A practical approach to communicating benefit-risk decisions of medicines to stakeholders.

© 2015 Leong, Walker and Salek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Purpose: The importance of a framework for a systematic structured assessment of the benefits and risks has been established, but in addition, it is necessary that the benefit-risk decisions and the processes to derive those decisions are documented and communicated to various stakeholders for accountability. Hence there is now a need to find appropriate tools to enhance communication between regulators and other stakeholders, in a manner that would uphold transparency, consistency and standards. Methods: A retrospective, non-comparative study was conducted to determine the applicability and practicality of a summary template in documenting benefit-risk assessment and communicating benefit-risk balance and conclusions for reviewers to other stakeholders. The benefit-risk (BR) Summary Template and its User Manual was evaluated by 12 reviewers within a regulatory agency in Singapore, the Health Sciences Authority (HSA). Results: The BR Summary Template was found to be adequate in documenting benefits, risks, relevant summaries and conclusions, while the User Manual was useful in guiding the reviewer in completing the template. The BR Summary Template was also considered a useful tool for communicating benefit-risk decisions to a variety of stakeholders. Conclusions: The use of a template may be of value for the communicating benefit-risk assessment of medicines to stakeholders.Peer reviewedFinal Published versio

The relationship between critical flicker fusion threshold and executive function across the autistic trait spectrum

Previous research by Mewborn et al. (2015) investigating the link between Critical Flicker Fusion Threshold (CFFT) and higher-order cognitive functions found a significant correlation between CFFT and executive function, as measured by scores from the Shifting Attention Task. Given the well-established links between autism and deficits in executive function, and the less well-established links between autism and flicker perception, this study explores the possible link between CFFT, executive function, and autistic traits. Using an achromatic flicker task, no relationship was found between CFFT and executive function and CFFT and self- rated autistic traits (as measured by the Autism Quotient; Baron-Cohen et al., 2019). This investigation also found no relationship between CFFT and processing speed (as measured by the processing speed index from the WAIS-IV; Wechsler, 2008), but the current study did find that processing speed significantly predicted executive function. These results cast some doubt on the notion that CFFT, a proxy measure of processing speed is related to executive function and that flicker perception is related to autistic traits. Further questions and additional research and theoretical ideas are developed, along with possible explanations for these, and previous findings

Optimised access to user analysis data using the gLite DPM

The ScotGrid distributed Tier-2 now provides more that 4MSI2K and 500TB for LHC computing, which is spread across three sites at Durham, Edinburgh and Glasgow. Tier-2 sites have a dual role to play in the computing models of the LHC VOs. Firstly, their CPU resources are used for the generation of Monte Carlo event data. Secondly, the end user analysis data is distributed across the grid to the site's storage system and held on disk ready for processing by physicists' analysis jobs. In this paper we show how we have designed the ScotGrid storage and data management resources in order to optimise access by physicists to LHC data. Within ScotGrid, all sites use the gLite DPM storage manager middleware. Using the EGEE grid to submit real ATLAS analysis code to process VO data stored on the ScotGrid sites, we present an analysis of the performance of the architecture at one site, and procedures that may be undertaken to improve such. The results will be presented from the point of view of the end user (in terms of number of events processed/second) and from the point of view of the site, which wishes to minimise load and the impact that analysis activity has on other users of the system

The Measurement of Eye Movements in Mild Traumatic Brain Injury: A Structured Review of an Emerging Area

Mild traumatic brain injury (mTBI), or concussion, occurs following a direct or indirect force to the head that causes a change in brain function. Many neurological signs and symptoms of mTBI can be subtle and transient, and some can persist beyond the usual recovery timeframe, such as balance, cognitive or sensory disturbance that may pre-dispose to further injury in the future. There is currently no accepted definition or diagnostic criteria for mTBI and therefore no single assessment has been developed or accepted as being able to identify those with an mTBI. Eye-movement assessment may be useful, as specific eye-movements and their metrics can be attributed to specific brain regions or functions, and eye-movement involves a multitude of brain regions. Recently, research has focused on quantitative eye-movement assessments using eye-tracking technology for diagnosis and monitoring symptoms of an mTBI. However, the approaches taken to objectively measure eye-movements varies with respect to instrumentation, protocols and recognition of factors that may influence results, such as cognitive function or basic visual function. This review aimed to examine previous work that has measured eye-movements within those with mTBI to inform the development of robust or standardized testing protocols. Medline/PubMed, CINAHL, PsychInfo and Scopus databases were searched. Twenty-two articles met inclusion/exclusion criteria and were reviewed, which examined saccades, smooth pursuits, fixations and nystagmus in mTBI compared to controls. Current methodologies for data collection, analysis and interpretation from eye-tracking technology in individuals following an mTBI are discussed. In brief, a wide range of eye-movement instruments and outcome measures were reported, but validity and reliability of devices and metrics were insufficiently reported across studies. Interpretation of outcomes was complicated by poor study reporting of demographics, mTBI-related features (e.g., time since injury), and few studies considered the influence that cognitive or visual functions may have on eye-movements. The reviewed evidence suggests that eye-movements are impaired in mTBI, but future research is required to accurately and robustly establish findings. Standardization and reporting of eye-movement instruments, data collection procedures, processing algorithms and analysis methods are required. Recommendations also include comprehensive reporting of demographics, mTBI-related features, and confounding variables

South African Regulatory Authority: The Impact of Reliance on the Review Process Leading to Improved Patient Access

Background: The aims of this study were to compare the overall regulatory review timelines achieved by the South African Health Products Regulatory Authority (SAHPRA) in 2020 to the timelines historically achieved by the Medicines Control Council (MCC). This study also aimed to evaluate the regulatory review processes and the good review practices that have been implemented by SAHPRA to support the assessment of new chemical entities and generic product applications for market authorization in the business-as-usual and backlog process streams. Methods: A questionnaire was completed and verified by SAHPRA to describe the structure of the organization, the resources available, the process for regulatory review of new chemical entities and generic products and the level of implementation of good review practices and regulatory decision-making practices for market authorization. Data were collected and analyzed on the overall approval timelines for new chemical entities and generic products registered by SAHPRA in 2020 in the business-as-usual and backlog process streams. Results: A full, independent scientific review was conducted for all new chemical entities and generic product applications in the business-as-usual stream. Facilitated regulatory pathways were introduced for the review of new chemical entities and generic products in the backlog stream. As a result, the timelines for approval of applications in the backlog stream were 68% quicker for both new chemical entities and generics, using facilitated regulatory pathways, such as abridged and verification review models. Conclusion: The comparisons made through this study provided insight into the improvements that have been made through the establishment of SAHPRA and the transition in 2018 from the MCC. The re-engineered processes that have been developed and implemented by SAHPRA to address the backlog in the review of the applications for market authorization have demonstrated a decrease in the overall median approval times. The expansion of these processes into the routine review of medical products will contribute to the enhanced regulatory performance of SAHPRA and patients’ access to new medicines.Peer reviewe

On the Indeterministic Nature of Star Formation on the Cloud Scale

Molecular clouds are turbulent structures whose star formation efficiency (SFE) is strongly affected by internal stellar feedback processes. In this paper we determine how sensitive the SFE of molecular clouds is to randomised inputs in the star formation feedback loop, and to what extent relationships between emergent cloud properties and the SFE can be recovered. We introduce the yule suite of 26 radiative magnetohydrodynamic (RMHD) simulations of a 10,000 solar mass cloud similar to those in the solar neighbourhood. We use the same initial global properties in every simulation but vary the initial mass function (IMF) sampling and initial cloud velocity structure. The final SFE lies between 6 and 23 percent when either of these parameters are changed. We use Bayesian mixed-effects models to uncover trends in the SFE. The number of photons emitted early in the cluster's life and the length of the cloud provide are the strongest predictors of the SFE. The HII regions evolve following an analytic model of expansion into a roughly isothermal density field. The more efficient feedback is at evaporating the cloud, the less the star cluster is dispersed. We argue that this is because if the gas is evaporated slowly, the stars are dragged outwards towards surviving gas clumps due to the gravitational attraction between the stars and gas. While star formation and feedback efficiencies are dependent on nonlinear processes, statistical models describing cloud-scale processes can be constructed.Comment: 24 pages, 16 figures, 6 tables. Accepted to MNRAS, version updated with published titl

Executive control of walking in people with Parkinson’s disease with freezing of gait

Background: Walking abnormalities in people with Parkinson’s disease (PD) are characterized by a shift in locomotor control from healthy automaticity to compensatory prefrontal executive control. Indirect measures of automaticity of walking (e.g., step-to-step variability and dual-task cost) suggest that freezing of gait (FoG) may be associated with reduced automaticity of walking. However, the influence of FoG status on actual prefrontal cortex (PFC) activity during walking remains unclear. Objective: To investigate the influence of FoG status on automaticity of walking in people with PD. Methods: Forty-seven people with PD were distributed into two groups based on FoG status, which was assessed by the New Freezing of Gait Questionnaire: PD-FoG (n=23; UPDRS-III=35) and PD+FoG (n=24; UPDRS-III=43.1). Participants walked over a 9m straight path (with a 180° turn at each end) for 80s. Two conditions were tested Off medication: single- and dual-task walking (i.e., with a concomitant cognitive task). A portable functional near-infrared spectroscopy system recorded PFC activity while walking (including turns). Wearable inertial sensors were used to calculate spatiotemporal gait parameters. Results: PD+FoG had greater PFC activation during both single and dual-task walking than PD-FoG (p=0.031). There were no differences in gait between PD-FoG and PD+FoG. Both groups decreased gait speed (p=0.029) and stride length (p<0.001) during dual-task walking compared to single-task walking. Conclusions: These findings suggest that PD+FoG have reduced automaticity of walking, even in absence of FoG episodes. PFC activity while walking seems to be more sensitive than gait measures in identifying reduction in automaticity of walking in PD+FoG

What is the perceived impact of Alexander technique lessons on health status, costs and pain management in the real life setting of an English hospital? The results of a mixed methods evaluation of an Alexander technique service for those with chronic bac

© 2015 McClean et al. Background: Randomised controlled trial evidence indicates that Alexander Technique is clinically and cost effective for chronic back pain. The aim of this mixed methods evaluation was to explore the role and perceived impact of Alexander Technique lessons in the naturalistic setting of an acute hospital Pain Management Clinic in England. Methods: To capture changes in health status and resource use amongst service users, 43 service users were administered three widely used questionnaires (Brief Pain Inventory, MYMOP and Client Service Resource Inventory) at three time points: baseline, six weeks and three months after baseline. We also carried out 27 telephone interviews with service users and seven face-to-face interviews with pain clinic staff and Alexander Technique teachers. Quantitative data were analysed using descriptive statistics and qualitative data were analysed thematically. Results: Those taking Alexander Technique lessons reported small improvements in health outcomes, and condition-related costs fell. However, due to the non-randomised, uncontrolled nature of the study design, changes cannot be attributed to the Alexander Technique lessons. Service users stated that their relationship to pain and pain management had changed, especially those who were more committed to practising the techniques regularly. These changes may explain the reported reduction in pain-related service use and the corresponding lower associated costs. Conclusions: Alexander Technique lessons may be used as another approach to pain management. The findings suggests that Alexander Technique lessons can help improve self-efficacy for those who are sufficiently motivated, which in turn may have an impact on service utilisation levels

A protocol to examine vision and gait in Parkinson’s disease: impact of cognition and response to visual cues

Background Cognitive and visual impairments are common in Parkinson's disease (PD) and contribute to gait deficit and falls. To date, cognition and vision in gait in PD have been assessed separately. Impact of both functions (which we term 'visuo-cognition') on gait however is likely interactive and can be tested using visual sampling (specifically saccadic eye movements) to provide an online behavioural measure of performance. Although experiments using static paradigms show saccadic impairment in PD, few studies have quantified visual sampling during dynamic motor tasks such as gait. This article describes a protocol developed for testing visuo-cognition during gait in order to examine the: 1) independent roles of cognition and vision in gait in PD, 2) interaction between both functions, and 3) role of visuo-cognition in gait in PD. Methods Two groups of older adults (≥50 years old) were recruited; non-demented people with PD (n=60) and age-matched controls (n=40). Participants attended one session and a sub-group (n=25) attended two further sessions in order to establish mobile eye-tracker reliability. Participants walked in a gait laboratory under different attentional (single and dual task), environmental (walk straight, through a door and turning), and cueing (no visual cues and visual cues) conditions. Visual sampling was recorded using synchronised mobile eye-tracker and electrooculography systems, and gait was measured using 3D motion analysis. Discussion This exploratory study examined visuo-cognitive processes and their impact on gait in PD. Improved understanding of the influence of cognitive and visual functions on visual sampling during gait and gait in PD will assist in development of interventions to improve gait and reduce falls risk. This study will also help establish robust mobile eye-tracking methods in older adults and people with PD