Diagnostic accuracy and clinical impact of MRI-based technologies for patients with non-alcoholic fatty liver disease: systematic review and economic evaluation.

Background: Magnetic resonance imaging-based technologies are non-invasive diagnostic tests that can be used to assess non-alcoholic fatty liver disease. Objectives: The study objectives were to assess the diagnostic test accuracy, clinical impact and cost-effectiveness of two magnetic resonance imaging-based technologies (LiverMultiScan and magnetic resonance elastography) for patients with non-alcoholic fatty liver disease for whom advanced fibrosis or cirrhosis had not been diagnosed and who had indeterminate results from fibrosis testing, or for whom transient elastography or acoustic radiation force impulse was unsuitable, or who had discordant results from fibrosis testing. Data sources: The data sources searched were MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment. Methods: A systematic review was conducted using established methods. Diagnostic test accuracy estimates were calculated using bivariate models and a summary receiver operating characteristic curve was calculated using a hierarchical model. A simple decision-tree model was developed to generate cost-effectiveness results. Results: The diagnostic test accuracy review (13 studies) and the clinical impact review (11 studies) only included one study that provided evidence for patients who had indeterminate or discordant results from fibrosis testing. No studies of patients for whom transient elastography or acoustic radiation force impulse were unsuitable were identified. Depending on fibrosis level, relevant published LiverMultiScan diagnostic test accuracy results ranged from 50% to 88% (sensitivity) and from 42% to 75% (specificity). No magnetic resonance elastography diagnostic test accuracy data were available for the specific population of interest. Results from the clinical impact review suggested that acceptability of LiverMultiScan was generally positive. To explore how the decision to proceed to biopsy is influenced by magnetic resonance imaging-based technologies, the External Assessment Group presented cost-effectiveness analyses for LiverMultiScan plus biopsy versus biopsy only. Base-case incremental cost-effectiveness ratio per quality-adjusted life year gained results for seven of the eight diagnostic test strategies considered showed that LiverMultiScan plus biopsy was dominated by biopsy only; for the remaining strategy (Brunt grade ≥2), the incremental cost-effectiveness ratio per quality-adjusted life year gained was £1,266,511. Results from threshold and scenario analyses demonstrated that External Assessment Group base-case results were robust to plausible variations in the magnitude of key parameters. Limitations: Diagnostic test accuracy, clinical impact and cost-effectiveness data for magnetic resonance imaging-based technologies for the population that is the focus of this assessment were limited. Conclusions: Magnetic resonance imaging-based technologies may be useful to identify patients who may benefit from additional testing in the form of liver biopsy and those for whom this additional testing may not be necessary. However, there is a paucity of diagnostic test accuracy and clinical impact data for patients who have indeterminate results from fibrosis testing, for whom transient elastography or acoustic radiation force impulse are unsuitable or who had discordant results from fibrosis testing. Given the External Assessment Group cost-effectiveness analyses assumptions, the use of LiverMultiScan and magnetic resonance elastography for assessing non-alcoholic fatty liver disease for patients with inconclusive results from previous fibrosis testing is unlikely to be a cost-effective use of National Health Service resources compared with liver biopsy only. Study registration: This study is registered as PROSPERO CRD42021286891. Funding: Funding for this study was provided by the Evidence Synthesis Programme of the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 10. See the NIHR Journals Library website for further project information.

Non-alcoholic fatty liver disease includes a range of conditions that are caused by a build-up of fat in the liver, and not by alcohol consumption. This build-up of fat can cause inflammation. Persistent inflammation can cause scar tissue (fibrosis) to develop. It is important to identify patients with fibrosis because severe fibrosis can cause permanent liver damage (cirrhosis), which can lead to liver failure and liver cancer. In the National Health Service, patients with non-alcoholic fatty liver disease undergo tests to determine whether they have fibrosis. The test results are not always accurate and multiple tests can give conflicting results. Some of the tests may not be suitable for patients who have a very high body mass index. In the National Health Service, a liver biopsy may be offered to patients with inconclusive or conflicting test results or to those patients for whom other tests are unsuitable. However, liver biopsy is expensive, and is associated with side-effects such as pain and bleeding. Magnetic resonance imaging-based testing could be used as an extra test to help clinicians assess non-alcoholic fatty liver disease and identify patients who may need a liver biopsy. We assessed two magnetic resonance imaging-based diagnostic tests, LiverMultiScan and magnetic resonance elastography. LiverMultiScan is imaging software that is used alongside magnetic resonance imaging to measure markers of liver disease. Magnetic resonance elastography is used in some National Health Service centres to assess liver fibrosis; however, magnetic resonance elastography requires more equipment than just an magnetic resonance imaging scanner. We reviewed all studies examining how well LiverMultiScan and magnetic resonance elastography assess patients with non-alcoholic fatty liver disease. We also built an economic model to estimate the costs and benefits of using LiverMultiScan to identify patients who should be sent for a biopsy. Results from the model showed that LiverMultiScan may not provide good value for money to the National Health Service.

Derivation and independent validation of kidneyintelX.dkd: A prognostic test for the assessment of diabetic kidney disease progression.

AIMS: To develop and validate an updated version of KidneyIntelX (kidneyintelX.dkd) to stratify patients for risk of progression of diabetic kidney disease (DKD) stages 1 to 3, to simplify the test for clinical adoption and support an application to the US Food and Drug Administration regulatory pathway. METHODS: We used plasma biomarkers and clinical data from the Penn Medicine Biobank (PMBB) for training, and independent cohorts (BioMe and CANVAS) for validation. The primary outcome was progressive decline in kidney function (PDKF), defined by a ≥40% sustained decline in estimated glomerular filtration rate or end-stage kidney disease within 5 years of follow-up. RESULTS: In 573 PMBB participants with DKD, 15.4% experienced PDKF over a median of 3.7 years. We trained a random forest model using biomarkers and clinical variables. Among 657 BioMe participants and 1197 CANVAS participants, 11.7% and 7.5%, respectively, experienced PDKF. Based on training cut-offs, 57%, 35% and 8% of BioMe participants, and 56%, 38% and 6% of CANVAS participants were classified as having low-, moderate- and high-risk levels, respectively. The cumulative incidence at these risk levels was 5.9%, 21.2% and 66.9% in BioMe and 6.7%, 13.1% and 59.6% in CANVAS. After clinical risk factor adjustment, the adjusted hazard ratios were 7.7 (95% confidence interval [CI] 3.0-19.6) and 3.7 (95% CI 2.0-6.8) in BioMe, and 5.4 (95% CI 2.5-11.9) and 2.3 (95% CI 1.4-3.9) in CANVAS, for high- versus low-risk and moderate- versus low-risk levels, respectively. CONCLUSIONS: Using two independent cohorts and a clinical trial population, we validated an updated KidneyIntelX test (named kidneyintelX.dkd), which significantly enhanced risk stratification in patients with DKD for PDKF, independently from known risk factors for progression.

Cognitive-behavioural therapy for a variety of conditions: an overview of systematic reviews and panoramic meta-analysis.

BACKGROUND: Cognitive-behavioural therapy aims to increase quality of life by changing cognitive and behavioural factors that maintain problematic symptoms. A previous overview of cognitive-behavioural therapy systematic reviews suggested that cognitive-behavioural therapy was effective for many conditions. However, few of the included reviews synthesised randomised controlled trials. OBJECTIVES: This project was undertaken to map the quality and gaps in the cognitive-behavioural therapy systematic review of randomised controlled trial evidence base. Panoramic meta-analyses were also conducted to identify any across-condition general effects of cognitive-behavioural therapy. DATA SOURCES: The overview was designed with cognitive-behavioural therapy patients, clinicians and researchers. The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Child Development & Adolescent Studies, Database of Abstracts of Reviews of Effects and OpenGrey databases were searched from 1992 to January 2019. REVIEW METHODS: Study inclusion criteria were as follows: (1) fulfil the Centre for Reviews and Dissemination criteria; (2) intervention reported as cognitive-behavioural therapy or including one cognitive and one behavioural element; (3) include a synthesis of cognitive-behavioural therapy trials; (4) include either health-related quality of life, depression, anxiety or pain outcome; and (5) available in English. Review quality was assessed with A MeaSurement Tool to Assess systematic Reviews (AMSTAR)-2. Reviews were quality assessed and data were extracted in duplicate by two independent researchers, and then mapped according to condition, population, context and quality. The effects from high-quality reviews were pooled within condition groups, using a random-effect panoramic meta-analysis. If the across-condition heterogeneity was I2 < 75%, we pooled across conditions. Subgroup analyses were conducted for age, delivery format, comparator type and length of follow-up, and a sensitivity analysis was performed for quality. RESULTS: A total of 494 reviews were mapped, representing 68% (27/40) of the categories of the International Classification of Diseases, Eleventh Revision, Mortality and Morbidity Statistics. Most reviews (71%, 351/494) were of lower quality. Research on older adults, using cognitive-behavioural therapy preventatively, ethnic minorities and people living outside Europe, North America or Australasia was limited. Out of 494 reviews, 71 were included in the primary panoramic meta-analyses. A modest effect was found in favour of cognitive-behavioural therapy for health-related quality of life (standardised mean difference 0.23, 95% confidence interval 0.05 to 0.41, prediction interval -0.05 to 0.50, I2 = 32%), anxiety (standardised mean difference 0.30, 95% confidence interval 0.18 to 0.43, prediction interval -0.28 to 0.88, I2 = 62%) and pain (standardised mean difference 0.23, 95% confidence interval 0.05 to 0.41, prediction interval -0.28 to 0.74, I2 = 64%) outcomes. All condition, subgroup and sensitivity effect estimates remained consistent with the general effect. A statistically significant interaction effect was evident between the active and non-active comparator groups for the health-related quality-of-life outcome. A general effect for depression outcomes was not produced as a result of considerable heterogeneity across reviews and conditions. LIMITATIONS: Data extraction and analysis were conducted at the review level, rather than returning to the individual trial data. This meant that the risk of bias of the individual trials could not be accounted for, but only the quality of the systematic reviews that synthesised them. CONCLUSION: Owing to the consistency and homogeneity of the highest-quality evidence, it is proposed that cognitive-behavioural therapy can produce a modest general, across-condition benefit in health-related quality-of-life, anxiety and pain outcomes. FUTURE WORK: Future research should focus on how the modest effect sizes seen with cognitive-behavioural therapy can be increased, for example identifying alternative delivery formats to increase adherence and reduce dropout, and pursuing novel methods to assess intervention fidelity and quality. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017078690. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 9. See the NIHR Journals Library website for further project information.

This report is a summary of research examining if a psychological therapy called cognitive­behavioural therapy can improve the quality of life of people living with physical and/or mental conditions. Cognitive­behavioural therapy uses a set of techniques that help individuals to identify and change problematic thoughts or behaviour patterns that might contribute to and maintain their physical or mental symptoms. It can be delivered face to face or through mediums such as the internet. We aimed to understand if cognitive­behavioural therapy helps patients with specific conditions only, or if it can help patients with any condition. We searched relevant databases to find articles that combine the results from multiple trials testing cognitive­behavioural therapy. These are known as systematic reviews. We graded these reviews as providing good- or poor-quality evidence. We identified the conditions for which we had good-quality evidence on whether or not cognitive­behavioural therapy was helpful. From each review, we took numerical data that told us if cognitive­behavioural therapy improved quality of life for that specific condition. Next, we combined all the numerical data together, across all the conditions, to see if there was a consistent benefit of cognitive­behavioural therapy. The statistical analyses found that cognitive­behavioural therapy consistently improved quality of life across all the conditions where it has been tested. We have evidence that it can help children, adolescents and adults, of either sex, who are living in Europe, North America and Australasia. We are unsure if it will help older adults or people living in Africa, Asia or South America, nor do we know if cognitive­behavioural therapy is equally effective across different ethnic groups. It is recommended that future research should prioritise understanding how cognitive­behavioural therapy works, why some people do not want to use cognitive­behavioural therapy and why some patients do not benefit from it.

Treatment of first-time traumatic anterior shoulder dislocation: the UK TASH-D cohort study.

BACKGROUND: Shoulder dislocations are the most common joint dislocations seen in emergency departments. Most traumatic cases are anterior and cause recurrent dislocations. Management options include surgical and conservative treatments. There is a lack of evidence about which method is most effective after the first traumatic anterior shoulder dislocation (TASD). OBJECTIVES: To produce UK age- and sex-specific incidence rates for TASD. To assess whether or not surgery within 6 months of a first-time TASD decreases re-dislocation rates compared with no surgery. To identify clinical predictors of recurrent dislocation. DESIGN: A population-based cohort study of first-time TASD patients in the UK. An initial validation study and subsequent propensity-score-matched analysis to compare re-dislocation rates between surgery and no surgery after a first-time TASD. Prediction modelling was used to identify potential predictors of recurrent dislocation. SETTING: UK primary and secondary care data. PARTICIPANTS: Patients with a first-time TASD between 1997 and 2015. INTERVENTIONS: Stabilisation surgery within 6 months of a first-time TASD (compared with no surgery). Stabilisation surgery within 12 months of a first-time TASD was also carried out as a sensitivity analysis. MAIN OUTCOME MEASURE: Re-dislocation rate up to 2 years after the first TASD. METHODS: Eligible patients were identified from the Clinical Practice Research Datalink (CPRD) (1997-2015). Accuracy of shoulder dislocation coding was internally validated using the CPRD General Practitioner questionnaire service. UK age- and sex-specific incidence rates for TASD were externally validated against rates from the USA and Canada. A propensity-score-matched analysis using linked CPRD and Hospital Episode Statistics (HES) data compared re-dislocation rates for patients aged 16-35 years, comparing surgery with no surgery. Multivariable Cox regression models for predicting re-dislocation were developed for the surgical and non-surgical cohorts. RESULTS: Shoulder dislocation was coded correctly for 89% of cases in the CPRD [95% confidence interval (CI) 83% to 95%], with a 'primary' dislocation confirmed for 76% of cases (95% CI 67% to 85%). Far fewer patients than expected received stabilisation surgery within 6 months of a first TASD, leading to an underpowered study. Around 20% of re-dislocation rates were observed for both surgical and non-surgical patients. The sensitivity analysis at 12 months also showed little difference in re-dislocation rates. Missing data on risk factors limited the value of the prediction modelling; however, younger age, epilepsy and sex (male) were identified as statistically significant predictors of re-dislocation. LIMITATIONS: Far fewer than the expected number of patients had surgery after a first-time TASD, resulting in an underpowered study. This and residual confounding from missing risk factors mean that it is not possible to draw valid conclusions. CONCLUSIONS: This study provides, for the first time, UK data on the age- and sex-specific incidence rates for TASD. Most TASD occurs in men, but an unexpected increased incidence was observed in women aged > 50 years. Surgery after a first-time TASD is uncommon in the NHS. Re-dislocation rates for patients receiving surgery after their first TASD are higher than previously expected; however, important residual confounding risk factors were not recorded in NHS primary and secondary care databases, thus preventing useful recommendations. FUTURE WORK: The high incidence of TASD justifies investigation into preventative measures for young men participating in contact sports, as well as investigating the risk factors in women aged > 50 years. A randomised controlled trial would account for key confounders missing from CPRD and HES data. A national TASD registry would allow for a more relevant data capture for this patient group. STUDY REGISTRATION: Independent Scientific Advisory Committee (ISAC) for the Medicines and Healthcare Products Regulatory Agency (ISAC protocol 15_0260). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Traumatic anterior shoulder dislocation (TASD) happens when the top of the arm bone is forced frontwards out of the shoulder socket. After a TASD, the shoulder joint can become 'unstable' and keep dislocating. The main treatments are surgery or physiotherapy; however, we do not know which treatment is best at stopping more dislocations. Two large NHS computer databases were studied to assess this problem. This has allowed us to produce information on the extent of this problem in the UK. We also looked for any differences in the number of people who suffered more shoulder dislocations when treated with either surgery or no surgery. The results showed that young men aged 16­20 years and women aged > 50 years suffer the most with this problem. In young people, the cause is thought to be due to sports injuries. These findings in women aged > 50 years are new and suggest that further research is needed to discover what puts them at a greater risk of TASD. When patients who had surgery and those who did not were compared, there appeared to be no difference in the number of people suffering a re-dislocation. Although, overall, this might suggest that surgery after only one dislocation does not have any extra benefit in preventing more dislocations, this research discovered that important information used to help decide on whether or not surgical treatment is needed is not reported in the databases. Some patients may be at a greater risk of more dislocations than other patients based on risk factors, such as sport and occupation, and this information is not recorded in the NHS databases. Therefore, the research question cannot be answered by studying these NHS databases and so other methods, such as a research trial or a custom database built especially for shoulder dislocation patients, would be needed.

UK podiatrists' experiences of podiatry services for people living with arthritis: a qualitative investigation.

BACKGROUND: Provision of podiatry services, like other therapies in the UK, is an area that lacks guidance by the National Institute for Health and Care Excellence. Many individuals living with arthritis in the UK are not eligible to access NHS podiatry services. The primary aim of this investigation was to understand the views of podiatry clinicians on their experiences of referral, access, provision and treatment for foot problems for patients who have arthritis. METHODS: Focus groups were undertaken to explore, in-depth, individual views of podiatrists working in the UK to gain feedback on experiences of barriers and facilitators to referral, access, provision and treatment for foot problems for individuals living with arthritis. A purposive sampling strategy was adopted and two, semi-structured, focus group interviews conducted, involving 12 podiatrists from both NHS and independent sectors. To account for geographical variations one focus group took place in each of 2 predetermined 'zones' of the UK; Yorkshire and Hampshire. Thematic analysis was employed to identify key meanings and report patterns within the data. RESULTS: The key themes derived from the podiatry clinician focus groups suggest a variety of factors influencing demand for, and burden of, foot pain within the UK. Participants expressed frustration on having a service that accepts and treats patients according to their condition, rather than their complaint. Additionally, concern was conveyed over variations in the understanding of stakeholders' views of what podiatry is and what podiatrists aim to achieve for patients. CONCLUSION: Podiatrists interviewed believed that many individuals living with arthritis in the UK are not eligible to access NHS podiatry services and that this may be, in part, due to confusion over what is known about podiatry and access criteria. Essentially, podiatrists interviewed called for a timely renaissance of current systems, to newer models of care that meet the foot care needs of individual patients' circumstances and incorporate national multi-disciplinary guidance. Through this project, we have formulated key recommendations that are directed towards improving what other stakeholders (including GPs, commissioners and users of podiatry services) know about the effectiveness of podiatry and also to futureproof the profession of podiatry.

The cost-effectiveness of exercise-based cardiac rehabilitation: a systematic review of the characteristics and methodological quality of published literature.

AIM: This descriptive review aimed to assess the characteristics and methodological quality of economic evaluations of cardiac rehabilitation (CR) programs according to updated economic guidelines for healthcare interventions. Recommendations will be made to inform future research addressing the impact of a physical exercise component on cost-effectiveness. METHODS: Electronic databases were searched for economic evaluations of exercise-based CR programs published in English between 2000 and 2014. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to review the methodological quality of included economic evaluations. RESULTS: Fifteen economic evaluations met the review inclusion criteria. Assessed study characteristics exhibited wide variability, particularly in their economic perspective, time horizon, setting, comparators and included costs, with significant heterogeneity in exercise dose across interventions. Ten evaluations were based on randomised controlled trials (RCTs) spanning 6-24 months but often with weak or inconclusive results; two were modelling studies; and the final three utilised longer time horizons of 3.5-5 years from which findings suggest that long-term exercise-based CR results in lower costs, reduced hospitalisations and a longer cumulative patient lifetime. None of the 15 articles met all the CHEERS quality criteria, with the majority either fully or partially meeting a selection of the assessed variables. CONCLUSION: Evidence exists supporting the cost-effectiveness of exercise-based CR for cardiovascular disease patients. However, variability in CR program delivery and weak consistency between study perspective and design limits study comparability and therefore the accumulation of evidence in support of a particular exercise regime. The generalisability of study findings was limited due to the exclusion of patients with comorbidities as would typically be found in a real-world setting. The use of longer time-horizons would be more comparable with a chronic condition and enable economic assessments of the long-term effects of CR. As none of the articles met recent reporting standards for the economic assessment of healthcare interventions, it is recommended that future studies adhere to such guidelines.

Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS).

UNLABELLED: Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine. OBJECTIVE: We sought to determine if the causal relationships between the vaccine and the AEFI reported to VAERS could be assessed through expert review. DESIGN: A stratified random sample of 100 VAERS reports received in 2004 contained 13 fatal cases, 19 cases with non-fatal disabilities, 39 other serious non-fatal cases and 29 non-serious cases. Experts knowledgeable about vaccines and clinical outcomes, reviewed each VAERS report and available medical records. MAIN OUTCOME MEASURES: Modified World Health Organization criteria were used to classify the causal relationship between vaccines and AEFI as definite, probable, possible, unlikely or unrelated. Five independent reviewers evaluated each report. If they did not reach a majority agreement on causality after initial review, the report was discussed on a telephone conference to achieve agreement. RESULTS: 108 AEFIs were identified in the selected 100 VAERS reports. After initial review majority agreement was achieved for 83% of the AEFI and 17% required further discussion. In the end, only 3 (3%) of the AEFI were classified as definitely causally related to vaccine received. Of the remaining AEFI 22 (20%) were classified as probably and 22 (20%) were classified as possibly related to vaccine received; a majority (53%) were classified as either unlikely or unrelated to a vaccine received. CONCLUSIONS: Using VAERS reports and additional documentation, causality could be assessed by expert review in the majority of VAERS reports. Assessment of VAERS reports identified that causality was thought to be probable or definite in less than one quarter of reports, and these were dominated by local reactions, allergic reactions, or symptoms known to be associated with the vaccine administered.

Estrogen receptor-alpha distribution in male rodents is associated with social organization.

It has been hypothesized that site-specific reduction of estrogen receptor-alpha (ERalpha) is associated with the expression of male prosocial behaviors. Specifically, highly social males are predicted to express significantly lower levels of ERalpha than females and less social males in brain regions associated with prosocial behavior including the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). This hypothesis was tested by comparing ERalpha immunoreactivity (IR) in three species of microtines, the polygynous montane (Microtus montanus) and meadow (M. pennsylvanicus) voles and the monogamous pine vole (M. pinetorum), and two species of cricetines that differ in the extent of social pair-bond formation, Siberian (Phodopus sungorus) and Djungarian (P. campbelli) hamsters. As predicted, ERalpha-IR was sexually dimorphic in the BST and MeA of the highly social species, with females expressing more ERalpha-IR cells than males. Male and female montane voles did not differ. Male and female meadow voles differed in the ventromedial hypothalamus, with females expressing more ERalpha-IR cells. Male pine voles expressed lower levels of ERalpha-IR in the MeA than male montane and meadow voles and in the BST relative to montane males. Male Djungarian hamsters, which show higher levels of parental care, had fewer ERalpha-IR cells in the BST than male Siberian hamsters. Results indicate that the distribution of ERalpha differs relative to the continuum of species-typical affiliative behavior and supports the hypothesis that ERalpha has a significant role in regulating species-specific social organization.