bluuebunny/crossref_metadata_2025_split huggingface dataset:
How Can We Optimize the Value Assessment and Appraisal of Orphan Drugs for Reimbursement Purposes? A Qualitative Interview Study Across European Countries
Authors: Blonda Alessandra , Denier Yvonne , Huys Isabelle , Kawalec Pawel , Simoens Steven 
Published: July 2022

Introduction: The expansion of orphan drug treatment at increasing prices, together with uncertainties regarding their (cost-)effectiveness raises difficulties for decision-makers to assess these drugs for reimbursement. The present qualitative study aims to gain better insight into current value assessment and appraisal frameworks for orphan drugs, and provides guidance for improvement.Methods: 22 European experts from 19 different countries were included in a qualitative survey, followed by in-depth semi-structured interviews. These experts were academics, members of reimbursement agencies or health authorities, or members of regulatory or health/social insurance institutions. Adopting a Grounded Theory approach, transcripts were analysed according to the QUAGOL method, supported by the qualitative data analysis software Nvivo.Results: Although participants indicated several good practices (e.g., the involvement of patients and the presence of structure and consistency), several barriers (e.g., the lack of transparency) lead to questions regarding the efficiency of the overall reimbursement process. In addition, the study identified a number of “contextual” determinants (e.g., bias, perverse effects of the orphan drug legislation, and an inadequate consideration of the opportunity cost), which may undermine the legitimacy of orphan drug reimbursement decisions.Conclusion: The present study provides guidance for decision-makers to improve the efficiency of orphan drug reimbursement. In particular, decision-makers can generate quick wins by limiting the impact of contextual determinants rather than improving the methods included in the HTA. When implemented into a framework that promotes “Accountability for Reasonableness” (A4R), this allows decision-makers to improve the legitimacy of reimbursement decisions concerning future orphan drugs.
A Multicenter Study of 239 Patients Aged Over 70 Years With Diffuse Large B-Cell Lymphoma in China
Authors: Yang Chunli , Li Qiaoer , Xie Ke , Zhang Yakun , Xiang Dania , Han Yunwei , Zou Liqun 
Published: July 2022

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma subtype worldwide and occurs frequently in the elderly population. However, there are limited data on the clinical profiles of patients with DLBCL over 70 years of age. Our objective was to summarize the clinical characteristics, treatment strategies and survival outcomes of this population in China.Methods: This multicenter retrospective study was conducted in China from January 2012 to July 2020 to investigate the clinical characteristics and survival outcomes. A total of 239 patients with DLBCL aged over 70 years underwent pretreatment evaluations, treatment, and follow-up at local hospitals. The primary endpoints were the progression-free survival (PFS) and the overall survival (OS) rates at 2 years. Secondary endpoints included median PFS and OS, the estimated PFS and OS rates at 5 years, and adverse events during treatment.Results: With a median follow-up of 50 months (range, 1–102 months), the 2-year PFS and OS rates were 53.0% and 65.5%, respectively. The median PFS and OS were 42.1 and 96.4 months, respectively; and the estimated 5-year PFS and OS rates were 44.7% and 56.1%, respectively. Hematological toxicities were the most common adverse effects in this study, accounting for 90.4%; and leukopenia was the most frequently observed ≥ grade 3 event. Furthermore, we found that regimens without rituximab and chemotherapy cycles &lt; 6 were significantly associated with worse survival. Additionally, in the 70–80-year group, reduction in chemotherapy dose was associated with a significantly shorter OS, with a 2-year OS rate of 74.4% in the full dose group, compared to 67.1% for the decreased-dose group (p = 0.044).Conclusion: Our study presents the clinical profiles and survival outcomes of elderly patients with DLBCL in China. Treatment of these patients requires careful evaluation of toxicities and benefits. To this end, a prognosis model, such as comprehensive geriatric assessment, is required in clinical practice to optimally manage elderly patients with DLBCL.
Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age
Authors: Liu Shujing , Xiao Tao , Huang Shanqing , Li Xiaolin , Kong Wan , Yang Ye , Zhang Zi , Ni Xiaojia , Lu Haoyang , Zhang Ming , Shang Dewei , Wen Yuguan 
Published: July 2022

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range.Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations.Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients.Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.
SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice
Authors: Shi Chunxia , Jiao Fangzhou , Wang Yao , Chen Qian , Wang Luwen , Gong Zuojiong 
Published: July 2022

The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1β) were measured by ELISA and Western blotting. The cell type expression of IL-1β in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.
Temporal associations between objectively measured physical activity and depressive symptoms: An experience sampling study
Authors: Li Yu-Mei , Konstabel Kenn , Mõttus René , Lemola Sakari 
Published: July 2022

BackgroundThis study aimed to examine the relationship between the timing of physical activity and within-individual differences in depressive symptoms, positive affect, and negative affect in individuals with different baseline levels of depressive symptoms.MethodsExperience sampling methodology (ESM) was used to measure real-time depressive symptoms, positive affect, and negative affect in a convenience sample of 78 healthy adults (aged M = 25.46 years, SD = 6.18; 57 females) five times per day for 14 days. We measured physical activity throughout the 14 days by using activity sensors. Baseline levels of depressive symptoms were assessed with the PHQ-9 to build subgroups with low vs. mild-moderate depressive symptoms.ResultsPhysical activity predicted decreased depressive symptom levels, negative affect, and increased positive affect. Associations were stronger for individuals with higher baseline levels of depressive symptoms and for physical activity between 0 and 30 min compared to physical activity between 30 and 180 min before the mood rating. Conversely, levels of depressive symptoms, positive and negative affect did not predict physical activity.LimitationsThe convenience sample may not have been representative of the general population or people with depression. Accelerometers may not have detected some types of physical activities such as bicycling. Causality could not be inferred because of the observational study design.ConclusionIndividuals with higher levels of depressive symptoms may benefit from physical activity. While the effects were strongest for physical activity immediately before the mood ratings, the effects were in the same direction for up to 3 h before the mood ratings.
Improving control over euthanasia of persons with psychiatric illness: Lessons from the first Belgian criminal court case concerning euthanasia
Authors: De Hert Marc , Loos Sien , Sterckx Sigrid , Thys Erik , Van Assche Kristof 
Published: July 2022

BackgroundBelgium is one of very few countries that legally allow euthanasia for suffering caused by psychiatric illness. In the first criminal trial in Belgium of physicians involved in euthanasia, three physicians recently faced the accusation of “murder by poisoning,” for allegedly having failed to comply with several requirements of the Belgian Euthanasia Law in granting the euthanasia request a woman suffering from psychiatric illness. Although all three physicians were acquitted, the case generated much debate among policy makers, medical professionals, and the general public.MethodWe use this trial as the starting point for a critical analysis of the adequacy of the three-level control system established in the Euthanasia Law, as it is applied in the evaluation of euthanasia requests from persons who suffer unbearably from a psychiatric illness. This analysis is based on information presented during the criminal trial as well as information on the euthanasia that was published in the press.ResultsOur analysis highlights substantial problems in the assessment and granting of the euthanasia request. The patient was euthanized without it having been substantiated that her psychiatric illness had no prospect of improvement and that her suffering could not be alleviated. The three-step control system enshrined in the Law and promoted by the Federal Control and Evaluation Commission for Euthanasia appears to have failed at each level.ConclusionTo evaluate requests for euthanasia for mental suffering caused by psychiatric illness, the requirements of the Belgian Euthanasia Law should be complemented by mandating the advice of two psychiatrists, and face-to-face discussions between all physicians involved. In parallel with the process of evaluating the euthanasia request, a treatment track should be guaranteed where reasonable evidence-based treatments and recovery-oriented options are tried.
Symptom severity is associated with leftward lateralization upon contextual modulation of visual vertical in patients with schizophrenia
Authors: Razzak Abdul Rima , Jahrami Haitham , Husni Mariwan , Ali Maryam Ebrahim , Bagust Jeff 
Published: July 2022

BackgroundContextual processing dysfunction in patients with schizophrenia (SCZ) is not uniform and task-dependent. In SCZ, studies on the rod and frame test (RFT), which evaluates contextual modulation of verticality perception, are sparse. A main study that utilized a two-alternative forced choice design for judging rod verticality reported equivalent strength of RFT contextual modulation in healthy controls and SCZ. The current study aims to uncover any potential differences in contextual modulation between controls and SCZ with an adjustment method on a computerized RFT.Materials and methodsA total of 17 healthy controls and 15 SCZ aligned an oriented rod to their perceived vertical with a computer mouse under four randomized frame presentations: absent frame, non-tilted (Frame0°), or tilted by 18 degrees leftward (Frame–18°) or rightward (Frame+18°). Rod deviation error was assigned a negative or positive value when aligned leftward or rightward, respectively, of 0°. Signed and absolute errors, the rod and frame effect (RFE), and intra-individual variability (inconsistency) were used for analysis.ResultsThere was no group difference in rod alignment errors or derived measures, except that SCZ displayed greater inconsistency in rod alignment, compared to controls. The negative symptom scale (PANSS-N) scores correlated positively with the variability measure and with unsigned Frame–18° error.ConclusionsOnly the variability measure was sensitive enough to distinguish between controls and SCZ. SCZ with more severe negative symptoms had larger variability in rod alignment, probably reflecting a state of indifference. The larger deviation errors only with a leftward tilted frame, as PANSS-N scores increased, may indicate a lateralized attentional abnormality that is correlated with severity of symptoms in SCZ.
Experience of using a smartphone WeChat applet for dental anxiety assessment and preoperative evaluation: A nationwide multicenter study
Authors: Huang Xilu , Zeng Jie , Zhao Nan , Fan Lin , Ruan Dijiao , Wang Jing , Hong Xiaomei , Yu Cong 
Published: July 2022

IntroductionDental anxiety is a multivariate phenomenon that regularly occurs during a dental procedure. Although it may lead to patients' safety concerns and adverse events in routine treatment, it is often ignored. The purpose of this research is to develop a novel WeChat Applet for dental anxiety (WADA) with the following features and aims: (1) to help patients with dental anxiety management; (2) provide patient with a physical status self-evaluation; and(3) provide a platform for online assessment and tele-consultancy by dentists. We aimed to test and verify whether such an applet could play a beneficial role before and after a dental procedure and facilitate management of high-risk patients during the COVID-19 pandemic.Materials and methodsDuring the 12-month survey period (August 2020 to July 2021), a total of 180 patients aged 3–74 years from eight different cities (n = 180 at the end of treatment, n = 25 for the System Usability Scale (SUS) and follow-up interview) and 20 medical staff from eight different cities (n =20 for follow-up interview) were evaluated by WADA. At the end of the survey period, the results of the interviews were analyzed thematically.ResultsWADA assessment results from 180 patients and follow-up interview results from 45 participants were analyzed. In this study with a male to female ratio of 2:3, 75% were found to be suffering from dental anxiety, 86% were found with postoperative complications, and 11 cases were found to have contraindications to surgery. The total SUS score for WADA is 72.25 above the mean score, proving that WADA is a relevant and useful tool before and after dental treatment. Based on the results of the interviews, the following themes were identified: patient satisfaction; dentists' effectiveness; multi-center data integration; and increase its frequency of usage.ConclusionsThe WADA was developed for dental procedures and is effective for reducing treatment risks, improving patients' satisfaction and dentists' convenience, especially in terms of facilitating management of high-risk patient during the COVID-19 pandemic.
A Metapopulation Model for Preventing the Reintroduction of Bovine Viral Diarrhea Virus to Naïve Herds: Scotland Case Study
Authors: Puspitarani Gavrila A. , Kao Rowland R. , Colman Ewan 
Published: July 2022

BackgroundBovine viral diarrhea (BVD) virus is one of the most problematic infectious pathogens for cattle. Since 2013, a mandatory BVD eradication program has successfully reduced the number of infected cattle living on Scottish farms; however, England remains at high prevalence and presents a risk to Scotland through animal movement.MethodsWe analyze cattle movements in the UK from 2008 to 2017 and recorded incidence of BVD in Scotland from 2017 to 2020. To simulate BVD reintroduction into Scotland, we developed an epidemiological model that combines transmission between cattle and animal movements between farms. A total of four control strategies were implemented in the model: no intervention, import restriction, targeted vaccination, and combined strategy.ResultsDuring the course of the eradication scheme, movements into Scotland became increasingly distributed in regions close to the England–Scotland border. The prevalence of BVD in this region decreased at a slower rate than the rest of Scotland during the eradication scheme. Our model showed that the change in the prevalence is expected, given that the change in the patterns of movement and if vaccination is targeted to the border areas that decrease in the prevalence will be seen throughout the whole of Scotland.ConclusionScottish farms are susceptible to BVD virus reintroduction through animal imports from non-BVD-free nations with farms in border areas being the most vulnerable. Protecting the border regions provides direct and indirect protection to the rest of Scottish farms by interrupting chains of transmission.
Modelling and Simulation of the Structural Elements and the Operating Processes of Mining Machines
Authors: András Endre 
Published: July 2022

Abstract
The paper deals with theoretical bases of the implementation in mining equipment design of up-to-date methods using modelling and simulation, supported by examples of personal research. This has become necessary due to the structural complexity of this equipment, and the variety and aggressiveness of their operating environment. The presented examples refer to different kinds of the equipment used in the mechanical extraction of mineral raw materials, from overall system to working part or tool.
Chromatic Discrimination Towards the Confusion Points
Authors: Urbin Ágnes , Nagy Balázs Vince 
Published: July 2022

Abstract
In this paper chromatic discrimination thresholds of normal colour-observers are analysed. Measurements were obtained with the Cambridge Colour Test, in different reference points. The results show differences in terms of the reference chromaticities. Reference points within the gamut of a CRT display were found where thresholds of normal colour observers measured towards the confusion points exceeded the normative upper threshold limit of normal colour observers. The discrimination thresholds estimated towards the confusion lines based on Trivector measurements exceeded the thresholds estimated by the Ellipse tests. Our results indicate that in case of determination of discrimination ellipses, measurements towards the confusion points are recommended.
The First Complete Chloroplast Genome Sequence and Phylogenetic Analysis of Pistachio (Pistacia vera)
Authors: Zarei Abdolkarim , Ebrahimi Aziz , Mathur Samarth , Lawson Shaneka 
Published: July 2022

Pistachio is one of the most economically important nut crops worldwide. However, there are no reports describing the chloroplast genome of this important fruit tree. In this investigation, we assembled and characterized the complete pistachio chloroplast sequence. The Pistacia vera chloroplast genome was 160,598 bp in size, similar to other members of Anacardiaceae (149,011–172,199 bp) and exhibited the typical four section structure, including a large single copy region (88,174 bp), a small single copy region (19,330 bp), and a pair of inverted repeats regions (26,547 bp). The genome contains 121 genes comprised of 87 protein-coding genes, 30 tRNA genes and 4 rRNA genes. Thirteen intron-containing genes were identified in the genome wherein two genes had more than two introns. The genomic patterns of GC content resembled those for other Anacardiaceae. P. vera displayed the highest number of simple sequence repeats (SSRs) among the genera studied, which may be useful for molecular marker development and future population studies. Amino acid analysis revealed that Leucine is the most frequent (10.69%) amino acid in the chloroplast genome followed by Isoleucine (8.53%) and Serine (7.77%). Cysteine (1.30%) and Tryptophan (1.74%) were the least frequent amino acids. Phylogenetic analysis revealed P. vera is most like its taxonomically close relative P. weinmaniifolia, followed by Rhus chinensis; all placed taxonomically in the tribe Rhoeae. Members of Anacardiaceae were most closely related to Rhoeae, followed by members of Spondieae. The reports of this chloroplast genome will be useful for future conservation studies, genetic evaluation and breeding of P. vera, and more comprehensive phylogenetic analysis of the Pistacia species and its closely-related genera.