bluuebunny/crossref_metadata_2025 huggingface dataset:
Pilot evaluation of a HER2 testing in non-small-cell lung cancer
Authors: Hotta Katsuyuki , Yanai Hiroyuki , Ohashi Kadoaki , Ninomiya Kiichiro , Nakashima Hiromi , Kayatani Hiroe , Takata Minoru , Kiura Katsuyuki
Published: December 2019

Aims

HER2-positivity pattern in the specimens of immunohistochemistry (IHC) and ﬂuorescence in situ hybridisation (FISH) has been hardly reported in non-small-cell lung cancer (NSCLC).

Methods

We evaluated the characteristics of HER2-positivity pattern in formalin-ﬁxed parafﬁn-embedded samples using IHC and FISH in 15 patients enrolled in a larger prospective cohort study to survey a HER2-positive NSCLC.

Results

As for the immunostaining pattern, most specimens (79%) demonstrated incomplete or mixed-typed membranous immunoreactivity with heterogeneity, resembling that observed in gastric cancer rather than breast cancer. Concordance between IHC-positivity and FISH-positivity was 87.5% according to the criteria for breast cancer scoring system. On application of the gastric cancer scoring system to the examined tumours, the IHC score increased in the seven (43.8%) specimens, and the concordance between IHC positivity and FISH positivity rose to 93.8%.

Conclusions

In our pilot series, the pattern of IHC reactivity closely resembled that observed in gastric cancer rather than breast cancer.

Trial registration number

000017003.
Autoantibody clustering of lupus-associated pulmonary hypertension
Authors: Mizus Marisa , Li Jessica , Goldman Daniel , Petri Michelle A
Published: December 2019

Objective

To define the SLE phenotype associated with pulmonary hypertension using multiple autoantibodies.

Methods

207 (8%) patients with SLE with pulmonary hypertension, defined as a right ventricular systolic pressure greater than 40 mm Hg on transthoracic echocardiogram or as pulmonary artery dilatation on CT of the chest, were identified from the Hopkins Lupus Cohort (94.2% female; 56.5% African–American, 39% Caucasian; mean age 45.6 years). 53 patients were excluded from the clustering analysis due to incomplete autoantibody profiles. Agglomerative hierarchical clustering algorithm with Ward’s method was used to cluster the patients with pulmonary hypertension, based on their autoantibodies. Autoantibodies used in the clustering analysis included lupus anticoagulant, anticardiolipin, anti-beta 2 glycoprotein I, antidouble-stranded DNA, anti-Sm (anti-Smith), antiribonucleoprotein, false positive-rapid plasma reagin, anti-Ro, anti-La and hypocomplementaemia (C3 ever low or C4 ever low). The Dunn index was used to internally validate the clusters. Bootstrap resampling derived the mean Jaccard coefficient for each cluster. All analyses were performed in R V.3.6.1 using the packages cluster, fpc and gplots.

Results

A significantly higher prevalence of pulmonary hypertension in African–American patients with SLE, compared with Caucasian patients with SLE (11.5% vs 5.9%, p<0.0001), was found. Based on equivalent Dunn indices, the 154 patients with SLE-associated pulmonary hypertension with complete autoantibody data were divided into five clusters, three of which had mean Jaccard coefficients greater than 0.6. Hypocomplementaemia, renal disorder and age at diagnosis significantly differed across clusters. One cluster was defined by antiphospholipid antibodies. One cluster was defined by anti-Ro and anti-La. One cluster had low frequencies of all antibodies.

Conclusion

SLE-associated pulmonary hypertension disproportionately affects African–American patients. Pulmonary hypertension in SLE is defined by five autoantibody clusters. Antiphospholipid antibodies, anti-Ro and anti-La positivity, serological activity, and age at pulmonary hypertension diagnosis significantly differed across clusters, possibly indicating different pathophysiological mechanisms.
Lackadaisical quantum walk for spatial search
Authors: Giri Pulak Ranjan , Korepin Vladimir
Published: December 2019

Lackadaisical quantum walk (LQW) has been an efficient technique in searching for a target state in a database which is distributed in a two-dimensional lattice. We numerically study the quantum search algorithm based on the lackadaisical quantum walk in one and two dimensions. It is observed that specific values of the self-loop weight at each vertex of the graph is responsible for such a speedup of the algorithm. Searching for a target state in one-dimensional lattice with periodic boundary conditions is possible using lackadaisical quantum walk, which can find a target state with [Formula: see text] success probability after [Formula: see text] time steps. In two dimensions, our numerical simulation up to [Formula: see text] for specific sets of target states suggests that the lackadaisical quantum walk can search one of the [Formula: see text] target states in [Formula: see text] time steps.
QCD, from its inception to its stubbornly unsolved problems
Authors: De Rújula A.
Published: December 2019

Whenever one has witnessed some event and then sees it reported in the media, one’s reaction is the same: it was not quite like that. It is in this spirit of a frequent first-hand witness that I write this article. I discuss a few selected points which — to my judgement — illustrate well the QCD evolution (in time) from the theoretical, phenomenological and experimental points of view.
First-principles study of hydrogen incorporation into the Ti3SiC2/Zr heterojunction
Authors: Li Yingying , Yang Xuxin , Wang Zihao , Hu Yonghong , Mao Caixia , Wang Juntao , Li Huailin , Wu Yunyi
Published: December 2019

The geometric structure, energy barrier and electronic properties of H-incorporated [Formula: see text] heterojunctions were investigated by first-principles calculations. Hydrogen atom settles in [Formula: see text] as interstitial impurity due to its small radius. Through calculating and analyzing the total energies of H-incorporated [Formula: see text] heterojunction, a much higher potential barrier (1.75 eV) was found when H atom diffuses from the interface into the [Formula: see text] material than that (0.25 eV) into the Zr metal. The encountered potential barriers of H atom diffusing from vacuum into the [Formula: see text] and Zr metal are also calculated, and they are both positive. These findings indicate that [Formula: see text] is a suitable coating material to prevent the hydrogen embrittlement and corrosion in Zr metal. The electronic properties and valence bond properties of H-incorporated [Formula: see text] were analyzed based on the band structure, electronic density of states and Mulliken distribution. The calculated results show that all the H-incorporated [Formula: see text] heterojunctions exhibit metallic, covalent and ionic properties. These investigations may provide new insight into the underlying mechanisms of hydrogen diffusion in the [Formula: see text] heterojunction.
A Guideline-Based Approach for Assisting with the Reproducibility of Experiments in Recommender Systems Evaluation
Authors: Polatidis Nikolaos , Pimenidis Elias , Fish Andrew , Kapetanakis Stelios
Published: December 2019

Recommender systems’ evaluation is usually based on predictive accuracy and information retrieval metrics, with better scores meaning recommendations are of higher quality. However, new algorithms are constantly developed and the comparison of results of algorithms within an evaluation framework is difficult since different settings are used in the design and implementation of experiments. In this paper, we propose a guidelines-based approach that can be followed to reproduce experiments and results within an evaluation framework. We have evaluated our approach using a real dataset, and well-known recommendation algorithms and metrics; to show that it can be difficult to reproduce results if certain settings are missing, thus resulting in more evaluation cycles required to identify the optimal settings.
Practical one-step synthesis of multipartite entangled states on superconducting circuits
Authors: Tao Rui , Mo Xiao-Tao , Xue Zheng-Yuan , Zhou Jian
Published: December 2019

Quantum entanglement is an important resource for quantum information processing tasks. However, realistic multipartite entangled state production is very difficult. In this paper, we propose an efficient single-step scheme for generating many body Greenberger–Horne–Zeilinger (GHZ) states on superconducting circuits by using a superconducting transmission-line resonator (TLR) interact with [Formula: see text] superconducting transmon qubits. The distinct merit of our proposal is that it does not require the qubit-resonator coupling strengths to be the same, which is usually impractical experimentally, and thus is one of the main reasons for entanglement generation infidelity in previous single-step schemes. The removing of the uniform interaction requirement is achieved by modulating the qubits splitting frequencies with ac microwave fields, which results in tunable individual qubit-resonator coupling strength, and thus effective uniform qubit–qubit interaction Hamiltonian can be obtained. Since microwave control is conventional nowadays, our proposal can be directly tested experimentally, which makes previous multipartite entangled states generation schemes more efficient.
The Power of Human Cancer Genetics as Revealed by Low-Grade Gliomas
Authors: Jones David T.W. , Bandopadhayay Pratiti , Jabado Nada
Published: December 2019

The human brain contains a vast number of cells and shows extraordinary cellular diversity to facilitate the many cognitive and automatic commands governing our bodily functions. This complexity arises partly from large-scale structural variations in the genome, evolutionary processes to increase brain size, function, and cognition. Not surprisingly given recent technical advances, low-grade gliomas (LGGs), which arise from the glia (the most abundant cell type in the brain), have undergone a recent revolution in their classification and therapy, especially in the pediatric setting. Next-generation sequencing has uncovered previously unappreciated diverse LGG entities, unraveling genetic subgroups and multiple molecular alterations and altered pathways, including many amenable to therapeutic targeting. In this article we review these novel entities, in which oncogenic processes show striking age-related neuroanatomical specificity (highlighting their close interplay with development); the opportunities they provide for targeted therapies, some of which are already practiced at the bedside; and the challenges of implementing molecular pathology in the clinic.
Physiological Characteristics and Nonparametric Test for Master-Slave Driving Task’s Mental Workload Evaluation in Mountain Area Highway at Night
Authors: Wang Haiwei , Liu Jianrong , You Feng
Published: December 2019

With the rapid development of advanced mobile intelligent terminals, driving tasks are diverse, and new traffic safety problems occur. We propose a new research on physiological characteristics and nonparametric tests for the master-slave driving task, especially for evaluation of drivers’ mental workload in mountain area highway in nighttime scenario. First, we establish the experimental platform based driving simulator and design the master-slave driving task. Second, based on the physiological data and subjective evaluation for mental workload, we use statistical methods to composite the physical changes evolution analysis in a driving simulator. Finally, we finished nonparametric test of the drivers’ psychological load and road test. The results show that in compassion with the daytime scenario, drivers should pay much effort to driving skills and risk identification in the nighttime scenario. Thus, in the same driving condition, drivers should bear the higher level of mental workload, and it has been subjected to even greater pressures and intensity of emotions.
Knowledge, Perceived Risk and Utilization of Prostate Cancer Screening Services among Men in Dar Es Salaam, Tanzania
Authors: Bugoye Fidelis Charles , Leyna Germana Henry , Moen Kåre , Mmbaga Elia John
Published: December 2019

Background. Late diagnosis of prostate cancer is common in low and middle income countries and contributes to high morbidity and mortality of the disease. Utilization of prostate cancer screening services plays a major role in prevention of adverse outcomes. However, there is limited information on the knowledge about, the perceived risk of, and the utilization of prostate cancer screening in Tanzania. Objective. To determine knowledge and perceived risk of prostate cancer, and the utilization of prostate cancer screening services, and associated factors, among men in Dar es Salaam, Tanzania. Design. A population-based cross-sectional study involving men aged 40 years and above living in Dar es Salaam was conducted between May and August, 2018. Methodology. Participants were recruited through multistage random sampling and took part in structured face-to-face interviews. Categorical variables were summarized using proportions while continuous variables were summarized as medians and inter-quarterly range (IQR). Chi square test was used to compare differences between proportions, and logistic regression modelling was used to determine factors associated with utilization of prostate cancer screening. Both crude and adjusted odds ratios (OR), with corresponding 95% confidence intervals, are reported. All analyses were two-tailed and the significance level set at 5%. Results. A total of 388 men with a median age of 53 years (IQR 44–55) participated. Half (52.1%) had poor knowledge about prostate cancer and prostate cancer screening. A third (32.3%, n=125) perceived the risk of prostate cancer to be low. Only 30 respondents (7.7%) had ever been screened for prostate cancer. Utilization of prostate cancer screening services was independently associated with age above 60 years [AOR = 21.46, 95% CI: 6.23, 73.93], monthly income above 305 US Dollars [AOR = 15.68, 95% CI: 4.60, 53.48], the perceived risk of prostate cancer [AOR = 16.34, 95% CI: 7.82, 14.92] and knowledge about prostate cancer [AOR = 67.71, 95% CI: 8.20, 559.57]. Conclusions. Knowledge about prostate cancer and prostate cancer screening services was low among men in Dar es Salaam with a third perceiving themselves to be at no risk for the disease. Utilization of screening services was low and associated with low income, younger age, low perceived risk of prostate cancer and low knowledge about the disease. Intervention measures aiming to increase knowledge about prostate cancer and screening services, and affordable provision of services, are urgently called for.
Polymers for Regenerative Medicine Structures Made via Multiphoton 3D Lithography
Authors: Merkininkaitė Greta , Gailevičius Darius , Šakirzanovas Simas , Jonušauskas Linas
Published: December 2019

Multiphoton 3D lithography is becoming a tool of choice in a wide variety of fields. Regenerative medicine is one of them. Its true 3D structuring capabilities beyond diffraction can be exploited to produce structures with diverse functionality. Furthermore, these objects can be produced from unique materials allowing expanded performance. Here, we review current trends in this research area. We pay particular attention to the interplay between the technology and materials used. Thus, we extensively discuss undergoing light-matter interactions and peculiarities of setups needed to induce it. Then, we continue with the most popular resins, photoinitiators, and general material functionalization, with emphasis on their potential usage in regenerative medicine. Furthermore, we provide extensive discussion of current advances in the field as well as prospects showing how the correct choice of the polymer can play a vital role in the structure’s functionality. Overall, this review highlights the interplay between the structure’s architecture and material choice when trying to achieve the maximum result in the field of regenerative medicine.
Dynamic Transmission of Correlation between Investor Attention and Stock Price: Evidence from China’s Energy Industry Typical Stocks
Authors: Qi Yajie , Li Huajiao , Guo Sui , Feng Sida
Published: December 2019

The relationship between investor attention and stock prices has been a topic of interest in economics. Previous studies have shown that the correlation relationship between the two changes with time. However, there are few studies to explore the time‐varying evolution of the relationship, as well as the transmission characteristics under important cycles. Thus, this paper is dedicated to discover the dynamic transmission characteristics of the correlation between investor attention and stock price. We selected the typical stocks of China’s energy industry, PetroChina and Sinopec, as the research objects, as they occupy a large market share and are representative. And the transaction data and attention data are used to build investor attention indicator. In order to reproduce the dynamic transmission process of correlation at different cycles, sliding time window and complex network are applied. The results show that PetroChina and Sinopec stocks have a weakly negative correlation between investor attention and stock price from 2017 to 2018. However, from the perspective of different cycles, the correlation has time‐varying characteristics. As the cycle grows, the types of transmission patterns of the five consecutive days of correlation between the two become less, but the transmission intensity between the modes increases and the transition becomes more regular and inclined. In addition, by mining the important transmission modes and main transmission paths under important periods, we find that the series modes of uncorrelated or weakly positive correlation for five consecutive days dominate the transition of modes in the networks. Also, the closed loop formed by these two important modes and related modes is the main transmission path. These findings can reveal the rules of the typical stock market in China’s energy industry and help investors with different investment cycle preferences make sound decisions.
Biases in the Simulation and Analysis of Fractal Processes
Authors: Roume Clément , Ezzina Samar , Blain Hubert , Delignières Didier
Published: December 2019

Fractal processes have recently received a growing interest, especially in the domain of rehabilitation. More precisely, the evolution of fractality with aging and disease, suggesting a loss of complexity, has inspired a number of studies that tried, for example, to entrain patients with fractal rhythms. This kind of study requires relevant methods for generating fractal signals and for assessing the fractality of the series produced by participants. In the present work, we engaged a cross validation of three methods of generation and three methods of analysis. We generated exact fractal series with the Davies–Harte (DH) algorithm, the spectral synthesis method (SSM), and the ARFIMA simulation method. The series were analyzed by detrended fluctuation analysis (DFA), power spectral density (PSD) method, and ARFIMA modeling. Results show that some methods of generation present systematic biases: DH presented a strong bias toward white noise in fBm series close to the 1/f boundary and SSM produced series with a larger variability around the expected exponent, as compared with other methods. In contrast, ARFIMA simulations provided quite accurate series, without major bias. Concerning the methods of analysis, DFA tended to systematically underestimate fBm series. In contrast, PSD yielded overestimates for fBm series. With DFA, the variability of estimates tended to increase for fGn series as they approached the 1/f boundary and reached unacceptable levels for fBm series. The highest levels of variability were produced by PSD. Finally, ARFIMA methods generated the best series and provided the most accurate and less variable estimates.
Weisheng-Tang Ameliorates Acute Ischemic Brain Damage in Mice by Maintaining Blood-Brain Barrier Integrity
Authors: Kim Min Jae , Park Ki Hyun , Lee Ji Yun , Ha Ki-Tae , Choi Byung Tae , Baek Jin Ung , Yun Young Ju , Lee Seo-Yeon , Shin Hwa Kyoung
Published: December 2019

Stroke is one of the major causes of death and long-term disability worldwide; the associated breakdown of the blood-brain barrier (BBB) aggravates ischemic brain damage. Accordingly, many medicinal herbs and formulas have been used to treat stroke-related symptoms. In this study, we selected two Korean herbal medicine formulas, Weisheng-tang and Tongxuewan, through Dongeuibogam text-mining analysis, and evaluated their protective effect on BBB disruption and brain damage in stroke. Ischemic brain damage was induced in mice by photothrombotic cortical ischemia. The infarct volume, brain edema, neurological deficits, and motor function 24 h after ischemic injury were analyzed. We investigated BBB breakdown by measuring Evans blue extravasation in addition to endothelial cells, tight junction proteins, protease-activated receptor-1 (PAR-1), and matrix metalloproteinase-9 (MMP-9) using immunofluorescence staining and confocal microscopy. Pretreatment with Weisheng-tang significantly reduced infarct volume and edema and improved neurological and motor functions; however, Tongxuewan did not. In addition, Weisheng-tang decreased brain infarction and edema and recovered neurological and motor deficit in a dose-dependent manner (30, 100, and 300 mg/kg). Weisheng-tang pretreatment resulted in significantly less BBB damage and higher brain microvasculature after focal cerebral ischemia. Tight junction proteins, such as zonula occludens-1 (ZO-1) and claudin-5, were preserved in Weisheng-tang-pretreated mice. Moreover, the ischemic brain in these mice showed suppressed PAR-1 and MMP-9 expression. In conclusion, our findings show that Weisheng-tang, which was selected through literature analysis but has not previously been used as a stroke remedy, exerts protective effects against ischemic brain damage and suggest its possible application for potential stroke patients, especially in the elderly.
Prediction Efficiency of Postoperative Acute Kidney Injury in Acute Stanford Type A Aortic Dissection Patients with Renal Resistive Index and Semiquantitative Color Doppler
Authors: Qin Huai , Li Yaqiong , Zhang Nan , Wang Tiezhu , Fan Zhanming
Published: December 2019

Objectives. This study is aimed to evaluate the efficiency in early prediction of postoperative persistent acute kidney injury (PAKI) after surgery in acute Stanford type A aortic dissection (AAAD) patients by using Doppler renal resistive index (RRI) and semiquantitative color (SQC) Doppler grade, respectively. Methods. 84 AAAD patients received Sun’s surgical management, and 67 patients were enrolled. RRI and SQC Doppler grade were evaluated by ultrasonography, respectively, at 6 hours after surgery. Serum creatinine (sCr) was recorded before operation and at 24 hours, 48 hours, and 72 hours after operation. AKI grade was evaluated according to the classifications of the Acute Kidney Injury Network (AKIN). PAKI is defined as persistent oliguria and/or sCr elevation after 3 days. RRI and SQC Doppler grade were compared, respectively, between the PAKI and non-PAKI groups. Potential predictors were first tested by univariate logistic regression analysis, and a multivariate model was identified to determine the independent predictive ability of RRI and SQC Doppler grade for the PAKI. Receiver operating characteristic (ROC) analysis was performed to compare the diagnostic accuracy between RRI and SQC Doppler grade in early prediction of PAKI by using AKIN classifications as the reference standard. Results. Of a total of 67 patients enrolled during the study period, 21 (31.3%) patients suffered from PAKI and 8 (11.9%) patients required dialysis. There are significant differences in RRI (0.80 ± 0.09 vs. 0.70 ± 0.05, P=0.002) and SQC Doppler grade (x2=12.193, P=0.007) between the 2 groups with and without PAKI. Univariate analysis showed that RRI, SQC Doppler grade, length of stay in ICU, time of CPB, and length of stay in hospital were significant predictors of PAKI. RRI and the SQC Doppler grade remained independent predictors of PAKI. Area under the curve (AUC) of RRI was 0.855 (95% CI, 0.74–0.96) with cutoff value 0.725 (sensitivity 90.9% and specificity 71.1%), AUC of SQC Doppler grade was 0.642 (95% CI, 0.49–0.79) with cutoff value grade 2 (sensitivity 50% and specificity 73.3%). Conclusion. Both postoperative RRI and SQC Doppler grade are independent predictors for PAKI after surgery in AAAD patients. Both postoperative RRI and SQC Doppler grade can be obtained rapidly by bedside ultrasound, which is a good tool for early prediction for postoperative PAKI.
Multiaircraft Optimal 4D Trajectory Planning Using Logical Constraints
Authors: Seenivasan Dinesh B. , Olivares Alberto , Staffetti Ernesto
Published: December 2019

This paper studies the trajectory planning problem for multiple aircraft with logical constraints in disjunctive form which arise in modeling passage through waypoints, distance-based and time-based separation constraints, decision-making processes, conflict resolution policies, no-fly zones, or obstacle or storm avoidance. Enforcing separation between aircraft, passage through waypoints, and obstacle avoidance is especially demanding in terms of modeling efforts. Indeed, in general, separation constraints require the introduction of auxiliary integer variables in the model; for passage constraints, a multiphase optimal control approach is used, and for obstacle avoidance constraints, geometric approximations of the obstacles are introduced. Multiple phases increase model complexity, and the presence of integer variables in the model has the drawback of combinatorial complexity of the corresponding mixed-integer optimal control problem. In this paper, an embedding approach is employed to transform logical constraints in disjunctive form into inequality and equality constraints which involve only continuous auxiliary variables. In this way, the optimal control problem with logical constraints is converted into a smooth optimal control problem which is solved using traditional techniques, thereby reducing the computational complexity of finding the solution. The effectiveness of the approach is demonstrated through several numerical experiments by computing the optimal trajectories of multiple aircraft in converging and intersecting arrival routes with time-based separation constraints, distance-based separation constraints, and operational constraints.
Exposure of Fluoride with Streptozotocin-Induced Diabetes Aggravates Testicular Damage and Spermatozoa Parameters in Mice
Authors: Sánchez-Gutiérrez Manuel , Martínez-Loredo Evelia , Madrigal-Santillán Eduardo Osiris , Betanzos-Cabrera Gabriel , Hernández-Zavala Araceli , Mojica-Villegas María Angélica , Izquierdo-Vega Jeannett Alejandra
Published: December 2019

Diabetes mellitus is the most common chronic disease worldwide that causes numerous complications, including male infertility. The prevalence of DM is 451 million people and estimated that would increase to 693 million in 2045. Fluorosis caused by drinking water contaminated with inorganic fluoride is a public health problem in many areas around the world. Previous studies have shown that fluoride exposure damages the male reproductive function. This study aimed to evaluate the fluoride sub-chronic exposure on the spermatozoa function in streptozotocin (STZ)-induced diabetic mice. After confirming diabetes by measuring blood glucose levels, the male mice received 45.2 ppm of fluoride added or deionized water. We evaluated several parameters in diabetic mice exposed to fluoride: standard quality analysis, the mitochondrial transmembrane potential (ψm), the caspase activity in spermatozoa, urinary fluoride excretion, and histological evaluation in the testes. After 60 days of fluoride-exposure, diabetic mice, significantly decreased sperm quality (motility, viability, and concentration). Spermatozoa from fluoride-exposure in diabetic mice presented a significant decrease in ψm and a significant increase in activity caspase 3/7. Urinary fluoride excretion was decreased in diabetic mice exposed to fluoride. Subchronic fluoride exposure of mice with STZ-induced diabetes aggravated testicular damage and the spermatozoa function.
Tear Film Instability and Meibomian Gland Dysfunction Correlate with the Pterygium Size and Thickness Pre- and Postexcision in Patients with Pterygium
Authors: Li Ning , Wang Tao , Wang Ruixue , Duan Xuanchu
Published: December 2019

Purpose. This study aimed to evaluate the effects of excision on dry eye and meibomian gland dysfunction (MGD) in individuals with pterygium, before and after surgery. It also aimed to investigate how these effects correlate with the size and thickness of the pterygium. Subjects and Methods. 63 eyes from 63 patients with primary nasal pterygium and 45 eyes from 45 healthy volunteers without ocular pathologies were enrolled in this study. 63 eyes from 63 patients underwent pterygium surgery. ImageJ software was used to calculate the pterygium size based on images of the anterior segments. Anterior segment spectral domain optical coherence tomography (SD-OCT) was performed preoperatively to measure the thickness of the pterygium 1 mm anterior to the nasal scleral spur. The ocular surface disease index (OSDI), Schirmer I Test (SIT), and MGD grade were used to evaluate the eyes, and the eyes were imaged using the noninvasive keratograph average tear film breakup time (NIBUTav), tear meniscus height (TMH), meiboscore, and lipid layer grading tools of the Oculus® Keratograph 5M, preoperatively and at 1, 3, and 6 months postoperatively. Results. The OSDI, NIBUTav, lid margin abnormality, meiboscore, and lipid layer grading values differed significantly in the pterygium patients in comparison with the controls (p<0.01 for all scores). However, the SIT and TMH values were unchanged between the two groups (all p>0.05). Multivariate regression analysis demonstrated that the NIBUTav, meiboscore, and lipid layer grading score was significantly correlated with the pterygium parameters, such as size and thickness. The postoperative OSDI, NIBUTav, lid margin abnormality, and lipid layer grading values improved significantly (p<0.05 for all scores). The SIT, TMH, and meiboscore results did not differ significantly between the pre- and postoperative values (p>0.05). Among the conventional and automated indexes, at 1 month postoperatively, SIT and TMH were significantly correlated with the pterygium parameters, but no correlation was observed at 3 and 6 months postoperatively. The OSDI, NIBUTav, meiboscore, and lipid layer grading values at 1, 3, and 6 months postoperatively were significantly correlated with the pterygium parameters. Conclusion. Abnormal tear film and meibomian gland (MG) function improved following pterygium excision in the patients with primary pterygium, which was associated with uncomfortable ocular symptoms. Pterygium parameters, such as size and thickness, correlated with the dry eye and MGD indexes in patients pre- and postoperatively, potentially offering a novel strategy for clinical implementation of pterygium excision surgery.
Patients’ Experiences of Living with Atrial Fibrillation: A Mixed Methods Study
Authors: Stridsman Marie , Strömberg Anna , Hendriks Jeroen , Walfridsson Ulla
Published: December 2019

Introduction. Awareness of epidemiological and clinical consequences of atrial fibrillation (AF) has increased, as have disease-related costs. Less attention has been paid to patient-related issues, such as understanding how symptoms, different therapies, and lifestyle adjustments affect daily life. We aimed to describe patients’ experiences of living with AF. Methods. The study design used a parallel convergent mixed methods approach. Patients with AF were included in the SMURF study and referred for catheter ablation. Patients completed questionnaires on symptoms, health-related quality of life, depression, anxiety, and perceived control and were interviewed. The datasets were analysed separately using inductive content analysis and descriptive statistics. Data were merged to obtain a final interpretation. Results. Nineteen patients were interviewed and 18 completed questionnaires. Twelve of the patients were male, mean age 60 years (45–75 years). Inductive qualitative analysis revealed three categories: (i) symptoms and concerns limiting life, (ii) dimensions of worries, and (iii) strategies for management. The most common symptoms were tiredness, weakness/fatigue, and breathlessness during activities, and the most pronounced negative impacts on health-related quality of life (HRQOL) were physically related, shown in the ASTA questionnaire. The most negative SF-36 scores were found in role limitations due to physical health problems and vitality. HADS revealed five patients with some degree of anxiety and four with some degree of depression. Patients had lower scores on perceived control than perceived helplessness in CAS. Patients’ perceived control was higher than their families’, and families experienced more helplessness. Conclusions. The mixed methods design deepens our understanding of challenges faced by patients. Patients experienced a limited ability to perform activities of daily living due to AF which created different kinds of worries that encouraged the use of various strategies to manage their lives. Healthcare providers need to be aware that relationships between patients and their relatives can change, and therefore they need to be supported and integrated into the care system.
Evaluating Traditional Chinese Medicine and Herbal Products for the Treatment of Gestational Diabetes Mellitus
Authors: Xu Yang Xin Zi , Xi Shengyan , Qian Xiaoyan
Published: December 2019

Gestational diabetes mellitus is the most common metabolic disorder during pregnancy with health consequences for both lives during and after pregnancy. Studies found that many pregnant women turn to complementary and alternative medicine for health maintenance or symptom relief, such as herbal medicine and acupuncture from traditional Chinese medicine. With the growing popularity of traditional Chinese medicine, we conducted a systemic search in PubMed, Web of Science, and Embase databases on research studies that investigated traditional Chinese medicine during pregnancy. The resultant hits were further searched in relation to all diabetes mellitus. In total, we found three major herbal medicine/herbal products that were associated with glycemic control in gestational diabetes, including Zuo Gui Wan, red raspberry leaves, and Orthosiphon stamineus. We further reviewed them and their relatives in relation to type 2 diabetes mellitus and found more evidence of metabolic benefits. None of the herbal medicine and products examined reported toxicity in the experimental models. Overall, treatments of gestational diabetes by western or alternative interventions are grossly understudied. It is critical to have a standardized protocol when evaluating efficacy of herbal medicine and produce quality results for women and their health-care providers to make informed treatment decisions.
Differential Diagnosis of Autoimmune Encephalitis from Infectious Lymphocytic Encephalitis by Analysing the Lymphocyte Subsets of Cerebrospinal Fluid
Authors: Zhang Qiao-quan , Zhang Yan-fang , Yu Nian , Lin Xing-jian , Di Qing
Published: December 2019

This study is aimed at investigating the lymphocyte subsets of cerebrospinal fluid (CSF) to provide possible differential diagnostic values and better understand the pathophysiological mechanism underlying autoimmune encephalitis (AE) and infectious lymphocytic encephalitis. A series of CD markers, including CD3/4/8/20 representing different types and developmental stages of lymphocytes, were used to count the corresponding subpopulations of CSF from clinical and laboratory confirmed cases of anti-N-methyl-D-aspartate receptor AE (NMDAR-AE), herpes simplex virus encephalitis (HSVE), and tuberculous meningitis (TBM). The percentages of lymphocytes observed and the CD4 : CD8 ratios were compared between the three groups. There were no significant differences of the percentage of total lymphocytes, CD3 cells, and CD4 cells of CSF among each group. However, there were strongly statistical differences of the CD4 : CD8 ratio in CSF of each group with 0.6 : 1 in NMDAR-AE, 0.9 : 1 in HSVE, and 3.2 : 1 in TBM. The percentage of CD20 B lymphocytes in NMDAR-AE was statistically higher than that of other groups. The distinct percentages of lymphocyte subpopulations of CSF appeared to be characteristic and could potentially serve as diagnostic indicators. Further verification and research will be necessary to clarify the significance and nature of CD4 : CD8 ratios and B lymphocytes in CSF between AE and the infectious lymphocytic encephalitis.
Phytochemistry, Antioxidant Activity, Antiproliferative Effect, and Acute Toxicity Testing of Two Moroccan Aristolochia Species
Authors: Bourhia Mohammed , Laasri Fatima Ezzahra , Moussa Samir Iben , Ullah Riaz , Bari Ahmed , Saeed Ali Syed , Kaoutar Aghmih , Haj Said Amal Ait , El Mzibri Mohammed , Said Gmouh , Khlil Naima , Benbacer Laila
Published: December 2019

Ethnopharmacological Relevance. Aristolochia baetica (A. baetica) and Aristolochia paucinervis (A. paucinervis) have been largely used in Moroccan folk medicine. The objective of the study was to investigate the phytochemical composition, the antioxidant activity, the antiproliferative effect, and the acute toxicity of the methanolic extract of A. baetica and A. paucinervis roots. Materials and Methods. Phytochemical composition of the methanolic extract of A. baetica and A. paucinervis roots were studied using qualitative and quantitative methods, the antioxidant activity was evaluated using DPPH assay, the antiproliferative effects against human cancer cell lines (T-24, HT-29, and Hep G-2) was assessed using WST1 assay, and the acute toxicity was carried out orally by gavage of single dose 2000 mg/kg to mice for 14 days. Results. The two studied plants have different classes of secondary metabolites. The concentrations of the total polyphenolic content of A. baetica and A. paucinervis root extracts were estimated at 360 ± 20 mg GAE/g and 280 ± 27 mg GAE/g, respectively. The total flavonoids content of A. baetica and A. paucinervis extracts were estimated at 35 ± 8 mg QE/g and 235 ± 7 mg QE/g, respectively. A. baetica and A. paucinervis extracts exhibited promising DPPH activity with IC50 values of 150 ± 8 μg/ml and 160 ± 10 μg/ml, respectively. The extracts exerted also antiproliferative effects on all tested cancer cell lines (T-24, HT-29, and Hep G-2) with IC50 values ranging from 6 ± 1 μg/ml to 380 ± 7 μg/ml. Regarding the results of acute toxicity study, no signs of toxicities nor mortalities were observed on the oral treated mice with 2000 mg/kg of the two investigated exacts. Conclusion. The methanolic extracts of A. baetica and A. paucinervis possess several phytochemicals that exhibited promising free radical scavenging activity and antiproliferative effects.
FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence
Authors: Fouillade Charles , Curras-Alonso Sandra , Giuranno Lorena , Quelennec Eddy , Heinrich Sophie , Bonnet-Boissinot Sarah , Beddok Arnaud , Leboucher Sophie , Karakurt Hamza Umut , Bohec Mylène , Baulande Sylvain , Vooijs Marc , Verrelle Pierre , Dutreix Marie , Londoño-Vallejo Arturo , Favaudon Vincent
Published: December 2019

Purpose:

One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. “FLASH” irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity.

Experimental Design:

Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc−/− mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro.

Results:

In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc−/− mice harboring critically short telomeres and lack of telomerase activity.

Conclusions:

The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.
Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression
Authors: Chakraborty Goutam , Armenia Joshua , Mazzu Ying Z. , Nandakumar Subhiksha , Stopsack Konrad H. , Atiq Mohammad O. , Komura Kazumasa , Jehane Lina , Hirani Rahim , Chadalavada Kalyani , Yoshikawa Yuki , Khan Nabeela A. , Chen Yu , Abida Wassim , Mucci Lorelei A. , Lee Gwo-Shu Mary , Nanjangud Gouri J. , Kantoff Philip W.
Published: December 2019

Purpose:

Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC). BRCA2, a DDR and cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that patients with prostate cancer who have lost a copy of BRCA2 frequently lose a copy of tumor suppressor gene RB1; importantly, for the first time, we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis.

Experimental Design:

We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of BRCA2 and RB1 in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to in vitro studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of BRCA2 and RB1 in prostate cancer cells and patient-derived mCRPC organoids.

Results:

In human prostate cancer cell lines (LNCaP and LAPC4), loss of BRCA2 leads to the castration-resistant phenotype. Co-loss of BRCA2-RB1 in human prostate cancer cells induces an epithelial-to-mesenchymal transition, which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes.

Conclusions:

Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor–based therapy.

See related commentary by Mandigo and Knudsen, p. 1784
First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies
Authors: Papadopoulos Kyriakos P. , Johnson Melissa L. , Lockhart Albert C. , Moore Kathleen , Falchook Gerald S. , Formenti Silvia C. , Naing Aung , Carvajal Richard D. , Rosen Lee S. , Weiss Glen J. , Leidner Rom S. , Li Jingjin , Paccaly Anne , Feng Minjie , Stankevich Elizabeth , Lowy Israel , Fury Matthew G. , Crittenden Marka R.
Published: December 2019

Purpose:

This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors.

Patients and Methods:

Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1.

Results:

Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3–84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients.

Conclusions:

The safety profile of cemiplimab was comparable with other anti–PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer
Authors: Hong David S. , Concin Nicole , Vergote Ignace , de Bono Johann S. , Slomovitz Brian M. , Drew Yvette , Arkenau Hendrik-Tobias , Machiels Jean-Pascal , Spicer James F. , Jones Robert , Forster Martin D. , Cornez Nathalie , Gennigens Christine , Johnson Melissa L. , Thistlethwaite Fiona C. , Rangwala Reshma A. , Ghatta Srinivas , Windfeld Kristian , Harris Jeffrey R. , Lassen Ulrik Niels , Coleman Robert L.
Published: December 2019

Purpose:

Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody–drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).

Patients and Methods:

Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.

Results:

Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%−37%]. Median duration of response (DOR) was 4.2 months (range: 1.0+−9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%−43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%−35%), median DOR of 6.0 months (range: 1.0+−9.7), and 6-month PFS rate of 40% (95% CI: 24%−55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.

Conclusions:

Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.