bluuebunny/crossref_metadata_2025_split huggingface dataset:
An evidence map of randomised controlled trials evaluating genetic therapies
Authors: Apaydin Eric A. , Richardson Andrea S. , Baxi Sangita , Vockley Jerry , Akinniranye Olamigoke , Ross Rachel , Larkin Jody , Motala Aneesa , Azhar Gulrez , Hempel Susanne 
Published: November 2020

Objectives
Genetic therapies replace or inactivate disease-causing genes or introduce new or modified genes. These therapies have the potential to cure in a single application rather than treating symptoms through repeated administrations. This evidence map provides a broad overview of the genetic therapies that have been evaluated in randomised controlled trials (RCTs) for efficacy and safety.

Eligibility criteria
Two independent reviewers screened publications using predetermined eligibility criteria. Study details and data on safety and efficacy were abstracted from included trials. Results were visualised in an evidence map.

Information sources
We searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov and grey literature to November 2018.

Risk of bias
Only RCTs were included in this review to reduce the risk of selection bias in the evaluation of genetic therapy safety and efficacy.

Included studies
We identified 119 RCTs evaluating genetic therapies for a variety of clinical conditions.

Synthesis of results
On average, samples included 107 participants (range: 1–1022), and were followed for 15 months (range: 0–124). Interventions using adenoviruses (40%) to treat cardiovascular diseases (29%) were the most common.

Description of the effect
In RCTs reporting safety and efficacy outcomes, in the majority (60%) genetic therapies were associated with improved symptoms but in nearly half (45%) serious adverse event (SAEs) were also reported. Improvement was reported in trials treating cancer, cardiovascular, ocular and muscular diseases. However, only 19 trials reported symptom improvement for at least 1 year.

Strengths and limitations of evidence
This is the first comprehensive evidence map of RCTs evaluating the safety and efficacy of genetic therapies. Evidence for long-term effectiveness and safety is still sparse. This lack of evidence has implications for the use, ethics, pricing and logistics of genetic therapies.

Interpretation
This evidence map provides a broad overview of research studies that allow strong evidence statements regarding the safety and efficacy of genetic therapies. Most interventions improve symptoms, but SAE are also common. More research is needed to evaluate genetic therapies with regard to the potential to cure diseases.
A Notch-Dependent Inflammatory Feedback Circuit between Macrophages and Cancer Cells Regulates Pancreatic Cancer Metastasis
Authors: Geng Yawen , Fan Jie , Chen Lianyu , Zhang Chenyue , Qu Chao , Qian Ling , Chen Kun , Meng Zhiqiang , Chen Zhen , Wang Peng 
Published: November 2020

Abstract

Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages, which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1. Autoamplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream IL8, CCL2, IL1α, and uPA paracrine signaling. In turn, activated macrophage-derived IL6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell epithelial–mesenchymal transition and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis.

Significance:
This study provided potential therapeutic targets and robust preclinical evidence for PDAC treatment by interrupting feedback signaling between cancer cells and macrophages with targeted inhibitors.
MET Exon 14–altered Lung Cancers and MET Inhibitor Resistance
Authors: Guo Robin , Offin Michael , Brannon A. Rose , Chang Jason , Chow Andrew , Delasos Lukas , Girshman Jeffrey , Wilkins Olivia , McCarthy Caroline G. , Makhnin Alex , Falcon Christina , Scott Kerry , Tian Yuan , Cecchi Fabiola , Hembrough Todd , Alex Deepu , Shen Ronglai , Benayed Ryma , Li Bob T. , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Rekhtman Natasha , Paik Paul , Zehir Ahmet , Drilon Alexander 
Published: November 2020

Abstract

Purpose:
MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14–altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed.

Experimental Design:
We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of MET exon 14–altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.

Results:
Seventy-five of 168 MET exon 14–altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (P &gt; 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (N = 15) or immunochemistry (N = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; P = 0.02).

Conclusions:
In MET exon 14–altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
Impact of Diabetes Mellitus on Antithrombotic Management Patterns and Long‐Term Clinical Outcomes in Patients With Acute Coronary Syndrome: Insights From the EPICOR Asia Study
Authors: Guan Shaoyi , Xu Xiaoming , Li Yi , Li Jing , Guan Mingzi , Wang Xiaozeng , Jing Quanmin , Huo Yong , Han Yaling 
Published: November 2020

Background
Long‐term use of antiplatelet agents after acute coronary syndrome in diabetic patients is not well known. Here, we describe antiplatelet use and outcomes in such patients enrolled in the EPICOR Asia (Long‐Term Follow‐up of Antithrombotic Management Patterns in Acute Coronary Syndrome Patients in Asia) registry.

Methods and Results
EPICOR Asia is a prospective, observational study of 12 922 patients with acute coronary syndrome surviving to discharge, from 8 countries/regions in Asia. The present analysis included 3162 patients with diabetes mellitus (DM) and 9602 patients without DM. The impact of DM on use of antiplatelet agents and events (composite of death, myocardial infarction, and stroke, with or without any revascularization; individual components, and bleeding) was evaluated. Significant baseline differences were seen between patients with DM and patients without DM for age, sex, body mass index, cardiovascular history, angiographic findings, and use of percutaneous coronary intervention. At discharge, ≈90% of patients in each group received dual antiplatelet therapy. At 2‐year follow‐up, more patients with DM tended to still receive dual antiplatelet therapy (60% versus 56%). DM was associated with increased risk from ischemic but not major bleeding events. Independent predictors of the composite end point of death, myocardial infarction, and stroke in patients with DM were age ≥65 years and use of diuretics at discharge.

Conclusions
Antiplatelet agent use is broadly comparable in patients with DM and patients without DM, although patients with DM are more likely to be on dual antiplatelet therapy at 2 years. Patients with DM are at increased risk of ischemic events, suggesting an unmet need for improved antithrombotic treatment.

Registration

URL:
https://www.clini​caltr​ials.gov
; Unique identifier: NCT01361386.
Sex Differences in Longitudinal Determinants of Carotid Intima Medial Thickening With Aging in a Community‐Dwelling Population: The Baltimore Longitudinal Study on Aging
Authors: Karikkineth Ajoy C. , AlGhatrif Majd , Oberdier Matt T. , Morrell Chris , Palchamy Elango , Strait James B. , Ferrucci Luigi , Lakatta Edward G. 
Published: November 2020

Background
Common carotid intima medial thickness (IMT) increases with aging. However, the longitudinal association between IMT and other age‐associated hemodynamic alterations in men and in women are not fully explored.

Methods and Results

We analyzed repeated measures of IMT, blood pressure, and carotid‐femoral pulse wave velocity over a 20‐year period in 1067 men and women of the Baltimore Longitudinal Study on Aging; participants were ages 20 to 92 years at entry and free of overt cardiovascular disease. Linear mixed‐effects models were used to calculate the individual rates of change (
Change
) of IMT, pulse pressure, mean arterial pressure, and pulse wave velocity, among other covariates. Multivariate regression analysis was used to examine the association of IMT
Change
with baseline and rates of change of hemodynamic parameters and cardiovascular risk factors. IMT increased at accelerating rates from 0.02 mm/decade at age 50 years to 0.05 mm/decade at age 80 years greater rates in men than in women. IMT
Change
was positively associated with baseline low‐density lipoprotein, low‐density lipoprotein
Change
, and baseline systolic blood pressure and systolic blood pressure
Change
, but inversely with baseline diastolic blood pressure and diastolic blood pressure
Change
. When blood pressure was expressed as pulse pressure and MAP, IMT
Change
was positively associated with baseline pulse pressure and pulse pressure
Change
and inversely with baseline mean arterial pressure and mean arterial pressure
Change
. In sex‐specific analysis, these associations were observed in women, but not in men.

Conclusions
In summary, our analyses showed that IMT increases at accelerating rates with aging. Age‐associated changes in IMT were modulated by concurrent changes of low‐density lipoprotein in both sexes, and of pulsatile and mean blood pressure in women but not men.
Risk Factors for Delirium and Cognitive Decline Following Coronary Artery Bypass Grafting Surgery: A Systematic Review and Meta‐Analysis
Authors: Greaves Danielle , Psaltis Peter J. , Davis Daniel H. J. , Ross Tyler J. , Ghezzi Erica S. , Lampit Amit , Smith Ashleigh E. , Keage Hannah A. D. 
Published: November 2020

Background
Coronary artery bypass grafting (CABG) is known to improve heart function and quality of life, while rates of surgery‐related mortality are low. However, delirium and cognitive decline are common complications. We sought to identify preoperative, intraoperative, and postoperative risk or protective factors associated with delirium and cognitive decline (across time) in patients undergoing CABG.

Methods and Results
We conducted a systematic search of Medline, PsycINFO, EMBASE, and Cochrane (March 26, 2019) for peer‐reviewed, English publications reporting post‐CABG delirium or cognitive decline data, for at least one risk factor. Random‐effects meta‐analyses estimated pooled odds ratio for categorical data and mean difference or standardized mean difference for continuous data. Ninety‐seven studies, comprising data from 60 479 patients who underwent CABG, were included. Moderate to large and statistically significant risk factors for delirium were as follows: (1) preoperative cognitive impairment, depression, stroke history, and higher European System for Cardiac Operative Risk Evaluation (EuroSCORE) score, (2) intraoperative increase in intubation time, and (3) postoperative presence of arrythmia and increased days in the intensive care unit; higher preoperative cognitive performance was protective for delirium. Moderate to large and statistically significant risk factors for acute cognitive decline were as follows: (1) preoperative depression and older age, (2) intraoperative increase in intubation time, and (3) postoperative presence of delirium and increased days in the intensive care unit. Presence of depression preoperatively was a moderate risk factor for midterm (1–6 months) post‐CABG cognitive decline.

Conclusions
This meta‐analysis identified several key risk factors for delirium and cognitive decline following CABG, most of which are nonmodifiable. Future research should target preoperative risk factors, such as depression or cognitive impairment, which are potentially modifiable.

Registration

URL:
https://www.crd.york.ac.uk/prosp​ero/
; Unique identifier: CRD42020149276.
No Future for Bethulia? Judith and Queer Time
Authors: Tamber-Rosenau Caryn 
Published: November 2020

Abstract
The Book of Judith and its main character are fascinating for the ways in which they play with time and history. This article argues that theoretical frameworks of queer temporality are instructive for understanding Judith. Judith’s childlessness, her aberrant daily schedule, and her refusal to work on her enemies’ time mark her as someone resisting normative time and a focus on the future. At the same time, however, Judith does ensure a future for Bethulia, and, by extension, for Israel. Consequently, this article also explores how the Book of Judith itself plays with the idea of history, calling into question the very future Judith supposedly ensures. The article also highlights the absence of eschatological thinking in the Book of Judith. Finally, this article discusses the implications of such an erring, queer narrative for thinking about Jewish history and the biblical canon.
Aristotle on the Unity of the Nutritive and Reproductive Functions
Authors: Coates Cameron F. , Lennox James G. 
Published: November 2020

Abstract
In De Anima 2.4, Aristotle claims that nutritive soul encompasses two distinct biological functions: nutrition and reproduction. We challenge a pervasive interpretation which posits ‘nutrients’ as the correlative object (antikeimenon) of the nutritive capacity. Instead, the shared object of nutrition and reproduction is that which is nourished and reproduced: the ensouled body, qua ensouled. Both functions aim at preserving this object, and thus at preserving the form, life, and being of the individual organism. In each case, we show how Aristotle’s detailed biological analysis supports this ontological argument.
Zeno Beach
Authors: Rosen Jacob 
Published: November 2020

Abstract
On Zeno Beach there are infinitely many grains of sand, each half the size of the last. Supposing Aristotle denied the possibility of Zeno Beach, did he have a good argument for the denial? Three arguments, each of ancient origin, are examined: (1) the beach would be infinitely large; (2) the beach would be impossible to walk across; (3) the beach would contain a part equal to the whole, whereas parts must be lesser. It is attempted to show that none of these arguments was Aristotle’s. Indeed, perhaps Aristotle’s finitism applied to magnitude only, not plurality.
Simple isolation for two forms of malic enzyme from crustacean abdomen muscle
Authors: Gronczewska Jadwiga , Skorkowski Edward F. 
Published: November 2020

Abstract
Two forms of NADP-dependent malic enzyme (ME, EC 1.1.1.40) were purified from the abdomen muscle of the crayfish Orconectes limosus (Rafinesque, 1817) and the shrimp Crangon crangon L., 1758 by affinity chromatography on 2′,5′-ADP-Sepharose 4B, with good qualitative recovery in a single step, using a substrate activation method with a malate–manganese chloride pair. The enzymes were identified by native polyacrylamide gel electrophoresis stained for protein and enzyme activity. The faster migrating mitochondrial enzyme from crayfish is inhibited by sulfhydryl reagent and loses its activity. Ellman’s Reagent, 5,5′-Dithiobis-(2-nitrobenzoic acid) (DTNB), can be used for the differentiation and measurement of cytoplasmic and mitochondrial malic enzyme in decapod crustacean tissue.
Optimal Decision of Agricultural Machinery Product Quality under the Regulation of Government Subsidy Policy
Authors: Tong Hongzhi , Qian Xiao-Duo , Chen Yujun , Wei Qi , Xia Senmao , Qian Nige , Li Jiaru 
Published: November 2020

Abstract
Some studies have shown that financial subsidy can promote the technology or product innovation of enterprises, and then improve the product quality. However, in the market competition of subsidized and non-subsidized agricultural machinery products, it is of great practical significance to study whether the enterprises subsidized by the government will improve the product quality. Considering that government provides subsidies for agricultural machinery products, a decision- making model for quality of agricultural machinery manufacturers is established. The relationship between government subsidy and quality of agricultural machinery products is analysed by numerical examples. Results show that the product quality and expected cost of agricultural machinery manufacturers are affected by the government’s financial support, but the relationship between financial subsidy and quality of agricultural machinery products is not monotonic. The increase of government subsidy standard has a negative effect on manufacturers improving the quality of agricultural machinery products in the diffusion region of subsidized agricultural machinery products, but the profits of manufacturers will continue to increase with the increase of subsidies. Government subsidies can promote agricultural machinery manufacturers to improve product quality in the non-subsidized agricultural machinery products diffusion region.
Traditionalism in Brazil
Authors: Sedgwick Mark 
Published: November 2020

Abstract
The Traditionalist movement that derives from the French esoteric philosopher René Guénon is known to have been influential in Europe and North America, especially through the activities of religious groups, usually of Sufi origin, and also through the growing impact of the political version of Traditionalism first developed by the Italian esoteric philosopher Julius Evola. This article looks at Traditionalism beyond Europe and North America, taking the important case of Brazil during the 1980s and 1990s, where one of the main Traditionalist Sufi groups, the US-based Maryamiyya, became established, and where two local groups developed, one of which focused exclusively on doctrine, and one of which turned not to Sufism but to T’ai chi and Brazilian indigenous religion. The article also considers a new and important political philosopher, Olavo de Carvalho, who emerged from the Brazilian Traditionalist milieu. Carvalho applied Guénon to political issues rather as Evola had, but unlike Evola combined Traditionalism with Roman Catholicism, a development also found in Argentina during the early twentieth century. During the 2010s, Carvalho’s radical rightist philosophy became widely known in Brazil, where his admirers included the president, Jair Bolsonaro.
Ambiguity in Insider Trading Regulations: Saudi Arabia as a Case Study
Authors: Alomari Yahya A. 
Published: November 2020

Abstract
The Saudi legal system recognises insider trading as a crime and has established laws in order to prevent it. Yet, the complicated nature of insider trading makes it challenging to enact regulations that cover all of the aspects of the crime and clearly identify criminal conduct. This article analyses insider trading regulations in Saudi Arabia and addresses their ambiguities. This article specifies current Saudi regulations pertaining to the crimes of insider trading and disclosing material information, as well as analysing both crimes. It addresses ambiguities found in the language of the law as well as in case law. This article also criticises the definition of insider information under the law. The issue of ‘use’ versus ‘possession’ is discussed: namely, whether what is prohibited is trading on the basis of material non-public information or trading while in possession of material non-public information.
Reverse Mission? Missio Dei and the Spread of African Pentecostalism in the West
Authors: Bangura Joseph Bosco 
Published: November 2020

Abstract
Although mission is no longer a linear stream that flows from North to South, rarely are Southern missionaries in the West construed as participants in God’s mission. Using the concept of missio Dei, this article contests the claim that Southern missionaries in the West are engaged in reverse mission. Beginning with a brief overview of the missio Dei concept, it discusses the meaning, uses and limitations of the various models of reverse mission. Assessing the spread of African Pentecostalism in the West, it contends that mission cannot be reversed if it is of God. The article concludes that mission is a continuum of what God has done in Christ for the oikos throughout the ages, to which humans are privileged participants.
Unholy Territory
Authors: van der Linden David 
Published: November 2020

Abstract
This article studies the mission of French Discalced Carmelite friars in the seventeenth-century Dutch Republic. Established from 1647 onwards in The Hague, Leiden, and Amsterdam, the missionaries’ aim was to minister to the French-speaking Catholics of Holland, but they also sought to convert expatriate French Protestants as part of the wider Counter-Reformation campaign to win back souls lost to the Reformation. Despite conflict with the Walloon churches, however, the Carmelite mission was surprisingly successful in converting Huguenots to the Church of Rome, repatriating many of them to France in the wake of the Revocation. As such, this article sheds new light on the relationship between expatriate communities in Holland, arguing that the Dutch Republic was not only a safe haven for refugees, but also the scene of ongoing conflict between French Protestants and Catholics during the reign of Louis XIV.
Shadows, Highlights and Faces: the Contribution of a ‘Human in the Loop’ to Digital Art History
Authors: Wijntjes M.W.A. 
Published: November 2020

Abstract
While automatic computational techniques appear to reveal novel insights in digital art history, a complementary approach seems to get less attention: that of human annotation. We argue and exemplify that a ‘human in the loop’ can reveal insights that may be difficult to detect automatically. Specifically, we focused on perceptual aspects within pictorial art. Using rather simple annotation tasks (e.g. delineate human heights, indicate highlights and classify gaze direction) we could both replicate earlier findings and reveal novel insights into pictorial conventions. We found that Canaletto depicted human figures in rather accurate perspective, varied viewpoint elevation between approximately 3 and 9 m and highly preferred light directions parallel to the projection plane. Furthermore, we found that taking the averaged images of leftward-looking faces reveals a woman, and for rightward-looking faces showed a male, confirming earlier accounts on lateral gender bias in pictorial art. Lastly, we confirmed and refined the well-known light-from-the-top-left bias. Together, the annotations, analyses and results exemplify how manual annotations can contribute and complement to digital art history.