New Medicines in Wales: The All Wales Medicines Strategy Group (AWMSG) Appraisal Process and Outcomes.

BACKGROUND: The All Wales Medicines Strategy Group (AWMSG) develops prescribing advice and is responsible for appraising new medicines for use in Wales. In this article, we examine the medicines appraisal process in Wales, its timeliness and its impact on medicines availability in Wales, and compare its processes and recommendations with the two other UK health technology appraisal bodies [the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC)]. METHODS: We reviewed the medicines appraisals conducted by AWMSG between October 2010 and September 2015. The duration of the process and the recommendations made by AWMSG were compared with those of NICE and SMC. Only publicly available data were considered in this review. RESULTS: AWMSG conducted 171 single technology appraisals for 137 medicines during the study period (34 were for medicines previously appraised by AWMSG but these were for new indications). Of these, 152 appraisals were supported for use in NHS Wales (33 with restrictions) and 19 were not supported. Recommendations broadly concurred with SMC and NICE for the majority of appraisals. Compared with NICE recommendations, the median time advantage gained in Wales for those medicines that received a positive AWMSG recommendation and which were subsequently superseded by NICE advice was 10.6 months (range 3.5-48.3 months; n = 17). CONCLUSION: This review highlights the work carried out by AWMSG over a 5-year period, and provides evidence to support the effectiveness of the appraisal process in terms of patients in Wales gaining earlier access to medicines and efficiency through reduced duplication with NICE.

Distinct contributions of the fornix and inferior longitudinal fasciculus to episodic and semantic autobiographical memory.

Autobiographical memory (AM) is multifaceted, incorporating the vivid retrieval of contextual detail (episodic AM), together with semantic knowledge that infuses meaning and coherence into past events (semantic AM). While neuropsychological evidence highlights a role for the hippocampus and anterior temporal lobe (ATL) in episodic and semantic AM, respectively, it is unclear whether these constitute dissociable large-scale AM networks. We used high angular resolution diffusion-weighted imaging and constrained spherical deconvolution-based tractography to assess white matter microstructure in 27 healthy young adult participants who were asked to recall past experiences using word cues. Inter-individual variation in the microstructure of the fornix (the main hippocampal input/output pathway) related to the amount of episodic, but not semantic, detail in AMs - independent of memory age. Conversely, microstructure of the inferior longitudinal fasciculus, linking occipitotemporal regions with ATL, correlated with semantic, but not episodic, AMs. Further, these significant correlations remained when controlling for hippocampal and ATL grey matter volume, respectively. This striking correlational double dissociation supports the view that distinct, large-scale distributed brain circuits underpin context and concepts in AM.

Neural responses to a modified Stroop paradigm in patients with complex chronic musculoskeletal pain compared to matched controls: an experimental functional magnetic resonance imaging study.

BACKGROUND: Chronic musculoskeletal pain (CMSKP) is attentionally demanding, complex and multi-factorial; neuroimaging research in the population seen in pain clinics is sparse. A better understanding of the neural activity underlying attentional processes to pain related information compared to healthy controls may help inform diagnosis and management in the future. METHODS: Blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) compared brain responses in patients with CMSKP (n = 15) and healthy controls (n = 14) while completing a modified Stroop task using pain-related, positive-emotional, and neutral control words. RESULTS: Response times in the Stroop task were no different for CMSKP patients compared with controls, but patients were less accurate in their responses to all word types. BOLD fMRI responses during presentation of pain-related words suggested increases in neural activation in patients compared to controls in regions previously reported as being involved in pain perception and emotion: the anterior cingulate cortex, insula and primary and secondary somatosensory cortex. No fMRI differences were seen between groups in response to positive or control words. CONCLUSIONS: Using this modified Stroop tasks, specific differences were identified in brain activity between CMSKP patients and controls in response to pain-related information using fMRI. This provided evidence of differences in the way that pain-related information is processed in those with chronic complex musculoskeletal pain that were not detectable using the behavioural measures of speed and accuracy. The study may be helpful in gaining new insights into the impact of attention in those living with chronic pain.

A Functional Magnetic Resonance Imaging Study to Investigate the Utility of a Picture Imagination Task in Investigating Neural Responses in Patients with Chronic Musculoskeletal Pain to Daily Physical Activity Photographs.

Pain-related anxiety and fear are associated with increased difficulties in attention, increased awareness of pain, impaired disengagement from pain, and can moderate the effects of attentional coping attempts. Accurately assessing the direct impact of pain-related anxiety and fear on pain behavior has proved difficult. Studies have demonstrated no or limited influence of pain-related fear and anxiety on behavior but this may be due to inherent problems with the scales used. Neuroimaging has improved the understanding of neural processes underlying the factors that influence pain perception. This study aimed to establish if a Picture and Imagination Task (PIT), largely developed from the Photographs of Daily Activity (PHODA) assessment tool, could help explore how people living with chronic pain process information about daily activities. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to compare brain responses in patients with chronic musculoskeletal pain (CMSKP) (n = 15) and healthy controls (n = 15). Subjects were asked to imagine how they would feel mentally and physically if asked to perform daily activities illustrated in PIT. The results found that a number of regions involved in pain processing saw increased BOLD activation in patients compared with controls when undertaking the task and included the insula, anterior cingulate cortex, thalamus and inferior and superior parietal cortices. Similarly, increased BOLD responses in patients compared to controls in the frontal pole, paracingulate and the supplementary motor cortex may be suggestive of a memory component to the responses The amygdala, orbitofrontal cortex, substantia nigra/ventral tegmentum, putamen, thalamus, pallidum, inferior parietal (supramarginal and angular gyrus) and cingulate cortex were also seen to have greater differences in BOLD signal changes in patients compared with controls and many of these regions are also associated with general phobic responses. Therefore, we suggest that PIT is a useful task to explore pain- and movement-related anxiety and fear in fMRI studies. Regions in the Default Mode Network remained active or were less deactivated during the PIT task in patients with CMSKP compared to healthy controls supporting the contention that the DMN is abnormal in patients with CMSKP.

The Predictive Nature of Pseudoneglect for Visual Neglect: Evidence from Parietal Theta Burst Stimulation.

Following parietal damage most patients with visual neglect bisect horizontal lines significantly away from the true centre. Neurologically intact individuals also misbisect lines; a phenomenon referred to as 'pseudoneglect'. In this study we examined the relationship between neglect and pseudoneglect by testing how patterns of pre-existing visuospatial asymmetry predict asymmetry caused by parietal interference. Twenty-four participants completed line bisection and Landmark tasks before receiving continuous theta burst stimulation to the left or right angular gyrus. Results showed that a pre-existing pattern of left pseudoneglect (i.e. right bias), but not right pseudoneglect, predicts left neglect-like behaviour during line bisection following right parietal cTBS. This correlation is consistent with the view that neglect and pseudoneglect arise via a common or linked neural mechanism.

Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation.

OBJECTIVES: Past research has largely neglected to investigate mild adverse effects (MAEs) to transcranial magnetic stimulation (TMS), including headache and nausea. Here we explored the relationship between MAEs, participant characteristics (age and gender) and protocol parameters, including mode of application, coil geometry, stimulated brain region, TMS frequency, TMS intensity, and active vs. sham stimulation. METHODS: Data from 1270 standard post-monitoring forms was obtained from 113 healthy participants. Analyses aimed to identify the risk factors associated with MAE reports and specific symptoms. RESULTS: The overall rate of MAEs across TMS sessions was ∼5%, with ∼78% of symptoms occurring post-session. Initial TMS sessions were followed by a higher MAE incidence rate relative to later testing sessions. No associations between participant characteristics, TMS frequency, or intensity were observed. CONCLUSIONS: TMS-related MAEs are relatively common and may be exacerbated by initial expectations or anxieties of participants. A significant proportion of MAEs may reflect reporting of coincidental phenomena that are unrelated to TMS. Recommendations for future safety studies are proposed and monitoring documentation is provided. SIGNIFICANCE: Our findings illustrate the importance of standardized monitoring of MAEs. Such research aids our understanding of how MAEs arise and may lead to interventions for reducing their incidence.

Reliability of the 'observation of movement' method for determining motor threshold using transcranial magnetic stimulation.

The aim of this study was to establish the reliability of the observation of movement (OM) method for obtaining motor threshold (MT) in transcranial magnetic stimulation (TMS). MTs were obtained on separate days, following separate hunting procedures, for both left and right motor cortex (M1), with one or multiple estimates obtained from the same hemisphere within a single session. MTs obtained using the OM method were highly reliable and reproducible on different days (left M1: r=.98, p<.0001; right M1: r=.97, p<.0001). MTs were not influenced by the order of acquisition when two hemispheres were stimulated in the same session [F(1,22)=.12, p=.73] or by the collection of additional MTs as part of the distance-adjusted procedure [F(1,23)=.74, p=.40]. The results verify the reliability of the OM method and confirm its viability for the safe and efficient application of TMS to the left and right M1. The OM method is a reliable technique for obtaining MT and is relatively simple and quick to run. It therefore provides an effective procedure for research and clinical applications.

Impacts on work absence and performance: what really matters?

BACKGROUND: A number of factors influence an individual's decision to take sickness absence or to remain at work while ill. The relationship between health, work characteristics, individual perceptions of work and sickness absence and performance is complex and further clarification of the interactions between these factors is necessary. AIMS: To assess the relative impact of health, work characteristics and perceptions of work on absence and performance. METHODS: Cross-sectional survey of two public sector organizations (n = 505). Data were analysed using multivariate linear regression to assess the individual and combined influence of each class of independent variables on the following: days sickness absence, spells of sickness absence, VAS performance and presenteeism. RESULTS: Characteristics of work were weakly associated with days absence and performance. Perceptions of work were more strongly associated with performance than absence. Measures of mental health, rather than physical health, had the greatest influence on ability to work. Poor health had a greater impact on work performance than work absence. When considered together, health variables accounted for the largest proportion of explained variance in both absence and performance when compared with characteristics of work and work perceptions. CONCLUSIONS: Using absence as a marker of health-associated compromise at work may lead to an underestimation of the impact of health on work. This study demonstrates the need to manage the impact of health problems on the workforce not only from a bio-medical perspective but also in terms of the psychological pressures and the social context in which employees work.

Examination of the Work Organization Assessment Questionnaire in public sector workers.

OBJECTIVE: To investigate the utility of the Work and Organization Assessment Questionnaire (WOAQ) for public sector data. METHODS: A cross-sectional survey was performed in public sector organizations measuring demographics, work characteristics, work perceptions (WOAQ), sickness absence, and work performance. RESULTS: Confirmatory factor analysis of the WOAQ showed that factor structure derived for the manufacturing sector, for which the questionnaire was developed, could be replicated moderately well with public sector data. The study then considered whether a better more specific fit for public sector data was possible. Principal components analysis of the public sector data identified a two-factor structure linked to four of the five scales of the WOAQ assessing Management and Work Design, and Work Culture. These two factors may offer a context-sensitive scoring method for the WOAQ in public sector populations. These two factors were found to have good internal consistency, and correlated with the full WOAQ scales and the measures of performance and absence. CONCLUSIONS: The WOAQ is a useful and potentially transferable tool. The modified scoring may be used to assess work and organizational factors in the public sector.

Line bisection: does introspection inform cognitive strategy?

Line bisection is widely used to diagnose and quantify hemispatial neglect, yet there is little consensus as to the cognitive mechanisms used to perform this simple task. Current cognitive accounts have been deduced solely from behavioural measures. The aim of this study was to discover if subject's own knowledge of the mental strategies used to perform the task actually informs behavioural performance. One hundred and forty healthy volunteers bisected a set of lines and were asked to describe the mental strategies used. Three distinct strategies were identified. These were (1) comparing two segments, (2) computing the centre of mass, and (3) externally centred strategies. Strategies 1 and 2 have previously been described but externally centred strategies have not been reported as a distinct strategy in bisection. Although none of the three strategies predicted performance this may have been due to the fact that 44% of subjects failed to describe any strategy. Men and women bisected lines equally well, however more men than women reported use of externally centred strategies.

Working with Musculoskeletal Pain.

Pain has a significant impact on work in terms of presenteeism, sickness absence, and long-term incapacity for workA bio-psychosocial approach is required in understanding pain-related disability and incapacity for workLong-term absence from work is associated with a number of negative outcomes including; poverty, social exclusion and poorer physical and psychosocial well-beingReturn to work can improve recovery for people with musculoskeletal complaints and painInterventions to reduce the impact of pain on work can operate at clinical, worker, workplace, and wider systems levelsA broader whole systems approach to pain management needs to be adopted, with a greater focus on work retention as well as rehabilitation.

Comparative measures of represented linear extent: implications for clinical assessment.

Although line copying provides a simple and direct perceptual estimate of linear extent, line bisection is the most common clinical test traditionally used to quantify visuospatial neglect. This study aimed to establish whether the two tasks tap similar aspects of linear extent and determine which approximates actual stimulus length. One hundred and forty healthy controls were tested. Misrepresentations when copying were more than double those misrepresentations when bisecting, suggesting that the task demands involved in bisection may be less demanding than those involved in copying. Moreover, bisection performance provided the best approximation to the stimulus length used. It is suggested that the (midpoint) computational requirement of bisection facilitates a more accurate representation of linear extent by engaging implicit cues within the task. The fact that line bisection provides for a more accurate measure of represented linear extent attests to its value as a clinical test for patients with visuospatial neglect.

Influence of age and sex on line bisection: a study of normal performance with implications for visuospatial neglect.

Line bisection is an established clinical task used to diagnose visuospatial neglect. To date, few studies have considered the extent to which age and sex as background variables contribute to bisection performance. Both variables affect the neural substrates underlying cognitive processes and hence the behavioural performance of bisection. The purpose of this study was to examine the effects of age and sex on normal bisection performance, using three different line lengths to elucidate the influence of these potential contributing factors. Seventy men and 70 women, divided equally into seven age-cohorts between 14 and 80 years, bisected lines. Results indicated clear age- and sex-related differences both in the magnitude and direction of bisection deviations across the three line lengths. Differences are discussed in terms of neural changes across the adult lifespan including hemispheric differences and hormonally mediated changes.