bluuebunny/crossref_metadata_2025 huggingface dataset:
Guide to interventional radiology in cats and dogs
Authors: Kent Andrew
Published: November 2020

Background

Interventional radiology covers a group of procedures that are performed under imaging guidance, including fluoroscopy, endoscopy, ultrasound and computed tomography. The procedures are minimally invasive and tend to use percutaneous access or natural orifices to access the target area and deliver a treatment.

Aim of the article

This article provides a review of the currently performed interventional radiology procedures, including cardiorespiratory, urogenital, hepatobiliary/gastrointestinal and vascular techniques.
Cross-validation of four different survey methods used to estimate illicit cigarette consumption in Brazil
Authors: Szklo André Salem , Iglesias Roberto Magno , Stoklosa Michal , Figueiredo Valeska Carvalho , Welding Kevin , de Souza Junior Paulo Roberto Borges , Machado Alessandra Trindade , Martins Luis Felipe Leite , Nascimento Hannah , Drope Jeffrey
Published: November 2020

Objective

To cross-validate estimates of the size of the illicit cigarette trade based on the results of four different survey methods.

Methods

In 2018/2019, four non-industry-funded, large-scale studies were conducted in selected Brazilian cities: packs discarded in household garbage/PDG (1 city), packs littered in the streets/PLS (5 cities), a phone survey of tobacco users’ purchase behaviors/VIGITEL (5 cities), and a face-to-face household survey of tobacco users’ purchase behaviors/FTF-household (2 cities). The proportions of illicit cigarettes consumed were based on the price paid by smokers in their last purchase (VIGITEL or FTF-household) and/or direct observation of brand names and health warnings (PDG, PLS or FTF-household).

Results

Based on PLS, the share of packs that avoided taxation ranged from 30.4% (95% CI 25.6% to 35.7%) in Rio de Janeiro to 70.1% (95% CI 64.6% to 75.0%) in Campo Grande; and PDG conducted in Rio de Janeiro found an even lower proportion point estimate of illicit cigarette use (26.8%, 95% CI 25.1% to 28.6%). In FTF-household, the share of illicit cigarette consumption based on the self-reported price ranged from 29.1% (95% CI 22.4% to 35.7%) in Rio de Janeiro to 37.5% (95% CI 31.2% to 43.7%) in São Paulo, while estimates based on pack observation ranged from 29.9% (95% CI 23.3% to 36.5%) in Rio de Janeiro to 40.7% (95% CI 34.3% to 47.0%) in São Paulo. For all cities, VIGITEL presented the lowest levels of illicit consumption, and most illicit brands were produced in Paraguay.

Conclusions

Small differences in the estimated levels of illicit trade across methods were found, except for the phone survey. The cross-validation of estimates from independent studies is important to help effectively implement tobacco excise tax policy in Brazil and other low-income and middle-income countries.
BVA AGM notice
Authors: Thorpe Derek
Published: November 2020

The 2020 Annual General Meeting of the British Veterinary Association will be held as a Zoom meeting on Wednesday 9 December 2020, at 10:30. Please visit www.bit.ly/BVAAGM2020 to register your attendance.
Neonatal pain modulates in adolescent rats the antinociceptive effects of fluoxetine and buspirone administrated to their depressive dams during gestation
Authors: Butkevich Irina P. , Mikhailenko Viktor A. , Vershinina Elena A.
Published: November 2020

Previously, we have shown that the administration of a selective serotonin reuptake inhibitor fluoxetine or a 5-HT1A receptor agonist buspirone to stressed rats during gestation causes in the offspring alleviation of formalin-induced pain, strengthened by prenatal stress. We have also found that neonatal inflammatory pain strengthens formalin-induced pain in prenatally unstressed rats in later life. In the present study, we investigated the effect of neonatal inflammatory pain on the time-course of the biphasic pain response in the formalin test in prenatally stressed adolescent rats of both sexes to evaluate whether neonatal pain affects the antinociceptive properties of these drugs administered to their depressed mothers during gestation. Our findings demonstrate that neonatal pain modulates in prenatally stressed rats the antinociceptive effect of fluoxetine and buspirone depending on the level of organization of pain response in the central nervous system, the phase of the time-course of the formalin-induced pain, and sex of the rat.
Gravitational dynamics in the toy model of the Higgs-dark matter sector: the field theoretic perspective
Authors: Nakonieczna Anna , Nakonieczny Łukasz
Published: November 2020

The objective of the paper was to examine gravitational evolutions in the Higgs-dark matter sector toy model. The real part of the Higgs doublet was modelled by a neutral scalar. Two dark matter candidates introduced were the dark photon and a charged complex scalar. Non-minimal couplings of both scalars to gravity were included. The coupling channels between the ordinary and dark matter sectors were kinetic mixing between the electromagnetic and dark U(1) fields and the Higgs portal coupling among the scalars. The structures of emerging singular spacetimes were either of Schwarzschild or Reissner–Nordström types. The non-minimal scalar–gravity couplings led to an appearance of timelike portions of apparent horizons where they transform from spacelike to null. The features of dynamical black holes were described as functions of the model parameters. The black holes formed later and their radii and masses were smaller as the mass parameter of the complex scalar increased. The dependencies on the coupling of the Higgs field to gravity exhibited extrema, which were a maximum for the time of the black holes formation and minima in the cases of their radii and masses. A set of quantities associated with an observer moving with the evolving matter was proposed. The energy density, radial pressure and pressure anisotropy within dynamical spacetimes get bigger as the singularity is approached. The increase is more considerable in the Reissner–Nordström spacetimes. The apparent horizon local temperature changes monotonically in the minimally coupled case and non-monotonically when non-minimal scalar–gravity couplings are involved.
Effect of different welding energy on microstructure and toughness of HAZ of low carbon bainitic steel
Authors: Wang Hong , Yang Liang
Published: November 2020

Low carbon bainitic steel (LCBS) with excellent combined properties is the first choice for materials of pipeline transiting geological disaster. However, welding will worsen its toughness. In this paper, three kinds of welding heat input were designed to study the relationship between the toughness and microstructure in the coarse grain zone of welding heat affect zone (CGHAZ) of LCBS. The evolution characteristics of the microstructure of LCBS and the CGHAZ, and impact fracture were investigated by optical microscopy (OM), scanning electron microscopy (SEM). The results indicated that microstructure of LCBS consists mainly of bainite ferrite (BF) and granular bainite (GB). Heat input for 22 kJ/cm, the original austenite grains become coarsening, the microstructure is a small amount of quasi polygonal ferrite (QF) and polygonal ferrite (PF), which exhibits low Charpy impact toughness. However, for heat input of 19 kJ/cm, the degree of grain coarsening is small and distribution of martensite-austenite (M-A) constituents is the chain. The statistics of image software show that with the increase of heat input (16–22 kJ/cm), the average grain size of original austenite is basically the same (25 um), which is mainly due to Nb solute drag restraint the growth of austenite grain.
Effect of spin–orbit coupling on the hot-electron energy relaxation in nanowires
Authors: Vartanian A. L. , Asatryan A. L. , Stepanyan A. G. , Vardanyan K. A. , Kirakosyan A. A.
Published: November 2020

The energy relaxation of hot electrons is proposed based on the spin–orbit (SO) interaction of both Rashba and Dresselhaus types with the effect of hot phonons. A continuum theory of optical phonons in nanowires taking into account the influence of confinement is used to study the hot-electron energy relaxation. The energy relaxation due to both confined (CO) and interface (IO) optical phonon emission on nanowire radius, electrical field strength, parameters of SO couplings and electron temperature is calculated. For considered values of the nanowire radius as well as other system parameters, scattering by IO phonons prevails over scattering by CO phonons. The presence of an electric field leads to the decrease of power loss in transitions between states with the same spin quantum numbers. With the increase of the electric field strength, the influence of the Dresselhaus SO interaction on the energy relaxation rate decreases. The effect of SO interaction does not change the previously obtained increasing dependence of power loss on electron temperature. The sensitivity of energy relaxation to the electric field also through the Rashba parameter allows controlling the rate of energy by electric field.
Animal Models and Their Role in Understanding the Pathophysiology of Cystic Fibrosis–Associated Gastrointestinal Lesions
Authors: Gibson-Corley Katherine N. , Engelhardt John F.
Published: November 2020

The life expectancy of cystic fibrosis (CF) patients has greatly increased over the past decade, and researchers and clinicians must now navigate complex disease manifestations that were not a concern prior to the development of modern therapies. Explosive growth in the number of CF animal models has also occurred over this time span, clarifying CF disease pathophysiology and creating opportunities to understand more complex disease processes associated with an aging CF population. This review focuses on the CF-associated pathologies of the gastrointestinal system and how animal models have increased our understanding of this complex multisystemic disease. Although CF is primarily recognized as a pulmonary disease, gastrointestinal pathology occurs very commonly and can affect the quality of life for these patients. Furthermore, we discuss how next-generation genetic engineering of larger animal models will impact the field's understanding of CF disease pathophysiology and the development of novel therapeutic strategies.
Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease
Authors: Unterschemmann Kerstin , Ehrmann Alexander , Herzig Ina , Andreevski Anna-Lena , Lustig Klemens , Schmeck Carsten , Eitner Frank , Grundmann Manuel
Published: November 2020

Oxidative stress is a key concept in basic, translational, and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. Although attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically have gained further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells, and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress-related acute or chronic kidney injury as well. By studying renal ischemia-reperfusion injury in Col4α3−/−(Alport syndrome) mice and in vitro hypoxia-reoxygenation in human proximal tubular cells we found that treatment with a selective and potent Vanin-1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.
CD4+ T cells cause renal and placental mitochondrial oxidative stress as mechanisms of hypertension in response to placental ischemia
Authors: Deer Evangeline , Reeve Kristin E. , Amaral Lorena , Vaka Venkata Ramana , Franks Michael , Campbell Nathan , Fitzgerald Sarah , Herrock Owen , Ibrahim Tarek , Cornelius Denise , LaMarca Babbette
Published: November 2020

The reduced uterine perfusion pressure (RUPP) rat model and normal pregnant (NP) rat recipients of RUPP CD4+ T cells recapitulate many characteristics of preeclampsia such as hypertension and oxidative stress. We have shown an important hypertensive role for natural killer (NK) cells to cause mitochondrial dysfunction in RUPP rats; however, the role for RUPP CD4+ T cells to stimulate NK cells is unknown. Therefore, we hypothesized that RUPP-induced CD4+ T cells activate NK cells to cause mitochondrial dysfunction/reactive oxygen species (ROS) as mechanisms of hypertension during pregnancy. We tested our hypothesis by adoptive transfer of RUPP CD4+ T cells into NP rats or by inhibiting the activation of RUPP CD4+ T cells with Orencia (abatacept) and examining hypertension, NK cells, and mitochondrial function. RUPP was performed on gestation day (GD) 14, and splenic CD4+ T cells were isolated on GD 19 and injected into NP rats on GD 13. In a separate group of rats, Orencia was infused and the RUPP procedure was performed. Mean arterial pressure and placental and renal mitochondrial ROS increased in RUPP ( n = 7, P < 0.05) and NP + RUPP CD4+ T-cell recipients ( n = 13, P < 0.05) compared with control NP ( n = 7) and NP + NP CD4+ T-cell recipients ( n = 5) but was reduced with Orencia ( n = 13, P < 0.05). Placental and renal respiration was reduced in RUPP ( n = 6, P < 0.05) and NP + RUPP CD4+ T-cell recipients ( n = 6, state 3 P < 0.05) compared with NP ( n = 5) and NP + NP CD4+ T-cell recipients ( n = 5) but improved with Orencia ( n = 9, n = 8 P < 0.05). These data indicate that CD4+ T cells, independent of NK cells, cause mitochondrial dysfunction/ROS contributing to hypertension in response to placental ischemia during pregnancy.
Contribution of CT Features in the Diagnosis of COVID-19
Authors: Zuo Houdong
Published: November 2020

The outbreak of novel coronavirus disease 2019 (COVID-19) first occurred in Wuhan, Hubei Province, China, and spread across the country and worldwide quickly. It has been defined as a major global health emergency by the World Health Organization (WHO). As this is a novel virus, its diagnosis is crucial to clinical treatment and management. To date, real-time reverse transcription-polymerase chain reaction (RT-PCR) has been recognized as the diagnostic criterion for COVID-19. However, the results of RT-PCR can be complemented by the features obtained in chest computed tomography (CT). In this review, we aim to discuss the diagnosis and main CT features of patients with COVID-19 based on the results of the published literature, in order to enhance the understanding of COVID-19 and provide more detailed information regarding treatment.
Identifying Genetic Risk Factors for Diabetic Macular Edema and the Response to Treatment
Authors: Gurung Rajya L. , FitzGerald Liesel M. , McComish Bennet J. , Verma Nitin , Burdon Kathryn P.
Published: November 2020

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). DR is complex and the term encompasses several clinical subtypes of diabetic eye disease, including diabetic macular edema (DME), the most frequent cause of central vision loss in DR patients. Both genetic and environmental factors contribute to the pathophysiology of DR and its subtypes. While numerous studies have identified several susceptibility genes for DR, few have investigated the impact of genetics on DME susceptibility. This review will focus on the current literature surrounding genetic risk factors associated with DME. We will also highlight the small number of studies investigating the genetics of response to antivascular endothelial growth factor (anti-VEGF) injection, which is used to treat DME.
1D CNN-Based Intracranial Aneurysms Detection in 3D TOF-MRA
Authors: Hou Wenguang , Mei Shaojie , Gui Qiuling , Zou Yingcheng , Wang Yifan , Deng Xianbo , Cheng Qimin
Published: November 2020

How to automatically detect intracranial aneurysms from Three-Dimension Time of Flight Magnetic Resonance Angiography (3D TOF MRA) images is a typical 3D image classification problem. Currently, the commonly used method is the Maximum Intensity Projection- (MIP-) based way. It transfers 3D classification into 2D case by projecting the 3D patch into 2D planes along different directions on the basis of voxel’s intensity. After then, the 2D Convolutional Neural Network (CNN) is established to do classification. It has been shown that the MIP-based method can reduce the demands for the samples and increase the computation efficiency. Meanwhile, the accuracy is comparable with that of 3D image classification. Inspired by the strategy of MIP, we want to further reduce the demands for samples and accelerate the training by transferring the 2D image classification into 1D case, i.e., we want to generate the 1D vectors from the MIP images and then establish a 1D CNN to do intracranial aneurysm detection and classification for 3D TOF MRA image. Specifically, our method first extracts a series of patches as the Region of Interests (ROIs) along the blood vessels from the original 3D TOF MRA 3D image. The corresponding MIP images of each ROI will be obtained through maximum intensity projecting. Then, we generate a series of 1D vectors by accumulating each MIP image along different directions. Meanwhile, a 1D CNN is established to detect aneurysms, in which, the input is the obtained 1D vectors and the output is the binary classification result denoting whether there are intracranial aneurysms in the considered patch. Generally, compared with 2D- and 3D-CNN, the 1D CNN-based way greatly accelerates the training and shows stronger robustness in the case of fewer samples. The efficiency of the proposed method outperforms the 2D CNN about 10 times in CPU training. Yet, their accuracies are close.
Immunomodulatory Activity of the Marine Sponge, Haliclona (Soestella) sp. (Haplosclerida: Chalinidae), from Sri Lanka in Wistar Albino Rats: Immunosuppression and Th1-Skewed Cytokine Response
Authors: Gunathilake Varuni , Bertolino Marco , Bavestrello Giorgio , Udagama Preethi
Published: November 2020

Natural secondary metabolites of sponges of the genus Haliclona are associated with an array of biological activity with therapeutic usage. We investigated the immunopharmacological properties of a presumably novel marine sponge species from Sri Lanka, Haliclona (Soestella) sp. Sponge material was collected from southern Sri Lanka by scuba diving. Sponge identification was based on spicule and skeleton morphology using light microscopy. Selected in vivo and ex vivo tests investigated nonfunctional and functional immunomodulatory activity of the Haliclona (Soestella) sp. crude extract (HSCE) in the Wistar rat model. Compared to the controls, rats orally gavaged daily for 14 consecutive days with 15 mg/kg dose of the HSCE manifested a significant reduction of immune cell counts of total WBCs (by 17%;

p
<
0.01

), lymphocytes (38%), platelets (52%), splenocytes (20%), and bone marrow cells (BMC; 60%) (

p
<
0.001

), with a concurrent increase in the neutrophil : lymphocyte ratio (

p
<
0.05

); RBC counts abated by 53% (

p
<
0.001

). A significant reduction of the splenosomatic index was evident with the 10 and 15 mg/kg doses (

p
<
0.001

). Rat plasma TNF-α cytokine level was augmented by tenfold (

p
<
0.001

), IL-6 level by twofold (

p
<
0.01

) with the 15 mg/kg HSCE treatment, while IL-10 was detectable in rat plasma only with this treatment; the corresponding Th1 : Th2 cytokine ratio (TNF-α : IL-10) was indicative of an unequivocal Th1-skewed cytokine response (

p
<
0.01

). Ex vivo bone marrow cell and splenocyte proliferation were significantly and dose dependently impaired by HSCE (

I

C

50

0.719 and 0.931 μg/mL, respectively;

p
<
0.05

). Subacute toxicity testing established that HSCE was devoid of general toxic, hepatotoxic, and nephrotoxic effects. In conclusion, HSCE was orally active, nontoxic, and effectively suppressed nonfunctional and functional immunological parameters of Wistar rats, suggestive of the potential use of the HSCE as an immunosuppressant drug lead.
Effects of the Traditional Chinese Medical Prescription Linba Fang as a Treatment for Lymphedema
Authors: Luo Y. , Zhao L. , Liu N. F.
Published: November 2020

Lymphedema can lead to a series of complicated and irreversible chronic pathological changes, including lymphatic fluid retention, infiltration of inflammatory cells, lipid deposition, and fibrosis of the surrounding tissues. Typically, compression physiotherapy is recommended for early lymphedema. However, the chronic fluid compartments will lead to fat deposition, skin fibrosis, and hyperkeratosis. Few treatment methods are available for patients with lymphedema. Previous studies have attempted to apply diuretics, diosmin, and sodium β‐aescinate to treatment for venous edema, but the curative effect was unsatisfactory. There is currently no established effective treatment for lymphedema. In this paper, we investigated the effects of the traditional Chinese medical prescription Linba Fang as a treatment for lymphedema using a mouse model. A lymphedema model was established in C57BL/6 mice through lymphatic ablation at the base of tails. Negative controls were administered with 0.5% sodium carboxymethyl cellulose solution by gavage twice daily, positive controls with aescuvenforte, and test mice with Linba Fang. Aescuvenforte and Linba Fang were dissolved in 0.5% sodium carboxymethyl cellulose solution to produce a homogeneous mixture. After treatment for 2–4 weeks, tail diameter and weight, inflammatory cytokine levels (IL‐1, IL‐6, and TNF‐α), lipid deposition, and fibrosis were evaluated. The results showed that none of the mice died during the treatment with Linba Fang. The levels of tail swelling, inflammation, lipid deposition, and fibrosis in mice treated with Linba Fang were significantly decreased compared with negative and positive controls. Among mice treated with the same dose of Linba Fang, the levels of tail swelling, inflammation, lipid deposition, and fibrosis in mice treated for 4 weeks were significantly lower than those treated for 2 weeks. Among mice treated for the same duration of time, the levels of tail swelling, inflammation, lipid deposition, and fibrosis showed a decreasing tendency following increasing doses. Notably, the inflammation in tail tissues decreased to the similar level of normal group after treatment for 4 weeks using the high dose of Linba Fang. In conclusion, the traditional Chinese medical prescription Linba Fang could inhibit the pathological changes caused by lymphedema, including swelling, inflammation, lipid deposition, and fibrosis.
Fats and Mets, KRAS-Driven Lipid Dysregulation Affects Metastatic Potential in Pancreatic Cancer
Authors: Man Jennifer , Pajic Marina , Joshua Anthony M.
Published: November 2020

In this issue of Cancer Research, Rozeveld and colleagues present intriguing evidence of the importance of lipid droplets and hormone-sensitive lipase (HSL) in regulating the aggressive nature of pancreatic cancer. Initially demonstrating a dependency of preloaded lipids on an invasive phenotype, the authors then establish that oncogenic KRAS mutation downregulates HSL, thereby facilitating lipid storage during steady state. Thereafter, a phenotypic switch to oxidative metabolism with lipid utilization to fuel invasion and metastasis occurs. Experimentally, blocking the KRAS–HSL axis results in fewer lipid droplets, as well as metabolic reprogramming of the invasive cell phenotype, effectively reducing invasive capacity of KRAS-mutant pancreatic cancer. Of note, HSL overexpression in tumor cells also inhibited invasion, due to depletion of lipid droplets and the stored lipids, which are essential during invasion. Collectively, these novel findings highlight the importance of energy metabolism and its dynamic regulation in the evolution of the metastatic capacity of pancreatic cancer.

See related article by Rozeveld et al., p. 4932
Premature Years of Life Lost Due to Cancer in the United States in 2017
Authors: Song Minkyo , Hildesheim Allan , Shiels Meredith S.
Published: November 2020

Background:

Burden of cancer mortality is often measured by death counts or mortality rates, but potential years of life lost (PYLL) and PYLL per death may be more useful to estimate the impact of cancer-related deaths occurring at younger ages.

Methods:

We used U.S. national death certificate data. A total of 45 categories of common cancers were grouped for cancer-specific calculations of PYLL and PYLL per death. PYLL was defined as the sum of the total years of life lost prior to age 75 years.

Results:

The largest number of PYLL in 2017 was due to deaths from cancers of the lung/bronchus (891,313; 20.8%), colon/rectum (409,538; 9.6%), and breast (400,643; 9.4%). Cancers with the highest PYLLs generally also caused the largest number of deaths and had the highest mortality rates, with the exception of prostate cancer (5.1% of deaths, 2.0% of PYLL). In contrast, PYLLs per death were greatest for deaths due to cancers of testis (mean = 34.0 years), bones/joints (26.4), and other endocrine sites including thymus (25.2).

Conclusions:

Although PYLLs generally reflect mortality rates, they more heavily weigh cancers that occur at younger ages. In contrast, PYLL per death, which is an average quantification of life years lost for individual patients with cancer, shows a different pattern.

Impact:

Mortality rates, PYLL, and PYLL per death are complementary measures of the burden of deaths due to cancer that should be considered in tandem to prioritize public health interventions focused on preventing premature mortality.
The Role of Gallstones in Gallbladder Cancer in India: A Mendelian Randomization Study
Authors: Mhatre Sharayu , Richmond Rebecca C. , Chatterjee Nilanjan , Rajaraman Preetha , Wang Zhaoming , Zhang Haoyu , Badwe Rajendra , Goel Mahesh , Patkar Shraddha , Shrikhande Shailesh V. , Patil Prachi S. , Davey Smith George , Relton Caroline L. , Dikshit Rajesh P.
Published: November 2020

Background:

Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population.

Methods:

To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case–control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases = 1,170; controls = 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case–control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population.

Results:

We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR = 4.5; 95% confidence interval (CI) = 3.5–5.8] and with objective measures of gallstone presence using imaging techniques (OR = 2.0; 95% CI = 1.5–2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3–1.6.

Conclusions:

Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis.

Impact:

Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.
Cervical Cancer Screening: Comparison of Conventional Pap Smear Test, Liquid-Based Cytology, and Human Papillomavirus Testing as Stand-alone or Cotesting Strategies
Authors: Liang Linda A. , Einzmann Thomas , Franzen Arno , Schwarzer Katja , Schauberger Gunther , Schriefer Dirk , Radde Kathrin , Zeissig Sylke R. , Ikenberg Hans , Meijer Chris J.L.M. , Kirkpatrick Charles J. , Kölbl Heinz , Blettner Maria , Klug Stefanie J.
Published: November 2020

Background:

Some countries have implemented stand-alone human papillomavirus (HPV) testing while others consider cotesting for cervical cancer screening. We compared both strategies within a population-based study.

Methods:

The MARZY cohort study was conducted in Germany. Randomly selected women from population registries aged ≥30 years (n = 5,275) were invited to screening with Pap smear, liquid-based cytology (LBC, ThinPrep), and HPV testing (Hybrid Capture2, HC2). Screen-positive participants [ASC-US+ or high-risk HC2 (hrHC2)] and a random 5% sample of screen-negatives were referred to colposcopy. Post hoc HPV genotyping was conducted by GP5+/6+ PCR-EIA with reverse line blotting. Sensitivity, specificity (adjusted for verification bias), and potential harms, including number of colposcopies needed to detect 1 precancerous lesion (NNC), were calculated.

Results:

In 2,627 screened women, cytological sensitivities (Pap, LBC: 47%) were lower than HC2 (95%) and PCR (79%) for CIN2+. Cotesting demonstrated higher sensitivities (HC2 cotesting: 99%; PCR cotesting: 84%), but at the cost of lower specificities (92%–95%) compared with HPV stand-alone (HC2: 95%; PCR: 94%) and cytology (97% or 99%). Cotesting versus HPV stand-alone showed equivalent relative sensitivity [HC2: 1.06, 95% confidence interval (CI), 1.00–1.21; PCR: 1.07, 95% CI, 1.00–1.27]. Relative specificity of Pap cotesting with either HPV test was inferior to stand-alone HPV. LBC cotesting demonstrated equivalent specificity (both tests: 0.99, 95% CI, 0.99–1.00). NNC was highest for Pap cotesting.

Conclusions:

Cotesting offers no benefit in detection over stand-alone HPV testing, resulting in more false positive results and colposcopy referrals.

Impact:

HPV stand-alone screening offers a better balance of benefits and harms than cotesting.

See related commentary by Wentzensen and Clarke, p. 432
Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples
Authors: Semaan Alexander , Bernard Vincent , Lee Jaewon J. , Wong Justin W. , Huang Jonathan , Swartzlander Daniel B. , Stephens Bret M. , Monberg Maria E. , Weston Brian R. , Bhutani Manoop S. , Chang Kyle , Scheet Paul A. , Maitra Anirban , Jakubek Yasminka A. , Guerrero Paola A.
Published: November 2020

Purpose:

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials.

Experimental Design:

Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC.

Results:

Potentially actionable mutations were identified in >20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort.

Conclusions:

Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
Senescent T Cells as a Resistance Mechanism to Lung Cancer Immunotherapy
Authors: Salas-Benito Diego , Eguren-Santamaria Iñaki , Sanmamed Miguel F.
Published: November 2020

It has been reported that a group of patients with advanced non–small cell lung cancer showed circulating T cells with a senescent phenotype, and an abundance of such cells is associated with worse clinical response to immune checkpoint inhibitors. This study encourages further analysis of the role of senescent T cells in resistance to lung cancer immunotherapy.

See related article by Ferrara et al., p. 492
FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1
Authors: Mishra Mukul , Thacker Gatha , Sharma Akshay , Singh Anil Kumar , Upadhyay Vishal , Sanyal Sabyasachi , Verma Shailendra Prasad , Tripathi Anil Kumar , Bhatt Madan Lal Brahma , Trivedi Arun Kumar
Published: November 2020

Glycogen synthase kinase 3β (GSK3β), an ubiquitously expressed serine/threonine kinase is reported to be overexpressed and hyperactivated in cancers including acute myeloid leukemia (AML) where it promotes self-renewal, growth, and survival of AML cells. Therefore, GSK3β inhibition results in AML cell growth inhibition and myeloid differentiation. Here we identified master transcription factor PU.1 of monocyte–macrophage differentiation pathway as potential GSK3β target. We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. This GSK3-dependent degradation of PU.1 by FBW7 inhibited monocyte–macrophage differentiation. We further showed that a phospho-deficient PU.1 mutant (PU.1-S41, S140A) neither bound to FBW7 nor was degraded by it. Consequently, PU.1-S41, S140A retained its transactivation, DNA-binding ability and promoted monocyte–macrophage differentiation of U937 cells even without phorbol 12-myristate 13-acetate (PMA) treatment. We further showed that FBW7 overexpression inhibited both PMA as well as M-CSF–induced macrophage differentiation of myeloid cell lines and peripheral blood mononuclear cells (PBMC) from healthy volunteers, respectively. Contrarily, FBW7 depletion promoted differentiation of these cells even without any inducer suggesting for a robust role of GSK3β–FBW7 axis in negatively regulating myeloid differentiation. Furthermore, we also recapitulated these findings in PBMCs isolated from patients with leukemia where FBW7 overexpression markedly inhibited endogenous PU.1 protein levels. In addition, PBMCs also showed enhanced differentiation when treated with M-CSF and GSK3 inhibitor (SB216763) together compared with M-CSF treatment alone.

Implications:

Our data demonstrate a plausible mechanism behind PU.1 restoration and induction of myeloid differentiation upon GSK3β inhibition and further substantiates potential of GSK3β as a therapeutic target in AML.
The Association between Serum Uric Acid and Appendicular Skeletal Muscle Mass and the Effect of Their Interaction on Mortality in Patients on Peritoneal Dialysis
Authors: Xiao Xi , Yi Chunyan , Peng Yuan , Ye Hongjian , Wu Haishan , Wu Meiju , Huang Xuan , Yu Xueqing , Yang Xiao
Published: November 2020

Background: Serum uric acid (SUA) has been revealed to be positively associated with the body composition parameters in hemodialysis patients, but few studies have investigated that in patients on peritoneal dialysis (PD). The aim of this study was to identify the relationship between SUA and appendicular skeletal muscle mass (ASM) and the effect of their interaction on mortality in PD patients. Methods: This was a single-center retrospective cohort study. Patients who underwent multifrequency bioelectrical impedance analysis between January 1, 2013, and December 31, 2016, and had data on SUA values were enrolled. All patients were followed up until December 31, 2019. Results: In total, 802 prevalent PD patients (57.9% male), with mean age of 46.2 ± 14.2 years were enrolled. The average SUA and ASM were 6.8 ± 1.3 mg/dL and 21.2 ± 4.9 kg. According to multiple linear regression models, SUA was positively associated with relative ASM in middle-aged and older PD patients (standardized coefficients [β] 0.117; 95% confidence interval [CI] 0.027, 0.200; p = 0.010). Further sex-stratified analysis showed that the association existed only in males (β 0.161; 95% CI 0.017, 0.227; p = 0.023). Moreover, the presence of hyperuricemia was found to predict lower risk of all-cause mortality (hazard ratio [HR] 0.514, 95% CI 0.272, 0.970; p = 0.040) only in patients with lower relative ASM. And, the adjusted HR of every 1 mg/dL elevated SUA level was 0.770 (95% CI 0.609, 0.972; p = 0.028) for all-cause mortality in the lower relative ASM subgroup. Conclusions: There exists a positive association between the SUA and ASM, and the ASM significantly affected the association between SUA and all-cause PD mortality.
A longa história da cultura jurídica medieval
Authors: Lopes José Reinaldo de Lima
Published: November 2020

O texto traça um panorama do direito medieval destacando seu caráter erudito e filosofante, o qual determina que os juristas sejam atores públicos importantes naquele período, usem o método filosófico com certa desenvoltura, e façam uso de gêneros literários definidos. O texto aponta para a diferença da experiência inglesa e termina referindo ao humanismo jurídico, escola que expressamente rejeita parte da tradição medieval.
A interdisciplinaridade nos estudos sociojurídicos: a experiência editorial da revista Droit et Société
Authors: Villas Bôas Filho Orlando
Published: November 2020

Este artigo tem o intuito de analisar a questão da interdisciplinaridade nos estudos sociojurídicos a partir da expressiva experiência editorial da revista Droit et Société. Para tanto, em primeiro lugar, realiza uma concisa alusão à proposta de André-Jean Arnaud de desenvolvimento dos estudos sociojurídicos como um “campo de pesquisa interdisciplinar” e à “sociologia política do direito” de Jacques Commaille. Em seguida, com o propósito de explicitar uma das razões fundamentais da escolha dos trabalhos de Susan Silbey como objeto do dossiê do centésimo número da referida publicação, o artigo faz uma breve incursão pela obra da autora americana ressaltando, fundamentalmente, o seu contorno interdisciplinar. Por fim, o artigo consigna um sucinto exame da recepção dos Legal Consciousness Studies e, em particular, do pensamento de Susan Silbey, no âmbito dos estudos sociojurídicos na França, com especial ênfase nas afinidades existentes entre eles e a “sociologia política do direito” proposta por Jacques Commaille.
Noninvasive Echocardiographic Left Ventricular Stroke Work Index Predicts Mortality in Cardiac Intensive Care Unit Patients
Authors: Jentzer Jacob C. , Anavekar Nandan S. , Burstein Barry J. , Borlaug Barry A. , Oh Jae K.
Published: November 2020

Background:

Reduced left ventricular stroke work index (LVSWI) has been associated with adverse outcomes in several populations of patients with chronic heart disease, but no prior studies have examined this metric in cardiac intensive care unit (CICU) patients. We sought to determine whether a low LVSWI, as measured noninvasively using transthoracic echocardiography, is associated with higher mortality in CICU patients.

Methods:

Using a database of unique Mayo Clinic CICU admissions from 2007 to 2018, we identified patients with LVSWI measured by transthoracic echocardiography within 1 day of CICU admission. Hospital mortality was analyzed using multivariable logistic regression, and 1-year mortality was analyzed using multivariable Cox proportional-hazards analysis, adjusted for left ventricular ejection fraction and known predictors of hospital mortality.

Results:

We included 4536 patients with a mean age of 68±14 years (36% women). Admission diagnoses (not mutually exclusive) included acute coronary syndrome in 62%, heart failure in 46%, and cardiogenic shock in 11%. The mean LVSWI was 38±14 g×min/m
2
, and in-hospital mortality occurred in 6% of patients. LVSWI had better discrimination for hospital mortality than left ventricular ejection fraction (
P
<0.001 by De Long test). Higher LVSWI was associated with lower in-hospital mortality (adjusted odds ratio, 0.72 per 10 g×min/m
2
higher [95% CI, 0.61–0.84];
P
<0.001) and lower 1-year mortality (adjusted hazard ratio, 0.812 per 1 g×min/m
2
higher [95% CI, 0.759–0.868];
P
<0.001). Stepwise decreases in hospital and 1-year mortality were observed with higher LVSWI.

Conclusions:

Low LVSWI, reflecting poor left ventricular systolic and diastolic performance, is associated with increased short-term and long-term mortality among CICU patients. This emphasizes the importance of Doppler transthoracic echocardiography as a predictor of outcomes among critically ill patients. Further study is required to determine whether early interventions to optimize LVSWI can improve outcomes in the CICU setting.
Sulle varianti d’autore
Authors: Fera Vincenzo
Published: November 2020

The aim of this paper is to explore the nature of author variants in the humanistic age, starting from a survey of the variants added by Petrarch to his unfinished work Africa during the revision of the text around the mid-fourteenth century. In particular, two new definitions of variant, which were presented in a previous paper, are here outlined and discussed, that is, ‘active variants’ and ‘working variants’. Furthermore, the so-called Scevola Mariotti’s norm in relation to the author variants’ authenticity is reviewed.
Effects of Liposomal Simvastatin Nanoparticles on Vascular Endothelial Function and Arterial Smooth Muscle Cell Apoptosis in Rats with Arteriosclerotic Occlusive Disease of Lower Limb via P38 Mitogen-Activated Protein Kinase Nuclear Factor Kappa-B Pathway
Authors: Wu Jiawen , Liao Sheng , Hu Qiang , Wu Senyan , Qiu Shuiwei , Cheng Guobing , Li Xiaoyang , Lu Wei
Published: November 2020

This article prepared a simvastatin-NLCs for the treatment of arteriosclerotic occlusive disease of lower limbs. Taking the size distribution, polydispersity coefficient, encapsulation efficiency and drug loading of simvastatin-NLCs as evaluation indicators, various prescription factors
of simvastatin-NLCs were investigated. The in vitro release behavior and stability of simvastatin-NLCs were also investigated. A hyperlipidemia rat model was established using high-fat diets. SD rats fed ordinary diet were set as normal control groups. 20 rats, 20 in the simvastatin
group and 20 in the simvastatin nanocarrier group. After 5 weeks of drug intervention, the rats were sacrificed and the aorta was taken to determine the smooth muscle cell apoptosis rate. Studies have shown that simvastatin nanocarriers can more effectively reduce blood lipids in hyperlipidemia
rats, increase the rate of smooth muscle cell apoptosis in hyperlipidemia rats, and delay the onset of atherosclerosis.
Effects of Nano-α-Linolenic Acid and miR-146 on Mice with Viral Myocarditis
Authors: Li Li , Zhong Mingjiang , Zuo Qiyu , Ma Wenxue , Jiang Zhigao , Xiao Junhui
Published: November 2020

Micro RNA-146 (miR-146) is involved in mediating many innate and adaptive immune and inflammatory responses in the body. It is associated with a variety of systemic inflammation or autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and type 2 diabetes.
In recent years, microRNAs (miRNAs) and nanotechnology have become research hotspots in cardiovascular pathology. The close relationship between host miRNAs and coxsackie virus B3 has gradually been discovered by scientists, which may provide new directions for the treatment and prevention
of viral myocarditis. At the same time, recent studies have also found that nano-α-linolenic acid and its metabolites can inhibit the production of inflammatory cytokines such as TNF-α and IL-17; At the same time, they also have anti-lipid peroxidation effects. Therefore,
in order to further explore the role of miR-146 and nano-α-linolenic acid in the occurrence and development of viral myocarditis, in this study, a mouse model of viral myocarditis was used to establish a VMC mouse model using coxsackie virus B3. Intervention with different
doses of nano-α-linolenic acid, the control group was injected with the same amount of sodium chloride buffer, and the changes in cardiac function and inflammation indexes were compared to evaluate the role in the pathogenesis of viral myocarditis. The results showed that this
study suggested that serum miR-146 concentration in viral myocarditis mice is increased and is positively correlated with serum IL-17 and TNF-α concentrations. This suggest that miR-146 in the circulation may be involved in the pathogenesis of viral myocarditis through IL-17 and
TNF-α, providing a theoretical basis for the role of miR-146 in viral myocarditis, but its specific mechanism of action needs to be further studied. At the same time, the research in this experiment showed that nano-α-linolenic acid significantly improves the survival
rate of CVB3 infected mice and reduces myocardial damage. And with the increase of the dosage of nano-α-linolenic acid, the effect is more significant, showing a significant dose-effect relationship.
The Role of Nanoparticles-Mediated Ligustrazine in the Treatment of Knee Osteoarthritis and Its Effect on Matrix Metalloproteinases and Upstream NF-κB Signaling Pathway in Knee Osteoarthritis
Authors: Ji Lei , Li Weihua , Qian Wenbin , Feng Shuang , Shi Hui , Wang Yuhai
Published: November 2020

Knee osteoarthritis (KOA) is a joint degenerative arthropathy, characterized by cartilage degeneration of knee joint. Ligustrazine is an effective component of traditional Chinese medicine chuanqiong. It is reported that ligustrazine is used as a kind of anti-inflammatory medicine in
folk prescription, especially in the treatment of knee osteoarthritis. The study is aimed to study the therapeutic effect of ligustrazine mediated by nanoparticle on knee osteoarthritis and its impact on MMPs and upstream NF-κB signaling pathway in synovial fluid. Nanoparticle-mediated
system is a kind of nano traditional Chinese medicine preparation, which is made by taking nanoparticle and combining with the effective components, effective parts, raw materials, and their compounds in a certain way. We found that the combination of nanoparticle and ligustrazine can improve
its bioavailability and targeting, reduce the adverse reactions in the treatment of knee osteoarthritis. The ligustrazine mediated by nanoparticle can effectively alleviate knee osteoarthritis by reducing the level of MMPs in synovial fluid and the expression of NF-κB
in upstream NF-κB signaling pathway.