bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical trial risk in leukemia: Biomarkers and trial design
Authors: Li Alice J. , Dhanraj Jasper P. , Lopes Gilberto , Parker Jayson L.
Published: October 2020

This study analyzed the risk of clinical trial failure for leukemia drug development between January 1999 and January 2020. The specific leukemia subtypes of interest were acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Drug development was investigated using data obtained from https://www.clinicaltrials.gov and other publicly available databases. Drug compounds were excluded if they began phase I testing for the indication of interest before January 1999, if they were not industry sponsored, or if they treated secondary complications of the disease. Further analysis was conducted on biomarker usage, drug mechanisms of action, and line of treatment. Drugs were identified following our inclusion criteria for ALL (72), CLL (106), AML (159), and CML (47). The likelihood (cumulative pass rate), a drug would pass all phases of clinical testing and obtain Food and Drug Administration approval, was 18% (ALL), 10% (CLL), 7% (AML), and 12% (CML). Biomarker targeted therapies improved the success rates by three‐ and sevenfold, for ALL and AML, respectively. Enzyme inhibitors doubled the cumulative success rate for AML. First‐line therapy and kinase inhibitors both independently doubled the cumulative success rate for CLL. Oncologists enrolling patients in clinical trials can increase success rates by up to sevenfold by prioritizing participation in trials involving biomarker usage, while consideration of factors such as drug mechanism of action and line of therapy can further double the clinical trial success rate.
Mixed convective heat transfer enhancement in a ventilated cavity by flow modulation via rotating plate
Authors: Islam Aminul , Rony Monoranjan Debnath , Islam Mahmudul , Chowdhury Emdadul Haque , Hasan Mohammad Nasim
Published: October 2020

The present study numerically explores the mixed convection phenomena in a differentially heated ventilated square cavity with active flow modulation via a rotating plate. Forced convection flow in the cavity is attained by maintaining external fluid flow through an opening at the bottom of the left cavity wall while leaving it through another opening at the right cavity wall. A counter‐clockwise rotating plate at the center of the cavity acts as an active flow modulator. Moving mesh approach is used for the rotation of the plate and the numerical solution is achieved using arbitrary Lagrangian‐Eulerian finite element formulation with a quadrilateral discretization scheme. Transient parametric simulations have been performed for various frequency of the rotating plate for a fixed Reynolds number (Re) of 100 based on maximum inlet flow velocity while the Richardson number (Ri) is maintained at unity. Heat transfer performance has been evaluated in terms of spatially averaged Nusselt number and time‐averaged Nusselt number along the heated wall. Power spectrum analysis in the frequency domain obtained from the fast Fourier transform analysis indicates that thermal frequency and plate frequency start to deviate from each other at higher values of velocity ratio (>4).
Role of nuclear factor of activated T cells 2 (NFATc2) in allergic asthma
Authors: Jakobi Marielena , Kiefer Alexander , Mirzakhani Hooman , Rauh Manfred , Zimmermann Theodor , Xepapadaki Paraskevi , Stanic Barbara , Akdis Mubeccel , Papadopoulos Nikolaos G. , Raby Benjamin A. , Weiss Scott T. , Finotto Susetta
Published: October 2020

Background

We recently described increased NFATc1, IRF4, and NIP45 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) of asthmatic children and adults with multiple allergies.

Objective

NFATc2 has been described to associate with IRF4 to induce interleukin‐4, and to be inhibited by T‐bet. Here, we analyzed the role of NFATc2 in asthmatic children and adults.

Methods

PBMCs were isolated from the blood of control of asthmatics subjects. Some PBMCs were analyzed untreated and some cultured with and without phytohemagglutinin. Then, RNA was extracted from the cells and cytokines were measured in the supernatants via enzyme‐linked immunosorbent assay or multiplex analysis. RNA was then reverse‐transcribed and NFATc1, NFATC2, IRF4, and T‐bet mRNA were analyzed by real‐time polymerase chain reaction. In addition, in peripheral blood cells, NFATc2 expression was analyzed, in a population of asthmatic children and adults from the Asthma BRIDGE study.

Results

In addition to NFATc1 and NIP45, also NFATc2 was found upregulated in PBMCs and peripheral blood cells from asthmatic children and adults with allergic asthma. Moreover, NFATc1 directly correlated with lymphocytes number whereas NFATc2 correlated with peripheral eosinophilia in asthma.

Conclusions

In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 mRNA correlated with lymphocytes both in control and asthma, and NFATC1 and NFATc2 mRNA showed a direct correlation with eosinophils in controls but not in asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma.

Clinical Significance

Targeting NFATc2 in T lymphocytes might ameliorate the allergic phenotype in asthmatic subjects.
Synthesis of 3,4‐Functionalized Benzothiazines through C−H Activation
Authors: Son Jeong‐Yu , Jeon Da‐Hye , Jang Haeun , Lee Phil Ho
Published: October 2020

A method for the synthesis of a wide range of 1,2‐benzothiazines bearing pyridyl, amide, sulfonamide, alkenyl, as well as aryl groups in 3,4‐position has been developed using transition metal‐catalyzed C−H activation reactions of pyridylbenzothiazines with dioxazolones, tosyl azide, alkenes, alkynes, and diaryliodonium salts. The present reaction provides an efficient method for the synthesis of a variety of 3,4‐functionalized benzothiazines from readily available starting materials and benefits a broad substrate scope, high functional group tolerance, and good regioselectivity.
The performance of UK stock recommendation revisions: Does brokerage house reputation matter?
Authors: Su Chen , Zhang Hanxiong , Joseph Nathan Lael
Published: October 2020

Our study examines the impact of brokerage house (BH) reputation on the performance of investment strategies following stock recommendation revisions in the UK stock market. We develop two alternative proxies for BH reputation based either on the past positions on the annual Institutional Investor (II) All‐Europe Research Team or on the past recommendation performance of BHs. We find that BH reputation proxied by the past II rankings has no significant impact on the recommendation performance, suggesting that the II rankings are largely “popularity contests”. However, BH reputation proxied by the past year recommendation performance of BHs has a significantly positive impact on the recommendation performance in the next year, implying that the recommendation performance of BHs in the UK market is persistent. The bootstrap simulations further confirm that the observed performance persistence could be due to BH skill rather than BH luck (i.e., random chance).
Azacitidine regulates DNA methylation of GADD45γ in myelodysplastic syndromes
Authors: Yang Yanli , Li Jun , Geng Yinghua , Liu Lin , Li Dianming
Published: October 2020

Background

Myelodysplastic syndrome (MDS) is a heterogeneous clonal disease originated from hematopoietic stem cells. Epigenetic studies had demonstrated that DNA methylation and histone acetylation were abnormal in MDS. Azacitidine is an effective drug in the treatment of demethylation.

Methods

RT‐PCR was performed to determine GADD45γ in 15 MDS clinical samples. Myelodysplastic syndrome cell lines SKM‐1 and HS‐5 were transfected with GADD45γ eukaryotic expression vector and/or GADD45γ shRNA interference plasmid, and treated with azacitidine. Proliferation and apoptosis were examined by CCK‐8 and Western blot analysis to confirm the function role of GADD45γ and azacitidine. The methylation level of GADD45γ gene was detected by bisulfite conversion and PCR.

Results

This study found that GADD45γ gene was down‐expressed in MDS patients' bone marrow and MDS cell lines, and the down‐regulation of GADD45γ in MDS could inhibit MDS cell apoptosis and promote proliferation. Azacitidine, a demethylation drug, could restore the expression of GADD45γ in MDS cells and inhibit the proliferation of MDS cells by inducing apoptosis, which was related to prognosis and transformation.

Conclusion

This study indicated that GADD45γ was expected to become a new target of MDS‐targeted therapy. The findings of this study provided a new direction for the research and development of new MDS clinical drugs, and gave a new idea for the development of MDS demethylation drug to realize precise treatment.
Psychological, educational, and alternative interventions for reducing fear of childbirth in pregnant women: A systematic review
Authors: Aguilera‐Martín Ángel , Gálvez‐Lara Mario , Blanco‐Ruiz Marisol , García‐Torres Francisco
Published: October 2020

Objective

This review aims to identify non‐medical interventions that may reduce the fear of childbirth, directly or indirectly (through its factors).

Methods

This review followed the PRISMA guidance and a rigorous protocol that was registered in PROSPERO. Searches were done in ProQuest, the International Clinical Trials Registry Platform, and Google Scholar. All RCTs published in the last 5 years, in English or Spanish, regarding women with a low‐risk pregnancy and without mental disorders were included.

Results

From 5147 articles found, only 69 were full‐text assessed. Finally, 18 studies were included suggesting that prenatal education, psychoeducation, and counseling might be effective, whereas cognitive‐behavioral therapy and some alternative therapies require more research. The results of relaxation techniques were contradictory. Results also suggest that social support and exposure (through education) might have an important role in the efficacy of interventions.

Conclusions

More appropriately randomized and blinded trials are necessary that use a prespecified definition of fear of childbirth and comprehensive measurement tools specific for pregnant women.
IL‐8/CXCR2 mediates tropism of human bone marrow‐derived mesenchymal stem cells toward CD133+/CD44+ Colon cancer stem cells
Authors: Ma Xiaoying , Chen Jingyun , Liu Jiajun , Xu Baixue , Liang Xinyu , Yang Xiaotong , Feng Yun , Liang Xin , Liu Jianwen
Published: October 2020

In cancer treatment, the most attractive feature of mesenchymal stem cells (MSCs) is it's homing to tumor tissues. MSC is an important part of the “colon cancer stem cell niche”, but little research has been done on the tropism of human MSCs toward colon cancer stem cells (CCSCs). In this study, we first compared the effects of three tissue‐derived MSCs (bone marrow, adipose tissue, and placenta) in vivo on colon tumor xenograft growth. Then, we analyzed the tropism of bone marrow‐derived MSCs (BMSCs) toward normal intestinal epithelial cells (NCM460), parental colon cancer cells, CD133−/CD44−, and CD133+/CD44+ colon cancer cells in vitro. Microarray analysis and in vitro experiments explored the mechanism of mediating the homing of BMSCs toward CCSCs. Compared with the parental and CD133−/CD44− colon cancer cells, CD133+/CD44+ cells have a stronger ability to recruit BMSCs. In addition, BMSCs were significantly transformed into cancer‐associated fibroblasts after being recruited by CCSCs. After coculture of BMSCs and CCSCs, the expression of interleukin (IL)‐6, IL‐8, IL‐32, and CCL20 was significantly increased. Compared with parental strains, CD133−/CD44− cells, and NCM460, BMSC secreted significantly more IL‐8 after coculture with CD133+/CD44+ cells. Low concentration of IL‐8 peptide inhibitors (100 ng/ml) and CXC receptor 2 (CXCR2) inhibitors have little effect on the migration of BMSCs, but can effectively weaken CCSC stemness and promote dormant CSCs in the coculture system to re‐enter into the cell cycle. The endogenous IL‐8 knockout in BMSCs or BMSCs loaded with IL‐8 and/or CXCR2 inhibitors will make the therapy of BMSC targeting CCSCs function at its best.
Mechanisms of COVID‐19‐induced cardiovascular disease: Is sepsis or exosome the missing link?
Authors: Patil Mallikarjun , Singh Sarojini , Henderson John , Krishnamurthy Prasanna
Published: October 2020

Coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has reached a pandemic level, spreading across the globe by affecting over 33 million people and causing over 1,009,270 deaths. SARS‐CoV‐2 is highly infectious with a high basic reproduction number (R0) of 2.2–5.7 that has led to its exponential spread. Besides, very little is known about it in terms of immunogenicity and its molecular targets. SARS‐CoV‐2 causes acute respiratory distress syndrome, followed by multiple organ failure and death in a small percentage of individuals. Cardiac injury has emerged as another dreaded outcome of COVID‐19 complications. However, a thorough understanding of the pathogenesis of SARS‐CoV‐2 is lacking. In this review, we discuss the virus, possible mechanisms of COVID‐19‐induced cardiac injury, and potential therapeutic strategies, and we explore if exosomes could be targeted to treat symptoms of COVID‐19. Furthermore, we discussed the virus‐induced sepsis, which may be the cause of multiple organ failure, including myocardial injury.
Association of vaspin rs2236242 gene variants and circulating serum vaspin concentrations with coronary artery disease in a Turkish population
Authors: Akcılar Raziye , Yümün Gündüz , Bayat Zeynep , Donbaloğlu Okan , Gür Özcan , Gürkan Selami , Arık Özlem
Published: October 2020

Coronary artery disease (CAD) is the primary cause of death worldwide. Vaspin was a recently described adipokine, playing a protective role in many metabolic and cardiovascular diseases. This study aimed to assess the relation of serum vaspin levels and vaspin rs2236242 polymorphisms with CAD. The study included 105 healthy subjects and 105 CAD patients. Serum vaspin concentrations and vaspin rs2236242 polymorphisms were determined by enzyme‐linked immunosorbent assay and polymerase chain reaction, respectively. There was a statistically significant difference between the genotypes of CAD patients (TT 26.7%, TA 71.4%, and AA 1.9%) and controls (TT 70.5%, TA 28.6%, and AA 1%; χ2 = 40.3; df = 2; p = .000). The TA genotype increased the risk of CAD (odds ratio [OR] = 6.60; 95% confidence interval [CI] = 3.60–12.1; p = .000) as compared to the TT genotype. There was a statistically significant difference between the allelic distribution of CAD patients (T 62.4% and A 37.6%) and controls (T 84.8% and A 15.2%; χ2 = 27.0; df = 1; p = .000). Those carrying the A allele had a higher risk of CAD compared to those with the T allele (OR = 3.35; 95% CI = 2.10–5.36; p = .000). The serum vaspin concentrations of the patients with TT, TA, and AA genotypes were 30.4 ± 1.72, 28.4 ± 2.89, and 36.4 ± 6.38 pg/ml, respectively, and there was no significant difference between the serum vaspin levels and vaspin genotypes (p = .696). All of the above suggested that the vaspin rs2236242 polymorphism was associated with CAD in the Turkish population.
β‐Catenin signaling is important for osteogenesis and hematopoiesis recovery following methotrexate chemotherapy in rats
Authors: Fan Jian , Su Yu‐Wen , Hassanshahi Mohammadhossein , Fan Chia‐Ming , Peymanfar Yaser , Piergentili Alessandro , Del Bello Fabio , Quaglia Wilma , Xian Cory J.
Published: October 2020

Cancer chemotherapy can significantly impair the bone formation and cause myelosuppression; however, their recovery potentials and mechanisms remain unclear. This study investigated the roles of the β‐catenin signaling pathway in bone and bone marrow recovery potentials in rats treated with antimetabolite methotrexate (MTX) (five once‐daily injections, 0.75 mg/kg) with/without β‐catenin inhibitor indocyanine green (ICG)‐001 (oral, 200 mg/kg/day). ICG alone reduced trabecular bone volume and bone marrow cellularity. In MTX‐treated rats, ICG suppressed bone volume recovery on Day 11 after the first MTX injection. ICG exacerbated MTX‐induced decreases on Day 9 osteoblast numbers on bone surfaces, their formation in vitro from bone marrow stromal cells (osteogenic differentiation/mineralization), as well as expression of osteogenesis‐related markers Runx2, Osx, and OCN in bone, and it suppressed their subsequent recoveries on Day 11. On the other hand, ICG did not affect MTX‐induced increased osteoclast density and the level of the osteoclastogenic signal (RANKL/OPG expression ratio) in bone, suggesting that ICG inhibition of β‐catenin does nothing to abate the increased bone resorption induced by MTX. ICG also attenuated bone marrow cellularity recovery on Day 11, which was associated with the suppressed recovery of CD34+ or c‐Kit+ hematopoietic progenitor cell contents. Thus, β‐catenin signaling is important for osteogenesis and hematopoiesis recoveries following MTX chemotherapy.
Transient receptor potential vanilloid 4 channel deletion regulates pathological but not developmental retinal angiogenesis
Authors: Cappelli Holly C. , Guarino Brianna D. , Kanugula Anantha K. , Adapala Ravi K. , Perera Vidushani , Smith Matthew A. , Paruchuri Sailaja , Thodeti Charles K.
Published: October 2020

Transient receptor potential vanilloid 4 (TRPV4) channels are mechanosensitive ion channels that regulate systemic endothelial cell (EC) functions such as vasodilation, permeability, and angiogenesis. TRPV4 is expressed in retinal ganglion cells, Müller glia, pigment epithelium, microvascular ECs, and modulates cell volume regulation, calcium homeostasis, and survival. TRPV4‐mediated physiological or pathological retinal angiogenesis remains poorly understood. Here, we demonstrate that TRPV4 is expressed, functional, and mechanosensitive in retinal ECs. The genetic deletion of TRPV4 did not affect postnatal developmental angiogenesis but increased pathological neovascularization in response to oxygen‐induced retinopathy (OIR). Retinal vessels from TRPV4 knockout mice subjected to OIR exhibited neovascular tufts that projected into the vitreous humor and displayed reduced pericyte coverage compared with wild‐type mice. These results suggest that TRPV4 is a regulator of retinal angiogenesis, its deletion augments pathological retinal angiogenesis, and that TRPV4 could be a novel target for the development of therapies against neovascular ocular diseases.
Structural evaluation of polymeric microbial films grown on kefir loaded with Maytenus rigida extract
Authors: da Silva Mário R. P. , Matos Robert S. , Estevam Charles S. , Santos Samuel B. , da Silva Felipe M. A. , de Sousa Igor G. P. P. , da Fonseca Filho Henrique D. , Almeida Luís E.
Published: October 2020

Kefir is a probiotic that has several health promising properties. Its grains can form microbial films on different types of substrates. In the present work, the surface characteristics of kefir biofilms associated with Maytenus rigida Mart. extract were minutely studied. Three different concentrations of plant extract were included in the biofilm forming solutions, where fresh grains of kefir were inoculated. The results showed that the plant extract was successfully incorporated into the exopolysaccharide matrix of the biofilm. The main chemical components found linked to the plant extract were triterpenes. The crystallinity of biofilms increased with the addition of the plant extract. The morphology revealed that at low concentrations of the extract there was a prevalence of lactobacilli, while at high concentrations yeasts were more observed. Adhesion and wettability were higher for biofilm with less extract. These results revealed that a combination of plant extract and kefir's exopolysaccharide could form biofilms with chemical and topographic properties of great interest in regenerative medicine.
A simplified approach using deep neural network for fast and accurate shape from focus
Authors: Mutahira Husna , Muhammad Mannan Saeed , Li Mikhail , Shin Dong‐Ryeol
Published: October 2020

Three‐dimensional shape recovery is an important issue in the field of computer vision. Shape from Focus (SFF) is one of the passive techniques that uses focus information to estimate the three‐dimensional shape of an object in the scene. Images are taken at multiple positions along the optical axis of the imaging device and are stored in a stack. In order to reconstruct the three dimensional shape of the object, the best‐focused positions are acquired by maximizing the focus curves obtained via application of a focus measure operator. In this article, Deep Neural Network (DNN) is employed to extract the more accurate depth of each object point in the image stack. The size of each image in the stack is first reduced and then provided to the proposed DNN network to aggregate the shape. The initial shape is refined by applying a median filter, and later the reconstructed shape is sized back to original by utilizing bi‐linear interpolation. The results are compared with commonly used focus measure operators by employing root mean squared error (RMSE), correlation, and image quality index (Q). Compared to other methods, the proposed SFF method using DNN shows higher precision and low computational time consumption.
The influence of perceived host country political risk on foreign subunits' supplier development strategies
Authors: Charpin Remi , Powell E. Erin , Roth Aleda V.
Published: October 2020

Recent protectionist trends (e.g., trade wars, Brexit) have challenged the stability of the global supply chains (SCs) of multinational corporations. While the SC and operations management (SC/OM) literature has examined how such sources of political risk influence strategic SC/OM decisions at the global level, we know little about how host country political risk influences the SC/OM practices of foreign subunits at the local level. We conducted an exploratory, multiple‐case study of western subunits operating in China to investigate whether managers of foreign subunits in a host country perceive political risk; and if so, how they adapt their SC/OM strategic choices to reduce its impact on their subunits. Our empirical findings suggest that variations in political risk perceptions create different political legitimacy goals that subunits attempt to meet by adapting their supplier development strategies. We induct a process model and identify three archetypes of supplier development strategy—self‐centered, collaborative, and voluntary—adopted by subunits to shape their legitimacy and mitigate political risk. We contribute to the SC/OM literature by theorizing SC/OM managers' perceived political risk, showing how foreign subunits may use supplier development to influence how the host government views them, and by complementing traditional “corporate” legitimacy‐seeking strategies with new “SC/OM” legitimacy‐seeking strategies.
Impact of the COVID‐19 pandemic during Spain's state of emergency on the diagnosis of colorectal cancer
Authors: Suárez Javier , Mata Elena , Guerra Ana , Jiménez Gloria , Montes Marta , Arias Fernando , Ciga Miguel A. , Ursúa Eugenia , Ederra María , Arín Beñat , Laiglesia Matilde , Sanz Asunción , Vera Ruth
Published: October 2020

Introduction

We evaluate the impact of COVID‐epidemic in colorectal cancer (CRC) diagnosis during Spain's state of emergency.

Methods

We compared newly diagnosed patients with patients diagnosed in the same period of 2019.

Results

A new diagnosis of CRC decreased 48% with a higher rate of patients diagnosed in the emergency setting (12.1% vs. 3.6%; p = .048) and a lower rate diagnosed in the screening program (5.2% vs. 33.3%; p = .000).

Conclusions

Fewer patients have been diagnosed with CRC, with a higher rate of patients diagnosed in an emergency setting.
A Longitudinal Study of Suicidal Ideation in Sexually Abused Adolescent Girls: Depressive Symptoms and Affect Dysregulation as Predictors
Authors: Girard Marianne , Hébert Martine , Godbout Natacha , Cyr Mireille , Frappier Jean‐Yves
Published: October 2020

Child sexual abuse (CSA) is associated with many repercussions on adolescents’ mental health, including suicidal ideation. Yet, the mechanisms linking CSA to adverse outcomes have rarely been investigated within a longitudinal design. The current study aimed to examine the role of affect dysregulation in the association between depressive symptoms and suicidal ideation 1year after the first assessment in a sample of 119 sexually abused adolescent girls. An integrative mediational model was conceptualized to examine the explicatory role of affect dysregulation (Time 2) in the association between depressive symptoms (Time 1) and suicidal ideation (Time 3). Approximately 31% of the girls reported suicidal ideation at Time 3. Path analysis with logistic regressions revealed that the association between depressive symptoms and suicidal ideation presence was partly explained by affect dysregulation, which increased the risk of suicidal ideation presence by 18.4%, OR = 1.18, 95% CI [1.07, 1.33]. The integrative model explained 21.5% of the variance in suicidal ideation. These findings identify potential predictors of suicidal ideation among sexually abused adolescent girls. This present study highlights the role of affect dysregulation in the presence of suicidal ideation and provides potential targets for intervention practices when working with adolescent girl victims of CSA. As such, interventions for this vulnerable population should aim to decrease depressive symptoms and affect dysregulation to reduce suicidal risk.
Evaluation of Tendon Disorders With Ultrasonography and Elastography
Authors: Balaban Mehtap , Cilengir Atilla Hikmet , Idilman Ilkay S.
Published: October 2020

The frequency of musculoskeletal system ultrasonography (US) has increased over time. The most common reason for musculoskeletal US is the evaluation of tendons. The superficial location of tendons makes US the most suitable diagnostic tool, and US is generally the initial imaging modality for tendon disorders. The primary advantages of US are its low cost, easy accessibility, rapidity, repeatability, freedom from x‐rays, and enabling of a dynamic inspection. In addition, Doppler US and elastography can be performed simultaneously with US. We aimed to demonstrate the US and elastographic findings of tendon disorders that we frequently encounter in different regions.
Dissipation of wave energy by a hybrid artificial reef in a wave simulator: implications for coastal resilience and shoreline protection
Authors: Ghiasian Mohammad , Carrick Jane , Rhode‐Barbarigos Landolf , Haus Brian , Baker Andrew C. , Lirman Diego
Published: October 2020

Coastal cities are susceptible to the impacts of waves, flooding, storm surge, and sea‐level rise. In response to these threats, coastal jurisdictions have invested in engineered shoreline defenses such as breakwaters and sea walls that are costly to implement and maintain. Thus, there is an increasing recognition that nature‐based defenses provided by healthy ecosystems like coral reefs can be an effective and cost‐efficient alternative to mitigate the impacts of climatic hazards while simultaneously restoring ecosystem services. Unfortunately, coral reefs have experienced degradation worldwide, lowering their potential for wave‐energy dissipation. As coastal vulnerability increases with the loss of natural barriers, it is imperative to design and test novel resilience solutions. Our study quantifies the benefits of hybrid artificial reefs for wave mitigation in a wave‐tank simulator using periodic waves of three heights (0.10, 0.16, and 0.24 m) at two water levels (0.55 and 0.65 m) defined considering the Froude similarity with a prototype reef structure in South Florida. Experiments showed that an artificial trapezoidal reef model reduces wave height (> 35%) and wave energy (up to 63%) under realistic wave conditions. Moreover, adding coral skeletons of Acropora cervicornis to simulate reef restoration onto the model mitigates up to an additional 10% of wave height and 14% of wave energy through increased friction, supporting the use of hybrid approaches that integrate both gray and green infrastructure to enhance coastal resilience. Exploring wave‐tank simulations provides a better understanding of wave effects before implementing larger and more costly projects in the field.
A novel long noncoding RNA, LOC440173, promotes the progression of esophageal squamous cell carcinoma by modulating the miR‐30d‐5p/HDAC9 axis and the epithelial–mesenchymal transition
Authors: Wang Gaoyan , Feng Bo , Niu Yunfeng , Wu Jianhua , Yang Yang , Shen Supeng , Guo Yanli , Liang Jia , Guo Wei , Dong Zhiming
Published: October 2020

Countless evidence suggests that long noncoding RNAs (lncRNAs) are involved in human malignant cancers, including esophageal squamous cell carcinoma (ESCC), although their exact function remains unclear. In the present study, we aimed to investigate the roles and molecular mechanisms of the lncRNA LOC440173 in ESCC progression. Microarray analysis and quantitative real‐time polymerase chain reaction were conducted to measure the expression levels of LOC440173 and miR‐30d‐5p. The biological function of this lncRNA was investigated using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium, clone formation, and transwell assays, as well as flow cytometry and Western blot analysis. The function of LOC440173 was validated in vivo using tumor xenografts. The regulatory network of LOC440173/miR‐30d‐5p/HDAC9 was established using bioinformatic analysis and verified with dual‐luciferase reporter assays, RNA immunoprecipitation assay, and rescue experiments. The expression level of LOC440173 was significantly increased in ESCC tissues and esophageal carcinoma cells. High LOC440173 expression was correlated with histological grade, tumor invasion depth, lymph node metastasis, and TNM stage. Overexpression of LOC440173 promoted esophageal cancer cell proliferation, migration, and invasion, as well as the epithelial–mesenchymal transition (EMT) process in vitro, and facilitated tumor growth in vivo. MicroRNA‐30d‐5p (miR‐30d‐5p) was downregulated in ESCC tissues and acted as a direct binding target of LOC440173 during the regulation of HDAC9 expression in esophageal carcinoma cells. In conclusion, LOC440173 exerts a promotive role in ESCC tumorigenesis by targeting the miR‐30d‐5p/HDAC9 axis and regulating the EMT process. LOC440173 might be a new therapeutic target for the treatment of ESCC.
Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease
Authors: Shribman Samuel , Heller Carolin , Burrows Maggie , Heslegrave Amanda , Swift Imogen , Foiani Martha S. , Gillett Godfrey T. , Tsochatzis Emmanuel A. , Rowe James B. , Gerhard Alex , Butler Chris R. , Masellis Mario , Bremner Fion , Martin Alison , Jung Lynne , Cook Paul , Zetterberg Henrik , Bandmann Oliver , Rohrer Jonathan D. , Warner Thomas T.
Published: October 2020

Background

Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end‐organ damage.

Objective

To identify a biomarker for neurological involvement in WD.

Methods

Neuronal and glial‐specific proteins were measured in plasma samples from 40 patients and 38 age‐matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non‐adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded.

Results

Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients.

Conclusion

NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
The Beneficial Effects of Apical Sodium‐Dependent Bile Acid Transporter Inactivation Depend on Dietary Fat Composition
Authors: van de Peppel Ivo P. , Rao Anuradha , Dommerholt Marleen B. , Bongiovanni Laura , Thomas Rachel , de Bruin Alain , Karpen Saul J. , Dawson Paul A. , Verkade Henkjan J. , Jonker Johan W.
Published: October 2020

Scope

The apical sodium‐dependent bile acid transporter (ASBT, SLC10A2) is important in the enterohepatic cycling of bile acids and thereby in the intestinal absorption of lipids. ASBT inhibition has been shown to improve aspects of the metabolic syndrome, but the underlying mechanisms have remained unclear. Here, the effect of ASBT inhibition on the uptake of specific fatty acids and its consequences for diet‐induced obesity and non‐alcoholic fatty liver disease (NAFLD) are investigated.

Methods

Intestinal fat absorption is determined in mice receiving an ASBT inhibitor and in Asbt−/− mice. Metabolic disease development is determined in Asbt−/− mice receiving a low‐fat control diet (LFD) or high‐fat diet (HFD) rich in saturated fatty acids (SFAs) or PUFAs.

Results

Both ASBT inhibition and Asbt gene inactivation reduce total fat absorption, particularly of SFAs. Asbt gene inactivation lowers bodyweight gain, improves insulin sensitivity, and decreases the NAFLD activity score upon feeding a HFD rich in SFAs, but not in PUFAs.

Conclusions

The beneficial metabolic effects of ASBT inactivation on diet‐induced obesity depend on decreased intestinal absorption of SFAs, and thus on the dietary fatty acid composition. These findings highlight the importance of dietary fatty acid composition in the therapeutic effects of ASBT inhibition.
Generating anthropomorphic phantoms using fully unsupervised deformable image registration with convolutional neural networks
Authors: Chen Junyu , Li Ye , Du Yong , Frey Eric C.
Published: October 2020

Purpose

Computerized phantoms have been widely used in nuclear medicine imaging for imaging system optimization and validation. Although the existing computerized phantoms can model anatomical variations through organ and phantom scaling, they do not provide a way to fully reproduce the anatomical variations and details seen in humans. In this work, we present a novel registration‐based method for creating highly anatomically detailed computerized phantoms. We experimentally show substantially improved image similarity of the generated phantom to a patient image.

Methods

We propose a deep‐learning‐based unsupervised registration method to generate a highly anatomically detailed computerized phantom by warping an XCAT phantom to a patient computed tomography (CT) scan. We implemented and evaluated the proposed method using the NURBS‐based XCAT phantom and a publicly available low‐dose CT dataset from TCIA. A rigorous tradeoff analysis between image similarity and deformation regularization was conducted to select the loss function and regularization term for the proposed method. A novel SSIM‐based unsupervised objective function was proposed. Finally, ablation studies were conducted to evaluate the performance of the proposed method (using the optimal regularization and loss function) and the current state‐of‐the‐art unsupervised registration methods.

Results

The proposed method outperformed the state‐of‐the‐art registration methods, such as SyN and VoxelMorph, by more than 8%, measured by the SSIM and less than 30%, by the MSE. The phantom generated by the proposed method was highly detailed and was almost identical in appearance to a patient image.

Conclusions

A deep‐learning‐based unsupervised registration method was developed to create anthropomorphic phantoms with anatomies labels that can be used as the basis for modeling organ properties. Experimental results demonstrate the effectiveness of the proposed method. The resulting anthropomorphic phantom is highly realistic. Combined with realistic simulations of the image formation process, the generated phantoms could serve in many applications of medical imaging research.
Characterization of symptom severity and impact on four fecal incontinence phenotypes in women presenting for evaluation
Authors: Hoke Tanya P. , Meyer Isuzu , Blanchard Christina T. , Szychowski Jeff M. , Richter Holly E.
Published: October 2020

Aim

To characterize symptom‐specific distress and impact on quality of life (QOL) among women with urge, passive, and combined urge/passive fecal incontinence (FI) phenotypes. A secondary aim was to characterize FI symptom‐specific distress and impact on women with a novel fourth phenotype, stress FI.

Methods

Women with at least monthly FI from 2003 to 2017 were included. Participants completed the Modified Manchester Health Questionnaire (MMHQ) including MHQ and Fecal Incontinence Severity Index (FISI). Anorectal manometry (ARM) and endoanal ultrasound (EAUS) testing was performed. Total MHQ and FISI scores were compared across FI subtypes controlling for pertinent baseline covariates.

Results

The cohort included 404 subjects, 220 meeting criteria for urge FI, 67 passive FI, and 117 combined urge/passive FI. On MHQ, women with combined urge/passive FI were most impacted (p < 0.01). FISI scores were significantly different from combined urge/passive FI having the greatest impact (38.1 ± 12.5) and urge FI (31.1 ± 11.3), p < 0.01 having the least. No differences were observed in ARM measurements or anal sphincter defects among the three groups (all p > 0.05). Twenty‐nine subjects were identified with stress FI. There were no differences in overall MHQ or FISI scores or anal sphincter evaluation among the urge, passive, and stress FI groups (all p > 0.05).

Conclusion

Women with combined urge/passive FI have higher symptom distress and impact on QOL than urge or passive FI alone. Further research is needed to determine the significance of stress FI as a subtype and response to treatment.
Effects on body weight, eating behavior, and quality of life of a low‐energy diet combined with behavioral group treatment of persons with class II or III obesity: A 2‐year pilot study
Authors: Karlsson Jan , Galavazi Marije , Jansson Stefan , Jendle Johan
Published: October 2020

Objective

Obesity is associated with reduced health‐related quality of life (HRQoL). Outcomes of nonsurgical weight loss treatment on HRQoL are inconsistent and it is unclear how much weight reduction, or what type of treatment, is required for significant improvements. This study aimed to evaluate the effects of a lifestyle intervention program on weight, eating behaviors, and HRQoL, and to describe participants' experiences of treatment.

Methods

This 2‐year intervention trial in persons with class II or III obesity comprised a 3‐month liquid low‐energy diet (880 kcal/d) followed by a 3‐month reintroduction to regular foods, combined with behavioral group treatment.

Results

Fifty‐five participants (73% women) were included, mean (SD) age 43.2 (12.4) years, and mean body mass index 42.0 (6.0) kg/m2. Mean weight loss at 6, 12, and 24 months was 18.9%, 13.7%, and 7.2%, respectively. Short‐ and long‐term effects on eating behavior were favorable. Twelve of 14 HRQoL domains were improved at 6 months, compared to eight domains at 12 months. After 24 months, 2 of 14 domains, physical and psychosocial functioning, were improved. The treatment program was well accepted by the participants.

Conclusions

Substantial weight loss after 6 months was associated with extensive improvements in HRQoL, comprising the physical, psychosocial, and mental domains. Significant weight regain was observed between 6 and 24 months follow‐up. Modest weight loss after 24 months was associated with moderate improvement in physical functioning and large improvement in psychosocial functioning. The effect on psychosocial functioning is most likely related to both weight loss and behavioral treatment.
Shear‐induced textures and viscoelasticity in the nematic and isotropic phase of semiflexible thermotropic polymers. A rheo‐optical study
Authors: Romo‐Uribe Angel
Published: October 2020

The striking similarities in response to shear flow of nematic semi‐flexible thermotropic liquid crystalline polymers (LCPs) is reported. Insights into their complex flow was gained by in‐situ polarized optical microscopy (POM) whereas spatial correlations below optical resolution were characterized by small‐angle light scattering (SALS). The LCPs contained mesogenic units separated by ten (10) alkyl spacers, the polyether TPB10 of = 17 kDa and the polyester PSHQ10 of = 53 kDa. The quiescent nematic phase consisted of microdomains randomly oriented, that is, polydomain texture. Shear stretched and aligned the μm‐sized domains. After cessation of shear the texture sprang back and relaxed, PSHQ10 produced banded texture, whereas TPB10 only produced a disordered texture. Strikingly, high shear rate induced monodomains. Upon shear cessation the monodomain in PSHQ10 slowly relaxed to a polydomain, whereas TPB10 maintained a defect free texture. Shear reversal induced crisscross structure in both LCPs and SALS showed asymmetric “butterfly” patterns revealing a tilted microstructure. Shear rheometry in the nematic phase revealed that: (i) PSHQ10 displayed a terminal and rubbery regime, indicating the existence of entanglements; (ii) TPB10 exhibited only a liquid‐like behavior where G″ ≫ G′. The rubbery modulus Ge of PSHQ10 was ca. five times higher in the isotropic than in the nematic phase indicating that a change of conformation is involved in the nematic‐to‐isotropic transition. This study has resulted in correlations between rheological properties and shear‐induced microstructure thus developing new insights into their underlying deformation mechanisms.
Long‐term effect of first‐line injectable multiple sclerosis treatments: Input of a time‐dependent propensity score
Authors: Lefort Mathilde , Foucher Yohann , Lenain Remi , Vukusic Sandra , Edan Gilles , Leray Emmanuelle
Published: October 2020

Purpose

The long‐term effect of beta‐interferon and glatiramer acetate on multiple sclerosis (MS) disability progression has resulted in controversial results, probably due to a lack of appropriate control of biases as raised in observational studies. In particular, the time of the therapeutic decision is difficult to define when the controls are not treated.

Methods

This retrospective observational study was based on a series of patients from the MS expert center in Rennes, France. We used a time‐dependent propensity score defined as the linear predictor of a Cox model estimating the hazard of being treated at each time from MS onset. The matching procedure resulted in two groups: patients matched as treated and as not yet treated. The restricted mean times (RMST) to reach a moderate level of disability or worsening of the disability were compared between the two groups in an intention‐to‐treat analysis.

Results

Of the 2383 patients included in the study, 556 were matched as treated. The matching procedure provided a good balance of both the time‐fixed and the time‐dependent covariates. A slight difference was observed for the time to reach a moderate level of disability, in favor of the “not yet treated” group (difference in the RMST: −0.62 [−0.91; −0.33]) while no difference was found in terms of worsening of the disability (−0.03 [−0.24; 0.33]).

Conclusion

This unexpected result is probably due to unmeasured confounders. However, this time‐dependent PS warrants consideration in long‐term effectiveness studies.
Prescription Medication Use in Older Adults Without Major Cardiovascular Disease Enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) Clinical Trial
Authors: Lockery Jessica E. , Ernst Michael E. , Broder Jonathan C. , Orchard Suzanne G. , Murray Anne , Nelson Mark R. , Stocks Nigel P. , Wolfe Rory , Reid Christopher M. , Liew Danny , Woods Robyn L. ,   the ASPREE Investigator Group
Published: October 2020

Background

Efforts to minimize medication risks among older adults include avoidance of potentially inappropriate medications. Contemporary analysis of medication use in community‐dwelling older people compared with the general population is lacking.

Participants

A total of 19,114 community‐dwelling adults in Australia and the United States aged 70 years or older (65 years or older for U.S. minorities) without histories of major cardiovascular disease, cognitive impairment, or disability participated in a randomized, placebo‐controlled trial of aspirin: ASPirin in Reducing Events in the Elderly study.

Measurements

Prescribed baseline medications obtained by self‐report and medical record review were grouped by World Health Organization Anatomic and Therapeutic Chemical category. Potentially inappropriate medications were defined using a modified American Geriatrics Society Beers Criteria. Polypharmacy was defined as 5 or more medications, and hyperpolypharmacy defined as 10 or more medications. Cross‐sectional descriptive statistics and adjusted odds ratios were computed.

Results

The median number of prescription medications per participant was three, regardless of age. Women had a higher medication prevalence. Cardiovascular drugs (primarily antihypertensives) were the most commonly reported (64%). Overall, 39% of the cohort reported taking at least one potentially inappropriate medication, with proton‐pump inhibitors being the most commonly reported (21.2% of cohort). Of the cohort, 27% had polypharmacy, and 2% hyperpolypharmacy. Age 75 years or older, less than 12 years of education, hypertension, diabetes mellitus, chronic kidney disease, frailty, gastrointestinal complaint, and depressive symptoms were associated with an increased likelihood of potentially inappropriate medications and polypharmacy. For almost all medication classes, prevalence was equivalent or lower than the general older population.

Conclusion

Overall medication burden and polypharmacy are low in older adults free of major cardiovascular disease, disability, and cognitive impairment. The prevalence of potentially inappropriate medications is higher than previously reported and similar to more vulnerable populations as a result of the introduction of proton‐pump inhibitors to the American Geriatrics Society Beers Criteria. Longitudinal follow‐up is required to further understand the balance of benefits and risks for potentially inappropriate medications and polypharmacy in community‐dwelling older people.