bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamically generated inflation from non-Riemannian volume forms
Authors: Benisty D. , Guendelman E. I. , Nissimov E. , Pacheva S.
Published: September 2019

We propose a simple modified gravity model without any initial matter fields in terms of several alternative non-Riemannian spacetime volume elements within the metric (second order) formalism. We show how the non-Riemannian volume-elements, when passing to the physical Einstein frame, create a canonical scalar field and produce dynamically a non-trivial inflationary-type potential for the latter with a large flat region and a stable low-lying minimum. We study the evolution of the cosmological solutions from the point of view of theory of dynamical systems. The theory predicts the spectral index $$n_s \approx 0.96$$ns≈0.96 and the tensor-to-scalar ratio $$r \approx 0.002$$r≈0.002 for 60 e-folds, which is in accordance with the observational data. In the future Euclid and SPHEREx missions or the BICEP3 experiment are expected to provide experimental evidence to test those predictions.
Three-loop contribution of the Faddeev–Popov ghosts to the $$\beta $$-function of $$\mathcal{N}=1$$ supersymmetric gauge theories and the NSVZ relation
Authors: Kuzmichev M. D. , Meshcheriakov N. P. , Novgorodtsev S. V. , Shirokov I. E. , Stepanyantz K. V.
Published: September 2019

We find the three-loop contribution to the $$\beta $$β-function of $$\mathcal{N}=1$$N=1 supersymmetric gauge theories regularized by higher covariant derivatives produced by the supergraphs containing loops of the Faddeev–Popov ghosts. This is done using a recently proposed algorithm, which essentially simplifies such multiloop calculations. The result is presented in the form of an integral of double total derivatives in the momentum space. The considered contribution to the $$\beta $$β-function is compared with the two-loop anomalous dimension of the Faddeev–Popov ghosts. This allows verifying the validity of the NSVZ equation written as a relation between the $$\beta $$β-function and the anomalous dimensions of the quantum superfields. It is demonstrated that in the considered approximation the NSVZ equation is satisfied for the renormalization group functions defined in terms of the bare couplings. The necessity of the nonlinear renormalization for the quantum gauge superfield is also confirmed.
Applied On-Chip Machine Learning for Dynamic Resource Control in Multithreaded Processors
Authors: Carroll Shane , Lin Wei-Ming
Published: October 2019

In this paper, we propose a machine learning algorithm to control instruction fetch bandwidth in a simultaneous multithreaded CPU. In a simultaneous multithreaded CPU, multiple threads occupy pools of hardware resources in the same clock cycle. Under some conditions, one or more threads may undergo a period of inefficiency, e.g., a cache miss, thereby inefficiently using shared resources and degrading the performance of other threads. If these inefficiencies can be identified at runtime, the offending thread can be temporarily blocked from fetching new instructions into the pipeline and given time to recover from its inefficiency, and prevent the shared system resources from being wasted on a stalled thread. In this paper, we propose a machine learning approach to determine when a thread should be blocked from fetching new instructions. The model is trained offline and the parameters embedded in a CPU, which can be queried with runtime statistics to determine if a thread is running inefficiently and should be temporarily blocked from fetching. We propose two models: a simple linear model and a higher-capacity neural network. We test each model in a simulation environment and show that system performance can increase by up to 19% on average with a feasible implementation of the proposed algorithm.
Systematic study of alpha decay half-lives using new universal decay law
Authors: Akrawy Dashty T. , Hassanabadi H. , Hosseini S. S. , Santhosh K. P.
Published: October 2019

We have performed a systematic calculation on the alpha decay half-lives of heavy mass nuclei with 106 [Formula: see text] 118, within the universal decay law (UDL) and modified universal decay law (MUDL). The calculated half-life values are found to be in agreement with the experimental data. The standard deviations of the logarithm of half-lives are found to be the least for MUDL in all cases of even–even, even–odd, odd–even and odd–odd, so the MUDL formula is better than UDL formula for alpha decay studies. We have predicted half-lives of some superheavy nuclei (SHN) in the region [Formula: see text]–118 that are not yet experimentally detected. The decay energies are computed using three different mass models. We hope this study will help future measurements on alpha decay half-lives of SHN.
Effects of the Size of Mixed-Reality Person Representations on Stress and Presence in Telecommunication
Authors: Joachimczak Michał , Liu Juan , Ando Hiroshi
Published: October 2019

We study how mixed reality (MR) telepresence can enhance long-distance human interaction and how altering 3D representations of a remote person can be used to modulate stress and anxiety during social interactions. To do so, we developed an MR telepresence system employing commodity depth sensors and Microsoft’s Hololens. A textured, polygonal 3D model of a person was reconstructed in real time and transmitted over network for rendering in remote location using HoloLens. In this study, we used mock job interview paradigm to induce stress in human–subjects interacting with an interviewer presented as an MR hologram. Participants were exposed to three different types of real-time reconstructed virtual holograms of the interviewer, a natural-sized 3D reconstruction (NR), a miniature 3D reconstruction (SR) and a 2D-display representation (LCD). Participants reported their subjective experience through questionnaires, while their biophysical responses were recorded. We found that the size of 3D representation of a remote interviewer had a significant effect on participants’ stress levels and their sense of presence. The questionnaire data showed that NR condition induced more stress and presence than SR condition and was significantly different from LCD condition. We also found consistent patterns in the biophysical data.
β2Adrenergic Receptor Complexes with the L-Type Ca2+Channel CaV1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions
Authors: Man Kwun Nok Mimi , Navedo Manuel F. , Horne Mary C. , Hell Johannes W.
Published: September 2019

Formation of signaling complexes is crucial for the orchestration of fast, efficient, and specific signal transduction. Pharmacological disruption of defined signaling complexes has the potential for specific intervention in selected regulatory pathways without affecting organism-wide disruption of parallel pathways. Signaling by epinephrine and norepinephrine through α and β adrenergic receptors acts on many signaling pathways in many cell types. Here, we initially provide an overview of the signaling complexes formed between the paradigmatic β2adrenergic receptor and two of its most important targets, the L-type Ca2+channel CaV1.2 and the AMPA-type glutamate receptor. Importantly, both complexes contain the trimeric Gsprotein, adenylyl cyclase, and the cAMP-dependent protein kinase, PKA. We then discuss the functional implications of the formation of these complexes, how those complexes can be specifically disrupted, and how such disruption could be utilized in the pharmacological treatment of disease.
Why Lungs Keep Time: Circadian Rhythms and Lung Immunity
Authors: Nosal Charles , Ehlers Anna , Haspel Jeffrey A.
Published: September 2019

Circadian rhythms are daily cycles in biological function that are ubiquitous in nature. Understood as a means for organisms to anticipate daily environmental changes, circadian rhythms are also important for orchestrating complex biological processes such as immunity. Nowhere is this more evident than in the respiratory system, where circadian rhythms in inflammatory lung disease have been appreciated since ancient times. In this focused review we examine how emerging research on circadian rhythms is being applied to the study of fundamental lung biology and respiratory disease. We begin with a general introduction to circadian rhythms and the molecular circadian clock that underpins them. We then focus on emerging data tying circadian clock function to immunologic activities within the respiratory system. We conclude by considering outstanding questions about biological timing in the lung and how a better command of chronobiology could inform our understanding of complex lung diseases.
Computational Identification of Metabolic Pathways ofPlasmodium falciparumusing thek-Shortest Path Algorithm
Authors: Oyelade Jelili , Isewon Itunuoluwa , Aromolaran Olufemi , Uwoghiren Efosa , Dokunmu Titilope , Rotimi Solomon , Aworunse Oluwadurotimi , Obembe Olawole , Adebiyi Ezekiel
Published: October 2019

Plasmodium falciparum, a malaria pathogen, has shown substantial resistance to treatment coupled with poor response to some vaccines thereby requiring urgent, holistic, and broad approach to prevent this endemic disease. Understanding the biology of the malaria parasite has been identified as a vital approach to overcome the threat of malaria. This study is aimed at identifying essential proteins unique to malaria parasites using a reconstructediPfagenome-scale metabolic model (GEM) of the 3D7 strain ofPlasmodium falciparumby filling gaps in the model with nineteen (19) metabolites and twenty-three (23) reactions obtained from the MetaCyc database. Twenty (20) currency metabolites were removed from the network because they have been identified to produce shortcuts that are biologically infeasible. The resulting modifiediPfaGEM was a model using thek-shortest path algorithm to identify possible alternative metabolic pathways in glycolysis and pentose phosphate pathways ofPlasmodium falciparum. Heuristic function was introduced for the optimal performance of the algorithm. To validate the prediction, the essentiality of the reactions in the reconstructed network was evaluated using betweenness centrality measure, which was applied to every reaction within the pathways considered in this study. Thirty-two (32) essential reactions were predicted among which our method validated fourteen (14) enzymes already predicted in the literature. The enzymatic proteins that catalyze these essential reactions were checked for homology with the host genome, and two (2) showed insignificant similarity, making them possible drug targets. In conclusion, the application of the intelligent search technique to the metabolic network ofP. falciparumpredicts potential biologically relevant alternative pathways using graph theory-based approach.
Early Real-World Experience with CoreValve Evolut PRO and R Systems for Transcatheter Aortic Valve Replacement
Authors: Rao Gaurav , Sheth Shikha , Donnelly Joseph , Scatola Andrew , Tariq Umair , Laighold Saaron , Grines Cindy , Rutkin Bruce
Published: October 2019

Objectives. The purpose of this study was to compare the efficacy and safety of the Evolut PRO to the Evolut R valve in a real-world setting. Background. The next-generation self-expanding transcatheter aortic valve replacement (TAVR) system, the CoreValve Evolut PRO was designed with an outer pericardial skirt to improve valve-sealing performance. Safety and efficacy of this valve have not previously been compared to its predecessor, the Evolut R valve. Methods. We retrospectively studied 134 patients who underwent TAVR with the Evolut PRO or Evolut R valve over one year at a tertiary center. Endpoints, defined by the Valve Academic Research Consortium-2 criteria, included device success, paravalvular leak (PVL), and a composite safety endpoint including mortality, stroke, major vascular complications, life-threatening bleeding, acute kidney injury, coronary artery obstruction, and repeat procedure for valve-related dysfunction. Results. 60 Evolut PRO and 56 Evolut R patients met the study criteria. Both groups had similar device success rates (90 vs. 89%, p=0.44). Incidence of moderate PVL was similar on discharge (5 vs. 11%, p=0.68) and at 30 days (11 vs. 13%, p=0.79), with nil incidence of severe PVL. There were no mortalities, and the VARC-2 safety endpoint at 30 days was comparable. Conclusion. Despite the additional pericardial skirt and larger sheath size of Evolut PRO, outcomes were comparable between the two Evolut systems, supporting adoption of the newest generation valve in the management of severe aortic stenosis as well as continued use of the Evolut R in patients with smaller vasculature warranting a lower profile device.
Comprehensive Analysis of Stability of Coal Seam Composite Roof Based on Analytic Hierarchy Process
Authors: Xiong Xianyu , Dai Jun , Wang Xin
Published: October 2019

The composite roof structure of coal roadway is complex, and its stability is related to lithology of strata, strata thickness, number of strata, strata location, and interlayer cohesive force. Based on a simplified model of the composite roof structure, simulation test, analytic hierarchy process (AHP), and Matlab, programs are employed to comprehensively analyze the structural stability of roofs. The structural stability of the composite roof is demonstrated to decrease with the lithology of strata, strata thickness, and interlayer cohesive force and increase in number of strata and distance of hard‐and‐thick strata from the roadway. The decreasing order of influence of these factors on the composite roof structure is as follows: lithology of strata, strata thickness, number of strata, strata location, and interlayer cohesive force. Lithology of strata is the main factor affecting stability. The bending strength decreases with the increase in number of strata, and the influence of strata position on stability decreases from the first layer to the fourth layer. According to the AHP, an expression for the comprehensive influence coefficient (k) for the stability of the composite roof structure is proposed, and the surrounding rocks are divided into three levels using this equation: grade I with 0.7 < k < 1 (stable), grade II with 0.4 < k < 0.7 (slightly stable), and grade III with 0 < k < 0.4 (unstable). A scientific basis to evaluate the stability and control of the composite roof of a complex structure is thus provided.
Trait Impulsivity Is Independent of Mild Cognitive Impairment in a Parkinson’s Disease Cohort
Authors: Jeyadevan Ashani , Bakeberg Megan C. , Byrnes Michelle , Kenna Jade , Ghosh Soumya , Stell Rick , Walters Sue , Evans Tess , McGregor Sarah , Horne Malcolm , Mastaglia Frank L. , Anderton Ryan S.
Published: October 2019

Introduction. Patients with Parkinson’s disease (PD) commonly experience cognitive deficits and some also develop impulse control disorders (ICDs); however, the relationship between impulsivity and cognitive dysfunction remains unclear. This study investigated whether trait impulsivity associates with mild cognitive impairment (MCI), or is altered in a PD patient cohort with MCI. Methods. A total of 302 patients with idiopathic PD were recruited sequentially from three Australian Movement Disorder clinics. Based on cognitive scores, participants were divided into two groups, one defined as having mild cognitive impairment (PD-MCI; n = 113) and the other with normal cognitive function (PD-C; n = 189). Trait impulsivity was evaluated using the Barrett Impulsiveness Scale 11 (BIS-11). Total impulsivity scores, as well as subscale scores, were compared between PD-C and PD-MCI groups. Results. The PD-MCI cohort had significantly lower scores in all cognitive domains, and mirrored expected clinical differences in medication, motor symptoms, and disease duration, when compared to the PD-C cohort. Self-reported impulsivity was not significantly different between groups, nor was there a difference within first-order subscale scores: attention p=0.137, cognitive instability p=0.787, self-control p=0.503, cognitive complexity p=0.157, motor impulsivity p=0.559, or perseverance p=0.734 between the PD-MCI and PD-C groups. Conclusions. These findings suggest that impulsive traits and behaviors are independent of changes in cognitive state and are not altered in PD patients with mild cognitive impairment.
Healing of Bone Defects in Pig’s Femur Using Mesenchymal Cells Originated from the Sinus Membrane with Different Scaffolds
Authors: Bou Assaf Rita , Zibara Kazem , Fayyad-Kazan Mohammad , Al-Nemer Fatima , Cordahi Manal , Khairallah Saad , Badran Bassam , Berbéri Antoine
Published: October 2019

Objective. Repairing bone defects, especially in older individuals with limited regenerative capacity, is still a big challenge. The use of biomimetic materials that can enhance the restoration of bone structure represents a promising clinical approach. In this study, we evaluated ectopic bone formation after the transplantation of human maxillary Schneiderian sinus membrane- (hMSSM-) derived cells embedded within various scaffolds in the femur of pigs. Methods. The scaffolds used were collagen, gelatin, and hydroxyapatite/tricalcium phosphate (HA/βTCP) where fibrin/thrombin was used as a control. Histological analysis was performed for the new bone formation. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were used to assess mRNA and protein levels of specific osteoblastic markers, respectively. Results. Histological analysis showed that the three scaffolds we used can support new bone formation with a more pronounced effect observed in the case of the gelatin scaffold. In addition, mRNA levels of the different tested osteoblastic markers Runt-Related Transcription Factor 2 (RUNX-2), osteonectin (ON), osteocalcin (OCN), osteopontin (OPN), alkaline phosphatase (ALP), and type 1 collagen (COL1) were higher, after 2 and 4 weeks, in cell-embedded scaffolds than in control cells seeded within the fibrin/thrombin scaffold. Moreover, there was a very clear and differential expression of RUNX-2, OCN, and vimentin in osteocytes, osteoblasts, hMSSM-derived cells, and bone matrix. Interestingly, the osteogenic markers were more abundant, at both time points, in cell-embedded gelatin scaffold than in other scaffolds (collagen, HA/βTCP, fibrin/thrombin). Conclusions. These results hold promise for the development of successful bone regeneration techniques using different scaffolds embedded with hMSSM-derived cells. This trial is registered with NCT02676921.
Effect of Spinal Anesthesia versus General Anesthesia on Blood Glucose Concentration in Patients Undergoing Elective Cesarean Section Surgery: A Prospective Comparative Study
Authors: El-Radaideh Khaled , Alhowary Ala’’a , Alsawalmeh Mohammad , Abokmael Ahmed , Odat Haitham , Sindiani Amer
Published: October 2019

Background. This prospective study compared the blood glucose concentration with spinal anesthesia or general anesthesia in patients undergoing elective cesarean section surgery. Methods. In total, 58 pregnant women who underwent elective cesarean section surgery were included in this prospective comparative study. Group S (n = 35) included patients who chose spinal anesthesia, and group G (n = 23) included patients who chose general anesthesia. The patients were allocated to the groups upon patients’ preference. For the group G, the blood glucose concentration (BGC) was obtained 5 minutes before induction, T1, and 5 minutes after induction T2. For the group S, the BGC was obtained immediately before the injection of the local anesthetic agent T1 and 5 minutes after the complete block T2. For both groups, BGC was measured 5 minutes before the end of surgery T3 and 30 minutes after the end of surgery T4. For BGC measurements, we used a blood glucose monitoring system with a lancet device to prick the finger. Results. There was no statistically significant difference in the mean blood glucose concentration between the groups S and G in T1 (78.3 ± 18.2 vs. 74.3 ± 14.7, p>0.05) and T2 (79.2 ± 18.3 vs. 84.9 ± 23.7, p>0.05). The mean BGC was statistically significantly higher in group G in comparison to group S in the times 5 minutes before (80.2 ± 18.1 vs. 108.4 ± 16.7, p<0.05) and 30 minutes after the end of surgery (80.9 ± 17.7 vs. 121.1 ± 17.4, p<0.05). Conclusion. There is a much lower increase in blood glucose concentration under spinal anesthesia than under general anesthesia. It is reasonable to suggest that the blood sugar concentration must be intraoperatively monitored in patients undergoing general anesthesia.
Florfenicol Resistance in Enterobacteriaceae and Whole-Genome Sequence Analysis of Florfenicol-Resistant Leclercia adecarboxylata Strain R25
Authors: Ying Yuanyuan , Wu Fei , Wu Chongyang , Jiang Yi , Yin Min , Zhou Wangxiao , Zhu Xinyi , Cheng Cong , Zhu Licheng , Li Kewei , Lu Junwan , Xu Teng , Bao Qiyu
Published: October 2019

Due to inappropriate use, florfenicol resistance is becoming increasingly serious among animal respiratory tract and gut bacteria. To detect the florfenicol resistance mechanism among Enterobacteriaceae bacteria, 292 isolates from animal feces were examined. The agar dilution method was conducted to determine the minimum inhibitory concentration (MIC) for florfenicol, and polymerase chain reaction (PCR) was performed to detect florfenicol resistance genes. To further explore the molecular mechanism of florfenicol resistance, the whole-genome Leclercia adecarboxylata R25 was sequenced. Of the strains tested, 61.6% (180/292) were resistant to florfenicol, 64.4% (188/292) were positive for floR, and 1.0% (3/292) for cfr. The whole-genome sequence analysis of L. adecarboxylata R25 revealed that the floR gene is carried by a transposon and located on a plasmid (pLA-64). Seven other resistance genes are also encoded on pLA-64, all of which were found to be related to mobile genetic elements. The sequences sharing the greatest similarities to pLA-64 are the plasmids p02085-tetA of Citrobacter freundii and p234 and p388, both from Enterobacter cloacae. The resistance gene-related mobile genetic elements also share homologous sequences from different species or genera of bacteria. These findings indicate that floR mainly contributes to the high rate of florfenicol resistance among Enterobacteriaceae. The resistance gene-related mobile genetic elements encoded by pLA-64 may be transferred among bacteria of different species or genera, resulting in resistance dissemination.
Today's Special on the Anticancer Menu: Immunomodulation by Antifolates
Authors: Buque Aitziber , Galluzzi Lorenzo , Casares Noelia
Published: September 2019

Pemetrexed is widely employed for the clinical management of mesothelioma and non–small cell lung carcinoma, largely based on its ability to curtail folate metabolism in highly proliferating cells. Recent preclinical findings suggest that the therapeutic efficacy of pemetrexed may involve an unsuspected immunologic component.

See related article by Schaer et al., p. 7175
Colon Capsule Endoscopy versus CT Colonography in Patients with Large Non-Polypoid Tumours: A Multicentre Prospective Comparative Study (4CN Study)
Authors: Utano Kenichi , Katsuki Shinichi , Matsuda Tomoki , Mitsuzaki Katsuhiko , Fujita Tomoki , Nemoto Daiki , Nagata Koichi , Lefor Alan Kawarai , Togashi Kazutomo
Published: October 2019

Background/Aims: Non-polypoid colon lesions compared with polypoid lesions has a high malignant potential. The diagnostic performance of colon capsule endoscopy (CCE) and CT colonography (CTC) for large colorectal non-polypoid tumours, that is, laterally spreading tumours is still unclear. The aim of this study is to evaluate the performance of CCE and CTC for the diagnosis of large non-polypoid tumours. Methods: Thirty patients referred for endoscopic submucosal dissection of non-polypoid tumours measuring ≥20 mm were enrolled. Patients first underwent CCE, then colonoscopy (without resection) and CTC on the same day. An experienced gastroenterologist in a third hospital evaluated the CCE and recorded the location, size and morphology of all lesions detected, blinded to the colonoscopic findings. An experienced radiologist read the CTC under the same conditions. Colonoscopic findings were defined as the reference. Results: A total of 30 lesions (T1 cancer: 3, Tis cancer: 7, adenoma: 14, sessile serrated adenoma/polyp: 6) in 27 patients were observed for evaluation. The capsule excretion rate within 8 h was 85% (23/27), and all capsules went beyond the target lesions. Non-polypoid tumours tend to be depicted as polypoid on CCE. Per patient sensitivities were 0.89 (24/27) by CCE and 0.70 (19/27) by CTC (p = 0.0253, McNemar), and per lesion sensitivities were 0.87 (26/30) and 0.67 (20/30) respectively (p = 0.0143). Most lesions missed by both modalities were located in the proximal colon. Conclusion: Eighty-seven per cent of non-polypoid tumours were detected by CCE, and the sensitivity using CCE was higher than that obtained using CTC (UMIN0000014772).
Poikilodermatous Mycosis Fungoides: Comparative Study of Clinical, Histopathological and Immunohistochemical Features
Authors: Vasconcelos Berg Roberta , Valente Neusa Yuriko Sakai , Fanelli Camilla , Wu Isabelle , Pereira Juliana , Zatz Roberto , Sanches José Antonio
Published: September 2019

Background: Poikilodermatous mycosis fungoides (pMF) is characterized by poikiloderma areas, typically involving the major flexural areas and trunk. Its presentation can be generalized or admixed with other forms of MF. Previous studies fail to correlate the clinical presentation with prognosis and laboratory findings. Some reports show pityriasis lichenoides chronica (PLC) preceding the poikiloderma. Objectives: Correlate prognostic, histopathological and molecular aspects of pMF with its clinical presentation. Methods: Retrospective analysis of 14 cases of generalized pMF (GpMF), 22 of localized pMF (LpMF) and 17 of pMF admixed with other forms of MF (mix-pMF). Results: Female predominance and lower age at diagnosis was found in all groups compared to classic MF, a high prevalence of PLC-like lesions in the GpMF group and a high rate of hypopigmented lesions in the mix-pMF group. There were 2 deaths within the GpMF group. Histology was similar to previously reported findings, as was the prevalence of CD4 T-cell infiltrate, compared to CD8. The T-cell clonality positivity was lower in the GpMF group, compared to other groups (27% GpMF, 80% LpMF and 100% mix-pMF). Discussion: This is the first article to categorize the different forms of pMF and correlate them with clinical and laboratory findings. The dermatological presentation differs among the groups. There was a high frequency of PLC-like lesions within the GpMF group and of hypopigmented lesions in mix-pMF. The histological and immunohistochemical findings were similar to those previously reported. Aggressive treatments are not recommended due to the good prognosis of all pMF forms. The low positivity of T-cell clonality in the GpMF group should be investigated.
Threshold Effects of Serum Uric Acid on Chronic Kidney Disease in US Women without Hypertension and Diabetes: A Cross-Sectional Study
Authors: Hu Guiping , Bai Yi , Chen Tian , Tang Shichuan , Hu Lihua
Published: September 2019

Background: Serum uric acid (SUA) has been associated with increased risk of chronic kidney disease (CKD) in observational studies; however, data in women without hypertension and diabetes are sparse. Purpose: To examine the association between SUA and CKD among women without hypertension and diabetes. Methods: In this cross-sectional study of 6,776 US women without hypertension and diabetes from the National Health and Nutrition Examination Survey (1999–2006), we investigated the relationship between SUA and CKD using multivariable logistic regression models. Moreover, a generalized additive model and smooth curve fitting (penalized spline method) and a 2 piecewise logistic regression models were conducted to address for nonlinearity. Results: The prevalence of CKD was 8.3%. Multiple logistic analyses showed that per 1 mg/dL increase in SUA was associated with 39% increased prevalence of CKD. Analyses using restricted cubic spline confirmed that the association between SUA and CKD was nonlinear. Further, threshold and saturation effect analysis showed that the inflection point of SUA was 4.5 mg/dL. The ORs (95% CIs) were 0.84 (0.66–1.08) on the left side of inflection point and 1.87 (1.56–2.24) on the right side of inflection point, respectively. Subgroup analysis showed that the stronger association between SUA and CKD was observed in elder women with never/former smoking and higher fasting blood glucose levels (all p values for interaction <0.05). Conclusion: Our study suggested threshold effects of SUA on the prevalence of CKD among US women without hypertension and diabetes. SUA levels >4.5 mg/dL were positively and independently associated with CKD.
High-Grade Neuroendocrine Carcinoma of the Head and Neck: Human Papillomavirus Status and PD-L1 Expression
Authors: Bahr Katharina , Zimmer Stefanie , Springer Erik , Fottner Christian , Becker Sven , Ernst Benjamin P. , Matthias Christoph , Künzel Julian
Published: September 2019

Background: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma represents an important subgroup of head and neck cancer, but HPV occurs also in the less common neuroendocrine carcinomas (NEC). The PD-1/PD-L1 pathway appears to be activated in pulmonary NEC and correlates with a higher mutation burden, but the potential of NEC to respond to checkpoint inhibitors is unknown to a large extent. Objectives: To determine the HPV status of NEC of the head and neck region and to investigate the expression of PD-1 and its ligands PD-L1 and PD-L2. Methods: Surgical tumor samples from 2006 to 2017 were analyzed. HPV status was determined by p16 immunohistochemistry (IHC) and multiplex PCR. IHC using the Cologne Score was performed for PD-1, PD-L1, and PD-L2. Results: Seven NEC tumor samples were analyzed, three of them showed HPV type 18. Expression of PD-1 and PD-L1 differed widely and showed no correlation to HPV status. IHC showed an overexpression of PD-L2 in most of the patients. Conclusions and Significance: A multicentric analysis of NEC is needed to further evaluate the role of HPV as well as immunocheckpoints with regard to inflammatory immune response in genesis and clinical course of this rare tumor entity. Biomarkers for selection of novel treatment regimens, including immunotherapeutic approaches, are warranted.
Updated Worldwide Epidemiology of Inherited Erythrocyte Disorders
Authors: Lippi Giuseppe , Mattiuzzi Camilla
Published: September 2019

Introduction: Timely diagnosis and effective treatment, based on epidemiologic data, consistently reduce the clinical, social and economic burden of inherited erythrocyte disorders. Objective: This article provides an overview on current worldwide epidemiology of the most frequent inherited erythrocyte disorders. Methods: Information was obtained from Global Health Data Exchange (GHDx) database. Results: Glucose-6-phosphate dehydrogenase (G6PD) deficiency has the largest worldwide incidence and prevalence. Sickle cell disorders (SCD) cause the highest cause-specific disability-adjusted life years (DALYs). Incidence and prevalence of SCD have recently increased, whilst DALYs and mortality remained stable. All epidemiologic measures of thalassemias have recently declined, whilst those of G6PD deficiency remained stable or increased. Africa has the highest incidence of G6PD deficiency and SCD, whilst thalassemias are more frequent in Western Pacific. The incidence of all inherited erythrocyte disorders is increasing in Africa and Eastern Mediterranean, whilst is decreasing in South-East Asia, Western Pacific and Europe. Thalassemias and SCD display a peak of prevalence and mortality between 0 and 15 years, whilst mortality for G6PD deficiencies and other hemoglobinopathies peaks between 45 and 75 years and >80 years, respectively. Men have higher burden of G6PD deficiencies, whilst sex distribution of SCD and thalassemias is similar. Conclusions: The worldwide epidemiologic burden of inherited erythrocyte disorders remains particularly high.
Influence of Living Environment during Childhood on Helicobacter pylori Infection in Japanese Young Adults
Authors: Ueno Takunori , Suzuki Hideo , Hirose Mitsuaki , Shida Takashi , Ikezawa Kazuto , Matsui Hirofumi , Mizokami Yuji , Yanaka Akinori
Published: September 2019

Introduction: Helicobacter pylori infection is usually established during childhood, for which certain responsible environmental factors have been identified. However, the details of the infection routes remain unclear. Objective: To determine the relation between H. pylori infection statuses and living environment of Japanese young adult. Methods: The subjects were 449 healthy young adult medical students of Tsukuba University (299 men and 150 women, mean age: 22.8 years). The H. pylori infection statuses were investigated using the rapid urease test or urine antibody. Questionnaires regarding sanitary conditions including usage of pit toilet or well water and experience of living with one’s grandparents during childhood were surveyed. Each item was compared between the H. pylori-positive and -negative groups. Results: Among all participants, 33 (7.3%) were H. pylori-positive. The usage rates of pit toilets were 12.1 and 3.1% for the H. pylori-positive and -negative groups respectively (p = 0.03; OR 4.35, 95% CI 1.33–14.22). The usage rates of well water were 24.2 and 13.7% for the H. pylori-positive and -negative groups respectively (p = 0.07; OR 2.12, 95% CI 0.91–4.98). The proportion of participants with a history of living with their grandparents was significantly greater in the H. pylori-positive group (46.7%) than in the -negative group (20.9%; p = 0.03; OR 3.28, 95% CI 1.13–9.54). Only a history of living with one’s grandparents during childhood showed statistical significance in the multivariate regression analysis (p = 0.04; OR 3.20, 95% CI 1.08–9.49). Conclusions: These results suggest that H. pylori infection is more strongly related to living with one’s grandparents than living in a hygienic environment.
Effect of Impairment-Oriented and Function-Oriented Exercises on Mouth Function in Subjects with Systemic Sclerosis
Authors: Vitali Chiara , Baldanzi Cinzia , Crispiatico Valeria , Polini Francesca , Ammenti Paola , Montesano Angelo , Cattaneo Davide
Published: September 2019

Purpose: The aim of this study was to develop an exercise protocol to improve maximal mouth opening (MMO), tongue protrusion (Tprot), tongue strength (Tstren), and lip strength (Lstren), and to assess its effects on subjects with scleroderma. Methods: We performed four replicated single-system studies in a consecutive sample of subjects with scleroderma. An instrumented assessment measured MMO, Tprot, Tstren, and Lstren. Each day, subjects were assessed and performed orofacial exercises conducted by speech therapists. Treatments were first aimed at improving mouth physical characteristics by impairment-oriented exercises and then to improve skills with function-oriented exercises. Results: The mean phase differences between assessment and treatment phases across subjects were from 0.88 to 9.56 mm in MMO, from 2.03 to 12.3 mm in Tprot, from –0.12 to 5.35 N in Tstren, and from –0.84 to 5.19 N in Lstren. After treatment, 3 subjects crossed the 5th percentile discriminating normal from abnormal performances for both Tstren and Tprot, while this occurred in 2 subjects for MMO and Lstren. Conclusions: The results of this study suggest that rehabilitation appears to be useful in reducing tongue and lip impairments and in improving oral functions in subjects with scleroderma.
Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo
Authors: Saxton Sophie N. , Withers Sarah B. , Nyvad Jakob , Mazur Aleksandra , Matchkov Vladimir , Heagerty Anthony M. , Aalkjær Christian
Published: September 2019

Background: Perivascular adipose tissue (PVAT) reduces vascular tone in isolated arteries in vitro, however there are no studies of PVAT effects on vascular tone in vivo. In vitro adipocyte β3-adrenoceptors play a role in PVAT function via secretion of the vasodilator adiponectin. Objective: We have investigated the effects of PVAT on vessel diameter in vivo, and the contributions of β3-adrenoceptors and adiponectin. Method: In anaesthetised rats, sections of the intact mesenteric bed were visualised and the diameter of arteries was recorded. Arteries were stimulated with electrical field stimulation (EFS), noradrenaline (NA), arginine-vasopressin (AVP), and acetylcholine (Ach). Results: We report that in vivo, stimulation of PVAT with EFS, NA, and AVP evokes a local anti-constrictive effect on the artery, whilst PVAT exerts a pro-contractile effect on arteries subjected to Ach. The anti-constrictive effect of PVAT stimulated with EFS and NA was significantly reduced using β3-adrenoceptor inhibition, and activation of β3-adrenoceptors potentiated the anti-constrictive effect of vessels stimulated with EFS, NA, and AVP. The β3-adrenoceptor agonist had no effect on mesenteric arteries with PVAT removed. A blocking peptide for adiponectin receptor 1 polyclonal antibody reduced the PVAT anti-constrictive effect in arteries stimulated with EFS and NA, indicating that adiponectin may be the anti-constrictive factor released upon β3-adrenoceptor activation. Conclusions: These results clearly demonstrate that PVAT plays a paracrine role in regulating local vascular tone in vivo, and therefore may contribute to the modulation of blood pressure. This effect is mediated via adipocyte β3-adrenoceptors, which may trigger release of the vasodilator adiponectin.
Platelet-Lymphocyte Ratio as a Predictor of Prognosis in Head and Neck Cancer: A Systematic Review and Meta-Analysis
Authors: Bardash Yonatan , Olson Caitlin , Herman Wendy , Khaymovich Julian , Costantino Peter , Tham Tristan
Published: September 2019

The aim of this systematic review and meta-analysis was to investigate the prognostic utility of the platelet-to-lymphocyte ratio (PLR) in head and neck cancer. Medline (via PubMed), EMBASE, Scopus, and the Cochrane Library databases were searched from their inception to May 2017 for relevant literature. A systematic review and meta-analysis were performed to generate the pooled hazard ratios (HR) for overall survival (OS) and disease-specific survival (DSS). The study was conducted in accordance with the Cochrane Handbook and PRISMA guidelines. Risk of bias was assessed using the QUIPS tool. The logarithm of the HR with standard error was used as the primary summary statistic. Heterogeneity was assessed using Cochran’s Q and Higgins’ I2. A total of 13 studies were included in the final analysis, combining data from 4,541 patients. The results demonstrated that an elevated PLR was significantly associated with poorer OS [HR 1.85, 95% CI 1.35–2.52, p < 0.00001] and DSS [HR 1.57, 95% CI 1.25–1.97, p < 0.0001]. Significant heterogeneity was detected for the pooled end points. Subgroup analysis demonstrated reduction of heterogeneity by controlling for sample size and cutoff value. 95% prediction intervals showed wide ranges crossing the null threshold.
Fine-Needle Aspiration Cytology of the Testes for the Classification of Azoospermia and Its Value in the Assessment of Male Infertility
Authors: Jashnani Kusum , Gundawar Rupesh , Kavishwar Vikas , Parameshwar Vivek
Published: September 2019

Background: Infertility is an ever-increasing problem in today’s world. It can be due to male or female causes. Azoospermia seen in 5–10% of infertile men is due to obstructive or non-obstructive causes. Traditionally, testicular biopsy is the gold standard for evaluation. Fine-needle aspiration (FNA), however, is minimally invasive, provides qualitative and quantitative information about spermatogenesis, and can aid in assisted reproductive techniques making it a novel technique for the evaluation of male infertility. Objective: We aimed to classify different causes of azoospermia into different patterns based upon FNA, and assess the utility of cell indices in classifying cases into different patterns. Method: We conducted a prospective and a retrospective study of 42 azoospermic males, confirmed on semen analysis, over a period of 5 years. Patients were subjected to FNA of the testes. Smears were prepared, air-dried, wet-fixed, and then stained with May-Grünwald Giemsa and Papanicolaou stains, respectively. Cells were identified using predetermined morphologic criteria, and various indices were calculated followed by statistical analysis of the observations. Results: The mean age of 40 patients who satisfied the adequacy criteria was 32.75 years (range 22–48 years). Thirty-four patients had primary infertility and 6 had secondary infertility. Of these, 12 had normal spermatogenesis, 8 had hypo-spermatogenesis, 3 had early and 7 had late maturation arrest, 6 had Sertoli cell-only syndrome (SCOS), and there were different results in each testicle in 4 cases. The Sperm Index (SI) was significantly higher in all cases of normal spermatogenesis than in any of the hypo-spermatogenesis cases (p = 0.009). The Sertoli Index (SEI) in cases of hypo-spermatogenesis and maturation arrest was significantly higher than in cases of normal spermatogenesis (p < 0.001). The Sperm-Sertoli Index (SSI) also showed significant differences between cases of hypo-spermatogenesis and normal spermatogenesis (p < 0.001). These indices were useful in categorising patients with azoospermia. Conclusion: FNA helps to easily and accurately identify all types of testicular cells without biopsy. SI, SEI, and SSI are powerful cell indices for assessing the extent of spermatogenesis and classifying various causes of azoospermia. Bilateral sampling and multiple aspirations give a better mapping of spermatogenesis within the testes. Testicular FNA can thus play a very important role in the evaluation of male infertility.
HER2 Regulates Cancer Stem Cell Activities via the Wnt Signaling Pathway in Gastric Cancer Cells
Authors: Jung Da Hyun , Bae Yoo Jin , Kim Jie-Hyun , Shin You Keun , Jeung Hei-Cheul
Published: September 2019

Introduction: Human epidermal growth factor 2 (HER2) gene overexpression in breast carcinoma cell lines has been shown to drive mammary carcinogenesis and tumor growth and invasion through its effects on mammary stem cells. Objective: Therefore, we investigated the mechanism by which HER2 regulates cancer stem cell (CSC) activity in gastric cancer cells. Methods: HER2 was transfected into MKN28 gastric cancer cells, and its role in regulating CSC activity was determined by characterizing the HER2-overexpressing cells. Results: The sphere formation assay revealed that the sphere sizes and frequency of sphere formation were significantly greater for the HER2-overexpressing cells than for the MKN28 control cells. The CSC markers Oct-4 and BMI1 were more highly expressed in the HER2-overexpressing cells, as were the EMT markers. This was accompanied by a significant enhancement in cellular invasion of the Matrigel and migration. The E-cadherin level was significantly downregulated, and the mesenchymal marker Snail upregulated, in the HER2-transfected cells. HER2 overexpression activated the well-characterized CSC-associated Wnt/β-catenin signaling pathway, as shown by the luciferase assay. After treatment of these cells with the Wnt signal inhibitor PRI-724, the BMI1 and Oct-4 levels were decreased for 24 h and Snail was also downregulated. Immunofluorescence staining revealed the significant restoration of E-cadherin levels in the HER2-transfected cells after PRI-724 treatment. Conclusions: These results established a role for HER2 in regulating gastric CSC activity, with Wnt/β-catenin signaling being mediated via a HER2-dependent pathway. In summary, HER2-overexpressing gastric cancer cells exhibited increased stemness and invasiveness and were regulated by Wnt/β-catenin signaling.
Validation of Spiked Postmortem Blood Samples from Cornea Donors on the Abbott ARCHITECT and m2000 Systems for Viral Infections
Authors: Schmack Ingo , Ballikaya Seda , Erber Brigitte , Voehringer Irina , Burkhardt Ulrich , Auffarth Gerd U. , Schnitzler Paul
Published: September 2019

Background: Transplantation of human corneal tissue is associated with the potential risk of transmittance of viral infections. In accordance with European directives and federal laws, in Germany each tissue donor has to be tested for infectious diseases such as hepatitis B and C virus (HBV and HCV) and human immunodeficiency virus (HIV) infection. However, most of the currently available CE-marked serologic and nucleic acid screening systems are only validated for antemortem blood. Methods: Twenty related and paired ante- and postmortem blood samples from cornea donors were obtained and subsequently analyzed for hepatitis B surface antigen (HBsAg), hepatitis B antibody (anti-HBc), anti-HCV, HCV RNA, anti-HIV-1/2, and HIV p24 Ag using Abbott test systems. The sera were also spiked with reference materials in concentrations giving low and high positivity for HBV, HCV, and HIV markers. Results: The spiked ante- and postmortem sera from related donors showed similar results for HBsAg, anti-HBc, anti-HCV, HCV RNA, anti-HIV, and HIV p24 Ag, indicating a high stability of viral markers in cadaveric specimens. Three cornea donors had a medical history of HBV infection and revealed anti-HBc at similar levels in the ante- and postmortem sera. In addition, there was a single postmortem sample demonstrating a weak signal of anti-HIV-1 and HIV-1 p24 Ag. False-positive or false-negative results were not detected. The results obtained with the Abbott ARCHITECT analyzer and Abbott RealTime HCV PCR showed no significant differences. Conclusion: The analyzed screening assays are suitable for the detection of infectious markers of HBV, HCV, and HIV at similar levels in spiked ante- and postmortem sera from cornea donors.
Healthcare System-Funded Preventive Genomic Screening: Challenges for Australia and Other Single-Payer Systems
Authors: Lacaze Paul , Tiller Jane , Winship Ingrid
Published: September 2019

The prospect of healthcare systems offering population-based preventive genomic testing to all adults is becoming feasible. Some single-payer or state-funded healthcare systems are already considering offering universal testing as part of routine care. In countries with public healthcare systems, there is a unique opportunity to provide such testing in the form of a national screening program, following existing national population health-screening frameworks. This paradigm, if achievable, could help deliver a degree of testing quality and equity-of-access that may not be possible in private-payer or direct-to-consumer models, to maximize prevention and health benefits. Here, we outline some of the major challenges ahead in considering this prospect and discuss the research that is helping shape the future direction in Australia and elsewhere.