bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
Authors: Shi Miaoying , Dong Yumeng , Bouwmeester Hans , Rietjens Ivonne M. C. M. , Strikwold Marije 
Published: May 2022

AbstractNew approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
Satellite tagging and flipper tag recoveries reveal migration patterns and foraging distribution of loggerhead sea turtles (Caretta caretta) from eastern Australia
Authors: Perez Michelle A. , Limpus Colin J. , Hofmeister Kate , Shimada Takahiro , Strydom Aub , Webster Emily , Hamann Mark 
Published: May 2022

AbstractMarine turtles encounter different threats during various life-history stages. Therefore, understanding their movements and spatial distribution is crucial for effectively managing these long-lived migratory organisms. This study combines satellite telemetry data with long-term capture-mark-recapture data derived from flipper tag studies to determine distribution patterns of endangered loggerhead turtles (Caretta caretta) during post-nesting migrations from different eastern Australian nesting sites. Individuals from the K’gari-Fraser Island and Great Barrier Reef island rookeries typically migrated northward, whereas individuals from mainland rookeries migrated equally northward and southward. Despite this difference in foraging distribution, loggerheads from the different rookeries did not differ substantially in their migration duration or distance travelled. The foraging distribution identified from successful satellite tag deployments represented 50% of the foraging distribution identified from a large long-term flipper tag recovery database. However, these satellite telemetry results have identified new migration and foraging habitats not previously recognised for loggerhead turtles nesting in eastern Australia. Additionally, they support the conclusion from a past study using flipper tag recovery data that the mainland nesting turtles migrate to different foraging grounds than the turtles nesting on Great Barrier Reef islands. Collectively, the two data sources provide valuable data on the migration route, habitat distribution and ecological range for a threatened genetic stock of loggerhead turtles.
Use of red, far-red, and near-infrared light in imaging of yeasts and filamentous fungi
Authors: Pócsi István , Szigeti Zsuzsa M. , Emri Tamás , Boczonádi Imre , Vereb György , Szöllősi János 
Published: May 2022

Abstract
While phototoxicity can be a useful therapeutic modality not only for eliminating malignant cells but also in treating fungal infections, mycologists aiming to observe morphological changes or molecular events in fungi, especially when long observation periods or high light fluxes are warranted, encounter problems owed to altered regulatory pathways or even cell death caused by various photosensing mechanisms. Consequently, the ever expanding repertoire of visible fluorescent protein toolboxes and high-resolution microscopy methods designed to investigate fungi in vitro and in vivo need to comply with an additional requirement: to decrease the unwanted side effects of illumination. In addition to optimizing exposure, an obvious solution is red-shifted illumination, which, however, does not come without compromises. This review summarizes the interactions of fungi with light and the various molecular biology and technology approaches developed for exploring their functions on the molecular, cellular, and in vivo microscopic levels, and outlines the progress towards reducing phototoxicity through applying far-red and near-infrared light.

Key points
• Fungal biological processes alter upon illumination, also under the microscope
• Red shifted fluorescent protein toolboxes decrease interference by illumination
• Innovations like two-photon, lightsheet, and near IR microscopy reduce phototoxicity
High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
Authors: Han Myung-Hoon , Min Kyueng-Whan , Noh Yung-Kyun , Kim Jae Min , Cheong Jin Hwan , Ryu Je Il , Won Yu Deok , Koh Seong-Ho , Myung Jae Kyung , Park Ji Young , Kwon Mi Jung 
Published: May 2022

Abstract
Background
Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM.

Methods
We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression.

Results
In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression.

Conclusions
These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.

Graphical abstract
Longitudinal effects of habitat quality, body condition, and parasites on colour patches of a multiornamented lizard
Authors: Megía-Palma Rodrigo , Merino Santiago , Barrientos Rafael 
Published: May 2022

AbstractOntogeny is expected to be a determinant factor affecting production of colour patches in lizards, while immune challenges or sudden weight loss may impair the maintenance of pigment-based coloration within a breeding season. We translocated males of the lizardPsammodromus algirusbetween two sampling plots that differed in distance to a road, vegetation structure, and predator abundance. We analysed variation in spectral reflectance of their colour patches the same and the following year. The change in the reflectance of the lizard colour patches within the first breeding season was explained by the interaction between plot and treatment, but not body condition. The maintenance of the breeding coloration was impaired only in those males translocated close to the road, probably reflecting that it is a poor-quality habitat forP. algirus. The following year, lizards that produced a more elaborate coloration were those that increased their body condition and controlled some parasitic infections, although suffered an increase of others. This study shows that colour patch production is plastic inP. algirus. Lizards increasing parasites or losing weight reduced pigmentation, although habitat quality can cushion these negative effects on pigmentation. However, not all parasites constrain the investment in coloration. In fact, some increased in those lizards that allocated more pigments to colour patches. In conclusion, longitudinal studies following experimental manipulation can contribute to understand pigment allocation rules in lizards.Significance statementPigments involved in colour patches of animals are limiting resources that can be reallocated off the skin to other functions. However, longitudinal evidence of this phenomenon is scarce in reptiles. We designed a manipulative mark-recapture experiment to investigate effects of habitat and parasitic infections on colour patch maintenance (within-year variation) and production (between-year variation) in male free-ranging lizards that were reciprocally translocated between two patches of habitat that differed in quality. During the first year, lizards translocated to the habitat with more predators and worse vegetation impoverished their coloration, while lizards translocated to the more favourable habitat maintained it despite all translocated lizards loose body condition. The next year we detected different effects on the coloration of three different parasites investigated, suggesting that coloration can reflect the virulence of the infections.
On the choice of TLS versus OLS in climate signal detection regression
Authors: McKitrick Ross 
Published: May 2022

AbstractTotal least squares (TLS) or multivariate orthogonal regression is widely used as a remedy for attenuation bias in climate signal detection or “optimal fingerprinting” regression. But under some circumstances it overcorrects and imparts an upward bias, as well as generating extremely unstable and imprecise coefficient estimates. While there has been increasing attention paid recently to the validity of TLS-based confidence intervals, there has been no corresponding examination of coefficient bias problems. This note explains why they are pertinent and presents a Monte Carlo simulation to illustrate the hazards of using TLS in a signal detection application without testing whether the modeling context makes it a suitable choice. TLS is not automatically preferred over OLS even when explanatory variables are believed to contain random errors. Notably it can be sufficiently biased to cause false positives when explanatory signals are negatively correlated, and the bias gets worse as the signal-noise ratio on the explanatory variables rises. Additionally TLS should not be used on its own for climate signal detection inferences since if the no-signal null is true, TLS is generally inconsistent whereas OLS attenuation bias disappears.
Patients with multiple sclerosis: a burden and cost of illness study
Authors: Battaglia Mario Alberto , Bezzini Daiana , Cecchini Isabella , Cordioli Cinzia , Fiorentino Francesca , Manacorda Tommaso , Nica Mihaela , Ponzio Michela , Ritrovato Daniela , Vassallo Chiara , Patti Francesco 
Published: May 2022

Abstract
Background
Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease negatively impacting patients’ physical, psychological and social well-being with a significant economic burden.

Objectives
The study estimates MS burden and cost of illness in Italy from a societal perspective in 2019.

Methods
Information on the impact of the disease on daily activities, symptoms, employment, resource utilization and the role of caregivers was collected through questionnaires completed by 944 patients and caregivers. Results were stratified according to both disease severity and payer. Mean costs and overall costs were extrapolated from the sample to the Italian MS population considering published distribution of severity.

Results
The study showed a great impact of the disease on daily and work activities increasing with the disability. The overwhelming burden of fatigue emerged. Mean annual costs were estimated at €39,307/patient (€29,676, €43,464 and €53,454 in mild, moderate and severe cases, respectively). Direct healthcare costs were the major component (€21,069), followed by indirect costs (€15,004). The overall cost of the disease in Italy was €4.8 billion. The National Healthcare System (NHS) sustained most of the costs (80%), most notably direct healthcare costs, while patients paid almost all non-healthcare expenses.

Conclusions
This study confirmed that MS carries a substantial burden to patients and society, highlighting the need for awareness of this disease.
The role of re-resection in recurrent hepatocellular carcinoma
Authors: Bednarsch Jan , Czigany Zoltan , Heij Lara R. , Amygdalos Iakovos , Heise Daniel , Bruners Philip , Ulmer Tom F. , Neumann Ulf P. , Lang Sven A. 
Published: May 2022

Abstract
Purpose
While liver resection is a well-established treatment for primary HCC, surgical treatment for recurrent HCC (rHCC) remains the topic of an ongoing debate. Thus, we investigated perioperative and long-term outcome in patients undergoing re-resection for rHCC in comparative analysis to patients with primary HCC treated by resection.

Methods
A monocentric cohort of 212 patients undergoing curative-intent liver resection for HCC between 2010 and 2020 in a large German hepatobiliary center were eligible for analysis. Patients with primary HCC (n = 189) were compared to individuals with rHCC (n = 23) regarding perioperative results by statistical group comparisons and oncological outcome using Kaplan–Meier analysis.

Results
Comparative analysis showed no statistical difference between the resection and re-resection group in terms of age (p = 0.204), gender (p = 0.180), ASA category (p = 0.346) as well as main preoperative tumor characteristics, liver function parameters, operative variables, and postoperative complications (p = 0.851). The perioperative morbidity (Clavien-Dindo ≥ 3a) and mortality were 21.7% (5/23) and 8.7% (2/23) in rHCC, while 25.4% (48/189) and 5.8% (11/189) in primary HCC, respectively (p = 0.851). The median overall survival (OS) and recurrence-free survival (RFS) in the resection group were 40 months and 26 months, while median OS and RFS were 41 months and 29 months in the re-resection group, respectively (p = 0.933; p = 0.607; log rank).

Conclusion
Re-resection is technically feasible and safe in patients with rHCC. Further, comparative analysis displayed similar oncological outcome in patients with primary and rHCC treated by liver resection. Re-resection should therefore be considered in European patients diagnosed with rHCC.
Ethische Fragen im Gesundheitswesen als Gegenstand interprofessionellen Lernens: Überblick zur Situation in Deutschland und Projektbericht
Authors: Seidlein Anna-Henrikje , Salloch Sabine 
Published: May 2022

ZusammenfassungInterprofessionelles Lernen von Auszubildenden der Pflegeberufe sowie Medizinstudierenden bietet vielfältige Chancen für die zukünftige Zusammenarbeit mit dem Ziel einer qualitativ hochwertigen Versorgung von Patient*innen. Expert*innengremien fordern daher eine frühzeitige Integration von interprofessionellen Lehr- und Lernformaten, um effektive und nachhaltige Verbesserungen in der Praxis erreichen zu können. In Deutschland wird interprofessionelle Lehre in der grundständigen Ausbildung der zwei Professionen in wachsendem Umfang in ausgewählten Fächern – obligat oder fakultativ – eingesetzt. Der Bereich der Ethik im Gesundheitswesen wird dabei bislang jedoch kaum berücksichtigt. Der Beitrag untersucht die Situation interprofessioneller Ethiklehre in Deutschland und beleuchtet deren Möglichkeiten und Grenzen vor dem Hintergrund eines Pilotprojektes.
Biomarker and compound-specific isotope records across the Toarcian CIE at the Dormettingen section in SW Germany
Authors: Ajuaba Stephen , Sachsenhofer Reinhard F. , Bechtel Achim , Galasso Francesca , Gross Doris , Misch David , Schneebeli-Hermann Elke 
Published: May 2022

AbstractThe Toarcian oceanic anoxic event (T-OAE) is associated with a prominent negative carbon isotope excursion (CIE; ~ 183 million years (Myr)). About 10-m-thick organic matter-rich sediments accumulated during the T-OAE in the Southwest German Basin (SWGB). Rock–Eval, maceral and biomarker analysis were used to determine variations of environmental conditions across the CIE interval. Carbon isotope records were determined for various n-alkanes, pristane and phytane to contribute to the reconstruction of the paleo-environment and to study the factors controlling molecular δ13C values. Geochemical redox indicators provide evidence for photic zone anoxia during the Toarcian CIE, which reached its maximum after deposition of the “Unterer Stein” marker horizon. The 2α-methylhopane index suggests enhanced activity of diazotrophic cyanobacteria, which is also supported by nitrogen isotope data. This distinguishes the SWGB from other basins with Toarcian black shale. Oxygen-depleted conditions, albeit with lower intensity continued after the CIE. All investigated compounds replicate the negative CIE, but the magnitudes vary considerably. The largest shift is observed for n-C27 (9‰) and reflects the combined effect of the global CIE and a major change in organic matter input (termination of terrigenous organic matter input). The shift for short-chain n-alkanes, pristane, and phytane, interpreted to reflect marine biomass, varies between 4.5 and 5.0‰. This is the highest value observed so far for any Toarcian section. δ13C values of pristane and phytane reach a minimum near the base of the CIE interval and increase upsection. Thus, the maximum negative isotope shift predates the strongest basin restriction by about 450 thousand years (kyr).
Compensatory biomechanics and spinal loading during dynamic maneuvers in patients with chronic low back pain
Authors: Nyayapati Priya , Booker Jacqueline , Wu Peter I-Kung , Theologis Alekos , Dziesinski Lucas , O’Neill Conor , Zheng Patricia , Lotz Jeffrey C. , Matthew Robert P. , Bailey Jeannie F. 
Published: May 2022

Abstract
Purpose
This study explores the biomechanics underlying the sit-to-stand (STS) functional maneuver in chronic LBP patients to understand how different spinal disorders and levels of pain severity relate to unique compensatory biomechanical behaviors. This work stands to further our understanding of the relationship between spinal loading and symptoms in LBP patients.

Methods
We collected in-clinic motion data from 44 non-specific LBP (NS-LBP) and 42 spinal deformity LBP (SD-LBP) patients during routine clinical visits. An RGB-depth camera tracked 3D joint positions from the frontal view during unassisted, repeated STS maneuvers. Patient-reported outcomes (PROs) for back pain (VAS) and low back disability (ODI) were collected during the same clinical visit.

Results
Between patient groups, SD-LBP patients had 14.3% greater dynamic sagittal vertical alignment (dSVA) and 10.1% greater peak spine torque compared to NS-LBP patients (p < 0.001). SD-LBP patients also had 11.8% greater hip torque (p < 0.001) and 86.7% greater knee torque (p = 0.04) compared to NS-LBP patients. There were no significant differences between patient groups in regard to anterior or vertical torso velocities, but anterior and vertical torso velocities correlated with both VAS (r = − 0.38, p < 0.001) and ODI (r = − 0.29, p = 0.01). PROs did not correlate with other variables.

Conclusion
Patients with LBP differ in movement biomechanics during an STS transfer as severity of symptoms may relate to different compensatory strategies that affect spinal loading. Further research aims to establish relationships between movement and PROs and to inform targeted rehabilitation approaches.
Zur Bedeutung der begleitenden Arbeit mit den Eltern in einer Kindertherapie. Eine Einzelfallstudie
Authors: Diem-Wille Gertraud 
Published: May 2022

ZusammenfassungDie Bedeutung der begleitenden Arbeit mit Eltern bei einer Kindertherapie wird beschrieben. Die Eltern sind das zweite Patientensystem, mit dem ein Therapeut/eine Therapeutin eine stabile Kooperationsbeziehung etablieren muss, um die weitere Therapie des Kindes zu ermöglichen. Wir gehen von der Annahme aus, dass die innere Welt des Kindes mit Repräsentanzen erfüllt ist, die durch Introjektionen der äußeren und inneren Erlebniswelten gebildet werden. Das bedeutet, dass auch die Symptome und Probleme des Kindes in enger Verflochtenheit mit der inneren Welt der Mutter und des Vaters gedacht werden müssen. Es wird beschrieben, wie der Vater und die Mutter Zugang zu eigenen Möglichkeiten in sich fanden, ihr Kind in adäquate Weise zu fördern. Das wurde möglich, nachdem der Vater sich mit seinen ungelösten Konflikten („unresolved conflicts“ Fraiberg 2011) mit seinem Vater auseinandersetzen konnte, die er in seiner Beziehung zu Patrik wiederholte. Die Hypothese der emotionalen Verstrickung zwischen dem Vater und Patrik wird untersucht und der Prozess zu deren Auflösung wird beschrieben.
Theory as a source of software and system requirements
Authors: Chitchyan Ruzanna , Bird Caroline 
Published: May 2022

AbstractToday, when undertaking requirements elicitation, engineers attend to the needs and wants of the user groups considered relevant for the software system. However, answers to some relevant questions (e.g., how to improve adoption of the intended system) cannot always be addressed through direct need and want elicitation. Using an example of energy demand-response systems, this paper demonstrates that use of grounded theory analysis can help address such questions. The theories emerging from such analysis produce a set of additional requirements which cannot be directly elicited from individuals/groups, and would otherwise be missed. Thus, we demonstrate that the theories generated through grounded theory analysis can serve as additional valuable sources of requirements for software and its wider system. This paper extends our previous work by demonstrating how several theories can be constructed and utilised for a single system analysis.