal Multiple Access
Authors: Deng Zhishan , Gong Qianyun , Li Quanzhong , Qin Jiayin
Published: May 2019

In this paper, a multiple-cluster downlink multiple-input single-output (MISO) nonorthogonal multiple access (NOMA) system is considered. In each cluster, there are one central user and one cell-edge user. The central user has a data buffer with finite storage units, which will decode the cell-edge user’s message and store it at the data buffer. To enhance the performance of the cell-edge user, the central user operates as a relay and helps forward the message to the cell-edge user. Our objective is to maximize the long-term average sum rates for the cell-edge users by designing the beamforming vectors and online power control, under the constraints of the data buffer causality, required information rates for central users, and transmit power at the base station and central users. Based on the current buffer state and the channel state information, we propose a low-complexity online Lyapunov optimization algorithm combined with a constrained concave-convex procedure (CCCP) to solve the causal and nonconvex problem. Furthermore, we verify the asymptotic optimality of the proposed online Lyapunov optimization algorithm. Simulation results demonstrate that our proposed scheme performs better than the greedy algorithm and the orthogonal multiple access (OMA) scheme.
Mesenchymal Stem Cell Therapy Overcomes Steroid Resistance in Severe Gastrointestinal Acute Graft-Versus-Host Disease
Authors: Moritani Kyoko , Miyawaki Reiji , Tokuda Kiriko , Ochi Fumihiro , Eguchi-Ishimae Minenori , Tauchi Hisamichi , Eguchi Mariko , Ishii Eiichi , Nagai Kozo
Published: May 2019

The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×106hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.
Comparison of Subconjunctival Aflibercept and Betamethasone for the Treatment of Formed Corneal Neovascularization in a Rabbit Model
Authors: Eiger-Moscovich Maya , Livny Eitan , Sella Ruti , Gal-Or Orly , Nisgav Yael , Livnat Tami , Bahar Irit
Published: May 2019

Aim: To compare the efficacy of aflibercept (Eylea®), a potent antivascular endothelial growth factor (VEGF) agent, with betamethasone (Celestone®) and placebo for the treatment of formed corneal neovascularization in a rabbit model. Methods: A central corneal chemical burn was created in the right eye of 24 New Zealand albino rabbits. Four weeks later, the rabbits were randomly divided into 4 equal groups for subconjunctival injection of aflibercept, betamethasone, aflibercept+ betamethasone, or saline (control). Digital photographs taken at weekly intervals were rated by 2 masked observers for extent, centricity, and density of corneal neovascularization according to a predefined scale. The percentage of corneal surface involved by neovascularization was quantified by image analysis software (Fiji-J). The change in corneal neovascularization from treatment administration (4 weeks after injury) to 4 weeks later (8 weeks after injury) was assessed. The rabbits were then euthanized, and their eyes were enucleated and processed for histopathological and immunofluorescence studies. Results: There was no significant difference in the change in corneal neovascularization after treatment among the 4 groups according to the digital images (p > 0.15) or histological evaluation with hematoxylin and eosin (p > 0.08). On immunofluorescence assay, a lower VEGF concentration was observed in all treatment groups compared to the control group. Conclusions: In this rabbit model, corneal neovascularization induced by chemical burn failed to regress with treatment with aflibercept, betamethasone, or their combination.
Short-Term Correlation of the Psoriasis Area Severity Index, the Nail Psoriasis Area Severity Index, and the Dermatology Life Quality Index , before and after Treatment, in Patients with Skin and Nail Psoriasis
Authors: Prevezas Christos , Katoulis Alexander C. , Papadavid Evangelia , Panagakis Pantelis , Rigopoulos Dimitrios
Published: May 2019

Background: The response to treatment in patients suffering from skin and nail psoriasis is quantitatively evaluated by monitoring clinical severity and quality of life indexes, especially in the context of clinical trials. Among them, the psoriasis area severity index (PASI), the nail psoriasis area severity index (NAPSI), and the dermatology life quality index (DLQI) are currently the most widely used indexes. Objective: To study the short-term correlation between PASI, NAPSI, and DLQI in patients with skin and nail psoriasis at baseline and 3 months after treatment initiation. Materials and Methods: This is a 2-center prospective, observational, cross-sectional study of 40 treatment-naive patients suffering from chronic plaque psoriasis with nail involvement and requiring systemic therapy. Disease activity and quality of life were assessed at baseline and 3 months after treatment initiation by measuring PASI, NAPSI, and DLQI scores. Statistical correlations between theses indexes were investigated using the appropriate statistical tests. Results: A positive, strong correlation was observed between DLQI and NAPSI at baseline (r = 0.579, p <0.001) and at 3 months (r = 0.484, p = 0.002). Similarly, a strong correlation was noted between DLQI and PASI at baseline (r = 0.496, p = 0.001) and at 3 months (r = 0.401, p = 0.01). Moreover, we observed a positive strong correlation (r = 0.515, p = 0.001) between DLQI at baseline and NAPSI at 3 months and a moderate correlation (r = 0.433, p = 0.005) between DLQI at baseline and PASI at 3 months. Conclusion: The observed positive correlations between PASI, NAPSI, and DLQI provide further evidence in support of their simultaneous utilization in clinical studies for skin and nail psoriasis. Moreover, the predictive value of DLQI at baseline emphasizes the importance of quality of life assessment when designing a therapeutic study as well as in the everyday clinical practice.
The International Academy of Cytology Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytopathology
Authors: Field Andrew S. , Raymond Wendy A. , Rickard Mary , Arnold Lauren , Brachtel Elena F. , Chaiwun Benjaporn , Chen Lan , Di Bonito Luigi , Kurtycz Daniel F.I. , Lee Andrew H.S. , Lim Elgene , Ljung Britt-Marie , Michelow Pamela M. , Osamura Robert Y. , Pinamonti Maurizio  , Sauer Torill , Segara Davendra , Tse Gary , Vielh Philippe , Chong Phek Y. , Schmitt Fernando
Published: May 2019

The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6–4.8%, benign 1.4–2.3%, atypical 13–15.7%, suspicious of malignancy 84.6–97.1%, and malignant 99.0–100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the “triple test” of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.
A Prediction Model for the Intraocular Pharmacokinetics of Intravitreally Injected Drugs Based on Molecular Physicochemical Properties
Authors: Kim Hyeong Min , Park Kyu Hyung , Chung Jae Yong , Woo Se Joon
Published: May 2019

Purpose: This study was aimed at determining the intraocular pharmacokinetics based on molecular physicochemical properties in a rabbit model. Methods: The entire dataset was obtained from previous literature, and research articles regarding 70 molecular compounds were investigated. The intravitreal half-lives in rabbit eyeballs of 22 macromolecules and 48 micromolecules were analyzed. Multiple linear regression analysis was carried out with non-collinear independent variables (molecular weight [MW] and lipophilicity) influencing intravitreal half-lives. The best-fit equations were selected based on the correlation coefficients and goodness-of-fit statistics. Results: The best-fit models obtained from the entire dataset, macromolecules, and micromolecules suggest the correlation between molecular physicochemical properties (MW and lipophilicity) and intravitreal half-life. Exclusion of outlier molecules (amphotericin B and foscarnet) leads to a better-fit correlation. MW is the definite single factor affecting intravitreal half-lives of macromolecules (Log t1/2 = 0.148 + 0.370 Log MW, R2 = 0.769), while both MW and lipophilicity influence the intraocular pharmacokinetics of micromolecules (Log t1/2 = –1.213 + 0.762 Log MW – 0.115 Log p, R2 = 0.554). Conclusion: The present study indicates that intravitreal half-life could be predicted based on molecular physicochemical properties (MW and lipophilicity). Also, increasing MW while reducing lipophilicity would be a reliable method for prolonging the intravitreal half-life of small chemical drugs, while MW is the single major determinant for large biologic drugs.
Neonatal Inhibition of Connexin 36 Ameliorates Fetal Brain Injury Induced by Maternal Noninfectious Fever in Mice
Authors: Wang Ruifen , Yang Yueqing , Xiao Min , Guo Binfang , Liu Weili , Wang Haiyan
Published: May 2019

Prenatal fever could result in brain function impairments in the offspring. The present study investigated the effect of interleukin-6 (IL-6)-induced maternal fever on the offspring and the involvement of connexin 36 in this process. Pregnant C57BL/6J mice were injected with IL-6 on gestational day 15. The levels of iNOS and COX-2 were measured as an index of neuroinflammation in the brain of newborn pups. Offspring were treated with the connexin 36 (Cx36) inhibitor mefloquine at postnatal day (P)1–P3 or at P40–P42. Rotarod, grip traction, and foot fault tests were carried out to evaluate the motor behavior of adult offspring. Injection of IL-6 led to an elevation of the core temperature in the pregnant dams. Offspring of these dams showed significantly increased COX-2 and iNOS mRNA expression and protein levels in the whole-brain samples and significantly increased Cx36 in the cerebellum. Moreover, offspring of these dams showed motor deficits at an adult age. Neonatal administration of the Cx36 inhibitor mefloquine could prevent these motor deficits. Maternal fever during pregnancy induced by IL-6 injection could lead to neuroinflammation and motor deficits in the offspring. Neonatal inhibition of Cx36 could ameliorate the motor deficits in the offspring, indicating an involvement of Cx36 in the IL-6-induced maternal fever.
Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study
Authors: Parmar Deven V. , Kansagra Kevinkumar A. , Patel Jatin C. , Joshi Shuchi N. , Sharma Nitin S. , Shelat Apeksha D. , Patel Nirav B. , Nakrani Vishal B. , Shaikh Farheen A. , Patel Harilal V. ,   on behalf of the ZYAN1 Trial Investigators
Published: May 2019

Background: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis. Methods: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6. Results: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial. Conclusion: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).
Successful Treatment with Topical Diphenylcyclopropenone for Three Cases of Anogenital Warts in Children
Authors: Miyata Kazunori , Go Usho , Fujita Masaru , Mitsuishi Tsuyoshi
Published: May 2019

Anogenital warts are caused by human papillomavirus types 6 and 11. They are rare in children, and treatment is difficult since conventional treatments are generally painful and require the patient to be anesthetized. Topical diphenylcyclopropenone (DPCP) is a contact immunotherapy used for treatments of recalcitrant warts and alopecia areata. We herein report 3 cases of anogenital warts in children successfully treated with topical DPCP. Our results suggest that topical DPCP may be a valuable option for the treatment of anogenital warts in children who have difficulty with painful destructive therapy.
Strategies for Treatment-Resistant Depression: Lessons Learned from Animal Models
Authors: Réus Gislaine Zilli , de Moura Airam Barbosa , Borba Laura Araújo , Abelaira Helena Mendes , Quevedo João
Published: May 2019

Around 300 million individuals are affected by major depressive disorder (MDD) in the world. Despite this high number of affected individuals, more than 50% of patients do not respond to antidepressants approved to treat MDD. Patients with MDD that do not respond to 2 or more first-line antidepressant treatments are considered to have treatment-resistant depression (TRD). Animal models of depression are important tools to better understand the pathophysiology of MDD as well as to help in the development of novel and fast antidepressants for TRD patients. This review will emphasize some discovery strategies for TRD from studies on animal models, including, antagonists of N-methyl-D-aspartate (NMDA) receptor (ketamine and memantine), electroconvulsive therapy (ECT), lithium, minocycline, quetiapine, and deep brain stimulation. Animal models of depression are not sufficient to represent all the traits of TRD, but they greatly aid in understanding the mechanism by which therapies that work for TRD exert antidepressant effects. Interestingly, these innovative therapies have mechanisms of action different from those of classic antidepressants. These effects are mainly related to the regulation of neurotransmitter activity, including general glutamate and increased connectivity, synaptic capacity, and neuroplasticity.
Positive Effect of Steroids in Posterior Reversible Encephalopathy Syndrome
Authors: Meyer Marco , Niemöller Ulrich , Stein Thomas , Schmetsdorf Stefanie , Arnold Andreas , El-Sheik Michael , Schuster Alexander , Adarkwah Charles Christian , Schramm Patrick , Tanislav Christian
Published: May 2019

We present a case of posterior reversible encephalopathy syndrome with severe clinical manifestation. Apart from initial aphasia, hemiparesis, and a generalized seizure, the patient had a prolonged loss of consciousness. Although blood pressure was normalized, the clinical status deteriorated continuously. After adding steroids to the therapy, the patient recovered rapidly, suggesting that this could have been a useful therapeutic approach. Even the vasogenic edema in the cerebral magnetic resonance imaging disappeared shortly within 6 days.
Mortality Risk Associated With Truncating Founder Mutations in Titin
Authors: Jansen Mark , Baas Annette F. , van Spaendonck-Zwarts Karin Y. , Ummels Amber S. , van den Wijngaard Arthur , Jongbloed Jan D.H. , van Slegtenhorst Marjon A. , Lekanne Deprez Ronald H. , Wessels Marja W. , Michels Michelle , Houweling Arjan C. , Hoorntje Edgar T. , Helderman-van den Enden Paula J.T.M. , Barge-Schaapveld Daniela Q.C.M. , Peter van Tintelen J. , van den Berg Maarten P. , Wilde Arthur A.M. , Ploos van Amstel Hans K. , Hennekam Eric A.M. , Asselbergs Folkert W. , Sijbrands Eric J.G. , Dooijes Dennis
Published: May 2019

Background

Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients.

Methods

Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method.

Results

The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95–1.18;
P
=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04–1.53;
P
=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01–1.35;
P
=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07–1.48;
P
=0.003), driven by subjects aged ≥60 years.

Conclusions

The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.
Association of a Home Monitoring Program With Interstage and Stage 2 Outcomes
Authors: Gardner Monique M. , Mercer‐Rosa Laura , Faerber Jennifer , DiLorenzo Michael P. , Bates Katherine E. , Stagg Alyson , Natarajan Shobha S. , Szwast Anita , Fuller Stephanie , Mascio Christopher E. , Fleck Desiree , Torowicz Deborah L. , Giglia Therese M. , Rome Jonathan J. , Ravishankar Chitra
Published: May 2019

Background

In shunt‐dependent, single‐ventricle patients, mortality remains high in the interstage period between discharge after neonatal surgery and stage 2 operation. We sought to evaluate the impact of our infant single‐ventricle management and monitoring program (
ISVMP
) on interstage mortality and stage 2 outcomes.

Methods and Results

This retrospective single‐center cohort study compared patients enrolled in
ISVMP
at hospital discharge with historical controls. The relationship of
ISVMP
to interstage mortality was determined with a bivariate probit model for the joint modeling of both groups, using an instrumental variables approach. We included 166
ISVMP
participants (December 1, 2010, to June 30, 2015) and 168 controls (January 1, 2007, to November 30, 2010). The groups did not differ by anatomy, gender, race, or genetic syndrome. Mortality was lower in the
ISVMP
group (5.4%) versus controls (13%). An
ISVMP
infant compared with a historical control had an average 29% lower predicted probability of interstage death (adjusted probability: −0.29; 95%
CI
, −0.52 to −0.057;
P
=0.015). On stratified analysis, mortality was lower in the hypoplastic left heart syndrome subgroup undergoing Norwood operation (4/84 [4.8%] versus 12/90 [14%],
P
=0.03) but not in those with initial palliation of shunt only (
P
=0.90).
ISVMP
participants were younger at the time of the stage 2 operation (138 versus 160 days,
P
<0.001), with no difference in postoperative mortality or length of stay.

Conclusions

In this single‐center study, we report significantly lower interstage mortality for participants with hypoplastic left heart syndrome enrolled in
ISVMP
. Younger age at stage 2 operation was not associated with postoperative mortality or longer length of stay.
Developmental Maturation of the Precuneus as a Functional Core of the Default Mode Network
Authors: Li Rosa , Utevsky Amanda V. , Huettel Scott A. , Braams Barbara R. , Peters Sabine , Crone Eveline A. , van Duijvenvoorde Anna C. K.
Published: May 2019

Efforts to map the functional architecture of the developing human brain have shown that connectivity between and within functional neural networks changes from childhood to adulthood. Although prior work has established that the adult precuneus distinctively modifies its connectivity during task versus rest states [Utevsky, A. V., Smith, D. V., & Huettel, S. A. Precuneus is a functional core of the default-mode network. Journal of Neuroscience, 34, 932–940, 2014], it remains unknown how these connectivity patterns emerge over development. Here, we use fMRI data collected at two longitudinal time points from over 250 participants between the ages of 8 and 26 years engaging in two cognitive tasks and a resting-state scan. By applying independent component analysis to both task and rest data, we identified three canonical networks of interest—the rest-based default mode network and the task-based left and right frontoparietal networks (LFPN and RFPN, respectively)—which we explored for developmental changes using dual regression analyses. We found systematic state-dependent functional connectivity in the precuneus, such that engaging in a task (compared with rest) resulted in greater precuneus–LFPN and precuneus–RFPN connectivity, whereas being at rest (compared with task) resulted in greater precuneus–default mode network connectivity. These cross-sectional results replicated across both tasks and at both developmental time points. Finally, we used longitudinal mixed models to show that the degree to which precuneus distinguishes between task and rest states increases with age, due to age-related increasing segregation between precuneus and LFPN at rest. Our results highlight the distinct role of the precuneus in tracking processing state, in a manner that is both present throughout and strengthened across development.
Gods and Talking Animals: the Pan-Cultural Recall Advantage of Supernatural Agent Concepts
Authors: Gregory Justin P. , Greenway Tyler S. , Keys Christina
Published: May 2019

Supernatural agent concepts are regarded as a defining trait of religion. The interaction of the minimally counterintuitive (MCI) mnemonic effect and the hypersensitive agency detection device (HADD) may be employed to explain the universal presence of concepts of gods and deities. Using the measure of free-recall, a broad model of cultural transmission investigated this pan-cultural transmission bias with a large age-representative sample (3 to 86 years; N = 764) in UK and China. Results were analyzed by four-way mixed ANOVA considering counterintuitiveness, familiarity, ontological category, and delay, and with age as a covariate. A significant interaction of counterintuitiveness × HADD was found for both UK and China samples. These findings support assertions that supernatural agent concepts are more easily transmitted than other concepts because the present study finds that concepts similar to supernatural agents were more readily recalled.
Where the Gods Dwell: a Research Report
Authors: Barrett Justin L. , Shaw R. Daniel , Pfeiffer Joseph , Grimes Jonathan
Published: May 2019

Are the places that superhuman beings purportedly act and dwell randomly or arbitrarily distributed? Inspired by theoretical work in cognitive science of religion, descriptions of superhuman beings (e.g., ancestors, demons, ghosts, gods, spirits) were solicited from informants in 20 countries on five continents, resulting in 108 usable descriptions, including information about these beings’ properties, their dwelling location, and whether they were the target of rituals. Whether superhuman beings are the subject of religious and ritual practices appeared to co-vary in relation to both features of physical geography and cognitive factors. Good gods were more likely the focus of religious practices than evil gods, and where the gods are thought to dwell mattered. If either the being was thought to dwell in a dangerous place or a resource rich place, it was more likely to have practices directed at it.