Long-term consequences of urinary tract infection in childhood: an electronic population-based cohort study in Welsh primary and secondary care.

BACKGROUND: Childhood urinary tract infection (UTI) can cause renal scarring, and possibly hypertension, chronic kidney disease (CKD), and end-stage renal failure (ESRF). Previous studies have focused on selected populations, with severe illness or underlying risk factors. The risk for most children with UTI is unclear. AIM: To examine the association between childhood UTI and outcomes in an unselected population of children. DESIGN AND SETTING: A retrospective population-based cohort study using linked GP, hospital, and microbiology records in Wales, UK. METHOD: Participants were all children born in 2005-2009, with follow-up until 31 December 2017. The exposure was microbiologically confirmed UTI before the age of 5 years. The key outcome measures were renal scarring, hypertension, CKD, and ESRF. RESULTS: In total, 159 201 children were included; 77 524 (48.7%) were female and 7% (n = 11 099) had UTI before the age of 5 years. A total of 0.16% (n = 245) were diagnosed with renal scarring by the age of 7 years. Odds of renal scarring were higher in children by age 7 years with UTI (1.24%; adjusted odds ratio 4.60 [95% confidence interval [CI] = 3.33 to 6.35]). Mean follow-up was 9.53 years. Adjusted hazard ratios were: 1.44 (95% CI = 0.84 to 2.46) for hypertension; 1.67 (95% CI = 0.85 to 3.31) for CKD; and 1.16 (95% CI = 0.56 to 2.37) for ESRF. CONCLUSION: The prevalence of renal scarring in an unselected population of children with UTI is low. Without underlying risk factors, UTI is not associated with CKD, hypertension, or ESRF by the age of 10 years. Further research with systematic scanning of children's kidneys, including those with less severe UTI and without UTI, is needed to increase the certainty of these results, as most children are not scanned. Longer follow-up is needed to establish if UTI, without additional risk factors, is associated with hypertension, CKD, or ESRF later in life.

Mental health and life satisfaction among 10-11-year-olds in Wales, before and one year after onset of the COVID-19 pandemic.

BACKGROUND: In many countries, including in the United Kingdom (UK), COVID-19 social distancing measures placed substantial restrictions on children's lives in 2020 and 2021, including closure of schools and limitations on play. Many children faced milestones such as transition to secondary school having missed several months of face-to-face schooling in the previous academic years. METHODS: This paper examines change in mental health difficulties, life satisfaction, school connectedness, and feelings about transition to secondary school among 10-11-year-olds in Wales, UK, using data from repeat cross-sectional surveys before and after the onset of the COVID-19 pandemic. Participants were 4032 10-11-year-old schoolchildren. The first cohort completed a school-based survey in 2019 (prior to introduction of social distancing measures), and the second in 2021 (following full return to school after two rounds of school closure). RESULTS: The percentage of children reporting elevated emotional difficulties rose from 17% in 2019 to 27% in 2021 (Odds Ratio = 1.65; 95%CI = 1.23 to 2.20). There was no evidence of increased behavioural difficulties (OR = 1.04; 95%CI = 0.73 to 1.46). There was a tendency toward declines in life satisfaction in all analyses, but this intersected the null (OR = 0.86; 95%CI = 0.70 to 1.07). Children reported a high degree of school connectedness before and after the pandemic, with no evidence of change in ratings of teacher relationships, pupil relationships or pupil involvement in school life. There was no evidence of impacts of the pandemic on children's feelings about the transition to secondary school, with feelings becoming more positive as transition neared. Most findings were robust to a range of sensitivity analyses. CONCLUSIONS: Supporting children's emotional recovery from the COVID-19 pandemic is a public health priority requiring urgent and effective action at multiple levels of society. Maintaining connectedness to school through the pandemic may have played a role in preventing a steeper increase in child mental health difficulties.

Nurse-led home-visitation programme for first-time mothers in reducing maltreatment and improving child health and development (BB:2-6): longer-term outcomes from a randomised cohort using data linkage.

OBJECTIVES: Measure effectiveness of family nurse partnership (FNP) home-visiting programme in reducing maltreatment and improving maternal health and child health, developmental and educational outcomes; explore effect moderators, mediators; describe costs. DESIGN: Follow-up of BB:0-2 trial cohort (ISRCTN:23019866) up to age 7 years in England using record linkage. PARTICIPANTS: 1618 mothers aged 19 years or younger and their firstborn child(ren) recruited to BB:0-2 trial at less than 25 weeks gestation and not mandatorily withdrawn from trial or opted out. Intervention families were offered up to a maximum of 64 home visits by specially trained nurses from pregnancy until firstborn child was 2 years old, plus usually provided health and social care support. Comparator was usual care alone. OUTCOME MEASURES: Primary outcome: state-verified child-in-need status recorded at any time during follow-up. SECONDARY OUTCOMES: referral to social services, child protection registration (plan), child-in-need categorisation, looked-after status, recorded injuries and ingestions any time during follow-up, early childcare and educational attendance, school readiness and attainment at key stage 1 (KS1), healthcare costs. RESULTS: Match rates for 1547 eligible children (1517 singletons, 15 sets of twins) were 98.3% (NHS Digital) and 97.4% (National Pupil Database). There was no difference between study arms in the proportion of children being registered as in need (adjusted OR 0.98, 95% CI 0.74 to 1.31), or for any other measure of maltreatment. Children in the FNP arm were more likely to achieve a good level of development at reception age (school readiness) (adjusted OR 1.24, 95% CI 1.01 to 1.52). After adjusting for birth month, children in FNP arm were more likely to reach the expected standard in reading at KS1 (adjusted OR 1.26, 95% CI 1.02 to 1.57). We found no trial arm differences for resource use and costs. CONCLUSIONS: FNP did not improve maltreatment or maternal outcomes. There was evidence of small advantages in school readiness and attainment at KS1. TRIAL REGISTRATION NUMBER: ISRCTN23019866.

Socio-Economic Status, Mental Health Difficulties and Feelings about Transition to Secondary School among 10-11 Year Olds in Wales: Multi-Level Analysis of a Cross Sectional Survey.

Transition between primary and secondary school represents an important milestone in young people's development. While most young people look forward to this transition, it is a source of anxiety for many. Drawing on a nationally representative survey of 2218 children in 73 schools in Wales, this study aimed to understand the extent to which 10-11 year old children worried about and/or looked forward to their imminent transition to secondary school, the things they worried about and/or looked forward to, and how feelings about transition differed by socioeconomic status, as well as by emotional and behavioural difficulties. About a third of children reported being quite or very worried about transition to secondary school, while approximately two-thirds reported looking forward to it quite a bit or very much. These items were only moderately correlated, with many children both looking forward to and worrying about transition, or neither. Major sources of worry about transition centred around bullying and impact on existing friendships, while forming new friendships or joining existing friends in their new school were key things children looked forward to. Children from poorer backgrounds, attending poorer schools and reporting more emotional difficulties were significantly more likely to report worries about transition. Children from poorer families, and children reporting more emotional difficulties and behavioural difficulties, were less likely to look forward to transition. Interventions to support children in transition to secondary school need to be sensitive to the needs of children from poorer backgrounds and children with mental health difficulties.

Changes in childhood experimentation with, and exposure to, tobacco and e-cigarettes and perceived smoking norms: a repeated cross-sectional study of 10-11 year olds' in Wales.

BACKGROUND: Today's primary school children have grown up in a climate of strong smoking restrictions, decreasing tobacco use, and the emergence of e-cigarettes. Children's exposure to tobacco declined substantially in years following the introduction of smoke-free legislation, with smoking uptake and perceived smoking norms declining. There is debate regarding whether emergence of e-cigarettes may interrupt trends in children's smoking perceptions, or offer a means for adults to limit children's exposure to tobacco. This study examines change in children's tobacco and e-cigarettes experimentation (ever use), exposure to secondhand smoking and vaping, and perceived smoking norms. METHODS: Data from four, repeat cross-sectional surveys of Year 6 primary school pupils (age 10-11 years) in Wales in 2007, 2008, 2014 and 2019 (n = 6741) were combined. E-cigarette use and perceptions were included in 2014 and 2019 surveys. Analyses used binary logistic regression analyses, adjusted for school-level clustering. RESULTS: Child tobacco experimentation and most indicators of exposure to tobacco smoke indicated a graded decreasing trend over time from 2007 to 2019. Exposure to e-cigarettes increased from 2014 to 2019, as did pupil awareness of e-cigarettes (OR = 2.56, 95%CI = 2.12-3.10), and parental use (OR = 1.26, 95%CI = 1.00-1.57). A decrease in child e-cigarette experimentation was not significant (OR = 0.80, 95%CI = 0.57-1.13). Children's normative perceptions for smoking by adults and children indicated a graded decrease over time (OR = 0.66, 95%CI = 0.54-0.80; OR = 0.69, 95%CI = 0.55-0.86; respectively from 2014 to 2019). However, fewer reported disapproval of people smoking around them in 2019 relative to 2014 (OR = 0.68, 95%CI = 0.53-0.88). Higher exposure to tobacco cigarettes and e-cigarettes in public places, cars and households were associated with favourable normative perceptions for tobacco smoking; however in models adjusted for exposure to both associations of e-cigarette exposure were attenuated. CONCLUSION: Children's experimentation with and exposure to tobacco, and their perceptions of smoking as a normative behaviour, have continued to decline alongside growth in exposure to e-cigarettes. Although a large majority of pupils reported they minded people smoking around them, there was some evidence of diminishing disapproval of secondhand smoke since 2007. Further research is needed to understand whether use of e-cigarettes in cars and homes is displacing prior smoking or being introduced into environments where smoking had been eliminated.

Ecological Exploration of Knowledge and Attitudes Towards Tobacco and E-Cigarettes Among Primary School Children, Teachers, and Parents in Wales: A Qualitative Study.

Experimentation with e-cigarettes has grown rapidly among UK adolescents. To date, this topic has been primarily researched in secondary schools, with less understanding of development of attitudes and behaviours at an earlier age. This research reports qualitative data from interviews with pupils, parents, and teachers at 4 case study schools in Wales (N = 42). It draws on Bronfenbrenner's Ecological Systems Theory to consider how the intersection of systems surrounding primary school-age children and their interaction with these systems, shape knowledge, and attitudes towards e-cigarettes and tobacco. Findings indicate that consistent messaging on smoking from school and family was reflected in strong disapproval among pupils and clear understanding of harms. This was less evident for e-cigarettes, where messages were mixed and inconsistent between home and school, with concerns over what to tell children about e-cigarettes in light of mixed messages and absence of official guidance. Implications of findings for policy and teaching are discussed.

Associations of Socioeconomic Status, Parental Smoking and Parental E-Cigarette Use with 10-11-Year-Old Children's Perceptions of Tobacco Cigarettes and E-Cigarettes: Cross Sectional Analysis of the CHETS Wales 3 Survey.

BACKGROUND: This study examines primary schoolchildren's perceptions of e-cigarettes and tobacco cigarettes, and associations with parental smoking, vaping and socioeconomic status. METHODS: Survey of 2218 10-11-year-old children in 73 schools in Wales. RESULTS: Overall, 36% reported that a parent figure smoked compared to 21% for vaping, with parental smoking lower in affluent families (OR = 0.72; 95% CI = 0.68 to 0.76). Overall, 1% had tried a cigarette, while 5% had tried an e-cigarette. Most said they would not smoke or vape in 2 years' time; susceptibility to vaping (20%) was higher than smoking (12%). Exposure to and perceptions of tobacco cigarettes were more positive for children of smokers. Having a parent who vaped was associated with exposure to and positive perceptions of e-cigarettes, but not smoking. Most children perceived e-cigarettes as used by adults to stop smoking (64%). Susceptibility to smoking (OR = 0.57; 95% CI = 0.41 to 0.79) and vaping (OR = 0.78; 95% CI = 0.62 to 0.99) were lower among children who perceived e-cigarettes as cessation aids. CONCLUSIONS: Parental smoking continues to be concentrated in poorer families. This study provides no evidence that parental vaping in the absence of smoking is associated with more positive perceptions of tobacco cigarettes. Communicating to children the role of e-cigarettes as cessation devices for smokers may help to limit their appeal to young people.

Long-term outcomes of urinary tract infection (UTI) in Childhood (LUCI): protocol for an electronic record-linked cohort study.

INTRODUCTION: Current guidelines advise the prompt diagnosis and treatment of urinary tract infection (UTI) in children to improve both short and longer term outcomes. However, the risk of long-term complications following childhood UTI is unclear.UTI is relatively common but difficult to diagnose in children as symptoms are non-specific. Diagnosis requires a urine sample, but sampling is difficult and infrequent, and it is not clear if sampling should be given greater priority in primary care. The LUCI study will assess the short, medium and longer term outcomes of childhood UTI associated with routine and systematic sampling practices. METHODS AND ANALYSIS: Two data sets will be established. The first will consist of routinely collected data (hospital, general practice (GP), microbiology) from children born and resident in Wales, linked via the Secure Anonymised Information Linkage (SAIL) Databank (an 'e-cohort'). Urine sampling in this data set reflects normal practice 'routine sampling'. Outcomes (including renal scarring, hypertension, end-stage renal failure, hospital admissions, GP consultations, antibiotic prescriptions) for children with at least one UTI confirmed with microbiological culture (mcUTI) or no mcUTI before the age of 5 will be compared.The second will combine data from two prospective observational studies ('DUTY' and 'EURICA') employing systematic urine sampling for children presenting to primary care with acute, undifferentiated illness, linked to routine data via SAIL (Wales) and NHS Digital (England). Outcomes (as above, plus features of mcUTI) for children with an mcUTI in this data set, identified through systematic urine sampling, will be compared with those with an mcUTI identified through routine urine sampling (data set 1). ETHICS AND DISSEMINATION: The study protocol has been approved by NHS Wales Research Ethics Committee and the Health Research Authority's Confidentiality Advisory Group. Methods of innovative study design and findings will be disseminated through peer-review journals and conferences. Results will be of interest to clinical and policy stakeholders in the UK.

Assessing the impact of specialist home visiting upon maltreatment in England: a feasibility study of data linkage from a public health trial to routine health and social care data.

BACKGROUND: Follow-up for public health trials may benefit from greater use of routine data. Our trial of a home-visiting intervention for first-time teenage mothers assessed outcomes to the child's second birthday. To examine its medium-term impact, particularly upon maltreatment outcomes, we designed a study using routine records. METHODS: We aimed to establish the feasibility of our study design, which combines trial data with routine health, social care and education data using a dissent-based linkage model. Trial participant identifiers were linked to routine health, social care and education data if women did not dissent. Data were forwarded to a safe haven and further linked to de-identified trial outcome data. The feasibility study aimed first to establish the acceptability of data linkage through a discussion group of young mothers and by levels of dissent received by the research team. Second, we assessed levels of accurate linkage to both health (via NHS Digital) and education and social care (both via National Pupil Database, NPD). Third, we assessed the availability of data and levels of missingness for key outcomes received for a sample of target study years. RESULTS: Of 1545 mother-child dyads contacted, eight women opted out. The engagement exercise with stakeholders found support for the principle of data linkage, including in the context of maltreatment. Some contributors preferred opt-in consent. Most (99.9%) health records were matched on either three or all four identifiers. Fifty participants were not matched to any health data. Primary outcome data from NPD are derived from any one of three fields, all of which were satisfactorily returned and provided an indication of cases for analysis. Missing data for secondary outcomes varied from 0% (Child looked after status) to 70% (Anatomical Area A&E diagnosis) however when combined with other variables the levels of missingness for outcome decrease. CONCLUSIONS: Through study set-up and in this pilot, we provide evidence that the main study is feasible, satisfies governance requirements and is likely to generate data of sufficient quality to address our main research questions. Observed levels of missingness or low event rates are likely to affect some secondary analysis (e.g. state transition modelling) although overall were satisfactory.

Challenges in accessing routinely collected data from multiple providers in the UK for primary studies: Managing the morass.

INTRODUCTION: Researchers are increasingly using routinely collected data in addition to, or instead of, other data collection methods. The UK government continues to invest in research centres to encourage use of these data, and trials and cohort studies utilise data linkage methods in the follow-up of participants. This does not come without its limitations and challenges, such as data access delays. OBJECTIVE: This paper outlines the challenges faced by three projects utilising individual-level routinely-collected linked data for the longer-term follow-up of participants. METHODS: These studies are varied in design, study population and data providers. One researcher was common to the three studies and collated relevant study correspondence, formal documentary evidence such as data sharing agreements and, where relevant, meeting records to review. Key themes were identified and reviewed by other members of the research teams. Mitigating strategies were identified and discussed with a data provider representative and a broader group of researchers to finalise the recommendations presented. RESULTS: The challenges discussed are grouped into five themes: Data application process; Project timelines; Dependencies and considerations related to consent; Information Governance; Contractual. In presenting our results descriptively we summarise each case study, identify the main cross-cutting themes and consider the potential for mitigation of challenges. CONCLUSIONS: We make recommendations that identify responsibilities for both researchers and data providers for mitigating and managing data access challenges. A continued conversation within the research community and with data providers is needed to continue to enable researchers to access and utilise the wealth of routinely-collected data available. The suggestions made in this paper will help researchers be better prepared to deal with the challenges of applying for data from multiple data providers.

A pilot randomised controlled trial of community-led ANtipsychotic Drug REduction for Adults with Learning Disabilities.

BACKGROUND: Data suggest that approximately 50,000 adults with learning disabilities (LDs) in England and Wales are currently prescribed antipsychotic medication. Illness in this population is common, including significant rates of challenging behaviour and mental illness, but there is particular concern over the use of antipsychotics prescribed for reasons other than the treatment of psychosis. Control of challenging behaviour is the primary reason why such medications are prescribed despite the absence of good evidence for any therapeutic effect for this purpose. OBJECTIVES: To assess the feasibility of recruitment and retention and to explore non-efficacy-based barriers to a blinded antipsychotic medication withdrawal programme for adults with LDs without psychosis compared with treatment as usual. A secondary objective was to compare trial arms regarding clinical outcomes. DESIGN: A two-arm individually randomised double-blind placebo-controlled drug reduction trial. SETTING: Recruitment was through community learning disability teams (CLDTs) in south Wales and south-west England. PARTICIPANTS: Adults with LDs who are prescribed risperidone for treatment of challenging behaviour with no known current psychosis or previous recurrence of psychosis following prior drug reduction. INTERVENTION: A double-blind drug reduction programme leading to full withdrawal within 6 months. Treatment in the intervention group was gradually reduced over a 6-month period and then maintained at the same level for a further 3 months, still under blind conditions. In the control group, the baseline level of medication was maintained throughout the 9-month period. The blind was broken at 9 months, following final data collection. MAIN OUTCOME MEASURES: Feasibility outcomes were (1) the number and proportion of general practices/CLDTs that progressed from initial approach to recruitment of participants and (2) the number and proportion of recruited participants who progressed through the various stages of the study. Trial arms were also compared regarding clinical outcomes, the Modified Overt Aggression Scale, the Aberrant Behaviour Checklist, the Psychiatric Assessment Schedule for Adults with Developmental Disability checklist, the Antipsychotic Side-effect Checklist, the Dyskinesia Identification System Condensed User Scale, the Client Service Receipt Inventory, use of other interventions to manage challenging behaviour, use of as-required (pro re nata) medication and level of psychotropic medication use. RESULTS: Of the 22 participants randomised (intervention, n = 11; control, n = 11), 13 (59%) achieved progression through all four stages of reduction. Follow-up data at 6 and 9 months were obtained for 17 participants (intervention, n = 10; and control, n = 7; 77% of those randomised). There were no clinically important changes in participants' levels of aggression or challenging behaviour at the end of the study. There were no expedited safety reports. Four adverse events and one serious adverse event were reported during the trial. LIMITATIONS: Recruitment was challenging, which was largely a result of difficulty in identifying appropriate persons to consent and carer concerns regarding re-emergence of challenging behaviour. Reduced recruitment meant that the full trial became an exploratory pilot study. CONCLUSIONS: The results indicate that drug reduction is possible and safe. However, concerns about taking part were probably exacerbated by limited availability of alternative (behavioural) interventions to manage behaviour; therefore, focused support and alternative interventions are required. The results of the qualitative study provide important insights into the experiences of people taking part in drug reduction studies that should influence future trial development. FUTURE WORK: We recommend that further work focuses on support for practitioners, carers and patients in reducing antipsychotic medication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38126962. 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. 21, No. 47. See the NIHR Journals Library website for further project information.

Seal or Varnish? A randomised controlled trial to determine the relative cost and effectiveness of pit and fissure sealant and fluoride varnish in preventing dental decay.

BACKGROUND: Fissure sealant (FS) and fluoride varnish (FV) have been shown to be effective in preventing dental caries when tested against a no-treatment control. However, the relative clinical effectiveness and cost-effectiveness of these interventions is unknown. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of FS and FV in preventing dental caries in first permanent molars (FPMs) in 6- and 7-year-olds and to determine their acceptability. DESIGN: A randomised controlled allocation-blinded clinical trial with two parallel arms. SETTING: A targeted population programme using mobile dental clinics (MDCs) in schools located in areas of high social and economic deprivation in South Wales. PARTICIPANTS: In total, 1016 children were randomised, but one parent subsequently withdrew permission and so the analysis was based on 1015 children. The randomisation of participants was stratified by school and balanced for sex and primary dentition baseline caries levels using minimisation in a 1 : 1 ratio for treatments. A random component was added to the minimisation algorithm, such that it was not completely deterministic. Of the participants, 514 were randomised to receive FS and 502 were randomised to receive FV. INTERVENTIONS: Resin-based FS was applied to caries-free FPMs and maintained at 6-monthly intervals. FV was applied at baseline and at 6-month intervals over the course of 3 years. MAIN OUTCOME MEASURES: The proportion of children developing caries into dentine (decayed, missing, filled teeth in permanent dentition, i.e. D4-6MFT) on any one of up to four treated FPMs after 36 months. The assessors were blinded to treatment allocation; however, the presence or absence of FS at assessment would obviously indicate the probable treatment received. Economic measures established the costs and budget impact of FS and FV and the relative cost-effectiveness of these technologies. Qualitative interviews determined the acceptability of the interventions. RESULTS: At 36 months, 835 (82%) children remained in the trial: 417 in the FS arm and 418 in the FV arm. The proportion of children who developed caries into dentine on a least one FPM was lower in the FV arm (73; 17.5%) than in the FS arm (82, 19.6%) [odds ratio (OR) 0.84, 95% confidence interval (CI) 0.59 to 1.21; p = 0.35] but the difference was not statistically significant. The results were similar when the numbers of newly decayed teeth (OR 0.86, 95% CI 0.60 to 1.22) and tooth surfaces (OR 0.85, 95% CI 0.59 to 1.21) were examined. Trial fidelity was high: 95% of participants received five or six of the six scheduled treatments. Between 74% and 93% of sealants (upper and lower teeth) were intact at 36 months. The costs of the two technologies showed a small but statistically significant difference; the mean cost to the NHS (including intervention costs) per child was £500 for FS, compared with £432 for FV, a difference of £68.13 (95% CI £5.63 to £130.63; p = 0.033) in favour of FV. The budget impact analysis suggests that there is a cost saving of £68.13 (95% CI £5.63 to £130.63; p = 0.033) per child treated if using FV compared with the application of FS over this time period. An acceptability score completed by the children immediately after treatment and subsequent interviews demonstrated that both interventions were acceptable to the children. No adverse effects were reported. LIMITATIONS: There are no important limitations to this study. CONCLUSIONS: In a community oral health programme utilising MDCs and targeted at children with high caries risk, the twice-yearly application of FV resulted in caries prevention that is not significantly different from that obtained by applying and maintaining FSs after 36 months. FV proved less expensive. FUTURE WORK: The clinical effectiveness and cost-effectiveness of FS and FV following the cessation of active intervention merits investigation. TRIAL REGISTRATION: EudraCT number 2010-023476-23, Current Controlled Trials ISRCTN17029222 and UKCRN reference 9273. 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. 21, No. 21. See the NIHR Journals Library website for further project information.

The use of everolimus in the treatment of neurocognitive problems in tuberous sclerosis (TRON): study protocol for a randomised controlled trial.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder affecting about 1 in 6000 people and is characterised by the development of tumours in many organs, including the skin and kidneys, and by a range of neurological and neuropsychiatric manifestations. TSC-associated neuropsychiatric disorders (TAND) occur in the majority of those with TSC, and they have a significant impact on patients and their families, given the everyday impact of TAND on education, employment, family and social life. The potential benefits of better treatment for TAND therefore include reduction in health care demands and wider benefits for patients and their carers. METHODS/DESIGN: We have planned a single-centre, two-arm, individually randomised, phase II, double-blind, placebo-controlled trial of everolimus versus placebo in the treatment of neurocognitive problems in patients with tuberous sclerosis. Everolimus is a licensed medicine in this patient group, but for a different target of effect. The present trial is a proof-of-principle study developed to provide effect size estimates which may be used to inform the design of subsequent trials. Forty-eight patients aged 16-60 years with tuberous sclerosis who have an IQ >60 and a significant deficit (at least -2 SD) in one or more primary outcome measures will be randomly allocated in a ratio of 2:1 to receive everolimus or placebo, respectively. Participants will be assessed for eligibility and then be started on study medication 4 weeks later. They will then be randomised and receive placebo or everolimus for 24 weeks. Neurocognitive and safety assessments will be carried out at baseline and weeks 4, 12, 24 and 36. DISCUSSION: This study is designed to determine the effect sizes of treatment with everolimus or placebo for 6 months on specific neurocognitive functions-recall memory (verbal and non-verbal) and executive function-in people affected by TSC who have significant deficits in these functions. These data will provide new evidence to determine whether larger-scale trials are indicated and to explore suitable outcome measures and analytical methods for neurocognitive trial design. TRIAL REGISTRATION: ISRCTN09739757 . Registered on 28 Dec 2011.