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 extreme concentration from a source in a turbulent flow over rough wall

The concentration fluctuations in passive plumes from an elevated and a groundlevel source in a turbulent boundary layer over a rough wall were studied using large eddy simulation and wind tunnel experiment. The predictions of statistics up to second order moments were thereby validated. In addition, the trend of relative fluctuations far downstream for a ground level source was estimated using dimensional analysis. The techniques of extreme value theory were then applied to predict extreme concentrations by modelling the upper tail of the probability density function of the concentration time series by the Generalised Pareto Distribution. Data obtained from both the simulations and experiments were analysed in this manner. The predicted maximum concentration (?0) normalized by the local mean concentration (Cm) or by the local r.m.s of concentration fluctuation (crms), was extensively investigated. Values for ?0/Cm and ?0/crms as large as 50 and 20 respectively were found for the elevated source and 10 and 15 respectively for the ground-level source

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

Lahaina groundwater tracer study -- Lahaina, Maui, Hawaii

The studies presented in this report provide the positive establishment of hydrologic connections between the municipal wastewater injection from the LWRF and the nearshore region of the Kaanapali coast on the Island of Maui, Hawaii, and provide the results from the study’s principal objectives, which have been to: (1) implement a tracer dye study from the LWRF (Section 3), (2) conduct continuous monitoring for the emergence of the injected tracer dyes at the most probable points of emergence at nearshore sites within the coastal reaches of the LWRF (Section 2), (3) conduct an airborne infrared sea surface temperature mapping survey of coastal zone fronting the LWRF in an effort to detect cool and/or warm temperature anomalies that may be indicative of cool submarine groundwater discharge and warm wastewater effluent (Section 4), (4) complete radon and radium radiochemical surveys to detect the emergence points and flow rates of the naturally occurring submarine groundwater along the coastal zone (Section 5), (5) complete geochemical and stable isotopic analyses of LWRF effluent, upland well waters, terrestrial surface waters, marine waters, and submarine groundwater discharge in an effort to help partition the relative contribution of effluent waters to the ocean (Section 6), and (6) combine complete dye emergence breakthrough curves with which to develop groundwater models to determine the LWRFs effluent flow paths and rates of emergence to the coastal zone (Section 7).U.S. Environmental Protection AgencyDepartment of Health, State of HawaiiU.S. Army Engineer Research and Development Cente

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

Applying multi-phase DES approach for modelling the patient journey through accident and emergency departments

Accident and Emergency departments (A&ED) are in charge of providing access to patients requiring urgent acute care. A&ED are difficult to model due to the presence of interactions, different pathways and the multiple outcomes that patients may undertake depending on their health status. In addition, public concern has focused on the presence of overcrowding, long waiting times, patient dissatisfaction and cost overruns associated with A&ED. There is then a need for tackling these problems through developing integrated and explicit models supporting healthcare planning. However, the studies directly concentrating on modelling the A&EDs are largely limited. Therefore, this paper presents the use of a multi-phase DES framework for modelling the A&ED and facilitating the assessment of potential improvement strategies. Initially, the main components, critical variables and different states of the A&ED are identified to correctly model the entire patient journey. In this step, it is also necessary to characterize the demand in order to categorize the patients into pipelines. After this, a discrete-event simulation (DES) model is developed. Then, validation is conducted through the 2-sample t test to demonstrate whether the model is statistically comparable with the real-world A&ED department. This is followed by the use of Markov phase-type models for calculating the total costs of the whole system. Finally, various scenarios are explored to assess their potential impact on multiple outcomes of interest. A case study of a mixed-patient environment in a private A&E department is provided to validate the effectiveness of the multi-phase DES approach

Core outcome domains for early-phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus

Background: The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is therefore to develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. Methods: The ‘Core Outcome Measures in Tinnitus: International Delphi’ (COMIT’ID) study will use a mixed methods approach that incorporates input from healthcare users at the pre-Delphi stage, a modified three round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following core outcome set publication. Discussion: The COMIT’ID study aims to develop a Core Outcome Domain Set that are agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the core outcome set in the long term. Trial registration: This project has been registered in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative

Definition of strategies for the reduction of operational inefficiencies in a stroke unit

Stroke disease is the second common cause of death in the world and is then of particular concern to policy-makers. Additionally, it is a meaningful problem leaving a high number of people with severe disabilities, placing a heavy burden on society and incurring prolonged length of stay. In this respect, it is necessary to develop analytic models providing information on care system behavior in order to detect potential operational inefficiencies along the stroke patient journey and subsequently design improvement strategies. However, modeling stroke care is highly complex due to the multiple clinical outcomes and different pathways. Therefore, this paper presents an integrated approach between Discrete-event Simulation (DES) and Markov models so that integrated planning of healthcare services relating to stroke care and the evaluation of potential improvement scenarios can be facilitated, made more logically robust and easy to understand. First, a stroke care system from Colombia was characterized by identifying the exogenous and endogenous variables of the process. Afterward, an input analysis was conducted to define the probability distributions of the aforementioned variables. Then, both DES and Markov models were designed and validated to provide deeper analysis of the entire patient journey. Finally, the possible adoption of thrombolytic treatment on patients with stroke disease was assessed based on the proposed approaches within this paper. The results evidenced that the length of stay (LOS) decreased by 12,89% and the mortality ratio was diminished by 21,52%. Evaluation of treatment cost per patient is also carried out

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment