bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing post-discharge care following acute kidney injury in England: a single-centre qualitative evaluation
Authors: Elvey Rebecca , Howard Susan J , Martindale Anne-Marie , Blakeman Thomas
Published: August 2020

Objectives

We sought to understand the factors influencing the implementation of a primary care intervention to improve post-discharge care following acute kidney injury (AKI).

Design

Qualitative study using semi-structured interviews and thematic analysis.

Setting

General practices in one Clinical Commissioning Group area in England.

Participants

A total of 18 healthcare staff took part in interviews. Participants were practice pharmacists, general practitioners, practice managers and administrators involved in implementing the intervention.

Results

We identified three main factors influencing implementation: differentiation of the new intervention from other practice work; development of skill mix and communication across organisations. Overall, post-AKI processes of care were deemed straightforward to embed into existing practice. However, it was also important to separate the intervention from other work in general practice. Dedicating staff time to proactively identify AKI on discharge summaries and to coordinate the provision of care enabled implementation of the intervention. The post-AKI intervention provided an opportunity for practice pharmacists to expand their primary care role. Working in a new setting also brought challenges; time to develop trusting relationships including an understanding of boundaries of clinical expertise influenced pharmacists’ roles. Unclear and inconsistent information on discharge summaries contributed to concerns about additional work in primary care.

Conclusions

The research highlights challenges around post-discharge management in the primary care context. Coordination and communication were key factors for improving follow-up care following AKI. Further consideration is required to understand patient experiences of the interface between secondary and primary care. The issues pertaining to discharge care following AKI are relevant to practitioners and commissioners as they work to improve transitions of care for vulnerable patient populations.
Productivity losses among people with back pain and among population-based references: a register-based study in Sweden
Authors: Gedin Filip , Alexanderson Kristina , Zethraeus Niklas , Karampampa Korinna
Published: August 2020

Objective

Back pain is the leading cause for years lived with disability globally and among the main reasons for sickness absence (SA) and disability pension (DP). The objective of this study was to explore the occurrence of SA and DP and to estimate productivity losses among individuals with back pain compared with among matched population-based references.

Design

Explorative prospective cohort study using register microdata.

Participants and setting

A total of 23 176 people, aged 19–60 years, with a first visit to inpatient or specialised outpatient healthcare for back pain (International Statistical Classification of Diseases and Related Health Problems code M54) in 2010 in Sweden and a matched population-based reference group (n=115 880).

Outcomes

Long-term SA (in SA spells >14 days) and DP and productivity losses, measured in € (2018 prices) by multiplying the SA and DP net days by the societal cost of each such day.

Results

In the back-pain group, 42% had SA or DP days; in the reference group, the corresponding proportion was 15%. Productivity loss per patient with back pain was €8928 during the 12-month follow-up period; in the reference group, it was €3499 (p<0.0001).

Conclusions

SA and DP, leading to excess productivity losses among people with back pain, reflect the challenges these patients are facing to maintain their work capacity. Interventions to promote that individuals with back pain remain in paid work should be a priority in order to address the high costs.
Children’s unscheduled primary and emergency care in Ireland: a multimethod approach to understanding decision making, trends, outcomes and parental perspectives (CUPID): project protocol
Authors: McAuliffe Eilish , Hamza Moayed , McDonnell Thérèse , Nicholson Emma , De Brún Aoife , Barrett Michael , Brunsdon Christopher , Bury Gerard , Collins Claire , Deasy Conor , Fitzsimons John , Galligan Marie , Hensey Conor
Published: August 2020

Introduction

The aim of this project is to determine the patterns, decision-making processes and parental preferences associated with unscheduled paediatric healthcare utilisation in Ireland. Unscheduled paediatric healthcare is outpatient care provided within primary care settings by general practitioners (GPs), emergency departments (EDs) located in paediatric and general hospitals, and out-of-hours services provided by cooperatives of GPs operating on a regional basis. This project will take a multimethod approach to analysing the utilisation of unscheduled paediatric healthcare nationally within the context of a significant change to the provision of healthcare for young children in Ireland—the introduction of free at the point of delivery GP care for all children aged under 6.

Methods and analysis

A multimethod approach consisting of three work packages will be employed. Using patient-level data, work package 1 will describe patterns of attendance at primary care, out-of-hours medical services and at EDs. Applying a difference-in-difference methodology, the impact of the introduction of free GP care for children under 6 on attendance will be assessed. Work package 2 will explore geospatial trends of attendance at EDs, identifying disparities in ED attendance by local area and demographic characteristics. Work package 3 will employ two discrete choice experiments to examine parental preferences for unscheduled paediatric healthcare and GP decision making when referring a child to the ED. The insights gained by each of the work packages individually and collectively will inform evidence-based health policy for the organisation of paediatric care and resource allocation.

Ethics and dissemination

Ethical approval for this research has been granted by University College Dublin, The Irish College of General Practitioners and the five participating hospitals. Results will be disseminated via publication in peer-reviewed journals, national and international conferences, and to relevant stakeholders and interest groups.
Calgary Normative Study: design of a prospective longitudinal study to characterise potential quantitative MR biomarkers of neurodegeneration over the adult lifespan
Authors: McCreary Cheryl R , Salluzzi Marina , Andersen Linda B , Gobbi David , Lauzon Louis , Saad Feryal , Smith Eric E , Frayne Richard
Published: August 2020

Introduction

A number of MRI methods have been proposed to be useful, quantitative biomarkers of neurodegeneration in ageing. The Calgary Normative Study (CNS) is an ongoing single-centre, prospective, longitudinal study that seeks to develop, test and assess quantitative magnetic resonance (MR) methods as potential biomarkers of neurodegeneration. The CNS has three objectives: first and foremost, to evaluate and characterise the dependence of the selected quantitative neuroimaging biomarkers on age over the adult lifespan; second, to evaluate the precision, variability and repeatability of quantitative neuroimaging biomarkers as part of biomarker validation providing proof-of-concept and proof-of-principle; and third, provide a shared repository of normative data for comparison to various disease cohorts.

Methods and analysis

Quantitative MR mapping of the brain including longitudinal relaxation time (T1), transverse relaxation time (T2), T2*, magnetic susceptibility (QSM), diffusion and perfusion measurements, as well as morphological assessments are performed. The Montreal Cognitive Assessment (MoCA) and a brief, self-report medical history will be collected. Mixed regression models will be used to characterise changes in quantitative MR biomarker measures over the adult lifespan. In this report, we describe the study design, strategies to recruit and perform changes to the acquisition protocol from inception to 31 December 2018, planned statistical approach and data sharing procedures for the study.

Ethics and dissemination

Participants provide signed informed consent. Changes in quantitative MR biomarkers measured over the adult lifespan as well as estimates of measurement variance and repeatability will be disseminated through peer-reviewed scientific publication.
The GALANT trial: study protocol of a randomised placebo-controlled trial in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma on the effect of lanreotide on tumour size
Authors: Boertien Tessel M , Drent Madeleine L , Booij Jan , Majoie Charles B L M , Stokkel Marcel P M , Hoogmoed Jantien , Pereira Alberto , Biermasz Nienke R , Simsek Suat , Groote Veldman Ronald , Tanck Michael W T , Fliers Eric , Bisschop Peter H
Published: August 2020

Introduction

At present, there is no approved medical treatment option for patients with non-functioning pituitary adenoma. A number of open-label studies suggest that treatment with somatostatin analogues may prevent tumour progression. In vivo somatostatin receptor imaging using 68Ga-DOTATATE PET (PET, positron emission tomography) could help in preselecting patients potentially responsive to treatment. Our aim is to investigate the effect of the somatostatin analogue lanreotide as compared with placebo on tumour size in patients with a 68Ga-DOTATATE PET-positive non-functioning pituitary macroadenoma (NFMA).

Methods and analysis

The GALANT study is a multicentre, randomised, double-blind, placebo-controlled trial in adult patients with a suprasellar extending NFMA. Included patients undergo a 68Ga-DOTATATE PET/CT of the head and tracer uptake is assessed after coregistration with pituitary MRI. Forty-four patients with a 68Ga-DOTATATE PET-positive NFMA are randomised in a 1:1 ratio between lanreotide 120 mg or placebo, both administered as subcutaneous injections every 28 days for 72 weeks. The primary outcome is the change in cranio-caudal tumour diameter on pituitary MRI after treatment. Secondary outcomes are change in tumour volume, time to tumour progression, change in quality of life and number of adverse events. Final results are expected in the second half of 2021.

Ethics and dissemination

The study protocol has been approved by the Medical Research Ethics Committee of the Academic Medical Centre (AMC) of the Amsterdam University Medical Centres and by the Dutch competent authority. It is an investigator-initiated study with financial support by Ipsen Farmaceutica BV. The AMC, as sponsor, remains owner of all data. Results will be submitted for publication in a peer-reviewed journal.

Trial registration number

NL5136 (Netherlands Trial Register); pre-recruitment.
Effectiveness of physical therapy in addition to occlusal splint in myogenic temporomandibular disorders: protocol of a randomised controlled trial
Authors: Incorvati Cristina , Romeo Antonio , Fabrizi Adele , Defila Luca , Vanti Carla , Gatto Maria Rosaria Antonella , Marchetti Claudio , Pillastrini Paolo
Published: August 2020

Introduction

Temporomandibular disorders (TMDs) are considered a collection of musculoskeletal conditions involving the masticatory muscles, the temporomandibular joint and associated structures. The myogenous group appears to represent the most frequently diagnosed category. In the context of a multimodal approach, splint therapy and musculoskeletal physiotherapy are often considered as a preferred therapy. The purpose of this study will be to investigate the effects of musculoskeletal physiotherapy combined with occlusal splint and education versus occlusal splint and education alone in the treatment of chronic myogenous TMD on pain and mandibular range of motion.

Methods and analysis

All consecutive adults complaining of TMDs presented to the Department of Biomedical and Neuromotor Sciences of the University of Bologna will be considered eligible. Inclusion criteria shall be based on the presence of myogenous TMDs, as diagnosed through clinical examination in reference to the international diagnostic criteria of TMDs. Randomisation, concealed allocation, blinded assessment and intention-to-treat analysis will be employed. The splint therapy will consist of the use of the splint every night and concurrent delivery of an educational programme; the protocol shall have a duration of three consecutive months. The combined musculoskeletal physiotherapy, splint therapy and education will additionally consist of manual therapy techniques and exercise; such protocol shall consist of a duration of three consecutive months, inclusive of 10 sessions for the enhanced elements. All outcome measures will be collected at baseline, after treatment and at a 6 months follow-up.

Ethics and dissemination

Ethical approval has been obtained from the Independent Ethic Committee in Clinical Research of AUSL Bologna-Italy (47/2018/SPER/AUSLBO). Pursuant to applicable rules,we will obtain informed consent from each participant and collect data anonymously to maintain privacy. Results will be disseminated to clinicians and researchers through peer-reviewed publications and conferences.

Trial registration number

NCT03726060
Neurosurgeons’ experiences of conducting and disseminating clinical research in low- and middle-income countries: a qualitative study protocol
Authors: Whiffin Charlotte J , Smith Brandon G , Esene Ignatius N , Karekezi Claire , Bashford Tom , Khan Muhammad Mukhtar , Fontoura Solla Davi J , Hutchinson Peter J , Kolias Angelos
Published: August 2020

Introduction

Low-income and middle-income countries (LMICs) face the greatest burden of neurotrauma. However, most of the research published in scientific journals originates from high-income countries, suggesting those in LMICs are either not engaging in research or are not publishing it. Evidence originating in high-income countries may not be generalisable to LMICs; therefore, it is important to nurture research capacity in LMICs so that a relevant evidence base can be developed. However, little is published about specific challenges or contextual issues relevant to increasing research activity of neurosurgeons in LMICs. Therefore, the aim of this study was to understand neurosurgeons’ experiences of, aspirations for and ability to conduct and disseminate clinical research in LMICs.

Methods and analysis

This is a pragmatic qualitative study situated within the naturalistic paradigm using focus groups and interviews with a purposive sample of neurosurgeons from LMICs. First, we will conduct asynchronous online focus groups with 36 neurosurgeons to broadly explore issues relevant to the study aim. Second, we will select 20 participants for follow-up semistructured interviews to explore concepts in more depth and detail than could be achieved in the focus group. Interviews will be audio-recorded and transcribed verbatim. A thematic analysis will be conducted following Braun and Clarke’s six stages and will be supported by NVIVO software.

Ethics and dissemination

The University of Cambridge Psychology Research Ethics Committee reviewed this study and provided a favourable opinion in January 2020 (REF PRE.2020.006). Participants will provide informed consent, be able to withdraw at any time and will have their contributions kept confidential. The findings of the study will be shared with relevant stakeholders and disseminated in conference presentations and journal publications.
Protocol for systematic review and meta-analysis: impact of statins as immune-modulatory agents on inflammatory markers in adults with chronic diseases
Authors: Sabeel Solima , Motaung Bongani , Ozturk Mumin , Mukasa Sandra , Kengne Andre Pascal , Blom Dirk , Sliwa Karen , Nepolo Emmanuel , Günther Gunar , Wilkinson Robert J. , Schacht Claudia , Thienemann Friedrich , Guler Reto
Published: August 2020

Introduction

Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, are lipid-lowering agents that are central in preventing or reducing the complications of atherosclerotic cardiovascular disease. Because statins have anti-inflammatory properties, there is considerable interest in their therapeutic potential in other chronic inflammatory conditions. We aim to identify the statin with the greatest ability to reduce systemic inflammation, independent of the underlying disease entity.

Methods and analysis

We aim to conduct a comprehensive search of published and peer-reviewed randomised controlled clinical trials, with at least one intervention arm of a Food & Drug Administration-licensed or European Medicines Agency-licensed statin and a minimum treatment duration of 12 weeks. Our objective is to investigate the effect of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) on lipid profile, particularly, cholesterol low-density lipoprotein and inflammation markers such as high-sensitive C reactive protein (hsCRP), CRP, tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, soluble cluster of differentiation 14 (sCD14) or sCD16 in adults, published in the last 20 years (between January 1999 and December 2019). We aim to identify the most potent statin to reduce systemic inflammation and optimal dosing. The following databases will be searched: Medline, Scopus, Web of Science and Cochrane Library of Systematic Reviews. The risk of bias of included studies will be assessed by Cochrane Risk of Bias Tool and Quality Assessment Tool for Quantitative Studies. The quality of studies will be assessed, to show uncertainty, by the Jadad Score. If sufficient evidence is identified, a meta-analysis will be conducted with risk ratios or ORs with 95% CIs in addition to mean differences.

Ethics and dissemination

Ethics approval is not required as no primary data will be collected. Results will be presented at conferences and published in a peer-reviewed journal.

PROSPERO registration number

CRD42020169919
‘Too male, too pale, too stale’: a qualitative exploration of student experiences of gender bias within medical education
Authors: Brown Megan E L , Hunt George E G , Hughes Ffion , Finn Gabrielle M
Published: August 2020

Objective

To explore medical student perceptions and experiences of gender bias within medical education.

Setting

Gender bias—‘prejudiced actions or thoughts based on the perception that women are not equal to men’—is a widespread issue. Within medicine, the pay gap, under-representation of women in senior roles and sexual harassment are among the most concerning issues demonstrating its presence and impact. While research investigating experiences of clinicians is gaining traction, investigation of medical students’ experiences is lacking. This qualitative study analyses medical students’ experiences of gender bias within their education to discern any patterns to this bias. Illuminating the current state of medical education gender bias will hopefully highlight areas in which student experience could be improved. Constructivist thematic analysis was used to analyse data, informed by William’s patterns of gender bias, intersectional feminism and communities of practice theory.

Participants

Thirty-two medical students from multiple UK medical schools participated in individual interviews. Nine faculty members were also interviewed to triangulate data.

Results

Gender bias has an overt presence during medical student education, manifesting in line with William’s patterns of bias, impacting career aspirations. Physical environments serve to manifest organisational values, sending implicit messages regarding who is most welcome—currently, this imagery remains ‘too male, too pale…too stale’. Existing gender initiatives require careful scrutiny, as this work identifies the superficial application of positive action, and a failure to affect meaningful change.

Conclusions

Despite progress having been made regarding overt gender discrimination, implicit bias persists, with existing positive action inadequate in promoting the advancement of women. Institutions should mandate participation in implicit bias education programmes for all staff and must strive to revise the imagery within physical environments to better represent society. Gender initiatives, like Athena Scientific Women’s Academic Network, also require large-scale evaluation regarding their impact, which this work found to be lacking.
TASCI—transcutaneous tibial nerve stimulation in patients with acute spinal cord injury to prevent neurogenic detrusor overactivity: protocol for a nationwide, randomised, sham-controlled, double-blind clinical trial
Authors: Birkhäuser Veronika , Liechti Martina D , Anderson Collene E , Bachmann Lucas M , Baumann Sarah , Baumberger Michael , Birder Lori A , Botter Sander M , Büeler Silvan , Cruz Célia D , David Gergely , Freund Patrick , Friedl Susanne , Gross Oliver , Hund-Georgiadis Margret , Husmann Knut , Jordan Xavier , Koschorke Miriam , Leitner Lorenz , Luca Eugenia , Mehnert Ulrich , Möhr Sandra , Mohammadzada Freschta , Monastyrskaya Katia , Pfender Nikolai , Pohl Daniel , Sadri Helen , Sartori Andrea M , Schubert Martin , Sprengel Kai , Stalder Stephanie A , Stoyanov Jivko , Stress Cornelia , Tatu Aurora , Tawadros Cécile , van der Lely Stéphanie , Wöllner Jens , Zubler Veronika , Curt Armin , Pannek Jürgen , Brinkhof Martin W G , Kessler Thomas M
Published: August 2020

Introduction

Neurogenic lower urinary tract dysfunction (NLUTD), including neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia, is one of the most frequent and devastating sequelae of spinal cord injury (SCI), as it can lead to urinary incontinence and secondary damage such as renal failure. Transcutaneous tibial nerve stimulation (TTNS) is a promising, non-invasive neuromodulatory intervention that may prevent the emergence of the C-fibre evoked bladder reflexes that are thought to cause NDO. This paper presents the protocol for TTNS in acute SCI (TASCI), which will evaluate the efficacy of TTNS in preventing NDO. Furthermore, TASCI will provide insight into the mechanisms underlying TTNS, and the course of NLUTD development after SCI.

Methods and analysis

TASCI is a nationwide, randomised, sham-controlled, double-blind clinical trial, conducted at all four SCI centres in Switzerland. The longitudinal design includes a baseline assessment period 5–39 days after acute SCI and follow-up assessments occurring 3, 6 and 12 months after SCI. A planned 114 participants will be randomised into verum or sham TTNS groups (1:1 ratio), stratified on study centre and lower extremity motor score. TTNS is performed for 30 min/day, 5 days/week, for 6–9 weeks starting within 40 days after SCI. The primary outcome is the occurrence of NDO jeopardising the upper urinary tract at 1 year after SCI, assessed by urodynamic investigation. Secondary outcome measures assess bladder and bowel function and symptoms, sexual function, neurological structure and function, functional independence, quality of life, as well as changes in biomarkers in the urine, blood, stool and bladder tissue. Safety of TTNS is the tertiary outcome.

Ethics and dissemination

TASCI is approved by the Swiss Ethics Committee for Northwest/Central Switzerland, the Swiss Ethics Committee Vaud and the Swiss Ethics Committee Zürich (#2019-00074). Findings will be disseminated through peer-reviewed publications.

Trial registration number

NCT03965299.
Evaluating the validity, reliability and clinical utility of the Music therapy Sensory Instrument for Cognition, Consciousness and Awareness (MuSICCA): protocol of a validation study
Authors: Pool Jonathan Wain , Siegert Richard John , Taylor Steven , Dunford Carolyn , Magee Wendy
Published: August 2020

Introduction

A growing number of children and young people are surviving severe acquired brain injuries due to advances in healthcare. However, many fail to emerge from coma and continue to live with disorders of consciousness (DOC). Diagnostic, clinical and ethical challenges are prominent in this group. Misdiagnosis can have severe consequences for children and their families, including inadequate care, insufficient access to rehabilitation and stimulation, reduced accessibility to services and inappropriately limited opportunities for participation. The proposed project will develop and validate a diagnostic measure that supports detailed goal-planning—the Music therapy Sensory Instrument for Cognition, Consciousness and Awareness (MuSICCA).

Methods and analysis

Face validity will be assessed using a short questionnaire and the MuSICCA will be amended if face validity is insufficient. Once face validity is sufficient, 80 participants with suspected DOC will be recruited from multiple sites around the UK, USA and Ireland.

Validity will be assessed using external reference standards (Coma Recovery Scale-Revised, Coma Near-Coma Scale and Nociception Coma Scale). Intra-rater reliability will be established using repeated ratings of video recordings from the assessment sessions. Inter-rater reliability will be assessed through video ratings by a second blinded assessor. In addition to these analyses, the clinical utility of the MuSICCA will be evaluated using a questionnaire to be completed by clinicians and relatives of the participants following the completion of the MuSICCA assessment.

Ethics and dissemination

Ethical approval has been obtained for this study from the Research Ethics Committee and Health Research Authority of the National Health Service of the UK (ID: 167534). Results will be presented at national and international conferences, published in scientific journals and disseminated to participant representatives, clinicians, educators and care providers.

Trial registration details

This study was registered at ClinicalTrials.gov Protocol Registration and Results System on 7th August 2019 (ID: NCT04050995); Pre-results.
Simulation training in non-cancer palliative care for healthcare workers: a systematic review of controlled studies
Authors: Tropea Joanne , Bicknell Ross , Nestel Debra , Brand Caroline A , Johnson Christina E , Paul Sanjoy K , Le Brian H , Lim Wen Kwang
Published: August 2020

Background

The need for healthcare workers (HCWs) to have skills and knowledge in non-cancer palliative care has been recognised. Simulation is increasingly being used for palliative care training, offering participants the opportunity to learn in a realistic environment and fully interactive way.

Objective

The aim of this systematic review was to summarise and critically appraise controlled studies on simulation training in non-cancer palliative care for HCWs.

Selection

Medline, CINAHL, PubMed and Cochrane Library databases were searched using palliative care and simulation terms. Randomised controlled trials (RCTs), non-randomised RCTs and controlled before-and-after (CBA) studies were included. Two reviewers independently screened titles and abstracts and undertook full article review using predefined selection criteria. Studies that met the inclusion criteria had data extracted and risk of bias assessed using the Cochrane Effective Practice and Organisation of Care risk of bias criteria.

Findings

Five articles were included: three RCTs and two CBA studies. All studies assessed learners’ palliative care communication skills, most studies evaluated learners’ perception of change in skills and one study assessed impact on patient outcomes and learners’ change in behaviour when applied in practice. There was variation in intervention content, intensity and duration, outcome measures and study design, making it difficult to compare and synthesise results.

Conclusion

There is a paucity of evidence to support simulation training to improve non-cancer palliative care. This review highlights the need for more robust research, including multicentre studies that use standardised outcome measures to assess clinician skills, changes in clinical practice and patient-related outcomes.
CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer
Authors: Huang Jin , Chen Pan , Liu Ke , Liu Jiao , Zhou Borong , Wu Runliu , Peng Qiu , Liu Ze-Xian , Li Changfeng , Kroemer Guido , Lotze Michael , Zeh Herbert , Kang Rui , Tang Daolin
Published: August 2020

Objective

Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).

Design

We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-inducedIDO1andCD274expression in 24 human and mouse cancer cell lines as well as in primary cancer cells from patients with PDAC or ovarian carcinoma. We tested the effects of dinaciclib on IFNG-induced signal transducer and activator of transcription 1 activation and immunological cell death, and investigated the potential utility of dinaciclib in combination with IFNG for pancreatic cancer therapy in vivo, and compared gene expression levels between human cancer tissues with patient survival times using the Cancer Genome Atlas datasets.

Results

Pharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically ‘cold’ tumour microenvironment into a ‘hot’ one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC.

Conclusion

CDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.
Cost-effectiveness of cardiovascular imaging for stable coronary heart disease
Authors: Walker Simon , Cox Edward , Rothwell Ben , Berry Colin , McCann Gerry P , Bucciarelli-Ducci Chiara , Dall’Armellina Erica , Prasad Abhiram , Foley James Robert John , Mangion Kenneth , Bijsterveld Petra , Everett Colin , Stocken Deborah , Plein Sven , Greenwood John P , Sculpher Mark
Published: August 2020

Objective

To assess the cost-effectiveness of management strategies for patients presenting with chest pain and suspected coronary heart disease (CHD): (1) cardiovascular magnetic resonance (CMR); (2) myocardial perfusion scintigraphy (MPS); and (3) UK National Institute for Health and Care Excellence (NICE) guideline-guided care.

Methods

Using UK data for 1202 patients from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 trial, we conducted an economic evaluation to assess the cost-effectiveness of CMR, MPS and NICE guidelines. Health outcomes were expressed as quality-adjusted life-years (QALYs), and costs reflected UK pound sterling in 2016–2017. Cost-effectiveness results were presented as incremental cost-effectiveness ratios and incremental net health benefits overall and for low, medium and high pretest likelihood of CHD subgroups.

Results

CMR had the highest estimated QALY gain overall (2.21 (95% credible interval 2.15, 2.26) compared with 2.07 (1.92, 2.20) for NICE and 2.11 (2.01, 2.22) for MPS) and incurred comparable costs (overall £1625 (£1431, £1824) compared with £1753 (£1473, £2032) for NICE and £1768 (£1572, £1989) for MPS). Overall, CMR was the cost-effective strategy, being the dominant strategy (more effective, less costly) with incremental net health benefits per patient of 0.146 QALYs (−0.18, 0.406) compared with NICE guidelines at a cost-effectiveness threshold of £15 000 per QALY (93% probability of cost-effectiveness). Results were similar in the pretest likelihood subgroups.

Conclusions

CMR-guided care is cost-effective overall and across all pretest likelihood subgroups, compared with MPS and NICE guidelines.
Residual risks of ischaemic stroke and systemic embolism among atrial fibrillation patients with anticoagulation: large-scale real-world data (F-CREATE project)
Authors: Maeda Toshiki , Nishi Takumi , Funakoshi Shunsuke , Tada Kazuhiro , Tsuji Masayoshi , Satoh Atsushi , Kawazoe Miki , Yoshimura Chikara , Arima Hisatomi
Published: August 2020

Objective

Among patients with atrial fibrillation, the risks of ischaemic stroke and systemic embolism (IS/SE) are high even with effective anticoagulation. Using large-scale, real-world data from Japan, this study aims to clarify residual risks of IS/SE attributable to modifiable risk factors among patients with atrial fibrillation who are taking oral anticoagulants.

Methods

The study design we employed was a retrospective cohort. Health check-ups and insurance claims data of Japanese health insurance companies were accumulated from January 2005 to June 2017. We identified 11 848 participants with atrial fibrillation who were on oral anticoagulants during the study period. We set the modifiable risk factors as hypertension, diabetes and dyslipidaemia. A Cox proportional hazards model was used to obtain the effects of the risk factors for IS/SE.

Results

During an average of 3 years’ follow-up, 200 cases of IS/SE occurred (incidence rate 0.57 per 100 person-years). In multivariable analyses, older age (65–74 vs <65 years; adjusted HR 2.02 (95% CI 1.49 to 2.73)), hypertension (adjusted HR 1.41 (1.04 to 1.92)) and dyslipidaemia (adjusted HR 1.46 (1.07 to 1.98)) were significantly associated with increased risk of IS/SE. Percentage of IS/SE risk attributable to modifiable risk factors (hypertension, diabetes and dyslipidaemia) was 30.0% (16.1% to 41.6%).

Conclusion

Among patients with atrial fibrillation on anticoagulant therapy, approximately one-third of the residual risks were estimated to be attributable to modifiable risk factors such as hypertension, diabetes and dyslipidaemia.
Ageing trajectories of health—longitudinal opportunities and synergies (ATHLOS) Healthy Ageing Scale in adults from 16 international cohorts representing 38 countries worldwide
Authors: Critselis Elena , Panaretos Dimitris , Sánchez-Niubò Albert , Giné-Vázquez Iago , Ayuso-Mateos José Luis , Caballero Francisco Felix , de la Fuente Javier , Haro Josep Maria , Panagiotakos Demosthenes
Published: August 2020

Background

Uniform international measurement tools for assessing healthy ageing are currently lacking.

Objectives

The study assessed the novel comprehensive global Ageing Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) Healthy Ageing Scale, using an Item Response Theory approach, for evaluating healthy ageing across populations.

Design

Pooled analysis of 16 international longitudinal studies.

Setting

38 countries in five continents.

Subjects

International cohort (n=355 314), including 44.4% (n=153 597) males, aged (mean±SD) 61.7±11.5 years old.

Methods

The ATHLOS Healthy Ageing Scale (including 41 items related to intrinsic capacity and functional ability) was evaluated in a pooled international cohort (n=355 314 from 16 studies) according to gender, country of residence and age group. It was also assessed in a subset of eight cohorts with ≥3 waves of follow-up assessment. The independent samples t-test and Mann–Whitney test were applied for comparing normally and skewed continuous variables between groups, respectively.

Results

The ATHLOS Scale (range: 12.49–68.84) had a mean (±SD) value of 50.2±10.0, with males and individuals >65 years old exhibiting higher and lower mean scores, respectively. Highest mean scores were detected in Switzerland, Japan and Denmark, while lowest in Ghana, India and Russia. When the ATHLOS Scale was evaluated in a subset of cohorts with ≥3 study waves, mean scores were significantly higher than those of the baseline cohort (mean scores in ≥3 study waves vs baseline: 51.6±9.4 vs 50.2±10.0; p<0.01).

Conclusions

The ATHLOS Healthy Ageing Scale may be adequately applied for assessing healthy ageing across populations.
Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes
Authors: Klaver Yarne , Rijnders Maud , Oostvogels Astrid , Wijers Rebecca , Smid Marcel , Grünhagen Dirk , Verhoef Cornelis , Sleijfer Stefan , Lamers Cor , Debets Reno
Published: August 2020

Introduction

Local T-cell immunity is recognized for its contribution to the evolution and therapy response of various carcinomas. Here, we investigated characteristics of tumor-infiltrating lymphocytes (TILs), as well as T-cell evasive mechanisms in different soft tissue sarcoma (STS) subtypes.

Methods

Liposarcoma, gastrointestinal stromal tumor (GIST), leiomyosarcoma, myxofibrosarcoma and pleomorphic sarcomas were assessed for T-cell numbers and phenotypes using flow cytometry. Next-generation sequencing was used to analyze T-cell receptor repertoire, mutational load, immune cell frequencies, and expression of immune-related genes.

Results

GIST, myxofibrosarcoma and pleomorphic sarcoma showed high numbers of CD8+ TILs, with GIST having the lowest fraction of effector memory T cells. These TILs coexpress the immune checkpoints PD1, TIM3, and LAG3 in myxofibrosarcoma and pleomorphic sarcoma, yet TILs coexpressing these checkpoints were near negligible in GIST. Fractions of dominant T-cell clones among STS subtypes were lowest in GIST and liposarcoma, whereas mutational load was relatively low in all STS subtypes. Furthermore, myeloid-derived cells and expression of the costimulatory ligands CD86, ICOS-L and 41BB-L were lowest in GIST when compared with other STS subtypes.

Conclusion

STS subtypes differ with respect to number and phenotypical signs of antitumor responsiveness of CD8+ TILs. Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is accompanied with a relatively low expression of costimulatory ligands.
Enhanced immunotherapeutic profile of oncolytic virus-based cancer vaccination using cyclophosphamide preconditioning
Authors: Pol Jonathan G , Atherton Matthew J , Stephenson Kyle B , Bridle Byram W , Workenhe Samuel T , Kazdhan Natasha , McGray AJ Robert , Wan Yonghong , Kroemer Guido , Lichty Brian D
Published: August 2020

Despite a sizeable body of research, the efficacy of therapeutic cancer vaccines remains limited when applied as sole agents. By using a prime:boost approach involving two viral cancer vaccines, we were able to generate large tumor-specific CD8+T-cell responses in a murine model of disseminated pulmonary melanoma. Significant increases in the number and quality of circulating effector T-cells were documented when low-dose cyclophosphamide (CTX) was administered pre-vaccination to tumor-bearing but not tumor-free hosts. Interestingly, tumor-bearing mice receiving CTX and co-primed with a melanoma differentiation antigen together with an irrelevant control antigen exhibited significantly enhanced immunity against the tumor, but not the control antigen, in secondary lymphoid organs. This result highlighted an increased cancer-specific reactivity of vaccine-induced T-cell responses following CTX preconditioning. Additionally, an acute reduction of the frequency of peripheral regulatory T-cells (Tregs) was noticeable, particularly in the proliferating, presumably tumour-reactive, subset. Enhanced infiltration of lungs with multifunctional T-cells resulted in overt reduction in metastatic burden in mice pretreated with CTX. Despite doubling the median survival in comparison to untreated controls, most vaccinated mice ultimately succumbed to cancer progression. However, preconditioning of the virus-based vaccination with CTX resulted in a remarkable improvement of the therapeutic activity leading to complete remission in the majority of the animals. Collectively, these data reveal how CTX can potentiate specific cellular immunity in an antigen-restricted manner that is only observed in vaccinated tumor-bearing hosts while depleting replicating Tregs. A single low dose of CTX enhances antitumor immunity and the efficacy of this potent prime:boost platform by modulating the kinetics of the vaccine-specific responses. Clinical assessment of CTX combined with next-generation cancer vaccines is indicated.
Morbidity and mortality associated with sequential flow reduction embolization technique of cerebral arteriovenous malformations using n-butyl cyanoacrylate
Authors: See Alfred P , Mohammaden Mahmoud H , Rizko Mark , Stapleton Christopher J , Amin-Hanjani Sepideh , Charbel Fady T , Aletich Victor , Alaraj Ali
Published: August 2020

Background

Endovascular embolization of cerebral arteriovenous malformations (AVM) with liquid n-butyl cyanoacrylate (n-BCA) serves multiple purposes including AVM occlusion and flow reduction in preparation for other treatment modalities. The objective was to study the clinical, structural, and angiographic factors affecting complications associated with AVM treatment by sequential n-BCA embolizations for nidal occlusion versus quantitative flow reduction in preparation for surgical resection or radiosurgery.

Methods

We performed a retrospective review of all patients who underwent endovascular embolization of cerebral AVM at our institution between 1998 and 2019, during which time the technique of traditional embolization evolved to a strategy of targeted sequential flow reduction guided by serial flow imaging based on quantitative magnetic resonance angiography, in conjunction with a shift away from nidal penetration.

Results

Among 251 patients, 47.8% of patients presented with ruptured AVM. On average, each patient underwent 2.4 embolizations, for a total of 613 sessions. Major morbidity related to embolization occurred in 18 (7.2%) patients, but this occurred disproportionately in the traditional embolization strategy (n=16, 8%) in contrast with the flow-targeting strategy (n=2, 3.8%). Four patients (1.6%) died in the overall group, and these all occurred with the traditional embolization strategy (2% of 199 patients); no deaths occurred in the flow-targeting strategy (n=52).

Conclusion

Embolization with n-BCA targeted to sequential flow reduction and feeder occlusion with limited nidal penetration prior to definitive surgical or radiosurgical treatment can be safely performed with low overall morbidity and mortality.
Cardiovascular drug treatment, statins and biopsy-confirmed giant cell arteritis: a population-based case–control study
Authors: Turkiewicz Aleksandra , Stamatis Pavlos , Mohammad Aladdin J
Published: August 2020

Objective

To determine whether exposure to cardiovascular medications and statins is associated with increased risk of giant cell arteritis (GCA).

Design

The population-based case–control study comprised a cohort of patients with biopsy-confirmed GCA linked to the Swedish Prescribed Drug Register to identify all exposure to drugs prior to diagnosis of GCA. Ten controls per GCA case, matched for age, sex and residential area, were included. Using corresponding Anatomical Therapeutic Chemical codes, ACE inhibitors, angiotensin II receptor blockers, beta-blocking agents, calcium antagonists, diuretics, statins and cardiac therapy drugs were investigated from July 1, 2005 to the diagnosis/index date. A conditional logistic regression model was fitted adjusted for income, education level and marital status. We repeated the analyses including only new drug users excluding those with any prescription during the year from July 1, 2005 to July 1, 2006.

Results

574 cases (29% men) of diagnosed GCA and 5740 controls (29% men) were included. The mean age at diagnosis is 75 years (SD 8). Of the GCA cases, 71% had at least one dispensation of a cardiovascular drug prior to the index date, compared to 74% of controls. The ORs for the association of target drug exposure with GCA were <1 for most drugs, but close to 1 in the analysis of new users. Statins were consistently associated with lower risk of GCA, OR 0.74 (95% CI 0.61 to 0.90).

Conclusion

Statins may be associated with lower risk of incident biopsy-confirmed GCA. No association was evident for other studied drugs.
Differences in atheroma between Caucasian and Asian subjects with anterior stroke: A vessel wall MRI study
Authors: Watase Hiroko , Shen Mi , Sui Binbin , Gao Peiyi , Zhang Dong , Sun Jie , Balu Niranjan , Hippe Daniel S , Jarvik Gail P , Zhao Xihai , Li Rui , Chen Shuo , Yuan Chun , Hatsukami Thomas S
Published: August 2020

Background and purpose

While extracranial carotid artery stenosis is more common among Caucasians and intracranial artery stenosis is more common among Asians, the differences in atherosclerotic plaque characteristics have not yet been extensively examined. We sought to investigate plaque location and characteristics within extracranial carotid and intracranial arteries in symptomatic Caucasians and Chinese using vessel wall MRI.

Methods

Subjects with recent anterior circulation ischaemic stroke were recruited and imaged at two sites in the USA and China using similar protocols. Both extracranial carotid and intracranial arteries were reviewed to determine plaque location and characteristics.

Results

The prevalence of extracranial carotid plaque in Caucasians and Chinese was 73.1% and 49.1%, respectively (p=0.055). Prevalence of intracranial plaque was 38.5% and 69.1% in Caucasians and Chinese, respectively (p=0.02). Furthermore, 42% of Caucasians and 16% of Chinese had high-risk plaque (HRP) features (intraplaque haemorrhage, luminal surface disruption) in the extracranial carotid artery (p=0.03). The prevalence of HRP features in intracranial arteries was not significantly different between the two cohorts (4% vs 11%; p=0.42).

Conclusions

Differences in the location and characteristics of cerebrovascular atherosclerosis were identified by vessel wall MRI in US Caucasian and Chinese subjects with recent anterior circulation ischaemic stroke. Extracranial carotid plaques with HRP features were more common in Caucasians. Intracranial plaques were more common in Chinese subjects, but no significant difference between the two cohorts in intracranial HRP prevalence was found. Larger studies using vessel wall imaging to investigate racial differences in cerebrovascular disease may inform underlying mechanisms of HRP development and may ultimately help guide appropriate therapy.