Cognition in children with attentional difficulties with particular reference to working memory.

This research investigated cognitive function in children with observed and rated behavioural manifestations associated with inattention, hyperactivity and impulsivity. The aims were firstly to assess whether there were children in mainstream classrooms who displayed these behaviours, and secondly, to assess executive function and working memory in these children compared to a control group. It was anticipated that the findings could provide a basis for the development of a new model to explain cognitive function in children with attentional difficulties.A group of children with attentional difficulties who were part of the normal population but who did have cognitive difficulties in comparison to controls were identified. It was concluded that these children constituted part of a normal continuum of attentional skills and were not diagnosable. Using the working memory model (Baddeley and Hitch, 1974, Baddeley, 2000) the nature of the cognitive difficulties in children with attentional difficulties was established. Specifically it was revealed that children with attentional difficulties had difficulties on spatial working memory tasks but not on visual working memory tasks. Central executive function was initially proposed to explain differences between the groups, however when this explanation was explored the Supervisory Attentional System (Norman and Shallice, 1980) emerged as a better model to explain the data. Limitations of Barkley's (1997) inhibition model were also identified.It was hypothesised that children with attentional difficulties have difficulties associated with 'executive attentional control' mechanisms which impinge on their ability to complete central executive working memory tasks. Existing models were incorporated into a new model to more accurately explain these difficulties.It is intended that these findings will be followed up longitudinally to assess the development of executive attentional control in children with attentional difficulties and to incorporate these findings into a developmental model

Erratum to: The clinical and cost effectiveness of group art therapy for people with non-psychotic mental health disorders: a systematic review and cost-effectiveness analysis.

Background The majority of mental health problems are non-psychotic (e.g., depression, anxiety, and phobias). For some people, art therapy may be a more acceptable alternative form of psychological therapy than standard forms of treatment, such as talking therapies. This study was part of a health technology assessment commissioned by the National Institute for Health Research, UK and aimed to systematically appraise the clinical and cost-effective evidence for art therapy for people with non-psychotic mental health disorders. Methods Comprehensive literature searches for studies examining art therapy in populations with non-psychotic mental health disorders were performed in May 2013. A quantitative systematic review of clinical effectiveness and a systematic review of studies evaluating the cost-effectiveness of group art therapy were conducted. Results Eleven randomised controlled trials were included (533 patients). Meta-analysis was not possible due to clinical heterogeneity and insufficient comparable data on outcome measures across studies. The control groups varied between studies but included: no treatment/wait-list, attention placebo controls and psychological therapy comparators. Art therapy was associated with significant positive changes relative to the control group in mental health symptoms in 7 of the 11 studies. A de novo model was constructed and populated with data identified from the clinical review. Scenario analyses were conducted allowing comparisons of group art therapy with wait-list control and group art therapy with group verbal therapy. Group art-therapy appeared cost-effective compared with wait-list control with high certainty although generalisability to the target population was unclear; group verbal therapy appeared more cost-effective than art therapy but there was considerable uncertainty and a sizeable probability that art therapy was more cost effective. Conclusions From the limited available evidence art therapy was associated with positive effects compared with control in a number of studies in patients with different clinical profiles. The included trials were generally of poor quality and are therefore likely to be at high risk of bias. Art therapy appeared to be cost-effective versus wait-list but further studies are needed to confirm this finding in the target population. There was insufficient evidence to make an informed comparison of the cost-effectiveness of group art therapy with group verbal therapy. Trial registration HTA project no. 12/27/16; PROSPERO registration no. CRD42013003957

Evidence for the impact of interventions and medicines reconciliation on problematic polypharmacy in the UK: A rapid review of systematic reviews

This was a rapid review of systematic reviews (SRs) on problematic polypharmacy (PP) in the UK. The commissioner-defined topics were burden of PP, interventions to reduce PP, implementation activities to increase uptake of interventions, and efficient handover between primary and secondary care to reduce PP. Databases including Medline were searched to June 2019, SR quality was assessed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) and a narrative synthesis was undertaken. Except for burden of PP (SRs had to include UK studies), there were no restrictions on country, location of care or outcomes. Nine SRs were included. On burden, three SRs (including six UK studies) found a high prevalence of polypharmacy in long term care. PP was associated with mortality, although unclear if causal, with no information on costs or health consequences. On interventions, six reviews (27 UK studies) found that interventions can reduce PP, but no effects on health outcomes. On handover between primary and secondary care, one review (two UK studies) found medicine reconciliation activities to reduce medication discrepancies at care transitions reduce PP, although the evidence is low quality. No SRs on implementation activities to increase uptake of interventions were found. SR quality was variable, with some concerns regarding meta-analysis methods. Evidence of the extent of PP in the UK, and what interventions to address it are effective in the UK, is limited. Future UK research is needed on the prevalence and consequences of PP, the effectiveness and cost-effectiveness of interventions to reduce PP, and barriers and activities to ensure uptake

Gene expression profiling and expanded immunohistochemistry tests to guide selection of chemotherapy regimens in breast cancer management: a systematic review

OBJECTIVES: The aim of this report was to assess the clinical effectiveness of two Gene expression profiling (GEP) and two expanded immunohistochemistry (IHC) tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer. METHODS: A systematic review of the evidence on clinical effectiveness of OncotypeDX, IHC4, MammaPrint and Mammostrat, compared with current clinical practice using clinicopathological parameters, in women with early breast cancer was conducted. Ten databases were searched to include citations to May 2016. RESULTS: Searches identified 7064 citations, of which 41 citations satisfied the criteria for the review. A narrative synthesis was performed. Evidence for OncotypeDX demonstrated the impact of the test on decision-making and there was some support for OncotypeDX predicting chemotherapy benefit. There were relatively lower levels of evidence for the other three tests included in the analysis. MammaPrint, Mammostrat and IHC4 tests were limited to a small number of studies. Limitations in relation to study design were identified for all tests. CONCLUSIONS: The evidence base for OncotypeDX is considered to be the most robust. Methodological weaknesses relating to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence were identified. Further evidence is required for all of the tests using prospective randomised controlled trial data

The acceptability of primary care or community-based behavioural interventions for persistent physical symptoms: Qualitative systematic review.

PURPOSE: Persistent physical symptoms (PPS) are often associated with profound physical disability and psychological distress. Interventions for PPS that promote behavioural change aim to reduce levels of symptoms and improve overall functioning in patients. The evidence for these interventions is mixed, with effective relationships between patients and health practitioners (HPs) reported as the key to the success of primary care interventions. The objectives of this systematic review were to synthesize the qualitative evidence and to evaluate the acceptability of behavioural interventions for PPS in primary care, from the perspective of both patients and HPs. METHODS: A comprehensive literature search was conducted in seven major electronic bibliographic databases, to February 2019. The aim was to identify a broad range of literature including, qualitative research, mixed methods research, and qualitative data embedded in trial reports or process evaluations. Fifty-eight full papers were screened against the inclusion criteria. Nine studies were included and quality-assessed. A qualitative evidence synthesis was conducted using thematic synthesis. RESULTS: Some patients and HPs reported positive gains from taking part in or delivering interventions, with appropriate support and explanation of their symptoms important for patients. Barriers appeared to be underpinned by the relationship between the patients and HPs, and by beliefs and attitudes held by both parties. CONCLUSIONS: Patients should be provided with adequate information to make an informed decision about whether an intervention is appropriate for them, and interventions should not end suddenly or without adequate follow-up. HPs should receive training and supervision to address their lack of confidence, and improve their knowledge of PPS

Issues Related to the Frequency of Exploratory Analyses by Evidence Review Groups in the NICE Single Technology Appraisal Process

BACKGROUND: Evidence Review Groups (ERGs) critically appraise company submissions as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal (STA) process. As part of their critique of the evidence submitted by companies, the ERGs undertake exploratory analyses to explore uncertainties in the company's model. The aim of this study was to explore pre-defined factors that might influence or predict the extent of ERG exploratory analyses. OBJECTIVE: The aim of this study was to explore predefined factors that might influence or predict the extent of ERG exploratory analyses. METHODS: We undertook content analysis of over 400 documents, including ERG reports and related documentation for the 100 most recent STAs (2009-2014) for which guidance has been published. Relevant data were extracted from the documents and narrative synthesis was used to summarise the extracted data. All data were extracted and checked by two researchers. RESULTS: Forty different companies submitted documents as part of the NICE STA process. The most common disease area covered by the STAs was cancer (44%), and most ERG reports (n = 93) contained at least one exploratory analysis. The incidence and frequency of ERG exploratory analyses does not appear to be related to any developments in the appraisal process, the disease area covered by the STA, or the company's base-case incremental cost-effectiveness ratio (ICER). However, there does appear to be a pattern in the mean number of analyses conducted by particular ERGs, but the reasons for this are unclear and potentially complex. CONCLUSIONS: No clear patterns were identified regarding the presence or frequency of exploratory analyses, apart from the mean number conducted by individual ERGs. More research is needed to understand this relationship

Is group cognitive behaviour therapy for postnatal depression evidence-based practice? A systematic review

Background: There is evidence that psychological therapies including cognitive behaviour therapy (CBT) may be effective in reducing postnatal depression (PND) when offered to individuals. In clinical practice, this is also implemented in a group therapy format, which, although not recommended in guidelines, is seen as a cost-effective alternative. To consider the extent to which group methods can be seen as evidence-based, we systematically review and synthesise the evidence for the efficacy of group CBT compared to currently used packages of care for women with PND, and we discuss further factors which may contribute to clinician confidence in implementing an intervention. Methods: Seventeen electronic databases were searched. All full papers were read by two reviewers and a third reviewer was consulted in the event of a disagreement on inclusion. Selected studies were quality assessed, using the Cochrane Risk of Bias Tool, were data extracted by two reviewers using a standardised data extraction form and statistically synthesised where appropriate using the fixed-effect inverse-variance method. Results: Seven studies met the inclusion criteria. Meta-analyses showed group CBT to be effective in reducing depression compared to routine primary care, usual care or waiting list groups. A pooled effect size of d = 0.57 (95% CI 0.34 to 0.80, p < 0.001) was observed at 10–13 weeks post-randomisation, reducing to d = 0.28 (95% CI 0.03 to 0.53, p = 0.025) at 6 months. The non-randomised comparisons against waiting list controls at 10–13 weeks was associated with a larger effect size of d = 0.94 (95% CI 0.42 to 1.47, p < 0.001). However due to the limitations of the available data, such as ill-specified definitions of the CBT component of the group programmes, these results should be interpreted with caution. Conclusions: Although the evidence available is limited, group CBT was shown to be effective. We argue, therefore, that there is sufficient evidence to implement group CBT, conditional upon routinely collected outcomes being benchmarked against those obtained in trials of individual CBT, and with other important factors such as patient preference, clinical experience, and information from the local context taken into account when making the treatment decision

Behavioural modification interventions for medically unexplained symptoms in primary care: Systematic reviews and economic evaluation

Background: The term 'medically unexplained symptoms' is used to cover a wide range of persistent bodily complaints for which adequate examination and appropriate investigations do not reveal sufficiently explanatory structural or other specified pathologies. A wide range of interventions may be delivered to patients presenting with medically unexplained symptoms in primary care. Many of these therapies aim to change the behaviours of the individual who may have worsening symptoms. Objectives: An evidence synthesis to determine the clinical effectiveness and cost-effectiveness of behavioural modification interventions for medically unexplained symptoms delivered in primary care settings was undertaken. Barriers to and facilitators of the effectiveness and acceptability of these interventions from the perspective of patients and service providers were evaluated through qualitative review and realist synthesis. Data sources: Full search strategies were developed to identify relevant literature. Eleven electronic sources were searched. Eligibility criteria - for the review of clinical effectiveness, randomised controlled trials were sought. For the qualitative review, UK studies of any design were included. For the cost-effectiveness review, papers were restricted to UK studies reporting outcomes as quality-adjusted life-year gains. Clinical searches were conducted in November 2015 and December 2015, qualitative searches were conducted in July 2016 and economic searches were conducted in August 2016. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE. Updated searches were conducted in February 2019 and March 2019. Participants: Adult participants meeting the criteria for medically unexplained symptoms, including somatoform disorders, chronic unexplained pain and functional somatic syndromes. Interventions: Behavioural interventions were categorised into types. These included psychotherapies, exercise-based interventions, multimodal therapies (consisting of more than one intervention type), relaxation/stretching/social support/emotional support, guided self-help and general practitioner interventions, such as reattribution. Evidence synthesis: a network meta-analysis was conducted to allow a simultaneous comparison of all evaluated interventions in a single coherent analysis. Separate network meta-analyses were performed at three time points: end of treatment, short-term follow-up (< 6 months since the end of treatment) and long-term follow-up (= 6 months after the end of treatment). Outcomes included physical and psychological symptoms, physical functioning and impact of the illness on daily activities. Economic evaluation: within-trial estimates of cost-effectiveness were generated for the subset of studies where utility values (or quality-adjusted life-years) were reported or where these could be estimated by mapping from Short Form questionnaire-36 items or Short Form questionnaire-12 items outcomes. Results: Fifty-nine studies involving 9077 patients were included in the clinical effectiveness review. There was a large degree of heterogeneity both between and within intervention types, and the networks were sparse across all outcomes. At the end of treatment, behavioural interventions showed some beneficial effects when compared with usual care, in particular for improvement of specific physical symptoms [(1) pain: high-intensity cognitive-behavioural therapy (CBTHI) standardised mean difference (SMD) 0.54 [95% credible interval (CrI) 0.28 to 0.84], multimodal SMD 0.52 (95% CrI 0.19 to 0.89); and (2) fatigue: low-intensity cognitive-behavioural therapy (CBTLI) SMD 0.72 (95% CrI 0.27 to 1.21), relaxation/stretching/social support/emotional support SMD 0.87 (95% CrI 0.20 to 1.55), graded activity SMD 0.51 (95% CrI 0.14 to 0.93), multimodal SMD 0.52 (95% CrI 0.14 to 0.92)] and psychological outcomes [(1) anxiety CBTHI SMD 0.52 (95% CrI 0.06 to 0.96); (2) depression CBTHI SMD 0.80 (95% CrI 0.26 to 1.38); and (3) emotional distress other psychotherapy SMD 0.58 (95% CrI 0.05 to 1.13), relaxation/ stretching/social support/emotional support SMD 0.66 (95% CrI 0.18 to 1.28) and sport/exercise SMD 0.49 (95% CrI 0.03 to 1.01)]. At short-term follow-up, behavioural interventions showed some beneficial effects for specific physical symptoms [(1) pain: CBTHI SMD 0.73 (95% CrI 0.10 to 1.39); (2) fatigue: CBTLI SMD 0.62 (95% CrI 0.11 to 1.14), relaxation/stretching/social support/emotional support SMD 0.51 (95% CrI 0.06 to 1.00)] and psychological outcomes [(1) anxiety: CBTHI SMD 0.74 (95% CrI 0.14 to 1.34); (2) depression: CBTHI SMD 0.93 (95% CrI 0.37 to 1.52); and (3) emotional distress: relaxation/ stretching/social support/emotional support SMD 0.82 (95% CrI 0.02 to 1.65), multimodal SMD 0.43 (95% CrI 0.04 to 0.91)]. For physical functioning, only multimodal therapy showed beneficial effects: end-of-treatment SMD 0.33 (95% CrI 0.09 to 0.59); and short-term follow-up SMD 0.78 (95% CrI 0.23 to 1.40). For impact on daily activities, CBTHI was the only behavioural intervention to show beneficial effects [end-of-treatment SMD 1.30 (95% CrI 0.59 to 2.00); and short-term follow-up SMD 2.25 (95% CrI 1.34 to 3.16)]. Few effects remained at long-term follow-up. General practitioner interventions showed no significant beneficial effects for any outcome. No intervention group showed conclusive beneficial effects for measures of symptom load (somatisation). A large degree of heterogeneity was found across individual studies in the assessment of cost-effectiveness. Several studies suggested that the interventions produce fewer quality-adjusted life-years than usual care. For those interventions that generated quality-adjusted life-year gains, the mid-point incremental cost-effectiveness ratios (ICERs) ranged from £1397 to £129,267, but, where the mid-point ICER fell below £30,000, the exploratory assessment of uncertainty suggested that it may be above £30,000. Limitations: Sparse networks meant that it was not possible to conduct a metaregression to explain between-study differences in effects. Results were not consistent within intervention type, and there were considerable differences in characteristics between studies of the same type. There were moderate to high levels of statistical heterogeneity. Separate analyses were conducted for three time points and, therefore, analyses are not repeated-measures analyses and do not account for correlations between time points. Conclusions: Behavioural interventions showed some beneficial effects for specific medically unexplained symptoms, but no one behavioural intervention was effective across all medically unexplained symptoms. There was little evidence that these interventions are effective for measures of symptom load (somatisation). General practitioner-led interventions were not shown to be effective. Considerable heterogeneity in interventions, populations and sparse networks mean that results should be interpreted with caution. The relationship between patient and service provider is perceived to play a key role in facilitating a successful intervention. Future research should focus on testing the therapeutic effects of the general practitioner-patient relationship within trials of behavioural interventions, and explaining the observed between-study differences in effects within the same intervention type (e.g. with more detailed reporting of defined mechanisms of the interventions under study). © Queen's Printer and Controller of HMSO 2020

Vedolizumab for Treating Moderately to Severely Active Crohn’s Disease After Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe, active Crohn’s disease. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned as the Evidence Review Group (ERG) and produced a critical review of the evidence of the clinical effectiveness and cost effectiveness of the technology, based upon the company’s submission to NICE. The GEMINI II and III trials formed the main supporting evidence for the intervention. Both studies were phase III, randomised, double-blind, placebo-controlled, multicentre trials designed to evaluate the efficacy and safety of vedolizumab. They included patients who were naïve to tumour necrosis factor alpha antagonist (anti-TNF-α) therapy and patients who had an inadequate response to, loss of response to or intolerance of immunomodulators or anti-TNF-α agents. GEMINI II was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment (dosing at weeks 0 and 2, with assessment at week 6) and maintenance treatment (during weeks 6–52). In contrast, GEMINI III was designed to evaluate the efficacy and safety of vedolizumab as an induction treatment only, with doses at weeks 0, 2 and 6, and assessment at weeks 6 and 10. In the absence of any direct head-to-head, randomised, controlled trials comparing vedolizumab with other relevant biologic therapies (adalimumab and infliximab) for the treatment of moderate-to-severe Crohn’s disease, the company conducted a network meta-analysis, which compared vedolizumab, adalimumab, infliximab and placebo for the outcomes of clinical response, enhanced clinical response, clinical remission and discontinuation due to adverse events. The company model estimated the incremental cost-effectiveness ratio (ICER) for vedolizumab compared with the standard of care (consisting of 5-aminosalicylic acids, corticosteroids and immunosuppressants) to be £21,620 per quality-adjusted life-year (QALY) gained within the anti-TNF-α-failure population (which included a confidential patient access scheme for vedolizumab). The ICERs were above £30,000 per QALY gained for the mixed intention-to-treat population (including both anti-TNF-α-naïve and anti-TNF-α-failure populations) and in patients who were anti-TNF-α naïve only. The ERG identified a number of limitations that were believed to limit the robustness of the results presented by the company. These limitations could not be addressed by the ERG without major restructuring of the economic model. Therefore, the ERG concluded that the results from the company’s model needed to be interpreted with caution and that it was unclear whether the ICERs would increase or decrease following amendment of the identified structural issues

Cefiderocol for treating severe aerobic Gram-negative bacterial infections: technology evaluation to inform a novel subscription-style payment model.

BackgroundTo limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England.MethodsThe health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol.ResultsAmong Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years.ConclusionThis work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS.LimitationsGiven existing evidence, the estimates of the value of cefiderocol are highly uncertain.Future workFuture evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value.Study registrationNo registration of this study was undertaken.FundingThis award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information