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Summary: Background: Oral systemic immunomodulatory medication is regularly used off‐licence in children with severe atopic eczema. However, there is no firm evidence regarding the effectiveness, safety, cost‐effectiveness and impact on quality of life from an adequately powered randomized controlled trial (RCT) using systemic medication in children. Objectives: To assess whether there is a difference in the speed of onset, effectiveness, side‐effect profile and reduction in flares post‐treatment between ciclosporin (CyA) and methotrexate (MTX), and also the cost‐effectiveness of the drugs. Treatment impact on quality of life will also be examined in addition to whether FLG genotype influences treatment response. In addition, the trial studies the immune–metabolic effects of CyA and MTX. Methods: Multicentre, parallel group, assessor‐blind, pragmatic RCT of 36 weeks' duration with a 24‐week follow‐up period. In total, 102 children aged 2–16 years with moderate‐to‐severe atopic eczema, unresponsive to topical treatment will be randomized (1 : 1) to receive MTX (0·4 mg kg−1 per week) or CyA (4 mg kg−1 per day). Results: The trial has two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o‐SCORAD) and time to first significant flare following treatment cessation. Conclusions: This trial addresses important therapeutic questions, highlighted in systematic reviews and treatment guidelines for atopic eczema. The trial design is pragmatic to reflect current clinical practice. What's already known about this topic? Oral systemic immunomodulatory medication is regularly used off‐licence in children with severe atopic eczema.Ciclosporin is the commonest first‐line systemic agent used in this context, but methotrexate has emerged as an important therapeutic alternative.There is currently no adequately powered randomized controlled trial that compares both treatments in children. What does this study add? The TREatment of severe Atopic eczema Trial (TREAT) addresses this gap and compares the effectiveness, safety, cost‐effectiveness and impact on patient's quality of life of these two drugs.TREAT also examines the effects of both drugs using systemic and cutaneous markers of inflammation and the effect of filaggrin (FLG) genotype and T‐cell cytokine signatures on treatment response.Respond to this article Plain language summary available online [ABSTRACT FROM AUTHOR]

Abstract: Asthma management, education and environmental interventions have been reported as cost‐effective in a previous review (Pharm Pract (Granada), 2014;12:493), but methods used to estimate costs and outcomes were not discussed in detail. This review updates the previous review by providing economic evidence on the cost‐effectiveness of studies identified after 2012, and a detailed assessment of the methods used in all identified studies. Twelve databases were searched from 1990 to January 2016, and studies included economic evaluations, asthma subjects and nonpharmacological interventions written in English. Sixty‐four studies were included. Of these, 15 were found in addition to the earlier review; 53% were rated fair in quality and 47% high. Education and self‐management interventions were the most cost‐effective, in line with the earlier review. Self‐reporting was the most common method used to gather resource‐use data, accompanied by bottom‐up approaches to estimate costs. Main outcome measures were asthma‐related hospitalizations (69%), quality of life (41%) and utility (38%), with AQLQ and the EQ‐5D being the most common questionnaires measured prospectively at fixed time points. More rigorous costing methods are needed with a more common quality of life tool to aid greater replicability and comparability amongst asthma studies. [ABSTRACT FROM AUTHOR]

Background Quality of life (QoL) is one of the core outcome domains identified by the Harmonising Outcome Measures for Eczema (HOME) initiative to be assessed in every eczema trial. There is uncertainty about the most appropriate QoL instrument to measure this domain in infants, children and adolescents. Objectives To systematically evaluate the measurement properties of existing measurement instruments developed and/or validated for the measurement of QoL in infants, children and adolescents with eczema. Methods A systematic literature search in PubMed and Embase, complemented by a thorough hand search of reference lists, retrieved studies on measurement properties of eczema QoL instruments for infants, children and adolescents. For all eligible studies, we judged the adequacy of the measurement properties and the methodological study quality with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Results from different studies were summarized in a best-evidence synthesis and formed the basis to assign four degrees of recommendation. Results Seventeen articles, three of which were found by hand search, were included. These 17 articles reported on 24 instruments. No instrument can be recommended for use in all eczema trials because none fulfilled all required adequacy criteria. With adequate internal consistency, reliability and hypothesis testing, the U.S. version of the Childhood Atopic Dermatitis Impact Scale (CADIS), a proxy-reported instrument, has the potential to be recommended depending on the results of further validation studies. All other instruments, including all self-reported ones, lacked significant validation data. Conclusions Currently, no QoL instrument for infants, children and adolescents with eczema can be highly recommended. Future validation research should primarily focus on the CADIS, but also attempt to broaden the evidence base for the validity of self-reported instruments. [ABSTRACT FROM AUTHOR]

Objectives: To compare health-related and cost-related outcomes of consultations for symptoms suggestive of minor ailments in emergency departments (EDs), general practices and community pharmacies. Design: Observational study; prospective cohort design. Setting: EDs (n=2), general practices (n=6) and community pharmacies (n=10) in a mix of rural/urban and deprived/affluent areas across North East Scotland and East Anglia. Participants Adults (≥18 years) presenting between 09:00 and 18:00 (Monday-Friday) in general practices and 09:00-18:00 (Monday-Saturday) in pharmacies and EDs with ≥1 of the following: musculoskeletal pain; eye discomfort; gastrointestinal disturbance; or upper respiratory tract-related symptoms. Interventions: Participants completed three questionnaires: baseline (prior to index consultation); satisfaction with index consultation and follow-up (2 weeks after index consultation). Main outcome measures: Symptom resolution, quality of life, costs, satisfaction and influences on care-seeking behaviour. Results: 377 patients participated, recruited from EDs (81), general practices (162) and community pharmacies (134). The 2-week response rate was 70% (264/377). Symptom resolution was similar across all three settings: ED (37.3%), general practice (35.7%) and pharmacy (44.3%). Mean overall costs per consultation were significantly lower for pharmacy (£29.30 (95% CI £21.60 to £37.00)) compared with general practice (£82.34 (95% CI £63.10 to £101.58)) and ED (£147.09 (95% CI £125.32 to £168.85)). Satisfaction varied across settings and by measure used. Compared with pharmacy and general practice use, ED use was significantly (p<0.001) associated with first episode and short duration of symptom(s), as well as higher levels of perceived seriousness and urgency for seeking care. Convenience of location was the most common reason for choice of consultation setting. Conclusions: These results suggest similar health-related outcomes and substantially lower costs with pharmacy consultations for minor ailments. Effective strategies are now needed to shift demand for minor ailment management away from EDs and general practices to the community pharmacy setting. [ABSTRACT FROM AUTHOR]

AimThe aim of this study was to evaluate the cost-effectiveness of second-eye cataract surgery for older women with minimal visual dysfunction in the eye to be operated on from a Health and Personal Social Services perspective, compared to waiting list controls who had already undergone first-eye cataract surgery.MethodsA cost-utility analysis was undertaken alongside a randomized controlled trial of second-eye cataract surgery in secondary care ophthalmology clinics. A total of 239 women over 70 years old with one unoperated cataract were randomized to cataract surgery (expedited, approximately 4 weeks) or control (routine surgery, 12 months wait). Outcomes were measured in terms of quality-adjusted life years (QALYs), with health-related quality of life estimated using the EuroQol EQ-5D.ResultsThe operated group had costs which were, on average, £646 more than the control group (95% confidence interval, £16–1276, P<0.04) and had a mean QALY gain of 0.015 (95% confidence interval, −0.039 to 0.068, P=0.59) per patient over 1 year. Therefore, the incremental cost-utility ratio was £44 263 over the 1-year trial period. In an analysis modelling costs and benefits over patients’ expected lifetime, the incremental cost per QALY was £17 299, under conservative assumptions.ConclusionsSecond-eye cataract surgery is not likely to be cost-effective in the short term for those with mild visual dysfunction pre-operation. In the long term, second-eye cataract surgery appears to be cost-effective unless carer costs are included. [ABSTRACT FROM AUTHOR]

While cochlear implantation is an increasingly routine provision for profoundly deaf children in many countries, parents still require information about the procedure and likely outcomes in order to make an informed decision. Other parents can provide them with the insights of those who have undergone the process themselves and observed outcomes at first hand. The parents of 101 consecutively implanted children completed the questionnaire: Children with cochlear implants: parental perspectives. Average age at implantation was 4.7 years: range 1.3-12.4 years, with 86% percent congenitally deaf, and 14% acquired deafness. Parents responded to 74 statements on a Likert scale; the responses exploring the process of implantation have been reported in a previous paper. Those responses reporting the outcomes for children and families following implantation are analysed in this paper. Parents reported that they were largely satisfied with the outcomes from implantation: that their children developed greater confidence, were more independent, that the use of spoken language had developed greatly and that communication within the family had improved. The children did not need more support from their parents than before implantation and the support parents were giving was more productive. However, there still remained concerns: parents needed to be patient as progress took time, and a number remained concerned about future education and felt that outcomes from implantation had not met their expectations. The children were considered reliant on their implant systems and hence on the optimal functioning of the technology; this demands long-term management to ensure that those dealing with the technology on a daily basis have the skills and equipment to manage them optimally. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: To examine the cost-effectiveness of pediatric cochlear implantation over time.Methods: A prospective study based on ninety-eight children implanted between 1989 and 1996 at Nottingham's Paediatric Cochlear Implantation Programme, UK. The influence of outcomes and other variables on total costs was examined using multivariate regression analysis.Results: Having controlled for potential confounding variables, total cost was negatively related to year of implant and positively related to the number of hours of rehabilitation (p=.000).Conclusions: Having controlled for outcomes (Categories of Auditory Performance and Speech Intelligibility Rating), the cost-effectiveness improved over time. This finding may be due to a learning curve and have policy implications. [ABSTRACT FROM AUTHOR]

Summary: Atopic eczema is a skin disease affecting around 20% of UK children, 16% of whom have moderate to severe disease. Severe atopic eczema can cause sleep disturbance, poor school attendance and social withdrawal, as well as attention‐deficit hyperactivity disorder, anxiety and clinical depression. Skin can become infected and this can be a reason for hospital admission. Although most cases of atopic eczema can be treated with emollients, topical anti‐inflammatory treatments and/or ultraviolet (UV) therapy, around 2% of children require oral (taken by mouth) immuno‐suppressive treatment. The main treatment options of this type (called systemic agents) are Ciclosporin (CyA) and Methotrexate (MTX) and there is concern about their potential short‐ and long‐term side effects. This article explains an upcoming clinical trial called "The TREatment of severe Atopic eczema Trial" (TREAT). TREAT addresses key clinical questions for the management of children with severe atopic eczema using systemic medication, in particular whether there is a difference in speed of onset (how long the drug takes to start working), effectiveness, side‐effect profile and reduction in flares post‐treatment between CyA and MTX, and the cost‐effectiveness of the drugs. Furthermore, TREAT examines how both drugs go about reducing inflammation in the body and on the skin. The study will involve 102 children aged 2 to 16 years. Linked Article: Irvine et al. Br J Dermatol 2018; 179:1297–1306 [ABSTRACT FROM AUTHOR]

The article discusses research being done on eye cataract surgery. It references a study by T. H. Sash et al published in the 2008 issue of "British Journal of Ophthalmology." The objective of the research is to analyze the cost-effectiveness of first eye cataract surgery compared with no surgery from a health service and personal social services perspective. The outcome measures, relevant methodology and results of the study are revealed.

Background: Falls in hospitals are common, resulting in injury and anxiety to patients, and large costs to NHS organisations. More than half of all in-patient falls in elderly people in acute care settings occur at the bedside, during transfers or whilst getting up to go to the toilet. In the majority of cases these falls are unwitnessed. There is insufficient evidence underpinning the effectiveness of interventions to guide clinical staff regarding the reduction of falls in the elderly inpatient. New patient monitoring technologies have the potential to offer advances in falls prevention. Bedside sensor equipment can alert staff, not in the immediate vicinity, to a potential problem and avert a fall. However no studies utilizing this assistive technology have demonstrated a significant reduction in falls rates in a randomised controlled trial setting.Methods/design: The research design is an individual patient randomised controlled trial of bedside chair and bed pressure sensors, incorporating a radio-paging alerting mode to alert staff to patients rising from their bed or chair, across five acute elderly care wards in Nottingham University Hospitals NHS Trust. Participants will be randomised to bedside chair and bed sensors or to usual care (without the use of sensors). The primary outcome is the number of bedside in-patient falls.Discussion: The REFINE study is the first randomised controlled trial of bedside pressure sensors in elderly inpatients in an acute NHS Trust. We will assess whether falls can be successfully and cost effectively reduced using this technology, and report on its acceptability to both patients and staff. [ABSTRACT FROM AUTHOR]

Recombinant adeno-associated viral (AAV) vectors have emerged as prominent gene delivery vehicles for gene therapy. In the journey of an AAV vector, AAV vectors can be exposed to different proteolytic environments inside the production cells, during the cell lysis step, within the endosome, and finally inside the cell nucleus. The stability of a modified AAV serotype 2 (AAV2) capsid was evaluated via a proteolytic approach using trypsin and other proteases and both denaturing and non-denaturing analytical methods. Trypsin digestion of the AAV2 capsids resulted in clips of the capsid proteins at the C-terminus as confirmed by denaturing methods including SDS-PAGE, CE-SDS, Western blot, and RPLC-MS. It was found that the AAV2 capsid with clips not only remains structurally intact, as confirmed by non-denaturing methods including SEC, thermostability testing, and cryo-EM, but also remains potent, as confirmed in a cell-based potency assay. This finding reveals that AAV2 capsid with proteolytic cuts remains intact and potent since the icosahedral three-dimensional structural arrangement of AAV capsid proteins can protect the clipped fragment from being released from the capsid, such that the AAV capsid remains intact allowing for the functionality to be maintained to deliver the DNA in the host cell. Evaluation of AAV stability using a proteolytic approach and multiple denaturing and non-denaturing analytical methods can provide valuable information for engineering AAV capsids to develop AAV-based gene therapy., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate statement: No animal experiment was performed in this study. All methods were performed in accordance with the relevant guidelines and regulations., (© 2024. The Author(s).)

Competing Interests: Conflicts of interest The full list of authors’ conflicts of interest is provided in Appendix S2 in the Supporting Information.

Introduction: A key goal for working age stroke survivors is to return to work, yet only around 50% achieve this at 12 months. Currently, there is limited evidence of effectiveness of early stroke-specialist vocational rehabilitation (ESSVR) interventions from randomised controlled trials. This study examined fidelity to ESSVR and explored social and structural factors which may have influenced implementation in the RETurn to work After stroKE (RETAKE) randomised controlled trial., Methods: Mixed-methods process evaluation assessing intervention fidelity and incorporating longitudinal case-studies exploring stroke survivors' experiences of support to return to work. Normalisation Process Theory, and the Conceptual Model for Implementation Fidelity, informed data collection and analysis., Results: Sixteen sites across England and Wales participated in RETAKE. Forty-eight occupational therapists (OTs), supported by 6 mentors experienced in vocational rehabilitation (VR), delivered the intervention (duration 12 months) between February 2018 and April 2022. Twenty-six participants (15 ESSVR, 11 usual care (UC)) were included in longitudinal case-studies. An additional 18 participants (8 ESSVR and 10 UC) were interviewed once. Nineteen OTs, 6 mentors and 19 service managers were interviewed. Fidelity was measured for 39 ESSVR participants; mean fidelity score was 78.8% (SD:19.2%, range 31-100%). Comparison of the experiences of ESSVR and UC participants indicated duration and type of support to return to work were perceived to be better for ESSVR participants. They received early, co-ordinated support including employer liaison and workplace adjustments where appropriate. In contrast, UC participants reported limited or no VR or return to work support from health professionals. Typically, UC support lasted 2-8 weeks, with poor communication and co-ordination between rehabilitation providers. Mentor support for OTs appeared to increase fidelity. Service managers indicated ESSVR would enhance post-stroke services., Conclusions: ESSVR was valued by participants and was delivered with fidelity; implementation appeared to be facilitated by mentor support for OTs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Clarke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Acne is common, can cause significant impact on quality of life and is a frequent reason for long-term antibiotic use. Spironolactone has been prescribed for acne in women for many years, but robust evidence is lacking., Objective: To evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women., Design: Pragmatic, parallel, double-blind, randomised superiority trial., Setting: Primary and secondary healthcare and community settings (community and social media advertising)., Participants: Women aged 18 years and older with facial acne persisting for at least 6 months, judged to potentially warrant oral antibiotic treatment., Interventions: Participants were randomised 1 : 1, using an independent web-based procedure, to either 50 mg/day spironolactone or matched placebo until week 6, increasing to 100 mg/day spironolactone or matched placebo until week 24. Participants continued usual topical treatment., Main Outcome Measures: Primary outcome was the adjusted mean difference in Acne-Specific Quality of Life symptom subscale score at 12 weeks. Secondary outcomes included Acne-Specific Quality of Life total and subscales; participant self-assessed improvement; Investigator's Global Assessment; Participant's Global Assessment; satisfaction; adverse effects and cost-effectiveness., Results: Of 1267 women assessed for eligibility, 410 were randomised (201 intervention, 209 control), 342 in the primary analysis (176 intervention, 166 control). Mean age was 29.2 years (standard deviation 7.2) and 7.9% (28/356) were from non-white backgrounds. At baseline, Investigator's Global Assessment classified acne as mild in 46%, moderate in 40% and severe in 13%. At baseline, 82.9% were using topical treatments. Over 95% of participants in both groups tolerated the treatment and increased their dose. Mean baseline Acne-Specific Quality of Life symptom subscale was 13.0 (standard deviation 4.7) across both groups. Mean scores at week 12 were 19.2 (standard deviation 6.1) for spironolactone and 17.8 (standard deviation 5.6) for placebo [difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46) adjusting for baseline variables]. Mean scores at week 24 were 21.2 (standard deviation 5.9) in spironolactone group and 17.4 (standard deviation 5.8) in placebo group [adjusted difference 3.77 (95% confidence interval 2.50 to 5.03) adjusted]. Secondary outcomes also favoured spironolactone at 12 weeks with greater differences at 24 weeks. Participants taking spironolactone were more likely than those taking placebo to report overall acne improvement at 12 weeks {72.2% vs. 67.9% [adjusted odds ratio 1.16 (95% confidence interval 0.70 to 1.91)]} and at 24 weeks {81.9% vs. 63.3% [adjusted odds ratio 2.72 (95% confidence interval 1.50 to 4.93)]}. Investigator's Global Assessment was judged successful at week 12 for 31/201 (18.5%) taking spironolactone and 9/209 (5.6%) taking placebo [adjusted odds ratio 5.18 (95% confidence interval 2.18 to 12.28)]. Satisfaction with treatment improved in 70.6% of participants taking spironolactone compared with 43.1% taking placebo [adjusted odds ratio 3.12 (95% confidence interval 1.80 to 5.41)]. Adverse reactions were similar between groups, but headaches were reported more commonly on spironolactone (20.4% vs. 12.0%). No serious adverse reactions were reported. Taking account for missing data through multiple imputation gave an incremental cost per quality-adjusted life-year of £27,879 (adjusted) compared to placebo or £2683 per quality-adjusted life-year compared to oral antibiotics., Conclusions: Spironolactone resulted in better participant-reported and investigator-reported outcomes than placebo, with greater differences at week 24 than week 12., Trial Registration: This trial is registered as ISRCTN12892056 and EudraCT (2018-003630-33)., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/13/02) and is published in full in Health Technology Assessment ; Vol. 28, No. 56. See the NIHR Funding and Awards website for further award information.

Background: A small amount of evidence suggests that nasal sprays, or physical activity and stress management, could shorten the duration of respiratory infections. This study aimed to assess the effect of nasal sprays or a behavioural intervention promoting physical activity and stress management on respiratory illnesses, compared with usual care., Methods: This randomised, controlled, open-label, parallel-group trial was done at 332 general practitioner practices in the UK. Eligible adults (aged ≥18 years) had at least one comorbidity or risk factor increasing their risk of adverse outcomes due to respiratory illness (eg, immune compromise due to serious illness or medication; heart disease; asthma or lung disease; diabetes; mild hepatic impairment; stroke or severe neurological problem; obesity [BMI ≥30 kg/m 2 ]; or age ≥65 years) or at least three self-reported respiratory tract infections in a normal year (ie, any year before the COVID-19 pandemic). Participants were randomly assigned (1:1:1:1) using a computerised system to: usual care (brief advice about managing illness); gel-based spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); saline spray (two sprays per nostril at the first sign of an infection or after potential exposure to infection, up to 6 times per day); or a brief behavioural intervention in which participants were given access to a website promoting physical activity and stress management. The study was partially masked: neither investigators nor medical staff were aware of treatment allocation, and investigators who did the statistical analysis were unaware of treatment allocation. The sprays were relabelled to maintain participant masking. Outcomes were assessed using data from participants' completed monthly surveys and a survey at 6 months. The primary outcome was total number of days of illness due to self-reported respiratory tract illnesses (coughs, colds, sore throat, sinus or ear infections, influenza, or COVID-19) in the previous 6 months, assessed in the modified intention-to-treat population, which included all randomly assigned participants who had primary outcome data available. Key secondary outcomes were possible harms, including headache or facial pain, and antibiotic use, assessed in all randomly assigned participants. This trial was registered with ISRCTN, 17936080, and is closed to recruitment., Findings: Between Dec 12, 2020, and April 7, 2023, of 19 475 individuals screened for eligibility, 13 799 participants were randomly assigned to usual care (n=3451), gel-based nasal spray (n=3448), saline nasal spray (n=3450), or the digital intervention promoting physical activity and stress management (n=3450). 11 612 participants had complete data for the primary outcome and were included in the primary outcome analysis (usual care group, n=2983; gel-based spray group, n=2935; saline spray group, n=2967; behavioural website group, n=2727). Compared with participants in the usual care group, who had a mean of 8·2 (SD 16·1) days of illness, the number of days of illness was significantly lower in the gel-based spray group (mean 6·5 days [SD 12·8]; adjusted incidence rate ratio [IRR] 0·82 [99% CI 0·76-0·90]; p<0·0001) and the saline spray group (6·4 days [12·4]; 0·81 [0·74-0·88]; p<0·0001), but not in the group allocated to the behavioural website (7·4 days [14·7]; 0·97 [0·89-1·06]; p=0·46). The most common adverse event was headache or sinus pain in the gel-based group: 123 (4·8%) of 2556 participants in the usual care group; 199 (7·8%) of 2498 participants in the gel-based group (risk ratio 1·61 [95% CI 1·30-1·99]; p<0·0001); 101 (4·5%) of 2377 participants in the saline group (0·81 [0·63-1·05]; p=0·11); and 101 (4·5%) of 2091 participants in the behavioural intervention group (0·95 [0·74-1·22]; p=0·69). Compared with usual care, antibiotic use was lower for all interventions: IRR 0·65 (95% CI 0·50-0·84; p=0·001) for the gel-based spray group; 0·69 (0·45-0·88; p=0·003) for the saline spray group; and 0·74 (0·57-0·94; p=0·02) for the behavioural website group., Interpretation: Advice to use either nasal spray reduced illness duration and both sprays and the behavioural website reduced antibiotic use. Future research should aim to address the impact of the widespread implementation of these simple interventions., Funding: National Institute for Health and Care Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There is a lack of well-conducted randomized controlled trials evaluating the effectiveness of theory-based online interventions for eczema. To address these deficiencies, we previously developed and demonstrated the effectiveness of two online behavioural interventions: Eczema Care Online for parents/carers of children with eczema, and Eczema Care Online for young people with eczema., Objectives: To explore the views and experiences of people who have used the Eczema Care Online interventions to provide insights into how the interventions worked and identify contextual factors that may impede users' engagement with the interventions., Methods: Qualitative semistructured interviews were conducted with 17 parents/carers of children with eczema and 17 young people with eczema. Participants were purposively sampled from two randomized controlled trials of the interventions and recruited from GP surgeries in England. Transcripts were analysed using inductive thematic analysis, and intervention modifications were identified using the person-based approach table of changes method., Results: Both young people and parents/carers found the interventions easy to use, relatable and trustworthy, and perceived that they helped them to manage their eczema, thus suggesting that Eczema Care Online may be acceptable to its target groups. Our analysis suggested that the interventions may reduce eczema severity by facilitating empowerment among its users, specifically through improved understanding of, and confidence in, eczema management, reduced treatment concerns, and improved treatment adherence and management of irritants/triggers. Reading about the experiences of others with eczema helped people to feel 'normal' and less alone. Some (mainly young people) expressed firmly held negative beliefs about topical corticosteroids, views that were not influenced by the intervention. Minor improvements to the design and navigation of the Eczema Care Online interventions and content changes were identified and made, ready for wider implementation., Conclusions: People with eczema and their families can benefit from reliable information, specifically information on the best and safest ways to use their eczema treatments early in their eczema journey. Together, our findings from this study and the corresponding trials suggest wider implementation of Eczema Care Online (EczemaCareOnline.org.uk) is justified., Competing Interests: Conflicts of interest S.M.L. is a coinvestigator on the IMI Horizon 2020 project BIOMAP, but is not in receipt of industry funding. L.H. has received consultancy fees from the University of Oxford on an educational grant funded by Pfizer, unrelated to the submitted work. The remaining authors declare they have no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Objectives: This mixed-method process evaluation underpinned by normalisation process theory aims to measure fidelity to the intervention, understand the social and structural context in which the intervention is delivered and identify barriers and facilitators to intervention implementation., Setting: RETurn to work After stroKE (RETAKE) is a multicentre individual patient randomised controlled trial to determine whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care is a clinically and cost-effective therapy to facilitate return to work after stroke, compared with usual care alone. This protocol paper describes the embedded process evaluation., Participants and Outcome Measures: Intervention training for therapists will be observed and use of remote mentor support reviewed through documentary analysis. Fidelity will be assessed through participant questionnaires and analysis of therapy records, examining frequency, duration and content of ESSVR sessions. To understand the influence of social and structural contexts, the process evaluation will explore therapists' attitudes towards evidence-based practice, competency to deliver the intervention and evaluate potential sources of contamination. Longitudinal case studies incorporating non-participant observations will be conducted with a proportion of intervention and usual care participants. Semistructured interviews with stroke survivors, carers, occupational therapists, mentors, service managers and employers will explore their experiences as RETAKE participants. Analysis of qualitative data will draw on thematic and framework approaches. Quantitative data analysis will include regression models and descriptive statistics. Qualitative and quantitative data will be independently analysed by process evaluation and Clinical Trials Research Unit teams, respectively. Linked data, for example, fidelity and describing usual care will be synthesised by comparing and integrating quantitative descriptive data with the qualitative findings., Ethics and Dissemination: Approval obtained through the East Midlands-Nottingham 2 Research Ethics Committee (Ref: 18/EM/0019) and the National Health ServiceResearch Authority. Dissemination via journal publications, stroke conferences, social media and meetings with national Stroke clinical leads., Trial Registration Number: ISRCTN12464275., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To determine the clinical and cost effectiveness of a multifactorial fall prevention programme compared with usual care in long term care homes., Design: Multicentre, parallel, cluster randomised controlled trial., Setting: Long term care homes in the UK, registered to care for older people or those with dementia., Participants: 1657 consenting residents and 84 care homes. 39 were randomised to the intervention group and 45 were randomised to usual care., Interventions: Guide to Action for Care Homes (GtACH): a multifactorial fall prevention programme or usual care., Main Outcome Measures: Primary outcome measure was fall rate at 91-180 days after randomisation. The economic evaluation measured health related quality of life using quality adjusted life years (QALYs) derived from the five domain five level version of the EuroQoL index (EQ-5D-5L) or proxy version (EQ-5D-5L-P) and the Dementia Quality of Life utility measure (DEMQOL-U), which were self-completed by competent residents and by a care home staff member proxy (DEMQOL-P-U) for all residents (in case the ability to complete changed during the study) until 12 months after randomisation. Secondary outcome measures were falls at 1-90, 181-270, and 271-360 days after randomisation, Barthel index score, and the Physical Activity Measure-Residential Care Homes (PAM-RC) score at 91, 180, 270, and 360 days after randomisation., Results: Mean age of residents was 85 years. 32% were men. GtACH training was delivered to 1051/1480 staff (71%). Primary outcome data were available for 630 participants in the GtACH group and 712 in the usual care group. The unadjusted incidence rate ratio for falls between 91 and 180 days was 0.57 (95% confidence interval 0.45 to 0.71, P<0.001) in favour of the GtACH programme (GtACH: six falls/1000 residents v usual care: 10 falls/1000). Barthel activities of daily living indices and PAM-RC scores were similar between groups at all time points. The incremental cost was £108 (95% confidence interval -£271.06 to 487.58), incremental QALYs gained for EQ-5D-5L-P was 0.024 (95% confidence interval 0.004 to 0.044) and for DEMQOL-P-U was 0.005 (-0.019 to 0.03). The incremental costs per EQ-5D-5L-P and DEMQOL-P-U based QALY were £4544 and £20 889, respectively., Conclusions: The GtACH programme was associated with a reduction in fall rate and cost effectiveness, without a decrease in activity or increase in dependency., Trial Registration: ISRCTN34353836., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding from the National Institute for Health Research; no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Acne is one of the most common inflammatory skin diseases worldwide and can have significant psychosocial impact and cause permanent scarring. Spironolactone, a potassium-sparing diuretic, has antiandrogenic properties, potentially reducing sebum production and hyperkeratinisation in acne-prone follicles. Dermatologists have prescribed spironolactone for acne in women for over 30 years, but robust clinical study data are lacking. This study seeks to evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women., Methods and Analysis: Women (≥18 years) with persistent facial acne requiring systemic therapy are randomised to receive one tablet per day of 50 mg spironolactone or a matched placebo until week 6, increasing to up to two tablets per day (total of 100 mg spironolactone or matched placebo) until week 24, along with usual topical therapy if desired. Study treatment stops at week 24; participants are informed of their treatment allocation and enter an unblinded observational follow-up period for up to 6 months (up to week 52 after baseline). Primary outcome is the Acne-specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes include Acne-QoL total and subscales; participant acne self-assessment recorded on a 6-point Likert scale at 6, 12, 24 weeks and up to 52 weeks; Investigator's Global Assessment at weeks 6 and 12; cost and cost effectiveness are assessed over 24 weeks. Aiming to detect a group difference of 2 points on the Acne-QoL symptom subscale (SD 5.8, effect size 0.35), allowing for 20% loss to follow-up, gives a sample size of 398 participants., Ethics and Dissemination: This protocol was approved by Wales Research Ethics Committee (18/WA/0420). Follow-up to be completed in early 2022. Findings will be disseminated to participants, peer-reviewed journals, networks and patient groups, on social media, on the study website and the Southampton Clinical Trials Unit website to maximise impact., Trial Registration Number: ISRCTN12892056;Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Evidence for the effectiveness of vitiligo treatments is limited., Objectives: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo., Methods: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB-UVB), NB-UVB (NB-UVB + placebo TCS) or a combination (TCS + NB-UVB). TCS was applied once daily on alternating weeks; NB-UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant-reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015., Results: In total 517 participants were randomized to TCS (n = 173), NB-UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB-UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between-group difference 10·9% (95% confidence interval 1·0%-20·9%; P = 0·032; number needed to treat = 10). NB-UVB alone was not superior to TCS: adjusted between-group difference 5·2% (95% CI - 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment)., Conclusions: Combination treatment with home-based handheld NB-UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one-quarter of participants., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Economic evidence for vitiligo treatments is absent., Objectives: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo., Methods: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015., Results: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment., Conclusions: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Objectives: Health economics analysis plans (HEAPs) currently lack consistency, with uncertainty surrounding appropriate content. We aimed to develop a list of essential items that should be included in HEAPs for economic evaluations conducted alongside randomized trials., Methods: A list of potential items for inclusion was developed by examining existing HEAPs. An electronic Delphi survey was conducted among professional health economists. Respondents were asked to rate potential items from 1 (least important) to 9 (most important), suggest additional items, and comment on proposed items (round 1). A second survey (round 2) was emailed to participants, including the participant's own scores from round 1 along with summary results from the whole panel; participants were asked to rerate each item. Consensus criteria for inclusion in the final list were predefined as >70% of participants rating an item 7-9 and <15% rating it 1-3 after round 2. A final item selection meeting was held to scrutinize the results and adjudicate on items lacking consensus., Results: 62 participants completed round 1 of the survey. The initial list included 72 potential items; all 72 were carried forward to round 2, and no new items were added. 48 round 1 respondents (77.4%) completed round 2 and reached consensus on 53 items. At the final meeting, the expert panel (n = 9) agreed that 58 items should be included in the essential list, moved 9 items to an optional list, and dropped 5 items., Conclusions: Via expert consensus opinion, this study identified 58 items that are considered essential in a HEAP., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Eczema care requires management of triggers and various treatments. We developed two online behavioural interventions to support eczema care called ECO (Eczema Care Online) for young people and ECO for families. This protocol describes two randomised controlled trials (RCTs) aimed to evaluate clinical and cost-effectiveness of the two interventions. METHODS AND ANALYSIS: Design : Two independent, pragmatic, unmasked, parallel group RCTs with internal pilots and nested health economic and process evaluation studies. Setting : Participants will be recruited from general practitioner practices in England. Participants : Young people aged 13-25 years with eczema and parents and carers of children aged 0-12 years with eczema, excluding inactive or very mild eczema (five or less on Patient-Oriented Eczema Measure (POEM)). Interventions : Participants will be randomised to online intervention plus usual care or to usual eczema care alone. Outcome measures : Primary outcome is eczema severity over 24 weeks measured by POEM. Secondary outcomes include POEM 4-weekly for 52 weeks, quality of life, eczema control, itch intensity (young people only), patient enablement, health service and treatment use. Process measures include treatment adherence, barriers to adherence and intervention usage. Our sample sizes of 303 participants per trial are powered to detect a group difference of 2.5 (SD 6.5) in monthly POEM scores over 24 weeks (significance 0.05, power 0.9), allowing for 20% loss to follow-up. Cost-effectiveness analysis will be from a National Health Service and personal social service perspective. Qualitative and quantitative process evaluation will help understand the mechanisms of action and participant experiences and inform implementation., Ethics and Dissemination: The study has been approved by South Central Oxford A Research Ethics Committee (19/SC/0351). Recruitment is ongoing, and follow-up will be completed by mid-2022. Findings will be disseminated to participants, the public, dermatology and primary care journals, and policy makers., Trial Registration Number: ISRCTN79282252., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: With 70% of care home residents experiencing a medication error every day in the UK, better multi-professional working between medical practitioners, pharmacists and care homes was recommended. The aim of this study was to determine the effectiveness (falls reduction) and cost-effectiveness, of a multi-professional medication review (MPMR) service in care homes for older people., Method: A total of care homes in the East of England were cluster randomised to 'usual care' or two multi-professional (General practitioner, clinical pharmacist and care homes staff) medication reviews during the 12-month trial period. Target recruitment was 900 residents with 10% assumed loss to follow-up. Co-primary outcome measures were number of falls and potentially inappropriate prescribing assessed by the Screening Tool of Older Persons Prescriptions., Key Findings: A total of 826 care home residents were recruited with 324 lost to follow-up for at least one primary outcome measure. The mean number of falls per resident per annum was 3.3 for intervention and 3.0 for control (P = 0.947). Each resident was found to be prescribed 0.69 (intervention) and 0.85 (control) potentially inappropriate medicines after 12 months (P = 0.046). No significant difference identified in emergency hospital admissions or deaths. Estimated unadjusted incremental mean cost per resident was £374.26 higher in the intervention group., Conclusions: In line with other medication review based interventions in care homes, two MPMRs improved medication appropriateness but failed to demonstrate improvements in clinical outcomes. From a health system perspective costs where estimated to increase overall and therefore a different model of medicines management is required., (© 2020 The Authors. International Journal of Pharmacy Practice published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society.)

Purpose: Measuring quality of life in acute asthmatics is challenging, especially when asthma attacks can occur sporadically. Several questionnaires can be used to measure quality of life in this patient group; however, psychometric testing is limited on questionnaires that can be used to estimate Quality Adjusted Life years. The objective of this study is to assess the construct validity (convergent and discriminative validity) and responsiveness of the EuroQol-5-Dimensions 5-Level (EQ-5D-5L), Asthma Quality of Life Utility Index-5 Dimensions (AQL-5D) and Time Trade-Off (TTO) in acute asthma patients., Methods: Data from a prospective cohort study were used to test the validity and responsiveness of the EQ-5D-5L, AQL-5D and TTO in asthma patients who were recruited from UK accident & emergency departments or hospital wards. The spearman's rank correlation coefficient, the Kruskal-Wallis test statistic and the standardized response mean were used to test for convergent validity, discriminative validity and responsiveness, respectively., Results: One hundred and twenty-one participants were included in the available case analysis. The EQ-5D-5L and AQL-5D showed moderate to strong correlations for convergent validity at baseline, week 4 and week 8. The AQL-5D and TTO showed moderate correlations at week 4 and week 8. No statistical significance was observed for discriminative validity at baseline. Both the EQ-5D-5L and the AQL-5D also showed that they were sensitive to change for the recovery responses., Conclusions: The EQ-5D-5L and AQL-5D showed stronger construct validity and responsiveness compared to the TTO. Therefore, both the EQ-5D-5L and AQL-5D should be considered for use in future economic evaluations.

Introduction: Cystic fibrosis (CF) is a life-limiting, hereditable condition, with the highest prevalence in Europe. CF treatments have led to improvements in clinical symptoms, disease management and decelerated disease progression. However, little is known about the health state utility (HSU) associated with CF disease states, adverse events, and changes in disease severity. Although HSU data have contributed to existing health economic modelling studies, a lack of such data have been highlighted. This systematic review aims to provide a summary of HSU-related research in CF and highlight related research gaps., Methods: Online searches were performed in six databases and studies in any of the following categories were included: (1) estimation of HSUs in CF; (2) mapping studies between patient-reported outcome measures (PROMs) and HSUs; (3) economic evaluations on the management of CF that report primary HSU data; and (4) any CF clinical trial that reported HSU as an outcome., Results: A total of 17 studies were reviewed, of which 12 provided HSU values for specific CF populations. The remaining five articles provided HSU data that were broken down by CF relevant health states, including lung transplantations, pulmonary exacerbation (PEx) events and forced expiratory volume in 1 s (FEV 1 )., Conclusion: Current HSU data in CF are limited and there is considerable scope for further research, both in providing HSU values for CF and in investigating methods for HSU elicitation/evaluation in CF populations.

The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) modelling taskforce suggests decision models should be thoroughly reported and transparent. However, the level of transparency and indeed how transparency should be assessed are yet to be defined. One way may be to attempt to replicate the model and its outputs. The ability to replicate a decision model could demonstrate adequate reporting transparency. This review aims to explore published definitions of replication success across all scientific disciplines and to consider how such a definition should be tailored for use in health economic models. A literature review was conducted to identify published definitions of a 'successful replication'. Using these as a foundation, several definitions of replication success were constructed, to be applicable to replications of economic decision models, with the associated strengths and weaknesses of such definitions discussed. A substantial body of literature discussing replicability was found; however, relatively few studies, ten, explicitly defined a successful replication. These definitions varied from subjective assessments to expecting exactly the same results to be reproduced. Whilst the definitions that have been found may help to construct a definition specific to health economics, no definition was found that completely encompassed the unique requirements for decision models. Replication is widely discussed in other scientific disciplines; however, as of yet, there is no consensus on how replicable models should be within health economics or what constitutes a successful replication. Replication studies can demonstrate how transparently a model is reported, identify potential calculation errors and inform future reporting practices. It may therefore be a useful adjunct to other transparency or quality measures.

Background: Atopic eczema is an inflammatory skin condition, with a similar impact on health-related quality of life as other chronic diseases. Increasing pressures on resources within the National Health Service increase the importance of having good economic evidence to inform their allocation., Objectives: To educate dermatologists about economic methods with reference to currently available economic evidence on eczema., Methods: The role of different types of economic evidence is illustrated by evidence found in a systematic literature search conducted across 12 online databases up to 22 May 2017. Primary empirical studies either reporting the results of a cost-of-illness study or evaluating the cost, utility or full economic evaluation of interventions for preventing or treating eczema were included. Two reviewers independently assessed studies for eligibility and performed data abstraction, with disagreements resolved by a third reviewer. Evidence tables of results were produced for narrative discussion. The reporting quality of economic evaluations was assessed., Results: Seventy-eight studies (described in 80 papers) were deemed eligible. Thirty-three (42%) were judged to be economic evaluations, 12 (15%) cost analyses, six (8%) utility analyses, 26 (33%) cost-of-illness studies and one a feasibility study (1%). The calcineurin inhibitors tacrolimus and pimecrolimus, as well as barrier creams, had the most economic evidence available. Partially hydrolysed infant formula was the most commonly evaluated prevention., Conclusions: The current level of economic evidence for interventions aimed at preventing and treating eczema is limited compared with that available for clinical outcomes, suggesting that greater collaboration between clinicians and economists might be beneficial., (© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Economic evaluations are used to identify which health treatments or preventions offer the most effective use of resources, or value for money. This is achieved by identifying, measuring and valuing the inputs and outcomes of alternative interventions. These evaluations are often conducted alongside clinical trials; however, these trials may end before the outcomes of economic interest have been observed and measured. An alternative to within trial economic evaluation is to use decision modelling, which can model the cost-effectiveness of interventions over an extended time period. This paper aims to provide an overview for clinicians of the different modelling techniques used within health economic evaluations and to introduce methods for critical appraisal. The most common modelling approaches, and their associated strengths and weaknesses, were discussed. Alongside this, practical examples specific to dermatology were given. These examples include studies where the model chosen or the methods used may not have been the most appropriate. Methods for critical appraisal were also highlighted. Common modelling approaches include Decision Trees, Markov Cohort, extensions to the Markov model (Monte Carlo Simulation) and Discrete Event Simulation models. Items of the Philips Checklist were discussed in the context of performing critical appraisal. Health economic decision models are multi-faceted and can often be complex. Full critical appraisal requires clinicians' unique knowledge, which is complementary to the knowledge of health economists., (© 2019 European Academy of Dermatology and Venereology.)

Background: Model replication is important because it enables researchers to check research integrity and transparency and, potentially, to inform the model conceptualization process when developing a new or updated model., Objective: The aim of this study was to evaluate the replicability of published decision analytic models and to identify the barriers and facilitators to replication., Methods: Replication attempts of 5 published economic modeling studies were made. The replications were conducted using only publicly available information within the manuscripts and supplementary materials. The replicator attempted to reproduce the key results detailed in the paper, for example, the total cost, total outcomes, and if applicable, incremental cost-effectiveness ratio reported. Although a replication attempt was not explicitly defined as a success or failure, the replicated results were compared for percentage difference to the original results., Results: In conducting the replication attempts, common barriers and facilitators emerged. For most case studies, the replicator needed to make additional assumptions when recreating the model. This was often exacerbated by conflicting information being presented in the text and the tables. Across the case studies, the variation between original and replicated results ranged from -4.54% to 108.00% for costs and -3.81% to 0.40% for outcomes., Conclusion: This study demonstrates that although models may appear to be comprehensively reported, it is often not enough to facilitate a precise replication. Further work is needed to understand how to improve model transparency and in turn increase the chances of replication, thus ensuring future usability., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)