Treating the Neurologic Manifestations of Wilson's Disease With Liver Transplantation.

Wilson's Disease (WD) manifests with systemic and neuropsychiatric symptoms, caused by an ATP7B genetic mutation, leading to an accumulation of copper. Presentations are diverse and the diagnosis should be considered in anyone under 50 with a new onset movement disorder. Early recognition and treatment can limit morbidity. While liver transplantation (LT) is recommended in WD patients with hepatic failure, its use for pure neurologic indication remains controversial. We present a patient who failed medical management and underwent LT for pure neurologic indications. Subsequent neurologic symptom improvement supports the use of LT for patients with pure neurologic manifestations of WD.

Baseline characteristics of people experiencing homelessness with a recent drug overdose in the PHOENIx pilot randomised controlled trial.

BACKGROUND: Drug-related deaths in Scotland are the highest in Europe. Half of all deaths in people experiencing homelessness are drug related, yet we know little about the unmet health needs of people experiencing homelessness with recent non-fatal overdose, limiting a tailored practice and policy response to a public health crisis. METHODS: People experiencing homelessness with at least one non-fatal street drug overdose in the previous 6 months were recruited from 20 venues in Glasgow, Scotland, and randomised into PHOENIx plus usual care, or usual care. PHOENIx is a collaborative assertive outreach intervention by independent prescriber NHS Pharmacists and third sector homelessness workers, offering repeated integrated, holistic physical, mental and addictions health and social care support including prescribing. We describe comprehensive baseline characteristics of randomised participants. RESULTS: One hundred and twenty-eight participants had a mean age of 42 years (SD 8.4); 71% male, homelessness for a median of 24 years (IQR 12-30). One hundred and eighteen (92%) lived in large, congregate city centre temporary accommodation. A quarter (25%) were not registered with a General Practitioner. Participants had overdosed a mean of 3.2 (SD 3.2) times in the preceding 6 months, using a median of 3 (IQR 2-4) non-prescription drugs concurrently: 112 (87.5%) street valium (benzodiazepine-type new psychoactive substances); 77 (60%) heroin; and 76 (59%) cocaine. Half (50%) were injecting, 50% into their groins. 90% were receiving care from Alcohol and Drug Recovery Services (ADRS), and in addition to using street drugs, 90% received opioid substitution therapy (OST), 10% diazepam for street valium use and one participant received heroin-assisted treatment. Participants had a mean of 2.2 (SD 1.3) mental health problems and 5.4 (SD 2.5) physical health problems; 50% received treatment for physical or mental health problems. Ninety-one per cent had at least one mental health problem; 66% had no specialist mental health support. Participants were frail (70%) or pre-frail (28%), with maximal levels of psychological distress, 44% received one or no daily meal, and 58% had previously attempted suicide. CONCLUSIONS: People at high risk of drug-related death continue to overdose repeatedly despite receiving OST. High levels of frailty, multimorbidity, unsuitable accommodation and unmet mental and physical health care needs require a reorientation of services informed by evidence of effectiveness and cost-effectiveness. Trial registration UK Clinical Trials Registry identifier: ISRCTN 10585019.

Protocol for a pilot randomised controlled trial to evaluate integrated support from pharmacist independent prescriber and third sector worker for people experiencing homelessness: the PHOENIx community pharmacy study.

BACKGROUND: People experiencing homelessness (PEH) have complex health and social care needs and most die in their early 40 s. PEH frequently use community pharmacies; however, evaluation of the delivery of structured, integrated, holistic health and social care intervention has not been previously undertaken in community pharmacies for PEH. PHOENIx (Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx) has been delivered and tested in Glasgow, Scotland, by NHS pharmacist independent prescribers and third sector homelessness support workers offering health and social care intervention in low threshold homeless drop-in venues, emergency accommodation and emergency departments, to PEH. Building on this work, this study aims to test recruitment, retention, intervention adherence and fidelity of community pharmacy-based PHOENIx intervention. METHODS: Randomised, multi-centre, open, parallel-group external pilot trial. A total of 100 PEH aged 18 years and over will be recruited from community pharmacies in Glasgow and Birmingham. PHOENIx intervention includes structured assessment in the community pharmacy of health, housing, benefits and activities, in addition to usual care, through weekly visits lasting up to six months. A primary outcome is whether to proceed to a definitive trial based on pre-specified progression criteria. Secondary outcomes include drug/alcohol treatment uptake and treatment retention; overdose rates; mortality and time to death; prison/criminal justice encounters; healthcare utilisation; housing tenure; patient-reported measures and intervention acceptability. Analysis will include descriptive statistics of recruitment and retention rates. Process evaluation will be conducted using Normalisation Process Theory. Health, social care and personal resource use data will be identified, measured and valued. DISCUSSION: If the findings of this pilot study suggest progression to a definitive trial, and if the definitive trial offers positive outcomes, it is intended that PHOENIx will be a publicly funded free-to-access service in community pharmacy for PEH. The study results will be shared with wider stakeholders and patients in addition to dissemination through medical journals and scientific conferences. TRIAL REGISTRATION: International Clinical Trial Registration ISRCTN88146807. Approved protocol version 2.0 dated July 19, 2022.

A systematic review of economic analyses of psychological interventions and therapies in health-related settings.

BACKGROUND: This review aims to synthesise evidence on the economic impact of psychological interventions and therapies when applied to a broad range of physical health conditions. METHODS: The following bibliographic databases were searched for relevant articles: MEDLINE (Ovid), EMBASE (Ovid) and PsycINFO (Ebsco). As this review was intended to update an earlier review, the date range for the search was restricted to between January 2012 and September 2018. Reference lists from the review articles were also searched for relevant articles. Study quality was evaluated using the Scottish Intercollegiate Network Guidelines (SIGN) appraisal checklists for both economic studies and Randomised Controlled Trials (RCTs). When the economic analyses did not provide sufficient detail for quality evaluation, the original RCT papers were sought and these were also evaluated. Half of the papers were quality rated by a second author. Initial agreement was high and all disagreements were resolved by discussion. RESULTS: This yielded 1408 unique articles, reduced to 134 following screening of the title and abstract. The full texts of the remaining articles were reviewed by at least one team member and all exclusions were discussed and agreed by the team. This left 46 original research articles, alongside five systematic reviews. Fifty-seven per cent of the articles were deemed to be of high quality, with the remainder of acceptable quality. Fifteen different medical conditions were covered, with chronic pain (10 articles) and cancer (9 articles) being the two most investigated health conditions. Three quarters of the papers reviewed showed evidence for the cost-effectiveness of psychological interventions in physical health, with the clearest evidence being in the field of chronic pain and cancer. CONCLUSIONS: This paper provides a comprehensive integration of the research on the cost-effectiveness of psychological therapies in physical health. Whilst the evidence for cost-effectiveness in chronic pain and cancer is encouraging, some health conditions require further study. Clearly, as the primary research is international, and was therefore conducted across varying health care systems, caution must be exercised when applying the results to counties outside of those covered. Despite this, the results are of potential relevance to service providers and funders.

Sublingual apomorphine in treatment of Parkinson's disease: a review.

PURPOSE: A majority of advanced Parkinson's disease (PD) patients on oral levodopa experience motor fluctuations, including sudden OFF and delayed ON periods. Fast-acting rescue medications are a vital part of the clinician's armamentarium in the treatment of motor fluctuations. Sublingual apomorphine is the first sublingual rescue medication on the market for the treatment of OFF times in PD.Materials and Methods: Here, we review the development and pharmacology of apomorphine in the treatment of PD as well as the safety and efficacy of sublingual apomorphine established in clinical trials. Finally, we compare sublingual apomorphine to the other rescue medications available and provide our opinion on the use of sublingual apomorphine in clinical practice.Results: Clinical trials have demonstrated that sublingual apomorphine is a safe and effective option in the treatment of motor fluctuations in PD. In a Phase II trial, 100% of patients who achieved a full ON response did so within 30 min and 40% did so within 15 min. The mean duration of effect was 50 min. In a Phase III trial, 77.3% of patients achieved a full ON response. Side effects such as nausea, dizziness and somnolence were common but were generally mild. No patients experienced worsening dyskinesia.Conclusions: Sublingual apomorphine will provide patients with motor fluctuations due to advanced PD another safe and effective option for the treatment of OFF times.

Efficiency and Health Economic Evaluations of BD OneFlow™ Flow Cytometry Reagents for Diagnosing Chronic Lymphoid Leukemia.

REASON FOR THE STUDY: To standardize the use of flow cytometry for classifying hematological malignancies and make the results reliable and reproducible across laboratories, the EuroFlow™ Consortium published a comprehensive specification of antibody-fluorochrome conjugates, standard protocols, and algorithms for analysis. The BD OneFlow™ system builds on, and further standardizes, the EuroFlow protocols. We aimed to assess the effects on safety, efficiency, and costs for laboratories of adopting the BD OneFlow reagent tubes (LST and B-CLPD T1) for diagnosing chronic lymphocytic leukemia. METHODS: We compared in-house laboratory processes and results with those using the LST and B-CLPD T1 reagent tubes with, and without, blood film morphology. Outcome measures included concordance in classification results, and efficiency within the laboratory, that is, resource usage, staff time, unwanted events, and cost-consequences. RESULTS: There was 100% concordance between the classifications made with in-house flow cytometry and those with the BD OneFlow reagent tubes. Using BD OneFlow tubes required 13 hours less staff time per month (i.e. for 100 samples) than the in-house process. Sensitivity analyses explored the effects of uncertainties in the price of the BD OneFlow tubes and the prevalence of CLL and identified the thresholds at which laboratories might expect cost-savings from adopting the BD OneFlow system. Laboratory and clinical staff considered the BD OneFlow system to be safe and effective. CONCLUSIONS: Laboratories adopting the BD OneFlow system for classifying patients with suspected CLL can expect safe, efficient processes that can be cost saving if the discount on the list price, and prevalence of CLL (which will both vary between sites and countries), is within the thresholds suggested by the health economics sensitivity analysis. © 2019 International Clinical Cytometry Society.

Robot Assisted Training for the Upper Limb after Stroke (RATULS): study protocol for a randomised controlled trial.

BACKGROUND: Loss of arm function is a common and distressing consequence of stroke. We describe the protocol for a pragmatic, multicentre randomised controlled trial to determine whether robot-assisted training improves upper limb function following stroke. METHODS/DESIGN: Study design: a pragmatic, three-arm, multicentre randomised controlled trial, economic analysis and process evaluation. SETTING: NHS stroke services. PARTICIPANTS: adults with acute or chronic first-ever stroke (1 week to 5 years post stroke) causing moderate to severe upper limb functional limitation. Randomisation groups: 1. Robot-assisted training using the InMotion robotic gym system for 45 min, three times/week for 12 weeks 2. Enhanced upper limb therapy for 45 min, three times/week for 12 weeks 3. Usual NHS care in accordance with local clinical practice Randomisation: individual participant randomisation stratified by centre, time since stroke, and severity of upper limb impairment. PRIMARY OUTCOME: upper limb function measured by the Action Research Arm Test (ARAT) at 3 months post randomisation. SECONDARY OUTCOMES: upper limb impairment (Fugl-Meyer Test), activities of daily living (Barthel ADL Index), quality of life (Stroke Impact Scale, EQ-5D-5L), resource use, cost per quality-adjusted life year and adverse events, at 3 and 6 months. Blinding: outcomes are undertaken by blinded assessors. Economic analysis: micro-costing and economic evaluation of interventions compared to usual NHS care. A within-trial analysis, with an economic model will be used to extrapolate longer-term costs and outcomes. Process evaluation: semi-structured interviews with participants and professionals to seek their views and experiences of the rehabilitation that they have received or provided, and factors affecting the implementation of the trial. SAMPLE SIZE: allowing for 10% attrition, 720 participants provide 80% power to detect a 15% difference in successful outcome between each of the treatment pairs. Successful outcome definition: baseline ARAT 0-7 must improve by 3 or more points; baseline ARAT 8-13 improve by 4 or more points; baseline ARAT 14-19 improve by 5 or more points; baseline ARAT 20-39 improve by 6 or more points. DISCUSSION: The results from this trial will determine whether robot-assisted training improves upper limb function post stroke. TRIAL REGISTRATION: ISRCTN, identifier: ISRCTN69371850 . Registered 4 October 2013.

Pharmaceutical regulation in 15 European countries review.

In the context of pharmaceutical care, policy-makers repeatedly face the challenge of balancing patient access to effective medicines with affordability and rising costs. With the aim of guiding the health policy discourse towards questions that are important to actual and potential patients, this study investigates a broad range of regulatory measures, spanning marketing authorization to generic substitution and resulting price levels in a sample of 16 European health systems (Austria, Belgium, Denmark, England, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Poland, Portugal, Scotland, Spain and Sweden). All countries employ a mix of regulatory mechanisms to contain pharmaceutical expenditure and ensure quality and efficiency in pharmaceutical care, albeit with varying configurations and rigour. This variation also influences the extent of publicly financed pharmaceutical costs. Overall, observed differences in pharmaceutical expenditure should be interpreted in conjunction with the differing volume and composition of consumption and price levels, as well as dispensation practices and their impact on measurement of pharmaceutical costs. No definitive evidence has yet been produced on the effects of different cost-containment measures on patient outcomes. Depending on the foremost policy concerns in each country, different levers will have to be used to enable the delivery of appropriate care at affordable prices.

Pharmaceutical regulation in 15 European countries: review

In the context of pharmaceutical care, policy-makers repeatedly facethe challenge of balancing patient access to effective medicines withaffordability and rising costs. With the aim of guiding the health policydiscourse towards questions that are important to actual and potential patients,this study investigates a broad range of regulatory measures, spanningmarketing authorization to generic substitution and resulting price levels in asample of 16 European health systems (Austria, Belgium, Denmark, England,Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Poland,Portugal, Scotland, Spain and Sweden).All countries employ a mix of regulatory mechanisms to containpharmaceutical expenditure and ensure quality and efficiency in pharmaceuticalcare, albeit with varying configurations and rigour. This variation alsoinfluences the extent of publicly financed pharmaceutical costs. Overall,observed differences in pharmaceutical expenditure should be interpreted inconjunction with the differing volume and composition of consumption andprice levels, as well as dispensation practices and their impact on measurementof pharmaceutical costs.No definitive evidence has yet been produced on the effects of differentcost-containment measures on patient outcomes. Depending on the foremostpolicy concerns in each country, different levers will have to be used to enablethe delivery of appropriate care at affordable prices.

Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review.

BACKGROUND: The randomised controlled trial (RCT) is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to the design and validity of a RCT is a calculation of the number of participants needed (the sample size). The value used to determine the sample size can be considered the 'target difference'. From both a scientific and an ethical standpoint, selecting an appropriate target difference is of crucial importance. Determination of the target difference, as opposed to statistical approaches to calculating the sample size, has been greatly neglected though a variety of approaches have been proposed the current state of the evidence is unclear. OBJECTIVES: The aim was to provide an overview of the current evidence regarding specifying the target difference in a RCT sample size calculation. The specific objectives were to conduct a systematic review of methods for specifying a target difference; to evaluate current practice by surveying triallists; to develop guidance on specifying the target difference in a RCT; and to identify future research needs. DESIGN: The biomedical and social science databases searched were MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, Education Resources Information Center (ERIC) and Scopus for in-press publications. All were searched from 1966 or the earliest date of the database coverage and searches were undertaken between November 2010 and January 2011. There were three interlinked components: (1) systematic review of methods for specifying a target difference for RCTs - a comprehensive search strategy involving an electronic literature search of biomedical and some non-biomedical databases and clinical trials textbooks was carried out; (2) identification of current trial practice using two surveys of triallists - members of the Society for Clinical Trials (SCT) were invited to complete an online survey and respondents were asked about their awareness and use of, and willingness to recommend, methods; one individual per triallist group [UK Clinical Research Collaboration (UKCRC)-registered Clinical Trials Units (CTUs), Medical Research Council (MRC) UK Hubs for Trials Methodology Research and National Institute for Health Research (NIHR) UK Research Design Services (RDS)] was invited to complete a survey; (3) production of a structured guidance document to aid the design of future trials - the draft guidance was developed utilising the results of the systematic review and surveys by the project steering and advisory groups. SETTING: Methodological review incorporating electronic searches, review of books and guidelines, two surveys of experts (membership of an international society and UK- and Ireland-based triallists) and development of guidance. PARTICIPANTS: The two surveys were sent out to membership of the SCT and UK- and Ireland-based triallists. INTERVENTIONS: The review focused on methods for specifying the target difference in a RCT. It was not restricted to any type of intervention or condition. MAIN OUTCOME MEASURES: Methods for specifying the target difference for a RCT were considered. RESULTS: The search identified 11,485 potentially relevant studies. In total, 1434 were selected for full-text assessment and 777 were included in the review. Seven methods to specify the target difference for a RCT were identified - anchor, distribution, health economic, opinion-seeking, pilot study, review of evidence base (RoEB) and standardised effect size (SES) - each having important variations in implementation. A total of 216 of the included studies used more than one method. A total of 180 (15%) responses to the SCT survey were received, representing 13 countries. Awareness of methods ranged from 38% (n =69) for the health economic method to 90% (n =162) for the pilot study. Of the 61 surveys sent out to UK triallist groups, 34 (56%) responses were received. Awareness ranged from 97% (n =33) for the RoEB and pilot study methods to only 41% (n =14) for the distribution method. Based on the most recent trial, all bar three groups (91%, n =30) used a formal method. Guidance was developed on the use of each method and the reporting of the sample size calculation in a trial protocol and results paper. CONCLUSIONS: There is a clear need for greater use of formal methods to determine the target difference and better reporting of its specification. Raising the standard of RCT sample size calculations and the corresponding reporting of them would aid health professionals, patients, researchers and funders in judging the strength of the evidence and ensuring better use of scarce resources. FUNDING: The Medical Research Council UK and the National Institute for Health Research Joint Methodology Research programme.

Use of methods for specifying the target difference in randomised controlled trial sample size calculations: Two surveys of trialists' practice.

BACKGROUND: Central to the design of a randomised controlled trial (RCT) is a calculation of the number of participants needed. This is typically achieved by specifying a target difference, which enables the trial to identify a difference of a particular magnitude should one exist. Seven methods have been proposed for formally determining what the target difference should be. However, in practice, it may be driven by convenience or some other informal basis. It is unclear how aware the trialist community is of these formal methods or whether they are used. PURPOSE: To determine current practice regarding the specification of the target difference by surveying trialists. METHODS: Two surveys were conducted: (1) Members of the Society for Clinical Trials (SCT): participants were invited to complete an online survey through the society's email distribution list. Respondents were asked about their awareness, use of, and willingness to recommend methods; (2) Leading UK- and Ireland-based trialists: the survey was sent to UK Clinical Research Collaboration registered Clinical Trials Units, Medical Research Council UK Hubs for Trial Methodology Research, and the Research Design Services of the National Institute for Health Research. This survey also included questions about the most recent trial developed by the respondent's group. RESULTS: Survey 1: Of the 1182 members on the SCT membership email distribution list, 180 responses were received (15%). Awareness of methods ranged from 69 (38%) for health economic methods to 162 (90%) for pilot study. Willingness to recommend among those who had used a particular method ranged from 56% for the opinion-seeking method to 89% for the review of evidence-base method. Survey 2: Of the 61 surveys sent out, 34 (56%) responses were received. Awareness of methods ranged from 33 (97%) for the review of evidence-base and pilot methods to 14 (41%) for the distribution method. The highest level of willingness to recommend among users was for the anchor method (87%). Based upon the most recent trial, the target difference was usually one viewed as important by a stakeholder group, mostly also viewed as a realistic difference given the interventions under evaluation, and sometimes one that led to an achievable sample size. LIMITATIONS: The response rates achieved were relatively low despite the surveys being short, well presented, and having utilised reminders. CONCLUSION: Substantial variations in practice exist with awareness, use, and willingness to recommend methods varying substantially. The findings support the view that sample size calculation is a more complex process than would appear to be the case from trial reports and protocols. Guidance on approaches for sample size estimation may increase both awareness and use of appropriate formal methods.

Systematic review of escalated imatinib doses compared with sunitinib or best supportive care, for the treatment of people with unresectable/metastatic gastrointestinal stromal tumours whose disease has progressed on the standard imatinib dose.

INTRODUCTION: We conducted a systematic review of evidence on the effectiveness of imatinib at escalated doses of 600 mg/day or 800 mg/day for treatment of adults with unresectable or metastatic gastrointestinal stromal tumours (GIST), following progression on imatinib at the 400 mg/day dose, compared with sunitinib and/or 'best supportive care'. METHODS: Electronic searches were undertaken to identify relevant randomised controlled trials (RCTs), non-randomised studies, and case series reporting outcome data on survival, quality of life or adverse events. Titles and abstracts were screened by two reviewers and full text reports of potentially relevant studies assessed for inclusion. Included studies were quality assessed by two reviewers and data were extracted. Five studies reported data on the relevant population and were included. RESULTS AND DISCUSSION: Median overall survival for imatinib (800 mg/day) and sunitinib both were less than 2 years. Around 25% of patients required either an imatinib dose delay or reduction. Approximately one-third of patients receiving dose escalated imatinib (either dose) showed either response or stable disease. Amongst those responding to the escalated 800 mg/day dose, median progression-free survival was over 25 months. The statistical likelihood of response may depend on exon mutational status. There were few data and those that were available were potentially biased, due to their non-randomised nature. Further data are needed to justify international guideline recommendations on imatinib dose escalation. CONCLUSION: A prospective audit of management and outcomes for unresectable GIST patients treated with dose escalation upon progression at 400 mg/day may be appropriate as an RCT may be unfeasible.