bluuebunny/crossref_metadata_2025_split huggingface dataset:
Democracy in Ireland
Authors: Stone Peter 
Published: August 2021

Abstract
How democratic is the political system of the Republic of Ireland? Answering this question requires recognizing that the term ‘democracy’ denotes both a normative ideal and a set of political practices aimed at advancing that ideal. In this chapter, I argue that the democratic ideal has both an individual and a collective component. At an individual level, a democracy must embody a conception of democratic equality. At a collective level, a democracy must embody popular sovereignty. I then relate this two-part ideal to Ireland’s political institutions. This task, I will argue, is complicated by the fact that Ireland, like most real-world democracies, employs several different democratic decision-making methods—what I will call direct democracy, electoral democracy, and aleatory democracy. It is difficult, I conclude, to specify how all three methods can be reconciled within a single story about the democratic ideal.
The Irish–British Dimension
Authors: Gillespie Paul 
Published: August 2021

Abstract
Power, scale, and wealth have moulded relations between Ireland and Britain historically and will continue to do so in future. Political relations between them have been determined by these asymmetric factors, giving much greater strength to the larger and richer island. Nevertheless, both islands exist within a larger European and transatlantic setting, a geopolitical fact that can mitigate or counteract Britain’s ability to act exclusively in its own interests. The chapter first explores this history and structure of the Irish–British relationship and then examines current political relations between the two islands, as seen in the intense joint efforts to bring peace to Northern Ireland and to regularize their interstate relations. Brexit rudely interrupts that new more normal relationship, as the third section argues, opening up several scenarios for changing constitutional futures within and between the two islands explored in the final one.
Ireland and European Governance
Authors: O’Brennan John 
Published: August 2021

Abstract
Irish membership of the European Communities in 1973 represented the most significant development in the life of the independent state, and it helped to refashion the economic, political, and social landscape. Membership of the EU brought considerable change to domestic politics, and also to the executive and administration. Adjusting to a dynamic rules-based supranational order required adaptability and pragmatism. This chapter evaluates the impact of ‘Europe’ on Ireland, and the extent to which there are patterns of ‘Europeanization’ in politics and public life as a result of almost five decades of EU membership. It argues that, domestically, Ireland used EU membership as a vehicle for modernization, while externally, the EU provided an increasingly important ‘geopolitical anchor’. And although this Europeanization has been far from uniform, the effect has been a move towards a more self-conscious ‘choice for Europe’. Brexit has confirmed this renewed commitment to European integration.
One Hundred Years of Empirical Aesthetics
Authors: Nadal Marcos , Ureña Esther 
Published: August 2021

Abstract
This article reviews the history of empirical aesthetics since its foundation by Fechner in 1876 to Berlyne’s new empirical aesthetics in the 1970s. The authors explain why and how Fechner founded the field, and how Wundt and Müller’s students continued his work in the early 20th century. In the United States, empirical aesthetics flourished as part of American functional psychology at first, and later as part of behaviorists’ interest in reward value. The heyday of behaviorism was also a golden age for the development of all sorts of tests for artistic and aesthetic aptitudes. The authors end the article by covering the contributions of Gestalt psychology and Berlyne’s motivational theory to empirical aesthetics.
Quantitative dissection of color patterning in the foliar ornamental coleus
Authors: Li Mao , Coneva Viktoriya , Robbins Kelly R , Clark David , Chitwood Dan , Frank Margaret 
Published: August 2021

Abstract
Coleus (Coleus scutellarioides) is a popular ornamental plant that exhibits a diverse array of foliar color patterns. New cultivars are currently hand selected by both amateur and experienced plant breeders. In this study, we reimagine breeding for color patterning using a quantitative color analysis framework. Despite impressive advances in high-throughput data collection and processing, complex color patterns remain challenging to extract from image datasets. Using a phenotyping approach called “ColourQuant,” we extract and analyze pigmentation patterns from one of the largest coleus breeding populations in the world. Working with this massive dataset, we can analyze quantitative relationships between maternal plants and their progeny, identify features that underlie breeder-selections, and collect and compare public input on trait preferences. This study is one of the most comprehensive explorations into complex color patterning in plant biology and provides insights and tools for exploring the color pallet of the plant kingdom.
Diversification of plant agronomic traits by genome editing of brassinosteroid signaling family genes in rice
Authors: Liu Dapu , Yu Zhikun , Zhang Guoxia , Yin Wenchao , Li Lulu , Niu Mei , Meng Wenjing , Zhang Xiaoxing , Dong Nana , Liu Jihong , Yang Yanzhao , Wang Shimei , Chu Chengcai , Tong Hongning 
Published: August 2021

Abstract
Brassinosteroids (BRs) regulate various agronomic traits such as plant height, leaf angle, and grain size in rice (Oryza sativa L.); thus, BR signaling components are promising targets for molecular rational design. However, genetic materials for BR-signaling genes or family members remain limited in rice. Here, by genome editing using clustered regularly interspaced short palindromic repeats (CRSPR)/Cas9 tools, we generated a panel of single, double, triple, or quadruple mutants within three BR signaling gene families, including GSK3/SHAGGY-LIKE KINASE1 (GSK1)–GSK4, BRASSINAZOLE-RESISTANT1 (OsBZR1)–OsBZR4, and protein phosphatases with kelch-like (PPKL)1–PPKL3, under the same background (Zhonghua11, japonica). The high-order mutants were produced by either simultaneously targeting multiple sites on different genes of one family (GSKs and PPKLs) or targeting the overlapping sequences of family members (OsBZRs). The mutants exhibited a diversity of plant height, leaf angle, and grain morphology. Comparison analysis of the phenotypes together with BR sensitivity tests suggested the existence of functional redundancy, differentiation, or dominancy among the members within each family. In addition, we generated a set of transgenic plants overexpressing GSK2, OsBZR1/2, and PPKL2, respectively, in wild-type or activated forms with fusion of different tags, and also verified the protein response to BR application. Collectively, these plants greatly enriched the diversity of important agronomic traits in rice. We propose that editing of BR-related family genes could be a feasible approach for screening of desired plants to meet different requirements. Release of these materials as well as the related information also provides valuable resources for further BR research and utilization.
Zfhx3 modulates retinal sensitivity and circadian responses to light
Authors: Hughes Steven , Edwards Jessica K. , Wilcox Ashleigh G. , Pothecary Carina A. , Barnard Alun R. , Joynson Russell , Joynson Greg , Hankins Mark W. , Peirson Stuart N. , Banks Gareth , Nolan Patrick M. 
Published: August 2021

AbstractMutations in transcription factors often exhibit pleiotropic effects related to their complex expression patterns and multiple regulatory targets. One such mutation in the zinc finger homeobox 3 (ZFHX3) transcription factor, short circuit (Sci, Zfhx3Sci/+), is associated with significant circadian deficits in mice. However, given evidence of its retinal expression, we set out to establish the effects of the mutation on retinal function using molecular, cellular, behavioral and electrophysiological measures. Immunohistochemistry confirms the expression of ZFHX3 in multiple retinal cell types, including GABAergic amacrine cells and retinal ganglion cells including intrinsically photosensitive retinal ganglion cells (ipRGCs). Zfhx3Sci/+mutants display reduced light responsiveness in locomotor activity and circadian entrainment, relatively normal electroretinogram and optomotor responses but exhibit an unexpected pupillary reflex phenotype with markedly increased sensitivity. Furthermore, multiple electrode array recordings of Zfhx3Sci/+retina show an increased sensitivity of ipRGC light responses.
Pneumonia initiates a tauopathy
Authors: Balczon Ron , Lin Mike T. , Lee Ji Young , Abbasi Adeel , Renema Phoibe , Voth Sarah B. , Zhou Chun , Koloteva Anna , Michael Francis C. , Sodha Neel R. , Pittet Jean‐Francois , Wagener Brant M. , Bell Jessica , Choi Chung‐Sik , Ventetuolo Corey E. , Stevens Troy 
Published: August 2021

AbstractPneumonia causes short‐ and long‐term cognitive dysfunction in a high proportion of patients, although the mechanism(s) responsible for this effect are unknown. Here, we tested the hypothesis that pneumonia‐elicited cytotoxic amyloid and tau variants: (1) are present in the circulation during infection; (2) lead to impairment of long‐term potentiation; and, (3) inhibit long‐term potentiation dependent upon tau. Cytotoxic amyloid and tau species were recovered from the blood and the hippocampus following pneumonia, and they were present in the extracorporeal membrane oxygenation oxygenators of patients with pneumonia, especially in those who died. Introduction of immunopurified blood‐borne amyloid and tau into either the airways or the blood of uninfected animals acutely and chronically impaired hippocampal information processing. In contrast, the infection did not impair long‐term potentiation in tau knockout mice and the amyloid‐ and tau‐dependent disruption in hippocampal signaling was less severe in tau knockout mice. Moreover, the infection did not elicit cytotoxic amyloid and tau variants in tau knockout mice. Therefore, pneumonia initiates a tauopathy that contributes to cognitive dysfunction.
Psychological Consequences Among Residents and Fellows During the COVID-19 Pandemic in New York City: Implications for Targeted Interventions
Authors: Kaplan Carly A. , Chan Chi C. , Feingold Jordyn H. , Kaye-Kauderer Halley , Pietrzak Robert H. , Peccoralo Lauren , Feder Adriana , Southwick Steven , Charney Dennis , Burka Larissa , Basist Madeleine , Ripp Jonathan , Akhtar Saadia 
Published: August 2021

Purpose
To examine the psychological impact of the COVID-19 pandemic on medical trainees (residents and fellows) working at Mount Sinai Hospital (MSH) in New York City (NYC), the initial epicenter of the United States pandemic.

Method
The authors administered a survey to 991 trainees in frontline specialties working at MSH in NYC between April and May 2020. The instrument assessed symptoms of major depressive disorder, generalized anxiety disorder, COVID-19-related posttraumatic stress disorder, and burnout. Psychiatric screens were aggregated into 1 composite measure, and meeting criteria on any of the 3 scales was considered a positive screen for psychiatric symptoms. The survey also assessed COVID-19-related exposures, worries, coping strategies, and desired interventions. Multivariable logistic regressions were conducted to identify factors associated with psychiatric symptoms and burnout.

Results
Of the 560 respondents (56.6% response rate), 29.7% screened positive for psychiatric symptoms and 35.8% screened positive for burnout. History of a mental illness, COVID-19-related duties and personal/career worries, and coping by substance use were associated with increased likelihood of screening positive for psychiatric symptoms. Positive emotion-focused coping and feeling valued by supervisors were associated with decreased likelihood. Internal medicine and surgical specialties, a history of mental illness, increased duty hours, duty-related worries, personal/career worries, coping via self-blame and venting, and coping via substance use were associated with higher odds of burnout. Feeling valued by supervisors was associated with decreased burnout odds. The most common crisis-related needs included access to personal protective equipment, food provisions, and financial support.

Conclusions
Psychological distress and burnout affected approximately one-third of trainees sampled during the height of the pandemic in NYC. As the pandemic surged beyond NYC, these findings suggest that interventions should include addressing basic needs, promoting leadership affirmation, moderating duty hours, supporting trainees financially, and enhancing mental health support.
Factors Associated With Leaving Against Medical Advice From Inpatient Substance Use Detoxification Treatment
Authors: Person Ulziibat Shirendeb , Lin Megan , Fogel Joshua , Parrill Allison , Bishev Daniel , Takhi Manpreet , Joshaghani Hesam , Korie Ijendu , Branch Romain , Ioannou Constantine , Kalash Glenn 
Published: August 2021

Objective:
The objective of this study was to identify factors associated with leaving against medical advice (AMA) from inpatient substance use detoxification treatment.

Methods:
A retrospective study of 832 adult patients discharged AMA from an inpatient substance use detoxification unit. Variables from the following factors were included: demographics, substance type, medical history, psychiatric history, tobacco use, detoxification protocol, legal history, and reason for discharge AMA. The outcome variable was days until discharge AMA.

Results:
For demographics, only increased age was significantly associated with increased days before leaving AMA (B=0.002, SE=0.001, P< 0.01). For detoxification protocol, lorazepam was significantly associated with increased days before leaving AMA (B=0.06, SE=0.03, P< 0.05). For reasons for discharge AMA, only personal obligation was significantly associated with increased days before leaving AMA (B=0.05, SE=0.02, P< 0.01). Medical history, substance type, psychiatric history, tobacco use, and legal history were each not significantly associated with days before leaving AMA.

Conclusions:
This study identified factors associated with leaving AMA from substance use detoxification units. Clinicians may find it useful to spend more time counseling younger patients to encourage engagement in the entire spectrum of care, including detoxification completion. Patients who cited personal obligations as a reason for leaving AMA stayed more days than those who did not cite personal obligations as a reason for leaving AMA. Clinicians may thus find it useful to assess the urgency of the patient’s personal obligations before initiating detoxification, highlight ways addiction impacts each patient’s personal obligations, and identify available supports in the community to promote treatment completion.
Immune Checkpoint Inhibitor–associated Diarrhea and Colitis: A Systematic Review and Meta-analysis of Observational Studies
Authors: Tran Ashley N. , Wang Melinda , Hundt Melanie , Chugh Rishika , Ohm Jonathan , Grimshaw Alyssa , Ciarleglio Maria , Hung Kenneth W. , Proctor Deborah D. , Price Christina C. , Laine Loren , Al-Bawardy Badr 
Published: August 2021

Background:
Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but are associated with diarrhea and colitis. The objective of our systematic review and meta-analysis was to determine the incidence and outcomes of ICI-associated diarrhea and colitis. Bibliographic databases were searched through August 13, 2019, for observational studies of ICI therapy reporting the incidence and/or treatment of diarrhea or colitis. The primary outcome was ICI-associated diarrhea and colitis. Meta-analyses were performed with random-effects models. Twenty-five studies (N=12,661) were included. All studies had a high risk of bias in at least 1 domain. The overall incidence of diarrhea/colitis was 12.8% [95% confidence interval (CI), 8.8–18.2, I
2=96.5]. The incidence was lower in patients treated with anti–programmed cell death 1/programmed death-ligand 1 (4.1%, 95% CI, 2.6–6.5) than in those treated with anti–cytotoxic T-cell lymphocyte–associated antigen 4 (20.1%, 95% CI, 15.9–25.1). The remission of diarrhea and/or colitis was higher in patients treated with corticosteroids plus biologics (88.4%, 95% CI, 79.4–93.8) than in those treated with corticosteroids alone (58.3%, 95% CI, 49.3–66.7, Q=18.7, P<0.001). ICI were permanently discontinued in 48.1% of patients (95% CI, 17.8–79.1). ICI were restarted after temporary interruption in 48.6% of patients (95% CI, 18.2–79.4) of whom 17.0% (95% CI, 6.4–30.0) experienced recurrence. Real-world incidence of ICI-associated diarrhea/colitis exceeds 10%. These events lead to permanent ICI discontinuation in just over 50% of patients, while <20% have recurrence of symptoms if ICI are resumed. Further studies are needed to identify patients who would benefit from early treatment with biologics as well as appropriate patients to resume ICI therapy.
Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease
Authors: De Tanima , Zhang Honghong , Alarcon Cristina , Lec Bianca , Avitia Juan , Smithberger Erin , Chen Chuyu , Horvath Minnie , Kwan Sara , Young Mary , Adhikari Sarbani , Kwon John , Pacheco Jennifer , Jarvik Gail , Wei Wei-Qi , Mentch Frank , Hakonarson Hakon , Sleiman Patrick , Gordon Adam , Harley John , Linneman Jim , Hebbring Scott , Parisiadou Loukia , Perera Minoli A. 
Published: August 2021

Objectives
Primary nonresponse (PNR) to antitumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR.

Patients and methods
Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS).

Results
We identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46–2.94, P = 2.43 × 10−7, [replication odds ratio: 1.8, 95% CI, 1.04–3.16, P = 0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy-related pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10−4], pigmentary iris degeneration [P = 5.9 × 10−4], diverticulum of esophagus [P = 7 × 10−4]).

Conclusions
We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD.
Exploring the Face Validity of the Pain Numeric Rating Scale Among Healthcare Providers
Authors: Link Peyton , Venkatachalam Aardhra M. , Aguilera Veronica , Stutzman Sonja E. , Olson DaiWai M. 
Published: August 2021

ABSTRACT

BACKGROUND: Healthcare providers (HCPs) use the numeric rating scale (NRS) under the assumption that it provides reliable information from which to make decisions regarding analgesic administration. METHODS: We explored the face validity of the NRS using a prospective single-blinded observational design. Pre and post NRS scores were obtained from HCPs who submerged their hand in a bucket of ice water (pain stimulus). RESULTS: Despite a consistent similar pain source, individual HCPs rated their pain very differently (range, 2–10), and there was a significant difference in self-estimated pain tolerance (μ = 7.06 [SD, 1.43]) and actual pain scores (μ = 6.35 [SD, 2.2]; t = 4.08, P < .001). CONCLUSION: The findings indicate a limitation in the face validity of the NRS. The high variance in NRS scores reaffirms the subjectivity of pain perception and brings into question the utility of using NRS scores when determining analgesic dosages.
Safety of Lubiprostone in Pediatric Patients With Functional Constipation
Authors: Hussain Sunny Z. , Labrum Barrett , Mareya Shadreck , Stripling Stephen , Clifford Robert 
Published: August 2021

ABSTRACTObjectives:Pediatric functional constipation (PFC) affects up to 30% of children. Current treatments often do not sustain symptomatic relief. Lubiprostone is a locally acting chloride channel activator that promotes fluid secretion into the small bowel without affecting serum electrolyte concentrations. We assessed the safety/tolerability of oral lubiprostone as treatment for PFC in a 24‐week study.Methods:This phase 3 open‐label safety trial conducted from April‐November 2016 at 13 US sites included patients (ages 6–17 years) diagnosed with PFC (Rome III criteria). Patients <50 and ≥50 kg received lubiprostone 12 or 24 mcg twice daily, respectively, for 24 weeks. Safety endpoints included incidence of treatment‐emergent adverse events (TEAEs) and changes from baseline in clinical laboratory parameters and vital signs.Results:Overall, 87 patients receiving lubiprostone, 64.3% (36/56) in the 12‐mcg group and 54.8% (17/31) in the 24‐mcg group, completed the study. Of 12 TEAEs leading to discontinuation, only upper abdominal pain occurred in >1 patient. TEAEs were mostly mild in intensity, with gastrointestinal disorders (diarrhea, vomiting) most frequently reported. No safety concerns were found in vital signs, abbreviated physical examinations, and laboratory tests. Subgroup analyses assessed an impact of age, sex, and race categories on TEAEs and treatment‐related adverse events. Mean investigators’ assessments of treatment effectiveness (scale of 0–4) for lubiprostone 12‐ and 24‐mcg groups, respectively, were 2.8 and 2.9 at week 12, and 2.7 and 2.2 at week 24.Conclusions:Lubiprostone was well tolerated in the pediatric population. The incidence of TEAEs was comparable to that observed in previous clinical trials and in adults.