Publications by authors named "Julia Brown"

223 Publications

Evaluating the Safety of West Nile Virus Immunity During Congenital Zika Virus Infection in Mice.

Front Immunol 2021 18;12:686411. Epub 2021 Jun 18.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Antibody-dependent enhancement (ADE) is a phenomenon that occurs when cross-reactive antibodies generated from a previous flaviviral infection increase the pathogenesis of a related virus. Zika virus (ZIKV) is the most recent flavivirus introduced to the Western Hemisphere and has become a significant public health threat due to the unanticipated impact on the developing fetus. West Nile virus (WNV) is the primary flavivirus that circulates in North America, and we and others have shown that antibodies against WNV are cross-reactive to ZIKV. Thus, there is concern that WNV immunity could increase the risk of severe ZIKV infection, particularly during pregnancy. In this study, we examined the extent to which WNV antibodies could impact ZIKV pathogenesis in a murine pregnancy model. To test this, we passively transferred WNV antibodies into pregnant mice on E6.5 prior to infection with ZIKV. Evaluation of pregnant dams showed weight loss following ZIKV infection; however, no differences in maternal weights or viral loads in the maternal brain, spleen, or spinal cord were observed in the presence of WNV antibodies. Resorption rates, and other fetal parameters, including fetal and placental size, were similarly unaffected. Further, the presence of WNV antibodies did not significantly alter the viral load or the inflammatory response in the placenta or the fetus in response to ZIKV. Our data suggest that pre-existing WNV immunity may not significantly impact the pathogenesis of ZIKV infection during pregnancy. Our findings are promising for the safety of implementing WNV vaccines in the continental US.
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http://dx.doi.org/10.3389/fimmu.2021.686411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250419PMC
June 2021

International perspectives on suboptimal patient-reported outcome trial design and reporting in cancer clinical trials: A qualitative study.

Cancer Med 2021 Jul 5. Epub 2021 Jul 5.

Centre for Patient-Reported Outcomes Research, Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Purpose: Evidence suggests that the patient-reported outcome (PRO) content of cancer trial protocols is frequently inadequate and non-reporting of PRO findings is widespread. This qualitative study examined the factors influencing suboptimal PRO protocol content, implementation, and reporting, and use of PRO data during clinical interactions.

Methods: Semi-structured interviews were conducted with four stakeholder groups: (1) trialists and chief investigators; (2) people with lived experience of cancer; (3) international experts in PRO cancer trial design; (4) journal editors, funding panelists, and regulatory agencies. Data were analyzed using directed thematic analysis with an iterative coding frame.

Results: Forty-four interviews were undertaken. Several factors were identified that could influenced effective integration of PROs into trials and subsequent findings. Participants described (1) late inclusion of PROs in trial design; (2) PROs being considered a lower priority outcome compared to survival; (3) trialists' reluctance to collect or report PROs due to participant burden, missing data, and perceived reticence of journals to publish; (4) lack of staff training. Strategies to address these included training research personnel and improved communication with site staff and patients regarding the value of PROs. Examples of good practice were identified.

Conclusion: Misconceptions relating to PRO methodology and its use may undermine their planning, collection, and reporting. There is a role for funding, regulatory, methodological, and journalistic institutions to address perceptions around the value of PROs, their position within the trial outcomes hierarchy, that PRO training and guidance is available, signposted, and readily accessible, with accompanying measures to ensure compliance with international best practice guidelines.
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http://dx.doi.org/10.1002/cam4.4111DOI Listing
July 2021

SPIRIT-PRO Extension explanation and elaboration: guidelines for inclusion of patient-reported outcomes in protocols of clinical trials.

BMJ Open 2021 Jun 30;11(6):e045105. Epub 2021 Jun 30.

Value Evidence and Outcomes-Patient Centered Outcomes, GSK, Collegeville, Pennsylvania, USA.

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients' symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item's importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs.
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http://dx.doi.org/10.1136/bmjopen-2020-045105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246371PMC
June 2021

Recommendations for designing and analysing multi-arm non-inferiority trials: a review of methodology and current practice.

Trials 2021 Jun 26;22(1):417. Epub 2021 Jun 26.

Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, LS2 9JT, UK.

Background And Purpose: Multi-arm non-inferiority (MANI) trials, here defined as non-inferiority trials with multiple experimental treatment arms, can be useful in situations where several viable treatments exist for a disease area or for testing different dose schedules. To maintain the statistical integrity of such trials, issues regarding both design and analysis must be considered, from both the multi-arm and the non-inferiority perspectives. Little guidance currently exists on exactly how these aspects should be addressed and it is the aim of this paper to provide recommendations to aid the design of future MANI trials.

Methods: A comprehensive literature review covering four databases was conducted to identify publications associated with MANI trials. Literature was split into methodological and trial publications in order to investigate the required design and analysis considerations for MANI trials and whether they were being addressed in practice.

Results: A number of issues were identified that if not properly addressed, could lead to issues with the FWER, power or bias. These ranged from the structuring of trial hypotheses at the design stage to the consideration of potential heterogeneous treatment variances at the analysis stage. One key issue of interest was adjustment for multiple testing at the analysis stage. There was little consensus concerning whether more powerful p value adjustment methods were preferred to approximate adjusted CIs when presenting and interpreting the results of MANI trials. We found 65 examples of previous MANI trials, of which 31 adjusted for multiple testing out of the 39 that were adjudged to require it. Trials generally preferred to utilise simple, well-known methods for study design and analysis and while some awareness was shown concerning FWER inflation and choice of power, many trials seemed not to consider the issues and did not provide sufficient definition of their chosen design and analysis approaches.

Conclusions: While MANI trials to date have shown some awareness of the issues raised within this paper, very few have satisfied the criteria of the outlined recommendations. Going forward, trials should consider the recommendations in this paper and ensure they clearly define and reason their choices of trial design and analysis techniques.
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http://dx.doi.org/10.1186/s13063-021-05364-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235859PMC
June 2021

Nuclear androgen and progestin receptors inversely affect aggression and social dominance in male zebrafish (Danio rerio).

Horm Behav 2021 Jun 18;134:105012. Epub 2021 Jun 18.

Department of Biology, East Carolina University, Greenville, NC 27285, USA. Electronic address:

Aggression is a fundamental behavior displayed universally among animal species, but hyper- or hypo-aggressiveness can be maladaptive with negative consequences for individuals and group members. While the social and ecological significance of aggression is well understood, the specific neurobiological and hormonal mechanisms responsible for mediating aggression have not been fully elucidated. Previous studies have shown a relationship between aggressive acts and circulating gonadal steroids, but whether classical nuclear steroid receptors regulate aggression in animals is still uncertain. We examined whether the nuclear androgen receptor (Ar) and nuclear progestin receptor (Pgr) were necessary for aggressive behaviors and maintenance of a dominance relationship in male zebrafish (Danio rerio). Dyadic social interactions of Ar knockout (ArKO), Pgr knockout (PgrKO) and wildtype (WT) controls were observed for two weeks (2-weeks). ArKO zebrafish were significantly less aggressive and had a less defined dominance relationship, whereas PgrKO dominant zebrafish were significantly and persistently more aggressive with a robust dominance relationship. Our results demonstrate the importance of nuclear steroid hormone receptors in regulating aggression of adult male zebrafish and provide new models for understanding of the mechanisms of aggression.
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http://dx.doi.org/10.1016/j.yhbeh.2021.105012DOI Listing
June 2021

Degradation of host translational machinery drives tRNA acquisition in viruses.

Cell Syst 2021 Jun 15. Epub 2021 Jun 15.

Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address:

Viruses are traditionally thought to be under selective pressure to maintain compact genomes and thus depend on host cell translational machinery for reproduction. However, some viruses encode abundant tRNA and other translation-related genes, potentially optimizing for codon usage differences between phage and host. Here, we systematically interrogate selective advantages that carrying 18 tRNAs may convey to a T4-like Vibriophage. Host DNA and RNA degrade upon infection, including host tRNAs, which are replaced by those of the phage. These tRNAs are expressed at levels slightly better adapted to phage codon usage, especially that of late genes. The phage is unlikely to randomly acquire as diverse an array of tRNAs as observed (p = 0.0017). Together, our results support that the main driver behind phage tRNA acquisition is pressure to sustain translation as host machinery degrades, a process resulting in a dynamically adapted codon usage strategy during the course of infection.
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http://dx.doi.org/10.1016/j.cels.2021.05.019DOI Listing
June 2021

A hypothesis test of feasibility for external pilot trials assessing recruitment, follow-up, and adherence rates.

Stat Med 2021 Jun 14. Epub 2021 Jun 14.

Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

The power of a large clinical trial can be adversely affected by low recruitment, follow-up, and adherence rates. External pilot trials estimate these rates and use them, via prespecified decision rules, to determine if the definitive trial is feasible and should go ahead. There is little methodological research underpinning how these decision rules, or the sample size of the pilot, should be chosen. In this article we propose a hypothesis test of the feasibility of a definitive trial, to be applied to the external pilot data and used to make progression decisions. We quantify feasibility by the power of the planned trial, as a function of recruitment, follow-up, and adherence rates. We use this measure to define hypotheses to test in the pilot, propose a test statistic, and show how the error rates of this test can be calculated for the common scenario of a two-arm parallel group definitive trial with a single normally distributed primary endpoint. We use our method to redesign TIGA-CUB, an external pilot trial comparing a psychotherapy with treatment as usual for children with conduct disorders. We then extend our formulation to include using the pilot data to estimate the standard deviation of the primary endpoint and incorporate this into the progression decision.
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http://dx.doi.org/10.1002/sim.9091DOI Listing
June 2021

Reply to H. Shojima et al.

J Clin Oncol 2021 May 12:JCO2100684. Epub 2021 May 12.

Kate Absolom, PhD, Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom, Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom; Lorraine Warrington, PhD, Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom; Eleanor Hudson, MSc, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom; Jenny Hewison, PhD, MSc, Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom; Patricia Holch, PhD, Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom, Psychology Group, School of Social Sciences, Faculty of Health and Social Sciences, Leeds Beckett University, Leeds, United Kingdom; Bryony Dawkins, MSc, Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom; Claire Hulme, MA, PhD, Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom, University of Exeter, St Luke's Campus, Exeter, United Kingdom; Julia Brown, MSc, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom; and Galina Velikova, MD, PhD, Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom, Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, St James's University Hospital, Leeds, United Kingdom.

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http://dx.doi.org/10.1200/JCO.21.00684DOI Listing
May 2021

Synthase-Selective Exploration of a Tunicate Microbiome by Activity-Guided Single-Cell Genomics.

ACS Chem Biol 2021 05 6;16(5):813-819. Epub 2021 May 6.

Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.

While thousands of environmental metagenomes have been mined for the presence of novel biosynthetic gene clusters, such computational predictions do not provide evidence of their biosynthetic functionality. Using fluorescent enzyme assay targeting carrier proteins common to polyketide (PKS) and nonribosomal peptide synthetases (NRPS), we applied fluorescence-activated cell sorting to tunicate microbiome to enrich for microbes with active secondary metabolic capabilities. Single-cell genomics uncovered the genetic basis for a wide biosynthetic diversity in the enzyme-active cells and revealed a member of marine harboring a novel NRPS gene cluster with high similarity to phylogenetically distant marine and terrestrial bacteria. Interestingly, this synthase belongs to a larger class of siderophore biosynthetic gene clusters commonly associated with pestilence and disease. This demonstrates activity-guided single-cell genomics as a tool to guide novel biosynthetic discovery.
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http://dx.doi.org/10.1021/acschembio.1c00157DOI Listing
May 2021

Evaluation of long-term welfare initiatives on working equid welfare and social transmission of knowledge in Mexico.

PLoS One 2021 4;16(5):e0251002. Epub 2021 May 4.

Department of Psychology, Centre for Comparative and Evolutionary Psychology, University of Portsmouth, Portsmouth, United Kingdom.

Working equids play an essential role in supporting livelihoods, providing resilience and income security to people around the world, yet their welfare is often poor. Consequently, animal welfare focussed NGOs employ a range of initiatives aimed at improving standards of working equid welfare. However, there is debate surrounding the efficacy of welfare initiatives utilised and long term monitoring and evaluation of initiatives is rarely undertaken. This study compares equid welfare and the social transmission of welfare information across Mexican communities that had previously received differing intervention histories (veterinary treatment plus educational initiatives, veterinary treatment only and control communities) in order to assess their efficacy. Indicators of equid welfare were assessed using the Equid Assessment Research and Scoping tool and included body condition score, skin alterations, lameness, general health status and reaction to observer approach. Owners were interviewed about their involvement in previous welfare initiatives, beliefs regarding equid emotions and pain, and the social transmission of welfare knowledge, including whether they ask advice about their equid or discuss its health with others and whether there is a specific individual that they consider to be 'good with equids' in their community. In total 266 owners were interviewed from 25 communities across three states. Better welfare (specifically body condition and skin alteration scores) was seen in communities where a history of combined free veterinary treatment and educational initiatives had taken place compared to those that had only received veterinary treatment or control communities. The social transfer of welfare knowledge was also higher in these communities, suggesting that the discussion and transfer of equid welfare advice within communities can act as a mechanism to disseminate good welfare practices more widely. Our results suggest that using a combined approach may enhance the success of welfare initiatives, a finding that may impact future NGO programming.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251002PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096037PMC
May 2021

Barriers to training in laparoscopic surgery in low- and middle-income countries: A systematic review.

Trop Doct 2021 Apr 13:49475521998186. Epub 2021 Apr 13.

Leeds Institute of Medical Research at St. James's, 4468University of Leeds, Leeds, UK.

Laparoscopic surgery has the potential to improve care in resource-deprived low- and-middle-income countries (LMICs). This study aims to analyse the barriers to training in laparoscopic surgery in LMICs. Medline, Embase, Global Health and Web of Science were searched using 'LMIC', 'Laparoscopy' and 'Training'. Two researchers screened results with mutual agreement. Included papers were in English, focused on abdominal laparoscopy and training in LMICs. PRISMA guidelines were followed; 2992 records were screened, and 86 full-text articles reviewed to give 26 key papers. Thematic grouping identified seven key barriers: ; availability and maintenance of ; local access to experienced laparoscopic ; ; lack of knowledge on effective ; and for trainees. In low-resource settings, technological advances may offer low-cost solutions in the successful implementation of laparoscopic training and improve access to surgical care.
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http://dx.doi.org/10.1177/0049475521998186DOI Listing
April 2021

Evolutionary stasis of a deep subsurface microbial lineage.

ISME J 2021 Apr 6. Epub 2021 Apr 6.

Bigelow Laboratory for Ocean Sciences, East Boothbay, ME, USA.

Sulfate-reducing bacteria Candidatus Desulforudis audaxviator (CDA) were originally discovered in deep fracture fluids accessed via South African gold mines and have since been found in geographically widespread deep subsurface locations. In order to constrain models for subsurface microbial evolution, we compared CDA genomes from Africa, North America and Eurasia using single cell genomics. Unexpectedly, 126 partial single amplified genomes from the three continents, a complete genome from of an isolate from Eurasia, and metagenome-assembled genomes from Africa and Eurasia shared >99.2% average nucleotide identity, low frequency of SNP's, and near-perfectly conserved prophages and CRISPRs. Our analyses reject sample cross-contamination, recent natural dispersal, and unusually strong purifying selection as likely explanations for these unexpected results. We therefore conclude that the analyzed CDA populations underwent only minimal evolution since their physical separation, potentially as far back as the breakup of Pangea between 165 and 55 Ma ago. High-fidelity DNA replication and repair mechanisms are the most plausible explanation for the highly conserved genome of CDA. CDA presents a stark contrast to the current model organisms in microbial evolutionary studies, which often develop adaptive traits over far shorter periods of time.
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http://dx.doi.org/10.1038/s41396-021-00965-3DOI Listing
April 2021

Opportunities and challenges for the computational interpretation of rare variation in clinically important genes.

Am J Hum Genet 2021 04;108(4):535-548

Departments of Bioengineering & Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address:

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059338PMC
April 2021

Sacral nerve stimulation versus the magnetic sphincter augmentation device for adult faecal incontinence: the SaFaRI RCT.

Health Technol Assess 2021 Mar;25(18):1-96

Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

Background: Preliminary studies using the FENIX™ (Torax Medical, Minneapolis, MN, USA) magnetic sphincter augmentation device suggest that it is safe to use for the treatment of adult faecal incontinence, but efficacy data are limited.

Objective: To compare FENIX with sacral nerve stimulation for the treatment of adult faecal incontinence in terms of safety, efficacy, quality of life and cost-effectiveness.

Design, Setting And Participants: Multicentre, parallel-group, unblinded, randomised trial comparing FENIX with sacral nerve stimulation in participants suffering moderate to severe faecal incontinence.

Interventions: Participants were randomised on an equal basis to either sacral nerve stimulation or FENIX. Follow-up occurred 2 weeks postoperatively and at 6, 12 and 18 months post randomisation.

Main Outcome And Measure: The primary outcome was success, defined as device in use and ≥ 50% improvement in Cleveland Clinic Incontinence Score at 18 months post randomisation. Secondary outcomes included complication rates, quality of life and cost-effectiveness. Between 30 October 2014 and 23 March 2017, 99 participants were randomised across 18 NHS sites (50 participants to FENIX vs. 49 participants to sacral nerve stimulation). The median time from randomisation to FENIX implantation was 57.0 days (range 4.0-416.0 days), and the median time from randomisation to permanent sacral nerve stimulation was 371.0 days (range 86.0-918.0 days). A total of 45 out of 50 participants underwent FENIX implantation and 29 out of 49 participants continued to permanent sacral nerve stimulation. The following results are reported, excluding participants for whom the corresponding outcome was not evaluable. Overall, there was success for 10 out of 80 (12.5%) participants, with no statistically significant difference between the two groups [FENIX 6/41 (14.6%) participants vs. sacral nerve stimulation 4/39 (10.3%) participants]. At least one postoperative complication was experienced by 33 out of 45 (73.3%) participants in the FENIX group and 9 out of 40 (22.5%) participants in the sacral nerve stimulation group. A total of 15 out of 50 (30%) participants in the FENIX group ultimately had to have their device explanted. Slightly higher costs and quality-adjusted life-years (incremental = £305.50 and 0.005, respectively) were observed in the FENIX group than in the sacral nerve stimulation group. This was reversed over the lifetime horizon (incremental = -£1306 and -0.23 for costs and quality-adjusted life-years, respectively), when sacral nerve stimulation was the optimal option (net monetary benefit = -£3283), with only a 45% chance of FENIX being cost-effective.

Limitations: The SaFaRI study was terminated in 2017, having recruited 99 participants of the target sample size of 350 participants. The study is, therefore, substantially underpowered to detect differences between the treatment groups, with significant uncertainty in the cost-effectiveness analysis.

Conclusions: The SaFaRI study revealed inefficiencies in the treatment pathways for faecal incontinence, particularly for sacral nerve stimulation. The success of both FENIX and sacral nerve stimulation was much lower than previously reported, with high postoperative morbidity in the FENIX group.

Future Work: Further research is needed to clarify the treatment pathways for sacral nerve stimulation and to determine its true clinical and cost-effectiveness.

Trial Registration: Current Controlled Trials ISRCTN16077538.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 18. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020198PMC
March 2021

Bayesian design and analysis of external pilot trials for complex interventions.

Stat Med 2021 05 17;40(12):2877-2892. Epub 2021 Mar 17.

Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

External pilot trials of complex interventions are used to help determine if and how a confirmatory trial should be undertaken, providing estimates of parameters such as recruitment, retention, and adherence rates. The decision to progress to the confirmatory trial is typically made by comparing these estimates to pre-specified thresholds known as progression criteria, although the statistical properties of such decision rules are rarely assessed. Such assessment is complicated by several methodological challenges, including the simultaneous evaluation of multiple endpoints, complex multi-level models, small sample sizes, and uncertainty in nuisance parameters. In response to these challenges, we describe a Bayesian approach to the design and analysis of external pilot trials. We show how progression decisions can be made by minimizing the expected value of a loss function, defined over the whole parameter space to allow for preferences and trade-offs between multiple parameters to be articulated and used in the decision-making process. The assessment of preferences is kept feasible by using a piecewise constant parametrization of the loss function, the parameters of which are chosen at the design stage to lead to desirable operating characteristics. We describe a flexible, yet computationally intensive, nested Monte Carlo algorithm for estimating operating characteristics. The method is used to revisit the design of an external pilot trial of a complex intervention designed to increase the physical activity of care home residents.
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http://dx.doi.org/10.1002/sim.8941DOI Listing
May 2021

What factors shape surgical access in West Africa? A qualitative study exploring patient and provider experiences of managing injuries in Sierra Leone.

BMJ Open 2021 03 1;11(3):e042402. Epub 2021 Mar 1.

School of Medicine, University of Leeds, Leeds, UK.

Introduction: Surgical access is central to universalising health coverage, yet 5 billion people lack timely access to safe surgical services. Surgical need is particularly acute in post conflict settings like Sierra Leone. There is limited understanding of the barriers and opportunities at the service delivery and community levels. Focusing on fractures and wound care which constitute an enormous disease burden in Sierra Leone as a proxy for general surgical need, we examine provider and patient perceived factors impeding or facilitating surgical care in the post-Ebola context of a weakened health system.

Methods: Across Western Area Urban (Freetown), Bo and Tonkolili districts, 60 participants were involved in 38 semistructured interviews and 22 participants in 5 focus group discussions. Respondents included surgical providers, district-level policy-makers, traditional healers and patients. Data were thematically analysed, combining deductive and inductive techniques to generate codes.

Results: Interacting demand-side and supply-side issues affected user access to surgical services. On the demand side, high cost of care at medical facilities combined with the affordability and convenient mode of payment to the traditional health practitioners hindered access to the medical facilities. On the supply side, capacity shortages and staff motivation were challenges at facilities. Problems were compounded by patients' delaying care mainly spurred by sociocultural beliefs in traditional practice and economic factors, thereby impeding early intervention for patients with surgical need. In the absence of formal support services, the onus of first aid and frontline trauma care is borne by lay citizens.

Conclusion: Within a resource-constrained context, supply-side strengthening need accompanying by demand-side measures involving community and traditional actors. On the supply side, non-specialists could be effectively utilised in surgical delivery. Existing human resource capacity can be enhanced through better incentives for non-physicians. Traditional provider networks can be deployed for community outreach. Developing a lay responder system for first-aid and front-line support could be a useful mechanism for prompt clinical intervention.
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http://dx.doi.org/10.1136/bmjopen-2020-042402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098971PMC
March 2021

The Development of a Multilevel Intervention to Optimise Participant Engagement with an Obesity Prevention Programme Delivered in UK children's Centres.

Prev Sci 2021 Apr 1;22(3):345-356. Epub 2021 Feb 1.

Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, LS2 9JT, UK.

Poor participant engagement threatens the potential impact and cost-effectiveness of public health programmes preventing meaningful evaluation and wider application. Although barriers and levers to engagement with public health programmes are well documented, there is a lack of proven strategies in the literature addressing these. This paper details the development of a participant engagement intervention aimed at promoting enrolment and attendance to a community-based pre-school obesity prevention programme delivered in UK children's centres; HENRY (Health, Exercise, Nutrition for the Really Young). The Behaviour Change Wheel framework was used to guide the development of the intervention. The findings of a coinciding focused ethnography study identified barriers and levers to engagement with HENRY that informed which behaviours should be targeted within the intervention to promote engagement. A COM-B behavioural analysis was undertaken to identify whether capability, opportunity or motivation would need to be influenced for the target behaviours to occur. APEASE criteria were used to agree on appropriate intervention functions and behaviour change techniques. A multi-level participant engagement intervention was developed to promote adoption of target behaviours that were proposed to promote engagement with HENRY, e.g. ensuring the programme is accurately portrayed when approaching individuals to attend and providing 'taster' sessions prior to each programme. At the local authority level, the intervention aimed to increase buy-in with HENRY to increase the level of resource dedicated to engagement efforts. At the centre level, managers were encouraged to widen promotion of the programme and ensure that staff promoted the programme accurately. HENRY facilitators received training to increase engagement during sessions, and parents that had attended HENRY were encouraged to recruit their peers. This paper describes one of the first attempts to develop a theory-based multi-level participant engagement intervention specifically designed to promote recruitment and retention to a community-based obesity prevention programme. Given the challenges to implementing public health programmes with sufficient reach, the process used to develop the intervention serves as an example of how programmes that are already widely commissioned could be optimised to enable greater impact.
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http://dx.doi.org/10.1007/s11121-021-01205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032563PMC
April 2021

A platform trial in practice: adding a new experimental research arm to the ongoing confirmatory FLAIR trial in chronic lymphocytic leukaemia.

Trials 2021 Jan 8;22(1):38. Epub 2021 Jan 8.

St James's Institute of Oncology, St James's University Hospital, Leeds, UK.

Background: The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success.

Methods: FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial.

Results: The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres.

Conclusions: FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community.

Trial Registration: ISRCTN Registry ISRCTN01844152 . Registered on August 08, 2014.
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http://dx.doi.org/10.1186/s13063-020-04971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792072PMC
January 2021

Phase III Randomized Controlled Trial of eRAPID: eHealth Intervention During Chemotherapy.

J Clin Oncol 2021 Mar 8;39(7):734-747. Epub 2021 Jan 8.

Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, United Kingdom.

Purpose: Electronic patient self-Reporting of Adverse-events: Patient Information and aDvice (eRAPID) is an online eHealth system for patients to self-report symptoms during cancer treatment. It provides automated severity-dependent patient advice guiding self-management or medical contact and displays the reports in electronic patient records. This trial evaluated the impact of eRAPID on symptom control, healthcare use, patient self-efficacy, and quality of life (QOL) in a patient population treated predominantly with curative intent.

Methods: Patients with colorectal, breast, or gynecological cancers commencing chemotherapy were randomly assigned to usual care (UC) or the addition of eRAPID (weekly online symptom reporting for 18 weeks). Primary outcome was symptom control (Functional Assessment of Cancer Therapy-General, Physical Well-Being subscale [FACT-PWB]) assessed at 6, 12, and 18 weeks. Secondary outcomes were processes of care (admissions or chemotherapy delivery), patient self-efficacy, and global quality of life (Functional Assessment of Cancer Therapy-General, EQ5D-VAS, and EORTC QLQ-C30 summary score). Multivariable mixed-effects repeated-measures models were used for analyses. Trial registration: ISRCTN88520246.

Results: Participants were 508 consenting patients (73.6% of 690 eligible) and 55 health professionals. eRAPID compared to UC showed improved physical well-being at 6 ( = .028) and 12 ( = .039) weeks and no difference at 18 weeks (primary end point) ( = .69). Fewer eRAPID patients (47%) had clinically meaningful physical well-being deterioration than UC (56%) at 12 weeks. Subgroup analysis found benefit in the nonmetastatic group at 6 weeks ( = .0426), but not in metastatic disease. There were no differences for admissions or chemotherapy delivery. At 18 weeks, patients using eRAPID reported better self-efficacy ( = .007) and better health on EQ5D-VAS ( = .009). Average patient compliance with weekly symptom reporting was 64.7%. Patient adherence was associated with clinician's data use and improved FACT-PWB at 12 weeks.

Conclusion: Real-time monitoring with electronic patient-reported outcomes improved physical well-being (6 and 12 weeks) and self-efficacy (18 weeks) in a patient population predominantly treated with curative intent, without increasing hospital workload.
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http://dx.doi.org/10.1200/JCO.20.02015DOI Listing
March 2021

The impact of public health palliative care interventions on health system outcomes: A systematic review.

Palliat Med 2021 03 23;35(3):473-485. Epub 2020 Dec 23.

Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia.

Background: Public health palliative care interventions are increasingly implemented, with growing recognition of the importance of building evidence to support their utility in end-of-life care. Previous efforts have focused on community outcomes.

Aim: To examine the impact of public health palliative care on patterns of health service use at the end of life (primary) and explore which outcomes are being measured within this field of research (secondary).

Design: Systematic review of studies reporting qualitative and quantitative data, analysed with a narrative synthesis method.

Data Sources: A systematic review conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guideline was undertaken using six electronic databases (MEDLINE, CINAHL, EMBASE, PsycINFO, INFORMIT and COCHRANE) up to February 2020.

Results: Searches yielded 2622 unique titles screened for eligibility, resulting in 35 studies measuring outcomes from a public health palliative care approach. Five (14%) studies assessed health system outcomes, and three reported some mixed evidence of impact, including reduced hospital emergency admissions, hospital bed days, hospital costs and increased home deaths. Most studies (86%) instead reported on conceptual (49%), knowledge (40%), programme participation (37%) and/or individual health outcomes (29%).

Conclusion: The impact of public health palliative care is an evolving area of empirical inquiry with currently only limited evidence that it improves healthcare utilisation outcomes at the end of life, and limited focus on measurement of these outcomes. Further empirical studies are needed to support the reorientation of health services, which remains an important component in realising 'whole of system change' to bring about quality end-of-life care for all.
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http://dx.doi.org/10.1177/0269216320981722DOI Listing
March 2021

Maternal Microbiome and Infections in Pregnancy.

Microorganisms 2020 Dec 15;8(12). Epub 2020 Dec 15.

Gale and Ira Drukier Institute for Children's Health, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Pregnancy induces unique changes in maternal immune responses and metabolism. Drastic physiologic adaptations, in an intricately coordinated fashion, allow the maternal body to support the healthy growth of the fetus. The gut microbiome plays a central role in the regulation of the immune system, metabolism, and resistance to infections. Studies have reported changes in the maternal microbiome in the gut, vagina, and oral cavity during pregnancy; it remains unclear whether/how these changes might be related to maternal immune responses, metabolism, and susceptibility to infections during pregnancy. Our understanding of the concerted adaption of these different aspects of the human physiology to promote a successful pregnant remains limited. Here, we provide a comprehensive documentation and discussion of changes in the maternal microbiome in the gut, oral cavity, and vagina during pregnancy, metabolic changes and complications in the mother and newborn that may be, in part, driven by maternal gut dysbiosis, and, lastly, common infections in pregnancy. This review aims to shed light on how dysregulation of the maternal microbiome may underlie obstetrical metabolic complications and infections.
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http://dx.doi.org/10.3390/microorganisms8121996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765218PMC
December 2020

Radical Cystectomy Against Intravesical BCG for High-Risk High-Grade Nonmuscle Invasive Bladder Cancer: Results From the Randomized Controlled BRAVO-Feasibility Study.

J Clin Oncol 2021 Jan 17;39(3):202-214. Epub 2020 Dec 17.

Clinical Trials Research Unit, Leeds Institute for Clinical Trials Research, University of Leeds, Leeds, United Kingdom.

Purpose: High-grade nonmuscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease. Treatments include intravesical maintenance (mBCG) and radical cystectomy (RC). We wanted to understand whether a randomized trial comparing these options was possible.

Materials And Methods: We conducted a two-arm, prospective multicenter randomized study to determine the feasibility in -naive patients. Participants had new high-risk HRNMIBC suitable for both treatments. Random assignment was stratified by age, sex, center, stage, presence of carcinoma in situ, and prior low-risk bladder cancer. Qualitative work investigated how to maintain equipoise. The primary outcome was the number of patients screened, eligible, recruited, and randomly assigned.

Results: We screened 407 patients, approached 185, and obtained consent from 51 (27.6%) patients. Of these, one did not proceed and therefore 50 were randomly assigned (1:1). In the mBCG arm, 23/25 (92.0%) patients received mBCG, four had nonmuscle invasive bladder cancer (NMIBC) after induction, three had NMIBC at 4 months, and four received RC. At closure, two patients had metastatic BC. In the RC arm, 20 (80.0%) participants received cystectomy, including five (25.0%) with no tumor, 13 (65.0%) with HRNMIBC, and two (10.0%) with muscle invasion in their specimen. At follow-up, all patients in the RC arm were free of disease. Adverse events were mostly mild and equally distributed (15/23 [65.2%] patients with mBCG and 13/20 [65.0%] patients with RC). The quality of life (QOL) of both arms was broadly similar at 12 months.

Conclusion: A randomized controlled trial comparing mBCG and RC will be challenging to recruit into. Around 10% of patients with high-risk HRNMIBC have a lethal disease and may be better treated by primary radical treatment. Conversely, many are suitable for bladder preservation and may maintain their prediagnosis QOL.

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http://dx.doi.org/10.1200/JCO.20.01665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078404PMC
January 2021

Efficient and flexible simulation-based sample size determination for clinical trials with multiple design parameters.

Stat Methods Med Res 2021 Mar 2;30(3):799-815. Epub 2020 Dec 2.

Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.

Simulation offers a simple and flexible way to estimate the power of a clinical trial when analytic formulae are not available. The computational burden of using simulation has, however, restricted its application to only the simplest of sample size determination problems, often minimising a single parameter (the overall sample size) subject to power being above a target level. We describe a general framework for solving simulation-based sample size determination problems with several design parameters over which to optimise and several conflicting criteria to be minimised. The method is based on an established global optimisation algorithm widely used in the design and analysis of computer experiments, using a non-parametric regression model as an approximation of the true underlying power function. The method is flexible, can be used for almost any problem for which power can be estimated using simulation, and can be implemented using existing statistical software packages. We illustrate its application to a sample size determination problem involving complex clustering structures, two primary endpoints and small sample considerations.
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http://dx.doi.org/10.1177/0962280220975790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008419PMC
March 2021

Single Cell Genomics Reveals Viruses Consumed by Marine Protists.

Front Microbiol 2020 24;11:524828. Epub 2020 Sep 24.

Bigelow Laboratory for Ocean Sciences, East Boothbay, ME, United States.

The predominant model of the role of viruses in the marine trophic web is that of the "viral shunt," where viral infection funnels a substantial fraction of the microbial primary and secondary production back to the pool of dissolved organic matter. Here, we analyzed the composition of non-eukaryotic DNA associated with individual cells of small, planktonic protists in the Gulf of Maine (GoM) and the Mediterranean Sea. We found viral DNA associated with a substantial fraction cells from the GoM (51%) and the Mediterranean Sea (35%). While Mediterranean SAGs contained a larger proportion of cells containing bacterial sequences (49%), a smaller fraction of cells contained bacterial sequences in the GoM (19%). In GoM cells, nearly identical bacteriophage and ssDNA virus sequences where found across diverse lineages of protists, suggesting many of these viruses are non-infective. The fraction of cells containing viral DNA varied among protistan lineages and reached 100% in Picozoa and Choanozoa. These two groups also contained significantly higher numbers of viral sequences than other identified taxa. We consider mechanisms that may explain the presence of viral DNA in protistan cells and conclude that protistan predation on free viral particles contributed to the observed patterns. These findings confirm prior experiments with protistan isolates and indicate that the viral shunt is complemented by a viral link in the marine microbial food web. This link may constitute a sink of viral particles in the ocean and has implications for the flow of carbon through the microbial food web.
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http://dx.doi.org/10.3389/fmicb.2020.524828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541821PMC
September 2020

Ancestral Absence of Electron Transport Chains in Patescibacteria and DPANN.

Front Microbiol 2020 17;11:1848. Epub 2020 Aug 17.

Bigelow Laboratory for Ocean Sciences, East Boothbay, ME, United States.

Recent discoveries suggest that the candidate superphyla Patescibacteria and DPANN constitute a large fraction of the phylogenetic diversity of Bacteria and Archaea. Their small genomes and limited coding potential have been hypothesized to be ancestral adaptations to obligate symbiotic lifestyles. To test this hypothesis, we performed cell-cell association, genomic, and phylogenetic analyses on 4,829 individual cells of Bacteria and Archaea from 46 globally distributed surface and subsurface field samples. This confirmed the ubiquity and abundance of Patescibacteria and DPANN in subsurface environments, the small size of their genomes and cells, and the divergence of their gene content from other Bacteria and Archaea. Our analyses suggest that most Patescibacteria and DPANN in the studied subsurface environments do not form specific physical associations with other microorganisms. These data also suggest that their unusual genomic features and prevalent auxotrophies may be a result of ancestral, minimal cellular energy transduction mechanisms that lack respiration, thus relying solely on fermentation for energy conservation.
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http://dx.doi.org/10.3389/fmicb.2020.01848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507113PMC
August 2020

Dengue and Zika virus infections are enhanced by live attenuated dengue vaccine but not by recombinant DSV4 vaccine candidate in mouse models.

EBioMedicine 2020 Oct 16;60:102991. Epub 2020 Sep 16.

Translational Health Group, Molecular Medicine Division, International Centre for Genetic Engineering & Biotechnology, New Delhi, India. Electronic address:

Background: A tetravalent live attenuated dengue vaccine, Dengvaxia, sensitised naïve recipients to severe dengue illness upon a subsequent natural dengue infection and is suspected to be due to antibody-dependent enhancement (ADE). ADE has also been implicated in the severe neurological outcomes of Zika virus (ZIKV) infection. It has become evident that cross-reactive antibodies targeting the viral pre-membrane protein and fusion-loop epitope are ADE-competent. A pre-clinical tetravalent dengue sub-unit vaccine candidate, DSV4, eliminates these ADE-competent epitopes.

Methods: We compared protective efficacy and ADE-competence of murine polyclonal antibodies induced by DSV4, Dengvaxia and an 'in house' tetravalent mixture of all four laboratory DENV strains, TV DENV, using established mouse models.

Findings: DSV4-induced antibodies, known to be predominantly type-specific, provided significant protection against lethal DENV challenge, but did not promote ADE of either DENV or ZIKV infection in vivo. Antibodies elicited by Dengvaxia and TV DENV, which are predominantly cross-reactive, not only failed to offer protection against lethal DENV challenge, but also promoted ADE of both DENV and ZIKV infection in vivo.

Interpretation: Protective efficacy against DENV infection may be linked to the induction of neutralising antibodies which are type-specific rather than cross-reactive. Whole virus-based dengue vaccines may be associated with ADE risk, despite their potent virus-neutralising capacity. Vaccines designed to eliminate ADE-competent epitopes may help eliminate/minimise ADE risk.

Funding: This study was supported partly by ICGEB, India, the National Biopharma Mission, DBT, Government of India, Sun Pharmaceutical Industries Limited, India, and NIAID, NIH, USA.
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http://dx.doi.org/10.1016/j.ebiom.2020.102991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501058PMC
October 2020

Debt Stress and Debt Illusion: The Role of Consumer Credit, Reverse and Standard Mortgages.

J Gerontol B Psychol Sci Soc Sci 2021 Apr;76(5):986-995

Department of Economics, University of Maryland, College Park.

Objectives: This study examines the relationship of debt stress and reverse mortgage borrowing and compares it to stress from standard mortgages and consumer debt. Debt stress is measured as a self-reported response to the amount of debt.

Methods: Using a unique national data set of 1,026 homeowners who chose whether to obtain a reverse mortgage in 2010, we estimate the relationship of 2014 levels of debt stress with various types of debt, assets, and income. Using an ordered probit model, we address the endogeneity of our measures of mortgage and consumer debt using an instrumental variables regression model.

Results: We found that consumer debt causes more stress per dollar of debt compared to mortgage debt. Reverse mortgages cause a relatively low level of stress per dollar of debt compared with standard mortgage debt. The average treatment effect of originating a reverse mortgage indicates statistically significantly higher probability of reporting no and not very much debt stress.

Discussion: Reverse mortgage debt causes a complex stress response. Stress per dollar of debt is lower for reverse than standard mortgages 4 years after origination. However, reverse mortgages' loan balance grows over time causing total stress to increase, while stress from a standard mortgage decreases as it is repaid. If an older adult uses reverse mortgage funds to repay consumer debt then total stress is reduced.
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http://dx.doi.org/10.1093/geronb/gbaa167DOI Listing
April 2021

Plasmonic enhancement of stability and brightness in organic light-emitting devices.

Nature 2020 09 16;585(7825):379-382. Epub 2020 Sep 16.

Universal Display Corporation, Ewing, NJ, USA.

The field of plasmonics, which studies the resonant interactions of electromagnetic waves and free electrons in solid-state materials, has yet to be put to large-scale commercial application owing to the large amount of loss that usually occurs in plasmonic materials. Organic light-emitting devices (OLEDs) have been incorporated into billions of commercial products because of their good colour saturation, versatile form factor and low power consumption, but could still be improved in terms of efficiency and stability. Although OLEDs incorporating organic phosphors achieve an internal charge-to-light conversion of unity, their refractive index contrast reduces the observable fraction of photons outside the device to around 25 per cent. Further, during OLED operation, a localized buildup of slow-decaying triplet excitons and charges gradually reduces the brightness of the device in a process called ageing, which can result in 'burn-in' effects on the display. Simultaneously improving device efficiency and stability is of paramount importance for OLED technology. Here we demonstrate an OLED that uses the decay rate enhancement of a plasmonic system to increase device stability, while maintaining efficiency by incorporating a nanoparticle-based out-coupling scheme to extract energy from the plasmon mode. Using an archetypal phosphorescent emitter, we achieve a two-fold increase in operational stability at the same brightness as a reference conventional device while simultaneously extracting 16 per cent of the energy from the plasmon mode as light. Our approach to increasing OLED stability avoids material-specific designs and is applicable to all commercial OLEDs that are currently used for lighting panels, televisions and mobile displays.
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http://dx.doi.org/10.1038/s41586-020-2684-zDOI Listing
September 2020

Electronic Patient Reporting of Adverse Events and Quality of Life: A Prospective Feasibility Study in General Oncology.

JCO Oncol Pract 2021 03 27;17(3):e386-e396. Epub 2020 Aug 27.

Section of Patient-Centered Outcomes Research, Patient Reported Outcomes Group, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.

Purpose: Adverse event (AE) reporting is essential in clinical trials. Clinician interpretation can result in under-reporting; therefore, the value of patient self-reporting has been recognized. The National Cancer Institute has developed a Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for direct patient AE reporting. A nonrandomized prospective cohort feasibility study aimed to explore the compliance and acceptability of an electronic (Internet or telephone) system for collecting patient self-reported AEs and quality of life (QOL).

Methods: Oncology patients undergoing treatment (chemotherapy, targeted agents, hormone therapy, radiotherapy, and/or surgery) at 2 hospitals were sent automated weekly reminders to complete PRO-CTCAE once a week and QOL (for a maximum of 12 weeks). Patients had to speak/understand English and have access to the Internet or a touch-tone telephone. Primary outcome was compliance (proportion of expected questionnaires), and recruitment rate, attrition, and patient/staff feedback were also explored.

Results: Of 520 patients, 249 consented (47.9%)-mean age was 62 years, 51% were male, and 70% were married-and 230 remained on the study at week 12. PRO-CTCAE was completed at 2,301 (74.9%) of 3,074 timepoints and QOL at 749 (79.1%) of 947 timepoints. Individual weekly/once every 4 weeks compliance reduced over time but was more than 60% throughout. Of 230 patients, 106 (46.1%) completed 13 or more PRO-CTCAE, and 136 (59.1%) of 230 patients completed 4 QOL questionnaires. Most were completed on the Internet (82.3%; mean age, 60.8 years), which was quicker, but older patients preferred the telephone option (mean age, 70.0 years). Positive feedback was received from patients and staff.

Conclusion: Self-reporting of AEs and QOL using an electronic home-based system is feasible and acceptable. Implementation of this approach in cancer clinical trials may improve the precision and accuracy of AE reporting.
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http://dx.doi.org/10.1200/OP.20.00118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202059PMC
March 2021

Liver resection surgery compared with thermal ablation in high surgical risk patients with colorectal liver metastases: the LAVA international RCT.

Health Technol Assess 2020 04;24(21):1-38

Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands.

Background: Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation.

Objectives: Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms.

Design: A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study.

Setting: Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands.

Participants: Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation.

Interventions: Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol.

Main Outcome Measures: Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study.

Results: In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial.

Conclusions: Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks.

Trial Registration: Current Controlled Trials ISRCTN52040363.

Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 21. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232132PMC
April 2020