bluuebunny/crossref_metadata_2025 huggingface dataset:
Open Government
Authors: Murphy Gary
Published: August 2021

Since Irish independence in 1922, governance structures have been excessively secretive. Political and civil service elites operated on a presumption of secrecy and a principle that the public did not need to know about decisions being taken in their name. In the last two decades, a number of policy innovations have gone some way towards providing for a more open polity. These include Ombudsman, regulation of lobbying, and freedom of information legislation, enacted over concerns about payments to politicians and a series of catastrophic public policy decisions that led to the bailout of the Irish economy by the International Monetary Fund, the European Commission, and the European Central Bank. This chapter assesses the importance of the principle of open government in modern Irish politics. It examines the nature of secrecy, assesses the tentative opening up of government since the 1980s, and analyses the open government proposals introduced since 2011.
What Kind of Ireland?
Authors: Hardiman Niamh , Farrell David M. , Carolan Eoin , Coakley John , Regan Aidan , Scott Colin , Tonra Ben , Zellentin Alexa
Published: August 2021

Modern Ireland is a relatively wealthy and politically stable democracy, but it bears the deep marks of its route to this point. This introductory chapter draws together some key themes that run through this volume and profiles the core contributions of each of its chapters. The overall story is one of contradictory influences. The political institutions of the state, notwithstanding much innovation over time, retain a bias toward a remarkably strong executive. The long-standing weaknesses of social democratic electoral mobilization both reflect and reinforce a conservative and market-oriented tilt in policy priorities. The ideas that animate public discourse show a creative but sometimes problematic tension between republican and communitarian ideals on the one hand, and liberal ideas and values on the other. Ireland has assumed a confident role on the world stage and especially within the European Union (EU), but relations with its nearest neighbour, the United Kingdom, can often be problematic, not least because of the complexity of the politics of Northern Ireland. And while on many measures Ireland is among the wealthiest of the EU member states, this is not the lived reality for a great many of its citizens, and the nuances of why this is so need to be carefully assessed. Overall, this introductory chapter offers an overview of the whole Handbook while also making an original contribution in its own right.
Democracy in Ireland
Authors: Stone Peter
Published: August 2021

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

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

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

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

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

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

Mutations 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

Pneumonia 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

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

Objectives:

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.
Attentional demands of cane-free walking and cane walking in subacute stroke patients who have just learned to walk without a cane
Authors: Chen Hui-Ya , Chen Hsiu-I , Fu Shu-Yi , Wang Chun-Hou , Hsieh Ya-Wen
Published: August 2021

This study compared the attentional demands between cane-free walking and cane walking in patients with stroke during the transitional period of cane weaning. Patients with stroke who had just learned to walk cane-free were recruited. Cross-sectional measurement was scheduled within 30 days since the patients were able to walk independently without a quad cane. The dual-tasking paradigm required participants to walk with and without a cane, as well as perform continuous subtractions by 1 s (low-demand) or 3 s (high-demand). The cognitive-motor interference (CMI) of walking velocity was calculated as [(low-demand − high-demand)/low-demand]  × 100%. Nine participants (average age, 53.4 ± 6.4 years; stroke onset, 38–131 days) were recruited, and eight showed positive CMI. The paired t-test confirmed a significantly smaller CMI during cane-free walking than during cane walking [t (8) = −3.168; P = 0.013]. The Pearson correlation tests revealed associations between age and CMI of cane walking (r = 0.751; P = 0.010) and CMI of cane-free walking (r = 0.584; P = 0.050). The time since independent cane-free walking was associated with CMI of cane walking (r = 0.699; P = 0.018). In conclusion, experience with cane-free walking leads to increased attentional demand for cane walking. In subacute stroke patients weaning use of a cane, the attentional demand for cane-free walking decreases to less than that of cane walking. During both cane and cane-free walking, the older the participant, the more the walking performance deteriorated due to dual-tasking.
Financial Toxicity in Adolescents and Young Adults With Cancer
Authors: Ghazal Lauren V. , Gormley Maurade , Merriman John D. , Santacroce Sheila J.
Published: August 2021

Background

A cancer diagnosis as an adolescent and young adult (AYA) poses exceptional challenges, including potential greater financial toxicity than older survivors experience who have had more time for career establishment and to build financial assets. Costs to patients have increased more than the past decade; prospects for AYA long-term survival have also increased. A better understanding of what financial toxicity is, how it presents, and the immediate and longer-term implications for AYAs is needed.

Objective

The aim of this study was to analyze the concept financial toxicity in AYAs diagnosed with cancer.

Methods

We used Rodgers’ evolutionary method and articles published between January 2013 and December 2020.

Results

We identified key antecedents, attributes, and consequences of financial toxicity in AYAs and review its related terms that have often been used as surrogate terms. Attributes were financial burden, financial distress, and competing financial pressures. Consequences were mostly adverse and persistent and included engaging in various financial problem-solving behaviors, material hardship and poor financial well-being, and deteriorated quality of life.

Conclusions

Results of this analysis clarify financial toxicity and provide guidance for a conceptual framework in the context of AYA cancer survivorship. Its consequences in AYAs with cancer are profound and will continue to evolve over time with changes in health systems and the economy.

Implications for Practice

Oncology nurses should understand the attributes and consequences of financial toxicity for AYAs throughout the cancer trajectory. Future research on financial toxicity should extend across AYAs living with other chronic illnesses and cancer survivors in other age groups.
Associations Between Intraluminal Tumor Cell Involvement in Serially Examined Fallopian Tubes and Endometrial Carcinoma Characteristics and Outcomes
Authors: Rodriquez Monica , Felix Ashley S. , Brett Mary Anne , Samimi Goli , Duggan Máire A.
Published: August 2021

Approximately 12% of routinely examined fallopian tubes of endometrial carcinoma (EC) cases have intraluminal tumor cells (ILTCs). ILTC associations with EC characteristics and outcomes are understudied, and unknown in serially examined and embedded tubal fimbriae. Glass slides of serially examined and embedded tubal fimbriae for 371 EC cases were independently reviewed by 2 pathologists who recorded ILTC presence and characterized them as mucosal if involved and floating if not. Disagreements were reviewed by a third pathologist, and agreement between any 2 determined final ILTC status. Clinico-pathologic associations and ILTC presence were tested for significance (P<0.05) by univariable analysis, and stage and histotype determinants were included in a multivariable analysis. The Kaplan-Meier estimates and log-rank tests compared overall and EC-specific survival, and Cox proportional regression estimated hazard ratios. ILTCs were present in 56 (15.1%) cases: 30 mucosal and 26 floating. FIGO stage 3/4, lymph-vascular space invasion, deep myometrial invasion, nonendometrioid histotype, and adjunctive chemotherapy were significantly associated with ILTC presence, and only stage was significant in the multivariable analysis. Overall, 61 women died: 30 of whom died of EC. ILTCs were nonsignificantly associated with higher overall and EC-specific mortality and mucosal ILTCs had the highest hazard ratios (1.64 and 1.89, respectively). Serially examined and embedded tubal fimbriae have a higher prevalence of ILTCs than routinely examined tubes, and high FIGO stage is an independent determinant. A prognostic effect was not found, but the higher trending hazard ratios suggest additional study is needed to determine whether ILTCs and in particular mucosal ILTCs adversely affect prognosis.
Variant landscape of theRYR1 genebased on whole genome sequencing of the Singaporean population
Authors: Yu Foo Claribel Tian , To Yi Hui , Irwanto Astrid , Ng Alvin Yu-Jin , Yan Benedict , Huey Chew Sophia Tsong , Liu Jianjun , Ti Lian Kah
Published: August 2021

Background

TheRYR1gene codes for a ryanodine receptor which is a calcium release channel in the skeletal muscle sarcoplasmic reticulum. It is associated with Malignant Hyperthermia (MH) and several congenital myopathies including Central Core Disease (CCD), Multiminicore Disease (MMD) and Congenital Fibre-Type Disproportion (CFTD). There is currently little information on the epidemiology ofRYR1variants in Asians. Our study aims to describe theRYR1variant landscape in a Singapore cohort unselected forRYR1-associated conditions.

Methods

Data was retrieved from the SG10K pilot project, where whole genome sequencing was performed on volunteers unselected and undetermined forRYR1-associated conditions. Variants were classified based on pathogenicity using databases ClinVar and InterVar. Allele frequencies of pathogenic variants were compared between Chinese, Indians and Malays. Using databases ExAC, GnomAD and GenomeAsia 100k study, we further compared local allele frequencies to those in Europe, America and Asia.

Results

Majority of theRYR1variants were missense mutations. We identified four pathogenic and four likely pathogenicRYR1variants. All were related to the aforementionedRYR1-associated conditions. There were 6 carriers ofRYR1pathogenic variants amongst 4810 individuals, corresponding to an allele frequency of 0.06%. The prevalence of pathogenic variants was the highest amongst Indians (4 in 1127 individuals). Majority of pathogenic and likely pathogenic mutations were missense and located in mutational hotspots. These variants also occurred at higher frequencies in Asians than globally.

Conclusion

This study describes the variant landscape of theRYR1gene in Singapore. This knowledge will facilitate local efforts in developing precision medicine.
Deep learning based behavioral profiling of rodent stroke recovery
Authors: Weber Rebecca Z , Mulders Geertje , Kaiser Julia , Tackenberg Christian , Rust Ruslan
Published: August 2021

Stroke research heavily relies on rodent behavior when assessing underlying disease mechanisms and treatment efficacy. Although functional motor recovery is considered the primary targeted outcome, tests in rodents are still poorly reproducible, and often unsuitable for unraveling the complex behavior after injury. Here, we provide a comprehensive 3D gait analysis of mice after focal cerebral ischemia based on the new deep learning-based software (DeepLabCut, DLC) that only requires basic behavioral equipment. We demonstrate a high precision 3D tracking of 10 body parts (including all relevant joints and reference landmarks) in several mouse strains with an accuracy of 99.4%. Building on this rigor motion tracking, a comprehensive post-analysis (with >100 parameters) unveils biologically relevant differences in locomotor profiles after a stroke over a time course of three weeks. We further refine the widely used ladder rung test using deep learning and compare its performance to human annotators. The generated DLC-assisted tests were then benchmarked to five widely used conventional behavioral set-ups (neurological scoring, rotarod, ladder rung walk, cylinder test, and single-pellet grasping) regarding sensitivity, accuracy, time use and costs. We conclude that deep learning-based motion tracking with comprehensive post-analysis provides accurate and sensitive data to describe the complex recovery of rodents following a stroke. The experimental set-up and analysis can also benefit a range of other neurological injuries that affect locomotion.
FragGeneScanRs: better and faster gene prediction for short reads
Authors: Van der Jeugt Felix , Dawyndt Peter , Mesuere Bart
Published: August 2021

FragGeneScanRs is a better and faster Rust implementation of the FragGeneScan gene prediction model for short and error-prone reads. Its command line interface is backward compatible and adds extra features for more flexible usage. Compared to the original C implementation, shotgun metagenomic reads are processed up to 22 times faster using a single thread, with better scaling for multithreaded execution.

Availability and implementation

The Rust code of FragGeneScanRs is freely available from GitHub under the GPL-3.0 license, with instructions for installation, usage and other documentation.
Modeling the SARS-CoV-2 mutation based on geographical regions and time
Authors: Wei Bomin , Sun Yuzhe , Gong Xiang
Published: August 2021

The Coronavirus Disease 2019 (COVID-19) epidemic was first detected in late-December 2019. So far, it has caused 203,815,431 confirmed cases and 4,310,623 deaths in the world. We collected sequences from 150,659 COVID-19 patients. Based on the previous phylogenomic analysis, we found three major branches of the virus RNA genomic mutation located in Asia, America, and Europe which is consistent with other studies. We selected sites with high mutation frequencies from Asia, America, and Europe. There are only 13 common mutation sites in these three regions. It infers that the viral mutations are highly dependent on their location and different locations have specific mutations. Most mutations can lead to amino acid substitutions, which occurred in 3/5’UTR, S/N/M protein, and ORF1ab/3a/8/10. Thus, the mutations may affect the pathogenesis of the virus. In addition, we applied an ARIMA model to predict the short-term frequency change of these top mutation sites during the spread of the disease. We tested a variety of settings of the ARIMA model to optimize the prediction effect of three patterns. This model can provide good help for predicting short-term mutation frequency changes.
Hippocampal and medial prefrontal cortices encode structural task representations following progressive and interleaved training schedules
Authors: Berens Sam C. , Bird Chris M.
Published: August 2021

Memory generalisations may be underpinned by either encoding- or retrieval-based generalisation mechanisms and different training schedules may bias some learners to favour one of these mechanisms over the other. We used a transitive inference task to investigate whether generalisation is influenced by progressive vs randomly interleaved training, and overnight consolidation. On consecutive days, participants learnt pairwise discriminations from two transitive hierarchies before being tested during fMRI. Inference performance was consistently better following progressive training, and for pairs further apart in the transitive hierarchy. BOLD pattern similarity correlated with hierarchical distances in the left hippocampus (HIP) and medial prefrontal cortex (MPFC) following both training schedules. These results are consistent with the use of structural representations that directly encode hierarchical relationships between task features. However, such effects were only observed in the MPFC for recently learnt relationships. Furthermore, the MPFC appeared to maintain structural representations in participants who performed at chance on the inference task. We conclude that humans preferentially employ encoding-based mechanisms to store map-like relational codes that can be used for memory generalisation. These codes are expressed in the HIP and MPFC following both progressive and interleaved training but are not sufficient for accurate inference.

Author summary

Integrating information across distinct situations allows both humans and non-human animals to solve novel problems. For instance, by observing that topaz is hard enough to scratch quartz, and that quartz is hard enough to scratch gypsum, one can infer that topaz must be harder than gypsum - even if these materials have never been seen together. This type of generalisation (transitive inference) can be achieved by combing different pieces of information either, 1) when an inference is actually needed (retrieval-based generalisation), or 2) when new information is first encountered (encoding-based generalisation). We predicted that the use of these generalisation mechanisms depends on the order in which information is presented and whether that information was learnt before an overnight rest. Contrary to our predictions, behavioural and neuroimaging analyses of a transitive inference task in humans showed convergent evidence for encoding-based generalisations in all conditions. While these conditions had a large impact on inferential ability, we found that brain regions involved in memory invariably learnt inferred relationships between items that had not been seen together. Strikingly, this appeared to be the case even when participants where unbale to make accurate inferences.
A method for the fast and photon-efficient analysis of time-domain fluorescence lifetime image data over large dynamic ranges
Authors: Laine Romain F. , Kaminski Clemens F.
Published: August 2021

Fluorescence lifetime imaging (FLIM) allows the quantification of subcellular processes in situ, in living cells. A number of approaches have been developed to extract the lifetime from time-domain FLIM data, but they are often limited in terms of dynamic range, speed, photon efficiency or precision. Here, we focus on one of the best performing methods in the field, the center-of-mass (CMM) method, that conveys advantages in terms of speed and photon efficiency over others. In this paper, however, we identify a loss of photon efficiency of CMM for short lifetimes when background noise is present. We sub-sequently present a new development and generalization of the CMM method that provides for the rapid and accurate extraction of fluorescence lifetime over a large lifetime dynamic range. We provide software tools to simulate, validate and analyze FLIM data sets and compare the performance of our approach against the standard CMM and the commonly employed leastsquare minimization (LSM) methods. Our method features a better photon efficiency than standard CMM and LSM and is robust in the presence of background noise. The algorithm is applicable to any time-domain FLIM dataset.
Female and male microglia are not different in the dentate gyrus of postnatal day 10 mice
Authors: Guez-Barber Danielle , Colon Lorianna M. , Raphael Dana , Wragan Max A. , Yun Sanghee , Eisch Amelia J.
Published: August 2021

Microglia, the resident immune cells of the brain, support normal brain function and the brain’s response to disease and injury. The hippocampal dentate gyrus (DG) is an area of microglial study due to its central role in many behavioral and cognitive functions. Interestingly, microglia and related cells are distinct in female vs. male rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia have been reported in certain hippocampal subregions at specific ages. However, sex differences in the DG have not yet been assessed at P10, a rodent developmental time point translationally relevant to human term gestation. To address this knowledge gap, Iba1+ cells in the DG (which are enriched in the Hilus and Molecular Layer) in female and male C57BL/6J mice were analyzed for their number (via stereology) and density (via stereology and via sampling). Next, Iba1+ cells were classified into published morphology categories. Finally, the percent of Iba1+ cells in each morphology category was multiplied by total cell number to generate a total number of Iba1+ cells in each morphological category. Results show no sex difference in Iba1+ cell number, density, or morphology in the P10 Hilus or Molecular Layer. The lack of sex difference in Iba1+ cells in P10 DG using commonly-employed methodologies (sampling, stereology, morphology classification) provides a baseline from which to interpret microglia changes seen after injury.

HIGHLIGHTS

Sex differences in Iba1+ cells were assessed in the dentate gyrus (DG) of P10 mice

Iba1+ cells were assessed in DG microglia-rich subregions: Hilus and Molecular Layer

Both stereology and sampling approaches were used to quantify Iba1+ cells

No sex difference found in Iba1+ cell number, density, or morphology in P10 mice DG
The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells
Authors: Simoneau Antoine , Xiong Rosalinda , Zou Lee
Published: August 2021

PARP inhibitor (PARPi) is widely used to treat BRCA1/2-deficient tumors, but why PARPi is more effective than other DNA-damaging drugs is unclear. Here, we show that PARPi generates DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner. During the first S phase after PARPi exposure, PARPi induces single-stranded DNA (ssDNA) gaps behind DNA replication forks. By trapping PARP on DNA, PARPi prevents the completion of gap repair until the next S phase, leading to collisions of replication forks with ssDNA gaps and a surge of DSBs. In the second S phase, BRCA1/2-deficient cells are unable to suppress origin firing through ATR, resulting in continuous DNA synthesis and more DSBs. Furthermore, BRCA1/2-deficient cells cannot recruit RAD51 to repair collapsed forks. Thus, PARPi induces DSBs progressively through trans cell cycle ssDNA gaps, and BRCA1/2-deficient cells fail to slow down and repair DSBs over multiple cell cycles, explaining the unique efficacy of PARPi in BRCA1/2-deficient cells.
REST is a major negative regulator of endocrine differentiation during pancreas organogenesis
Authors: Rovira Meritxell , Atla Goutham , Maestro Miguel Angel , Grau Vane , García-Hurtado Javier , Maqueda Maria , Mosquera Jose Luis , Yamada Yasuhiro , Kerr-Conte Julie , Pattou Francois , Ferrer Jorge
Published: August 2021

Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced β-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
Implications of inhibition of Rev1 interaction with Y family DNA polymerases for cisplatin chemotherapy
Authors: Yoon Jung-Hoon , Johnson Robert E. , Prakash Louise , Prakash Satya
Published: August 2021

Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.