Lee Silverman voice treatment versus NHS speech and language therapy versus control for dysarthria in people with Parkinson's disease (PD COMM): pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial.

OBJECTIVES: To assess the clinical effectiveness of two speech and language therapy approaches versus no speech and language therapy for dysarthria in people with Parkinson's disease. DESIGN: Pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial. SETTING: The speech and language therapy interventions were delivered in outpatient or home settings between 26 September 2016 and 16 March 2020. PARTICIPANTS: 388 people with Parkinson's disease and dysarthria. INTERVENTIONS: Participants were randomly assigned to one of three groups (1:1:1): 130 to Lee Silverman voice treatment (LSVT LOUD), 129 to NHS speech and language therapy, and 129 to no speech and language therapy. LSVT LOUD consisted of four, face-to-face or remote, 50 min sessions each week delivered over four weeks. Home based practice activities were set for up to 5-10 mins daily on treatment days and 15 mins twice daily on non-treatment days. Dosage for the NHS speech and language therapy was determined by the local therapist in response to the participants' needs (estimated from prior research that NHS speech and language therapy participants would receive an average of one session per week over six to eight weeks). Local practices for NHS speech and language therapy were accepted, except for those within the LSVT LOUD protocol. Analyses were based on the intention to treat principle. MAIN OUTCOME MEASURES: The primary outcome was total score at three months of self-reported voice handicap index. RESULTS: People who received LSVT LOUD reported lower voice handicap index scores at three months after randomisation than those who did not receive speech and language therapy (-8.0 points (99% confidence interval -13.3 to -2.6); P<0.001). No evidence suggests a difference in voice handicap index scores between NHS speech and language therapy and no speech and language therapy (1.7 points (-3.8 to 7.1); P=0.43). Patients in the LSVT LOUD group also reported lower voice handicap index scores than did those randomised to NHS speech and language therapy (-9.6 points (-14.9 to -4.4); P<0.001). 93 adverse events (predominately vocal strain) were reported in the LSVT LOUD group, 46 in the NHS speech and language therapy group, and none in the no speech and language therapy group. No serious adverse events were recorded. CONCLUSIONS: LSVT LOUD was more effective at reducing the participant reported impact of voice problems than was no speech and language therapy and NHS speech and language therapy. NHS speech and language therapy showed no evidence of benefit compared with no speech and language therapy. TRIAL REGISTRATION: ISRCTN registry ISRCTN12421382.

Bilateral remote ischemic conditioning in children: A two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery.

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis. Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants. Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 µg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 µg/L/h, n = 58) (mean difference, 13.2 µg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups. Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery.

Effectiveness and cost-effectiveness of Assets-based feeding help Before and After birth (ABA-feed) for improving breastfeeding initiation and continuation: protocol for a multicentre randomised controlled trial (Version 3.0).

INTRODUCTION: Breastfeeding has health benefits for infants and mothers, yet the UK has low rates with marked social inequalities. The Assets-based feeding help Before and After birth (ABA) feasibility study demonstrated the acceptability of a proactive, assets-based, woman-centred peer support intervention, inclusive of all feeding types, to mothers, peer supporters and maternity services. The ABA-feed study aims to assess the clinical and cost-effectiveness of the ABA-feed intervention compared with usual care in first-time mothers in a full trial. METHODS AND ANALYSIS: A multicentre randomised controlled trial with economic evaluation to explore clinical and cost-effectiveness, and embedded process evaluation to explore differences in implementation between sites. We aim to recruit 2730 primiparous women, regardless of feeding intention. Women will be recruited at 17 sites from antenatal clinics and various remote methods including social media and invitations from midwives and health visitors. Women will be randomised at a ratio of 1.43:1 to receive either ABA-feed intervention or usual care. A train the trainer model will be used to train local Infant Feeding Coordinators to train existing peer supporters to become 'infant feeding helpers' in the ABA-feed intervention. Infant feeding outcomes will be collected at 3 days, and 8, 16 and 24 weeks postbirth. The primary outcome will be any breastfeeding at 8 weeks postbirth. Secondary outcomes will include breastfeeding initiation, any and exclusive breastfeeding, formula feeding practices, anxiety, social support and healthcare utilisation. All analyses will be based on the intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol has been approved by the East of Scotland Research Ethics Committee. Trial results will be available through open-access publication in a peer-reviewed journal and presented at relevant meetings and conferences. TRIAL REGISTRATION NUMBER: ISRCTN17395671.

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial.

BACKGROUND: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. METHODS: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. DISCUSSION: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. TRIAL REGISTRATION: ISRCTN12682719 registration date 24/11/2020.

LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

BACKGROUND: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64-82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. METHODS/DESIGN: Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. DISCUSSION: If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8-4.6 million (€2.05-5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects. TRIAL REGISTRATION: EudraCT number: 2020-001006-39.

Economic Evaluation of Using Daily Prednisolone versus Placebo at the Time of an Upper Respiratory Tract Infection for the Management of Children with Steroid-Sensitive Nephrotic Syndrome: A Model-Based Analysis.

BACKGROUND: Childhood steroid-sensitive nephrotic syndrome is a frequently relapsing disease with significant short- and long-term complications, leading to high healthcare costs and reduced quality of life for patients. The majority of relapses are triggered by upper respiratory tract infections (URTIs) and evidence shows that daily low-dose prednisolone at the time of infection may reduce the risk of relapse. OBJECTIVE: The aim of this study was to assess the cost effectiveness of a 6-day course of low-dose prednisolone at the start of a URTI when compared with placebo. METHODS: A state-transition Markov model was developed to conduct a cost-utility analysis with the outcome measured in quality-adjusted life-years (QALYs). Resource use and outcome data were derived from the PREDNOS2 trial. The analysis was performed from a UK National Health Service perspective and the results were extrapolated to adulthood. Model parameter and structural uncertainty were assessed using sensitivity analyses. RESULTS: The base-case results showed that administering low-dose prednisolone at the time of a URTI generated more QALYs and a lower mean cost at 1 year compared with placebo. In the long-term, low-dose prednisolone was associated with a cost saving (£176) and increased effectiveness (0.01 QALYs) compared with placebo and thus remained the dominant treatment option. These findings were robust to all sensitivity analyses. CONCLUSION: A 6-day course of low-dose prednisolone at the time of a URTI in children with steroid-sensitive nephrotic syndrome has the potential to reduce healthcare costs and improve quality of life compared with placebo.

DNA metabarcoding reveals high relative abundance of trunk disease fungi in grapevines from Marlborough, New Zealand.

Grapevine trunk diseases (GTDs) are a threat to grape production worldwide, with a diverse collection of fungal species implicated in disease onset. Due to the long-term and complex nature of GTDs, simultaneous detection of multiple microbial species can enhance understanding of disease development. We used DNA metabarcoding of ribosomal internal transcribed spacer 1 (ITS1) sequences, supported by specific PCR and microbial isolation, to establish the presence of trunk pathogens across 11 vineyards (11-26 years old) over three years in Marlborough, the largest wine producing region in New Zealand. Using a reference database of trunk pathogen sequences, species previously associated with GTD, such as Cadophora luteo-olivacea, Diplodia seriata, Diplodia mutila, Neofusicoccum australe, and Seimatosporium vitis, were identified as highly represented across the vineyard region. The well-known pathogens Phaeomoniella chlamydospora and Eutypa lata had especially high relative abundance across the dataset, with P. chlamydospora reads present between 22 and 84% (average 52%) across the vineyards. Screening of sequences against broader, publicly available databases revealed further fungal species within families and orders known to contain pathogens, many of which appeared to be endemic to New Zealand. The presence of several wood-rotting basidiomycetes (mostly Hymenochaetales) was detected for the first time in the Marlborough vineyard region, notably, the native Inonotus nothofagii which was present at 1-2% relative abundance in two vineyards.

Daily low-dose prednisolone to prevent relapse of steroid-sensitive nephrotic syndrome in children with an upper respiratory tract infection: PREDNOS2 RCT.

BACKGROUND: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5-7 days during an upper respiratory tract infection reduces the risk of relapse. OBJECTIVES: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. DESIGN: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis. SETTING: A total of 122 UK paediatric departments, of which 91 recruited patients. PARTICIPANTS: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1 : 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). INTERVENTIONS: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m2) or an equivalent dose of placebo. MAIN OUTCOME MEASURES: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years. RESULTS: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference -0.024, 95% confidence interval -0.14 to 0.09; p = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. LIMITATIONS: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. CONCLUSIONS: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse. FUTURE WORK: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 3. See the NIHR Journals Library website for further project information.

Steroid-sensitive nephrotic syndrome is a kidney condition in which protein leaks into the urine, causing generalised swelling. In most children, the condition recurs or relapses. Relapses often occur following an upper respiratory tract infection (i.e. a cough, cold or sore throat). Research in tropical countries suggests that if children have a small dose of daily steroids for a week at the time of an upper respiratory tract infection then they are less likely to relapse. The selection of children for these studies and the different patterns of infection mean that we are not certain if this treatment would work in the UK. A total of 365 children with relapsing nephrotic syndrome took part. Half of the children took a steroid and the other half took dummy tablets (placebo) for 6 days at the start of an upper respiratory tract infection. We followed up the children for 12 months and collected information on relapses and other treatments and information from questionnaires about behaviour and quality of life. We also investigated whether or not there were cost savings with this treatment. There were 271 children who had an upper respiratory tract infection in the 12 months of the study and so only these children were included in the analyses. Giving 6 days of a low-dose steroid at the time of an upper respiratory tract infection did not reduce the risk of a relapse. There was also no effect on the overall number of relapses, the number of children needing to start extra preventative treatments or side effects of steroids. Although there was no clinical effect, the economic evaluation found that giving prednisolone led to lower treatment costs overall and higher quality of life and might, therefore, offer better value for money, but this has to be interpreted against the clinical evidence of no significant effect. Our conclusion is that there is no clinical benefit to giving children low-dose prednisolone at the time of an upper respiratory tract infection.

Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy: The PD MED Randomized Clinical Trial.

Importance: Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. Objective: To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. Design, Setting, and Participants: This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. Interventions: Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. Main Outcomes and Measures: Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. Results: Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. Conclusions and Relevance: In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. Trial Registration: isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.

Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome: The PREDNOS 2 Randomized Clinical Trial.

IMPORTANCE: In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. OBJECTIVE: To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection-related relapses. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. INTERVENTIONS: At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of first upper respiratory tract infection-related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. RESULTS: The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). CONCLUSIONS AND RELEVANCE: The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39.

Lee Silverman Voice Treatment versus standard speech and language therapy versus control in Parkinson's disease: preliminary cost-consequence analysis of the PD COMM pilot randomised controlled trial.

BACKGROUND: The PD COMM pilot randomised controlled trial compared Lee Silverman Voice Treatment (LSVT® LOUD) with standard NHS speech and language therapy (SLT) and a control arm in people with Parkinson's disease (PwPD) with self-reported problems with voice or speech. This analysis compares costs and quality of life outcomes between the trial arms, and considers the validity of the alternative outcome measures for economic evaluations. METHODS: A comparison of costs and outcomes was undertaken alongside the PD COMM pilot trial involving three arms: LSVT® LOUD treatment (n = 30); standard NHS SLT (n = 30); and a control arm (n = 29) excluded from receiving therapy for at least 6 months after randomisation unless deemed medically necessary. For all trial arms, resource use and NHS, social care and patient costs and quality of life were collected prospectively at baseline, 3, 6, and 12 months. Total economic costs and outcomes (EQ-5D-3L, ICECAP-O) were considered over the 12-month follow-up period from an NHS payer perspective. Quality of life measures for economic evaluation of SLT for people with Parkinson's disease were compared. RESULTS: Whilst there was no difference between arms in voice or quality of life outcomes at 12 months, there were indications of differences at 3 months in favour of SLT, which need to be confirmed in the main trial. The estimated mean cost of NHS care was £3288 per patient per year for the LSVT® LOUD arm, £2033 for NHS SLT, and £1788 for the control arm. EQ-5D-3L was more strongly correlated to voice impairment than ICECAP-O, and was sensitive to differences in voice impairment between arms. CONCLUSIONS: The pilot did not identify an effect of SLT on disease-specific or economic outcomes for PwPD at 12 months; however, there appeared to be improvements at 3 months. In addition to the sample size not powered to detect difference in cost-consequence analysis, many patients in the control arm started SLT during the 12-month period used for economic analysis, in line with the study protocol. The LSVT® LOUD intervention was more intense and therefore more costly. Early indications suggest that the preferred economic outcome measure for the full trial is EQ-5D-3L; however, the ICECAP-O should still be included to capture a broader measure of wellbeing. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register: ISRCTN75223808. Registered 22 March 2012.

Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction.

AIMS: The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers. METHODS AND RESULTS: We performed an unsupervised cluster analysis using 363 biomarkers from 429 patients with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over-representation analyses. We identified four distinct patient subgroups based on their biomarker profiles: cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age-related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels; and cluster 4 with highest prevalence of ischaemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT-proBNP and troponin levels. Over a median follow-up of 21 months, the occurrence of death or heart failure hospitalization was highest in clusters 1 and 4 (62.1% and 62.8%, respectively) and lowest in cluster 3 (25.6%). Pathway over-representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival. CONCLUSION: Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathways.

Bilateral Remote Ischaemic Conditioning in Children (BRICC) trial: protocol for a two-centre, double-blind, randomised controlled trial in young children undergoing cardiac surgery.

INTRODUCTION: Myocardial protection against ischaemic-reperfusion injury is a key determinant of heart function and outcome following cardiac surgery in children. However, with current strategies, myocardial injury occurs routinely following aortic cross-clamping, as demonstrated by the ubiquitous rise in circulating troponin. Remote ischaemic preconditioning, the application of brief, non-lethal cycles of ischaemia and reperfusion to a distant organ or tissue, is a simple, low-risk and readily available technique which may improve myocardial protection. The Bilateral Remote Ischaemic Conditioning in Children (BRICC) trial will assess whether remote ischaemic preconditioning, applied to both lower limbs immediately prior to surgery, reduces myocardial injury in cyanotic and acyanotic young children. METHODS AND ANALYSIS: The BRICC trial is a two-centre, double-blind, randomised controlled trial recruiting up to 120 young children (age 3 months to 3 years) undergoing primary repair of tetralogy of Fallot or surgical closure of an isolated ventricular septal defect. Participants will be randomised in a 1:1 ratio to either bilateral remote ischaemic preconditioning (3×5 min cycles) or sham immediately prior to surgery, with follow-up until discharge from hospital or 30 days, whichever is sooner. The primary outcome is reduction in area under the time-concentration curve for high-sensitivity (hs) troponin-T release in the first 24 hours after aortic cross-clamp release. Secondary outcome measures include peak hs-troponin-T, vasoactive inotrope score, arterial lactate and central venous oxygen saturations in the first 12 hours, and lengths of stay in the paediatric intensive care unit and the hospital. ETHICS AND DISSEMINATION: The trial was approved by the West Midlands-Solihull National Health Service Research Ethics Committee (16/WM/0309) on 5 August 2016. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Parents will be informed of the results through a newsletter in conjunction with a local charity. TRIAL REGISTRATION NUMBER: ISRCTN12923441.

11ß-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11ß-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: -4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: -0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11ß-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11ß-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure.

AIMS: Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non-ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. METHODS AND RESULTS: We performed a biological physical protein-protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT-CHF study, 715 of whom had ischaemic HF and 445 had non-ischaemic HF. Second, we constructed an enriched physical protein-protein interaction network, followed by a pathway over-representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non-ischaemic HF patients. We found 21/92 proteins to be up-regulated and 2/92 down-regulated in ischaemic relative to non-ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin-like growth factor binding protein-1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. CONCLUSIONS: Pathophysiological pathways distinguishing patients with ischaemic HF from those with non-ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF.

Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. DESIGN: Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. SETTING: 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. PARTICIPANTS: 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. INTERVENTIONS: Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. RESULTS: No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval -0.005 to 0.037) and cost savings (difference -£1673 ($2160; €1930), 95% confidence interval -£3455 to £109). CONCLUSIONS: Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. TRIAL REGISTRATION: ISRCTN16645249; EudraCT 2010-022489-29.

Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT.

BACKGROUND: The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS). OBJECTIVES: The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs. DESIGN: Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis. SETTING: One hundred and twenty-five UK paediatric departments. PARTICIPANTS: Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years). INTERVENTIONS: The control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1-4, 40 mg/m2 of prednisolone on alternate days in weeks 5-8 and matching placebo on alternate days in weeks 9-18 (total 2240 mg/m2). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1-4; started at 60 mg/m2 of prednisolone on alternate days in weeks 5-16, tapering by 10 mg/m2 every 2 weeks (total 3150 mg/m2). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse [Albustix® (Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months. RESULTS: There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank p = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; p = 0.7), SDNS (44% vs. 42%; p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%; p = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696). LIMITATIONS: Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating. CONCLUSIONS: This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit. FUTURE WORK: Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

Steroid-sensitive nephrotic syndrome (SSNS) is one of the most common childhood kidney diseases. The kidney filters leak protein into the urine, resulting in low levels of protein in the blood and generalised swelling. If untreated, this can lead to serious complications, including infection and blood clots. The disease responds well to prednisolone, a steroid drug; however, it is very common for disease to recur (called a relapse). Doctors are uncertain how long prednisolone should be given to treat children when they first present with nephrotic syndrome. In the UK, a 2-month course has traditionally been used. However, a number of research studies have suggested that giving prednisolone for ≥ 3 months may reduce the number of children who relapse and also the number who develop lots of relapses (called frequently relapsing nephrotic syndrome; FRNS). We recruited 237 children presenting with SSNS. Half were given an 8-week standard course of prednisolone and the other half a 16-week extended course (EC). We used placebo (dummy tablets) so that the participants and doctors did not know which treatment group they were in. Participants were followed for a minimum of 24 months and monitored for the development of relapses and prednisolone side effects, including behavioural problems. A cost analysis was performed. Giving EC prednisolone did not delay the development of disease relapse. There was also no difference in the number of children who developed FRNS or steroid-dependent nephrotic syndrome or who needed to be given other treatments. The rate of prednisolone side effects was the similar in the two treatment groups. EC treatment was, however, cheaper by £1673. Therefore, we conclude that there is no clinical benefit associated with the administration of EC prednisolone therapy in UK children presenting for the first time with SSNS. However, EC therapy was cheaper than the standard treatment.

Rating the intelligibility of dysarthic speech amongst people with Parkinson's Disease: a comparison of trained and untrained listeners.

Intelligibility of speech is a key outcome in speech and language therapy (SLT) and research. SLT students frequently participate as raters of intelligibility but we lack information about whether they rate intelligibility in the same way as the general public. This paper aims to determine if there is a difference in the intelligibility ratings made by SLT students (trained in speech related topics) compared to individuals from the general public (untrained). The SLT students were in year 2 of a BSc programme or the first 6 months of a MSc programme. We recorded 10 speakers with Parkinson's disease (PD) related speech reading aloud the words and sentences from the Assessment of Intelligibility of Dysarthric Speech. These speech recordings were rated for intelligibility by 'trained' raters and 'untrained' raters. The effort required to understand the speech was also reported. There were no significant differences in the measures of intelligibility from the trained and untrained raters for words or sentences after adjusting for speaker by including them as a covariate in the model. There was a slight increase in effort reported by the untrained raters for the sentences. This difference in reported effort was not evident with the words. SLT students can be recruited alongside individuals from the general public as naïve raters for evaluating intelligibility in people with speech disorders.

Role of the Deployed Aeromedical Response Team Squadron (DARTS) on Operation RUMAN.

In September 2017, the British Government called on the military to deliver aid and provide assistance to British Overseas Territories in the Caribbean affected by the devastating category 5 Hurricane, Irma.1 The military and humanitarian operation, named Op RUMAN, saw British military personnel from all services deploy at short notice to assess damage, reinstate vital infrastructure and help islanders get back on their feet as quickly as possible. Members of the Deployed Aeromedical Response Team Squadron (DARTS) were among the first troops deployed to the region. The aim of this paper is to describe the role of DARTS within this Op.