Publications by authors named "Hywel Williams"

362 Publications

Stabilising disproportionation of lipophilic ionic liquid salts in lipid-based formulations.

Int J Pharm 2021 Feb 11;597:120292. Epub 2021 Feb 11.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052 Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, 381 Royal Parade, Parkville, Victoria 3052 Australia. Electronic address:

Lipid based formulations (LBFs) can enhance oral bioavailability, however, their utility may be restricted by low drug loading in the formulation. Converting drugs to drug-ionic liquids (drug-ILs) or lipophilic salts can significantly increase lipid solubility but this approach is complicated in some cases by salt disproportionation, leading to a reduction in solubility and physical instability. Here we explore the physical stability of the weakly basic model drug, cinnarizine (CIN), when paired with a decanoate counterion (Dec) to form the drug-IL, cinnarizine decanoate (CIN.Dec). Consistent with published studies of salt disproportionation in aqueous solution, weakly acidic counterions such as Dec lead to the generation of drug-IL lipid solutions with pHs below pH. This leads to CIN deprotonation to the less soluble free base and precipitation. Subsequent studies however, show that these effects can be reversed by acidification of the formulation (either with excess decanoic acid or other lipid soluble acids), stimulating a pH shift to the salt plateau of CIN.Dec and the formation of stable lipid solutions of CIN.Dec. Altering formulation pH to more acidic conditions, therefore stabilises drug-ILs formed using weakly acidic lipophilic counterions, and is a viable method to promote formulation stability via inhibition of disproportionation of some drug-ILs.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120292DOI Listing
February 2021

A social Beaufort scale to detect high winds using language in social media posts.

Sci Rep 2021 Feb 11;11(1):3647. Epub 2021 Feb 11.

College of Engineering, Mathematics and Physical Sciences, University of Exeter, North Park Road, Exeter, EX4 4QF, UK.

People often talk about the weather on social media, using different vocabulary to describe different conditions. Here we combine a large collection of wind-related Twitter posts (tweets) and UK Met Office wind speed observations to explore the relationship between tweet volume, tweet language and wind speeds in the UK. We find that wind speeds are experienced subjectively relative to the local baseline, so that the same absolute wind speed is reported as stronger or weaker depending on the typical weather conditions in the local area. Different linguistic tokens (words and emojis) are associated with different wind speeds. These associations can be used to create a simple text classifier to detect 'high-wind' tweets with reasonable accuracy; this can be used to detect high winds in a locality using only a single tweet. We also construct a 'social Beaufort scale' to infer wind speeds based only on the language used in tweets. Together with the classifier, this demonstrates that language alone is indicative of weather conditions, independent of tweet volume. However, the number of high-wind tweets shows a strong temporal correlation with local wind speeds, increasing the ability of a combined language-plus-volume system to successfully detect high winds. Our findings complement previous work in social sensing of weather hazards that has focused on the relationship between tweet volume and severity. These results show that impacts of wind and storms are found in how people communicate and use language, a novel dimension in understanding the social impacts of extreme weather.
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http://dx.doi.org/10.1038/s41598-021-82808-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878797PMC
February 2021

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

Clin Exp Allergy 2021 Feb 6. Epub 2021 Feb 6.

National Heart and Lung Institute, Imperial College London, London, UK.

Objective: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy.

Design: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy.

Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020.

Eligibility Criteria For Selected Studies: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years.

Results: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I =0%; moderate certainty; 2728 participants, 6 trials).

Conclusion: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.
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http://dx.doi.org/10.1111/cea.13847DOI Listing
February 2021

Supporting self-care for eczema: protocol for two randomised controlled trials of ECO (Eczema Care Online) interventions for young people and parents/carers.

BMJ Open 2021 Feb 5;11(2):e045583. Epub 2021 Feb 5.

School of Primary Care, Population Health and Medical Education, University of Southampton, Southampton, UK.

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: : Two independent, pragmatic, unmasked, parallel group RCTs with internal pilots and nested health economic and process evaluation studies. : Participants will be recruited from general practitioner practices in England. : 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)). : Participants will be randomised to online intervention plus usual care or to usual eczema care alone. : 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.
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http://dx.doi.org/10.1136/bmjopen-2020-045583DOI Listing
February 2021

Skin care interventions in infants for preventing eczema and food allergy.

Cochrane Database Syst Rev 2021 Feb 5;2:CD013534. Epub 2021 Feb 5.

National Heart & Lung Institute, Section of Inflammation and Repair, Imperial College London, London, UK.

Background: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy.

Objectives: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy.

Search Methods: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials.

Selection Criteria: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required.

Data Collection And Analysis: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen.

Main Results: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy.

Authors' Conclusions: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.
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http://dx.doi.org/10.1002/14651858.CD013534.pub2DOI Listing
February 2021

Home-based narrowband UVB, topical corticosteroid or combination for children and adults with vitiligo: HI-Light Vitiligo three-arm RCT.

Health Technol Assess 2020 11;24(64):1-128

Background: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo.

Objective: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo.

Design: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up.

Setting: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community.

Participants: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area.

Interventions: Topical corticosteroids [mometasone furoate 0.1% (Elocon, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based.

Main Outcome Measures: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment).

Results: In total, 517 participants were randomised (adults,  = 398; and children,  =  119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%;  = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%;  = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective).

Limitations: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase.

Conclusion: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed.

Future Work: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed.

Trial Registration: Current Controlled Trials ISRCTN17160087.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750863PMC
November 2020

Interventions for basal cell carcinoma of the skin.

Cochrane Database Syst Rev 2020 11 17;11:CD003412. Epub 2020 Nov 17.

Emeritus Professor, Evidence Based Health Care, University of Nottingham, Nottingham, UK.

Background: Basal cell carcinoma (BCC) is the commonest cancer affecting white-skinned individuals, and worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. First-line treatment is usually surgical excision, but alternatives are available. New published studies and the development of non-surgical treatments meant an update of our Cochrane Review (first published in 2003, and previously updated in 2007) was timely.

Objectives: To assess the effects of interventions for BCC in immunocompetent adults.

Search Methods: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and LILACS.

Selection Criteria: Randomised controlled trials (RCTs) of interventions for BCC in immunocompetent adults with histologically-proven, primary BCC. Eligible comparators were placebo, active treatment, other treatments, or no treatment.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane. Primary outcome measures were recurrence at three years and five years (measured clinically) (we included recurrence data outside of these time points if there was no measurement at three or five years) and participant- and observer-rated good/excellent cosmetic outcome. Secondary outcomes included pain during and after treatment, early treatment failure within six months, and adverse effects (AEs). We used GRADE to assess evidence certainty for each outcome.

Main Results: We included 52 RCTs (26 new) involving 6690 participants (median 89) in this update. All studies recruited from secondary care outpatient clinics. More males than females were included. Study duration ranged from six weeks to 10 years (average 13 months). Most studies (48/52) included only low-risk BCC (superficial (sBCC) and nodular (nBCC) histological subtypes). The majority of studies were at low or unclear risk of bias for most domains. Twenty-two studies were industry-funded: commercial sponsors conducted most of the studies assessing imiquimod, and just under half of the photodynamic therapy (PDT) studies. Overall, surgical interventions have the lowest recurrence rates. For high-risk facial BCC (high-risk histological subtype or located in the facial 'H-zone' or both), there may be slightly fewer recurrences with Mohs micrographic surgery (MMS) compared to surgical excision (SE) at three years (1.9% versus 2.9%, respectively) (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.16 to 2.64; 1 study, 331 participants; low-certainty evidence) and at five years (3.2% versus 5.2%, respectively) (RR 0.61, 95% CI 0.18 to 2.04; 1 study, 259 participants; low-certainty evidence). However, the 95% CI also includes the possibility of increased risk of recurrence and no difference between treatments. There may be little to no difference regarding improvement of cosmetic outcomes between MMS and SE, judged by participants and observers 18 months post-operatively (one study; low-certainty evidence); however, no raw data were available for this outcome. When comparing imiquimod and SE for nBCC or sBCC at low-risk sites, imiquimod probably results in more recurrences than SE at three years (16.4% versus 1.6%, respectively) (RR 10.30, 95% CI 3.22 to 32.94; 1 study, 401 participants; moderate-certainty evidence) and five years (17.5% versus 2.3%, respectively) (RR 7.73, 95% CI 2.81 to 21.3; 1 study, 383 participants; moderate-certainty evidence). There may be little to no difference in the number of participant-rated good/excellent cosmetic outcomes (RR 1.00, 95% CI 0.94 to 1.06; 1 study, 326 participants; low-certainty evidence). However, imiquimod may result in greater numbers of good/excellent cosmetic outcomes compared to SE when observer-rated (60.6% versus 35.6%, respectively) (RR 1.70, 95% CI 1.35 to 2.15; 1 study, 344 participants; low-certainty evidence). Both cosmetic outcomes were measured at three years. Based on one study of 347 participants with high- and low-risk primary BCC of the face, radiotherapy may result in more recurrences compared to SE under frozen section margin control at three years (5.2% versus 0%, respectively) (RR 19.11, 95% CI 1.12 to 325.78; low-certainty evidence) and at four years (6.4% versus 0.6%, respectively) (RR 11.06, 95% CI 1.44 to 84.77; low-certainty evidence). Radiotherapy probably results in a smaller number of good participant- (RR 0.76, 95% CI 0.63 to 0.91; 50.3% versus 66.1%, respectively) or observer-rated (RR 0.48, 95% CI 0.37 to 0.62; 28.9% versus 60.3%, respectively) good/excellent cosmetic outcomes compared to SE, when measured at four years, where dyspigmentation and telangiectasia can occur (both moderate-certainty evidence). Methyl-aminolevulinate (MAL)-PDT may result in more recurrences compared to SE at three years (36.4% versus 0%, respectively) (RR 26.47, 95% CI 1.63 to 429.92; 1 study; 68 participants with low-risk nBCC in the head and neck area; low-certainty evidence). There were no useable data for measurement at five years. MAL-PDT probably results in greater numbers of participant- (RR 1.18, 95% CI 1.09 to 1.27; 97.3% versus 82.5%) or observer-rated (RR 1.87, 95% CI 1.54 to 2.26; 87.1% versus 46.6%) good/excellent cosmetic outcomes at one year compared to SE (2 studies, 309 participants with low-risk nBCC and sBCC; moderate-certainty evidence). Based on moderate-certainty evidence (single low-risk sBCC), imiquimod probably results in fewer recurrences at three years compared to MAL-PDT (22.8% versus 51.6%, respectively) (RR 0.44, 95% CI 0.32 to 0.62; 277 participants) and five years (28.6% versus 68.6%, respectively) (RR 0.42, 95% CI 0.31 to 0.57; 228 participants). There is probably little to no difference in numbers of observer-rated good/excellent cosmetic outcomes at one year (RR 0.98, 95% CI 0.84 to 1.16; 370 participants). Participant-rated cosmetic outcomes were not measured for this comparison. AEs with surgical interventions include wound infections, graft necrosis and post-operative bleeding. Local AEs such as itching, weeping, pain and redness occur frequently with non-surgical interventions. Treatment-related AEs resulting in study modification or withdrawal occurred with imiquimod and MAL-PDT.

Authors' Conclusions: Surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with MMS over SE for high-risk facial primary BCC (low-certainty evidence). Non-surgical treatments, when used for low-risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. Of the non-surgical treatments, imiquimod has the best evidence to support its efficacy. Overall, evidence certainty was low to moderate. Priorities for future research include core outcome measures and studies with longer-term follow-up.
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http://dx.doi.org/10.1002/14651858.CD003412.pub3DOI Listing
November 2020

Personalized prediction of daily eczema severity scores using a mechanistic machine learning model.

Clin Exp Allergy 2020 Nov 9;50(11):1258-1266. Epub 2020 Sep 9.

Department of Bioengineering, Imperial College London, London, UK.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease with periods of flares and remission. Designing personalized treatment strategies for AD is challenging, given the apparent unpredictability and large variation in AD symptoms and treatment responses within and across individuals. Better prediction of AD severity over time for individual patients could help to select optimum timing and type of treatment for improving disease control.

Objective: We aimed to develop a proof of principle mechanistic machine learning model that predicts the patient-specific evolution of AD severity scores on a daily basis.

Methods: We designed a probabilistic predictive model and trained it using Bayesian inference with the longitudinal data from two published clinical studies. The data consisted of daily recordings of AD severity scores and treatments used by 59 and 334 AD children over 6 months and 16 weeks, respectively. Validation of the predictive model was conducted in a forward-chaining setting.

Results: Our model was able to predict future severity scores at the individual level and improved chance-level forecast by 60%. Heterogeneous patterns in severity trajectories were captured with patient-specific parameters such as the short-term persistence of AD severity and responsiveness to topical steroids, calcineurin inhibitors and step-up treatment.

Conclusions: Our proof of principle model successfully predicted the daily evolution of AD severity scores at an individual level and could inform the design of personalized treatment strategies that can be tested in future studies. Our model-based approach can be applied to other diseases with apparent unpredictability and large variation in symptoms and treatment responses such as asthma.
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http://dx.doi.org/10.1111/cea.13717DOI Listing
November 2020

Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene.

Neurol Genet 2020 Aug 10;6(4):e448. Epub 2020 Jun 10.

UCL Great Ormond Street Institute of Child Health (Y.H., A.K., B.J., T.S.J., E.O., D.S., V.G., P.A.B., D.E.); Histopathology Department (O.O.), Great Ormond Street Hospital, London; Paediatric Neurology Department (A.A.M.), and Genetics Department (M.T., R.N.-E.), Bristol Royal Hospital for Children; Genetics Department (J.R.), Royal Devon and Exeter NHS Foundation Trust, Exeter; Centre for Translational Omics-GOSgene (H.J.W.), UCL GOS Institute of Child Health; and Centre for Adolescent Rheumatology Versus Arthritis (D.E.), London, United Kingdom.

Objective: To report a series of patients with cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma () gene and examine the functional role of the identified mutant Cbl protein. We hypothesized that mutated Cbl fails to act as a negative regulator of the RAS-mitogen-activated protein kinases (MAPK) signaling pathway, resulting in enhanced vascular fibroblast proliferation and migration and enhanced angiogenesis and collateral vessel formation.

Methods: We performed whole-exome sequencing in 11 separate families referred to Great Ormond Street Hospital, London, with suspected genetic cause for clinical presentation with severe progressive cerebral arteriopathy.

Results: We identified heterozygous variants in the gene in 5 affected cases from 3 families. We show that impaired -mediated degradation of cell surface tyrosine kinase receptors and dysregulated intracellular signaling through the RAS-MAPK pathway contribute to the pathogenesis of the observed arteriopathy. Mutated failed to control the angiogenic signal relay of vascular endothelial growth factor receptor 2, leading to prolonged tyrosine kinase signaling, thus driving angiogenesis and collateral vessel formation. Mutant Cbl promoted myofibroblast migration and proliferation contributing to vascular occlusive disease; these effects were abrogated following treatment with a RAF-RAS-MAPK pathway inhibitor.

Conclusions: We provide a possible mechanism for the arteriopathy associated with heterozygous variants. Identification of the key role for the RAS-MAPK pathway in -mediated cerebral arteriopathy could facilitate identification of novel or repurposed druggable targets for treating these patients and may also provide therapeutic clues for other cerebral arteriopathies.
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http://dx.doi.org/10.1212/NXG.0000000000000448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323481PMC
August 2020

Quality and Reporting Completeness of Systematic Reviews and Meta-Analyses in Dermatology.

J Invest Dermatol 2021 Jan 27;141(1):64-71. Epub 2020 Jun 27.

EA 7379 EpiDermE, UPEC, Créteil, France; Department of Dermatology, Hôpital Henri Mondor, Créteil, France. Electronic address:

We sought to assess the quality of dermatological systematic reviews (SRs) and identify factors that predict high methodological quality. We searched for all SRs published in 2017 using PubMed, Epistemonikos, and the Cochrane Database of SRs. We included studies identified as SRs or meta-analysis in the title or abstract and dealing with a dermatological topic. Study selection and data extraction were carried out and Preferred Reporting Items for SRs and Meta-Analyses and rating by A MeaSurement Tool to Assess SRs 2 were used independently by two authors. On the basis of A MeaSurement Tool to Assess SRs 2, confidence in SRs results was classified as high, moderate, low, or very low. We included 732 studies. We described a random sample of 140. The overall rating of confidence in the results according to a tool called A MeaSurement Tool to Assess SRs 2 was high or moderate for nine reviews (6%). A total of 20 reviews (15%) had a registered protocol. Independent factors associated with moderate or high rating of A MeaSurement Tool to Assess SRs 2 were publication in a journal where Preferred Reporting Items for SRs and Meta-Analyses was mandatory (OR [95% confidence interval] = 27.0 [1.4-528]) and journal impact factor (OR of 1.9 [1.3-3]) for each increase in one more point. The observation that 90% of published dermatology SRs are of very low quality is alarming. Review registration in the International Prospective Register of SRs and full reporting according to Preferred Items for SRs and Meta-Analyses should be mandatory for publication. This study is registered in the International Prospective Register of SRs (CRD42018093856).
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http://dx.doi.org/10.1016/j.jid.2020.05.109DOI Listing
January 2021

Pseudouridylation defect due to and mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

Proc Natl Acad Sci U S A 2020 06 17;117(26):15137-15147. Epub 2020 Jun 17.

MTA-SE Lendület Nephrogenetic Laboratory, Semmelweis University, HU 1083 Budapest, Hungary;

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in , , or cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with p.Glu206Lys and two children with homozygous p.Thr16Met. Females with heterozygous p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.
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http://dx.doi.org/10.1073/pnas.2002328117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334496PMC
June 2020

Two-by-two factorial randomised study within a trial (SWAT) to evaluate strategies for follow-up in a randomised prevention trial.

Trials 2020 Jun 8;21(1):529. Epub 2020 Jun 8.

Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, NG7 2RD, UK.

Background: Failure to collect outcome data in randomised trials can result in bias and loss of statistical power. Further evaluations of strategies to increase retention are required. We assessed the effectiveness of two strategies for retention in a randomised prevention trial using a two-by-two factorial randomised study within a trial (SWAT).

Methods: Parents of babies included in the host trial were randomised to (1) short message service (SMS) notification prior to sending questionnaires at 3, 6, 12 and 18 months versus no SMS notification and (2) a £10 voucher sent with the invitation letter for the primary follow-up visit at 24 months or given at the visit. The two co-primary outcomes were collection of host trial (1) questionnaire data at interim follow-up times and (2) primary outcome at 24 months during a home/clinic visit with a research nurse.

Results: Between November 2014 and November 2016, 1394 participants were randomised: 350 to no SMS + voucher at visit, 345 to SMS + voucher at visit, 352 to no SMS + voucher before visit and 347 to SMS + voucher before visit. Overall questionnaire data was collected at interim follow-up times for 75% in both the group allocated to the prior SMS notification and the group allocated to no SMS notification (odds ratio (OR) SMS versus none 1.02, 95% CI 0.83 to 1.25). Host trial primary outcome data was collected at a visit for 557 (80%) allocated to the voucher before the visit in the invitation letter and for 566 (81%) whose parents were allocated to receive the voucher at the visit (OR before versus at visit 0.89, 95% CI 0.69 to 1.17).

Conclusion: There was no evidence of a difference in retention according to SMS notification or voucher timing. Future synthesis of SWAT results is required to be able to detect small but important incremental effects of retention strategies.

Trial Registration: ISRCTN registry, ID: ISRCTN21528841. Registered on 25 July 2014. SWAT Repository Store ID 25.
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http://dx.doi.org/10.1186/s13063-020-04373-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296963PMC
June 2020

Projections of coral cover and habitat change on turbid reefs under future sea-level rise.

Proc Biol Sci 2020 06 17;287(1929):20200541. Epub 2020 Jun 17.

Land and Water Science, College of Science and Engineering, James Cook University, Townsville, Australia.

Global sea-level rise (SLR) is projected to increase water depths above coral reefs. Although the impacts of climate disturbance events on coral cover and three-dimensional complexity are well documented, knowledge of how higher sea levels will influence future reef habitat extent and bioconstruction is limited. Here, we use 31 reef cores, coupled with detailed benthic ecological data, from turbid reefs on the central Great Barrier Reef, Australia, to model broad-scale changes in reef habitat following adjustments to reef geomorphology under different SLR scenarios. Model outputs show that modest increases in relative water depth above reefs (Representative Concentration Pathway (RCP) 4.5) over the next 100 years will increase the spatial extent of habitats with low coral cover and generic diversity. More severe SLR (RCP8.5) will completely submerge reef flats and move reef slope coral communities below the euphotic depth, despite the high vertical accretion rates that characterize these reefs. Our findings suggest adverse future trajectories associated with high emission climate scenarios which could threaten turbid reefs globally and their capacity to act as coral refugia from climate change.
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http://dx.doi.org/10.1098/rspb.2020.0541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329041PMC
June 2020

Prevention of Atopic Dermatitis.

Acta Derm Venereol 2020 Jun 9;100(12):adv00166. Epub 2020 Jun 9.

Centre of Evidence-Based Dermatology, Queen's Medical Centre, University of Nottingham, NG7 2UH Nottingham, United Kingdom. E-mail:

Despite advances in atopic dermatitis (AD) treatments, research into AD prevention has been slow. Systematic reviews of prevention strategies promoting exclusive and prolonged breastfeeding, or interventions that reduce ingested or airborne allergens during pregnancy and after birth have generally not shown convincing benefit. Maternal/infant supplements such as Vitamin D have also not shown any benefit with the possible exception of omega-3 fatty acids. Systematic reviews suggest that probiotics could reduce AD incidence by around 20%, although the studies are quite variable and might benefit from individual patient data meta-analysis. Skin barrier enhancement from birth to prevent AD and food allergy has received recent interest, and results from national trials are awaited. It is possible that trying to influence major immunological changes that characterise AD at birth through infant-directed interventions may be too late, and more attention might be directed at fetal programming in utero.
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http://dx.doi.org/10.2340/00015555-3516DOI Listing
June 2020

Future of evidence ecosystem series: 3. From an evidence synthesis ecosystem to an evidence ecosystem.

J Clin Epidemiol 2020 07 6;123:153-161. Epub 2020 Mar 6.

INSERM, UMR1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), METHODS Team, Paris, France; Centre d'Epidémiologie Clinique, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Hôtel Dieu, Paris, France; Cochrane France, Paris, France; Université de Paris, Paris, France.

The "one-off" approach of systematic reviews is no longer sustainable; we need to move toward producing "living" evidence syntheses (i.e., comprehensive, based on rigorous methods, and up-to-date). This implies rethinking the evidence synthesis ecosystem, its infrastructure, and management. The three distinct production systems-primary research, evidence synthesis, and guideline development-should work together to allow for continuous refreshing of synthesized evidence and guidelines. A new evidence ecosystem, not just focusing on synthesis, should allow for bridging the gaps between evidence synthesis communities, primary researchers, guideline developers, health technology assessment agencies, and health policy authorities. This network of evidence synthesis stakeholders should select relevant clinical questions considered a priority topic. For each question, a multidisciplinary community including researchers, health professionals, guideline developers, policymakers, patients, and methodologists needs to be established and commit to performing the initial evidence synthesis and keeping it up-to-date. Encouraging communities to work together continuously with bidirectional interactions requires greater incentives, rewards, and the involvement of health care policy authorities to optimize resources. A better evidence ecosystem with collaborations and interactions between each partner of the network of evidence synthesis stakeholders should permit living evidence syntheses to justify their status in evidence-informed decision-making.
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http://dx.doi.org/10.1016/j.jclinepi.2020.01.027DOI Listing
July 2020

Future of evidence ecosystem series: 2. current opportunities and need for better tools and methods.

J Clin Epidemiol 2020 07 4;123:143-152. Epub 2020 Mar 4.

INSERM, UMR1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), METHODS team, Paris, France; French Cochrane Center, Paris, France; Direction de la recherche Clinique, Hôpital Foch, Suresnes, France; Centre d'Epidémiologie Clinique, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Hôtel Dieu, Paris, France; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. Electronic address:

To become user driven and more useful for decision-making, the current evidence synthesis ecosystem requires significant changes (Paper 1. Future of evidence ecosystem series). Reviewers have access to new sources of data (clinical trial registries, protocols, and clinical study reports from regulatory agencies or pharmaceutical companies) for more information on randomized control trials. With all these newly available data, the management of multiple and scattered trial reports is even more challenging. New types of data are also becoming available: individual patient data and routinely collected data. With the increasing number of diverse sources to be searched and the amount of data to be extracted, the process needs to be rethought. New approaches and tools, such as automation technologies and crowdsourcing, should help accelerate the process. The implementation of these new approaches and methods requires a substantial rethinking and redesign of the current evidence synthesis ecosystem. The concept of a "living" evidence synthesis enterprise, with living systematic review and living network meta-analysis, has recently emerged. Such an evidence synthesis ecosystem implies conceptualizing evidence synthesis as a continuous process built around a clinical question of interest and no longer as a small team independently answering a specific clinical question at a single point in time.
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http://dx.doi.org/10.1016/j.jclinepi.2020.01.023DOI Listing
July 2020

Future of evidence ecosystem series: 1. Introduction Evidence synthesis ecosystem needs dramatic change.

J Clin Epidemiol 2020 07 4;123:135-142. Epub 2020 Mar 4.

INSERM, UMR1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), METHODS Team, Paris, France; Centre d'Epidémiologie Clinique, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Hôtel Dieu, Paris, France; French Cochrane Center, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.

Objectives: This article presents why the planning, conduct, and reporting of systematic reviews and meta-analyses of therapeutic interventions are suboptimal.

Study Design And Setting: We present an overview of the limitations of the current system of evidence synthesis for therapeutic interventions.

Results: Systematic reviews and meta-analyses are a cornerstone of health care decisions. However, despite the increasing a number of published systematic reviews of therapeutic interventions, the current evidence synthesis ecosystem is not properly addressing stakeholders' needs. The current production process leads to a series of disparate systematic reviews because of erratic and inefficient planning with a process that is not always comprehensive and is prone to bias. Evidence synthesis depends on the quality of primary research, so primary research that is not available is biased or selectively reported raises important concerns. Moreover, the lack of interactions between the community of primary research producers and systematic reviewers impedes the optimal use of data. The context has considerably evolved, with ongoing research innovations, a new medical approach with the end of the one-size-fits-all approach, more available data, and new patient expectations. All these changes must be introduced into the future evidence ecosystem.

Conclusion: Dramatic changes are needed to enable this future ecosystem to become user driven and user oriented and more useful for decision-making.
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http://dx.doi.org/10.1016/j.jclinepi.2020.01.024DOI Listing
July 2020

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

Lancet 2020 03 19;395(10228):962-972. Epub 2020 Feb 19.

Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK. Electronic address:

Background: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children.

Methods: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment.

Findings: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09).

Interpretation: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn.

Funding: National Institute for Health Research Health Technology Assessment.
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http://dx.doi.org/10.1016/S0140-6736(19)32984-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086156PMC
March 2020

Algorithm based smartphone apps to assess risk of skin cancer in adults: systematic review of diagnostic accuracy studies.

BMJ 2020 02 10;368:m127. Epub 2020 Feb 10.

Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Objective: To examine the validity and findings of studies that examine the accuracy of algorithm based smartphone applications ("apps") to assess risk of skin cancer in suspicious skin lesions.

Design: Systematic review of diagnostic accuracy studies.

Data Sources: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, CPCI, Zetoc, Science Citation Index, and online trial registers (from database inception to 10 April 2019).

Eligibility Criteria For Selecting Studies: Studies of any design that evaluated algorithm based smartphone apps to assess images of skin lesions suspicious for skin cancer. Reference standards included histological diagnosis or follow-up, and expert recommendation for further investigation or intervention. Two authors independently extracted data and assessed validity using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2 tool). Estimates of sensitivity and specificity were reported for each app.

Results: Nine studies that evaluated six different identifiable smartphone apps were included. Six verified results by using histology or follow-up (n=725 lesions), and three verified results by using expert recommendations (n=407 lesions). Studies were small and of poor methodological quality, with selective recruitment, high rates of unevaluable images, and differential verification. Lesion selection and image acquisition were performed by clinicians rather than smartphone users. Two CE (Conformit Europenne) marked apps are available for download. SkinScan was evaluated in a single study (n=15, five melanomas) with 0% sensitivity and 100% specificity for the detection of melanoma. SkinVision was evaluated in two studies (n=252, 61 malignant or premalignant lesions) and achieved a sensitivity of 80% (95% confidence interval 63% to 92%) and a specificity of 78% (67% to 87%) for the detection of malignant or premalignant lesions. Accuracy of the SkinVision app verified against expert recommendations was poor (three studies).

Conclusions: Current algorithm based smartphone apps cannot be relied on to detect all cases of melanoma or other skin cancers. Test performance is likely to be poorer than reported here when used in clinically relevant populations and by the intended users of the apps. The current regulatory process for awarding the CE marking for algorithm based apps does not provide adequate protection to the public.

Systematic Review Registration: PROSPERO CRD42016033595.
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http://dx.doi.org/10.1136/bmj.m127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190019PMC
February 2020

An algorithm for diagnosing IgE-mediated food allergy in study participants who do not undergo food challenge.

Clin Exp Allergy 2020 03 13;50(3):334-342. Epub 2020 Feb 13.

Section of Inflammation, Repair & Development, National Heart & Lung Institute, Imperial College London, London, UK.

Background: Food allergy diagnosis in clinical studies can be challenging. Oral food challenges (OFC) are time-consuming, carry some risk and may, therefore, not be acceptable to all study participants.

Objective: To design and evaluate an algorithm for detecting IgE-mediated food allergy in clinical study participants who do not undergo OFC.

Methods: An algorithm for trial participants in the Barrier Enhancement for Eczema Prevention (BEEP) study who were unwilling or unable to attend OFC was developed. BEEP is a pragmatic, multi-centre, randomized-controlled trial of daily emollient for the first year of life for primary prevention of eczema and food allergy in high-risk infants (ISRCTN21528841). We built on the European iFAAM consensus guidance to develop a novel food allergy diagnosis algorithm using available information on previous allergenic food ingestion, food reaction(s) and sensitization status. This was implemented by a panel of food allergy experts blind to treatment allocation and OFC outcome. We then evaluated the algorithm's performance in both BEEP and Enquiring About Tolerance (EAT) study participants who did undergo OFC.

Results: In 31/69 (45%) BEEP and 44/55 (80%) EAT study control group participants who had an OFC the panel felt confident enough to categorize children as "probable food allergy" or "probable no food allergy". Algorithm-derived panel decisions showed high sensitivity 94% (95%CI 68, 100) BEEP; 90% (95%CI 72, 97) EAT and moderate specificity 67% (95%CI 39, 87) BEEP; 67% (95%CI 39, 87) EAT. Sensitivity and specificity were similar when all BEEP and EAT participants with OFC outcome were included.

Conclusion: We describe a new algorithm with high sensitivity for IgE-mediated food allergy in clinical study participants who do not undergo OFC.

Clinical Relevance: This may be a useful tool for excluding food allergy in future clinical studies where OFC is not conducted.
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http://dx.doi.org/10.1111/cea.13577DOI Listing
March 2020

Measuring atopic eczema symptoms in clinical practice: The first consensus statement from the Harmonising Outcome Measures for Eczema in clinical practice initiative.

J Am Acad Dermatol 2020 May 8;82(5):1181-1186. Epub 2020 Jan 8.

Department of Dermatology, Oregon Health & Science University, Portland, Oregon.

Background: Measuring patient-centered outcomes in clinical practice is valuable for monitoring patients and advancing real-world research. A new initiative from the Harmonising Outcome Measures for Eczema (HOME) group aims to recommend what might be recorded for atopic eczema patients in routine clinical care.

Objectives: Prioritize outcome domains to measure atopic eczema in clinical practice and select valid and practical outcome measurement instruments for the highest-priority domain.

Methods: An online survey of HOME members identified and ranked 21 possible health domains. Suitable instruments were then selected for the top-prioritized domain at the HOME VI meeting, using established consensus processes informed by systematic reviews of instrument quality.

Results: Patient-reported symptoms was the top-prioritized domain. In accordance with psychometric properties and feasibility, there was consensus that the recommended instruments to measure atopic eczema symptoms in clinical practice are the POEM, the PO-SCORAD index, or both. The numeric rating scale for itch received support pending definition and validation in atopic eczema.

Conclusion: Following the first step of the HOME Clinical Practice initiative, we endorse using the POEM, the PO-SCORAD index, or both for measuring atopic eczema symptoms in clinical practice. Additional high-priority domains for clinical practice will be assessed at subsequent HOME meetings.
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http://dx.doi.org/10.1016/j.jaad.2019.12.055DOI Listing
May 2020

Trial Forge Guidance 2: how to decide if a further Study Within A Trial (SWAT) is needed.

Trials 2020 Jan 7;21(1):33. Epub 2020 Jan 7.

Northern Ireland Methodology Hub, Queen's University Belfast, Belfast, UK.

The evidence base available to trialists to support trial process decisions-e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants-is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process.SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste.This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.
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http://dx.doi.org/10.1186/s13063-019-3980-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945587PMC
January 2020

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure.

Pharmaceutics 2019 Dec 22;12(1). Epub 2019 Dec 22.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2- to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine .
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http://dx.doi.org/10.3390/pharmaceutics12010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023222PMC
December 2019

Student engagement and wellbeing over time at a higher education institution.

PLoS One 2019 27;14(11):e0225770. Epub 2019 Nov 27.

Computer Science, University of Exeter, Exeter, United Kingdom.

Student engagement is an important factor for learning outcomes in higher education. Engagement with learning at campus-based higher education institutions is difficult to quantify due to the variety of forms that engagement might take (e.g. lecture attendance, self-study, usage of online/digital systems). Meanwhile, there are increasing concerns about student wellbeing within higher education, but the relationship between engagement and wellbeing is not well understood. Here we analyse results from a longitudinal survey of undergraduate students at a campus-based university in the UK, aiming to understand how engagement and wellbeing vary dynamically during an academic term. The survey included multiple dimensions of student engagement and wellbeing, with a deliberate focus on self-report measures to capture students' subjective experience. The results show a wide range of engagement with different systems and study activities, giving a broad view of student learning behaviour over time. Engagement and wellbeing vary during the term, with clear behavioural changes caused by assessments. Results indicate a positive interaction between engagement and happiness, with an unexpected negative relationship between engagement and academic outcomes. This study provides important insights into subjective aspects of the student experience and provides a contrast to the increasing focus on analysing educational processes using digital records.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225770PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881016PMC
March 2020

Best emollients for eczema (BEE) - comparing four types of emollients in children with eczema: protocol for randomised trial and nested qualitative study.

BMJ Open 2019 11 6;9(11):e033387. Epub 2019 Nov 6.

Centre of Evidence-Based Dermatology, University of Nottingham, Nottingham, UK.

Introduction: Atopic dermatitis/eczema affects around 20% of children and is characterised by inflamed, dry, itchy skin. Guidelines recommend 'leave-on' emollients that are applied directly to the skin to add or trap moisture and used regularly, they can soothe, enhance the skin barrier and may prevent disease 'flares'. However, the suitability of the many different emollients varies between people and there is little evidence to help prescribers and parents and carers decide which type to try first.

Methods And Analysis: Design: pragmatic, multicentre, individually randomised, parallel group superiority trial of four types of emollient (lotions, creams, gel or ointments).

Setting: general practitioner surgeries in England.

Participants: children aged over 6 months and less than 12 years with mild-to-severe eczema and no known sensitivity to study emollients.

Interventions: study-approved lotion, cream, gel or ointment as the only leave-on emollient for 16 weeks, with directions to apply twice daily and as required. Other treatments, such as topical corticosteroids, used as standard care.

Follow-up: 52 weeks.

Primary Outcome: validated patient-orientated eczema measure measured weekly for 16 weeks.

Secondary Outcomes: eczema signs (Eczema Area Severity Index) by masked researcher, treatment use, parent satisfaction, adverse events, child and family quality of life (Atopic Dermatitis Quality of Life, Child Health Utility 9D and Dermatitis Family Impact).

Sample Size: 520 participants (130 per group).

Analysis: intention-to-treat using linear mixed models for repeated measures.Nested qualitative study: audio-recording of sample of baseline appointments and up to 60 interviews with participants at 4 and 16 weeks, interviews to be transcribed and analysed thematically.

Ethics And Dissemination: Ethics approval granted by the NHS REC (South West - Central Bristol Research Ethics Committee 17/SW/0089). Findings will be presented at conferences, published in open-access peer-reviewed journals and the study website; and summaries shared with key stakeholders.

Trial Registration Number: ISRCTN84540529.
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http://dx.doi.org/10.1136/bmjopen-2019-033387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858146PMC
November 2019

Information Is the Resolution of Uncertainty: Whole Genome Approaches to Genetic Diagnosis on the PICU.

Pediatr Crit Care Med 2019 11;20(11):1087-1088

Respiratory Critical Care and Anaesthesia Unit, Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health; and Paediatric Intensive Care Unit, Heart and Lung Division, Great Ormond Street Hospital, London, United Kingdom Genetic and Genomic Medicine, School of Medicine, Cardiff University, Cardiff, United Kingdom.

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http://dx.doi.org/10.1097/PCC.0000000000002091DOI Listing
November 2019

Interventions to reduce Staphylococcus aureus in the management of eczema.

Cochrane Database Syst Rev 2019 10 29;2019(10). Epub 2019 Oct 29.

University of Nottingham, Centre of Evidence Based Dermatology, Queen's Medical Centre, Derby Road, Nottingham, UK, NG7 2UH.

Background: Staphylococcus aureus (S. aureus) can cause secondary infection in eczema, and may promote inflammation in eczema that does not look infected. There is no standard intervention to reduce S. aureus burden in eczema. It is unclear whether antimicrobial treatments help eczema or promote bacterial resistance. This is an update of a 2008 Cochrane Review.

Objectives: To assess the effects of interventions to reduce S. aureus for treating eczema.

Search Methods: We updated our searches of the following databases to October 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We searched five trials registers and three sets of conference proceedings. We checked references of trials and reviews for further relevant studies. We contacted pharmaceutical companies regarding ongoing and unpublished trials.

Selection Criteria: Randomised controlled trials of products intended to reduce S. aureus on the skin in people diagnosed with atopic eczema by a medical practitioner. Eligible comparators were a similar treatment regimen without the anti-staphylococcal agent.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane. Our key outcomes were participant- or assessor-rated global improvement in symptoms/signs, quality of life (QOL), severe adverse events requiring withdrawal, minor adverse events, and emergence of antibiotic-resistant micro-organisms.

Main Results: We included 41 studies (1753 analysed participants) covering 10 treatment categories. Studies were conducted mainly in secondary care in Western Europe; North America; the Far East; and elsewhere. Twelve studies recruited children; four, adults; 19, both; and six, unclear. Fifty-nine per cent of the studies reported the mean age of participants (range: 1.1 to 34.6 years). Eczema severity ranged from mild to severe. Many studies did not report our primary outcomes. Treatment durations ranged from 10 minutes to 3 months; total study durations ranged from 15 weeks to 27 months. We considered 33 studies at high risk of bias in at least one domain. We present results for three key comparisons. All time point measurements were taken from baseline. We classed outcomes as short-term when treatment duration was less than four weeks, and long-term when treatment was given for more than four weeks. Fourteen studies evaluated topical steroid/antibiotic combinations compared to topical steroids alone (infective status: infected (two studies), not infected (four studies), unspecified (eight studies)). Topical steroid/antibiotic combinations may lead to slightly greater global improvement in good or excellent signs/symptoms than topical steroid alone at 6 to 28 days follow-up (risk ratio (RR) 1.10, 95% confidence interval (CI) 1.00 to 1.21; 224 participants; 3 studies, low-quality evidence). There is probably little or no difference between groups for QOL in children, at 14 days follow-up (mean difference (MD) -0.18, 95% CI -0.40 to 0.04; 42 participants; 1 study, moderate-quality evidence). The subsequent results for this comparison were based on very low-quality evidence, meaning we are uncertain of their validity: severe adverse events were rare (follow-up: between 6 to 28 days): both groups reported flare of dermatitis, worsening of the condition, and folliculitis (325 participants; 4 studies). There were fewer minor adverse events (e.g. flare, stinging, itch, folliculitis) in the combination group at 14 days follow-up (218 participants; 2 studies). One study reported antibiotic resistance in children at three months follow-up, with similar results between the groups (65 participants; 1 study). Four studies evaluated oral antibiotics compared to placebo (infective status: infected eczema (two studies), uninfected (one study), one study's participants had colonisation but no clinical infection). Oral antibiotics may make no difference in terms of good or excellent global improvement in infants and children at 14 to 28 days follow-up compared to placebo (RR 0.80; 95% CI 0.18 to 3.50; 75 participants; 2 studies, low-quality evidence). There is probably little or no difference between groups for QOL (in infants and children) at 14 days follow-up (MD 0.11, 95% CI -0.10 to 0.32, 45 participants, 1 study, moderate-quality evidence). The subsequent results for this comparison were based on very low-quality evidence, meaning we are uncertain of their validity: adverse events requiring treatment withdrawal between 14 to 28 days follow-up were very rare, but included eczema worsening (both groups), loose stools (antibiotic group), and Henoch-Schönlein purpura (placebo group) (4 studies, 199 participants). Minor adverse events, including nausea, vomiting, diarrhoea, and stomach and joint pains, at 28 days follow-up were also rare and generally low in both groups (1 study, 68 infants and children). Antibiotic resistance at 14 days was reported as similar in both groups (2 studies, 98 infants and children). Of five studies evaluating bleach baths compared to placebo (water) or bath emollient (infective status: uninfected (two studies), unspecified (three studies)), one reported global improvement and showed that bleach baths may make no difference when compared with placebo at one month follow-up (RR 0.78, 95% CI 0.37 to 1.63; 36 participants; low-quality evidence). One study showed there is probably little or no difference in QOL at 28 days follow-up when comparing bleach baths to placebo (MD 0.90, 95% CI -1.32 to 3.12) (80 infants and children; moderate-quality evidence). We are uncertain if the groups differ in the likelihood of treatment withdrawals due to adverse events at two months follow-up (only one dropout reported due to worsening itch (placebo group)) as the quality of evidence was very low (1 study, 42 participants). One study reported that five participants in each group experienced burning/stinging or dry skin at two months follow-up, so there may be no difference in minor adverse events between groups (RR 1.00, 95% CI 0.35 to 2.87, 36 participants, low-quality evidence). Very low-quality evidence means we are also uncertain if antibiotic resistance at four weeks follow-up is different between groups (1 study, 80 participants ≤ 18 years).

Authors' Conclusions: We found insufficient evidence on the effects of anti-staphylococcal treatments for treating people with infected or uninfected eczema. Low-quality evidence, due to risk of bias, imprecise effect estimates and heterogeneity, made pooling of results difficult. Topical steroid/antibiotic combinations may be associated with possible small improvements in good or excellent signs/symptoms compared with topical steroid alone. High-quality trials evaluating efficacy, QOL, and antibiotic resistance are required.
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http://dx.doi.org/10.1002/14651858.CD003871.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818407PMC
October 2019

Which emollients are effective and acceptable for eczema in children?

BMJ 2019 Oct 24;367:l5882. Epub 2019 Oct 24.

Centre of Evidence Based Dermatology, University of Nottingham, UK.

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http://dx.doi.org/10.1136/bmj.l5882DOI Listing
October 2019

A behaviour change package to prevent hand dermatitis in nurses working in health care: the SCIN cluster RCT.

Health Technol Assess 2019 10;23(58):1-92

Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK.

Background: Although strategies have been developed to minimise the risk of occupational hand dermatitis in nurses, their clinical effectiveness and cost-effectiveness remain unclear.

Objectives: The Skin Care Intervention in Nurses trial tested the hypothesis that a behaviour change package intervention, coupled with provision of hand moisturisers, could reduce the point prevalence of hand dermatitis when compared with standard care among nurses working in the NHS. The secondary aim was to assess the impact of the intervention on participants' beliefs and behaviour regarding hand care, and the cost-effectiveness of the intervention in comparison with normal care.

Design: Cluster randomised controlled trial.

Setting: Thirty-five NHS hospital trusts/health boards/universities.

Participants: First-year student nurses with a history of atopic tendency, and full-time intensive care unit nurses.

Intervention: Sites were randomly allocated to be 'intervention plus' or 'intervention light'. Participants at 'intervention plus' sites received access to a bespoke online behaviour change package intervention, coupled with personal supplies of moisturising cream (student nurses) and optimal availability of moisturising cream (intensive care unit nurses). Nurses at 'intervention light' sites received usual care, including a dermatitis prevention leaflet.

Main Outcome Measure: The difference between intervention plus and intervention light sites in the change of point prevalence of visible hand dermatitis was measured from images taken at baseline and at follow-up.

Randomisation: Fourteen sites were randomised to the intervention plus arm, and 21 sites were randomised to the intervention light arm.

Blinding: The participants, trial statistician, methodologist and the dermatologists interpreting the hand photographs were blinded to intervention assignment.

Numbers Analysed: An intention-to-treat analysis was conducted on data from 845 student nurses and 1111 intensive care unit nurses.

Results: The intention-to-treat analysis showed no evidence that the risk of developing dermatitis was greater in the intervention light group than in the intervention plus group (student nurses: odds ratio 1.25, 95% confidence interval 0.59 to 2.69; intensive care unit nurses: odds ratio 1.41, 95% confidence interval 0.81 to 2.44). Both groups had high levels of baseline beliefs about the benefits of using hand moisturisers before, during and after work. The frequency of use of hand moisturisers before, during and after shifts was significantly higher in the intensive care unit nurses in the intervention plus arm at follow-up than in the comparator group nurses. For student nurses, the intervention plus group mean costs were £2 lower than those for the comparator and 0.00002 more quality-adjusted life-years were gained. For intensive care unit nurses, costs were £4 higher and 0.0016 fewer quality-adjusted life-years were gained.

Harms: No adverse events were reported.

Limitations: Only 44.5% of participants in the intervention plus arm accessed the behaviour change package.

Conclusion: The intervention did not result in a statistically significant decrease in the prevalence of hand dermatitis in the intervention plus group.

Future Work: Participants had a high level of baseline beliefs about the importance of using hand moisturisers before, during and after work. Future research should focus on how workplace culture can be changed in order for that knowledge to be actioned.

Trial Registration: Current Controlled Trials ISRCTN53303171.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 58. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta23580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843112PMC
October 2019

Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis.

J Clin Endocrinol Metab 2019 12;104(12):5737-5750

Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

Context: Congenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome, a group of X-linked disorders that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis.

Objective: We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients.

Patients: The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus.

Results: Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch.

Conclusion: We report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.
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http://dx.doi.org/10.1210/jc.2019-00631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916815PMC
December 2019