bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring alternative financing models and early access schemes for orphan drugs: a Belgian case study
Authors: Abdallah Khadidja , Claes Kathleen , Huys Isabelle , Follon Lennert , Calis Charlotte , Simoens Steven 
Published: December 2022

Abstract
Background
Although some jurisdictions have implemented particular adjustments to accommodate often-expensive orphan drugs in their healthcare systems, availability of these drugs remains complex. This study investigates alternative financing models and early access schemes for orphan drugs in the context of the Belgian healthcare system.

Methods
Three focus group discussions were held with a panel of eleven experts from the Belgian Drug Reimbursement Committee, the Colleges for Orphan Drugs, the pharmaceutical industry, physicians, ethicists and pharmacists. Retrieved data were pseudonymised, analysed and coded according to the Qualitative Analysis Guide of Leuven.

Results
Experts disfavoured the insulated fund as well as private insurance for financing orphan drugs, as, respectively, isolation of a separate budget and a mostly profit-driven mechanism would contradict the Belgian fundamental principle of solidarity. Moreover, an insulated fund could, albeit on a smaller scale, reproduce the same budgetary constraints as the general reimbursement system. As the Special Solidarity Fund is intended for urgent care and exclusively accommodates financial needs subject to eligibility criteria, its design would not allow general financing of orphan drugs. Overall, implementation of an alternative financing model was not endorsed, instead, improving the current reimbursement system was preferred. Suggestions mentioned were; increased collaboration and transparency, robust and quality real-world evidence but also digitalization of data. Alleviating administrative burden and simplifying the admission process of compassionate use program, medical need program and early treatment reimbursement should be prioritized to facilitate early access. Furthermore, a legal framework for off-label use could stimulate proper implementation. Efforts on collaboration of expertise centres and coordination of orphan drug databases across Europe could foster a robust data network to support orphan drug availability in individual countries.

Conclusions
This research reveals that reassessing current financing models and early access schemes by eliminating inadequacies, may be more conducive than establishing alternative systems to increase availability of orphan drugs in Belgium. Other jurisdictions may rely on this information to review their own models of early access and financing to cultivate a more sustainable delivery of orphan drugs.
Associations of aspirin and other anti-inflammatory medications with breast cancer risk by the status of COX-2 expression
Authors: Yaghjyan Lusine , Eliassen A. Heather , Colditz Graham , Rosner Bernard , Schedin Pepper , Wijayabahu Akemi , Tamimi Rulla M. 
Published: December 2022

Abstract
Background
We investigated the associations of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk by the status of COX-2 protein expression.

Methods
This study included 421 cases and 3,166 controls from a nested case–control study within the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) cohorts. Information on medication use was first collected in 1980 (NHS) and 1989 (NHSII) and was updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users using data collected from all biannual questionnaires preceding the reference date. Immunochemistry for COX-2 expression was performed using commercial antibody (Cayman Chemical and Thermo Fisher Scientific). We used polychotomous logistic regression to quantify associations of aspirin and NSAIDs with the risk of COX2+ and COX2− breast cancer tumors, while adjusting for known breast cancer risk factors. All tests of statistical significance were two-sided.

Results
In multivariate analysis, we found no differences in associations of the aspirin exposures and NSAIDs with breast cancer risk by COX2 expression status. In stratified analyses by COX2 status, significant associations of these medications with breast cancer risk were observed for dosage of aspirin among current users in COX2- tumors (OR for > 5 tablets per week vs. none 1.71, 95% CI 1.01–2.88, p-trend 0.04). Regular aspirin use was marginally associated with the risk of COX2- tumors (p-trend = 0.06).

Conclusions
Our findings suggested no differences in associations of aspirin and other NSAIDs with COX2+ and COX2− tumors.
Detailed statistical analysis plan for the neurological complications in endoscopic versus open radial artery harvest (NEO) randomised clinical trial
Authors: Carranza Christian L. , Ballegaard Martin , Werner Mads U. , Hasbak Philip , Kjaer Andreas , Kofoed Klaus , Olsen Markus Harboe , Gluud Christian , Jakobsen Janus Christian 
Published: December 2022

Abstract
Introduction
Coronary artery bypass grafting can be conducted using the radial artery as a bypass graft. However, it remains unclear which harvesting method is superior, i.e. endoscopic or open radial artery, and which site for proximal anastomosis of the radial artery has the greatest benefits?

Methods
The NEO Trial is a single site randomised clinical trial with a 2 × 2 factorial design. The first comparison assesses endoscopic versus open radial artery harvest with a primary outcome of hand function and secondary outcomes of neurological deficits through clinical exams and neurophysiological studies. The primary outcome is postoperatively hand function at three months. We anticipate a mean difference of 3 points with a standard deviation of 8 points, a power of 90%, and a type I error of 5%, resulting in a required sample size of 300 participants randomised 1:1. Secondary outcomes are neurological deficits (based on nerve conduction measurements, algometry test and von Frey hair test), clinical neurological examination of cutaneous sensibility, and registration of complications in the donor arm (haematoma formation, wound dehiscence, and/or infection).
The second comparison assesses two different proximal anastomotic sites, i.e. aorto-radial anastomosis versus mammario-radial anastomosis. The primary outcome is a composite of cerebrovascular events and the secondary outcome is graft patency evaluation by multi-slice computer tomography-scan. These outcomes will be assessed at 1 year postoperatively, and the results of this comparison will be exploratory only. Both comparisons will be analysed using intention-to-treat and intervention groups will be compared using linear regression, logistic regression, or Mann–Whitney U test depending on data type.
Two independent statisticians will follow the present plan and conduct the analyses which will hereafter be fused into a final analysis based on consensus.

Conclusion
This detailed analysis plan will increase the validity of the NEO trial results by predefining the statistical analysis in detail.

Trial registration
ClinicalTrials.gov identifier: NCT01848886. Registered 25 February 2013. Danish Ethics committee number: H-3–2012-116. Danish Data Protection Agency: 2007–58-0015/jr. n:30–0838.
Safety and efficacy of direct cardiac shockwave therapy in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (the CAST-HF trial): study protocol for a randomized controlled trial—an update
Authors: Nägele Felix , Pölzl Leo , Graber Michael , Hirsch Jakob , Mayr Agnes , Pamminger Mathias , Troger Felix , Theurl Markus , Schreinlechner Michael , Sappler Nikolay , Dorfmüller Christian , Mitrovic Martina , Ulmer Hanno , Grimm Michael , Gollmann-Tepeköylü Can , Holfeld Johannes 
Published: December 2022

Abstract
Background
Coronary artery disease (CAD) remains a severe socio-economic burden in the Western world. Coronary obstruction and subsequent myocardial ischemia result in the progressive replacement of contractile myocardium with dysfunctional, fibrotic scar tissue. Post-infarctional remodelling is causal for the concomitant decline of left-ventricular function and the fatal syndrome of heart failure. Available neurohumoral treatment strategies aim at the improvement of symptoms. Despite extensive research, therapeutic options for myocardial regeneration, including (stem)-cell therapy, gene therapy, cellular reprogramming or tissue engineering, remain purely experimental. Thus, there is an urgent clinical need for novel treatment options for inducing myocardial regeneration and improving left-ventricular function in ischemic cardiomyopathy. Shockwave therapy (SWT) is a well-established regenerative tool that is effective for the treatment of chronic tendonitis, long-bone non-union and wound-healing disorders. In preclinical trials, SWT regenerated ischemic myocardium via the induction of angiogenesis and the reduction of fibrotic scar tissue, resulting in improved left-ventricular function.

Methods
In this prospective, randomized controlled, single-blind, monocentric study, 80 patients with reduced left-ventricular ejection fraction (LVEF≤ 40%) are subjected to coronary-artery bypass-graft surgery (CABG) surgery and randomized in a 1:1 ratio to receive additional cardiac SWT (intervention group; 40 patients) or CABG surgery with sham treatment (control group; 40 patients). This study aims to evaluate (1) the safety and (2) the efficacy of cardiac SWT as adjunctive treatment during CABG surgery for the regeneration of ischemic myocardium. The primary endpoints of the study represent (1) major cardiac events and (2) changes in left-ventricular function 12 months after treatment. Secondary endpoints include 6-min walk test distance, improvement of symptoms and assessment of quality of life.

Discussion
This study aims to investigate the safety and efficacy of cardiac SWT during CABG surgery for myocardial regeneration. The induction of angiogenesis, decrease of fibrotic scar tissue formation and, thus, improvement of left-ventricular function could lead to improved quality of life and prognosis for patients with ischemic heart failure. Thus, it could become the first clinically available treatment strategy for the regeneration of ischemic myocardium alleviating the socio-economic burden of heart failure.

Trial registration
ClinicalTrials.gov NCT03859466. Registered on 1 March 2019.
A fast-convolution based space–time Chebyshev spectral method for peridynamic models
Authors: Lopez Luciano , Pellegrino Sabrina Francesca 
Published: December 2022

AbstractPeridynamics is a nonlocal generalization of continuum mechanics theory which addresses discontinuous problems without using partial derivatives and replacing them by an integral operator. As a consequence, it finds applications in the framework of the development and evolution of fractures and damages in elastic materials.In this paper we consider a one-dimensional nonlinear model of peridynamics and propose a suitable two-dimensional fast-convolution spectral method based on Chebyshev polynomials to solve the model. This choice allows us to gain the same accuracy both in space and time. We show the convergence of the method and perform several simulations to study the performance of the spectral scheme.
Parameter estimation for discretized geometric fractional Brownian motions with applications in Chinese financial markets
Authors: Sun Lin , Chen Jianxin , Lu Xianggang 
Published: December 2022

AbstractIt is widely accepted that financial data exhibit a long-memory property or a long-range dependence. In a continuous-time situation, the geometric fractional Brownian motion is an important model to characterize the long-memory property in finance. This paper thus considers the problem to estimate all unknown parameters in geometric fractional Brownian processes based on discrete observations. The estimation procedure is built upon the marriage between the bipower variation and the least-squares estimation. However, unlike the commonly used approximation of the likelihood and transition density methods, we do not require a small sampling interval. The strong consistency of these proposed estimators can be established as the sample size increases to infinity in a chosen sampling interval. A simulation study is also conducted to assess the performance of the derived method by comparing with two existing approaches proposed by Misiran et al. (International Conference on Optimization and Control 2010, pp. 573–586, 2010) and Xiao et al. (J. Stat. Comput. Simul. 85(2):269–283, 2015), respectively. Finally, we apply the proposed estimation approach in the analysis of Chinese financial markets to show the potential applications in realistic contexts.
Symptoms of anal incontinence and quality of life: a psychometric study of the Norwegian version of the ICIQ-B amongst hospital outpatients
Authors: Saga Susan , Vinsnes Anne Guttormsen , Norton Christine , Haugan Gørill 
Published: December 2022

Abstract
Background
The International Consultation on Incontinence Questionnaire-Bowel (ICIQ-B), a self-report, condition-specific questionnaire designed to assess symptoms of anal incontinence (AI), measures AI’s impact on quality of life (QoL) along with perceived bowel patterns and bowel control amongst individuals with AI. In our study, we aimed to translate the ICIQ-B to Norwegian and investigate the Norwegian version’s psychometric properties.

Methods
To establish a relevant, comprehensive, and understandable Norwegian ICIQ-B, cognitive interviews were conducted with 10 patients with AI, and six clinical experts reviewed the translated scale. The Norwegian ICIQ-B’s structural validity, scale reliability, and content validity were tested amongst patients with AI attending hospital outpatient clinics in three regions of Norway (N = 208).

Results
Assessing the Norwegian ICIQ-B’s content validity revealed that the questionnaire was relevant, comprehensive, and understandable. Missing data were infrequent (3.3%), and no floor or ceiling effects emerged. Three-factor and two-factor solution models, both with advantages and disadvantages, were found. The three-factor model offered the most parsimonious solution by covering most of the original scale, albeit with an unacceptably low reliability (α = .37) for the construct of bowel pattern. The two-factor model showed good reliability in terms of internal consistency for the constructs of bowel control (α = .80) and impact on QoL (α = .85) but was less parsimonious due to dismissing seven of the original 17 items and excluding the bowel pattern construct. Test–retest reliability demonstrates good stability for the Norwegian version, with an intra-class correlation coefficient of .90–.95 and weighted kappa of .39–.87 for single items.

Conclusions
Although the Norwegian version of ICIQ-B demonstrates good stability and content validity, the original constructs of bowel pattern and bowel control had to be adapted, whereas the construct of impact on QoL remained unchanged. Further psychometric testing of the Norwegian ICIQ-B’s factor structure is therefore recommended.
Multi-genome metabolic modeling predicts functional inter-dependencies in the Arabidopsis root microbiome
Authors: Mataigne Victor , Vannier Nathan , Vandenkoornhuyse Philippe , Hacquard Stéphane 
Published: December 2022

Abstract
Background
From a theoretical ecology point of view, microbiomes are far more complex than expected. Besides competition and competitive exclusion, cooperative microbe-microbe interactions have to be carefully considered. Metabolic dependencies among microbes likely explain co-existence in microbiota.

Methodology
In this in silico study, we explored genome-scale metabolic models (GEMs) of 193 bacteria isolated from Arabidopsis thaliana roots. We analyzed their predicted producible metabolites under simulated nutritional constraints including “root exudate-mimicking growth media” and assessed the potential of putative metabolic exchanges of by- and end-products to avoid those constraints.

Results
We found that the genome-encoded metabolic potential is quantitatively and qualitatively clustered by phylogeny, highlighting metabolic differentiation between taxonomic groups. Random, synthetic combinations of increasing numbers of strains (SynComs) indicated that the number of producible compounds by GEMs increased with average phylogenetic distance, but that most SynComs were centered around an optimal phylogenetic distance. Moreover, relatively small SynComs could reflect the capacity of the whole community due to metabolic redundancy. Inspection of 30 specific end-product metabolites (i.e., target metabolites: amino acids, vitamins, phytohormones) indicated that the majority of the strains had the genetic potential to produce almost all the targeted compounds. Their production was predicted (1) to depend on external nutritional constraints and (2) to be facilitated by nutritional constraints mimicking root exudates, suggesting nutrient availability and root exudates play a key role in determining the number of producible metabolites. An answer set programming solver enabled the identification of numerous combinations of strains predicted to depend on each other to produce these targeted compounds under severe nutritional constraints thus indicating a putative sub-community level of functional redundancy.

Conclusions
This study predicts metabolic restrictions caused by available nutrients in the environment. By extension, it highlights the importance of the environment for niche potential, realization, partitioning, and overlap. Our results also suggest that metabolic dependencies and cooperation among root microbiota members compensate for environmental constraints and help maintain co-existence in complex microbial communities.
Dynamics between reading and math proficiency over time in secondary education – observational evidence from continuous time models
Authors: Jindra Christoph , Sachse Karoline A. , Hecht Martin 
Published: December 2022

AbstractIntroductionReading and math proficiency are assumed to be crucial for the development of other academic skills. Further, different studies found reading and math development to be related. We contribute to the literature by looking at the relationship between reading and math using continuous time models. In contrast to previous studies, this allows us to (a) report estimates for autoregressive and cross-lagged effects for a range of possible time intervals while still only estimating one set of continuous time parameters and (b) identify peak effects for the relationship between the two. Using data from Starting Cohort 3 of the National Educational Panel Study, we find, in line with previous evidence, a larger effect of reading on math than the other way around. Furthermore, we identify peak standardized cross-lagged effects ($${a}_{reading\to math}\approx 0.30$$,$${a}_{math\to reading}\approx 0.13$$) for a time interval of approximately 6 months.
Self-assembled wide bandgap nanocoatings enabled outstanding dielectric characteristics in the sandwich-like structure polymer composites
Authors: Wang Tian-Yu , Li Xiao-Fen , Liu Shu-Ming , Liu Bai-Xin , Liang Xi-Dong , Li Shunning , Zhang Gui-Xin , Liu Jian-Bo , Dang Zhi-Min 
Published: December 2022

AbstractPolymer dielectrics are insulators or energy storage materials widely used in electrical and electronic devices. Polymer dielectrics are needed with outstanding dielectric characteristics than current technologies. In this study, the self-assembly of boron nitride nanosheets (BNNSs) was applied to form an inorganic–organic nanocoating on various common polymer dielectrics. It is inexpensive and easy to fabricate this thin coating on a large scale. The coating has a wide bandgap and thus can significantly improve the breakdown strength of polymer dielectrics. The charge characteristics and trapping parameters of nano-domains on the surfaces of polymer dielectrics were measured, and the coating had shallow trap levels. This facilitated the dissipation of surface charges and thus greatly increased the flashover voltage. The coating also effectively improved the temperature stability and dielectric constant of the polymer dielectric. This nanocoating shows potential as a method to effectively improve the dielectric characteristics of polymer dielectrics and outperform existing composite polymer dielectrics, which are crucial for large-scale applications in energy storage and power and electronic devices.
Optimization of operating parameters for biogas production using two-phase bench-scale anaerobic digestion of slaughterhouse wastewater: Focus on methanogenic step
Authors: Tsegaye Dejene , Leta Seyoum 
Published: December 2022

AbstractThe objective of the present study was an optimization of operating parameters and the performance of the methanogenesis reactor in phased anaerobic digestion (AD) of slaughterhouse wastewater at 37.5°C. Accordingly, the feedstock of the methanogenic reactor was effluent from the hydrolytic-acidogenic reactor operating at HRT of 3-days and OLR of 1789 mg/L. The methanogenesis phase was also investigated at different hydraulic retention time (HRT) values ranging from 12 to 3 days at 3-day intervals, and organic loading rates (OLR) of 149, 199, 298, and 596 mg of COD/L. The methanogenesis reactor effluent concentrations of TN, TP, PO4− 3, SO4− 2, and S2− 2 were ranging between 424–464, 83–117, 63–86, 130–197, and 0.98–1.02 mg/L, respectively. The removal efficiencies of TN and TP were vary from 10–17% to 17–21%, respectively. The average biogas production was 125 ± 16, 150 ± 10, 185 ± 4, and 154 ± 17 mL at HRT of 12, 9, 6, and 3 days, respectively. Methane quality (%) and yield (mg/L of COD) were 55–67% and 0.02–0.03, respectively. Furthermore, the average stability indicator parameter values of (total volatile fatty acid (TVFA) = 520 ± 19 mg/L, total alkalinity (TotA) = 1424 ± 10 mg/L, TVFA:TotA. Ratio = 0.36, salinity = 1172 mg/L, pH = 6.92) and performance indicator parameters removal efficiency (RE) for (chemical oxygen demand (COD) = 81%, volatile solid (VS) RE = 95%, biogas production = 185 ± 4 mL, methane yield = 0.03 per mg COD consumed) were achieved at HRT of 6 days and OLR of 298 mg of COD/L. Low removal efficiencies of TP and TN at all HRT/OLR were observed for the methanogenic reactor signifying further treatment system.
Graphical Abstract