bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain—a Game Changing Parameter for CNS Drug Discovery and Development
Authors: Loryan Irena , Reichel Andreas , Feng Bo , Bundgaard Christoffer , Shaffer Christopher , Kalvass Cory , Bednarczyk Dallas , Morrison Denise , Lesuisse Dominique , Hoppe Edmund , Terstappen Georg C. , Fischer Holger , Di Li , Colclough Nicola , Summerfield Scott , Buckley Stephen T. , Maurer Tristan S. , Fridén Markus 
Published: April 2022

Abstract
Purpose
More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (Kp,uu,brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, Kp,uu,brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations.

Methods
To understand the importance and impact of the Kp,uu,brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives.

Results and conclusions
From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of Kp,uu,brain as compared to other parameters related to brain exposure. Adoption of the Kp,uu,brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of Kp,uu,brain implementation in their companies as ‘game-changing’. Although most companies (74%) consider the current toolbox for Kp,uu,brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.
Construction and Functional Evaluation of a Three-Dimensional Blood–Brain Barrier Model Equipped With Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells
Authors: Kurosawa Toshiki , Sako Daiki , Tega Yuma , Debori Yasuyuki , Tomihara Yumi , Aoyama Kazunobu , Kubo Yoshiyuki , Amano Nobuyuki , Deguchi Yoshiharu 
Published: April 2022

Abstract
Purpose
The purpose of this study was to construct and validate an in vitro three-dimensional blood–brain barrier (3DBBB) model system equipped with brain microvascular endothelial cells derived from human induced pluripotent stem cells (hiPS-BMECs).

Methods
The 3D-BBB system was constructed by seeding hiPS-BMECs onto the capillary lane of a MIMETAS OrganoPlate® 3-lane coated with fibronectin/collagen IV. hiPS-BMECs were incubated under continuous switchback flow with an OrganoFlow® for 2 days. The 3D capillary structure and expression of tight-junction proteins and transporters were confirmed by immunocytochemistry. The mRNA expression of transporters in the 3D environment was determined using qRT-PCR, and the permeability of endogenous substances and drugs was evaluated under various conditions.

Results and Discussion
The expression of tight-junction proteins, including claudin-5 and ZO-1, was confirmed by immunohistochemistry. The permeability rate constant of lucifer yellow through hiPS-BMECs was undetectably low, indicating that paracellular transport is highly restricted by tight junctions in the 3D-BBB system. The mRNA expression levels of transporters and receptors in the 3D-BBB system differed from those in the 2D-culture system by 0.2- to 5.8-fold. The 3D-cultured hiPS-BMECs showed asymmetric transport of substrates of BCRP, CAT1 and LAT1 between the luminal (blood) and abluminal (brain) sides. Proton-coupled symport function of MCT1 was also confirmed.

Conclusion
The 3D-BBB system constructed in this study mimics several important characteristics of the human BBB, and is expected to be a useful high-throughput evaluation tool in the development of CNS drugs.
Finnish UNESCO school educators’ understanding of global citizenship education: Analysis through typologies, ecosocial understanding, and human rights
Authors: Kasa Tuija , Karilainen Laura , Rajala Antti , Cantell Hannele , Kallioniemi Arto 
Published: April 2022

AbstractThis article sheds light on the unexplored field of UNESCO schools in Finland, and the results clarify the relationships between curricula, international commitments, and the understanding of educators in the educational field. It examines how teachers and principals of UNESCO’s Associated Schools Network (ASPnet) in Finland describe their understanding of the role of global citizenship education (GCE). It draws on the typology proposed by Oxley and Morris in which forms of global education are divided into cosmopolitan types and—more critically—advocacy types and subtypes. The article also draws on concepts connected to GCE in the Finnish curricula (namely, ecosocial understanding and human rights). Findings indicate that educators perceived equality, democracy, and ecological sustainability as part of UNESCO schools and their own work. On the other hand, the need for increasing student-centered approaches was noted, racism was perceived as a difficult topic, and active deconstruction of inequalities was less referenced. When analyzing the results through typologies of global citizenship, the critical, spiritual, and economic aspects of GCE received less attention.
Descriptive multiscale modeling in data-driven neuroscience
Authors: Haueis Philipp 
Published: April 2022

AbstractMultiscale modeling techniques have attracted increasing attention by philosophers of science, but the resulting discussions have almost exclusively focused on issues surrounding explanation (e.g., reduction and emergence). In this paper, I argue that besides explanation, multiscale techniques can serve important exploratory functions when scientists model systems whose organization at different scales is ill-understood. My account distinguishes explanatory and descriptive multiscale modeling based on which epistemic goal scientists aim to achieve when using multiscale techniques. In explanatory multiscale modeling, scientists use multiscale techniques to select information that is relevant to explain a particular type of behavior of the target system. In descriptive multiscale modeling scientists use multiscale techniques to explore lower-scale features which could be explanatorily relevant to many different types of behavior, and to determine which features of a target system an upper-scale data pattern could refer to. Using multiscale models from data-driven neuroscience as a case study, I argue that descriptive multiscale models have an exploratory function because they are a sources of potential explanations and serve as tools to reassess our conception of the target system.
The transparency of expressivism
Authors: Freitag Wolfgang , Bräuer Felix 
Published: April 2022

AbstractThe paper argues that Gareth Evans’ argument for transparent self-knowledge is based on a conflation of doxastic transparency with ascriptive transparency.Doxastictransparency means that belief about one’s own doxastic state, e.g., the belief that one thinks that it will rain, can be warranted by ordinary empirical observation, e.g., of the weather. In contrast,ascriptivetransparency says that self-ascriptionsof belief, e.g., “I believe it will rain”, can be warranted by such observation. We first show that the thesis of doxastic transparency is ill-motivated and then offer a non-epistemic interpretation of ascriptive transparency by reference to the theory ofexplicit expressive acts: “I think it will rain” requires attendance to the weather because the utterance expresses a belief about the weather, not about ourselves. This will allow us to avoid what is often called “the puzzle of transparent self-knowledge” while remaining faithful to Evans’ linguistic observations.
Artificial intelligence assessment for early detection and prediction of renal impairment using electrocardiography
Authors: Kwon Joon-myoung , Kim Kyung-Hee , Jo Yong-Yeon , Jung Min-Seung , Cho Yong-Hyeon , Shin Jae-Hyun , Lee Yoon-Ji , Ban Jang-Hyeon , Lee Soo Youn , Park Jinsik , Oh Byung-Hee 
Published: April 2022

Abstract
Purpose
Although renal failure is a major healthcare burden globally and the cornerstone for preventing its irreversible progression is an early diagnosis, an adequate and noninvasive tool to screen renal impairment (RI) reliably and economically does not exist. We developed an interpretable deep learning model (DLM) using electrocardiography (ECG) and validated its performance.

Methods
This retrospective cohort study included two hospitals. We included 115,361 patients who had at least one ECG taken with an estimated glomerular filtration rate measurement within 30 min of the index ECG. A DLM was developed using 96,549 ECGs of 55,222 patients. The internal validation included 22,949 ECGs of 22,949 patients. Furthermore, we conducted an external validation with 37,190 ECGs of 37,190 patients from another hospital. The endpoint was to detect a moderate to severe RI (estimated glomerular filtration rate < 45 ml/min/1.73m2).

Results
The area under the receiver operating characteristic curve (AUC) of a DLM using a 12-lead ECG for detecting RI during the internal and external validation was 0.858 (95% confidence interval 0.851–0.866) and 0.906 (0.900–0.912), respectively. In the initial evaluation of 25,536 individuals without RI patients whose DLM was defined as having a higher risk had a significantly higher chance of developing RI than those in the low-risk group (17.2% vs. 2.4%, p < 0.001). The sensitivity map indicated that the DLM focused on the QRS complex and T-wave for detecting RI.

Conclusion
The DLM demonstrated high performance for RI detection and prediction using 12-, 6-, single-lead ECGs.
The Atrial Fibrillation Better Care (ABC) Pathway and Clinical Outcomes in Patients with Atrial Fibrillation: the Prospective Murcia AF Project Phase II Cohort
Authors: Rivera-Caravaca José Miguel , Roldán Vanessa , Martínez-Montesinos Lorena , Vicente Vicente , Lip Gregory Y.H. , Marín Francisco 
Published: April 2022

ABSTRACT

Background

The Atrial fibrillation Better Care (ABC) pathway was proposed for a more holistic or integrated care approach to atrial fibrillation (AF) management. We investigated whether adherence with the ABC pathway reduced the risk of adverse clinical outcomes in real-world AF patients starting vitamin K antagonist (VKAs) therapy.

Methods

Prospective cohort study including AF outpatients starting VKA therapy from July 2016 to June 2018. Patients were considered as adherent if all ABC pathway criteria (A: Avoid stroke; B: Better symptom control; and C: Cardiovascular risk factors/comorbidities management) were fulfilled. The primary endpoints were all-cause mortality, net clinical outcomes (NCOs), major adverse cardiovascular events (MACE), and composite thrombotic/thromboembolic events at 2 years.

Results

We enrolled 1045 patients (51.6% female; median age 77 [70–83] years). Of these, 63.0% (658) were adherent to the ABC pathway and 37% (387) were considered non-adherent. Compared to non-adherent patients, those who were ABC adherent had lower event rates for all-cause mortality (13.76 vs. 6.56; p<0.001), NCOs (19.65 vs. 11.94; p<0.001), and MACE (11.88 vs. 7.75; p=0.006) during the follow-up. Adjusted Cox regression analyses demonstrated that the ABC pathway adherent care reduced the risks of all-cause mortality (aHR 0.57, 95% CI 0.42–0.78), NCOs (aHR 0.72, 95% CI 0.56–0.92), and cardiovascular mortality (aHR 0.54, 95% CI 0.32–0.90). Event-free survivals for all-cause mortality, NCOs (both log-rank p-values <0.001), and MACE (log-rank p-value = 0.004) were also higher in ABC pathway adherent patients.

Conclusions
In this real-world prospective cohort of AF patients starting VKA therapy, adherence to the ABC pathway management at baseline significantly reduced the risk of NCOs, all-cause mortality, and cardiovascular death at 2 years.
Trainee Headache Education and Management Enhancement (THEME) Study
Authors: Todd Candice , Pavalaghanthan Hariesh , Lay Christine , Lagman-Bartolome Ana Marissa 
Published: April 2022

ABSTRACT:We investigated the association between clinical rotation at a specialized headache center and headache knowledge of resident trainees. Using standardized pre- and post-questionnaires, change in self-reported knowledge of headache disorders and management in 31 participants undertaking clinical rotations were evaluated. There was a statistically significant improvement in self-reported measures of headache disorder knowledge post-rotation [mean score (SD), 3.19(0.543), p < 0.001] and significant improvement in overall knowledge measured using case-based questionnaires pre- vs. post-rotation [7.1(1.4) vs. 7.9(1.5), p = 0.003]. Rotation at a specialized headache center improved trainees’ self-reported knowledge and test-based scores, suggesting that such rotation should be included in postgraduate curriculum.
Examining a collaborative community amongst music student teachers in Korea
Authors: Shin Jihae 
Published: April 2022

AbstractTeacher collaboration has been recognised as one of the most influential factors positively affecting school teaching practice. To add to the literature in this area, I investigated a collaborative community of Korean preservice music teachers. The results showed that the collaborative community was a place where these preservice music teachers were able to share their thoughts about their passion for music teaching and various philosophical issues closely related to the role of music in public education. In addition, the collaborative community played a role in helping preservice music teachers focus on the level of students’ current knowledge and understand the importance of instructional pacing. Finally, music student teachers freely and frequently expressed their worries and frustration about student teaching and gained emotional support from their peers.
Which choices merit deference? A comparison of three behavioural proxies of subjective welfare
Authors: Ferreira João V. 
Published: April 2022

AbstractRecently several authors have proposed proxies of welfare that equate some (as opposed to all) choices with welfare. In this paper, I first distinguish between two prominent proxies: one based oncontext-independent choicesand the other based onreason-based choices. I then propose an original proxy based on choices that individuals state they would want themselves to repeat at the time of the welfare/policy evaluation (confirmed choices). I articulate three complementary arguments that, I claim, support confirmed choices as a more reliable proxy of welfare than context-independent and reason-based choices. Finally, I discuss the implications of these arguments fornudgesandboosts.
Sportmedizinische Beratung nach akuter Rhabdomyolyse bei erblicher Myopathie – eine herausfordernde Leistungsdiagnostik
Authors: Schnadthorst Philipp Georg , Schulze Christoph , Grunwald Martina 
Published: April 2022

Zusammenfassung
Zusammenfassung Physiologische Erhöhungen der Kreatinin-Kinase nach körperlicher Betätigung sind häufig und ein sinnvoller Cut-off-Wert besteht dabei nicht. Die Stufendiagnostik bei einer seltenen Ursache hierfür und nach Auftreten einer Rhabdomyolyse wird in dieser Arbeit dargestellt.
Anamnese Ein 36-jähriger Soldat entwickelte nach starker körperlicher Belastung ein akutes Nierenversagen aufgrund einer Rhabdomyolyse.
Untersuchung und Diagnostik Sportlicher Habitus, CK-Elevation bei hochnormalen Retentionswerten. Nach Stufenbelastung auf dem Fahrradergometer massiver CK-Anstieg. Anschließend Sportkarenz und Einleitung einer Stufendiagnostik.
Therapie und Verlauf Die humangenetische Diagnostik konnte eine erbliche Myopathie des Fettstoffwechsels (VLCAD-Mangel) nachweisen. Eine individualisierte Leistungsdiagnostik ist zur Ermittlung der sicheren Belastungsgrenze herangezogen worden. In der sportlichen Erprobung dieser Leistungsgrenzen konnte keine übermäßige CK-Aktivierung festgestellt werden.
Folgerung Die hier bestehende spät auftretende Variante des VLCAD-Mangels ist durch rezidivierende Rhabdomyolysen gekennzeichnet, welche nach starker körperlicher Belastung, Fastenperioden oder Dehydratation auftreten können. Die körperliche Belastung kann nach Bestimmung der individuellen Toleranz fortgesetzt werden.
Eine unerwartete Komplikation: Kontralateraler Spannungspneumothorax nach transbronchialer Zangenbiopsie
Authors: Gutowski Jan-Philipp , Sachsenweger Jens , May Katharina , Lange Christoph , Heyckendorf Jan 
Published: April 2022

ZusammenfassungDer ipsilaterale Pneumothorax nach transbronchialer Zangenbiopsie ist keine außergewöhnliche Komplikation. In dem hier dargestellten Fall kam es nach zunächst komplikationsloser transbronchialer Zangenbiopsie neben einem ipsilateralen Pneumothorax zu einem kontralateralen Spannungspneumothorax und einem Pneumoperitoneum.
Post-polypectomy surveillance interval and advanced neoplasia detection rates: a multicenter, retrospective cohort study
Authors: Cross Amanda J. , Robbins Emma C. , Pack Kevin , Stenson Iain , Rutter Matthew D. , Veitch Andrew M. , Saunders Brian P. , Duffy Stephen W. , Wooldrage Kate 
Published: April 2022

Abstract
Background Longer post-polypectomy surveillance intervals are associated with increased colorectal neoplasia detection at surveillance in some studies. We investigated this association to inform optimal surveillance intervals.
Methods Patients who underwent colonoscopy and post-polypectomy surveillance at 17 UK hospitals were classified as low/high risk by baseline findings. We compared detection rates of advanced adenomas (≥ 10 mm, tubulovillous/villous, high grade dysplasia), high risk findings (HRFs: ≥ 2 serrated polyps/[adenomas] of which ≥ 1 is ≥ 10 mm or has [high grade] dysplasia; ≥ 5 serrated polyps/adenomas; or ≥ 1 nonpedunculated polyp ≥ 20 mm), or colorectal cancer (CRC) at surveillance colonoscopy by surveillance interval (< 18 months, 2, 3, 4, 5, 6 years). Risk ratios (RRs) were estimated using multivariable regression.
Results Of 11 214 patients, 7216 (64 %) were low risk and 3998 (36 %) were high risk. Among low risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 7.8 %, 3.7 %, and 1.1 %, respectively. Advanced adenoma detection increased with increasing surveillance interval, reaching 9.8 % with a 6-year interval (P trend < 0.001). Among high risk patients, advanced adenoma, HRF, and CRC detection rates at first surveillance were 15.3 %, 10.0 %, and 1.5 %, respectively. Advanced adenoma and CRC detection rates (P trends < 0.001) increased with increasing surveillance interval; RRs (95 % confidence intervals) for CRC were 1.54 (0.68–3.48), 4.44 (1.95–10.08), and 5.80 (2.51–13.40) with 3-, 4-, and 5-year intervals, respectively, versus an interval of < 18 months.
Conclusions Metachronous neoplasia was uncommon among low risk patients, even with long surveillance intervals, supporting recommendations for no surveillance in these patients. For high risk patients, a 3-year surveillance interval would ensure timely CRC detection.
Bacillus Calmette-Guerin (BCG) induces superior anti-tumour responses by Vδ2+ T cells compared with the aminobisphosphonate drug zoledronic acid
Authors: Fenn J , Ridgley L A , White A , Sarfas C , Dennis M , Dalgleish A , Reljic R , Sharpe S , Bodman-Smith M 
Published: April 2022

Abstract
Vδ2+ T cells can recognize malignantly transformed cells as well as those infected with mycobacteria. This cross-reactivity supports the idea of using mycobacteria to manipulate Vδ2+ T cells in cancer immunotherapy. To date, therapeutic interventions using Vδ2+ T cells in cancer have involved expanding these cells in or ex vivo using zoledronic acid (ZA). Here, we show that the mycobacterium Bacillus Calmette–Guérin (BCG) also causes Vδ2+ T-cell expansion in vitro and that resulting Vδ2+ cell populations are cytotoxic toward tumour cell lines. We show that both ZA and BCG-expanded Vδ2+ cells effectively killed both Daudi and THP-1 cells. THP-1 cell killing by both ZA and BCG-expanded Vδ2+ cells was enhanced by treatment of targets cells with ZA. Although no difference in cytotoxic activity between ZA- and BCG-expanded Vδ2+ cells was observed, BCG-expanded cells degranulated more and produced a more diverse range of cytokines upon tumour cell recognition compared to ZA-expanded cells. ZA-expanded Vδ2+ cells were shown to upregulate exhaustion marker CD57 to a greater extent than BCG-expanded Vδ2+ cells. Furthermore, ZA expansion was associated with upregulation of inhibitory markers PD-1 and TIM3 in a dose-dependent manner whereas PD-1 expression was not increased following expansion using BCG. Intradermal BCG vaccination of rhesus macaques caused in vivo expansion of Vδ2+ cells. In combination with the aforementioned in vitro data, this finding suggests that BCG treatment could induce expansion of Vδ2+ T cells with enhanced anti-tumour potential compared to ZA treatment and that either ZA or BCG could be used intratumourally as a means to potentiate stronger anti-tumour Vδ2+ T-cell responses.
1 Awardee Talk: Investigation of Pain and Analgesic Strategies in Cattle Undergoing Painful Husbandry Procedures and Disease Conditions
Authors: Martin Miriam S 
Published: April 2022

Abstract
Negative public perception of routine husbandry practices such as dehorning and castration is growing, increasing the need for the development of practices to relieve pain and suffering in livestock. The objective was to quantify pain associated with induced bacterial pneumonia, hot-iron dehorning, surgical castration, and hot-iron branding, and to investigate analgesic effectiveness. Calves were experimentally inoculated with Mannheimia haemolytica, cautery dehorned, surgically castrated, or hot-iron branded. Outcome variables were collected at baseline and following husbandry procedures and included serum cortisol; infrared thermography (IRT); mechanical nociceptive threshold (MNT); substance P; kinematic gait analysis; a visual analog scale (VAS); chute defense and behavior scoring; clinical illness score; computerized lung score; average activity and rumination; prostaglandin E2 metabolite (PGEM); plasma serum amyloid A and rectal temperature. Reduced activity levels, decreased force on calves’ right front limb, and increased VAS scores all support that bacterial pneumonia in cattle is painful. Differences in right front force were observed in calves challenged with M. haemolytica and treated with flunixin transdermal and those given a placebo, indicating that flunixin transdermal may attenuate specific pain biomarkers in cattle with respiratory disease. Pain from cautery dehorning and surgical castration can last up to 120 h post-dehorning indicated by changes in IRT, MNT, PGEM and gait analysis. Administration of bupivacaine liposome suspension as a local anesthetic block at the time of dehorning and castration was as effective at controlling pain as a multi-modal approach of lidocaine and meloxicam. Changes in IRT, MNT, lying time, step count, visual analog scale score and wound scoring all support that hot-iron branding cattle is painful. Oral meloxicam administration reduced IRT differences from the branding and control site and reduced lying bouts. Breed and sex effects were observed across a wide range of biomarkers. The need for long-acting analgesic options for cattle that demonstrate pain alleviation across multiple biomarkers is apparent and would be beneficial to alleviating pain and suffering.