bluuebunny/crossref_metadata_2025_split huggingface dataset:
Testicular adenosine acts as a pro-inflammatory molecule: role of testicular peritubular cells
Authors: Missel Annika , Walenta Lena , Eubler Katja , Mundt Nadine , Heikelä Hanna , Pickl Ulrich , Trottmann Matthias , Popper Bastian , Poutanen Matti , Strauss Leena , Köhn Frank-Michael , Kunz Lars , Spehr Marc , Mayerhofer Artur 
Published: May 2021

AbstractExtracellular ATP has been described to be involved in inflammatory cytokine production by human testicular peritubular cells (HTPCs). The ectonucleotidases ENTPD1 and NT5E degrade ATP and have been reported in rodent testicular peritubular cells. We hypothesized that if a similar situation exists in human testis, ATP metabolites may contribute to cytokine production. Indeed, ENTPD1 and NT5E were found in situ and in vitro in HTPCs. Malachite green assays confirmed enzyme activities in HTPCs. Pharmacological inhibition of ENTPD1 (by POM-1) significantly reduced pro-inflammatory cytokines evoked by ATP treatment, suggesting that metabolites of ATP, including adenosine, are likely involved. We focused on adenosine and detected three of the four known adenosine receptors in HTPCs. One, A2B, was also found in situ in peritubular cells of human testicular sections. The A2B agonist BAY60-6583 significantly elevated levels of IL6 and CXCL8, a result also obtained with adenosine and its analogue NECA. Results of siRNA-mediated A2B down-regulation support a role of this receptor. In mouse peritubular cells, in contrast to HTPCs, all four of the known adenosine receptors were detected; when challenged with adenosine, cytokine expression levels significantly increased. Organotypic short-term testis cultures yielded comparable results and indicate an overall pro-inflammatory action of adenosine in the mouse testis. If transferable to the in vivo situation, our results may implicate that interference with the generation of ATP metabolites or interference with adenosine receptors could reduce inflammatory events in the testis. These novel insights may provide new avenues for treatment of sterile inflammation in male subfertility and infertility.
eSkip-Finder: a machine learning-based web application and database to identify the optimal sequences of antisense oligonucleotides for exon skipping
Authors: Chiba Shuntaro , Lim Kenji Rowel Q , Sheri Narin , Anwar Saeed , Erkut Esra , Shah Md Nur Ahad , Aslesh Tejal , Woo Stanley , Sheikh Omar , Maruyama Rika , Takano Hiroaki , Kunitake Katsuhiko , Duddy William , Okuno Yasushi , Aoki Yoshitsugu , Yokota Toshifumi 
Published: May 2021

Abstract
Exon skipping using antisense oligonucleotides (ASOs) has recently proven to be a powerful tool for mRNA splicing modulation. Several exon-skipping ASOs have been approved to treat genetic diseases worldwide. However, a significant challenge is the difficulty in selecting an optimal sequence for exon skipping. The efficacy of ASOs is often unpredictable, because of the numerous factors involved in exon skipping. To address this gap, we have developed a computational method using machine-learning algorithms that factors in many parameters as well as experimental data to design highly effective ASOs for exon skipping. eSkip-Finder (https://eskip-finder.org) is the first web-based resource for helping researchers identify effective exon skipping ASOs. eSkip-Finder features two sections: (i) a predictor of the exon skipping efficacy of novel ASOs and (ii) a database of exon skipping ASOs. The predictor facilitates rapid analysis of a given set of exon/intron sequences and ASO lengths to identify effective ASOs for exon skipping based on a machine learning model trained by experimental data. We confirmed that predictions correlated well with in vitro skipping efficacy of sequences that were not included in the training data. The database enables users to search for ASOs using queries such as gene name, species, and exon number.
The Pervasiveness of Lordship (Italy, 1050–1500)
Authors: Carocci Sandro 
Published: May 2021

Abstract
The impact of medieval lordship on the society it dominated has not received the attention it deserves. This article stresses the need to look at lordship from the bottom up, making an effort to understand how much and in which ways lordship weighed on the life of subjects, by developing the notion of its ‘pervasiveness’. Such a concept is arguably the most effective if we want to evaluate how seigneurial power was more, or less, able and willing to deeply influence the people subject to it. It highlights that in the world of lordship there was a disconnect (or at least potentially) between political power and socio-economic domination. Which factors enabled lordships to become pervasive, and which lords, from which regions, were best equipped with these characteristics? Using the influential French historiographical framework as a starting point, the article considers as case studies a set of signorie in several Italian regions. It highlights the differences between the great territorial lordships of the counts of the Kingdom of Sicily, the barons of Rome and the lords of Lombardy, on the one side, and the innumerable knightly lordships at a lower level on the other. The use of pervasiveness helps us to re-conceptualize lordship itself with different criteria.
Identifying Shocks via Time-Varying Volatility
Authors: Lewis Daniel J 
Published: May 2021

Abstract
I propose to identify an SVAR, up to shock ordering, using the autocovariance structure of the squared innovations implied by an arbitrary stochastic process for the shock variances. These higher moments are available without parametric assumptions on the variance process. In contrast, previous approaches exploiting heteroskedasticity rely on the path of innovation covariances, which can only be recovered from the data under specific parametric assumptions on the variance process. The conditions for identification are testable. I compare the identification scheme to existing approaches in simulations and provide guidance for estimation and inference. I use the methodology to estimate fiscal multipliers peaking at 0.86 for tax cuts and 0.75 for government spending. I find that tax shocks explain more variation in output at longer horizons. The empirical implications of my estimates are more consistent with theory and the narrative record than those based on some leading approaches.
Trading Volume and Time Varying Betas
Authors: Hrdlicka Christopher 
Published: May 2021

Abstract
I show that increased turnover accompanies changes in stocks’ risk exposures. A one standard deviation decrease in a stock’s market beta increases turnover as much as 25%. The sensitivity of turnover to beta changes has grown over time. Market beta changes explain as much as 5% of the monthly cross-sectional variation in turnover. VAR decompositions of returns show turnover is more strongly associated with discount rate news than cash flow news. This mechanism provides a new channel for turnover combined with realized returns to predict long horizon returns and cash flow changes. Further, this mechanism can amplify many prior explored motives for trade.
Brain microstructural properties related to subjective well-being: diffusion tensor imaging analysis
Authors: Maeda Chiaki Terao , Takeuchi Hikaru , Nouchi Rui , Yokoyama Ryoichi , Kotozaki Yuka , Nakagawa Seishu , Sekiguchi Atsushi , Iizuka Kunio , Hanawa Sugiko , Araki Tsuyoshi , Miyauchi Carlos Makoto , Sakaki Kohei , Nozawa Takayuki , Ikeda Shigeyuki , Yokota Susumu , Magistro Daniele , Sassa Yuko , Taki Yasuyuki , Kawashima Ryuta 
Published: May 2021

Abstract
Although it is known that health is not merely the absence of disease, the positive aspects of mental health have been less comprehensively researched compared with its negative aspects. Subjective well-being (SWB) is one of the indicators of positive psychology, and high SWB is considered to benefit individuals in multiple ways. However, the neural mechanisms underlying individual differences in SWB remain unclear, particularly in terms of brain microstructural properties as detected by diffusion tensor imaging. The present study aimed to investigate the relationship between measurements of diffusion tensor imaging [mean diffusivity (MD) and fractional anisotropy] and the degree of SWB as measured using a questionnaire. Voxel-based analysis was used to investigate the association between MD and SWB scores in healthy young adults (age, 20.7 ± 1.8 years; 695 males and 514 females). Higher levels of SWB were found to be associated with lower MD in areas surrounding the right putamen, insula, globus pallidus, thalamus and caudate. These results indicated that individual SWB is associated with variability in brain microstructural properties.
Degradability, in vitro fermentation parameters, and kinetic degradation of diets with increasing levels of forage and chitosan
Authors: Jacaúna Amanna Gonzaga , de Goes Rafael Henrique de Tonissi e Buschinelli , Seno Leonardo de Oliveira , Ítavo Luis Carlos Vinhas , Gandra Jefferson Rodrigues , da Silva Nayara Gonçalves , Anschau Douglas Gabriel , de Oliveira Raquel Tenório , Bezerra Leilson Rocha , Oliveira Ronaldo Lopes 
Published: May 2021

Abstract
Chitosan is the second most important natural biopolymer in the world, extracted from crustaceans, shrimps, and crabs and can modulate rumen fermentation. Our hypothesis is that the addition of chitosan alters the fermentation patterns of different diets for ruminants. This study aimed to evaluate the effects of different levels of chitosan and forage on in vitro dry degradation kinetics and fermentation in a gas production system. The chitosan levels (0, 1625, 3,500, or 7,500 mg/kg of dry matter [DM]) were arranged in a completely randomized block design, and for in vitro ruminal fermentation assay, we used a split splot arrangement. Into the incubator, all chitosan levels were distributed in the four jars, and the forage levels varying on 100, 65, 50, 35, and 20 on DM basis. There was an interaction effect for chitosan and forage levels (P ≤ 0.05) on IVDMD; IVOMD. IVDCP and IVDNDF. Chitosan negatively affected IVDMD in all roughage levels evaluated. The pH and ammonia concentration present effect only for roughage levels and incubation hours. The chitosan did not change (P = 0.3631) the total short-chain fatty acid concentration (overall mean = 21.19 mmol/L) and the C2:C3 ratio (overall mean = 5.85). The IVDCP showed the same decreasing quadratic behavior (P &lt; 0.0001). The increasing chitosan addition increases (P &lt; 0.0001) the gas production and decreases (P &lt; 0.0001) the lag time (parameter C) of diets with greater concentrate participation, characterizing greater efficiency in the degradability of the diet, confirming its potential use in diets for ruminants. Chitosan changes in vitro dry degradation kinetics and fermentation at the minimum dose of 1,722 mg/kg DM for all diets. The roughage level influenced the in vitro nutrients degradability and cumulative gas production.
Triple Challenge: How Medical Students May Solve 3 Long-Standing Problems Bedeviling Health Systems and Medical Education
Authors: Elliott Victoria Stagg , Jackson Jasmyne , Santen Sally A. , Richardson Judee , Heckman Kevin , Hammoud Maya M. 
Published: May 2021

Medical education and the health system must address challenges that, despite significant effort, seem unsolvable. Health systems science (HSS)—the fundamental understanding of how care is delivered, how health professionals work together to deliver that care, and how the health system can improve patient care and health care delivery—is increasingly being recognized as a potential source of solutions to these challenges.
In this article, the authors review the 43 abstracts submitted to the American Medical Association Accelerating Change in Medical Education 2018 Health Systems Science Student Impact Competition that aligned with the goals of HSS. Their qualitative review identified 3 long-standing problems in medicine and medical education that were frequently addressed by the submissions: improving care for those with mental illness (5 submissions), improving diversity in medicine (4 submissions), and improving teamwork and interprofessional education (4 submissions). The authors extracted lessons learned from these abstracts.
Many of the projects detailed in this article continue to make an impact at multiple levels. While not all projects were scientifically rigorous enough to be published on their own and the quality of the data presented in the abstracts varied widely, many provide innovative ideas for potentially solving long-standing problems that may have been overlooked or not considered sufficiently.
These projects and their subsequent analysis demonstrate that not only do medical students make significant impacts on the health system, patients, and other health professionals when equipped with HSS skills, working in health care teams, and advised by mentors, but they also may be able to address some of medicine’s and medical education’s long-standing challenges. The fresh perspective and high energy of medical students are valuable and should be nurtured and encouraged.
Virtual Reality Tailored to the Needs of Post-ICU Patients: A Safety and Immersiveness Study in Healthy Volunteers
Authors: Vlake Johan H. , Wils Evert-Jan , van Bommel Jasper , Korevaar Tim I. M. , Gommers Diederik , van Genderen Michel E. 
Published: May 2021

Objectives:
ICU treatments frequently result in long-term psychologic impairments, negatively affecting quality of life. An effective treatment strategy is still lacking. The aim of this study was to describe and evaluate the safety and immersiveness of a newly designed ICU-specific virtual reality module.

Design:
A randomized controlled healthy volunteer trial.

Setting:
ICU of the Franciscus Gasthuis & Vlietland Hospital (Rotterdam, the Netherlands), a large teaching hospital.

Participants:
Forty-five virtual reality–naive healthy volunteers.

Interventions:
Volunteers were randomized to three arms: the head-mounted display virtual reality group (n = 15), the 2D group (n = 15), and the crossover group (n = 15). Safety was assessed by changes in vital signs and the occurrence of simulator sickness (Simulator Sickness Questionnaire). Immersiveness was assessed using the Igroup Presence Questionnaire.

Measurements and Main Results:
Volunteers in the head-mounted display virtual reality group experienced more mild symptoms of simulator sickness, expressed as symptoms of dizziness (p = 0.04) and stomach awareness (p = 0.04), than the 2D group. Nevertheless, none of the individual Simulator Sickness Questionnaire items were scored as being severe, no changes in vital signs were observed, and no sessions were prematurely stopped. Volunteers in the crossover group experienced a higher total presence (p < 0.001) when using head-mounted display virtual reality, expressed as a higher sense of presence (p < 0.001), more involvement (p < 0.01), and more experienced realism (p < 0.001).

Conclusions:
ICU-specific virtual reality appears safe and more immersive than 2D, implicating that ICU-specific virtual reality is feasible for clinical use. One should however be aware of simulator sickness-related symptoms. Future research is needed to confirm these findings in survivors of critical illness.
Leukocyte Activation Profile Assessed by Raman Spectroscopy Helps Diagnosing Infection and Sepsis
Authors: Ramoji Anuradha , Thomas-Rüddel Daniel , Ryabchykov Oleg , Bauer Michael , Arend Natalie , Giamarellos-Bourboulis Evangelos J. , Eugen-Olsen Jesper , Kiehntopf Michael , Bocklitz Thomas , Popp Jürgen , Bloos Frank , Neugebauer Ute 
Published: May 2021

Objectives:
Leukocytes are first responders to infection. Their activation state can reveal information about specific host immune response and identify dysregulation in sepsis. This study aims to use the Raman spectroscopic fingerprints of blood-derived leukocytes to differentiate inflammation, infection, and sepsis in hospitalized patients. Diagnostic sensitivity and specificity shall demonstrate the added value of the direct characterization of leukocyte’s phenotype.

Design:
Prospective nonrandomized, single-center, observational phase-II study (DRKS00006265).

Setting:
Jena University Hospital, Germany.

Patients:
Sixty-one hospitalized patients (19 with sterile inflammation, 23 with infection without organ dysfunction, 18 with sepsis according to Sepsis-3 definition).

Interventions:
None (blood withdrawal).

Measurements AND MAIN RESULTS:
Individual peripheral blood leukocytes were characterized by Raman spectroscopy. Reference diagnostics included established clinical scores, blood count, and biomarkers (C-reactive protein, procalcitonin and interleukin-6). Binary classification models using Raman data were able to distinguish patients with infection from patients without infection, as well as sepsis patients from patients without sepsis, with accuracies achieved with established biomarkers. Compared with biomarker information alone, an increase of 10% (to 93%) accuracy for the detection of infection and an increase of 18% (to 92%) for detection of sepsis were reached by adding the Raman information. Leukocytes from sepsis patients showed different Raman spectral features in comparison to the patients with infection that point to the special immune phenotype of sepsis patients.

Conclusions:
Raman spectroscopy can extract information on leukocyte’s activation state in a nondestructive, label-free manner to differentiate sterile inflammation, infection, and sepsis.
Optimizing Critical Illness Recovery: Perspectives and Solutions From the Caregivers of ICU Survivors
Authors: Sevin Carla M. , Boehm Leanne M. , Hibbert Elizabeth , Bastin Anthony J. , Jackson James C. , Meyer Joel , Quasim Tara , Bakhru Rita N. , Montgomery-Yates Ashley , Slack Andrew , Still Mary , Netzer Giora , Mikkelsen Mark E. , Iwashyna Theodore J. , Haines Kimberley J. , McPeake Joanne 
Published: May 2021

Objectives:
To understand the unmet needs of caregivers of ICU survivors, how they accessed support post ICU, and the key components of beneficial ICU recovery support systems as identified from a caregiver perspective.

Design:
International, qualitative study.

Subjects:
We conducted 20 semistructured interviews with a diverse group of caregivers in the United States, the United Kingdom, and Australia, 11 of whom had interacted with an ICU recovery program.

Setting:
Seven hospitals in the United States, United Kingdom, and Australia.

Interventions:
None.

Measurements and Main Results:
Content analysis was used to explore prevalent themes related to unmet needs, as well as perceived strategies to improve ICU outcomes. Post-ICU care was perceived to be generally inadequate. Desired caregiver support fell into two main categories: practical support and emotional support. Successful care delivery initiatives included structured programs, such as post discharge telephone calls, home health programs, post-ICU clinics, and peer support groups, and standing information resources, such as written educational materials and online resources.

Conclusions:
This qualitative, multicenter, international study of caregivers of critical illness survivors identified consistently unmet needs, means by which caregivers accessed support post ICU, and several care mechanisms identified by caregivers as supporting optimal ICU recovery.
Two or Three? Approaches to Staging of the Paramedian Forehead Flap for Nasal Reconstruction
Authors: Oleck Nicholas C. , Hernandez J. Andres , Cason Roger W. , Glener Adam D. , Shammas Ronnie L. , Avashia Yash J. , Marcus Jeffrey R. 
Published: May 2021

Summary
The paramedian forehead flap is a historic cornerstone of plastic surgery and a mainstay of complex nasal reconstruction. Although initially described as a 2-stage procedure, several procedural advancements and modifications have been proposed, with the most notable being the addition of a third, intermediate stage. Proponents of this 3-stage approach argue that the addition of an intermediate stage improves flap perfusion, expands lining and structural support options, and provides superior aesthetic outcomes. Although this technique has grown in popularity, studies comparing the 2- versus 3-stage approach are relatively scarce in the literature. Existing comparative studies seem to suggest that the 3-stage paramedian forehead flap may have advantages in large, complex nasal defects and patients at high risk for vascular compromise. Additionally, comparative analyses with respect to aesthetic outcome were found to be largely equivocal, suggesting that surgeon comfort and preference should guide flap selection.
The evaluation of a novel digital immunochromatographic assay with silver amplification to detect SARS-CoV-2
Authors: Kurihara Yoko , Kiyasu Yoshihiko , Akashi Yusaku , Takeuchi Yuto , Narahara Kenji , Mori Sunao , Takeshige Tomonori , Notake Shigeyuki , Ueda Atsuo , Nakamura Koji , Ishikawa Hiroichi , Suzuki Hiromichi 
Published: May 2021

AbstractIntroductionRapid antigen tests are convenient for diagnosing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they have lower sensitivities than nucleic acid amplification tests. In this study, we evaluated the diagnostic performance of Quick Chaser® Auto SARS-CoV-2, a novel digital immunochromatographic assay that is expected to have higher sensitivity than conventional antigen tests.MethodsA prospective observational study was conducted between February 8 and March 24, 2021. We simultaneously obtained two nasopharyngeal samples, one for evaluation with the QuickChaser® Auto SARS-CoV-2 antigen test and the other for assessment with reverse transcription PCR (RT-PCR), considered the gold-standard reference test. The limit of detection (LOD) of the new antigen test was compared with those of four other commercially available rapid antigen tests.ResultsA total of 1401 samples were analyzed. SARS-CoV-2 was detected by reference RT-PCR in 83 (5.9%) samples, of which 36 (43.4%) were collected from symptomatic patients. The sensitivity, specificity, positive predictive value, and negative predictive value were 74.7% (95% confidence interval (CI): 64.0–83.6%), 99.8% (95% CI: 99.5–100%), 96.9% (95% CI: 89.2–99.6%), and 98.4% (95% CI: 97.6–99.0%), respectively. When limited to samples with a cycle threshold (Ct) <30 or those from symptomatic patients, the sensitivity increased to 98.3% and 88.9%, respectively. The QuickChaser® Auto SARS-CoV-2 detected 34–120 copies/test, which indicated greater sensitivity than the other rapid antigen tests.ConclusionsQuickChaser® Auto SARS-CoV-2 showed sufficient sensitivity and specificity in clinical samples of symptomatic patients. The sensitivity was comparable to RT-PCR in samples with Ct<30.