Survey and online discussion groups to develop a patient-rated outcome measure on acceptability of treatment response in vitiligo

BackgroundVitiligo is a chronic depigmenting skin disorder which affects around 0.5-1% of the world’s population. The outcome measures used most commonly in trials to judge treatment success focus on repigmentation. Patient-reported outcome measures of treatment success are rarely used, although recommendations have been made for their inclusion in vitiligo trials. This study aimed to evaluate the face validity of a new patient-reported outcome measure of treatment response, for use in future trials and clinical practice. MethodAn online survey to gather initial views on what constitutes treatment success for people with vitiligo or their parents/carers, followed by online discussion groups with patients to reach consensus on what constitutes treatment success for individuals with vitiligo, and how this can be assessed in the context of trials. Participants were recruited from an existing database of vitiligo patients and through posts on the social network sites Facebook and Twitter. ResultsA total of 202 survey responses were received, of which 37 were excluded and 165 analysed. Three main themes emerged as important in assessing treatment response: a) the match between vitiligo and normal skin (how well it blends in); b) how noticeable the vitiligo is and c) a reduction in the size of the white patches. The majority of respondents said they would consider 80% or more repigmentation to be a worthwhile treatment response after 9 months of treatment. Three online discussion groups involving 12 participants led to consensus that treatment success is best measured by asking patients how noticeable their vitiligo is after treatment. This was judged to be best answered using a 5-point Likert scale, on which a score of 4 or 5 represents treatment success. ConclusionsThis study represents the first step in developing a patient reported measure of treatment success in vitiligo trials. Further work is now needed to assess its construct validity and responsiveness to change.<br/

Loss of residues 119 – 136, including the first β-strand of human prion protein, generates an aggregation-competent partially “open” form

In prion replication, the cellular form of prion protein (PrPC) must undergo a full conformational transition to its disease-associated fibrillar form. Transmembrane forms of PrP have been implicated in this structural conversion. The cooperative unfolding of a structural core in PrPC presents a substantial energy barrier to prion formation, with membrane insertion and detachment of parts of PrP presenting a plausible route to its reduction. Here, we examined the removal of residues 119 - 136 of PrP, a region which includes the first β-strand and a substantial portion of the conserved hydrophobic region of PrP, a region which associates with the ER membrane, on the structure, stability and self-association of the folded domain of PrPC. We see an "open" native-like conformer with increased solvent exposure which fibrilises more readily than the native state. These data suggest a stepwise folding transition, which is initiated by the conformational switch to this "open" form of PrPC

Porous Silicon Nanoparticles Embedded in Poly(lactic‐ co ‐glycolic acid) Nanofiber Scaffolds Deliver Neurotrophic Payloads to Enhance Neuronal Growth

Scaffolds made from biocompatible polymers provide physical cues to direct the extension of neurites and to encourage repair of damaged nerves. The inclusion of neurotrophic payloads in these scaffolds can substantially enhance regrowth and repair processes. However, many promising neurotrophic candidates are excluded from this approach due to incompatibilities with the polymer or with the polymer processing conditions. This work provides one solution to this problem by incorporating porous silicon nanoparticles (pSiNPs) that are pre-loaded with the therapeutic into a polymer scaffold during fabrication. The nanoparticle-drug-polymer hybrids are prepared in the form of oriented poly(lactic-co-glycolic acid) nanofiber scaffolds. We test three different therapeutic payloads: bpV(HOpic), a small molecule inhibitor of phosphatase and tensin homolog (PTEN); an RNA aptamer specific to tropomyosin-related kinase receptor type B (TrkB); and the protein nerve growth factor (NGF). Each therapeutic is loaded using a loading chemistry that is optimized to slow the rate of release of these water-soluble payloads. The drug-loaded pSiNP-nanofiber hybrids release approximately half of their TrkB aptamer, bpV(HOpic), or NGF payload in 2, 10, and >40 days, respectively. The nanofiber hybrids increase neurite extension relative to drug-free control nanofibers in a dorsal root ganglion explant assay

Quality of life in people with vitiligo: a systematic review and meta-analysis

Vitiligo is cosmetically disfiguring and has profound psychosocial effects due to stigmatization, problems in sexual function, anxiety, self-esteem and difficulty finding employment. Previous studies suggest a reduction in quality of life (QoL) due to vitiligo, but to date no systematic review has quantified this in comparison to people without vitiligo. Therefore, the aim of this review was to compare QoL in people with and without vitiligo

Using the Vitiligo Noticeability Scale in clinical trials: construct validity, interpretability, reliability and acceptability

Background: Validated outcome measures are needed for vitiligo trials. Objectives: To assess construct validity, interpretability, reliability and acceptability of the Vitiligo Noticeability Scale (VNS). Methods: We used images of vitiligo before and after treatment, plus outcome data, from the HI-Light Vitiligo trial. We compared outcome assessments made by trial participants with assessments of images by clinicians and people with vitiligo who were not trial participants [Patient and Public Involvement (PPI) panel]. Hypothesis testing assessed psychometric properties of the VNS, with κ statistics to assess agreement between outcomes. Three focus groups and two online discussion groups provided insight into the use of VNS by people with vitiligo. Results: Our hypothesis of a positive association between VNS and participant-reported global treatment success was supported for trial participants (κ = 0·41 if VNS success was defined as ≥ 4; κ = 0·71 if VNS success was defined as ≥ 3), but not for the blinded PPI panel (κ = 0·28). As hypothesized, the association with participant-reported global success was higher for VNS (κ = 0·41) than for clinician-reported percentage repigmentation (κ = 0·17). Seventy-five per cent of trial participants valued a VNS of 3 (partial response) as a treatment success. Test–retest reliability was good: κ = 0·69 (95% confidence interval 0·63–0·74). Age and skin phototype did not influence interpretation of the VNS scores. To people with vitiligo, the VNS is an acceptable and meaningful patient-reported outcome measure. Conclusions: Trial participants may assess their vitiligo differently compared with blinded assessors. A VNS score of 3 may be more highly valued by people undergoing vitiligo treatment than was previously thought. What is already known about this topic? Vitiligo is a common condition, and can have a considerable psychological impact. A Vitiligo Core Outcome Set is being developed, to enable the results of vitiligo trials to be compared and combined more easily. The Vitiligo Noticeability Scale (VNS) is a patient-reported outcome measure (PROM) developed in partnership with people with vitiligo; initial validation studies have been promising. What does this study add? The VNS shows good construct validity, reliability and acceptability; it can be used in all ages and skin phototypes. All five levels of the VNS scale should be reported for transparency, to aid interpretation of trial findings, and to facilitate meta-analysis in systematic reviews. VNS assessments made by trial participants and independent observers are likely to be qualitatively different, making blinded assessment of VNS by independent observers difficult to interpret. Blinding of participants to trial interventions is recommended whenever possible. What are the clinical implications of the work? The VNS can be used as a PROM to assess the cosmetic acceptability of repigmentation at individual patches of vitiligo. A VNS score of 3 or more is likely to be valued by patients as a treatment success

Quantification of drug metabolising enzymes and transporter proteins in the paediatric duodenum via LC-MS/MS proteomics using a QconCAT technique

Characterising the small intestine absorptive membrane is essential to enable prediction of the systemic exposure of oral formulations. In particular, the ontogeny of key intestinal Drug Metabolising Enzymes and Transporter (DMET) proteins involved in drug disposition needs to be elucidated to allow for accurate prediction of the PK profile of drugs in the paediatric cohort. Using pinch biopsies from the paediatric duodenum (n = 36; aged 11 months to 15 years), the abundance of 21 DMET proteins and two enterocyte markers were quantified via LC-MS/MS. An established LCMS nanoflow method was translated to enable analysis on a microflow LC system, and a new stable-isotope-labelled QconCAT standard developed to enable quantification of these proteins. Villin-1 was used to standardise abundancy values. The observed abundancies and ontogeny profiles, agreed with adult LC-MS/MS-based data, and historic paediatric data obtained via western blotting. A linear trend with age was observed for duodenal CYP3A4 and CES2 only. As this work quantified peptides on a pinch biopsy coupled with a microflow method, future studies using a wider population range are very feasible. Furthermore, this DMET ontogeny data can be used to inform paediatric PBPK modelling and to enhance the understanding of oral drug absorption and gut bioavailability in paediatric populations

Home interventions and light therapy for treatment of vitiligo (HI-Light Vitiligo Trial): study protocol for a randomized controlled trial

Vitiligo is a condition resulting in white patches on the skin. People with vitiligo can suffer from low self-esteem, psychological disturbance and diminished quality of life. Vitiligo is often poorly managed, partly due to lack of high quality evidence to inform clinical care. We describe here a large, independent, randomised controlled trial (RCT) assessing the comparative effectiveness of potent topical corticosteroid, home-based hand-held narrowband ultraviolet B-light (NB-UVB) or combination of the two, for the management of vitiligo. Methods and Analysis The HI-Light Vitiligo Trial is a multi-centre, three-arm, parallel group, pragmatic, placebo-controlled RCT. 516 adults and children with actively spreading, but limited, vitiligo are randomised (1:1:1) to one of three groups: mometasone furoate 0.1% ointment plus dummy NB-UVB light, vehicle ointment plus NB-UVB light, or mometasone furoate 0.1% ointment plus NB-UVB light. Treatment of up to three patches of vitiligo is continued for up to 9 months with clinic visits at baseline, 3, 6 and 9 months and four post treatment questionnaires. The HI-Light Vitiligo Trial assesses outcomes included in the vitiligo core outcome set and places emphasis on participants’ views of treatment success. The primary outcome is proportion of participants achieving treatment success (patient-rated Vitiligo Noticeability Scale) for a target patch of vitiligo at 9 months with further independent blinded assessment using digital images of the target lesion before and after treatment. Secondary outcomes include time to onset of treatment response, treatment success by body region, percentage repigmentation, quality of life, time-burden of treatment, maintenance of response, safety, and within-trial cost effectiveness. Ethics and Dissemination Approvals were granted by East Midlands–Derby Research Ethics Committee (14/EM/1173) and the MHRA (EudraCT 2014-003473-42). The trial was registered 8th January 2015 ISRCTN (17160087). Results will be published in full as open access in the NIHR Journal library and elsewhere

An examination of factors influencing the choice of therapy for patients with coronary artery disease

BACKGROUND: A diverse range of factors influence clinicians' decisions regarding the allocation of patients to different treatments for coronary artery disease in routine cardiology clinics. These include demographic measures, risk factors, co-morbidities, measures of objective cardiac disease, symptom reports and functional limitations. This study examined which of these factors differentiated patients receiving angioplasty from medication; bypass surgery from medication; and bypass surgery from angioplasty. METHODS: Univariate and multivariate logistic regression analyses were conducted on patient data from 214 coronary artery disease patients who at the time of recruitment had been received a clinical assessment and were reviewed by their cardiologist in order to determine the form of treatment they were to undergo: 70 would receive/continue medication, 71 were to undergo angioplasty and 73 were to undergo bypass surgery. RESULTS: Analyses differentiating patients receiving angioplasty from medication produced 9 significant univariate predictors, of which 5 were also multivariately significant (left anterior descending artery disease, previous coronary interventions, age, hypertension and frequency of angina). The analyses differentiating patients receiving surgery from angioplasty produced 12 significant univariate predictors, of which 4 were multivariately significant (limitations in mobility range, circumflex artery disease, previous coronary interventions and educational level). The analyses differentiating patients receiving surgery from medication produced 14 significant univariate predictors, of which 4 were multivariately significant (left anterior descending artery disease, previous cerebral events, limitations in mobility range and circumflex artery disease). CONCLUSION: Variables emphasised in clinical guidelines are clearly involved in coronary artery disease treatment decisions. However, variables beyond these may also be important factors when therapy decisions are undertaken thus their roles require further investigation

Silk garments plus standard care compared with standard care for treating eczema in children: a randomised controlled, observer blind, pragmatic trial (CLOTHES Trial)

Background The role of clothing in the management of eczema (syn. atopic dermatitis, atopic eczema) is poorly understood. This trial evaluated the effectiveness and cost-effectiveness of silk garments (in addition to standard care) for the management of eczema in children with moderate to severe disease. Methods and findings This was a parallel group randomised controlled, observer-blind trial. Children aged 1 to 15 years with moderate to severe eczema were recruited from secondary care and the community in five UK centres. Participants were allocated using on-line randomisation (1:1) to standard care, or standard care plus silk garments; stratified by age and recruiting centre. Silk garments were worn for 6 months. Primary outcome (eczema severity) was assessed at baseline, 2, 4 and 6 months, by nurses blinded to treatment allocation using the Eczema Area and Severity Index (EASI), which was log-transformed for analysis (intention-to-treat analysis). Safety outcome: number of skin infections. Three hundred children were randomised (26th Nov 2013 to 5th May 2015): 42% girls, 79% white, mean age 5 years. Primary analysis included 282/300 (94%) children (n = 141 in each group). The garments were worn more often at night than in the day (median of 81% of nights (25th to 75th centile 57% to 96%) and 34% of days (25th to 75th centile 10% to 76%)). Geometric mean EASI scores at baseline, 2, 4 and 6 months were 9·2, 6·4, 5·8, 5·4 for silk clothing and 8·4, 6·6, 6·0, 5·4 for standard care. There was no evidence of any difference between the groups in EASI score averaged over all follow up visits adjusted for baseline EASI score, age and centre (adjusted ratio of geometric means: 0·95, 95% CI 0·85 to 1·07). This confidence interval is equivalent to a difference of -1·5 to 0·5 in the original EASI scale units which is not clinically important. Skin infections occurred in 36/142 (25%) and 39/141 (28%) for silk clothing and standard care respectively. Even if the small observed treatment effect was genuine, the incremental cost per QALY was £56,881 in the base case analysis from an NHS perspective, suggesting that silk garments are unlikely to be cost-effective within currently accepted thresholds. Main limitations: whilst minimising detection bias, use of an objective primary outcome may have underestimated treatment effects. Conclusions Silk clothing is unlikely to provide additional benefit over standard care in children with moderate to severe eczema

N-terminal Domain of Prion Protein Directs Its Oligomeric Association

The self-association of prion protein (PrP) is a critical step in the pathology of prion diseases. It is increasingly recognized that small non-fibrillar ?-sheet-rich oligomers of PrP may be of crucial importance in the prion disease process. Here, we characterize the structure of a well defined ?-sheet-rich oligomer, containing ?12 PrP molecules, and often enclosing a central cavity, formed using full-length recombinant PrP. The N-terminal region of prion protein (residues 23-90) is required for the formation of this distinct oligomer; a truncated form comprising residues 91-231 forms a broad distribution of aggregated species. No infectivity or toxicity was found using cell and animal model systems. This study demonstrates that examination of the full repertoire of conformers and assembly states that can be accessed by PrP under specific experimental conditions should ideally be done using the full-length protein