AZTEC-azithromycin therapy for prevention of chronic lung disease of prematurity: a statistical analysis plan for clinical outcomes.

BACKGROUND: The AZTEC trial is a multi-centre, randomised, placebo-controlled trial of azithromycin to improve survival without development of chronic lung disease of prematurity (CLD) in preterm infants. The statistical analysis plan for the clinical outcomes of the AZTEC trial is described. METHODS AND DESIGN: A double-blind, randomised, placebo-controlled trial of a 10-day course of intravenous azithromycin (20 mg/kg for 3 days; 10 mg/kg for 7 days) administered to preterm infants born at < 30 weeks' gestational age across UK tertiary neonatal units. Following parental consent, infants are randomly allocated to azithromycin or placebo, with allocated treatment starting within 72 h of birth. The primary outcome is survival without moderate/severe CLD at 36 weeks' postmenstrual age (PMA). Serial respiratory fluid and stool samples are being collected up to 21 days of life. The target sample size is 796 infants, which is based on detecting a 12% absolute difference in survival without moderate/severe CLD at 36 weeks' PMA (90% power, two-sided alpha of 0.05) and includes 10% loss to follow-up. RESULTS: Baseline demographic and clinical characteristics will be summarised by treatment arm and in total. Categorical data will be summarised by numbers and percentages. Continuous data will be summarised by mean, standard deviation, if data are normal, or median, interquartile range, if data are skewed. Tests of statistical significance will not be undertaken for baseline characteristics. The primary analysis, on the intention to treat (ITT) population, will be analysed using multilevel logistic regression, within a multiple imputation framework. Adjusted odds ratios, 95% confidence intervals, and p-values will be presented. For all other analyses, the analysis population will be based on the complete case population, which is a modified ITT population. All analyses will be adjusted for gestational age and treatment arm and account for any clustering by centre and/or multiple births as a random effect. CONCLUSION: We describe the statistical analysis plan for the AZTEC trial, including the analysis principles, definitions of the key clinical outcomes, methods for primary analysis, pre-specified subgroup analysis, sensitivity analysis, and secondary analysis. The plan has been finalised prior to the completion of recruitment. TRIAL REGISTRATION: ISRCTN registry ISRCTN11650227. Registered on 31 July 2018.

Patient-Reported Outcome Measures in Dermatology: A Systematic Review.

By relying on data from existing patient-reported outcome measures of quality of life, the true impact of skin conditions on patients' lives may be underestimated. This study systematically reviewed all dermatology-specific (used across skin conditions) patient-reported outcome measures and makes evidence-based recommendations for their use. The study protocol is registered on PROSPERO (CRD42018108829). PubMed, PsycInfo and CINAHL were searched from inception to 25 June 2018. The Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) criteria were used to assess the measurement properties and methodological quality of studies. A total of 12,925 abstracts were identified. Zero patient-reported outcome measures were assigned to category A (ready for use without further validation), 31 to category B (recommended for use, but only with further validation) and 5 to category C (not recommended for use). There is no gold-standard dermatology-specific patient-reported outcome measure that can be recommended or used without caution. A new measure that can comprehensively capture the impact of dermatological conditions on the patient's life is needed.

Cost-effectiveness of home versus hospital management of children at onset of type 1 diabetes: the DECIDE randomised controlled trial.

OBJECTIVE: The aim of this economic evaluation was to assess whether home management could represent a cost-effective strategy in the patient pathway of type 1 diabetes (T1D). This is based on the Delivering Early Care In Diabetes Evaluation trial (ISRCTN78114042), which compared home versus hospital management from diagnosis in childhood diabetes and found no statistically significant difference in glycaemic control at 24 months. DESIGN: Cost-effectiveness analysis alongside a randomised controlled trial. SETTING: Eight paediatric diabetes centres in England, Wales and Northern Ireland. PARTICIPANTS: 203 clinically well children aged under 17 years, with newly diagnosed T1D and their carers. OUTCOME MEASURES: The base-case analysis adopted n National Health Service (NHS) perspective. A scenario analysis assessed costs from a broader societal perspective. The incremental cost-effectiveness ratio (ICER), expressed as cost per mmol/mol reduction in glycated haemoglobin (HbA1c), was based on the mean difference in costs between the home and hospital groups, divided by mean differences in effectiveness (HbA1c). Uncertainty was considered in terms of the probability of cost-effectiveness. RESULTS: At 24 months postintervention, the base-case analysis showed a difference in costs between home and hospital, in favour of home management (mean difference -£2,217; 95% CI -£2825 to -£1,609; p<0.001). Home care dominated, with an ICER of £7434 (saved) per mmol/mol reduction of HbA1c. The results of the scenario analysis also favoured home management. The greatest driver of cost differences was hospitalisation during the initiation period. CONCLUSIONS: Home management from diagnosis of children with T1D who are medically stable represents a less costly approach for the NHS in the UK, without impacting clinical effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN78114042.

Training results in increased practitioner confidence and identification of depression in people with low vision: a mixed methods study.

PURPOSE: The prevalence of depression in people with low vision is high and often goes undiagnosed. There is the potential for those who provide low vision services to perform concurrent depression screening. However, prior training in depression identification and suitable referral pathways is required. The aims of this study were: (1) to assess the impact of a training programme on practitioners' confidence and behaviour in addressing depression in patients with low vision, and (2) to review the training programme and identify areas for further development. METHODS: A convergent mixed methods approach was used. Questionnaires were completed by practitioners pre-, immediately post- and 6 months post- training (n = 40) to assess practitioner confidence in approaching depression in patients with low vision. Qualitative interviews were performed with a subset of practitioners 6 months post-training (n = 9). Additionally, routine data from the Low Vision Service Wales (LVSW) database was used to determine the change in the number of practitioners identifying depression in patients, and the change in the number of patients identified at risk of depression 6 months post-training. RESULTS: Of the 148 practitioners who completed low vision assessments pre- and post-training, 28 (18.9%) documented risk of depression in their patients pre-training, which increased substantially to 65 (43.9%) post-training (p < 0.0001). Mixed methods analysis confirmed increased documentation of depressive symptoms by practitioners. Practitioner confidence increased following training, with 92.3% feeling more confident to approach emotional issues with patients and 92.2% intending to use the recommended screening tool to identify depression. Interviews provided insight into areas where confidence was still lacking. Quantitative questionnaires revealed that training content was considered appropriate by 91% of participants. Interviews confirmed these findings while expanding upon possibilities for programme improvement. CONCLUSIONS: Training for depression screening was found to be time-efficient and acceptable for LVSW practitioners and shown to increase practitioner confidence in the identification of depression. Additionally, the programme changed behaviour, resulting in an increase in the identification of depression in patients with low vision. However, this is a complex topic and ongoing development is required to embed depression screening as an integral part of low vision services.

The development and validation of the CARe Burn Scale: Child Form: a parent-proxy-reported outcome measure assessing quality of life for children aged 8 years and under living with a burn injury.

PURPOSE: Patient-reported outcome measures (PROMs) identify patient needs and therapeutic progress. This paper outlines the development and validation of the CARe Burn Scale: Child Form, a parent-proxy-reported outcome measure that assesses quality of life in children aged 8 and under living with a burn injury. METHODS: A literature review and interviews with 12 parents of children with a burn and seven health professionals informed the development of a conceptual framework and draft PROM. Cognitive debriefing interviews with 18 parents and eight health professionals provided feedback to ascertain content validity, and 311 parents took part in field testing. Rasch and traditional psychometric analyses were conducted to create a shortened version. Further psychometric analyses with 133 parents tested the shortened CARe Burn Scale in relation to other parent-proxy measures. RESULTS: The final conceptual framework included 5 domains: Social and Emotional Difficulties, Social and Emotional Well-Being, Wound/Scar Discomfort, Wound/Scar Treatment and Physical Abilities. Two scales fulfilled Rasch and traditional psychometric analyses, providing evidence of construct validity, acceptability, and reliability. Three scales did not fulfil the Rasch criteria and were retained as checklists. Compared to other parent-proxy measures, individual CARe Burn Scales correlated moderately with similar constructs and had low correlations with dissimilar constructs, indicating evidence of criterion validity (concurrent and discriminant). CONCLUSIONS: The CARe Burn Scale: Child Form can be used to measure children's quality of life after having a burn injury which can inform rehabilitation and surgical decision-making.

Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants.

INTRODUCTION: Chronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia (BPD), is a cause of significant respiratory morbidity in childhood and beyond. Coupled with lung immaturity, infections (especially by Ureaplasma spp) are implicated in the pathogenesis of CLD through promotion of pulmonary inflammation. Azithromycin, which is a highly effective against Ureaplasma spp also has potent anti-inflammatory properties. Thus, azithromycin therapy may improve respiratory outcomes by targeting infective and inflammatory pathways. Previous trials using macrolides have not been sufficiently powered to definitively assess CLD rates. To address this, the azithromycin therapy for chronic lung disease of prematurity (AZTEC) trial aims to determine if a 10-day early course of intravenous azithromycin improves rates of survival without CLD when compared with placebo with an appropriately powered study. METHODS AND ANALYSIS: 796 infants born at less than 30 weeks' gestational age who require at least 2 hours of continuous respiratory support within the first 72 hours following birth are being enrolled by neonatal units in the UK. They are being randomised to receive a double-blind, once daily dose of intravenous azithromycin (20 mg/kg for 3 days, followed by 10 mg/kg for a further 7 days), or placebo. CLD is being assessed at 36 weeks' PMA. Whether colonisation with Ureaplasma spp prior to randomisation modifies the treatment effect of azithromycin compared with placebo will also be investigated. Secondary outcomes include necrotising enterocolitis, intraventricular/cerebral haemorrhage, retinopathy of prematurity and nosocomial infections, development of antibiotic resistance and adverse reactions will be monitored. ETHICS AND DISSEMINATION: Ethics permission has been granted by Wales Research Ethics Committee 2 (Ref 18/WA/0199), and regulatory permission by the Medicines and Healthcare Products Regulatory Agency (Clinical Trials Authorisation reference 21323/0050/001-0001). The study is registered on ISRCTN (ISRCTN11650227). The study is overseen by an independent Data Monitoring Committee and an independent Trial Steering Committee. We shall disseminate our findings via national and international peer-reviewed journals, and conferences. A summary of the findings will also be posted on the trial website.

Barriers to integrating routine depression screening into community low vision rehabilitation services: a mixed methods study.

BACKGROUND: Undetected depression is common in people with low vision and depression screening has been recommended. However, depression screening is a complex procedure for which low vision practitioners need training. This study examined the integration of routine depression screening, using two questions, and referral pathways into a national low vision service in Wales at 6 months following practitioner training, and identified key barriers to implementation. METHODS: This pre-post single group study employed a convergent mixed methods design to collect quantitative questionnaire and qualitative interview data on low vision practitioners' clinical practice and perceived barriers to implementing depression screening. Forty practitioners completed questionnaires pre-, immediately post- and 6 months post-training and nine engaged in interviews 6 months post-training. Ordinal questionnaire scores were Rasch-transformed into interval-level data before linear regression analyses were performed to determine the change in scores over time and the association between perceived barriers and clinical practice. Thematic Analysis was applied to the interviews and the narrative results merged with the questionnaire findings. RESULTS: Before training, only one third of practitioners (n = 15) identified depression in low vision patients, increasing to over 90% (n = 37) at 6 months post-training, with a corresponding increase in those using validated depression screening questions from 10% (n = 4) to 80% (n = 32). Six months post-training, practitioners reported taking significantly more action in response to suspected depression (difference in means = 2.77, 95% CI 1.93 to 3.61, p < 0.001) and perceived less barriers to addressing depression (difference in means = - 0.95, 95% CI - 1.32 to - 0.59, p < 0.001). However, the screening questions were not used consistently. Some barriers to implementation remained, including perceived patient reluctance to discuss depression, time constraints and lack of confidence in addressing depression. CONCLUSIONS: The introduction of depression screening service guidelines and training successfully increased the number of low vision practitioners identifying and addressing depression. However, standardized screening of all low vision attendees has not yet been achieved and several barriers remain. Healthcare services need to address these barriers when considering mental health screening, and further research could focus on the process from the patients' perspective, to determine the desire for and acceptability of screening.

Effectiveness of home or hospital initiation of treatment at diagnosis for children with type 1 diabetes (DECIDE trial): a multicentre individually randomised controlled trial.

OBJECTIVE: To determine whether, in children with newly diagnosed type 1 diabetes who were not acutely unwell, management at home for initiation of insulin treatment and education of the child and family, would result in improved clinical and psychological outcomes at 2 years postdiagnosis. DESIGN: A multicentre randomised controlled trial (January 2008/October 2013). SETTING: Eight paediatric diabetes centres in England, Wales and Northern Ireland. PARTICIPANTS: 203 clinically well children aged under 17 years, with newly diagnosed type 1 diabetes and their carers. INTERVENTION: Management of the initiation period from diagnosis at home, for a minimum of 3 days, to include at least six supervised injections and delivery of pragmatic educational care. MAIN OUTCOME MEASURES: Primary outcome was glycosylated haemoglobin (HbA1c) concentration at 24 months postdiagnosis. Secondary outcomes included coping, anxiety, quality of life and use of NHS resources. RESULTS: 203 children, newly diagnosed, were randomised to commence management at home (n=101) or in hospital (n=102). At the 24 month primary end point, there was one withdrawal and a follow-up rate of 194/202 (96%). Mean HbA1c in the home treatment arm was 72.1 mmol/mol and in the hospital treated arm 72.6 mmol/mol. There was a negligible difference between the mean HbA1c levels in the two arms adjusted for baseline (1.01, 95% CI 0.93 to 1.09). There were mostly no differences in secondary outcomes at 24 months, apart from better child self-esteem in the home-arm. No home-arm children were admitted to hospital during initiation and there were no adverse events at that time. The number of investigations was higher in hospital patients during the follow-up period. There were no differences in insulin regimens between the two arms. CONCLUSIONS: There is no evidence of a difference between home-based and hospital-based initiation of care in children newly diagnosed with type 1 diabetes across relevant outcomes. TRIAL REGISTRATION NUMBER: ISRCTN78114042.

Perineural local anaesthetic catheter after major lower limb amputation trial (PLACEMENT): results from a randomised controlled feasibility trial.

OBJECTIVES: To determine the feasibility of undertaking a randomised controlled effectiveness trial evaluating the use of a perineural catheter (PNC) after major lower limb amputation with postoperative pain as the primary outcome. DESIGN: Randomised controlled feasibility trial. SETTING: Two vascular Centres in South Wales, UK. PARTICIPANTS: 50 patients scheduled for major lower limb amputation (below or above knee) for complications of peripheral vascular disease. INTERVENTIONS: The treatment arm received a PNC placed adjacent to the sciatic or tibial nerve at the time of surgery, with continuous infusion of levobupivacaine hydrochloride 0.125% for up to 5 days. The control arm received neither local anaesthetic nor PNC. Both arms received usual perioperative anaesthesia and postoperative analgesia. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of eligible patients who were randomised and the proportion of recruited patients who provided primary effectiveness outcome data. Secondary outcomes were: the proportion of recruited patients reaching 2 and 6 month follow-up and supplying pain data; identification of key cost drivers; development of an economic analysis framework for a future effectiveness trial; identification of barriers to recruitment and site set-up; and identification of the best way to measure postoperative pain. RESULTS: Seventy-six of 103 screened patients were deemed eligible over a 10 month period. Fifty (64.5%) of these patients were randomised, with one excluded in the perioperative period. Forty-five (91.3%) of 49 recruited patients provided enough pain scores on a 4-point verbal rating scale to allow primary effectiveness outcome evaluation. Attrition rates were high; 18 patients supplied data at 6 month follow-up. Costs were dominated by length of hospital stay. Patients and healthcare professionals reported that trial processes were acceptable. CONCLUSIONS: Recruitment of patients into a trial comparing PNC use to usual care after major lower limb amputation with postoperative pain measured on a 4-point verbal rating scale is feasible. Evaluation of longer-term symptoms is difficult. TRIAL REGISTRATION NUMBER: ISRCTN: 85 710 690. EudraCT: 2016-003544-37.

The Development and Validation of the CARe Burn Scale-Adult Form: A Patient-Reported Outcome Measure (PROM) to Assess Quality of Life for Adults Living with a Burn Injury.

Patient-Reported Outcome Measures (PROMs) identify vital information about patient needs and therapeutic progress. This paper outlines the development and validation of the CARe Burn Scale-Adult Form: a PROM that assesses quality of life in adults living with a burn injury. Eleven patients, 10 family members and 4 health professional interviews, and a systematic review informed the development of a conceptual framework and a draft measure. Cognitive debriefing interviews conducted with three adult burn patients, one family member, and eight health professionals provided feedback to ascertain content validity of the measure. The measure was then field tested with 304 adult burn patients. Rasch psychometric analysis was conducted for scale reduction, and traditional psychometric analyses provided a comparison with other measures. Further psychometric testing with an additional 118 adult burn patients tested the shortened CARe Burn Scale in relation to other quality of life PROMs. The conceptual framework outlined 14 domains; 12 of which fulfilled Rasch and traditional psychometric analyses. Two individual scales did not fulfill the Rasch criteria and were retained as checklists. Individual CARe Burn Scales correlated moderately-to-highly with other quality of life scales measuring similar constructs, and had low-to-no correlations with dissimilar constructs and the majority of sociodemographic factors, indicating evidence of concurrent and divergent validity. The CARe Burn Scale-Adult Form can help identify patient needs and provides burns-specialist health professionals with a tool to assess quality of life and therapeutic progress after a burn event and related treatment.

How do community-based eye care practitioners approach depression in patients with low vision? A mixed methods study.

BACKGROUND: Clinically significant depressive symptoms are prevalent in people attending low vision clinics and often go undetected. The Low Vision Service Wales (LVSW) plans to introduce depression screening and management pathways. Prior to implementation there is an unmet need to understand how eye care practitioners providing the service currently address depression with patients, and the characteristics and beliefs that influence their practice. METHODS: A mixed methods convergent design was employed. Twelve low vision practitioners were purposively selected to engage in individual semi-structured interviews which were analysed using thematic analysis. A further 167 practitioners were invited to complete a questionnaire assessing professional background, current practice, confidence and perceived barriers in working with people with low vision and suspected depression. Multiple regression analyses were performed to determine the characteristics related to the Rasch-transformed questionnaire scores. RESULTS: Of the 122 practitioners that responded to the questionnaire, 33% aimed to identify depression in patients, and those who were more confident were more likely to do so. Those who scored higher on the perceived barriers scale and lower on confidence were less likely to report acting in response to suspected depression (all p < 0.05). Three qualitative themes were identified; depression is an understandable response to low vision, patients themselves are a barrier to addressing depression and practitioners lacked confidence in their knowledge and skills to address depression. The qualitative data largely expanded the quantitative findings. CONCLUSIONS: Practitioners viewed their own lack of knowledge and confidence as a barrier to the identification and management of depression and expressed a need for training prior to the implementation of service changes. The study findings will help to inform the development of a training programme to support low vision practitioners and those working with other chronic illness in Wales, and internationally, in the identification and management of people with depression.

Pragmatic RAndomised controlled trial of a trauma-focused guided self-help Programme versus InDividual trauma-focused cognitive Behavioural therapy for post-traumatic stress disorder (RAPID): trial protocol.

BACKGROUND: There is good evidence that trauma-focused therapies for Post-Traumatic Stress Disorder are effective. However, they are not always feasible to deliver due a shortage of trained therapists and demands on the patient. An online trauma-focused Guided Self-Help (GSH) programme which could overcome these barriers has shown promise in a pilot study. This study will be the first to evaluate GSH against standard face-to-face therapy to assess its suitability for use in the NHS. METHODS: The study is a large-scale multi-centre pragmatic randomised controlled non-inferiority trial, with assessors masked to treatment allocation. One hundred and ninety-two participants will be randomly allocated to receive either face-to-face trauma-focused cognitive behaviour therapy (TFCBT) or trauma-focused online guided self-help (GSH). The primary outcome will be the severity of symptoms of PTSD over the previous week as measured by the Clinician Administered PTSD Scale for DSM5 (CAPS-5) at 16 weeks post-randomisation. Secondary outcome measures include PTSD symptoms over the previous month as measured by the CAPS-5 at 52 weeks plus the Impact of Event Scale - revised (IES-R), Work and Social Adjustment Scale (WSAS), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 (GAD-7), Alcohol Use Disorders Test (AUDIT-O), Multidimensional Scale for Perceived Social Support (MSPSS), short Post-Traumatic Cognitions Inventory (PTCI), Insomnia Severity Index (ISI) and General Self Efficacy Scale (GSES) measured at 16 and 52 weeks post-randomisation. Changes in health-related quality of life will be measured by the EQ-5D and the level of healthcare resource utilisation for health economic analysis will be determined by an amended version of the Client Socio-Demographic and Service Receipt Inventory European Version. The Client Satisfaction Questionnaire (CSQ) will be collected at 16 weeks post-randomisation to evaluate treatment satisfaction. DISCUSSION: This study will be the first to compare online GSH with usual face-to-face therapy for PTSD. The strengths are that it will test a rigorously developed intervention in a real world setting to inform NHS commissioning. The potential challenges of delivering such a pragmatic study may include participant recruitment, retention and adherence, therapist retention, and fidelity of intervention delivery. TRIAL REGISTRATION: ISRCTN13697710 registered on 20/12/2016.

Point-of-care urine culture for managing urinary tract infection in primary care: a randomised controlled trial of clinical and cost-effectiveness.

BACKGROUND: The effectiveness of using point-of-care (POC) urine culture in primary care on appropriate antibiotic use is unknown. AIM: To assess whether use of the Flexicult™ SSI-Urinary Kit, which quantifies bacterial growth and determines antibiotic susceptibility at the point of care, achieves antibiotic use that is more often concordant with laboratory culture results, when compared with standard care. DESIGN AND SETTING: Individually randomised trial of females with uncomplicated urinary tract infection (UTI) in primary care research networks (PCRNs) in England, the Netherlands, Spain, and Wales. METHOD: Multilevel regression compared outcomes between the two groups while controlling for clustering. RESULTS: In total, 329 participants were randomised to POC testing (POCT) and 325 to standard care, and 324 and 319 analysed. Fewer females randomised to the POCT arm than those who received standard care were prescribed antibiotics at the initial consultation (267/324 [82.4%] versus 282/319 [88.4%], odds ratio [OR] 0.56, 95% confidence interval [CI] = 0.35 to 0.88). Clinicians indicated the POCT result changed their management for 190/301 (63.1%). Despite this, there was no statistically significant difference between study arms in antibiotic use that was concordant with laboratory culture results (primary outcome) at day 3 (39.3% POCT versus 44.1% standard care, OR 0.84, 95% CI = 0.58 to 1.20), and there was no evidence of any differences in recovery, patient enablement, UTI recurrences, re-consultation, antibiotic resistance, and hospitalisations at follow-up. POCT culture was not cost-effective. CONCLUSION: Point-of-care urine culture was not effective when used mainly to adjust immediate antibiotic prescriptions. Further research should evaluate use of the test to guide initiation of 'delayed antibiotics'.

Feasibility and acceptability of text messaging to support antenatal healthcare in Iraqi pregnant women: a pilot study.

OBJECTIVE: To determine the feasibility and acceptability of mobile health technology and its potential to improve antenatal care (ANC) services in Iraq. METHODS: This was a controlled experimental study conducted at primary health care centers. One hundred pregnant women who attended those centres for ANC were exposed to weekly text messages varying in content, depending on the week of gestation, while 150 women were recruited for the unexposed group. The number of ANC visits in the intervention and control groups, was the main outcome measure. The Mann-Whitney test and the Poisson regression model were the two main statistical tests used. RESULTS: More than 85% of recipients were in agreement with the following statements: "the client recommends this program for other pregnant women", "personal rating for the message as a whole" and "obtained benefit from the messages". There was a statistically significant increase in the median number of antenatal clinic visits from two to four per pregnancy, in addition to being relatively of low cost, and could be provided for a larger population with not much difference in the efforts. CONCLUSIONS: Text messaging is feasible, low cost and reasonably acceptable to Iraqi pregnant women, and encourages their ANC visits.

Variations in presentation, management, and patient outcomes of urinary tract infection: a prospective four-country primary care observational cohort study.

BACKGROUND: Regional variations in the presentation of uncomplicated urinary tract infection (UTI) and pathogen sensitivity to antibiotics have been cited as reasons to justify differences in how the infections are managed, which includes the prescription of broad-spectrum antibiotics. AIM: To describe presentation and management of UTI in primary care settings, and explore the association with patient recovery, taking microbiological findings and case mix into account. DESIGN AND SETTING: Prospective observational study of females with symptoms of uncomplicated UTI presenting to primary care networks in England, Wales, the Netherlands, and Spain. METHOD: Clinicians recorded history, symptom severity, management, and requested mid-stream urine culture. Participants recorded, in a diary, symptom severity each day for 14 days. Time to recovery was compared between patient characteristics and between countries using two-level Cox proportional hazards models, with patients nested within practices. RESULTS: In total, 797 females attending primary care networks in England (n = 246, 30.9% of cohort), Wales (n = 213, 26.7%), the Netherlands (n = 133, 16.7%), and Spain (n = 205, 25.7%) were included. In total, 259 (35.8%, 95% confidence interval 32.3 to 39.2) of 726 females for whom there was a result were urine culture positive for UTI. Pathogens and antibiotic sensitivities were similar. Empirical antibiotics were prescribed for 95.1% in England, 92.9% in Wales, 95.1% in Spain, and 59.4% in the Netherlands There were no meaningful differences at a country network level before and after controlling for severity, prior UTIs, and antibiotic prescribing. CONCLUSION: Variation in presentation and management of uncomplicated UTI at a country primary care network level is clinically unwarranted and highlights a lack of consensus concerning optimal symptom control and antibiotic prescribing.

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.

Clinicians' interpretations of point of care urine culture versus laboratory culture results: analysis from the four-country POETIC trial of diagnosis of uncomplicated urinary tract infection in primary care.

Background: Urine culture at the point of care minimises delay between obtaining the sample and agar inoculation in a microbiology laboratory, and quantification and sensitivity results can be available more rapidly in primary care. Objective: To identify the degree to which clinicians' interpretations of a point-of-care-test (POCT) urine culture (Flexicult™ SSI-Urinary Kit) agrees with laboratory culture in women presenting to primary care with symptoms of uncomplicated urinary tract infections (UTI). Methods: Primary care clinicians used the Flexicult™-POCT, recorded their findings and took a photograph of the result, which was interpreted by microbiology laboratory technicians. Urine samples were additionally processed in routine care laboratories. Cross tabulations were used to identify important differences in organism identification, quantification and antibiotic susceptibility between these three sources of data. The influence of various laboratory definitions for UTI on culture were assessed. Results: Primary care clinicians identified 202/289 urine samples (69.9%) as positive for UTI using the Flexicult™-POCT, whereas laboratory culture identified 94-190 (32.5-65.7%) as positive, depending on definition thresholds. 82.9% of samples identified positive for E. coli on laboratory culture were also considered positive for E. coli using the Flexicult™ -POCT, and susceptibilities were reasonably concordant. There were major discrepancies between laboratory staff interpretation of Flexicult™ photographs, clinicians' interpretation of the Flexicult™ test, and laboratory culture results. Conclusion: Flexicult™-POCT overestimated the positivity rate of urine samples for UTI when laboratory culture was used as the reference standard. However, it is unclear whether point-of-care or laboratory based urine culture provides the most valid diagnostic information.

Comparison of microbiological diagnosis of urinary tract infection in young children by routine health service laboratories and a research laboratory: Diagnostic cohort study.

OBJECTIVES: To compare the validity of diagnosis of urinary tract infection (UTI) through urine culture between samples processed in routine health service laboratories and those processed in a research laboratory. POPULATION AND METHODS: We conducted a prospective diagnostic cohort study in 4808 acutely ill children aged <5 years attending UK primary health care. UTI, defined as pure/predominant growth ≥105 CFU/mL of a uropathogen (the reference standard), was diagnosed at routine health service laboratories and a central research laboratory by culture of urine samples. We calculated areas under the receiver-operator curve (AUC) for UTI predicted by pre-specified symptoms, signs and dipstick test results (the "index test"), separately according to whether samples were obtained by clean catch or nappy (diaper) pads. RESULTS: 251 (5.2%) and 88 (1.8%) children were classified as UTI positive by health service and research laboratories respectively. Agreement between laboratories was moderate (kappa = 0.36; 95% confidence interval [CI] 0.29, 0.43), and better for clean catch (0.54; 0.45, 0.63) than nappy pad samples (0.20; 0.12, 0.28). In clean catch samples, the AUC was lower for health service laboratories (AUC = 0.75; 95% CI 0.69, 0.80) than the research laboratory (0.86; 0.79, 0.92). Values of AUC were lower in nappy pad samples (0.65 [0.61, 0.70] and 0.79 [0.70, 0.88] for health service and research laboratory positivity, respectively) than clean catch samples. CONCLUSIONS: The agreement of microbiological diagnosis of UTI comparing routine health service laboratories with a research laboratory was moderate for clean catch samples and poor for nappy pad samples and reliability is lower for nappy pad than for clean catch samples. Positive results from the research laboratory appear more likely to reflect real UTIs than those from routine health service laboratories, many of which (particularly from nappy pad samples) could be due to contamination. Health service laboratories should consider adopting procedures used in the research laboratory for paediatric urine samples. Primary care clinicians should try to obtain clean catch samples, even in very young children.

Nappy pad urine samples for investigation and treatment of UTI in young children: the 'DUTY' prospective diagnostic cohort study.

BACKGROUND: The added diagnostic utility of nappy pad urine samples and the proportion that are contaminated is unknown. AIM: To develop a clinical prediction rule for the diagnosis of urinary tract infection (UTI) based on sampling using the nappy pad method. DESIGN AND SETTING: Acutely unwell children <5 years presenting to 233 UK primary care sites. METHOD: Logistic regression to identify independent associations of symptoms, signs, and urine dipstick test results with UTI; diagnostic utility quantified as area under the receiver operator curves (AUROC). Nappy pad rule characteristics, AUROC, and contamination, compared with findings from clean-catch samples. RESULTS: Nappy pad samples were obtained from 3205 children (82% aged <2 years; 48% female), culture results were available for 2277 (71.0%) and 30 (1.3%) had a UTI on culture. Female sex, smelly urine, darker urine, and the absence of nappy rash were independently associated with a UTI, with an internally-validated, coefficient model AUROC of 0.81 (0.87 for clean-catch), which increased to 0.87 (0.90 for clean-catch) with the addition of dipstick results. GPs' 'working diagnosis' had an AUROC 0.63 (95% confidence intervals [CI] = 0.53 to 0.72). A total of 12.2% of nappy pad and 1.8% of clean-catch samples were 'frankly contaminated' (risk ratio 6.66; 95% CI = 4.95 to 8.96; P<0.001). CONCLUSION: Nappy pad urine culture results, with features that can be reported by parents and dipstick tests, can be clinically useful, but are less accurate and more often contaminated compared with clean-catch urine culture.