bluuebunny/crossref_metadata_2025_split huggingface dataset:
Not one, but many: developing a multi-indication pricing model for medicines in Belgium
Authors: Maes Ingrid , Kok Eline , De Torck Pieter-Jan , Mestre-Ferrandiz Jorge , Simoens Steven 
Published: September 2023

Back ground: Current pricing and reimbursement models that focus on one indication at a time are not suited to address the market access of multi-indication medicines. Therefore, the aim of this study is to co-create with Belgian stakeholders a multi-indication pricing model and procedural pathway, to identify conditions for implementation, and to illustrate the multi-indication pricing model with a case study.Methods: Different multi-indication pricing models were identified from the literature, case studies and pilots in other countries. Semi-structured interviews were conducted with 21 representatives from the National Institute for Health and Disability Insurance, insurance funds, clinicians, patients, the policy cell of the Minister of Health, pharmaceutical industry and academia. These provided insight in the opinions of stakeholders about possible multi-indication pricing models and their feasibility in the Belgian context. Agreement on the preferred multi-indication pricing model and procedural pathway was reached in a multi-stakeholder round table.Results: The international review generated four main multi-indication pricing models that vary in terms of whether a uniform price or differential prices are applied, whether prices are adjusted for the volume and/or value of the medicine in each indication, and whether a proactive or retroactive dynamic pricing approach is used. However, Belgian stakeholders preferred a fifth model, which sets a single price as the volume- and value-weighted average price across all indications at launch. Over time, the price is adapted based on volume and value of the medicine in real-life practice for each indication. To implement this model, a legal framework, horizon scanning and early dialogue, data infrastructure, an evidence plan for the medicine, technical expertise and governance model need to be developed.Conclusion: Although the multi-indication pricing model preferred by Belgian stakeholders raises the administrative burden, it allows for the price of a medicine to vary during the lifecycle based on its initial and real-life performance in multiple indications.
Recent advances in medicinal compounds related to corneal crosslinking
Authors: Qin Danyi , Han Yi , Wang Lixiang , Yin Hongbo 
Published: September 2023

Corneal crosslinking (CXL) is the recognized technique to strengthen corneal collagen fibers through photodynamic reaction, aiming to halt progressive and irregular changes in corneal shape. CXL has greatly changed the treatment for keratoconus (KCN) since it was introduced in the late 1990’s. Numerous improvements of CXL have been made during its developing course of more than 20 years. CXL involves quite a lot of materials, including crosslinking agents, enhancers, and supplements. A general summary of existing common crosslinking agents, enhancers, and supplements helps give a more comprehensive picture of CXL. Either innovative use of existing materials or research and development of new materials will further improve the safety, effectiveness, stability, and general applicability of CXL, and finally benefit the patients.
Therapeutic potential of Ganoderma lucidum polysaccharide peptide in Doxorubicin-induced nephropathy: modulation of renin-angiotensin system and proteinuria
Authors: Fang Hui , Lin Dongmei , Li Xinxuan , Wang Lianfu , Yang Teng 
Published: September 2023

Introduction: In the Doxorubicin (DOX)-induced nephropathy model, proteinuria is a manifestation of progressive kidney injury. The pathophysiology of renal illness is heavily influenced by the renin-angiotensin system (RAS). To reduce renal RAS activation and proteinuria caused by DOX, this study evaluated the effectiveness of Ganoderma lucidum polysaccharide peptide (GL-PP), a new glycopeptide produced from Ganoderma lucidum grown on grass.Methods: Three groups of BALB/c male mice were created: control, DOX, and DOX + GL-PP. GL-PP (100 mg/kg) was administered to mice by intraperitoneal injection for 4 weeks following a single intravenous injection of DOX (10 mg/kg via the tail vein).Results: After 4 weeks, full-length and soluble pro(renin) receptor (fPRR/sPRR) overexpression in DOX mouse kidneys, which is crucial for the RAS pathway, was dramatically inhibited by GL-PP therapy. Additionally, GL-PP successfully reduced elevation of urinary renin activity and angiotensin II levels, supporting the idea that GL-PP inhibits RAS activation. Moreover, GL-PP showed a considerable downregulation of nicotinamide adenine nucleotide phosphate oxidase 4 (NOX4) expression and a decrease in hydrogen peroxide (H2O2) levels. GL-PP treatment effectively reduced glomerular and tubular injury induced by DOX, as evidenced by decreased proteinuria, podocyte damage, inflammation, oxidative stress, apoptosis, and fibrosis.Discussion: GL-PP inhibits intrarenal PRR/sPRR-RAS activation and upregulation of NOX4 and H2O2, suggesting potential therapeutic approaches against DOX-induced nephropathy.
Establishment of targeted mutagenesis in soybean protoplasts using CRISPR/Cas9 RNP delivery via electro−transfection
Authors: Subburaj Saminathan , Agapito-Tenfen Sarah Zanon 
Published: September 2023

The soybean (Glycine max L.) is an important crop with high agronomic value. The improvement of agronomic traits through gene editing techniques has broad application prospects in soybean. The polyethylene glycol (PEG)-mediated cell transfection has been successfully used to deliver the CRISPR/Cas9-based ribonucleoprotein (RNP) into soybean protoplasts. However, several downstream analyses or further cell regeneration protocols might be hampered by PEG contamination within the samples. Here in this study, we attempted to transfect CRISPR/Cas9 RNPs into trifoliate leaf-derived soybean protoplasts using Neon electroporation to overcome the need for PEG transfection for the first time. We investigated different electroporation parameters including pulsing voltage (V), strength and duration of pulses regarding protoplast morphology, viability, and delivery of CRISPR/Cas9. Electroporation at various pulsing voltages with 3 pulses and 10 ms per pulse was found optimal for protoplast electro-transfection. Following electro-transfection at various pulsing voltages (500 V, 700 V, 1,000 V, and 1,300 V), intact protoplasts were observed at all treatments. However, the relative frequency of cell viability and initial cell divisions decreased with increasing voltages. Confocal laser scanning microscopy (CLSM) confirmed that the green fluorescent protein (GFP)-tagged Cas9 was successfully internalized into the protoplasts. Targeted deep sequencing results revealed that on-target insertion/deletion (InDel) frequencies were increased with increasing voltages in protoplasts electro-transfected with CRISPR/Cas9 RNPs targeting constitutive pathogen response 5 (CPR5). InDel patterns ranged from +1 bp to −6 bp at three different target sites in CPR5 locus with frequencies ranging from 3.8% to 8.1% following electro-transfection at 1,300 V and 2.1% to 3.8% for 700 V and 1,000 V, respectively. Taken together, our results demonstrate that the CRISPR/Cas9 RNP system can be delivered into soybean protoplasts by the Neon electroporation system for efficient and effective gene editing. The electro-transfection system developed in this study would also further facilitate and serve as an alternative delivery method for DNA-free genome editing of soybean and other related species for genetic screens and potential trait improvement.
Fine mapping of the major gene BhHLS1 controlling seed size in wax gourd (Benincasa hispida)
Authors: Yang Wenrui , Wang Peng , Liu Ting , Nong Lifeng , Cheng Zhikui , Su Liwen , Bai Wenhui , Deng Yan , Chen Zhihao , Liu Zhengguo 
Published: September 2023

Introduction/BackgroundThe seed size of wax gourds is an important agronomic trait; however, the associated genes have not yet been reported.MethodsIn this study, we used a high-density genetic map constructed based on F8 recombinant inbred line populations derived from a cross between MY-1 (large seed) and GX-71 (small seed) strains to detect quantitative trait locis (QTLs) for seed-size-related traits in wax gourd over a two-year period.ResultsTwo stable QTLs (qSL10 and qSW10) for seed length (SL) and seed width (SW) on chromosome 10 were repeatedly detected over two years (2021–2022). qSL10 had a phenotypic variation rate of 75.30% and 80.80% in 2021 and 2022, respectively. Whereas, qSW10 had a phenotypic variation rate of 66.60% and 73.80% in 2021 and 2022, respectively. Further, a single nucleotide polymorphism mutation was found to cause early termination of Bch10G006400 (BhHLS1) translation in GX-71 through sequencing analysis of candidate genes. Based on gene functional annotation and quantitative real-time PCR analyses, BhHLS1 encoded a probable N-acetyltransferase HLS1-like protein and its expression level was significantly different between parents. Therefore, BhHLS1 is a major candidate gene associated with a one-factor polymorphism regulating the SL and SW of wax gourds. Finally, based on variation in the BhHLS1 sequence, a cleaved amplified polymorphic sequence marker was developed for the molecular marker-assisted breeding of wax gourds.DiscussionOverall, this study is of great significance for the genetic improvement of seed size, verification of gene functions, and cultivation of specific germplasm resources for wax gourds.
Intra- and inter-brain coupling and activity dynamics during improvisational music therapy with a person with dementia: an explorative EEG-hyperscanning single case study
Authors: Maidhof Clemens , Müller Viktor , Lartillot Olivier , Agres Kat , Bloska Jodie , Asano Rie , Odell-Miller Helen , Fachner Jörg 
Published: September 2023

ObjectiveReal-life research into the underlying neural dynamics of improvisational music therapy, used with various clinical populations, is largely lacking. This single case study explored within-session differences in musical features and in within- and between-brain coupling between a Person with Dementia (PwD) and a music therapist during a music therapy session.MethodsDual-EEG from a music therapist and a PwD (male, 31 years) was recorded. Note density, pulse clarity and synchronicity were extracted from audio-visual data. Three music therapists identified moments of interest and no interest (MOI/MONI) in two drum improvisations. The Integrative Coupling Index, reflecting time-lagged neural synchronization, and musical features were compared between the MOI and MONI.ResultsBetween-brain coupling of 2 Hz activity was increased during the MOI, showing anteriority of the therapist’s neural activity. Within-brain coupling for the PwD was stronger from frontal and central areas during the MOI, but within-brain coupling for the therapist was stronger during MONI. Differences in musical features indicated that both acted musically more similar to one another during the MOI.ConclusionWithin-session differences in neural synchronization and musical features highlight the dynamic nature of music therapy.SignificanceThe findings contribute to a better understanding of social and affective processes in the brain and (interactive) musical behaviors during specific moments in a real-life music therapy session. This may provide insights into the role of such moments for relational-therapeutic processes.
Organizational culture and leadership behaviors: is manager’s psychological health the missing piece?
Authors: Dextras-Gauthier Julie , Gilbert Marie-Hélène , Dima Justine , Adou Laetitia Bomoya 
Published: September 2023

BackgroundIn a context where organizations struggle to attract and retain highly qualified workers, organizations need to prioritize the psychological health of employees as a retention factor. To do so, they need to provide a healthy work environment. As an integral part of the employee experience, managers are an important factor in employee retention. In past studies, researchers have focused on the importance of leadership in boosting employees’ health without, however, considering factors encouraging such behavior in managers. Recently, some scholars have become interested in managers’ health as a resource allowing them to adopt good leadership behavior. Indeed, these studies reveal interesting links between managers’ emotional state and their behavior as leaders. Other studies, underscore the importance of considering the organizational context to better understand managers’ psychological health that may influence their leadership behaviors. This study proposes to examine the complex process by which organizational culture influences managers’ psychological health, which acts as a resource favoring the adoption of good leadership behaviors that are known to be constructive and have positive effects on employee.MethodsPath analyses with the CALIS procedure SAS software, version 9.4 were conducted on a sample of 522 managers in three healthcare facilities in the province of Quebec, Canada.ResultsThe results revealed that group culture is associated with the two indicators of managers’ psychological health at work. The results also demonstrated that managers’ psychological distress at work is positively related to transactional and laissez-faire leadership styles whereas psychological well-being at work is positively related to transformational and transactional leadership. Concerning indirect associations, there is a significant and positive indirect association between group culture and transformational leadership and there is also a significant and negative association between group culture and laissez-faire leadership. Finally, there is also an indirect association between hierarchical culture and transactional leadership.ConclusionOur study provides a more in-depth understanding of the relationship between organizational culture and leadership styles. More specifically, our findings highlight the benefits of implementing a group organizational culture to enhance psychological well-being, reduce psychological distress symptoms and promote good leadership behaviors.
Mediterranean diet is associated with better gastrointestinal health and quality of life, and less nutrient deficiency in children/adolescents with disabilities
Authors: Bakırhan Hande , Özkaya Volkan , Pehlivan Merve 
Published: September 2023

BackgroundChildren and adolescents with disabilities face various nutritional problems. This study aimed to examine dietary characteristics, nutritional status and problems, gastrointestinal health, and quality of life in children and adolescents with disabilities.MethodsThis study included 5–18 years old children and adolescents (n = 1,991) with disabilities. We used the Mediterranean Diet Quality Index (KIDMED), the Gastrointestinal Symptom Rating Scale (GSRS), and the Pediatric Quality of Life Inventory (PedsQL) to assess diet characteristics, gastrointestinal problems, and life quality. We collected retrospective 24-h food record to assess energy and nutrient intakes.ResultsThe rate of stunting in children with disabilities varies between 16.5% and 19.8%. When comparing disability types, more children with physical disabilities were underweight (8.8% vs. 6.7%) and stunted (19.8% vs. 16.5%), while more children with intellectual disabilities were tall (7.9% vs. 5.5%) and overweight/obese (21.1 vs. 17.2%; p &lt; 0.05). Wasting (9.3%) and overweight/obesity (23.8%) were more common in children with disabilities aged 5–7 years (p &lt; 0.001). Eating problems such as loss of appetite, food refusal, food neophobia, and food selectivity were more common in children aged 5–7 years, and problems with fast eating and overeating were more common in adolescents aged 13–18 years (p &lt; 0.05). Among children and adolescents with disabilities, the nutrients with inadequate intakes were vitamin E, vitamin B1, folate, potassium, calcium, and iron, while the nutrients with intakes above the requirements were proteins, carbohydrates, vitamins A, B2, B6, B12, and C, phosphorus, zinc, and sodium. Participants with good Mediterranean diet quality had higher energy and nutrient intakes and higher percentages of meeting nutrient requirements (p &lt; 0.05). KIDMED scores were negatively correlated with GSRS total (r = −0.14, p &lt; 0.001) and subcomponent scores (abdominal pain, diarrhea, reflux, indigestion, and constipation; p &lt; 0.05), and significantly and positively correlated with PedsQL total (r = 0.12, p &lt; 0.001). A one-unit increase in the GSRS score resulted in a 14.4 times decrease in the PedsQL score, and a one-unit increase in the KIDMED score resulted in a 10.8 times increase in the PedsQL score (p = 0.001).ConclusionOverweight/obesity, stunting/wasting, nutritional problems, and deficiencies are common among disabled children and adolescents. Mediterranean diet is associated with a better quality of life, and gastrointestinal health in children with disabilities.
‘‘I felt marvellous e-cycling. If I had long hair I would have flicked it”: a qualitative investigation of the factors associated with e-cycling engagement among adults with type 2 diabetes
Authors: Bourne Jessica E. , Leary Sam , England Clare , Searle Aidan 
Published: September 2023

BackgroundPhysical activity (PA) is a key component in the management of type 2 diabetes. However, this population have low rates of PA engagement. Electrically assisted cycling has been identified as a means through which to increase PA by incorporating activity into daily life, while overcoming some of the barriers to conventional cycling. The determinants of e-cycling among people living with chronic disease are largely unknown. The aim of this research was to explore the determinants of e-cycling among individuals with type 2 diabetes using the Theoretical Domains Framework (TDF) and the Capability, Opportunity and Motivation for Behaviour change model (COM-B). This information is important for determining the suitability of future e-cycling initiatives and, if appropriate, inform future e-cycling interventions.MethodOne-to-one semi structured interviews were conducted with 16 participants from the e-cycling arm of a pilot randomised controlled trial between September 2019 and April 2020. The TDF was used to develop the interview guide. The framework method of analysis was used, incorporating both deductive and inductive reasoning. A conceptual model of the factors that influence e-cycling in this population was created.ResultsThe most commonly reported TDF domains were skills, knowledge, belief about capabilities, belief about consequences and environmental context and resources. Specifically, e-bike training facilitated e-cycling engagement by providing participants with the skills, knowledge, and confidence needed to ride the e-bike and ride on the road. In addition, the enjoyment of e-cycling was a key facilitator to engagement. Participants engaged in e-cycling to improve their health rather than for environmental reasons. Most barriers to e-cycling related to the natural or physical environment.ConclusionThis study provides insight into the personal, social, and environmental factors associated with e-cycling in this population. The findings of this study can be used to develop a more refined e-cycling intervention targeting the factors identified as influencing e-cycling engagement. In addition, this information will help in the selection of mechanistic outcome measures for evaluation.
Pharmacokinetic–pharmacodynamic analysis of cefmetazole against extended-spectrum β-lactamase-producing Enterobacteriaceae in dogs using Monte Carlo Simulation
Authors: Kusumoto Mizuki , Motegi Tomoki , Uno Haruna , Yokono Mizuki , Harada Kazuki 
Published: September 2023

IntroductionThe spread of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) is a serious concern in companion animal medicine owing to their ability to develop multidrug resistance. Cefmetazole (CMZ) is a candidate drug for treating ESBL-E infections; however, its regimen in dogs has not been established. In this study, we investigated the pharmacokinetic (PK) indices of CMZ in dogs and performed PK–pharmacodynamic (PD) analyses using Monte Carlo Simulation (MCS).MethodsIn total, six healthy dogs received an intravenous bolus dose of CMZ (40 mg/kg body weight). Serum CMZ concentrations were evaluated using liquid chromatography–mass spectrometry, and PK indices were determined based on non-compartmental analysis. The PK–PD cut-off (COPD) values were calculated as the highest minimum inhibitory concentration (MIC) that achieved ≥90% probability of target attainment for a target value of unbounded drug concentration exceeding 40% of the dosing interval. The cumulative fraction of response (CFR) was calculated based on the MIC distribution of wild-type ESBL-E from companion animals.ResultsThe area under the concentration–time curve and elimination half-time were 103.36 ± 7.49 mg·h/L and 0.84 ± 0.07 h, respectively. MCS analysis revealed that COPD values for regimens of 40 mg/kg q12, q8h, and q6h were ≤ 0.5, ≤2, and ≤ 4 μg/mL, respectively. A regimen of 40 mg/kg q6h was estimated to achieve a CFR of 80–90% for Escherichia coli and Klebsiella pneumoniae. By contrast, all regimens exhibited a CFR of ≤70% for Proteus mirabilis and Enterobacter cloacae.DiscussionWe conclude that CMZ at 40 mg/kg q6h could be a viable treatment regimen for dogs infected with ESBL-producing Escherichia coli and Klebsiella pneumoniae.
First Report and Characterization of the mcr-1 Positive Multidrug-Resistant Escherichia coli Strain Isolated from Pigs in Croatia
Authors: Kompes Gordan , Duvnjak Sanja , Reil Irena , Hendriksen Rene S. , Sørensen Lauge Holm , Zdelar-Tuk Maja , Habrun Boris , Cvetnić Luka , Bagarić Antonela , Špičić Silvio 
Published: September 2023

The emergence and rapid spread of the plasmid-mediated colistin-resistant mcr-1 gene introduced a serious threat to public health. In 2021, a multi-drug resistant, mcr-1 positive Escherichia coli EC1945 strain, was isolated from pig caecal content in Croatia. Antimicrobial susceptibility testing and whole genome sequencing were performed. Bioinformatics tools were used to determine the presence of resistance genes, plasmid Inc groups, serotype, sequence type, virulence factors, and plasmid reconstruction. The isolated strain showed phenotypic and genotypic resistance to nine antimicrobial classes. It was resistant to colistin, gentamicin, ampicillin, cefepime, cefotaxime, ceftazidime, sulfamethoxazole, chloramphenicol, nalidixic acid, and ciprofloxacin. Antimicrobial resistance genes included mcr-1, blaTEM-1B, blaCTX-M-1, aac(3)-IId, aph(3’)-Ia, aadA5, sul2, catA1, gyrA (S83L, D87N), and parC (A56T, S80I). The mcr-1 gene was located within the conjugative IncX4 plasmid. IncI1, IncFIB, and IncFII plasmids were also detected. The isolate also harbored 14 virulence genes and was classified as ST744 and O101:H10. ST744 is a member of the ST10 group which includes commensal, extraintestinal pathogenic E. coli isolates that play a crucial role as a reservoir of genes. Further efforts are needed to identify mcr-1-carrying E. coli isolates in Croatia, especially in food-producing animals to identify such gene reservoirs.