Extension of PRISM by Synthesis of Optimal Timeouts in Fixed-Delay CTMC

We present a practically appealing extension of the probabilistic model checker PRISM rendering it to handle fixed-delay continuous-time Markov chains (fdCTMCs) with rewards, the equivalent formalism to the deterministic and stochastic Petri nets (DSPNs). fdCTMCs allow transitions with fixed-delays (or timeouts) on top of the traditional transitions with exponential rates. Our extension supports an evaluation of expected reward until reaching a given set of target states. The main contribution is that, considering the fixed-delays as parameters, we implemented a synthesis algorithm that computes the epsilon-optimal values of the fixed-delays minimizing the expected reward. We provide a performance evaluation of the synthesis on practical examples

Modelling modal gating of ion channels with hierarchical Markov models

Many ion channels spontaneously switch between different levels of activity. Although this behaviour known as modal gating has been observed for a long time it is currently not well understood. Despite the fact that appropriately representing activity changes is essential for accurately capturing time course data from ion channels, systematic approaches for modelling modal gating are currently not available. In this paper, we develop a modular approach for building such a model in an iterative process. First, stochastic switching between modes and stochastic opening and closing within modes are represented in separate aggregated Markov models. Second, the continuous-time hierarchical Markov model, a new modelling framework proposed here, then enables us to combine these components so that in the integrated model both mode switching as well as the kinetics within modes are appropriately represented. A mathematical analysis reveals that the behaviour of the hierarchical Markov model naturally depends on the properties of its components. We also demonstrate how a hierarchical Markov model can be parametrized using experimental data and show that it provides a better representation than a previous model of the same dataset. Because evidence is increasing that modal gating reflects underlying molecular properties of the channel protein, it is likely that biophysical processes are better captured by our new approach than in earlier models

Addressing Comorbidities in People with Parkinson’s Disease: Considerations From An Expert Panel

In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson’s disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient’s individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients’ outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson’s (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP

Tinnitus and stress in adults: a scoping review

ObjectiveTinnitus and stress are recurrently reported together. The strength and direction of this relationship is not clear. The aim of this review is to catalogue the evidence of this relationship, how it has been described in adults and which instruments were used.DesignFive-stage framework was followed. An online search of databases and published journals were conducted. The main inclusion criteria were original studies published in English and conducted in an adult human population, in which both tinnitus and stress were measured using different instruments.Study samples5699 records were identified in the searching stage and 50 studies were eligible for data extraction.ResultsMeasurements of perceived stress were most frequently used. Tinnitus patients tend to report louder and more bothersome tinnitus when they are stressed, but not all tinnitus patients associated stress with the onset or the severity of their tinnitus. Any positive correlation reported between stress and tinnitus levels varied in strength according to the used instrument. Post-intervention changes in stress and tinnitus levels showed inconsistency.ConclusionThere is considerable room for further research to study the relationship between stress and tinnitus. We highlight principal issues that should be considered in future studies

Device-based interventions that seek to restore bilateral and binaural hearing in adults with single-sided deafness: a conceptual analysis

Single-sided deafness (SSD) is defined by severe-to-profound sensorineural hearing loss in one ear only. This article outlines the etiologies and associated functional, psychological, social, and other consequences of SSD in adulthood. The available hearing aids and auditory implants for SSD are described, alongside an overview of the methods adopted by clinicians and researchers to define and measure their benefits and harms. Current concepts and issues to consider in the field of rerouting and restoring device-based interventions are explored. A contemporary overview of the current challenges in outcome measurement of all available interventions in the field is also provided, and cost effectiveness of SSD interventions is discussed briefly. This article therefore proves a comprehensive summary of the current knowledge on interventions and outcome measurement for SSD for those interested or actively working in the field, and recommendations for future trials. These include recommendations on the timescale of measurements, long-term benefits (or harms), cost utility, and the use of the internationally agreed core outcome domain set for all future clinical trials of device-based interventions for SSD

Noninvasive options for ‘wearing-off’ in Parkinson's disease: a clinical consensus from a panel of UK Parkinson's disease specialists

In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales

Complex network analysis of wind tunnel experiments on the passive scalar dispersion in a turbulent boundary layer

In this work, data of passive scalar plumes in a turbulent boundary layer are investigated. The experiments are performed in a&nbsp;wind tunnel where a passive scalar is injected through an L-shaped tube. Two source configurations&nbsp;are analysed for two different tube diameters. The passive scalar concentration is then measured at different distances from the source and wall-normal locations. By exploiting the recent advances of complex networks theory, the concentration time-series are mapped into networks, through the visibility algorithm. The resulting networks inherit the temporal features of the mapped time-series, revealing non-trivial information about the underlying transport process. This work represents an example of the great potentialities of the complex network approach for the analysis of turbulent transport and mixing.</p

Identifying and prioritising unanswered research questions for people with hyperacusis: James Lind Alliance Hyperacusis Priority Setting Partnership

Objective To determine research priorities in hyperacusis that key stakeholders agree are the most important. Design/setting A priority setting partnership using two international surveys, and a UK prioritisation workshop, adhering to the six-staged methodology outlined by the James Lind Alliance. Participants People with lived experience of hyperacusis, parents/carers, family and friends, educational professionals and healthcare professionals who support and/or treat adults and children who experience hyperacusis, including but not limited to surgeons, audiologists, psychologists and hearing therapists. Methods The priority setting partnership was conducted from August 2017 to July 2018. An international identification survey asked respondents to submit any questions/uncertainties about hyperacusis. Uncertainties were categorised, refined and rephrased into representative indicative questions using thematic analysis techniques. These questions were verified as ‘unanswered’ through searches of current evidence. A second international survey asked respondents to vote for their top 10 priority questions. A shortlist of questions that represented votes from all stakeholder groups was prioritised into a top 10 at the final prioritisation workshop (UK). Results In the identification survey, 312 respondents submitted 2730 uncertainties. Of those uncertainties, 593 were removed as out of scope, and the remaining were refined into 85 indicative questions. None of the indicative questions had already been answered in research. The second survey collected votes from 327 respondents, which resulted in a shortlist of 28 representative questions for the final workshop. Consensus was reached on the top 10 priorities for future research, including identifying causes and underlying mechanisms, effective management and training for healthcare professionals. Conclusions These priorities were identified and shaped by people with lived experience, parents/carers and healthcare professionals, and as such are an essential resource for directing future research in hyperacusis. Researchers and funders should focus on addressing these priorities.Additional co-authors: Tracey Pollard, Helen Henshaw, Toto A Gronlund, Derek J Hoar

Defining and evaluating novel procedures for involving patients in Core Outcome Set research: creating a meaningful long list of candidate outcome domains

Background Tinnitus is a complex audiological condition affecting many different domains of everyday life. Clinical trials of tinnitus interventions measure and report those outcome domains inconsistently and this hinders direct comparison between study findings. To address this problem, an ongoing project is developing a Core Outcome Set; an agreed list of outcome domains to be measured and reported in all future trials. Part of this project uses a consensus methodology (‘Delphi’ survey), whereby all relevant stakeholders identify important and critical outcome domains from a long list of candidates. This article addresses a gap in the patient involvement literature by describing and reflecting on our involvement of patients to create a meaningful long list of candidate outcome domains. Methods Two Public Research Partners with lived experience of tinnitus reviewed an initial list of 124 outcome domains over two face-to-face workshops. With the Study Management Team, they interpreted each candidate outcome domain and generated a plain language description. Following this, the domain names and descriptions underwent an additional lay review by 14 patients and 5 clinical experts, via an online survey platform. Results Insights gained from the workshops and survey feedback prompted substantial, unforeseen modifications to the long list. These included the reduction of the number of outcome domains (from 124 to 66) via the exclusion of broad concepts and consolidation of equivalent domains or domains outside the scope of the study. Reviewers also applied their lived experience of tinnitus to bring clarity and relevance to domain names and plain language descriptions. Four impacts on the Delphi survey were observed: recruitment exceeded the target by 171%, there were equivalent numbers of patient and professional participants (n=358 and n=312, respectively), feedback was mostly positive, and retention was high (87%). Conclusions Patient involvement was an integral and transformative step of the study design process. Patient involvement was impactful because the online Delphi survey was successful in recruiting and retaining participants, and there were many comments about a positive participatory experience. Seven general methodological features are highlighted which fit with general principles of good patient involvement. These can benefit other Core Outcome Set developers