bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating clinician support with intervention design as part of a programme testing stratified care for musculoskeletal pain in general practice
Authors: Protheroe Joanne , Saunders Benjamin , Hill Jonathan C. , Chudyk Adrian , Foster Nadine E. , Bartlam Bernadette , Wathall Simon , Cooper Vincent 
Published: July 2021

Abstract
Background
Stratified care involves subgrouping patients based on key characteristics, e.g. prognostic risk, and matching these subgroups to early treatment options. The STarT-MSK programme developed and tested a new stratified primary care intervention for patients with common musculoskeletal (MSK) conditions in general practice. Stratified care involves changing General Practitioners’ (GPs) behaviour, away from the current ‘stepped’ care approach to identifying early treatment options matched to patients’ risk of persistent pain. Changing healthcare practice is challenging, and to aid the successful delivery of stratified care, education and support for GPs was required. This paper details the iterative development of a clinician support package throughout the lifespan of the programme, to support GPs in delivering the stratified care intervention. We argue that clinician support is a crucial aspect of the intervention itself, which is often overlooked.

Methods
Qualitative research with patients and GPs identified barriers and facilitators to the adoption of stratified care, which were mapped onto the Theoretical Domains Framework (TDF). Identified domains were ‘translated’ into an educational paradigm, and an initial version of the support package developed. This was further refined following a feasibility and pilot RCT, and a finalised support package was developed for the main RCT.

Results
The clinician support package comprised face-to-face sessions combining adult-learning principles with behaviour change theory in a multimethod approach, which included group discussion, simulated consultations, patient vignettes and model consultation videos. Structured support for GPs was crucial to facilitate fidelity and, ultimately, a successful trial. Clinician support is a two-way process– the study team can learn from and adapt to specific local factors and issues not previously identified. The support from senior clinicians was required to ensure ‘buy in’. Monitoring of GP performance, provision of regular feedback and remedial support are important aspects of effective clinician support.

Conclusion
Designing effective clinician support from the onset of trial intervention design, in an evidence-based, theory-informed manner, is crucial to encourage active engagement and intervention fidelity within the trial, enabling the delivery of a robust and reliable proof-of-principle trial. We offer practical recommendations for future general practice interventions.
Cost-effectiveness of group-based exercise to prevent falls in elderly community-dwelling people
Authors: Scheckel Benjamin , Stock Stephanie , Müller Dirk 
Published: July 2021

Abstract
Background
Clinical studies indicate that strength-balance training for active fall prevention can prevent fractures in older people. The present modelling study evaluates the cost-effectiveness of fall prevention exercise (FPE) provided to independently living older people compared to no intervention in Germany.

Method
We designed a Markov model to evaluate the cost-effectiveness of a group-based FPE-program provided to independently living people ≥75 years from the perspective of the German statutory health insurance (SHI). Input data was obtained from public databases, clinical trials and official statistics. The incremental cost-effectiveness ratio (ICER) was presented as costs per avoided hip fracture. Additionally, we performed deterministic and probabilistic sensitivity analyses and, estimated monetary consequences for the SHI in a budget impact analysis (BIA).

Results
For women, the costs per hip fracture avoided amounted to €52,864 (men: €169,805). Results of deterministic and probabilistic sensitivity analyses confirmed the robustness of the results. According to the BIA, for the reimbursement of FPE additional costs of €3.0 million (women) and €7.8 million (men) are expected for the SHI.

Conclusions
Group-based FPE appears to be no cost-effective option to prevent fall-related hip fractures in independently living elderly. To allow a more comprehensive statement on the cost effectiveness of FPE fracture types other than hip should be increasingly evaluated in clinical trials.
Inner diameters of the normal carotid arteries measured using three-dimensional digital subtraction catheter angiography: a retrospective analysis
Authors: Tan Qingjing , Qin Chao , Yang Junwei , Wang Tianbao , Lin Haohai , Lin Cuiting , Chen Xiangren 
Published: July 2021

Abstract
Purpose
To obtain normal ranges for the inner diameters of the carotid arteries.

Methods
This retrospective analysis included consecutive patients with disease-free carotid arteries who had undergone 3D-DSA at two hospitals in Nanning, Guangxi, between March 2013 and March 2018. Demographic and clinical characteristics, including Essen Stroke Risk Score (ESRS), were extracted from the medical records. The 3D-DSA data were used to calculate the inner diameters of the carotid arteries.

Results
The analysis included 1182 patients (837 males) aged 58.81 ± 11.02 years. The inner diameters of the proximal carotid sinus (CS), CS bulge, distal CS, and common carotid artery (CCA) were larger on the right than on the left (P < 0.05). The inner diameters of the proximal CS, CS bulge, distal CS, and CCA on both sides were larger for males than females (P < 0.05). The inner diameters of the proximal CS, CS bulge, and distal CS on both sides were smaller for patients aged > 65 years than for patients aged ≤ 55 years (P < 0.05). Right CCA inner diameter did not vary with age, whereas left CCA inner diameter was larger for patients aged > 55 years than for patients aged ≤ 45 years (P < 0.05). The inner diameters of the proximal CS, CS bulge, and distal CS on both sides were smaller for patients with ESRS ≥ 3 than those with ESRS < 3 (P < 0.05).

Conclusion
This study provides reference values for the internal diameters of normal carotid arteries. Carotid artery diameters varied with side, sex, and age.
Integration of RNA-Seq and proteomics data identifies glioblastoma multiforme surfaceome signature
Authors: Syafruddin Saiful Effendi , Nazarie Wan Fahmi Wan Mohamad , Moidu Nurshahirah Ashikin , Soon Bee Hong , Mohtar M. Aiman 
Published: July 2021

AbstractBackgroundGlioblastoma multiforme (GBM) is a highly lethal, stage IV brain tumour with a prevalence of approximately 2 per 10,000 people globally. The cell surface proteins or surfaceome serve as information gateway in many oncogenic signalling pathways and are important in modulating cancer phenotypes. Dysregulation in surfaceome expression and activity have been shown to promote tumorigenesis. The expression of GBM surfaceome is a case in point; OMICS screening in a cell-based system identified that this sub-proteome is largely perturbed in GBM. Additionally, since these cell surface proteins have ‘direct’ access to drugs, they are appealing targets for cancer therapy. However, a comprehensive GBM surfaceome landscape has not been fully defined yet. Thus, this study aimed to define GBM-associated surfaceome genes and identify key cell-surface genes that could potentially be developed as novel GBM biomarkers for therapeutic purposes.MethodsWe integrated the RNA-Seq data from TCGA GBM (n = 166) and GTEx normal brain cortex (n = 408) databases to identify the significantly dysregulated surfaceome in GBM. This was followed by an integrative analysis that combines transcriptomics, proteomics and protein-protein interaction network data to prioritize the high-confidence GBM surfaceome signature.ResultsOf the 2381 significantly dysregulated genes in GBM, 395 genes were classified as surfaceome. Via the integrative analysis, we identified 6 high-confidence GBM molecular signature, HLA-DRA, CD44, SLC1A5, EGFR, ITGB2, PTPRJ, which were significantly upregulated in GBM. The expression of these genes was validated in an independent transcriptomics database, which confirmed their upregulated expression in GBM. Importantly, high expression of CD44, PTPRJ and HLA-DRA is significantly associated with poor disease-free survival. Last, using the Drugbank database, we identified several clinically-approved drugs targeting the GBM molecular signature suggesting potential drug repurposing.ConclusionsIn summary, we identified and highlighted the key GBM surface-enriched repertoires that could be biologically relevant in supporting GBM pathogenesis. These genes could be further interrogated experimentally in future studies that could lead to efficient diagnostic/prognostic markers or potential treatment options for GBM.
Meta-analysis and indirect treatment comparison of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel as first-line chemotherapy in advanced pancreatic cancer
Authors: Chen Jiayuan , Hua Qingling , Wang Haihong , Zhang Dejun , Zhao Lei , Yu Dandan , Pi Guoliang , Zhang Tao , Lin Zhenyu 
Published: July 2021

Abstract
Background
Modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB.

Methods
The eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study.

Results
Twenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78–1.63; PFS: HR: 1.19; 95% CI: 0.85–1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04–1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB.

Conclusions
The current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC.
Improving the catalytic characteristics of phenolic acid decarboxylase from Bacillus amyloliquefaciens by the engineering of N-terminus and C-terminus
Authors: Li Qin , Xia Ying , Zhao Ting , Gong Yuanyuan , Fang Shangling , Chen Maobin 
Published: July 2021

AbstractBackground4-vinylphenols produced by phenolic acid degradation catalyzed by phenolic acid decarboxylase can be used in food additives as well as flavor and fragrance industry. Improving the catalytic characters of phenolic acid decarboxylase is of great significance to enhance its practical application.ResultsA phenolic acid decarboxylase (P-WT) was created fromBacillus amyloliquefaciensZJH-01. Mutants such as P-C, P-N, P-m1, P-m2, P-Nm1, and P-Nm2 were constructed by site-directed mutagenesis of P-WT. P-C showed better substrate affinities and higher turnover rates than P-WT for p-coumaric acid, ferulic acid, and sinapic acid; however, P-N had reduced affinity toward p-coumaric acid. The extension of the C-terminus increased its acid resistance, whereas the extension of the N-terminus contributed to the alkali resistance and heat resistance. The affinity of P-m1 to four substrates and that of P-m2 to p-coumaric acid and ferulic acid were greatly improved. However, the affinity of P-Nm2 to four phenolic acids was greatly reduced. The residual enzyme activities of P-Nm1 and P-Nm2 considerably improved compared with those of P-m1 and P-m2 after incubation at 50 °C for 60 min.ConclusionsThe extension of the N-terminus may be more conducive to the combination of the binding cavity with the substrate in an alkaline environment and may make its structure more stable.
Genome-Wide Association Study (GWAS) of dental caries in diverse populations
Authors: Alotaibi Rasha N. , Howe Brian J. , Chernus Jonathan M. , Mukhopadhyay Nandita , Sanchez Carla , Deleyiannis Frederic W. B. , Neiswanger Katherine , Padilla Carmencita , Poletta Fernando A. , Orioli Ieda M. , Buxó Carmen J. , Hecht Jacqueline T. , Wehby George L. , Long Ross E. , Vieira Alexandre R. , Weinberg Seth M. , Shaffer John R. , Moreno Uribe Lina M. , Marazita Mary L. 
Published: July 2021

Abstract
Background
Dental caries is one of the most common chronic diseases and is influenced by a complex interplay of genetic and environmental factors. Most previous genetic studies of caries have focused on identifying genes that contribute to dental caries in specific ethnic groups, usually of European descent.

Methods
The aim of this study is to conduct a genome-wide association study (GWAS) to identify associations affecting susceptibility to caries in a large multiethnic population from Argentina, the Philippines, Guatemala, Hungary, and the USA, originally recruited for studies of orofacial clefts (POFC, N = 3686). Ages of the participants ranged from 2 to 12 years for analysis of the primary dentition, and 18–60 years for analysis of the permanent dentition. For each participant, dental caries was assessed by counts of decayed and filled teeth (dft/DFT) and genetic variants (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Caries was analyzed separately for the primary and permanent dentitions, with age, gender, and presence/absence of any type of OFC treated as covariates. Efficient Mixed-Model Association eXpedited (EMMAX) was used to test genetic association, while simultaneously accounting for relatedness and stratification.

Results
We identified several suggestive loci (5 × 10−8 < P < 5 × 10−6) within or near genes with plausible biological roles for dental caries, including a cluster of taste receptor genes (TAS2R38, TAS2R3, TAS2R4, TASR25) on chromosome 7 for the permanent dentition analysis, and DLX3 and DLX4 on chromosome 17 for the primary dentition analysis. Genome-wide significant results were seen with SNPs in the primary dentition only; however, none of the identified genes near these variants have known roles in cariogenesis.

Conclusion
The results of this study warrant further investigation and may lead to a better understanding of cariogenesis in diverse populations, and help to improve dental caries prediction, prevention, and/or treatment in future.
Shaping ability of three nickel-titanium rotary instruments in simulated L-shaped canals: OneShape, Hero Shaper, and Revo-S
Authors: Vakili-Gilani Pouyan , Tavanafar Saeid , Saleh Abdul Rahman Mohammad , Karimpour Hamideh 
Published: July 2021

Abstract
Background
Shaping ability of a file plays an important role during instrumentation in an endodontic treatment. This study aimed to compare the shaping ability of OneShape (OS), Hero Shaper (HS), and Revo-S (RS) instruments in simulated L-shaped canals.

Methods
Forty-eight simulated L-shaped canals were prepared to an apical size of 25 using OS, HS, and RS (all from Micro-Mega SA, Besançon, France), (n = 16 canals/group) systems. The amount of resin removed after each canal's preparation was measured and compared after producing a composite image made from the superimposition of pre and post-instrumented canals. Canal aberrations and the preparation time were also recorded. The data were statistically analysed by using ANOVA, Tukey, and Chi-square tests.

Results
One file fractured during instrumentation in the RS group. A significant difference was found at the apical end of the prepared simulated canal between the groups, with RS showing the least amount of resin removal from the inner side of the canals and HS showing the highest amount of resin removal from the outer side (P < 0.05). Regarding the total width of the canals after preparation, a significant difference was found between the groups at the apical end and the straight portion of the canals, and RS removed the least amount of resin at the straight portion of the canals (P < 0.05). No statistically significant differences were found between the different instruments regarding canal aberrations' incidence (P > 0.05).

Conclusions
All of the files showed a tendency to straighten the canals, whereas OS files maintained the original canal curvatures well.
Undisclosed probing into decision-making capacity: a dilemma in secondary care
Authors: Talukdar Sandip 
Published: July 2021

AbstractBackgroundThe assessment of patients’ decision-making capacity is ubiquitous in contemporary healthcare. This paper examines the ethics of undisclosed probing of capacity by psychiatrists. The discussion will refer to the law in England and Wales, though the highlighted issues are likely to be relevant in similar jurisdictions.Main textDecision-making capacity is a private attribute, and patients may not necessarily be aware that one of their personal abilities is being explored. Routine exploration of capacity has not historically been a part of psychiatric examination, but it is now difficult to avoid during psychiatric interview.Ethical practice and shared decision-making require patients to be aware that their decision-making may be evaluated by the doctor at some point, and the potential implications of an objective professional conclusion of incapacity. Case law directs that patients should be informed about any assessment of their decision-making ability, though the extent to which this has translated into practice is unclear. However, explanation about the assessment may cause a patient to react negatively, which may impede therapeutic engagement and constitute an ethical dilemma. It is argued that in the absence of systemic measures, professionals should retain the discretion to decide whether a particular patient should be informed about the impending probe into their decision-making ability, or not. In the latter instance, concealment of information about the assessment or its purpose should be subject to the caveats and safeguards associated with any recourse to therapeutic exception.ConclusionThe necessity to mandatorily inform patients about assessment of their capacity introduces a novel ethical dilemma for psychiatrists. The negotiation of this dilemma should not be the prerogative of the clinician, and requires systemic initiatives to ensure universal awareness of patients about the possibility of their capacity being assessed during their journeys through healthcare systems.
AUY922 induces retinal toxicity through attenuating TRPM1
Authors: Shen Che-Hung , Hsieh Chi-Che , Jiang Kuan-Ying , Lin Chih-Yu , Chiang Nai-Jung , Li Ting-Wei , Yen Chun-Ting , Chen Wan-Ju , Hwang Daw-Yang , Chen Li-Tzong 
Published: July 2021

Abstract
Background
Ocular adverse events are common dose-limiting toxicities in cancer patients treated with HSP90 inhibitors, such as AUY922; however, the pathology and molecular mechanisms that mediate AUY922-induced retinal toxicity remain undescribed.

Methods
The impact of AUY922 on mouse retinas and cell lines was comprehensively investigated using isobaric tags for relative and absolute quantitation (iTRAQ)‑based proteomic profiling and pathway enrichment analysis, immunohistochemistry and immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, MTT assay, colony formation assay, and western blot analysis. The effect of AUY922 on the Transient Receptor Potential cation channel subfamily M member 1 (TRPM1)-HSP90 chaperone complex was characterized by coimmunoprecipitation. TRPM1-regulated gene expression was analyzed by RNAseq analysis and gene set enrichment analysis (GSEA). The role of TRPM1 was assessed using both loss-of-function and gain-of-function approaches.

Results
Here, we show that the treatment with AUY922 induced retinal damage and cell apoptosis, dysregulated the photoreceptor and retinal pigment epithelium (RPE) layers, and reduced TRPM1 expression. Proteomic profiling and functional annotation of differentially expressed proteins reveals that those related to stress responses, protein folding processes, regulation of apoptosis, cell cycle and growth, reactive oxygen species (ROS) response, cell junction assembly and adhesion regulation, and proton transmembrane transport were significantly enriched in AUY922-treated cells. We found that AUY922 triggered caspase-3-dependent cell apoptosis, increased ROS production and inhibited cell growth. We determined that TRPM1 is a bona fide HSP90 client and characterized that AUY922 may reduce TRPM1 expression by disrupting the CDC37-HSP90 chaperone complex. Additionally, GSEA revealed that TRPM1-regulated genes were associated with retinal morphogenesis in camera-type eyes and the JAK-STAT cascade. Finally, gain-of-function and loss-of-function analyses validated the finding that TRPM1 mediated the cell apoptosis, ROS production and growth inhibition induced by AUY922.

Conclusions
Our study demonstrates the pathology of AUY922-induced retinal toxicity in vivo. TRPM1 is an HSP90 client, regulates photoreceptor morphology and function, and mediates AUY922-induced cytotoxicity.