bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implementation opportunities and challenges identified by key stakeholders in scaling up HIV Treatment as Prevention in British Columbia, Canada: a qualitative study
Authors: Chayama Koharu Loulou , McNeil Ryan , Shoveller Jean , Small Will , Knight Rod 
Published: June 2020

Abstract
Background
The province of British Columbia (BC), Canada, was among the first jurisdictions to scale up HIV Treatment as Prevention (TasP) to the population level, including funding and policy commitments that enhanced HIV testing efforts (e.g., expansion of routine, opt-out testing), while also making antiretroviral therapy universally available to all people living with HIV. As such, BC represents a critical context within which to identify factors that influenced the scalability of TasP (e.g., acceptability, adoption, fidelity, equitable reach, sustainability), including key opportunities and challenges.

Methods
We draw on in-depth, semi-structured interviews with 10 key stakeholders, comprised policymakers at the local and provincial levels and representatives from community-based organizations. Using the Consolidated Framework for Implementation Research (CFIR) to guide data collection, coding, and analysis, we identified key factors that influenced practice transformation and scale up.

Results
Key factors that contributed to the successful scale up of TasP included: (i) opportunities that enhanced stakeholder buy-in based on features of the intervention characteristics, including with regard to assessments about the quality and strength of evidence supporting TasP; (ii) an inner setting implementation climate that was, in part, shaped by the large and highly symbolic government investments into TasP; (iii) features of the outer setting such as external policies (e.g., harm reduction) that cultivated opportunities to implement new “systems-level” approaches to HIV intervention; (iv) the personal attributes of some “middle-level” influencers, including a team that was comprised of some highly motivated and social justice-oriented individuals (e.g., folks who were deeply committed to serving marginalized populations); and (v) the capacity to develop various implementation processes that could maintain “nimble and evidence-informed” adaptations across a highly decentralized service delivery system, while also creating opportunities to adapt features of TasP programming based on “real time” program data.

Conclusion
Constructs across all five domains of CFIR (intervention characteristics, outer setting, inner setting, characteristics of individuals, and process) were identified to influence the success of TasP in BC. Our findings provide important insights into how BC can successfully implement and scale up other systems-level interventions that have demonstrated efficacy, while also offering insights for other jurisdictions that are currently or planning to scale up TasP.
Clinical diagnosis of Lewy body dementia
Authors: Surendranathan Ajenthan , Kane Joseph P. M. , Bentley Allison , Barker Sally A. H. , Taylor John-Paul , Thomas Alan J. , Allan Louise M. , McNally Richard J. , James Peter W. , McKeith Ian G. , Burn David J. , O'Brien John T. 
Published: June 2020

Background
Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series.

Aims
This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences.

Method
We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions.

Results
The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs.

Conclusions
Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.
The Effect of Cross-linking Efficiency of Drug-Loaded Novel Freeze Gelated Chitosan Templates for Periodontal Tissue Regeneration
Authors: Qasim Syed Saad B. , Nogueria Liebert Parreiras , Fawzy Amr S. , Daood Umer 
Published: June 2020

AbstractInnovative strategies for periodontal regeneration have been the focus of research clusters across the globe for decades. In order to overcome the drawbacks of currently available options, investigators have suggested a novel concept of functionally graded membrane (FGM) templates with different structural and morphological gradients. Chitosan (CH) has been used in the past for similar purpose. However, the composite formulation of composite and tetracycline when cross-linked with glutaraldehyde have received little attention. Therefore, the purpose of the study was to investigate the drug loading and release characteristics of novel freeze gelated chitosan templates at different percentages of glutaraldehyde. These were cross-linked with 0.1 and 1% glutaraldehyde and loaded with doxycycline hyclate. The electron micrographs depicted porous morphology of neat templates. After cross-linking, these templates showed compressed ultrastructures. Computerized tomography analysis showed that the templates had 88 to 92% porosity with average pore diameter decreased from 78 to 44.9 μm with increasing concentration. Fourier transform infrared spectroscopy showed alterations in the glycosidic segment of chitosan fingerprint region which after drug loading showed a dominant doxycycline spectral composite profile. Interestingly, swelling profile was not affected by cross-linking either at 0.1 and 1% glutaraldehyde and template showed a swelling ratio of 80%, which gained equilibrium after 15 min. The drug release pattern also showed a 40 μg/mL of release after 24 h. These doxycycline-loaded templates show their tendency to be used in a functionally graded membrane facing the defect site.
Overexpression of Wnt7a enhances radiosensitivity of non-small-cell lung cancer via the Wnt/JNK pathway
Authors: Ai Pingping , Xu Xianhua , Xu Shijie , Wei Zhixia , Tan Shun , Li Junzhe 
Published: June 2020

ABSTRACT
The Wingless-type protein 7a (Wnt7a) plays an antiproliferative role in non-small-cell lung cancer (NSCLC). Previous studies have indicated that Wnt7a expression was downregulated in radiation-resistant NSCLC cells. However, little is known about its biological functions and molecular mechanisms in radiosensitivity of NSCLC. Thus, NSCLC cell proliferation and apoptosis in response to Wnt7a overexpression and/or radiation were determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyl-tertazolium bromide (MTT) assay and flow cytometry, respectively. The activation of the Wnt/cJun N-terminal kinase (JNK) and Wnt/β-catenin signaling pathways were further examined by western blot in NSCLC cell lines H1650 and A549. Wnt7a overexpression combined with radiation-inhibited cell proliferation and induced apoptosis in NSCLC cell lines compared to Wnt7a overexpression or radiotherapy alone. In addition, the phosphorylation of JNK, but not β-catenin, was congruent with the changes in Wnt7a overexpression and/or radiation. Moreover, the Wnt/JNK pathway could induce the apoptosis of NSCLC cells through the mitochondrial pathway. Inhibition of the Wnt/JNK signaling pathway by SP600125, a JNK inhibitor, contributed to proliferation induction in NSCLC cells. Taken together, these results showed that Wnt7a overexpression sensitized NSCLC cell lines to radiotherapy through the Wnt/JNK signaling pathway.
Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor
Authors: Tamir Tigist Y. , Bowman Brittany M. , Agajanian Megan J. , Goldfarb Dennis , Schrank Travis P. , Stohrer Trent , Hale Andrew E. , Siesser Priscila F. , Weir Seth J. , Murphy Ryan M. , LaPak Kyle M. , Weissman Bernard E. , Moorman Nathaniel J. , Major M. Ben 
Published: June 2020

ABSTRACT
Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, but conversely NRF2 activity diminishes with age and in neurodegenerative and metabolic disorders. Although NRF2-activating drugs are clinically beneficial, NRF2 inhibitors do not yet exist. Here, we describe use of a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the under-studied protein kinase brain-specific kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives 5′-AMP-activated protein kinase α2 (AMPK) signaling and suppresses the mTOR pathway. As a result, BRSK2 kinase activation suppresses ribosome-RNA complexes, global protein synthesis and NRF2 protein levels. Collectively, our data illuminate the BRSK2 and BRSK1 kinases, in part by functionally connecting them to NRF2 signaling and mTOR. This signaling axis might prove useful for therapeutically targeting NRF2 in human disease.
This article has an associated First Person interview with the first author of the paper.
Primary operator radiation dose in the cardiac catheter laboratory
Authors: Crowhurst James A , Whitby Mark , Aroney Nicholas , Dautov Rustem , Walters Darren , Raffel Owen 
Published: June 2020

Objectives:
Radiation from cardiac angiography procedures is harmful to patients and the staff performing them. This study sought to investigate operator radiation dose for a range of procedures and different operators in order to investigate trends and optimise dose.

Methods:
Real-time dosemeters (RTDs) were worn by operators for angiography procedures for 3 years. Dose–area product (DAP) and RTD were collected. RTD was normalised to DAP (RTD/DAP) to compare radiation dose and radiation protection measures. Comparisons were made across procedure categories and individual operators.

Results:
In 7626 procedures, median and 75th percentile levels were established for operator dose for 8 procedure categories. There was a significant difference in all operator dose measures and DAP across procedure categories (p&lt;0.001). DAP, RTD, and RTD/DAP were significantly different across 22 individual operators (p&lt;0.001).

Conclusion:
DAP was significantly different across procedure categories and a higher RTD was seen with higher DAP. RTD/DAP can demonstrate radiation protection effectiveness and identified differences between procedures and individual operators with this measure. Procedures and individuals were identified where further optimisation of radiation protection measures may be beneficial. A reference level for operator dose can be created and audited against on a regular basis.

Advances in knowledge:
This study demonstrates that operator dose can be easily and routinely measured on a case by case basis to investigate dose trends for different procedures. Normalising the operator dose to DAP demonstrates radiation protection effectiveness for the individual operator which can then be optimised as part of an ongoing audit program.
Comparison of radiographer interobserver image registration variability using cone beam CT and MR for cervix radiotherapy
Authors: Rodgers John , Hales Rosie , Whiteside Lee , Parker Jacqui , McHugh Louise , Cree Anthea , van Herk Marcel , Choudhury Ananya , Hoskin Peter , McWilliam Alan , Eccles Cynthia L 
Published: June 2020

Objectives:
The aim of this study was to assess the consistency of therapy radiographers performing image registration using cone beam computed tomography (CBCT)-CT, magnetic resonance (MR)-CT, and MR-MR image guidance for cervix cancer radiotherapy and to assess that MR-based image guidance is not inferior to CBCT standard practice.

Methods:
10 patients receiving cervix radiation therapy underwent daily CBCT guidance and magnetic resonance (MR) imaging weekly during treatment. Offline registration of each MR image, and corresponding CBCT, to planning CT was performed by five radiographers. MR images were also registered to the earliest MR interobserver variation was assessed using modified Bland–Altman analysis with clinically acceptable 95% limits of agreement (LoA) defined as ±5.0 mm.

Results:
30 CBCT-CT, 30 MR-CT and 20 MR–MR registrations were performed by each observer. Registration variations between CBCT-CT and MR-CT were minor and both strategies resulted in 95% LoA over the clinical threshold in the anteroposterior direction (CBCT-CT ±5.8 mm, MR-CT ±5.4 mm). MR–MR registrations achieved a significantly improved 95% LoA in the anteroposterior direction (±4.3 mm). All strategies demonstrated similar results in lateral and longitudinal directions.

Conclusion:
The magnitude of interobserver variations between CBCT-CT and MR-CT were similar, confirming that MR-CT radiotherapy workflows are comparable to CBCT-CT image-guided radiotherapy. Our results suggest MR–MR radiotherapy workflows may be a superior registration strategy.

Advances in knowledge:
This is the first publication quantifying interobserver registration of multimodality image registration strategies for cervix radical radiotherapy patients.
Influence of windowing and metal artefact reduction algorithms on the volumetric dimensions of five different high-density materials: a cone-beam CT study
Authors: Coelho-Silva Fernanda , Martins Luciano Augusto Cano , Braga Daniela Azeredo , Zandonade Eliana , Haiter-Neto Francisco , de-Azevedo-Vaz Sergio Lins 
Published: June 2020

Objective: To assess the influence of windowing and metal artefact reduction (MAR) algorithms on the volumetric dimensions of high-density materials using two CBCT systems. Methods: Four cylinders of amalgam, cobalt-chromium, gutta-percha, titanium and zirconium, were manufactured and their physical volumes (PV) were measured. A polymethyl methacrylate phantom containing the cylinders was submitted to CBCT acquisitions with Picasso Trio and OP300 units with their MAR enabled and disabled. The tomographic volume (TV) of all the cylinders was obtained by semi-automatic segmentation using two windowing adjustments: W1—large window width and upper window level; W2—narrow window width and low window level. Volumetric distortion was expressed as the difference between TV and PV. Statistics comprised intraclass correlation coefficient (ICC) and analysis of variance (ANOVA) for repeated measures with Tukey post hoc test (α = 5%). Results: The ICC values ​​indicated excellent reproducibility of TV. Gutta-percha and titanium resulted in the smallest volumetric distortion. Using W1 provided less volumetric distortion for almost all experimental conditions (p < 0.05). Activating MAR algorithm of Picasso Trio underestimated gutta-percha and titanium TV (p < 0.05) and was inefficient in significantly reducing the volumetric distortion of the other materials (p > 0.05). Disabling MAR algorithm of OP300 resulted in smaller volumetric distortion for almost all experimental conditions (p < 0.05). Conclusions: The TV of gutta-percha and titanium were closer to the PV. In general, the MAR algorithms of both systems were inefficient in significantly reducing the volumetric distortion of high-density materials. We encourage the use of large window width and upper window level to evaluate high-density materials.
Neuronal regulation of bone marrow stem cell niches
Authors: Fielding Claire , Méndez-Ferrer Simón 
Published: June 2020

The bone marrow (BM) is the primary site of postnatal hematopoiesis and hematopoietic stem cell (HSC) maintenance. The BM HSC niche is an essential microenvironment which evolves and responds to the physiological demands of HSCs. It is responsible for orchestrating the fate of HSCs and tightly regulates the processes that occur in the BM, including self-renewal, quiescence, engraftment, and lineage differentiation. However, the BM HSC niche is disturbed following hematological stress such as hematological malignancies, ionizing radiation, and chemotherapy, causing the cellular composition to alter and remodeling to occur. Consequently, hematopoietic recovery has been the focus of many recent studies and elucidating these mechanisms has great biological and clinical relevance, namely to exploit these mechanisms as a therapeutic treatment for hematopoietic malignancies and improve regeneration following BM injury. The sympathetic nervous system innervates the BM niche and regulates the migration of HSCs in and out of the BM under steady state. However, recent studies have investigated how sympathetic innervation and signaling are dysregulated under stress and the subsequent effect they have on hematopoiesis. Here, we provide an overview of distinct BM niches and how they contribute to HSC regulatory processes with a particular focus on neuronal regulation of HSCs under steady state and stress hematopoiesis.
Comparison of WHO growth standard and national Indonesian growth reference in determining prevalence and determinants of stunting and underweight in children under five: a cross-sectional study from Musi sub-district
Authors: Flynn Jeannie , Alkaff Firas Farisi , Sukmajaya William Putera , Salamah Sovia 
Published: June 2020

Background:Determination of stunting and wasting always uses the WHO growth standard in Indonesia. However, it is believed that Indonesian children are “below” the global standard, thus the WHO standard is not reliable to present the actual prevalence. This study aims to compare the prevalence and determinants of stunting and underweight using WHO growth standard and national Indonesian growth reference.Methods:This was a cross-sectional study carried out in Musi sub-district, East Nusa Tenggara province in July 2019. East Nusa Tenggara province had the highest prevalence of stunting and underweight in Indonesia. The study population were children under five, and total sampling method was used for this study. Length/height-for-age and weight-for-age were plotted using WHO standard and national Indonesian reference. Univariate and multivariate binomial logistic regression were used for statistical analysis.Results:The prevalence of stunting and underweight were higher for the WHO standard than the national reference (53.9% vs 10.7% and 29.17% vs 17.7%; all p < 0.001). After adjusted for confounding factors, when the WHO standard was used, determinants of stunting were maternal mid-upper arm circumference below 23.5cm and maternal height below 150cm; determinants of underweight were intrauterine growth restriction, young maternal age during pregnancy, and multiple parities. When the national reference was used, no determinants was found for stunting; the determinants of underweight were intrauterine growth restriction and maternal education.Conclusions:The WHO standard is not suitable for representing child growth in Musi sub-district. Future studies should be done to re-evaluate the prevalence and determinants of stunting and underweight nationwide using the national Indonesian reference.
Including a pen and/or cover letter, containing social incentive text, had no effect on questionnaire response rate: a factorial randomised controlled Study within a Trial
Authors: James Sophie , Parker Adwoa , Cockayne Sarah , Rodgers Sara , Fairhurst Caroline , Torgerson David J. , Rhodes Sarah , Cotterill Sarah 
Published: June 2020

Background: Postal questionnaires are frequently used in randomised controlled trials to collect outcome data on participants; however, poor response can introduce bias, affect generalisability and validity, and reduce statistical power. The objective of this study was to assess whether a pen and/or social incentive text cover letter sent with a postal follow-up questionnaire increased response rates in a trial. Method: A two-by-two factorial randomised controlled trial was embedded within the OTIS host trial. Participants due their 12-month (final) follow-up questionnaire were randomised to be sent: a pen; a social incentive text cover letter; both; or neither. The primary outcome measure was the proportion of participants in each group who returned the questionnaire. Secondary outcomes were: time to return, completeness of the questionnaire, necessity of a reminder letter, and the cost effectiveness. Results: The overall 12-month questionnaire response rate was 721 out of 755 (95.5%). Neither the pen nor social incentive cover letter had a statistically significant effect on response rate: pen 95.2% vs. no pen 95.8%, adjusted OR 0.90 (95% CI 0.45 to 1.80; p=0.77); social incentive cover letter 95.2% vs. no social incentive cover letter 95.8%, adjusted OR 0.84 (95% CI 0.42 to 1.69, p=0.63). No statistically significant differences were observed between either of the intervention groups on time to response, need for a reminder or completeness. Therefore, neither intervention was cost-effective. Conclusions: We found no evidence of a difference in response rates associated with the inclusion of a pen and/or social incentive cover letter with the final follow-up postal questionnaire of the host trial. However, when these results are combined with previous SWATs, the meta-analysis evidence remains that including a pen increases response rates. The social incentive cover letter warrants further investigation to determine effectiveness. Trial registration: ISRCTN22202133 (21st June 2020).