Publications by authors named "Victoria Cornelius"

106 Publications

Rehabilitation in childhood-onset hyperkinetic movement disorders including dystonia: Treatment change in outcomes across the ICF and feasibility of outcomes for full trial evaluation.

Eur J Paediatr Neurol 2021 May 6. Epub 2021 May 6.

Department of Psychology, Institute of Psychiatry, Psychology and Neurosciences, King's College London, London, UK; South London and Maudsley NHS Foundation Trust, London, UK.

Background: Childhood-onset hyperkinetic movement disorders (HMD), including dystonia are notoriously difficult to treat and there are limited studies showing successful medical, surgical or non-pharmacological interventions.

Methods: This prospective study used grouped data (n = 22) from two studies of the Cognitive Orientation to daily Occupational Performance (CO-OP) Approach for patient-selected goals. Eligibility included aged 6-21 years, deep brain stimulation in place, with manual ability classification system level I-IV. Outcome was assessed on a range of patient-reported and clinician-rated measures across the International Classification of Function at end-treatment (10 weekly sessions) (series 1 and 2) and 3-month follow-up (series 1). Feasibility of outcomes to be used in a full trial were explored.

Findings: Nineteen participants completed the intervention and were included in the analysis. Of the primary outcome measures, the self-reported Canadian Occupational Performance Measure showed improvement in goal performance (mean change 4.08, 95% CI [3.37,4.79] post-; 4.18 [5.10,5.26] follow-up), and satisfaction (4.03 [3.04,5.03) post-; 4.44 [3.07,5.82] follow-up]. The Assessment of Motor and Process Skills showed improved motor score (0.52 [0.01,1.03] at follow-up only, while the process score did not change. Objective blind-rated pooled data using the Performance Quality Rating Scale-individualized indicated significant change for trained goals (3.79 [3.37,4.21] post-; (4.01,5.10) follow-up] and untrained goals (1.90 [1.24,2.55] post 1.91 [0.23,3.60] follow-up]. Motor impairment assessed by the Burke-Fahn Motor Disability Rating Scale was unchanged (-3.26 [-6.62,0.09] post-; -1.11 [-8.05,5.82] follow-up). Improvement was also observed in self-efficacy (0.97 [0.47,1.47] post-; 1.37 [1.91-0.83] follow-up) and Quality of Life (0.12 [0.03-0.22] follow-up). Goal improvement; self-efficacy and quality of life captured significant change post-intervention. This improvement was shown despite no change on impairment-related measures and were shown to be feasible measures to use in a larger study of CO-OP for this population.
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http://dx.doi.org/10.1016/j.ejpn.2021.04.009DOI Listing
May 2021

RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease.

Biology (Basel) 2021 Apr 24;10(5). Epub 2021 Apr 24.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

RNA-binding proteins (RBPs) are multi-faceted proteins in the regulation of RNA or its RNA splicing, localisation, stability, and translation. Amassing proof from many recent and dedicated studies reinforces the perception of RBPs exerting control through differing expression levels, cellular localization and post-transcriptional alterations. However, since the regulation of RBPs is reliant on the micro-environment and events like stress response and metabolism, their binding affinities and the resulting RNA-RBP networks may be affected. Therefore, any misregulation and disruption in the features of RNA and its related homeostasis can lead to a number of diseases that include diabetes, cardiovascular disease, and other disorders such as cancer and neurodegenerative diseases. As such, correct regulation of RNA and RBPs is crucial to good health as the effect RBPs exert through loss of function can cause pathogenesis. In this review, we will discuss the significance of RBPs and their typical function and how this can be disrupted in disease.
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http://dx.doi.org/10.3390/biology10050366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146904PMC
April 2021

A review of the use of controlled multiple imputation in randomised controlled trials with missing outcome data.

BMC Med Res Methodol 2021 Apr 15;21(1):72. Epub 2021 Apr 15.

Imperial Clinical Trials Unit, Imperial College London, Stadium House, 68 Wood Lane, London, UK.

Background: Missing data are common in randomised controlled trials (RCTs) and can bias results if not handled appropriately. A statistically valid analysis under the primary missing-data assumptions should be conducted, followed by sensitivity analysis under alternative justified assumptions to assess the robustness of results. Controlled Multiple Imputation (MI) procedures, including delta-based and reference-based approaches, have been developed for analysis under missing-not-at-random assumptions. However, it is unclear how often these methods are used, how they are reported, and what their impact is on trial results. This review evaluates the current use and reporting of MI and controlled MI in RCTs.

Methods: A targeted review of phase II-IV RCTs (non-cluster randomised) published in two leading general medical journals (The Lancet and New England Journal of Medicine) between January 2014 and December 2019 using MI. Data was extracted on imputation methods, analysis status, and reporting of results. Results of primary and sensitivity analyses for trials using controlled MI analyses were compared.

Results: A total of 118 RCTs (9% of published RCTs) used some form of MI. MI under missing-at-random was used in 110 trials; this was for primary analysis in 43/118 (36%), and in sensitivity analysis for 70/118 (59%) (3 used in both). Sixteen studies performed controlled MI (1.3% of published RCTs), either with a delta-based (n = 9) or reference-based approach (n = 7). Controlled MI was mostly used in sensitivity analysis (n = 14/16). Two trials used controlled MI for primary analysis, including one reporting no sensitivity analysis whilst the other reported similar results without imputation. Of the 14 trials using controlled MI in sensitivity analysis, 12 yielded comparable results to the primary analysis whereas 2 demonstrated contradicting results. Only 5/110 (5%) trials using missing-at-random MI and 5/16 (31%) trials using controlled MI reported complete details on MI methods.

Conclusions: Controlled MI enabled the impact of accessible contextually relevant missing data assumptions to be examined on trial results. The use of controlled MI is increasing but is still infrequent and poorly reported where used. There is a need for improved reporting on the implementation of MI analyses and choice of controlled MI parameters.
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http://dx.doi.org/10.1186/s12874-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048273PMC
April 2021

Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial.

Trials 2021 Apr 12;22(1):270. Epub 2021 Apr 12.

Imperial College, London and Imperial NHS Trust, London, UK.

Objectives: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia.

Trial Design: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care.

Participants: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust.

Inclusion: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug.

Exclusion: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible.

Intervention And Comparator: RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis.

Main Outcomes: Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O saturation < 90% on ≥60% inspired oxygen RANDOMISATION: Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (<65 and ≥65 years) and site.

Blinding (masking): No participants or caregivers are blinded to group assignment. Clinical outcomes will be compared blind to group assignment.

Numbers To Be Randomised (sample Size): For an early informal dose examination by the Data Monitoring Committee a minimum of 30 participants will be recruited. For Stage 1 of this multi-arm multi-stage study, 171 participants will be randomised, with 57 participants in each arm. If at least one experimental intervention shows promise, then Stage 2 will recruit a further 95 participants per arm. Sample size calculations are given in the protocol.

Trial Status: Recruitment is ongoing and started 2 October 2020. We anticipate completion of Stage 1 by July 2021 and Stage 2 by April 2022. The current protocol version 2.0 of 11 February 2021 is appended.

Trial Registration: EudraCT: 2020-001750-22 , 9 July 2020 ClinicalTrials.gov: NCT04581954 , 9 October 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039797PMC
April 2021

Applicability and cost-effectiveness of the Systolic Blood Pressure Intervention Trial (SPRINT) in the Chinese population: A cost-effectiveness modeling study.

PLoS Med 2021 Mar 4;18(3):e1003515. Epub 2021 Mar 4.

Department of Epidemiology and Health Statistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China.

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) showed significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of <120 mm Hg compared with a SBP goal of <140 mm Hg. Our study aimed to assess the applicability of SPRINT to Chinese adults. Additionally, we sought to predict the medical and economic implications of this intensive SBP treatment among those meeting SPRINT eligibility.

Methods And Findings: We used nationally representative baseline data from the China Health and Retirement Longitudinal Study (CHARLS) (2011-2012) to estimate the prevalence and number of Chinese adults aged 45 years and older who meet SPRINT criteria. A validated microsimulation model was employed to project costs, clinical outcomes, and quality-adjusted life-years (QALYs) among SPRINT-eligible adults, under 2 alternative treatment strategies (SBP goal of <120 mm Hg [intensive treatment] and SBP goal of <140 mm Hg [standard treatment]). Overall, 22.2% met the SPRINT criteria, representing 116.2 (95% CI 107.5 to 124.8) million people in China. Of these, 66.4%, representing 77.2 (95% CI 69.3 to 85.0) million, were not being treated for hypertension, and 22.9%, representing 26.6 (95% CI 22.4 to 30.7) million, had a SBP between 130 and 139 mm Hg, yet were not taking antihypertensive medication. We estimated that over 5 years, compared to standard treatment, intensive treatment would reduce heart failure incidence by 0.84 (95% CI 0.42 to 1.25) million cases, reduce CVD deaths by 2.03 (95% CI 1.44 to 2.63) million cases, and save 3.84 (95% CI 1.53 to 6.34) million life-years. Estimated reductions of 0.069 (95% CI -0.28, 0.42) million myocardial infarction cases and 0.36 (95% CI -0.10, 0.82) million stroke cases were not statistically significant. Furthermore, over a lifetime, moving from standard to intensive treatment increased the mean QALYs from 9.51 to 9.87 (an increment of 0.38 [95% CI 0.13 to 0.71]), at a cost of Int$10,997 per QALY gained. Of all 1-way sensitivity analyses, high antihypertensive drug cost and lower treatment efficacy for CVD death resulted in the 2 most unfavorable results (Int$25,291 and Int$18,995 per QALY were gained, respectively). Simulation results indicated that intensive treatment could be cost-effective (82.8% probability of being below the willingness-to-pay threshold of Int$16,782 [1× GDP per capita in China in 2017]), with a lower probability in people with SBP 130-139 mm Hg (72.9%) but a higher probability among females (91.2%). Main limitations include lack of specific SPRINT eligibility information in the CHARLS survey, uncertainty about the implications of different blood pressure measurement techniques, the use of several sources of data with large reliance on findings from SPPRINT, limited information about the serious adverse event rate, and lack of information and evidence for medication effectiveness on renal disease.

Conclusions: Although adoption of the SPRINT treatment strategy would increase the number of Chinese adults requiring SBP treatment intensification, this approach has the potential to prevent CVD events, to produce gains in life-years, and to be cost-effective under common thresholds.
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http://dx.doi.org/10.1371/journal.pmed.1003515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971845PMC
March 2021

Cognitive Strategy Training in Childhood-Onset Movement Disorders: Replication Across Therapists.

Front Pediatr 2020 21;8:600337. Epub 2021 Jan 21.

Department of Psychology, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom.

To explore preliminary effectiveness of the Cognitive Orientation to daily Occupational Performance (CO-OP) Approach in improving outcomes in childhood-onset hyperkinetic movement disorders (HMDs) including dyskinetic cerebral palsy following deep brain stimulation (DBS) across UK clinical occupational therapists. Randomized, multiple-baseline, Single Case Experimental Design N-of-1 trial with replications across participants. Five self-selected goals were identified: three goals were worked on during CO-OP and two goals were left untreated and used to assess skills transfer. Participants were between 6 and 21 years and had received DBS surgery with baseline Manual Ability Classification System (MACS) levels I-IV. Participants were randomized to typical or extended baseline (2 vs. 6 weeks), followed by 10 weekly individual CO-OP sessions. The primary outcome was functional performance measured by the Performance Quality Rating Scale-Individualized (PQRS-I), assessed before, during, and following treatment. Outcome assessors were blinded to baseline allocation, session number, and assessment time. A non-overlapping index, Tau-, was used to measure effect size. Of the 12 participants recruited, 10 commenced and completed treatment. In total, 63% of trained goals improved with effect sizes 0.66-1.00 ("moderate" to "large" effect), seen for all children in at least one goal. Skills transfer was found in 37% of the untrained goals in six participants. Cognitive strategy use improved participant-selected functional goals in childhood-onset HMD, more than just practice during baseline. Preliminary effectiveness is shown when the intervention is delivered in clinical practice by different therapists in routine clinical settings.
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http://dx.doi.org/10.3389/fped.2020.600337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861040PMC
January 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 Mar 25;51(3):402-418. Epub 2021 Feb 25.

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
March 2021

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

Cochrane Database Syst Rev 2021 02 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094581PMC
February 2021

Fused deposition modelling for the development of drug loaded cardiovascular prosthesis.

Int J Pharm 2021 Feb 21;595:120243. Epub 2021 Jan 21.

School of Pharmacy, Queen's University Belfast, Lisburn Road 97, Belfast BT9 7BL, UK. Electronic address:

Cardiovascular diseases constitute a number of conditions which are the leading cause of death globally. To combat these diseases and improve the quality and duration of life, several cardiac implants have been developed, including stents, vascular grafts and valvular prostheses. The implantation of these vascular prosthesis has associated risks such as infection or blood clot formation. In order to overcome these limitations medicated vascular prosthesis have been previously used. The present paper describes a 3D printing method to develop medicated vascular prosthesis using fused deposition modelling (FDM) technology. For this purpose, rifampicin (RIF) was selected as a model molecule as it can be used to prevent vascular graft prosthesis infection. Thermoplastic polyurethane (TPU) and RIF were combined using hot melt extrusion (HME) to obtain filaments containing RIF concentrations ranging between 0 and 1% (w/w). These materials are capable of providing RIF release for periods ranging between 30 and 80 days. Moreover, TPU-based materials containing RIF were capable of inhibiting the growth of Staphylococcus aureus. This behaviour was observed even for TPU-based materials containing RIF concentrations of 0.1% (w/w). TPU containing 1% (w/w) of RIF showed antimicrobial properties even after 30 days of RIF release. Alternatively, these methods were used to prepare dipyridamole containing TPU filaments. Finally, using a dual extrusion 3D printer vascular grafts containing both drugs were prepared.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120243DOI Listing
February 2021

Diabetic endotheliopathy: RNA-binding proteins as new therapeutic targets.

Int J Biochem Cell Biol 2021 02 26;131:105907. Epub 2020 Dec 26.

The Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, BT9 7BL, UK. Electronic address:

Diabetic Endotheliopathy is widely regarded as a principal contributor to cardiovascular disease pathogenesis in individuals with Diabetes mellitus. The endothelium, the innermost lining of blood vessels, consists of an extensive monolayer of endothelial cells. Previously regarded as an interface, the endothelium is now accepted as an organ system with critical roles in vascular health; its dysfunction therefore is detrimental. Endothelial dysfunction induces blood vessel damage resulting in a restriction of blood and oxygen supply to tissues, the central pathology of cardiovascular disease. Hyperglycemic conditions have repeatedly been isolated as a pivotal inducer of endothelial cell dysfunction. Numerous studies have since proven hyperglycemic conditions to significantly alter the gene expression profile of endothelial cells, with this being largely attributable to the post-transcriptional regulation of RNA-binding proteins. In particular, the RBP Quaking-7 has recently emerged as a crucial mediator of diabetic endotheliopathy, with great potential to become a therapeutic target.
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http://dx.doi.org/10.1016/j.biocel.2020.105907DOI Listing
February 2021

Advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials.

Trials 2020 Dec 22;21(1):1028. Epub 2020 Dec 22.

Imperial Clinical Trials Unit, Imperial College London, 1st Floor Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Background: Randomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data.

Methods: In this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata.

Results/case Study: Visualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors' conclusion. In the Parkinson's disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary.

Conclusions: Visualisations can better support investigators to assimilate large volumes of data and enable improved informal between-arm comparisons compared to tables. We endorse increased uptake for use in trial publications. Care in construction of visual displays needs to be taken as there can be potential to overemphasise treatment effects in some circumstances.
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http://dx.doi.org/10.1186/s13063-020-04903-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754702PMC
December 2020

Factors affecting the use of neurally adjusted ventilatory assist in the adult critical care unit: a clinician survey.

BMJ Open Respir Res 2020 12;7(1)

King's College London, Centre for Human and Applied Physiological Sciences, London, UK.

Background: Neurally adjusted ventilatory assist (NAVA) involves an intricate interaction between patient, clinician and technology. To improve our understanding of this complex intervention and to inform future trials, this survey aimed to examine clinician attitudes, beliefs and barriers to NAVA use in critically ill adults within an institution with significant NAVA experience.

Methods: A survey of nurses, doctors and physiotherapists in four Intensive Care Units (ICUs) of one UK university-affiliated hospital (75 NAVA equipped beds). The survey consisted of 39 mixed open and structured questions. The hospital had 8 years of NAVA experience prior to the survey.

Results: Of 466 distributed questionnaires, 301 (64.6%) were returned from 236 nurses (78.4%), 53 doctors (17.6%) and 12 physiotherapists (4.0%). Overall, 207/294 (70.4%) reported clinical experience. Most agreed that NAVA was safe (136/177, 76.8%) and clinically effective (99/176, 56.3%) and most perceived 'improved synchrony', 'improved comfort' and 'monitoring the diaphragm' to be key advantages of NAVA. 'Technical issues' (129/189, 68.3%) and 'NAVA signal problems' (94/180, 52.2%) were the most cited clinical disadvantage and cause of mode cross-over to Pressure Support Ventilation (PSV), respectively. Most perceived NAVA to be more difficult to use than PSV (105/174, 60.3%), although results were mixed when compared across different tasks. More participants preferred PSV to NAVA for initiating ventilator weaning (93/171 (54.4%) vs 29/171 (17.0%)). A key barrier to use and a consistent theme throughout was 'low confidence' in relation to NAVA use.

Conclusions: In addition to broad clinician support for NAVA, this survey describes technical concerns, low confidence and a perception of difficulty above that associated with PSV. In this context, high-quality training and usage algorithms are critically important to the design and of future trials, to clinician acceptance and to the clinical implementation and future success of NAVA.
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http://dx.doi.org/10.1136/bmjresp-2020-000783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725091PMC
December 2020

Development and internal validation of a predictive risk model for anxiety after completion of treatment for early stage breast cancer.

J Patient Rep Outcomes 2020 Dec 4;4(1):103. Epub 2020 Dec 4.

School of Health Sciences, Faculty of Health and Medical Sciences, University of Surrey, Kate Granger Building, Priestley Road, Guildford, Surrey, GU2 7YH, UK.

Objective: To develop a predictive risk model (PRM) for patient-reported anxiety after treatment completion for early stage breast cancer suitable for use in practice and underpinned by advances in data science and risk prediction.

Methods: Secondary analysis of a prospective survey of > 800 women at the end of treatment and again 6 months later using patient reported outcome (PRO) the hospital anxiety and depression scale-anxiety (HADS-A) and > 20 candidate predictors. Multiple imputation using chained equations (for missing data) and least absolute shrinkage and selection operator (LASSO) were used to select predictors. Final multivariable linear model performance was assessed (R) and bootstrapped for internal validation.

Results: Five predictors of anxiety selected by LASSO were HADS-A (Beta 0.73; 95% CI 0.681, 0.785); HAD-depression (Beta 0.095; 95% CI 0.020, 0.182) and having caring responsibilities (Beta 0.488; 95% CI 0.084, 0.866) increased risk, whereas being older (Beta - 0.010; 95% CI -0.028, 0.004) and owning a home (Beta 0.432; 95% CI -0.954, 0.078) reduced the risk. The final model explained 60% of variance and bias was low (- 0.006 to 0.002).

Conclusions: Different modelling approaches are needed to predict rather than explain patient reported outcomes. We developed a parsimonious and pragmatic PRM. External validation is required prior to translation to digital tool and evaluation of clinical implementation. The routine use of PROs and data driven PRM in practice provides a new opportunity to target supportive care and specialist interventions for cancer patients.
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http://dx.doi.org/10.1186/s41687-020-00267-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718350PMC
December 2020

Evidence generation for the clinical impact of myCOPD in patients with mild, moderate and newly diagnosed COPD: a randomised controlled trial.

ERJ Open Res 2020 Oct 26;6(4). Epub 2020 Oct 26.

mymhealth Limited, Bournemouth, UK.

Self-management interventions in COPD aim to improve patients' knowledge, skills and confidence to make correct decisions, thus improving health status and outcomes. myCOPD is a web-based self-management app known to improve inhaler use and exercise capacity in individuals with more severe COPD. We explored the impact of myCOPD in patients with mild-moderate or recently diagnosed COPD through a 12-week, open-label, parallel-group, randomised controlled trial of myCOPD compared with usual care. The co-primary outcomes were between-group differences in mean COPD assessment test (CAT) score at 90 days and critical inhaler errors. Key secondary outcomes were app usage and patient activation measurement (PAM) score. Sixty patients were randomised (29 myCOPD, 31 usual care). Groups were balanced for forced expiratory volume in 1 s (FEV % pred) but there was baseline imbalance between groups for exacerbation frequency and CAT score. There was no significant adjusted mean difference in CAT score at study completion, -1.27 (95% CI -4.47-1.92, p=0.44) lower in myCOPD. However, an increase in app use was associated with greater CAT score improvement. The odds of ≥1 critical inhaler error was lower in the myCOPD arm (adjusted OR 0.30 (95% CI 0.09-1.06, p=0.061)). The adjusted odds ratio for being in a higher PAM level at 90 days was 1.65 (95% CI 0.46-5.85) in favour of myCOPD. The small sample size and phenotypic difference between groups limited our ability to demonstrate statistically significant evidence of benefit beyond inhaler technique. However, our findings provide important insights into associations between increased app use and clinically meaningful benefit warranting further study in real world settings.
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http://dx.doi.org/10.1183/23120541.00460-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682704PMC
October 2020

Statistical methods for the analysis of adverse event data in randomised controlled trials: a scoping review and taxonomy.

BMC Med Res Methodol 2020 11 30;20(1):288. Epub 2020 Nov 30.

Imperial Clinical Trials Unit, Imperial College London, 1st Floor Stadium House, 68 Wood Lane, London, W12 7RH, United Kingdom.

Background: Statistical methods for the analysis of harm outcomes in randomised controlled trials (RCTs) are rarely used, and there is a reliance on simple approaches to display information such as in frequency tables. We aimed to identify whether any statistical methods had been specifically developed to analyse prespecified secondary harm outcomes and non-specific emerging adverse events (AEs).

Methods: A scoping review was undertaken to identify articles that proposed original methods or the original application of existing methods for the analysis of AEs that aimed to detect potential adverse drug reactions (ADRs) in phase II-IV parallel controlled group trials. Methods where harm outcomes were the (co)-primary outcome were excluded. Information was extracted on methodological characteristics such as: whether the method required the event to be prespecified or could be used to screen emerging events; and whether it was applied to individual events or the overall AE profile. Each statistical method was appraised and a taxonomy was developed for classification.

Results: Forty-four eligible articles proposing 73 individual methods were included. A taxonomy was developed and articles were categorised as: visual summary methods (8 articles proposing 20 methods); hypothesis testing methods (11 articles proposing 16 methods); estimation methods (15 articles proposing 24 methods); or methods that provide decision-making probabilities (10 articles proposing 13 methods). Methods were further classified according to whether they required a prespecified event (9 articles proposing 12 methods), or could be applied to emerging events (35 articles proposing 61 methods); and if they were (group) sequential methods (10 articles proposing 12 methods) or methods to perform final/one analyses (34 articles proposing 61 methods).

Conclusions: This review highlighted that a broad range of methods exist for AE analysis. Immediate implementation of some of these could lead to improved inference for AE data in RCTs. For example, a well-designed graphic can be an effective means to communicate complex AE data and methods appropriate for counts, time-to-event data and that avoid dichotomising continuous outcomes can improve efficiencies in analysis. Previous research has shown that adoption of such methods in the scientific press is limited and that strategies to support change are needed.

Trial Registration: PROSPERO registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=97442.
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http://dx.doi.org/10.1186/s12874-020-01167-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708917PMC
November 2020

Community psychosocial music intervention (CHIME) to reduce antenatal common mental disorder symptoms in The Gambia: a feasibility trial.

BMJ Open 2020 11 23;10(11):e040287. Epub 2020 Nov 23.

Psychology Department, Goldsmiths, University of London, London, UK.

Objectives: Examine the feasibility of a Community Health Intervention through Musical Engagement (CHIME) in The Gambia to reduce common mental disorder (CMD) symptoms in pregnant women.

Design: Feasibility trial testing a randomised stepped-wedge cluster design.

Setting: Four local antenatal clinics.

Participants: Women who were 14-24 weeks pregnant and spoke Mandinka or Wolof were recruited into the intervention (n=50) or control group (n=74).

Intervention: Music-based psychosocial support sessions designed and delivered by all-female fertility societies. Sessions lasted 1 hour and were held weekly for 6 weeks. Delivered to groups of women with no preselection. Sessions were designed to lift mood, build social connection and provide health messaging through participatory music making. The control group received standard antenatal care.

Outcomes: Demographic, feasibility, acceptability outcomes and the appropriateness of the study design were assessed. Translated measurement tools (Self-Reporting Questionnaire (SRQ-20); Edinburgh Postnatal Depression Scale (EPDS)) were used to assess CMD symptoms at baseline, post-intervention and 4-week follow-up.

Results: All clinics and 82% of women approached consented to take part. A 33% attrition rate across all time points was observed. 72% in the intervention group attended at least three sessions. Audio and video analysis confirmed fidelity of the intervention and a thematic analysis of participant interviews demonstrated acceptability and positive evaluation. Results showed a potential beneficial effect with a reduction of 2.13 points (95% CI (0.89 to 3.38), p<0.01, n=99) on the SRQ-20 and 1.98 points (95% CI (1.06 to 2.90), p<0.01, n=99) on the EPDS at the post-intervention time point for the intervention group compared with standard care.

Conclusion: Results demonstrate that CHIME is acceptable and feasible in The Gambia. To our knowledge, CHIME is the first example of a music-based psychosocial intervention to be applied to perinatal mental health in a low- and middle-income country context.

Trial Registration Number: Pan African Clinical Trials Registry (PACTR201901917619299).
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http://dx.doi.org/10.1136/bmjopen-2020-040287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684808PMC
November 2020

How to Develop Statistical Predictive Risk Models in Oncology Nursing to Enhance Psychosocial and Supportive Care.

Semin Oncol Nurs 2020 12 19;36(6):151089. Epub 2020 Nov 19.

Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, United Kingdom.

Objectives: Predictive risk models are advocated in psychosocial oncology practice to provide timely and appropriate support to those likely to experience the emotional and psychological consequences of cancer and its treatments. New digital technologies mean that large scale and routine data collection are becoming part of everyday clinical practice. Using these data to try to identify those at greatest risk for late psychosocial effects of cancer is an attractive proposition in a climate of unmet need and limited resource. In this paper, we present a framework to support the development of high-quality predictive risk models in psychosocial and supportive oncology. The aim is to provide awareness and increase accessibility of best practice literature to support researchers in psychosocial and supportive care to undertake a structured evidence-based approach.

Data Sources: Statistical prediction risk model publications.

Conclusion: In statistical modeling and data science different approaches are needed if the goal is to predict rather than explain. The deployment of a poorly developed and tested predictive risk model has the potential to do great harm. Recommendations for best practice to develop predictive risk models have been developed but there appears to be little application within psychosocial and supportive oncology care.

Implications For Nursing Practice: Use of best practice evidence will ensure the development and validation of predictive models that are robust as these are currently lacking. These models have the potential to enhance supportive oncology care through harnessing routine digital collection of patient-reported outcomes and the targeting of interventions according to risk characteristics.
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http://dx.doi.org/10.1016/j.soncn.2020.151089DOI Listing
December 2020

A randomised controlled feasibility trial of E-health application supported care vs usual care after exacerbation of COPD: the RESCUE trial.

NPJ Digit Med 2020 30;3:145. Epub 2020 Oct 30.

my mhealth Limited, Bournemouth, UK.

Exacerbations of COPD are one of the commonest causes of admission and readmission to hospital. The role of digital interventions to support self-management in improving outcomes is uncertain. We conducted an open, randomised controlled trial of a digital health platform application (app) in 41 COPD patients recruited following hospital admission with an acute exacerbation. Subjects were randomised to either receive usual care, including a written self-management plan ( = 21), or the myCOPD app ( = 20) for 90 days. The primary efficacy outcome was recovery rate of symptoms measured by COPD assessment test (CAT) score. Exacerbations, readmission, inhaler technique quality of life and patient activation (PAM) scores were also captured by a blinded team. The app was acceptable in this care setting and was used by 17 of the 20 patients with sustained use over the study period. The treatment effect on the CAT score was 4.49 (95% CI: -8.41, -0.58) points lower in the myCOPD arm. Patients' inhaler technique improved in the digital intervention arm (101 improving to 20 critical errors) compared to usual care (100 to 72 critical errors). Exacerbations tended to be less frequent in the digital arm compared to usual care; 34 vs 18 events. Hospital readmissions risk was numerically lower in the digital intervention arm: OR for readmission 0.383 (95% CI: 0.074, 1.987;  = 35). In this feasibility study of the digital self-management platform myCOPD, the app has proven acceptable to patients to use and use has improved exacerbation recovery rates, with strong signals of lower re-exacerbation and readmission rates over 90 days. myCOPD reduced the number of critical errors in inhaler technique compared to usual care with written self-management. This provides a strong basis for further exploration of the use of app interventions in the context of recently hospitalised patients with COPD and informs the potential design of a large multi-centre trial.
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http://dx.doi.org/10.1038/s41746-020-00347-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603326PMC
October 2020

Association of Clinical and Demographic Factors With the Severity of Palmoplantar Pustulosis.

JAMA Dermatol 2020 11;156(11):1216-1222

St John's Institute of Dermatology, King's College London, London, United Kingdom.

Importance: Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied.

Objective: To examine the factors associated with PPP severity.

Design, Setting, And Participants: An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020.

Main Outcomes And Measures: Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe).

Results: Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = -0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14).

Conclusions And Relevance: The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial.
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http://dx.doi.org/10.1001/jamadermatol.2020.3275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495329PMC
November 2020

A four-step strategy for handling missing outcome data in randomised trials affected by a pandemic.

BMC Med Res Methodol 2020 08 12;20(1):208. Epub 2020 Aug 12.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Background: The coronavirus pandemic (Covid-19) presents a variety of challenges for ongoing clinical trials, including an inevitably higher rate of missing outcome data, with new and non-standard reasons for missingness. International drug trial guidelines recommend trialists review plans for handling missing data in the conduct and statistical analysis, but clear recommendations are lacking.

Methods: We present a four-step strategy for handling missing outcome data in the analysis of randomised trials that are ongoing during a pandemic. We consider handling missing data arising due to (i) participant infection, (ii) treatment disruptions and (iii) loss to follow-up. We consider both settings where treatment effects for a 'pandemic-free world' and 'world including a pandemic' are of interest.

Results: In any trial, investigators should; (1) Clarify the treatment estimand of interest with respect to the occurrence of the pandemic; (2) Establish what data are missing for the chosen estimand; (3) Perform primary analysis under the most plausible missing data assumptions followed by; (4) Sensitivity analysis under alternative plausible assumptions. To obtain an estimate of the treatment effect in a 'pandemic-free world', participant data that are clinically affected by the pandemic (directly due to infection or indirectly via treatment disruptions) are not relevant and can be set to missing. For primary analysis, a missing-at-random assumption that conditions on all observed data that are expected to be associated with both the outcome and missingness may be most plausible. For the treatment effect in the 'world including a pandemic', all participant data is relevant and should be included in the analysis. For primary analysis, a missing-at-random assumption - potentially incorporating a pandemic time-period indicator and participant infection status - or a missing-not-at-random assumption with a poorer response may be most relevant, depending on the setting. In all scenarios, sensitivity analysis under credible missing-not-at-random assumptions should be used to evaluate the robustness of results. We highlight controlled multiple imputation as an accessible tool for conducting sensitivity analyses.

Conclusions: Missing data problems will be exacerbated for trials active during the Covid-19 pandemic. This four-step strategy will facilitate clear thinking about the appropriate analysis for relevant questions of interest.
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http://dx.doi.org/10.1186/s12874-020-01089-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422467PMC
August 2020

Understanding current practice, identifying barriers and exploring priorities for adverse event analysis in randomised controlled trials: an online, cross-sectional survey of statisticians from academia and industry.

BMJ Open 2020 06 11;10(6):e036875. Epub 2020 Jun 11.

Faculty of Medicine, School of Public Health, Imperial College London, London, UK.

Objectives: To gain a better understanding of current adverse event (AE) analysis practices and the reasons for the lack of use of sophisticated statistical methods for AE data analysis in randomised controlled trials (RCTs), with the aim of identifying priorities and solutions to improve practice.

Design: A cross-sectional, online survey of statisticians working in clinical trials, followed up with a workshop of senior statisticians working across the UK.

Participants: We aimed to recruit into the survey a minimum of one statistician from each of the 51 UK Clinical Research Collaboration registered clinical trial units (CTUs) and industry statisticians from both pharmaceuticals and clinical research organisations.

Outcomes: To gain a better understanding of current AE analysis practices, measure awareness of specialist methods for AE analysis and explore priorities, concerns and barriers when analysing AEs.

Results: Thirty-eight (38/51; 75%) CTUs, 5 (5/7; 71%) industry and 21 attendees at the 2019 Promoting Statistical Insights Conference participated in the survey. Of the 64 participants that took part, 46 participants were classified as public sector participants and 18 as industry participants. Participants indicated that they predominantly (80%) rely on subjective comparisons when comparing AEs between treatment groups. Thirty-eight per cent were aware of specialist methods for AE analysis, but only 13% had undertaken such analyses. All participants believed guidance on appropriate AE analysis and 97% thought training specifically for AE analysis is needed. These were both endorsed as solutions by workshop participants.

Conclusions: This research supports our earlier work that identified suboptimal AE analysis practices in RCTs and confirms the underuse of more sophisticated AE analysis approaches. Improvements are needed, and further research in this area is required to identify appropriate statistical methods. This research provides a unanimous call for the development of guidance, as well as training on suitable methods for AE analysis to support change.
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http://dx.doi.org/10.1136/bmjopen-2020-036875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295403PMC
June 2020

Current approaches to handling rescue medication in asthma and eczema randomized controlled trials are inadequate: a systematic review.

J Clin Epidemiol 2020 09 3;125:148-157. Epub 2020 Jun 3.

Imperial College London, Imperial College Clinical Trials Unit, 1st Floor Stadium House, 68 Wood Lane, London W12 7RH, UK. Electronic address:

Objectives: The objective of this study was to examine how rescue medication is defined, reported, and accounted for in randomized controlled trials (RCTs) in eczema and asthma populations.

Study Design And Setting: This is a systematic review of phase II/III RCTs evaluating monoclonal antibodies for treating chronic eczema or asthma. A search of EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials was conducted to identify eligible RCTs.

Results: Sixty published RCTs were identified, of which 60 (100%) allowed use of rescue medication but only 28 (47%) reported its use. Twenty-seven (45%) articles summarized rescue use by arm, with an average of 25% (95% CI (17%, 36%)) greater use in the placebo arm. Nine (15%) trials undertook an analysis that adjusted the primary treatment effect estimate for rescue medication use, but 8 of these used a suboptimal approach using single imputation, including 4 which used "last observation carried forward" after setting postrescue data to missing.

Conclusion: Rescue medication use in eczema and asthma trials evaluating monoclonal antibodies is often permitted, but not routinely reported. There is evidence of imbalance in rescue use between arms, but few articles attempted to estimate a rescue-adjusted treatment effect. In trials that did, the methods used were suboptimal which could introduce bias.
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http://dx.doi.org/10.1016/j.jclinepi.2020.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482905PMC
September 2020

Neurally adjusted ventilatory assist versus pressure support ventilation: a randomized controlled feasibility trial performed in patients at risk of prolonged mechanical ventilation.

Crit Care 2020 05 14;24(1):220. Epub 2020 May 14.

Centre for Human and Applied Physiological Sciences, King's College London, London, UK.

Background: The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV).

Methods: An open-label, parallel, feasibility RCT (n = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary-≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality.

Results: In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0-97.1%) and 100% (100-100%), and protocol compliance was 66.7% (50.3-80.0%) and 100% (89.0-100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0-11.0; p = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2-0.9; p = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV (p = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality.

Conclusions: This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted.

Trial Registration: ClinicalTrials.gov, NCT01826890. Registered 9 April 2013.
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http://dx.doi.org/10.1186/s13054-020-02923-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224141PMC
May 2020

An evaluation of inverse probability weighting using the propensity score for baseline covariate adjustment in smaller population randomised controlled trials with a continuous outcome.

BMC Med Res Methodol 2020 03 23;20(1):70. Epub 2020 Mar 23.

Imperial Clinical Trials Unit, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK.

Background: It is important to estimate the treatment effect of interest accurately and precisely within the analysis of randomised controlled trials. One way to increase precision in the estimate and thus improve the power for randomised trials with continuous outcomes is through adjustment for pre-specified prognostic baseline covariates. Typically covariate adjustment is conducted using regression analysis, however recently, Inverse Probability of Treatment Weighting (IPTW) using the propensity score has been proposed as an alternative method. For a continuous outcome it has been shown that the IPTW estimator has the same large sample statistical properties as that obtained via analysis of covariance. However the performance of IPTW has not been explored for smaller population trials (< 100 participants), where precise estimation of the treatment effect has potential for greater impact than in larger samples.

Methods: In this paper we explore the performance of the baseline adjusted treatment effect estimated using IPTW in smaller population trial settings. To do so we present a simulation study including a number of different trial scenarios with sample sizes ranging from 40 to 200 and adjustment for up to 6 covariates. We also re-analyse a paediatric eczema trial that includes 60 children.

Results: In the simulation study the performance of the IPTW variance estimator was sub-optimal with smaller sample sizes. The coverage of 95% CI's was marginally below 95% for sample sizes < 150 and ≥ 100. For sample sizes < 100 the coverage of 95% CI's was always significantly below 95% for all covariate settings. The minimum coverage obtained with IPTW was 89% with n = 40. In comparison, regression adjustment always resulted in 95% coverage. The analysis of the eczema trial confirmed discrepancies between the IPTW and regression estimators in a real life small population setting.

Conclusions: The IPTW variance estimator does not perform so well with small samples. Thus we caution against the use of IPTW in small sample settings when the sample size is less than 150 and particularly when sample size < 100.
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http://dx.doi.org/10.1186/s12874-020-00947-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092449PMC
March 2020

COPe-support - a multi-component digital intervention for family carers for people affected by psychosis: study protocol for a randomized controlled trial.

BMC Psychiatry 2020 03 17;20(1):129. Epub 2020 Mar 17.

Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, England, UK.

Background: Psychosis often causes significant distress and impacts not only in the individuals, but also those close to them. Many relatives and friends ('carers') provide long-term support and need resources to assist them. We have co-produced a digital mental health intervention called COPe-support (Carers fOr People with Psychosis e-support) to provide carers with flexible access to high quality psychoeducation and interactive support from experts and peers. This study evaluates the effectiveness of COPe-support to promote mental wellbeing and caregiving experiences in carers.

Methods: This study is a single-blind, parallel arm, individually randomized controlled trial (RCT) comparing COPe-support, with attention control. Both groups continue to receive usual care. COPe-support provides interactive web-based psychoeducation on psychosis-related issues, wellbeing-promotion and network support through forums. The attention-control is a non-interactive online information resource pack. Carers living in England are eligible if they provide at least weekly support to a family member or close friend affected by psychosis, and use internet communication (including emails) daily. All trial procedures are run online, including collection of outcome measurements which participants will directly input into our secure platform. Following baseline assessment, a web-based randomization system will be used to allocate 360 carers to either arm. Participants have unlimited access to the allocated condition for 40 weeks. Data collection is at three time points (10, 20, and 40 weeks after randomization). Analyses will be conducted by trial statisticians blinded to allocation. The primary outcome is mental wellbeing measured by Warwick Edinburgh Mental Wellbeing Scale (WEMWBS), at 20 weeks. As well as an intention-to-treat analysis, a complier average causal effect (CACE) analysis will be conducted to estimate the intervention effect in participants who have accessed COPe-support content twice or more. The secondary objectives and analysis will examine other health and caregiving-related outcomes and explore mechanisms. In a process evaluation, we will interview 20% of the intervention arm participants regarding the acceptability of COPe-support. We will explore in detail participants' usage patterns.

Discussion: The results of this trial will provide valuable information about the effectiveness of COPe-support in promoting wellbeing and caregiving experiences in carers.

Trial Registration: The RCT is registered with the Current Controlled Trials registration (ISRCTN 89563420, registration date: 02/03/2018).
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http://dx.doi.org/10.1186/s12888-020-02528-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079455PMC
March 2020

A randomised placebo controlled trial of anakinra for treating pustular psoriasis: statistical analysis plan for stage two of the APRICOT trial.

Trials 2020 Feb 10;21(1):158. Epub 2020 Feb 10.

Imperial Clinical Trials Unit, Imperial College London, W12 7RH, London, UK.

Background: Current treatment options for Palmoplantar Pustulosis (PPP), a debilitating chronic skin disease which affects the hands and feet, are limited. The Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) aims to determine the efficacy of anakinra in the treatment of PPP. This article describes the statistical analysis plan for the final analysis of this two-staged trial, which was determined prior to unblinding and database lock. This is an update to the published protocol and stage one analysis plan.

Methods: APRICOT is a randomised, double-blind, placebo-controlled trial of anakinra versus placebo, with two stages and an adaptive element. Stage one compared treatment arms to ensure proof-of-concept and determined the primary outcome for stage two of the trial. The primary outcome was selected to be the change in Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. Secondary outcomes include other investigator-assessed efficacy measures of disease severity, participant-reported measures of efficacy and safety measures. This manuscript describes in detail the outcomes, sample size, general analysis principles, the pre-specified statistical analysis plan for each of the outcomes, the handling of missing outcome data and the planned sensitivity and supplementary analyses for the second stage of the APRICOT trial.

Discussion: This statistical analysis plan was developed in compliance with international trial guidelines and is published to increase transparency of the trial analysis. The results of the trial analysis will indicate whether anakinra has a role in the treatment of PPP.

Trial Registration: ISCRTN, ISCRTN13127147. Registered on 1 August 2016. EudraCT Number 2015-003600-23. Registered on 1 April 2016.
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http://dx.doi.org/10.1186/s13063-020-4103-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011285PMC
February 2020

Treatment Effect of Omalizumab on Severe Pediatric Atopic Dermatitis: The ADAPT Randomized Clinical Trial.

JAMA Pediatr 2020 Jan;174(1):29-37

King's College London, School of Life Course Sciences & School of Immunology & Microbial Sciences, King's Health Partners, London, United Kingdom.

Importance: Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published.

Objective: To determine the effectiveness of omalizumab in treating severe atopic dermatitis in children.

Design, Setting, And Participants: The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) was a 24-week single-center, double-blind, placebo-controlled randomized clinical trial with a 24-week follow-up. Conducted from November 20, 2014, to August 31, 2017, at Guy's and St Thomas' Hospital NHS Foundation Trust and King's College London in the United Kingdom, this trial recruited participants after a screening visit. Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index >40) that was unresponsive to optimum therapy. Statistical analysis was conducted using the intention-to-treat principle.

Interventions: Subcutaneous omalizumab or placebo for 24 weeks. The drug manufacturer's dosing tables were used to determine the dosage based on total IgE (30-1500 IU/mL) and body weight (in kilograms) at randomization.

Main Outcomes And Measures: Objective SCORAD index after 24 weeks of treatment.

Results: In total, 62 children (mean [SD] age, 10.3 [4.2] years; 32 (52%) were male) were randomized to either omalizumab (n = 30) or placebo (n = 32). Five participants withdrew from treatment (4 [13%] from the placebo group, and 1 [3%] from the omalizumab group). Follow-up attendance was 97% at week 24 and 98% at week 48. After adjustment for baseline objective SCORAD index, age, and IgE level, the mean difference in objective SCORAD index improvement between groups at week 24 was -6.9 (95% CI, -12.2 to -1.5; P = .01), significantly favoring omalizumab therapy and reflecting the results in other assessments of atopic dermatitis severity. Improved quality-of-life scores were seen in the omalizumab group, as measured by the Children's Dermatology Life Quality Index/Dermatology Life Quality Index (-3.5; 95% CI, -6.4 to -0.5) and Pediatric Allergic Disease Quality of Life Questionnaire score (-0.5; 95% CI, -0.9 to -0.0). Improvements in disease severity occurred despite lower potent topical corticosteroid use in the omalizumab group compared with the placebo group (median [interquartile range (IQR)] percentage of body surface area covered, 16% [10%-46%] vs 31% [14%-55%]; median [IQR] number of days of use, 109 [34-164] days vs 161 [82-171] days).

Conclusions And Relevance: This randomized clinical trial found that omalizumab significantly reduced atopic dermatitis severity and improved quality of life in a pediatric population with atopy and severe eczema despite highly elevated total IgE levels at baseline. The result was associated with a potent topical corticosteroid sparing effect and may suggest that omalizumab is a treatment option for difficult-to-manage severe eczema in children with atopy.

Trial Registration: ClinicalTrials.gov identifier: NCT02300701.
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http://dx.doi.org/10.1001/jamapediatrics.2019.4476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902112PMC
January 2020

A study protocol for testing the feasibility of a randomised stepped wedge cluster design to investigate a Community Health Intervention through Musical Engagement (CHIME) for perinatal mental health in The Gambia.

Pilot Feasibility Stud 2019 7;5:124. Epub 2019 Nov 7.

1Goldsmiths, University of London, London, UK.

Background: Perinatal mental health problems affect up to one in five women worldwide. Mental health problems in the perinatal period are a particular challenge in low- and middle-income countries (LMICs) where they can be at least twice as frequent as in higher-income countries. It is thus of high priority to develop new low-cost, low-resource, non-stigmatising and culturally appropriate approaches to reduce symptoms of anxiety and depression perinatally, for the benefit of both mother and child. Music-centred approaches may be particularly useful in The Gambia since a range of musical practices that specifically engage pregnant women and new mothers already exist.

Methods: This protocol is for a study to examine the feasibility of undertaking a stepped wedge trial to test how a Community Health Intervention through Musical Engagement (CHIME) could be beneficial in alleviating perinatal mental distress in The Gambia. In this study, we plan to recruit 120 pregnant women ( = 60 intervention,  = 60 control) at four antenatal clinics over two 6-week stepped sequences. Women in the intervention will participate in weekly group-singing sessions, led by local Kanyeleng singing groups, for 6 weeks. The control group will receive standard care. We will assess symptoms of anxiety and depression using the Edinburgh Postnatal Depression Scale (EPDS) and the Self-Reporting Questionnaire (SRQ-20). The feasibility of the design will be assessed through recruitment, retention and attrition rates of participants, clinics' adherence to the schedule and completeness of data by site. Qualitative interviews and video and audio recordings will be used to evaluate the acceptability of the intervention.

Discussion: This feasibility trial will allow us to determine whether a larger trial with the same intervention and target group is feasible and acceptable in The Gambia.

Trial Registration: Retrospectively registered (24/01/2019) with Pan African Clinical Trials Registry (PACTR): PACTR201901917619299.
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http://dx.doi.org/10.1186/s40814-019-0515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839151PMC
November 2019

Comparison of Clinical Trial Changes in Primary Outcome and Reported Intervention Effect Size Between Trial Registration and Publication.

JAMA Netw Open 2019 07 3;2(7):e197242. Epub 2019 Jul 3.

Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, United Kingdom.

Importance: Primary outcome change could threaten the validity of a clinical trial; however, evidence about the consequences on the reported intervention effect size is unclear.

Objectives: To examine the status of randomized clinical trials whose primary outcome changed between trial registration and publication and to quantify the association of this change with the reported intervention effect size.

Design, Setting, And Participants: In this cross-sectional study on the primary report of randomized clinical trials with clear prospectively registered primary outcomes, PubMed and Embase were searched for articles published between January 1, 2011, and December 31, 2015. The search was conducted in January 2016, identifying randomized clinical trials and the combination of keywords and text words related to registry.

Main Outcomes And Measures: Based on the developed approach, trials were classified as having primary outcome change when there was a major discrepancy between the registered and published primary outcomes. Intervention effect was estimated or recalculated using the odds ratio (OR) for each comparison. Each component OR is structured so that an OR is less than 1 if the intervention group has a more favorable result than the control group. The ratio of ORs (ROR), which is the summary OR for trials with primary outcome change divided by those without, and its 95% CI were calculated, with a value less than 1 indicating a larger reported intervention effect size in trials with primary outcome change than those without.

Results: Among 29 749 searched articles (28 810 MEDLINE and 939 Embase), 1488 articles were randomly selected for review. Of 389 trials with clear primary outcomes prospectively described in the registry (416 outcomes reported), 33.4% (130 of 389) of trials had at least 1 primary outcome change. Most (66 of 130) of the changes were either not reporting or omitting the primary outcome. In total, 338 trials (365 outcomes and 487 comparisons) were available for quantitative analysis on the reported intervention effect size bias assessment. Compared with those without primary outcome change, trials with primary outcome change showed a 16% (pooled ROR, 0.84; 95% CI, 0.73-0.96) larger reported intervention effect size. The result persisted after adjustment for potential confounders (ROR, 0.81; 95% CI, 0.71-0.93) and other sensitivity and subgroup analyses.

Conclusions And Relevance: Results of this study suggest that inconsistencies between registered and published primary outcomes of clinical trials are common, and trials with primary outcome change are likely to have a larger intervention effect than those without.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.7242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646984PMC
July 2019