bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose optimisation for Loss of Response to Vedolizumab— Pharmacokinetics and Immune Mechanisms
Authors: Ungar Bella , Malickova Karin , Hanžel Jurij , Abu Arisha Muhammad , Paul Stephane , Rocha Catia , Ben Shatach Zohar , Abitbol Chaya Mushka , Haj Natour Ola , Selinger Limor , Yavzori Miri , Fudim Ella , Picard Orit , Shoval Irit , Eliakim Rami , Kopylov Uri , Magro Fernando , Roblin Xavier , Chowers Yehuda , Drobne David , Lukas Milan , Ben Horin Shomron 
Published: April 2021

Abstract

Background
Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations.

Methods
A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored.

Results
A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [n = 43], free α4β7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15], LP T cells [p = 0.88], and on PB eosinophils [p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalised and newly generated α4β7, but re-binding was still complete at very low concentrations.

Conclusions
These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab’s immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.
Four-dimensional flow analysis reveals mechanism and impact of turbulent flow in the dissected aorta
Authors: Takahashi Kenichiro , Sekine Tetsuro , Miyagi Yasuo , Shirai Sayaka , Otsuka Toshiaki , Kumita Shinichiro , Ishii Yosuke 
Published: April 2021

Abstract

OBJECTIVES
This study aimed to explore the flow dynamics factors affecting turbulence formation in the false lumen (FL) of aortic dissection using four-dimensional flow magnetic resonance imaging (4D flow MRI). This study also aimed to uncover risk factors affecting late complications of aortic dissection.

METHODS
Thirty-three aortic dissection patients were examined using 4D flow MRI for quantitative flow dynamics (gross flow, velocity and regurgitant fraction) and turbulence visualization (helix and vortex with three-point visual grading) in the FL. The incidence of late complications (rupture or prophylactic intervention) was also obtained prospectively.

RESULTS
The helix grade was correlated with FL gross flow (rS = 0.55, P &lt; 0.001) and FL velocity (rS = 0.45, P = 0.008). The vortex grade was also correlated with FL gross flow (rS = 0.70, P &lt; 0.001) and FL velocity (rS = 0.67, P &lt; 0.001). Comparative analysis of patients with complications and stable patients revealed that patients with complications exhibited higher FL gross flow [41.7 (interquartile range, IQR 29.1–59.7) vs 17.7 (IQR 9.0–42.0) ml/s; P = 0.01], higher helix grade [2 (IQR 1.25–2) vs 0 (IQR 0–1); P = 0.001] and higher vortex grade [2 (IQR 1–2) vs 0 (IQR 0–2); P = 0.01].

CONCLUSIONS
Using 4D flow MRI analysis, we showed that turbulence formation depends on flow volume and velocity in the FL. Patients with high-volume turbulent flow in their FL are at higher risk of late complications; therefore, close follow-up and aggressive prophylactic intervention may improve their survival.

Clinical trial registration number
Nippon Medical School Hospital Institutional Review Board approved this observational study in September 2018 (No. 30-08-986).
GENETIC REGULATION OF MUP PRODUCTION IN RECOMBINANT INBRED MICE
Authors: Szoka P R , Paigen K 
Published: April 2021

ABSTRACT
Inbred strains of mice excrete all three major urinary proteins (mups) when induced by testosterone, but differ as to the relative proportions and total levels of each mup present. We have now determined the urinary mup pheno-types before and after testosterone treatment of seven recombinant inbred strains derived from progenitor strains exhibiting different mup phenotypes. The results codirm previous observations indicating that total control of mup protein production is a multigenic process. One locus, Mup-a on chromosome 4, determines the relative mup protein proportions after induction by testoster- one. Mup-a, together with other genetic sites, determines the basal mup proportions. Genes other than Mup-a determine the kinetics of mup induction and total mup excretion.
Constitutional pluralism and loyal opposition
Authors: Flynn Tom 
Published: April 2021

Abstract
Constitutional pluralism has long been controversial, but has recently come under renewed attack. Critics allege that by justifying departure by national courts from the Court of Justice of the European Union’s (CJEU) orthodoxy on the primacy of EU law, constitutional pluralism is (at best) susceptible to abuse by autocratic member state governments, or is (at worst) a favored tool of Europe’s new authoritarians. This article is a defense of heterodoxy in European constitutional thought, and of constitutional pluralism in particular. It uses the concept of “loyal opposition” as a framing discourse, allowing us to see that heterodox approaches to EU constitutionalism and opposition to the received and dominant interpretation of the primacy of EU law are not necessarily any less “loyal” to the principles and values of European integration than agreement with the CJEU. A “legitimacy test” is proposed, by which we can determine whether a given instance of national judicial disagreement with the CJEU is loyal, principled opposition, or disloyal, abusive opposition.
Limited democracy and great distrust: John Hart Ely in Bolivia and Chile
Authors: Verdugo Sergio 
Published: April 2021

Abstract
This article shows that John Hart Ely’s defense of judicial review, as elaborated in his book Democracy and Distrust, has had little influence in Bolivia and Chile. However, that observation does not mean that a theory justifying judicial review when a political market failure is identified is useless for examining both countries’ judicial decisions. The author argues that an Ely-an procedural approach to judicial review can help justify or reject Chilean and Bolivian rulings—or judicial inactions—if certain conditions are taken into account to adapt Ely’s theory to both jurisdictions.
Reduction in total and major cause-specific mortality from tobacco smoking cessation: a pooled analysis of 16 population-based cohort studies in Asia
Authors: Yang Jae Jeong , Yu Danxia , Shu Xiao-Ou , Wen Wanqing , Rahman Shafiur , Abe Sarah , Saito Eiko , Gupta Prakash C , He Jiang , Tsugane Shoichiro , Gao Yu-Tang , Yuan Jian-Min , Koh Woon-Puay , Sadakane Atsuko , Tomata Yasutake , Tsuji Ichiro , Sugawara Yumi , Matsuo Keitaro , Ahn Yoon-Ok , Park Sue K , Chen Yu , Inoue Manami , Kang Daehee , Zheng Wei ,   remaining authors are listed at the end of the paper
Published: April 2021

Abstract

Background
Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia.

Methods
Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis.

Results
During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries.

Conclusions
Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.
Explicit Plancherel Formula for the Space of Symplectic Forms
Authors: Lapid Erez , Offen Omer 
Published: April 2021

Abstract
We provide a Plancherel decomposition for the space of symplectic bilinear forms of rank $2n$ over a local non-Archimedean field $F$ in terms of that of $\operatorname{GL}_n(F)$.
Microbial-based magnetic nanoparticles production: a mini-review
Authors: Chmykhalo Victor , Belanova Anna , Belousova Mariya , Butova Vera , Makarenko Yuriy , Khrenkova Vera , Soldatov Alexander , Zolotukhin Peter 
Published: April 2021

Abstract
The ever-increasing biomedical application of magnetic nanoparticles (MNPs) implies increasing demand in their scalable and high-throughput production, with finely tuned and well-controlled characteristics. One of the options to meet the demand is microbial production by nanoparticles-synthesizing bacteria. This approach has several benefits over the standard chemical synthesis methods, including improved homogeneity of synthesis, cost-effectiveness, safety and eco-friendliness. There are, however, specific challenges emanating from the nature of the approach that are to be accounted and resolved in each manufacturing instance. Most of the challenges can be resolved by proper selection of the producing organism and optimizing cell culture and nanoparticles extraction conditions. Other issues require development of proper continuous production equipment, medium usage optimization and precursor ions recycling. This mini-review focuses on the related topics in microbial synthesis of MNPs: producing organisms, culturing methods, nanoparticles characteristics tuning, nanoparticles yield and synthesis timeframe considerations, nanoparticles isolation as well as on the respective challenges and possible solutions.
When text simplification is not enough: could a graph-based visualization facilitate consumers’ comprehension of dietary supplement information?
Authors: He Xing , Zhang Rui , Alpert Jordan , Zhou Sicheng , Adam Terrence J , Raisa Aantaki , Peng Yifan , Zhang Hansi , Guo Yi , Bian Jiang 
Published: April 2021

AbstractObjectiveDietary supplements are widely used. However, dietary supplements are not always safe. For example, an estimated 23 000 emergency room visits every year in the United States were attributed to adverse events related to dietary supplement use. With the rapid development of the Internet, consumers usually seek health information including dietary supplement information online. To help consumers access quality online dietary supplement information, we have identified trustworthy dietary supplement information sources and built an evidence–based knowledge base of dietary supplement information—the integrated DIetary Supplement Knowledge base (iDISK) that integrates and standardizes dietary supplement related information across these different sources. However, as information in iDISK was collected from scientific sources, the complex medical jargon is a barrier for consumers’ comprehension. The objective of this study is to assess how different approaches to simplify and represent dietary supplement information from iDISK will affect lay consumers’ comprehension.Materials and MethodsUsing a crowdsourcing platform, we recruited participants to read dietary supplement information in 4 different representations from iDISK: (1) original text, (2) syntactic and lexical text simplification (TS), (3) manual TS, and (4) a graph–based visualization. We then assessed how the different simplification and representation strategies affected consumers’ comprehension of dietary supplement information in terms of accuracy and response time to a set of comprehension questions.ResultsWith responses from 690 qualified participants, our experiments confirmed that the manual approach, as expected, had the best performance for both accuracy and response time to the comprehension questions, while the graph–based approach ranked the second outperforming other representations. In some cases, the graph–based representation outperformed the manual approach in terms of response time.ConclusionsA hybrid approach that combines text and graph–based representations might be needed to accommodate consumers’ different information needs and information seeking behavior.
Midwives and Maternal Mortality: Evidence from a Midwifery Policy Experiment in 19th-century Sweden
Authors: Lorentzon Louise , Pettersson-Lidbom Per 
Published: April 2021

AbstractThis paper estimates the causal effect of a historical midwifery policy experiment on maternal mortality, infant mortality, and stillbirth during the period of 1830–1894 in Sweden. Exploiting sharp changes or “discontinuities” across time and place in the availability of trained and licensed midwives as an exogenous source of variation, we find that a doubling of trained midwives led to a 20%–40% reduction in maternal mortality and a 20% increase in the uptake of midwife-assisted homebirths. The results thus suggest that a 1% increase in the share of midwife-assisted homebirths decreased maternal mortality by as much as 2%, which is a remarkable finding given that midwife training was only 6–12 months at that time. The results of this study contribute to the current debate about the most effective strategy to reduce the unacceptably high rate of maternal mortality in many developing countries, especially in low-resource settings.
Idle Souls, Regulated Emotions of a Mind Industry: A new look at Ottoman materialism
Authors: Afacan Şeyma 
Published: April 2021

Abstract
The phenomenon of ‘materialism’ in the late Ottoman Empire has long been explained as the vehicle of fully-fledged modernization (i.e., Westernization and secularization) in allegedly essential opposition to tradition and religion. Amid growing intellectual interest in aspects of the individual such as mind, soul, brain, and emotions in the late Ottoman period, this paper shifts the explanatory focus from religious vs. nationalist ideologies to the discourse of ‘productivity’. It argues that before the discourse of national homogenization came to dominate intellectual writings in the late Ottoman Empire, a new language about the regulation of body and emotion was formulated with the aim of increasing labour productivity and rational conduct. The debate between materialism and spiritualism was embedded in this new language. The first section of the paper reviews relevant secondary literature to question what we know about the phenomenon of Ottoman materialism. The second moves on to the over-abundance of machine metaphors in materialist writings with particular focus on Abdullah Cevdet’s books on brain physiology, and in light of the spread of mechanistic views of human nature in the late nineteenth century. The final section presents Baha Tevfik’s problematization of sensibility (hassasiyet) as an obstacle to greater social harmony based on rational conduct as a case study of the regulation of emotion in the early 1910s, when interest in scientific and philosophical literature on human nature and the soul reached its zenith. This paper shows the ways in which Ottoman materialism became an important tool to imagine the individual as a unit of production, whose soul was rendered idle and whose emotions were subjected to regulation.
Oestrogen receptor alpha in papillary thyroid carcinoma: association with clinical features and BRAFV600E mutation
Authors: Liu Shiyang , Jiao Bo , Li Shuyu , Zhao Lu , Zheng Weihong , Wang Kun , Xu Jing , Tian Yao , Liu Chenguang , Gui Zhengwei , Zhang Lin 
Published: April 2021

Abstract

Background
Papillary thyroid cancer cells can express oestrogen receptor alpha, which is encoded by the ESR1 gene and may bind to oestrogen to induce the occurrence and development of papillary thyroid cancer. The BRAFV600E mutation is also an important biomarker for the occurrence and progression of papillary thyroid cancer. However, the association between the BRAFV600E mutation and oestrogen receptor alpha expression has not been identified. This study aims to investigate the association between ESR1 expression and the BRAFV600E mutation and its clinical significance.

Methods
Oestrogen receptor alpha and BRAFV600E proteins were detected by immunohistochemical staining of formalin-fixed paraffin-embedded thyroid tissues from 1105 patients with papillary thyroid cancer at our institution. Messenger RNA expression counts of ESR1 and clinicopathologic information were obtained from The Cancer Genome Atlas database.

Results
Oestrogen receptor alpha protein expression was significantly associated with BRAFV600E protein. The positive rate of oestrogen receptor alpha protein in papillary thyroid cancer patients was significantly higher in males, younger patients and patients with the multifocal type. In papillary thyroid cancer patients with positive BRAFV600E protein, oestrogen receptor alpha expression was significantly correlated with central lymph node metastasis. Data from the The Cancer Genome Atlas database also suggested that the ESR1 messenger RNA level was associated with the BRAFV600E mutation. Furthermore, classification analysis performed according to a tree-based classification method demonstrated that higher ESR1 messenger RNA expression indicated poorer overall survival in papillary thyroid cancer patients with the BRAFV600E mutation.

Conclusions
The percentage of BRAFV600E mutations is increased in patients with higher ESR1 messenger RNA levels, and the BRAFV600E protein might be co-expressed with oestrogen receptor alpha, which could be an indicator of cervical lymph node metastasis and poor overall survival in patients with papillary thyroid cancer.
Gender Differences in Treatment Allocation and Survival of Advanced Gastroesophageal Cancer: A Population-Based Study
Authors: Dijksterhuis Willemieke P M , Kalff Marianne C , Wagner Anna D , Verhoeven Rob H A , Lemmens Valery E P P , van Oijen Martijn G H , Gisbertz Suzanne S , van Berge Henegouwen Mark I , van Laarhoven Hanneke W M 
Published: April 2021

Abstract

Background
Biological sex and gender have been reported to affect incidence and overall survival (OS) of curatively treated gastroesophageal cancer. The aim of this study was to compare palliative treatment allocation and OS between women and men with advanced gastroesophageal cancer.

Methods
Patients with an unresectable or metastatic esophageal (including cardia) adenocarcinoma (EAC) or squamous cell carcinoma (ESCC) or gastric adenocarcinoma (GAC) diagnosed in 2015-2018 were identified in the Netherlands Cancer Registry. Treatment allocation was compared using χ2 tests and multivariable logistic regression analyses, and OS using the Kaplan-Meier method with log-rank test and Cox proportional hazards analysis. All statistical tests were 2-sided.

Results
Of patients with EAC (n = 3077), ESCC (n = 794), and GAC (n = 1836), 18.0%, 39.4%, and 39.1% were women, respectively. Women less often received systemic treatment compared with men for EAC (42.7% vs 47.4%, P = .045) and GAC (33.8% vs 38.8%, P = .03) but not for ESCC (33.2% vs 39.5%, P = .07). Women had a lower probability of receiving systemic treatment for GAC in multivariable analyses (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.62 to 1.00) but not for EAC (OR = 0.86, 95% CI = 0.69 to 1.06) and ESCC (OR = 0.81, 95% CI = 0.57 to 1.14). Median OS was lower in women with EAC (4.4 vs 5.2 months, P = .04) but did not differ after adjustment for patient and tumor characteristics and systemic treatment administration.

Conclusions
We observed statistically significant and clinically relevant gender differences in systemic treatment administration and OS in advanced gastroesophageal cancer. Causes of these disparities may be sex based (ie, related to tumor biology) as well as gender based (eg, related to differences in treatment choices).
Arbitration as an Alternative Dispute Settlement Mechanism at the WTO
Authors: Grey Felicia A 
Published: April 2021

Abstract
This study examines the WTO provisions for arbitration and their underutilisation when compared with litigation. It specifically assesses Articles 21.3(c), 22.6 and 25 of the Dispute Settlement Understanding (DSU). Of these provisions for arbitration, DSU Article 21.3(c) is most often invoked, while Article 25 is seldomly used. The paralysis in the Appellate Body and the proposed Multi-Party Interim Appeal Arbitration Arrangement (MPIA) have renewed the WTO s attention on Article 25. The study examines this new feature and makes some projections about the WTO s future. It argues that there is a direct relationship between MPIA s success and Article 25's increased usage. There is a concern, however, about whether MPIA s success will disincentivise interest and urgency in resolving the Appellate Body's gridlock. While MPIA Members have signalled their commitment to resolving the issue, it remains to be seen whether this will happen and whether the Appellate Body will become functional once again.