bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and cytopathological characteristics of HTLV‐1+ hodgkin lymphoma
Authors: Kobata Katsumi , Kimura Shoichi , Mihashi Yasuhito , Iwasaki Hiromi , Nonaka Shuichi , Matsumoto Shinji , Takamatsu Yasushi , Choi Ilseung , Kawauchi Shigeto , Ishitsuka Kenji , Takeshita Morishige
Published: June 2020

Background

Human T‐lymphotropic virus‐1 (HTLV‐1)+ Hodgkin lymphoma (HL) is difficult to differentiate from adult T‐cell leukemia/lymphoma (ATLL) with HL‐like histology (HL‐like ATLL).

Methods

Cytological and immunohistological features, HTLV‐1 proviral DNA integration, and rearrangements of the T‐cell receptor (TCR) Cβ1 gene were examined in 11 HTLV‐1+ patients with HL‐like disease.

Results

Six patients were classified as HTLV‐1+ HL and five as HL‐like ATLL in accordance with genetic findings of HTLV‐1 proviral DNA integration and rearrangements of the TCR Cβ1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV‐1+ HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL‐like ATLL specimens, small‐ and medium‐sized atypical lymphocytes with indented and irregular‐shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30+ and CD15+ Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein‐Barr virus infection. The 50% overall survival period was significantly longer for the HTLV‐1+ HL group (180 months) than for the HL‐like ATLL group (7.8 months; P = .004).

Conclusions

HTLV‐1+ HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25+ and CCR4+ lymphocytes. In HTLV‐1 endemic areas, distinguishing HTLV‐1+ HL from HL‐like ATLL is important because of their differing treatment strategies and prognoses.
NaBH4 Surface Modification on CeO2 Nanorods Supported Transition‐Metal Catalysts for Low Temperature CO Oxidation
Authors: Wang Yifan , Liu Zhongqi , Wang Ruigang
Published: June 2020

In this report, CeO2 nanorods (CeO2NR) were first chemically etched by different amounts (0.6, 3 and 6 wt %) of NaBH4, which were employed to understand the etching effect on the support structure, surface defects, and reducibility of modified CeO2NR supports. The 6 wt % NaBH4 etched CeO2NR was further used as support materials to load transition‐metals (TM: Cu, Co, Ni, Fe and Mn) catalysts, in order to investigate the support etching effect on the reducibility and catalytic performance of CeO2NR supported TM catalysts. In comparison with the catalytic performance of CeO2NR supported TM catalysts in literature, the 6 wt % NaBH4 etched CeO2NR supported catalysts show clearly enhanced CO oxidation performance at lower temperature, which is mainly attributed to the created surface defects by boron doped CeO2 surface during NaBH4 chemical etching and strong metal‐support interaction.
Interpretation of chemical data from glass analysis for forensic purposes
Authors: Akmeemana Anuradha , Weis Peter , Corzo Ruthmara , Ramos Daniel , Zoon Peter , Trejos Tatiana , Ernst Troy , Pollock Chip , Bakowska Ela , Neumann Cedric , Almirall Jose
Published: June 2020

The aims of evaluating forensic evidence are to provide a transparent, coherent, and unbiased opinion of the value of the evidence to fact‐finders. Measurements from glass evidence in a hit‐and‐run, for example, can help decide if a particular vehicle was involved in the accident. The evaluation involves the comparison of the physical, optical, and chemical properties of the glass recovered from the broken window with glass fragments suspected of originating from the window. A standard method (ASTM E2927‐16e1) describes a consensus‐based approach to sampling, sample preparation, quantitative analysis and “match” criterion for comparison of chemical properties. The result is a binary decision of either finding a difference in the elemental composition (exclusion) or a failure to exclude, based on elemental composition. This study demonstrates the utility of likelihood ratio (LR) calculations using novel datasets of glass samples of known manufacturing history. The LRs calculated from comparing glass manufactured at three different plants over relatively short periods (over 2‐6 weeks) range from very low values (LR ~ 10−3) when the glass are manufactured at different plants or manufactured weeks‐months apart in the same plant to very high values (LR ~ 103) when the glass samples are manufactured on the same day. Although the glass samples being compared may not originate from the same broken window source, they do exhibit chemical similarity within these lower and upper bounds and the LRs presented here, for the first time, closely correlate chemical relatedness to manufacturing history, specifically the time interval between production. The work presented here supports the use of the match criteria recommended within ASTM E2927‐16e1 and provides a data‐driven path forward to expand on the interpretation of glass using LRs.
Multifunctional Electrocatalytic Cathodes Derived from Metal–Organic Frameworks for Advanced Lithium‐Sulfur Batteries
Authors: Abdelkader Ahmed A. , Rodene Dylan D. , Norouzi Nazgol , Alzharani Ahmed , Weeraratne K. Shamara , Gupta Ram B. , El‐Kaderi Hani M.
Published: June 2020

The rechargeable lithium‐sulfur (Li‐S) battery is a promising candidate for the next generation of energy storage technology, owing to the high theoretical capacity, high specific energy density, and low cost of electrode materials. The main drawbacks in the development of long‐life Li‐S batteries are capacity fading and the sluggish kinetics at the cathode caused by the polysulfides shuttle. These limitations are addressed through the design of novel nanocages containing cobalt phosphide (CoP) nanoparticles embedded in highly porous nitrogen‐doped carbon (CoP‐N‐GC) by thermal annealing of ZIF‐67 in a reductive atmosphere followed by a phosphidation step using sodium hypophosphite. The CoP nanoparticles, with large surface area and uniform homogeneous distribution within the N‐doped nanocage graphitic carbon, act as electrocatalysts to suppress the shuttle of soluble polysulfides through strong chemical interactions and catalyze the sulfur redox. As a result, the S@CoP‐N‐GC electrode delivers an extremely high specific capacity of 1410 mA h g−1 at 0.1 C (1 C=1675 mA g−1) with an excellent coulombic efficiency of 99.7 %. Moreover, capacity retention from 864 to 678 mA h g−1 is obtained after 460 cycles with a very low decay rate of 0.046 % per cycle at 0.5 C. Therefore, the combination of the CoP catalyst and polar conductive porous carbon effectively stabilizes the sulfur cathode, enhancing the electrochemical performance and stability of the battery.
Next‐generation sequencing of residual cytologic fixative preserved DNA from pancreatic lesions: A pilot study
Authors: Fulmer Clifton G. , Park Kyung , Dilcher Thomas , Ho Mai , Mirabelli Susanna , Alperstein Susan , Hissong Erika M. , Pittman Meredith , Siddiqui Momin , Heymann Jonas J. , Yantiss Rhonda K. , Borczuk Alain C. , Fernandes Helen , Sigel Carlie , Song Wei , Mosquera Juan Miguel , Rao Rema
Published: June 2020

Background

Endoscopic ultrasound–guided fine needle aspiration (EUS‐FNA) is a sensitive and specific tool in the risk stratification of pancreatic lesions, including cysts. The sensitivity and specificity of EUS‐FNA has been shown to improve when cytology is combined with next‐generation sequencing (NGS). Ideally, fresh cyst fluid is used for NGS. In this pilot study, we explore the possibility of sequencing DNA derived from residual alcohol‐fixed pancreatic aspirates.

Methods

Residual cytologic fixatives (n = 42) from 39 patients who underwent EUS‐FNA for pancreatic lesions were collected along with demographics, imaging, and laboratory studies. Samples were designated as nonneoplastic/nonmucinous benign (NB), mucinous cyst (MC), pancreatic ductal adenocarcinoma (PDAC), or well‐differentiated neuroendocrine tumor (NET) on the basis of cytopathologic evaluation and sequenced on the Oncomine platform (ThermoFisher Scientific, Waltham, Massachusetts).

Results

Ten of 14 (71.4%) MCs exhibited clinically significant variants, including KRAS, GNAS, and TP53. Ten of 15 (66.7%) PDACs had KRAS alterations, and 9 of 15 (60%) showed variants in TP53. No variants were detected in any NETs. Only 1 of 9 (11.1%) NB aspirates showed variants in KRAS and MAP2K. Sequencing of formalin‐fixed, paraffin‐embedded tissue revealed variants identical to those detected in fixative‐derived DNA in 4 of 5 cases (80%).

Conclusion

Residual DNA from alcohol‐fixed aspirates are an underutilized source for NGS. Sequencing residual fixative‐derived DNA has the potential to be integrated into the workup of pancreatic aspirates, possibly impacting management.
Supervised link prediction using structured‐based feature extraction in social network
Authors: Kumari Anisha , Behera Ranjan Kumar , Sahoo Kshira Sagar , Nayyar Anand , Kumar Luhach Ashish , Prakash Sahoo Satya
Published: June 2020

Social network analysis (SNA) has attracted a lot of attention in several domains in the past decades. It can be of 2‐folds: one is content‐based, and another one is structured‐based analysis. Link prediction is one of the emerging research problems, which comes under structured‐based analysis that deals with predicting the missing link, which is likely to appear in the future. In this article, the supervised machine learning techniques have been implemented to predict the possibilities of establishing the links in future. The major contribution in this article lies in feature construction from the topological structure of the network. Several structured‐based similarity measures have been considered for preparing the feature vector for each nonexisting links in the network. The performance of the proposed algorithm has been extensively validated by comparing with other link prediction algorithms using both real‐world and synthetic data sets.
Detecting and mitigating poisoning attacks in federated learning using generative adversarial networks
Authors: Zhao Ying , Chen Junjun , Zhang Jiale , Wu Di , Blumenstein Michael , Yu Shui
Published: June 2020

In the age of the Internet of Things (IoT), large numbers of sensors and edge devices are deployed in various application scenarios; Therefore, collaborative learning is widely used in IoT to implement crowd intelligence by inviting multiple participants to complete a training task. As a collaborative learning framework, federated learning is designed to preserve user data privacy, where participants jointly train a global model without uploading their private training data to a third party server. Nevertheless, federated learning is under the threat of poisoning attacks, where adversaries can upload malicious model updates to contaminate the global model. To detect and mitigate poisoning attacks in federated learning, we propose a poisoning defense mechanism, which uses generative adversarial networks to generate auditing data in the training procedure and removes adversaries by auditing their model accuracy. Experiments conducted on two well‐known datasets, MNIST and Fashion‐MNIST, suggest that federated learning is vulnerable to the poisoning attack, and the proposed defense method can detect and mitigate the poisoning attack.
Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine
Authors: Frederiksen Trine , Areberg Johan , Schmidt Ellen , Bjerregaard Stage Tore , Brøsen Kim
Published: June 2020

Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6‐mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities of CYP2D6*9, CYP2D6*10, CYP2D6*17, and CYP2D6*41 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D6*10 was shown to be significantly greater than that of CYP2D6*17 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype‐phenotype classification systems particularly regarding decreased function alleles and the IM phenotype.
Cp2TiIIICl Catalysis in a New Light
Authors: Chen Yuqing , Lin Shuangjie , Li Fusheng , Zhang Xinhai , Lin Luqing , Shi Lei
Published: June 2020

Visible‐light‐mediated photogeneration of Cp2TiIIICl has opened new avenues for titanium catalysis. The synergistic utilization of dual photoredox and Cp2TiIIICl catalysis uses Hantzsch ester (HE) as an electron donor instead of traditional super‐stoichiometric metallic reductants. This new paradigm has found numerous applications in synthetic organic chemistry. The highly efficient photoinduced electron transfer process between light‐sensitive Cp2TiCl2 and an excited photocatalyst is the key to the success of such a photocatalytic system and ensures overall catalyst turnover. Comparisons between the metal reduction approach and photo reduction approach have been made.
Making predictive modelling ART: accurate, reliable, and transparent
Authors: Bodner Korryn , Fortin Marie‐Josée , Molnár Péter K.
Published: June 2020

Models are increasingly being used for prediction in ecological research. The ability to generate accurate and robust predictions is necessary to help respond to ecosystem change and to further scientific research. Successful predictive models are typically accurate, reliable, and transparent regarding their assumptions and expectations, indicating high predictive capacity, robustness, and clarity in their objectives and standards. Research on improving these properties is becoming more common, but often individual research projects are focused on a single aspect of the modelling process and are typically disseminated only within the field where the research originated. The goal of this review is to synthesize research from various disciplines and topics to provide a coherent framework for developing efficient predictive models. Our framework summarizes the process of creating predictive models into three main stages: (1) Framing the Question; (2) Model‐Building and Testing; and (3) Uncertainty Evaluation with proposed strategies associated with each stage to help produce more successful predictive models. The key strategies identified within our framework form specific guidelines, providing a new perspective to help researchers make predictive modelling more accurate, reliable, and transparent.
Prolonged suppression of the anti‐oxidant/anti‐inflammatory effects of BNP post‐Takotsubo syndrome
Authors: Liu Saifei , Ngo Doan , Chirkov Yuliy , Stansborough Jeanette , Chong Cher‐Rin , Horowitz John D.
Published: June 2020

Aims

Takotsubo syndrome (TTS) episodes are primarily initiated by ‘pulse’ release of catecholamines inducing neutrophil infiltration and myocardial inflammation in susceptible individuals (largely ageing women). Evidence of myocardial inflammation and associated energetic impairment persists for ≥ 3 months post‐acute TTS episodes, suggesting the existence of additional ‘perpetuating’ mechanisms. The effects of B‐type natriuretic peptide (BNP) in suppressing superoxide (O2−) release from neutrophils are transiently impaired in acute heart failure. We also evaluated the extent and duration of BNP‐induced suppression of O2− release post‐TTS.

Methods and results

TTS patients were studied acutely (n = 34) and 3 months thereafter (n = 13) and compared with control subjects (n = 25). O2− generation from neutrophils, triggered by N‐formyl‐methionyl‐leucyl‐phenylalanine and phorbol myristate acetate, and its suppression by BNP, were measured in vitro. Determinants of variability in BNP effect were sought via univariate and multivariate analyses.

Relative to control subjects, in TTS patients, BNP suppression of both phorbol myristate acetate and N‐formyl‐methionyl‐leucyl‐phenylalanine‐induced O2− release was impaired acutely (P < 0.05 for both); this did not improve over the 3‐month recovery period, despite treatment with conventional anti‐failure medication in 85% of patients. No significant correlates of BNP effect (other than TTS) were identified.

Conclusions

(1) While TTS is associated with marked and prolonged release of BNP, there is virtually total loss of the ability of BNP to suppress neutrophil O2− release and its impact on tissue inflammation. (2) BNP responses do not recover for at least 3 months post‐attacks, suggesting that this might contribute to perpetuation of myocardial inflammation in TTS patients.
Gateway and journey of patients with cardiac amyloidosis
Authors: Dang Daniel , Fournier Pauline , Cariou Eve , Huart Antoine , Ribes David , Cintas Pascal , Roussel Murielle , Colombat Magali , Lavie‐Badie Yoan , Carrié Didier , Galinier Michel , Lairez Olivier
Published: June 2020

Aims

Advances have been made over the last decade in the management of cardiac amyloidosis (CA), but a delayed diagnosis is still common. The aim of this study was to describe the journey to CA diagnosis from initial clinical and to analyse time to diagnosis.

Methods and results

Between January 2001 and May 2019, 270 consecutive patients with CA diagnosed at Toulouse University Hospital were retrospectively included in this cross‐sectional study: 111 (41%) light chain amyloidosis, 122 (45%) wild‐type transthyretin amyloidosis, and 37 (14%) hereditary transthyretin amyloidosis.

CA onset occurred mostly with dyspnoea (50%) or systematic follow‐up (10%). The cardiologist was the first line specialist in 68% of patients, followed by the nephrologist (9%) and neurologist (8%). Patients encountered a median (minimum–maximum) number of two (1–7) physician specialists and performed a median (minimum–maximum) number of three (1–8) tests before diagnosis. Median delay between symptom onset and CA diagnosis was 8 [IQR 5–14], 10 [IQR 3–34], and 18 [IQR 4–49] months, respectively, in light chain amyloidosis, wild‐type transthyretin amyloidosis, and hereditary transthyretin amyloidosis subgroups (P = .060). Having performed electromyography or spirometry was associated with a longer delay in diagnosis in the overall population: odds ratio = 1.13; 95% confidence interval 1.02 to 1.24; and odds ratio = 1.13; 1.03 to 1.24, respectively, probably due to non‐specific initial symptoms.

Conclusions

CA is a protean disease with various first line specialists causing a diagnostic wandering despite increasing medical community awareness. It requires a multidisciplinary specialist care networks to educate and manage symptoms and therapies.
An ultrasimple and cost‐effective µPAD by pasting hydrophilic channels to a hydrophobic basement
Authors: Zhang Daohong , Yan Lingzhi , Zhang Yongzhi , Li Tao , Wang Jianlong
Published: June 2020

The application of the paper‐based microfluidic device (µPAD) as a potentially significant platform for clinical diagnoses has gained a great interest during the recent years. This work presented a technically ultrasimple, low‐cost, effective, and rapid method for the µPADs fabrication by pasting a hydrophilic flower‐like paper mask to a hydrophobic PVC substrate, which was purchased with adhesive on it. The whole manufacture process could be implemented in a few seconds by untrained personnel. To demonstrate the feasibility of this method in real‐world situations, the developed paper device was employed for colorimetric assays of glucose in artificial urine and nitrite in artificial saliva. The main analysis parameters, for example, the optimum volumes of reagents, reaction time, and so forth, were seriatim optimized. Under optimal conditions, the detection limits were 0.9 mM and 19.5 µM for glucose and nitrite, respectively; the detection ranges were 0.9–30 mmol/L and 19.5–312.5 µmol/L for glucose and nitrite analyses, respectively. These results showed that this equipment‐free µPAD had great potentials for the qualitative or semiquantitative detection of glucose and nitrite in real samples.
Developing novel synbiotic low‐fat yogurt with fucoxylogalacturonan from tragacanth gum: Investigation of quality parameters and Lactobacillus casei survival
Authors: Ghaderi‐Ghahfarokhi Maryam , Yousefvand Amin , Ahmadi Gavlighi Hassan , Zarei Mehdi , Farhangnia Peyman
Published: June 2020

Tragacanth gum (TG) displayed a prebiotic activity, but its application was restricted due to high viscosity and deterioration of organoleptic and textural characteristics of food. In this study, TG was depolymerized by Pectinex Ultra Color enzyme followed by membrane separation (30 kDa) to get pectinase hydrolyzed fraction of tragacanth gum (PHFTG) with molecular weight more than 30 kDa. The average molecular weight of PHFTG was 147.7 ± 11.5 g/mol having a fucoxylogalacturonan structure. The prebiotic activity was tested using PHFTG, TG, and inulin as a carbon source. The results showed that the count of Lactobacillus casei in PHFTG‐ and inulin‐supplemented media increased significantly during the 48‐hr fermentation (p < .05). Five batches of low‐fat set yogurts were prepared by the following formulation: Control (without both L. casei and prebiotic), LC‐Cont (containing L. casei), LC‐PHFTG (containing L. casei + 0.5% PHFTG), LC‐TG (containing L. casei + 0.05% TG), and LC‐In (containing L. casei + 0.5% inulin), and L. casei population and physicochemical properties were monitored during 21‐day storage at 4°C. The number of L. casei remained highly acceptable (8.54–8.61 log CFU/g) during 7–21 days of storage in LC‐PHFTG. LC‐In and LC‐PHFTG presented significantly lower syneresis and higher sensory acceptability than LC‐Cont and Control during storage (p < .05). LC‐TG displayed weaker body and texture, lower sensory acceptability, and higher syneresis than other samples. This study provides support for expanding the utilization of PHFTG as a potential prebiotic and fat replacer in non‐ or low‐fat dairy products with satisfactory sensory quality.
Dying during Covid‐19
Authors: Moore Bryanna
Published: June 2020

I had been on the phone with Madeleine's mother for fifteen minutes, and she had sobbed throughout. She pleaded with me, “You won't even let our family visit her together. If you really want to help my daughter, you will let us stay with her.” Madeleine, who was twenty‐four years old, was dying of end‐stage acute myeloid leukemia and was intubated in one of our intensive care units. Her intensivist had requested a clinical ethics consultation for potentially inappropriate medical treatment—in my world of clinical ethics consultation, routine stuff. Except that, in March 2020, nothing was routine anymore. The Covid‐19 pandemic calls for creative thinking about ad hoc and post hoc bereavement efforts, and it may result in efforts to revise existing accounts of what constitutes a good death in order to accommodate patients’ and families’ experiences at the end of life during a pandemic.
Cotargeting BET proteins overcomes resistance arising from PI3K/mTOR blockade‐induced protumorigenic senescence in colorectal cancer
Authors: Lee Ho‐Sung , Lee Soobeom , Cho Kwang‐Hyun
Published: June 2020

Therapeutics targeting the phosphatidylinositol 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) pathway initially produce potent antitumor effects, but resistance frequently occurs. Using a phosphoproteome analysis, we found that colorectal cancer (CRC) cells exhibit resistance against PI3K/mTOR inhibition through feedback activation of multiple receptor tyrosine kinases, and their downstream focal adhesion kinase, Src and extracellular signal‐regulated kinases signaling. Unexpectedly, PI3K/mTOR blockade causes senescence, mediated by the activation of the stress kinase p38. The senescent cancer cells induce the secretion of various cytokines and this senescence‐associated secretome increases migration and invasion capabilities of CRC cells. We found that cotargeting PI3K/mTOR and bromodomain and extra‐terminal domain can suppress activation of many oncogenic kinases involved in resistance to the PI3K/mTOR inhibition, induce cell death in vitro and tumor regression in vivo, and further prolong the survival of xenograft models. Our findings provide a rationale for a novel therapeutic strategy to overcome resistance to the PI3K/mTOR inhibitors in CRC.
Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma
Authors: Zhang Xin , Zegar Tim , Weiser Tim , Hamdan Feda H. , Berger Benedict‐Tilman , Lucas Romain , Balourdas Dimitrios‐IIias , Ladigan Swetlana , Cheung Phyllis F. , Liffers Sven‐Thorsten , Trajkovic‐Arsic Marija , Scheffler Bjoern , Joerger Andreas C. , Hahn Stephan A. , Johnsen Steven A. , Knapp Stefan , Siveke Jens T.
Published: June 2020

Pancreatic ductal adenocarcinoma (PDAC) is resistant to virtually all chemo‐ and targeted therapeutic approaches. Epigenetic regulators represent a novel class of drug targets. Among them, BET and HDAC proteins are central regulators of chromatin structure and transcription, and preclinical evidence suggests effectiveness of combined BET and HDAC inhibition in PDAC. Here, we describe that TW9, a newly generated adduct of the BET inhibitor (+)‐JQ1 and class I HDAC inhibitor CI994, is a potent dual inhibitor simultaneously targeting BET and HDAC proteins. TW9 has a similar affinity to BRD4 bromodomains as (+)‐JQ1 and shares a conserved binding mode, but is significantly more active in inhibiting HDAC1 compared to the parental HDAC inhibitor CI994. TW9 was more potent in inhibiting tumor cell proliferation compared to (+)‐JQ1, CI994 alone or combined treatment of both inhibitors. Sequential administration of gemcitabine and TW9 showed additional synergistic antitumor effects. Microarray analysis revealed that dysregulation of a FOSL1‐directed transcriptional program contributed to the antitumor effects of TW9. Our results demonstrate the potential of a dual chromatin‐targeting strategy in the treatment of PDAC and provide a rationale for further development of multitarget inhibitors.
Evaluating polygenic risk scores in assessing risk of nine solid and hematologic cancers in European descendants
Authors: Choi Jungyoon , Jia Guochong , Wen Wanqing , Long Jirong , Zheng Wei
Published: June 2020

Genome‐wide association studies (GWAS) have identified many genetic risk variants for cancers. The utility of these variants in assessing risk of esophageal, gastric and endometrial cancers, as well as melanoma, glioma, diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphoid leukemia and multiple myeloma, has not been adequately investigated. We constructed a site‐specific polygenic risk score (PRS) for each of these nine cancers using their GWAS‐identified risk variants. Using data from 400 807 participants of European descent in the UK Biobank, a population‐based cohort study, we estimated the hazard ratios of each cancer associated with its PRS using Cox proportional hazard models. During a median follow‐up of 5.8 years, 3905 incident cases of these nine cancers were identified in the cohort. The area under the receiver operating characteristic curve ranged from 0.53 to 0.69 for these cancers. Except for esophageal cancer, significant dose‐response associations were observed between PRS and cancer risk. Compared to individuals in the middle quintile (40%‐60%) at an average risk, those among the highest 5% of the PRS had a twofold elevated risk of melanoma, glioma, follicular lymphoma or multiple myeloma, and a fourfold elevated risk of chronic lymphoid leukemia. Using PRS, 63.0% of the participants could be classified as having an over twofold elevated risk for at least one cancer. The PRS derived using risk variants identified to date by GWAS showed the potential in identifying individuals at a significantly elevated risk of cancer for prevention.
Composite likelihood methods for large Bayesian VARs with stochastic volatility
Authors: Chan Joshua C. C. , Eisenstat Eric , Hou Chenghan , Koop Gary
Published: June 2020

Adding multivariate stochastic volatility of a flexible form to large vector autoregressions (VARs) involving over 100 variables has proved challenging owing to computational considerations and overparametrization concerns. The existing literature works with either homoskedastic models or smaller models with restrictive forms for the stochastic volatility. In this paper, we develop composite likelihood methods for large VARs with multivariate stochastic volatility. These involve estimating large numbers of parsimonious models and then taking a weighted average across these models. We discuss various schemes for choosing the weights. In our empirical work involving VARs of up to 196 variables, we show that composite likelihood methods forecast much better than the most popular large VAR approach, which is computationally practical in very high dimensions: the homoskedastic VAR with Minnesota prior. We also compare our methods to various popular approaches that allow for stochastic volatility using medium and small VARs involving up to 20 variables. We find our methods to forecast appreciably better than these as well.
PCL/gelatin scaffolds and beta‐boswellic acid synergistically increase the efficiency of CGR8 stem cells differentiation into dopaminergic neuron: A new paradigm of Parkinson's disease cell therapy
Authors: Kheradmand Hamed , Babaloo Hamideh , Vojgani Yasaman , Mirzakhanlouei Sasan , Bayat Neda
Published: June 2020

Parkinson's disease is a progressive degenerative disorder in the central nervous system, which is distinguished by the death of dopamine‐producing nerve cells. Levodopa, a dopamine precursor drug, is the current standard of care of symptomatic treatment for Parkinson's disease. However, the long‐term use of the drug is associated with the development of motor fluctuations and dyskinesias. Cellular therapies aim to deploy fetal dopaminergic neurons as a means to replace the missing dopamine‐producing cells. The present study aims to study the impact of beta‐boswellic acid (BBA) coupled with poly ε‐caprolactone (PCL)/gelatin scaffolds on the dopaminergic differentiation course of CGR8 embryonic stem cells (ESCs). For this purpose, CGR8 ESCs were cultured on PCL/gelatin scaffolds and a five‐step protocol was employed to be promoted the neural differentiation of CGR8 ESCs. Gene expression analysis by real‐time qPCR demonstrated that PCL/gelatin scaffolds along with BBA treatment impose synergistic effects on the derivation of dopaminergic‐like cells from CGR8 ESCs. Reverse‐phase high‐performance liquid chromatography confirmed the functionality of the derived neurons by demonstrating the efficient secretion of dopamine in response to stimuli. Our results suggested that the generation of functional dopaminergic‐like cells from CGR8 ESCs was increased and supported by PCL/gelatin scaffolds and BBA treatment can heighten the efficiency. The result of this study may open insight into Parkinson's disease cell therapy and provide future directions for tissue engineering aimed at the treatment of Parkinson's disease.
Non‐stationary climate changes in summer high‐temperature extremes in Shanghai since the late 19th century
Authors: Tu Kai , Yan Zhongwei
Published: June 2020

Long‐term changes in daily high‐temperature extremes in the summers since the late 19th century in Shanghai and their relationships with decadal or multi‐decadal climatic oscillations have been investigated via non‐stationary statistical modelling based on parametric and nonparametric frameworks. Compared to stationary modelling with the assumption of an unchanging climate, time‐varying non‐stationary models based on the generalized extreme value (GEV) result in much more reasonable estimations of the temperature extremes for the present climate in terms of their return levels and return periods. However, nonparametric modelling with cubic spline smoothing reproduced even better multi‐decadal variability for different periods. The nonparametric method also reduces the biases of estimation, especially in the heavy tail of temperature extremes in parametric GEV models. Additionally, non‐stationary models with large‐scale climate indices indicate clear influences of the large‐scale climate indices, especially the last winter's strong signals from the tropical Pacific Ocean and Indian Ocean. The significant influences of multi‐decadal variabilities from the northern Atlantic in the parametric GEV model are probably also explained by spline terms in the nonparametric method. Further application to other areas in China indicates that the developed nonparametric model can fit their extremes correctly but notable biases also remain in the estimation of distributions and heavy tails.
Formation of corrosion pockets in FeNiCrAl at high temperatures investigated by 3D FIB‐SEM tomography
Authors: Jahns Katrin , Krupp Ulrich , Sundell Gustav , Geers Christine
Published: June 2020

A recently published study of high temperature nitridation of iron chromium aluminum alloys (FeCrAl) at 900°C in N2–H2 has redundantly shown the formation of locally confined corrosion pockets reaching several microns into the alloy. These nitrided pockets form underneath chromia islands laterally surrounded by the otherwise protective alumina scale. Chromia renders a nitrogen‐permeable defect under the given conditions and the presence of aluminum in the alloy. In light of these findings on FeCrAl, a focused ion beam–scanning electron microscope tomography study has been undertaken on an equally nitrided FeNiCrAl sample to characterize its nitridation corrosion features chemically and morphologically. The alloy is strengthened by a high number of chromium carbide precipitates, which are also preferential chromia formation sites. Besides the confirmation of the complete encapsulation of the corrosion pocket from the alloy by a closed and dense aluminum nitride rim, very large voids have been found in the said pockets. Furthermore, metallic particles comprising nickel and iron are deposited on top of the outer oxide scale above such void regions.
Corrosion damage of 316L steel surface examined using statistical methods and artificial neural network
Authors: Kubisztal Julian , Kubisztal Marian , Haneczok Grzegorz
Published: June 2020

Detailed examination of corrosion‐induced changes of the 316L steel surface (immersed in 5 wt% NaCl solution) is presented and discussed. The evolution of the stable pit depth (hav) with the immersion time (t) was established using 3D maps and statistic techniques. It was found that with n ≈ 0.5. Moreover, determination of the pit area allows estimating the curve current density (j) versus the immersion time and it was found that with m ≈ 1. A novel technique for surface corrosion degree determination is based on analysis of 2D grayscale images instead of black and white images showing that corrosion morphology was elaborated. For this purpose a three‐layered, feed‐forward neural network with the Levenberg–Marquardt backpropagation training algorithm was used. It was shown that a dependence corrosion degree versus immersion time (S‐type curve) can be fully described by the proposed procedure.
BIOANALYSIS AND BIOTRANSFORMATION OF OLIGONUCLEOTIDE THERAPEUTICS BY LIQUID CHROMATOGRAPHY‐MASS SPECTROMETRY
Authors: Sutton James Michael , Kim Jaeah , El Zahar Noha M. , Bartlett Michael G.
Published: June 2020

Since 2016, eight new oligonucleotide therapies have been approved which has led to increased interest in oligonucleotide analysis. There is a particular need for powerful bioanalytical tools to study the metabolism and biotransformation of these molecules. This review provides the background on the biological basis of these molecules as currently used in therapies. The article also reviews the current state of analytical methodology including state of the art sample preparation techniques, liquid chromatography‐mass spectrometry methods, and the current limits of detection/quantitation. Finally, the article summarizes the challenges in oligonucleotide bioanalysis and provides future perspectives for this emerging field. © 2020 John Wiley & Sons Ltd.
An interactive approach for inverse multiple criteria sorting problem
Authors: Özpeynirci Özgür , Özpeynirci Selin , Mousseau Vincent
Published: June 2020

Multiple criteria sorting is the problem of assigning objects that are evaluated on multiple criteria to ordered classes. In inverse multiple criteria sorting problem, the assignment of objects to classes is known. The decision maker (DM) can implement actions to improve the scores of objects on criteria, thus enabling the assignment of objects to better classes.

In inverse multiple criteria sorting problems, two types of questions arise: (1) What is the set of actions that will result in the desired classification with minimum cost? and 2) What is the set of actions to obtain the best classification without exceeding a predetermined budget? There exist two versions for each question: (i) Simple version, where the parameters of the sorting method are known and (ii) Robust version, where the parameters are not fully known.

In this article, we focus on the case where the DM does not provide any budget limitation or desired classifications a priori. By implementing more actions, that is, by spending more money, better classifications may be obtained. We aim to analyse the trade‐off between cost and classification, and determine the set of actions that will result in the most preferred cost‐classification compromise by the DM. We develop an approach that proceeds interactively with the DM, and determines such most preferred set of actions. The developed approach assumes the simple version and uses MR‐Sort as sorting model. We provide a detailed illustrative example on a real life problem and present the progress of the interactive algorithm.
Spatial Patterns in Relative Abundance and Habitat Use of Adult Gray Snapper off the Southeastern Coast of the United States
Authors: Bacheler Nathan M. , Gillum Zachary D. , Gregalis Kevan C. , Schobernd Christina M. , Schobernd Zebulon H. , Teer Bradford Z.
Published: June 2020

Gray Snapper Lutjanus griseus is an economically and ecologically important species in the estuarine and coastal environments of the southeastern United States. Previous research has focused primarily on juvenile Gray Snapper due to their accessible inshore distribution and ecological importance, while adults, which often occur offshore and are the main focus of fishing pressure, remain poorly understood. Seven years of baited underwater video data (2011–2017; N =8,379 videos; ~14,000 h of video) were collected along the continental shelf between North Carolina and Florida (~100,000 km2) to better understand the ways in which the relative abundance of Gray Snapper varied by space, time, habitats, and environmental conditions. Adult Gray Snapper were observed on 6.9% of the videos overall, but they were much more commonly observed in Florida (16.9% of the videos) compared with the states that are north of Florida (1.4% of the videos). We used delta-generalized additive models to determine that adult Gray Snapper primarily occurred in high-relief hardbottom sites south of St. Augustine, Florida, in warm water less than 50 m deep, after accounting for imperfect detection on video. Temporal variability was relatively minor despite relatively high precision (the mean annual coefficient of variation = 24%). Fifteen large aggregations of Gray Snapper (i.e., >20 individuals counted on a single frame) were observed on video, but it is unclear whether these aggregations indicated potential spawning aggregation sites. This work provides greater insight into the ecology of Gray Snapper during their important coastal-ocean adult life stage, which will improve their management and conservation.
Integrated Care in Parkinson's Disease: A Systematic Review and Meta‐Analysis
Authors: Rajan Roopa , Brennan Laura , Bloem Bastiaan R. , Dahodwala Nabila , Gardner Joan , Goldman Jennifer G. , Grimes David A. , Iansek Robert , Kovács Norbert , McGinley Jennifer , Parashos Sotirios A. , Piemonte Maria E.P. , Eggers Carsten
Published: June 2020

Background

Quality of life in Parkinson's disease (PD) is affected by motor and nonmotor symptoms, necessitating an integrated care approach. Existing care models vary considerably in numerous domains. The objectives of this study were to perform a systematic review and meta‐analysis of PD integrated care models and develop recommendations for a representative model.

Methods

We conducted a systematic review of published integrated care models and a meta‐analysis of randomized, controlled trials examining integrated care versus standard care. The primary outcome was health‐related quality of life using a validated PD scale. We evaluated levels of care integration using the Rainbow Model of Integrated Care.

Results

Forty‐eight publications were identified, including 8 randomized, controlled trials with health‐related quality of life data (n = 1,149 total PD patients). Qualitative evaluation of individual care model integration guided by the Rainbow Model of Integrated Care revealed frequent clinical and professional integration, but infrequent organizational and population‐based integration elements. Meta‐analysis of randomized, controlled trials revealed significant heterogeneity (I2 = 90%, P < 0.0001). Subgroup analysis including only outpatient care models (n = 5) indicated homogeneity of effects (I2 = 0%, P = 0.52) and improved health‐related quality of life favoring integrated care, with a small effect size (standardized mean difference [SMD], −0.17; 95% CI, −0.31 to −0.03; P = 0.02).

Conclusions

Outpatient integrated PD care models may improve patient‐reported health‐related quality of life compared with standard care; however, because of variable methodological approaches and a high risk of bias related to inherent difficulties in study design (eg, blinding of participants and interventionists), generalizability of these results are difficult to establish. The Rainbow Model of Integrated Care is a promising method of evaluating elements and levels of integration from individual patient care to population health in a PD context. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC. on behalf of International Parkinson and Movement Disorder Society.
Determination of mutations in iron regulating genes of beta thalassemia major patients of Khyber Pakhtunkhwa, Pakistan
Authors: Shah Maryam , Danish Lubna , Khan Najeeb U. , Zaman Fakhar , Ismail Muhammad , Hussain Mehfooz , Pervaiz Ruqiya , Iqbal Aqib
Published: June 2020

Background

Hepcidin and hemochromatosis (HFE) are iron regulatory proteins that are encoded by HAMP and HFE genes. Mutation in either HAMP gene or HFE gene causes Hepcidin protein deficiency that can lead to iron overload in beta thalassemia patients. The aim of this research work was to study the presence of G71D mutation of HAMP gene and H63D mutation of HFE gene in beta thalassemia major and minor group to check the association of these mutations with serum ferritin level of beta thalassemia patients.

Methods

The study was conducted on 42 beta thalassemia major and 20 beta thalassemia minor samples along with 20 control samples. The genotyping of both mutations has done by ARM‐PCR technique with specific set of primers.

Results

Significant effect of G71D and H63D mutations was observed on serum ferritin level of thalassemia major group. The risk allele of HAMP G71D and HFE H63D was found with high frequency (48% and 49%, respectively) in beta thalassemia major than in control group. High genotypic frequency of HAMP and HFE gene mutation gene mutation was observed in beta thalassemia major than beta thalassemia minor and control group (7% and 9%, respectively).

Conclusion

It can be concluded that both HAMP and HFE gene mutations show high frequency in beta thalassemia major patients and mean significant association between mutations and high serum ferritin level of beta thalassemia major patients but the nonsignificant results of Odd ratios showed that both mutations do not act as major risk factor in beta thalassemia major.
Global stability of a multistrain SIS model with superinfection and patch structure
Authors: Dénes Attila , Muroya Yoshiaki , Röst Gergely
Published: June 2020

We study the global stability of a multistrain SIS model with superinfection and patch structure. We establish an iterative procedure to obtain a sequence of threshold parameters. By a repeated application of a result by Takeuchi et al. [Nonlinear Anal Real World Appl. 2006;7:235–247], we show that these parameters completely determine the global dynamics of the system: for any number of patches and strains with different infectivities, any subset of the strains can stably coexist depending on the particular choice of the parameters.
Hyponormality on an annulus with a general radial weight
Authors: Sadraoui Houcine , Halouani Borhen
Published: June 2020

In this work, we consider the hyponormality of Toeplitz operators on the Bergman space of the annulus with a general radial weight. We give necessary conditions when the symbol is of the form
, where g1 and g2 are analytic on the annulus
.
“I've been to physical therapy before, but not for the knees.” A qualitative study exploring barriers and facilitators to physical therapy utilization for knee osteoarthritis
Authors: Christiansen Meredith B. , Dix Celeste , Master Hiral , Jakiela Jason T. , Habermann Barbara , Silbernagel Karin G. , White Daniel K.
Published: June 2020

Background

Physical therapy (PT) is recommended to reduce pain and improve function. However, only 10%–15% of adults with knee osteoarthritis (OA) use PT in the United States. The purpose of this study was to explore patient‐reported barriers and facilitators to PT utilization for knee OA, to understand why PT is underutilized.

Methods

Qualitative descriptive study using semi‐structured interviews was conducted, that is, one‐on‐one phone interviews with adults from local community centers. Participants were eligible if they were fluent in English and self‐reported knee OA (1) over 45 years of age, (2) have activity‐related knee pain, and (3) have no morning stiffness or morning stiffness in the knee(s) for ≤30 min. Interviews were audio‐recorded and transcribed. To identify barriers and facilitators to PT utilization for knee OA, a coding framework, thematic analysis, and a constant comparative approach were used.

Results

Of 22 participants with health insurance and who participated, 59% were considering PT, 23% refused PT, and 18% used PT for knee OA. Themes identified as either barriers or facilitators for participants were (1) previous experience with PT, (2) physician referral, (3) beliefs about treatment efficacy before and after knee replacement surgery, (4) insurance coverage, and (5) preference to avoid surgery.

Conclusion

A previous positive encounter with PT and a physician referral may facilitate PT utilization for adults with knee OA. Knowledge about and access to PT services were not identified as barriers related to PT utilization. Further research is necessary to confirm findings in a broader group of adults with knee OA.