Comparison of national surveillance systems for Lyme disease in humans in Europe and North America: a policy review.

BACKGROUND: Lyme disease incidence is increasing in Europe, the USA, and Canada. In 2010, a comparison of surveillance systems for Lyme disease (LD) in humans in 28 European countries showed that systems highly varied, making epidemiological comparisons difficult. Details by country were not published. In 2018, one of LD clinical manifestations, neuroborreliosis, was added under European Union (EU) surveillance to standardise definitions. In this study, we identified and compared, 10 years after the European inventory, the characteristics of national surveillance systems and policies for LD in humans, with additional countries. METHODS: Thirty-four European and North American countries were included. Information on national "traditional" systems (which compile data reported by clinicians and laboratories) and "public participatory" websites and mobile applications (which collect information directly from the public) were searched in MEDLINE, a systematic evidence map, and Google. An existing framework on LD surveillance was adapted to capture information on the administration level, indicators, reporting entities, coverage, and obligation to report. RESULTS: A surveillance system was found for 29 (85%) countries. Twenty-four had a traditional system alone, one had a public participatory system alone, and the remaining had both. Among countries with traditional systems, 23 (82%) administered them at the national level. Nineteen (68%) required mandatory reporting. Sixteen (57%) used both clinicians and laboratories as reporting entities. Eighteen (64%) employed case definitions, most of which considered both neuroborreliosis and erythema migrans (n = 14). Others monitored the number of positive laboratory tests and/or patient consultations. Public participatory systems were only implemented in countries employing either also sentinels or voluntary surveys, or no traditional system, suggesting their use as a complementary tool. Only 56% of EU countries had neuroborreliosis as an indicator. CONCLUSION: The situation remains similar to 2010 with persisting heterogeneity between systems, suggesting that countries prioritise different surveillance objectives for LD. Without a common indicator in Europe, it is difficult to get a clear epidemiological picture. We discuss four factors that potentially influence LD surveillance strategies: perceptions of severity, burden on resources, two-way communication, and the medical conflicts about LD. Addressing these with countries might help moving towards the adoption of common practices.

The efficacy of systemic glucocorticosteroids for pain in rheumatoid arthritis: a systematic literature review and meta-analysis.

OBJECTIVES: Glucocorticosteroids (GCs) are recommended to suppress inflammation in people with active RA. This systematic review and meta-analysis aimed to quantify the effects of systemic GCs on RA pain. METHODS: A systematic literature review of randomized controlled trials (RCTs) in RA comparing systemic GCs to inactive treatment. Three databases were and spontaneous pain and evoked pain outcomes were extracted. Standardized mean differences (SMDs) and mean differences were meta-analysed. Heterogeneity (I2, tau statistics) and bias (funnel plot, Egger's test) were assessed. Subgroup analyses investigated sources of variation. This study was pre-registered (PROSPERO CRD42019111562). RESULTS: A total of 18 903 titles, 880 abstracts and 226 full texts were assessed. Thirty-three RCTs suitable for the meta-analysis included 3123 participants. Pain scores (spontaneous pain) decreased in participants treated with oral GCs; SMD = -0.65 (15 studies, 95% CI -0.82, -0.49, P <0.001) with significant heterogeneity (I2 = 56%, P =0.0002). Efficacy displayed time-related decreases after GC initiation. Mean difference visual analogue scale pain was -15 mm (95% CI -20, -9) greater improvement in GC than control at ≤3 months, -8 mm (95% CI -12, -3) at >3-6 months and -7 mm (95% CI -13, 0) at >6 months. Similar findings were obtained when evoked pain outcomes were examined. Data from five RCTs suggested improvement also in fatigue during GC treatment. CONCLUSION: Oral GCs are analgesic in RA. The benefit is greatest shortly after initiation and GCs might not achieve clinically important pain relief beyond 3 months. Treatments other than anti-inflammatory GCs should be considered to reduce the long-term burden of pain in RA.

A method for extracting electronic patient record data from practice management software systems used in veterinary practice.

BACKGROUND: Data extracted from electronic patient records (EPRs) within practice management software systems are increasingly used in veterinary research. The use of real patient data gives the potential to generate research that can readily be applied to clinical practice. The use of veterinary EPRs for research in the United Kingdom is hindered by the number of different Practice Management System (PMS) providers used by practices, as obtaining and combining data from different systems electronically can be problematic. The use of extensible mark up language (XML) to extract clinical data for research would potentially resolve the compatibility issues between systems. The aim of this study was to establish and validate a method for the extraction of small animal patient records from a veterinary PMS that could potentially be used across multiple systems. An XML schema was designed to extract clinical information from EPRs. The schema was tested and validated in a test system, and was then tested in a real small animal practice where data was extracted for 16 weeks. A 10 % sample of the extracted records was then compared to paper copies provided by the practice. RESULTS: All 21 fields encoded by the XML schema, from all of the records in the test system, were extracted with 100 % accuracy. Over the 18 week data collection period 4946 records, from 1279 patients, were extracted from the small animal practice. The 10 % printed records checked and compared with the XML extracted records demonstrated all required data was present. No unrequired, sensitive information e.g. costs or services/products or personal client information was extracted. CONCLUSIONS: This is the first time a method for data extraction from EPRs in veterinary practice using an XML schema has been reported in the United Kingdom. This is an efficient and accurate way of extracting data which could be applied to all PMSs nationally and internationally.

Interventions for adults with a history of complex traumatic events: the INCiTE mixed-methods systematic review.

BACKGROUND: People with a history of complex traumatic events typically experience trauma and stressor disorders and additional mental comorbidities. It is not known if existing evidence-based treatments are effective and acceptable for this group of people. OBJECTIVE: To identify candidate psychological and non-pharmacological treatments for future research. DESIGN: Mixed-methods systematic review. PARTICIPANTS: Adults aged ≥ 18 years with a history of complex traumatic events. INTERVENTIONS: Psychological interventions versus control or active control; pharmacological interventions versus placebo. MAIN OUTCOME MEASURES: Post-traumatic stress disorder symptoms, common mental health problems and attrition. DATA SOURCES: Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1937 onwards); Cochrane Central Register of Controlled Trials (CENTRAL) (from inception); EMBASE (1974 to 2017 week 16); International Pharmaceutical Abstracts (1970 onwards); MEDLINE and MEDLINE Epub Ahead of Print and In-Process & Other Non-Indexed Citations (1946 to present); Published International Literature on Traumatic Stress (PILOTS) (1987 onwards); PsycINFO (1806 to April week 2 2017); and Science Citation Index (1900 onwards). Searches were conducted between April and August 2017. REVIEW METHODS: Eligible studies were singly screened and disagreements were resolved at consensus meetings. The risk of bias was assessed using the Cochrane risk-of-bias tool and a bespoke version of a quality appraisal checklist used by the National Institute for Health and Care Excellence. A meta-analysis was conducted across all populations for each intervention category and for population subgroups. Moderators of effectiveness were assessed using metaregression and a component network meta-analysis. A qualitative synthesis was undertaken to summarise the acceptability of interventions with the relevance of findings assessed by the GRADE-CERQual checklist. RESULTS: One hundred and four randomised controlled trials and nine non-randomised controlled trials were included. For the qualitative acceptability review, 4324 records were identified and nine studies were included. The population subgroups were veterans, childhood sexual abuse victims, war affected, refugees and domestic violence victims. Psychological interventions were superior to the control post treatment for reducing post-traumatic stress disorder symptoms (standardised mean difference -0.90, 95% confidence interval -1.14 to -0.66; number of trials = 39) and also for associated symptoms of depression, but not anxiety. Trauma-focused therapies were the most effective interventions across all populations for post-traumatic stress disorder and depression. Multicomponent and trauma-focused interventions were effective for negative self-concept. Phase-based approaches were also superior to the control for post-traumatic stress disorder and depression and showed the most benefit for managing emotional dysregulation and interpersonal problems. Only antipsychotic medication was effective for reducing post-traumatic stress disorder symptoms; medications were not effective for mental comorbidities. Eight qualitative studies were included. Interventions were more acceptable if service users could identify benefits and if they were delivered in ways that accommodated their personal and social needs. LIMITATIONS: Assessments about long-term effectiveness of interventions were not possible. Studies that included outcomes related to comorbid psychiatric states, such as borderline personality disorder, and populations from prisons and humanitarian crises were under-represented. CONCLUSIONS: Evidence-based psychological interventions are effective and acceptable post treatment for reducing post-traumatic stress disorder symptoms and depression and anxiety in people with complex trauma. These interventions were less effective in veterans and had less of an impact on symptoms associated with complex post-traumatic stress disorder. FUTURE WORK: Definitive trials of phase-based versus non-phase-based interventions with long-term follow-up for post-traumatic stress disorder and associated mental comorbidities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055523. 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. 24, No. 43. See the NIHR Journals Library website for further project information.

Traumatic events that happen often and that are difficult to escape from, such as childhood abuse, are sometimes known as complex traumatic events. People who have a history of complex traumatic events can develop post-traumatic stress disorder and can also suffer from other mental health problems. It is not known if people who experience complex traumatic events can benefit from existing psychological treatments or medications, or if these treatments are acceptable. This review aimed to find out which treatments are most effective and acceptable for mental health problems in people with complex trauma histories, and to identify the frontrunners for future research. We searched electronic databases for evidence about treatment effectiveness and acceptability in adults with a history of complex traumatic events. We found 104 randomised controlled trials and nine non-randomised controlled trials that tested the effectiveness of psychological and/or medications, as well as nine studies that used interviews and focus groups to describe the acceptability of psychological treatments. The studies were split across different populations that included veterans, refugees, people who had experienced childhood sexual abuse and domestic violence, and civilians affected by war. We found that psychological treatments that focused on improving symptoms associated with trauma were effective for reducing post-traumatic stress disorder symptoms and depression across all populations and fewer people dropped out of these treatments, suggesting that they are acceptable. However, trauma-focused treatments were less effective among veterans than among other groups and less effective for reducing other psychological symptoms commonly experienced by people with complex trauma histories. Phased treatments that first start with helping people to feel safe before focusing on trauma symptoms might be beneficial for both post-traumatic stress disorder and additional psychological symptoms. There was little evidence that medications, other than antipsychotics, were effective for post-traumatic stress disorder symptoms. Future work should test if phased treatments are more effective than non-phased treatments over the long term.

Hyperhidrosis quality of life measures: review and patient perspective.

PURPOSE: To identify the tools that have been used to measure quality of life in hyperhidrosis research and obtain patient insight on commonly used tools. METHODS: Twelve databases were searched to identify studies that reported measuring quality of life or described a quality of life tool in the context of hyperhidrosis. Data on the use of the tools were tabulated and hyperhidrosis-specific and dermatology-specific measures were summarized. A workshop was held to obtain the patients' perspective on the most commonly used tools and the newly developed HidroQoL tool. RESULTS: One hundred and eighty-two studies were included in the review. Twenty-two quality of life tools were identified; two or more tools were often used in combination. The most commonly used tools were the Hyperhidrosis Disease Severity Scale, the Dermatology Quality of Life Index and the Hyperhidrosis Quality-of-Life Questionnaire. Patient advisors preferred the new HidroQoL tool, which was considered to be easy to complete and most relevant to hyperhidrosis patients. CONCLUSIONS: There are several tools available for assessing quality of life in hyperhidrosis patients; disease specific measures are widely used and appear suitable. It is unclear which tool is the most reliable, although the HidroQoL tool was preferred by a small group of patient advisors.

Validation of text-mining and content analysis techniques using data collected from veterinary practice management software systems in the UK.

Electronic patient records from practice management software systems have been used extensively in medicine for the investigation of clinical problems leading to the creation of decision support frameworks. To date, technologies that have been utilised for this purpose such as text mining and content analysis have not been employed significantly in veterinary medicine. The aim of this research was to pilot the use of content analysis and text-mining software for the synthesis and analysis of information extracted from veterinary electronic patient records. The purpose of the work was to be able to validate this approach for future employment across a number of practices for the purposes of practice based research. The approach utilised content analysis (Prosuite) and text mining (WordStat) software to aggregate the extracted text. Text mining tools such as Keyword in Context (KWIC) and Keyword Retrieval (KR) were employed to identify specific occurrences of data across the records. Two different datasets were interrogated, a bespoke test dataset that had been set up specifically for the purpose of the research, and a functioning veterinary clinic dataset that had been extracted from one veterinary practice. Across both datasets, the KWIC analysis was found to have a high level of accuracy with the search resulting in a sensitivity of between 85.3-100%, a specificity of between 99.1-99.7%, a positive predictive value between 93.5-95.8% and a negative predictive value between 97.7-100%. The KR search, based on machine learning, was utilised for the clinic-based dataset and was found to perform slightly better than the KWIC analysis. This study is the first to demonstrate the application of content analysis and text mining software for validation purposes across a number of different datasets for the purpose of search and recall of specific information across electronic patient records. This has not been demonstrated previously for small animal veterinary epidemiological research for the purposes of large scale analysis for practice-based research. Extension of this work to investigate more complex diseases across larger populations is required to fully explore the use of this approach in veterinary practice.

Imaging tests for the detection of osteomyelitis: a systematic review.

BACKGROUND: Osteomyelitis is an infection of the bone. Medical imaging tests, such as radiography, ultrasound, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET), are often used to diagnose osteomyelitis. OBJECTIVES: To systematically review the evidence on the diagnostic accuracy, inter-rater reliability and implementation of imaging tests to diagnose osteomyelitis. DATA SOURCES: We conducted a systematic review of imaging tests to diagnose osteomyelitis. We searched MEDLINE and other databases from inception to July 2018. REVIEW METHODS: Risk of bias was assessed with QUADAS-2 [quality assessment of diagnostic accuracy studies (version 2)]. Diagnostic accuracy was assessed using bivariate regression models. Imaging tests were compared. Subgroup analyses were performed based on the location and nature of the suspected osteomyelitis. Studies of children, inter-rater reliability and implementation outcomes were synthesised narratively. RESULTS: Eighty-one studies were included (diagnostic accuracy: 77 studies; inter-rater reliability: 11 studies; implementation: one study; some studies were included in two reviews). One-quarter of diagnostic accuracy studies were rated as being at a high risk of bias. In adults, MRI had high diagnostic accuracy [95.6% sensitivity, 95% confidence interval (CI) 92.4% to 97.5%; 80.7% specificity, 95% CI 70.8% to 87.8%]. PET also had high accuracy (85.1% sensitivity, 95% CI 71.5% to 92.9%; 92.8% specificity, 95% CI 83.0% to 97.1%), as did SPECT (95.1% sensitivity, 95% CI 87.8% to 98.1%; 82.0% specificity, 95% CI 61.5% to 92.8%). There was similar diagnostic performance with MRI, PET and SPECT. Scintigraphy (83.6% sensitivity, 95% CI 71.8% to 91.1%; 70.6% specificity, 57.7% to 80.8%), computed tomography (69.7% sensitivity, 95% CI 40.1% to 88.7%; 90.2% specificity, 95% CI 57.6% to 98.4%) and radiography (70.4% sensitivity, 95% CI 61.6% to 77.8%; 81.5% specificity, 95% CI 69.6% to 89.5%) all had generally inferior diagnostic accuracy. Technetium-99m hexamethylpropyleneamine oxime white blood cell scintigraphy (87.3% sensitivity, 95% CI 75.1% to 94.0%; 94.7% specificity, 95% CI 84.9% to 98.3%) had higher diagnostic accuracy, similar to that of PET or MRI. There was no evidence that diagnostic accuracy varied by scan location or cause of osteomyelitis, although data on many scan locations were limited. Diagnostic accuracy in diabetic foot patients was similar to the overall results. Only three studies in children were identified; results were too limited to draw any conclusions. Eleven studies evaluated inter-rater reliability. MRI had acceptable inter-rater reliability. We found only one study on test implementation and no evidence on patient preferences or cost-effectiveness of imaging tests for osteomyelitis. LIMITATIONS: Most studies included < 50 participants and were poorly reported. There was limited evidence for children, ultrasonography and on clinical factors other than diagnostic accuracy. CONCLUSIONS: Osteomyelitis is reliably diagnosed by MRI, PET and SPECT. No clear reason to prefer one test over the other in terms of diagnostic accuracy was identified. The wider availability of MRI machines, and the fact that MRI does not expose patients to harmful ionising radiation, may mean that MRI is preferable in most cases. Diagnostic accuracy does not appear to vary with the potential cause of osteomyelitis or with the body part scanned. Considerable uncertainty remains over the diagnostic accuracy of imaging tests in children. Studies of diagnostic accuracy in children, particularly using MRI and ultrasound, are needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017068511. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 61. See the NIHR Journals Library website for further project information.

Osteomyelitis is an infection of the bone and is treated with antibiotics. Left untreated, it can cause permanent damage and can lead to amputation. The best method to diagnose osteomyelitis is to take a bone sample (bone biopsy) but this is invasive and painful. Imaging may help target the best locations for biopsies or remove the need for a biopsy entirely. Several methods are available, including radiography, ultrasound, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). This project systematically reviewed the relevant literature to determine which tests are the most accurate and relevant for clinical practice. All types of patients and all types of osteomyelitis were reviewed. Studies were pooled using statistical methods (meta-analyses) to estimate the overall accuracy of the imaging tests. The review identified 81 studies and concluded that MRI, PET and SPECT all had similar accuracy, correctly identifying over 85% of people who did have osteomyelitis and over 80% of people who did not have osteomyelitis. Radiography and computed tomography were less accurate. Modern forms of scintigraphy have accuracy similar to PET or MRI. There was no evidence that the accuracy of the imaging tests was different depending on the cause of osteomyelitis or which body part was affected. In particular, diagnostic accuracy in people with diabetic foot ulcers was similar to other types of osteomyelitis in adults. There was not enough evidence about which tests are most accurate in children, so further studies in children are needed.

Methodological challenges for the evaluation of clinical effectiveness in the context of accelerated regulatory approval: an overview.

BACKGROUND: Regulatory authorities are approving innovative therapies with limited evidence. Although this level of data is sufficient for the regulator to establish an acceptable risk-benefit balance, it is problematic for downstream health technology assessment, where assessment of cost-effectiveness requires reliable estimates of effectiveness relative to existing clinical practice. Some key issues associated with a limited evidence base include using data, from nonrandomized studies, from small single-arm trials, or from single-center trials; and using surrogate end points. METHODS: We examined these methodological challenges through a pragmatic review of the available literature. RESULTS: Methods to adjust nonrandomized studies for confounding are imperfect. The relative treatment effect generated from single-arm trials is uncertain and may be optimistic. Single-center trial results may not be generalizable. Surrogate end points, on average, overestimate treatment effects. Current methods for analyzing such data are limited, and effectiveness claims based on these suboptimal forms of evidence are likely to be subject to significant uncertainty. CONCLUSION: Assessments of cost-effectiveness, based on the modeling of such data, are likely to be subject to considerable uncertainty. This uncertainty must not be underestimated by decision makers: methods for its quantification are required and schemes to protect payers from the cost of uncertainty should be implemented.

Accuracy of the electronic patient record in a first opinion veterinary practice.

The use of electronic patient records (EPRs) in veterinary research is becoming more common place. To date no-one has investigated how accurately and completely they represent the clinical interactions that happen between veterinary professionals, and their clients and patients. The aim of this study was to compare data extracted from consultations within EPRs with data gathered by direct observation of the same consultation. A secondary aim was to establish the inter-rater reliability of two researchers who examined the data extracted from the EPRs. A convenience sample of 36 small animal consultations undertaken by 2 veterinary surgeons (83% by one veterinary surgeon) at a mixed veterinary practice in the United Kingdom was studied. All 36 consultations were observed by a single researcher using a standardised data collection tool. The information recorded in the EPRs was extracted from the Practice Management Software (PMS) systems using a validated XML schema. The XML extracted data was then converted into the same format as the observed data by two independent researchers who examined the extracted information and recorded their findings using the same tool as for the observation. The issues discussed and any action taken relating to those problems recorded in the observed and extracted datasets were then compared. In addition the inter-rater reliability of the two researchers who examined the extracted data was assessed. Only 64.4% of the observed problems discussed during the consultations were recorded in the EPR. The type of problem, who raised the problem and at what point in the consultation the problem was raised significantly affected whether the problem was recorded or not in the EPR. Only 58.3% of observed actions taken during the consultations were recorded in the EPR and the type of action significantly affected whether it would be recorded or not. There was moderate agreement between the two researchers who examined the extracted data. This is the first study that examines how much of the activity that occurs in small animal consultations is recorded in the EPR. Understanding the completeness, reliability and validity of EPRs is vital if they are to continue to be used for clinical research and the results to direct clinical care.

The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) commissioned a 'mock technology appraisal' to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal. METHODS: Our research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia. RESULTS: An assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the 'curative' and 'bridging to stem-cell transplantation' treatment approaches separately. Within each TPP, three 'hypothetical' evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision. CONCLUSIONS: It is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Interventions for hyperhidrosis in secondary care: a systematic review and value-of-information analysis.

BACKGROUND: Hyperhidrosis is uncontrollable excessive sweating that occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. The management of hyperhidrosis is uncertain and variable. OBJECTIVE: To establish the expected value of undertaking additional research to determine the most effective interventions for the management of refractory primary hyperhidrosis in secondary care. METHODS: A systematic review and economic model, including a value-of-information (VOI) analysis. Treatments to be prescribed by dermatologists and minor surgical treatments for hyperhidrosis of the hands, feet and axillae were reviewed; as endoscopic thoracic sympathectomy (ETS) is incontestably an end-of-line treatment, it was not reviewed further. Fifteen databases (e.g. CENTRAL, PubMed and PsycINFO), conference proceedings and trial registers were searched from inception to July 2016. Systematic review methods were followed. Pairwise meta-analyses were conducted for comparisons between botulinum toxin (BTX) injections and placebo for axillary hyperhidrosis, but otherwise, owing to evidence limitations, data were synthesised narratively. A decision-analytic model assessed the cost-effectiveness and VOI of five treatments (iontophoresis, medication, BTX, curettage, ETS) in 64 different sequences for axillary hyperhidrosis only. RESULTS AND CONCLUSIONS: Fifty studies were included in the effectiveness review: 32 randomised controlled trials (RCTs), 17 non-RCTs and one large prospective case series. Most studies were small, rated as having a high risk of bias and poorly reported. The interventions assessed in the review were iontophoresis, BTX, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland (e.g. laser, microwave). There is moderate-quality evidence of a large statistically significant effect of BTX on axillary hyperhidrosis symptoms, compared with placebo. There was weak but consistent evidence for iontophoresis for palmar hyperhidrosis. Evidence for other interventions was of low or very low quality. For axillary hyperhidrosis cost-effectiveness results indicated that iontophoresis, BTX, medication, curettage and ETS was the most cost-effective sequence (probability 0.8), with an incremental cost-effectiveness ratio of £9304 per quality-adjusted life-year. Uncertainty associated with study bias was not reflected in the economic results. Patients and clinicians attending an end-of-project workshop were satisfied with the sequence of treatments for axillary hyperhidrosis identified as being cost-effective. All patient advisors considered that the Hyperhidrosis Quality of Life Index was superior to other tools commonly used in hyperhidrosis research for assessing quality of life. LIMITATIONS: The evidence for the clinical effectiveness and safety of second-line treatments for primary hyperhidrosis is limited. This meant that there was insufficient evidence to draw conclusions for most interventions assessed and the cost-effectiveness analysis was restricted to hyperhidrosis of the axilla. FUTURE WORK: Based on anecdotal evidence and inference from evidence for the axillae, participants agreed that a trial of BTX (with anaesthesia) compared with iontophoresis for palmar hyperhidrosis would be most useful. The VOI analysis indicates that further research into the effectiveness of existing medications might be worthwhile, but it is unclear that such trials are of clinical importance. Research that established a robust estimate of the annual incidence of axillary hyperhidrosis in the UK population would reduce the uncertainty in future VOI analyses. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027803. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults.

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525 . Registered on 12 March 2015 revised on 15 March 2016.