"Hole" Exome Sequences: The Importance of Phenotyping to Fill the Gaps in Whole Exome Sequencing.

BACKGROUND: Whole exome sequencing (WES) is commonly used for patients with nonspecific clinical features and conditions with genetic heterogeneity. However, a nondiagnostic exome does not exclude a genetic diagnosis, so history and physical examination is crucial to selecting appropriate genetic testing. CASES: We report three patients with three recognizable phenotypes: a seven-year-old female with classic Rett syndrome; a 28-year-old male with neuropathy, ataxia, and retinitis pigmentosa; and a 16-year-old male with mosaic, segmental, paternal uniparental disomy 14 who had nondiagnostic WES. CONCLUSIONS: Despite recognizable phenotypes they had diagnostic delays due to incorrect selection of genetic testing. This case series highlights the limitations of WES and reinforces the importance of utilizing patient history and physical examination to select initial testing. We will discuss appropriate testing for these patients and a consistent diagnostic algorithm that can be applied when approaching patients with unknown or uncertain clinical presentations.

Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination.

Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.

Waning and boosting of functional humoral immunity to SARS-CoV-2.

Since the emergence of the SARS-CoV-2 virus, we have witnessed a revolution in vaccine development with the rapid emergence and deployment of both traditional and novel vaccine platforms. The inactivated CoronaVac vaccine and the mRNA-based Pfizer/BNT162b2 vaccine are among the most widely distributed vaccines, both demonstrating high, albeit variable, vaccine effectiveness against severe COVID-19 over time. Beyond the ability of the vaccines to generate neutralizing antibodies, antibodies can attenuate disease via their ability to recruit the cytotoxic and opsinophagocytic functions of the immune response. However, whether Fc-effector functions are induced differentially, wane with different kinetics, and are boostable, remains unknown. Here, using systems serology, we profiled the Fc-effector profiles induced by the CoronaVac and BNT162b2 vaccines, over time. Despite the significantly higher antibody functional responses induced by the BNT162b2 vaccine, CoronaVac responses waned more slowly, albeit still found at levels below those present in the systemic circulation of BNT162b2 immunized individuals. However, mRNA boosting of the CoronaVac vaccine responses resulted in the induction of significantly higher peak antibody functional responses with increased humoral breadth, including to Omicron. Collectively, the data presented here point to striking differences in vaccine platform-induced functional humoral immune responses, that wane with different kinetics, and can be functionally rescued and expanded with boosting.

Providing care for older adults in the Emergency Department: expert clinical recommendations from the European Task Force on Geriatric Emergency Medicine.

PURPOSE: Despite the rapidly expanding knowledge in the field of Geriatric Emergency Medicine in Europe, widespread implementation of change is still lacking. Many opportunities in everyday clinical care are missed to improve care for this susceptible and growing patient group. The aim was to develop expert clinical recommendations on Geriatric Emergency Medicine to be disseminated across Europe. METHODS: A group of multi-disciplinary experts in the field of Geriatric Emergency Medicine in Europe was assembled. Using a modified Delphi procedure, a prioritized list of topics related to Geriatric Emergency Medicine was created. Next, a multi-disciplinary group of nurses, geriatricians and emergency physicians performed a review of recent guidelines and literature to create recommendations. These recommendations were voted upon by a group of experts and placed on visually attractive posters. The expert group identified the following eight subject areas to develop expert recommendations on: Comprehensive Geriatric Assessment in the Emergency Department (ED), age/frailty adjusted risk stratification, delirium and cognitive impairment, medication reviews in the ED for older adults, family involvement, ED environment, silver trauma, end of life care in the acute setting. RESULTS: Eight posters with expert clinical recommendations on the most important topics in Geriatric Emergency Medicine are now available through https://posters.geriemeurope.eu/ . CONCLUSION: Expert clinical recommendations for Geriatric Emergency Medicine may help to improve care for older patients in the Emergency Department and are ready for dissemination across Europe.

Paediatric Head Injury and Traumatic Brain Injury.

Aim To determine prevalence of head injury presenting to paediatric emergency departments (PEDs) and characterise by demographics, triage category, disposition neuroimaging or re-attendance. Methods Presentations in 2014 and 2015, with diagnoses of head injury, intracranial bleed, skull fracture including single or re-attendances within 28 days post head injury to all national PEDs, were analysed. Demographics, triage score, imaging rate, admission, mechanisms and representation rate were recorded. Results Head injury was diagnosed in 13,392 of 224,860 (5.9%), median (IQR) age 3.9 (1.4 - 8.3) years. Regionally 3% of children <5 years attend each year. The total admitted/transferred was 10.8% (n=1460). Neuroimaging rate was 4.3% (n= 570). Falls predominated. Sport accounted for 12.2%. Conclusion One in twenty children PED presentations are head injury, over half in preschool children. A sizeable number were symptomatic reflected by admission, transfer, imaging or re-attendance. Observational management was favoured over imaging reflected in the higher admission versus imaging rate.

Trends in Mental Health Presentations to a Paediatric Emergency Department.

Aims This study aimed to analyse trends in mental health presentations to the Emergency Department (ED), which anecdotally had increased over the past decade. Methods The ED's electronic 'Symphony' system was used to identify the annual number of presentations categorised as having a mental health complaint from 2006-2017. A detailed analysis was performed on presentations over a one-year period. Results The number of presentations increased from 69 in 2006 to a peak of 432 in 2016 (526% increase). The overall admission rate was 33.3%(n=99), while 52.5%(n=156) of presentations occurred outside of standard working hours. Similar increases were documented by other ED's worldwide, and the WHO estimate that neuropsychiatric disorders will become one of the top five causes of morbidity, mortality and disability among children by 2020. Conclusion With the number of mental health presentations dramatically increasing, carefully designed and integrated strategies are required to pro-actively tackle this growing epidemic.

Introduction of the low risk ankle rule to a paediatric emergency department.

INTRODUCTION: Ankle injuries are a common presentation to the paediatric emergency department (PED), accounting for approximately 2% of presentations.1 X-rays are ordered for 85-95% of patients but only 12% of x-rays reveal a fracture. Clinical prediction rules, such as The Low Risk Ankle Rule (LRAR) exist to help clinicians safely reduce the frequency of radiography in these injuries. The LRAR has been shown to reduce imaging by up to 60% without missing any clinically significant fractures. We sought to introduce The LRAR into our department and study its outcomes on our practice. AIMS: To introduce the LRAR into our department and study its effects on our radiography rate and length of stay (LOS). METHODS: An audit of x-ray rates in ankle injuries in 2016 was performed to determine our department's baseline rate of radiography and LOS. We then conducted education sessions and created x-ray ordering prompts to encourage clinicians to use the LRAR. We introduced the LRAR, with a pilot period initially, and gathered data prospectively. RESULTS: 969 patients presented in with an ankle injury in 2016, 90.7% of these patients had an x-ray. The median LOS was 109 min. 92 patients presented during  the LRAR implementation period with an ankle injury. Nine patients had exclusion criteria from using the LRAR and the attending physician did not use the LRAR in four patients. Of the remaining 79 patients, 49 had a LRAR positive exam. Only one of these patients went on to have an x-ray, which was normal. The 30 patients with a LRAR negative exam all had an x-ray. Overall, our x-ray rate during the study period was 40/92 (43.4%), a reduction of 47.3%. The average LOS during the study was 101 min. No clinically significant fractures were missed. CONCLUSION: The LRAR can safely and effectively reduce the rate of radiography in ankle injuries, without missing any clinically significant fractures.

Patient, clinician and logistic barriers to blood pressure control among adult hypertensives in rural district hospitals in Rwanda: a cross-sectional study.

BACKGROUND: Hypertension management in rural, resource-poor settings is difficult. Detailed understanding of patient, clinician and logistic factors which pose barriers to effective blood pressure control could enable strategies to improve control to be implemented. METHODS: This cross-sectional, multifactorial, observational study was conducted at four rural Rwandan district hospitals, examining patient, clinician and logistic factors. Questionnaires were administered to consenting adult outpatient hypertensive patients, obtaining information on sociodemographic factors, past management for hypertension, and adherence (by Morisky Medication Adherence 8-item Scale (MMAS-8). Treating clinicians identified local difficulties in providing hypertension management from a standard World Health Organisation list and nominated their preferred treatment regimens. Blood pressure measurements and other clinical data were collected during the study visit and used to determine blood pressure control, according to goals from JNC-8 guidelines. Medication availability and cost at each hospital's pharmacy were reviewed as logistic barriers to treatment. RESULTS: The 112 participating patients were 80% female, with only 41% having completed primary education. Self-reported adherence by the MMAS-8 was high in 77% (86/112) and significantly associated) with literacy, lack of medication side effects and the particular hospital and pharmacy attended (all p < 0.05). However, of 89 patients with blood pressure data, only 26 (29%) had achieved goal blood pressure. No patient factor were statistically associated with poor blood pressure control. Among 30 participating clinicians, deficiencies in knowledge were evident; 43% (13/30) and 37% (11/30) chose a loop diuretic as their prescribed medication and as an ideal medication, respectively, for a newly diagnosed hypertensive patient without comorbidities, counter to JNC 8 recommendations, and 50% (15/30) identified clinician non-adherence to hypertension guidelines as a barrier. In the pharmacies, common anti-hypertensive medications were affordably available (> 6 out of 8 examined medications available in all pharmacies, cost

Methaemoglobinaemia: A Blue Light Emergency.

We present the case of a patient with severe methaemoglobinaemia secondary to "poppers". She presented with decreased level of consciousness and cyanosis. A methaemoglobin level was not available prior to treatment but the patient responded well and the diagnosis was confirmed afterwards.

Who's challenging who training for staff empathy towards adults with challenging behaviour: cluster randomised controlled trial.

BACKGROUND: One in five adults with intellectual disabilities (ID) known to services display challenging behaviours (CBs), and these individuals are at risk for restrictive practices and poor care. Staff attitudes may contribute to the development and/or maintenance of CBs. We investigated the effectiveness of co-produced Who's Challenging Who? training delivered by people with ID to staff. METHOD: This study involved a cluster randomised controlled trial (RCT) of Who's Challenging Who? training with follow-up at six and 20 weeks post-randomisation. PARTICIPANTS: two staff from each of 118 residential care settings for adults with ID at least one of whom displayed aggressive CB. PRIMARY OUTCOME: Self-reported Staff Empathy for people with Challenging Behaviour Questionnaire. ANALYSIS: intention to treat of all randomised settings. ISCRTN registration: ISRCTN53763600. RESULTS: 118 residential settings (including 236 staff) were randomised to either receive training (59 settings) or to receive training after a delay (59 settings). The primary analysis included data from 121 staff in 76 settings (51% of staff, 64% of settings). The adjusted mean difference on the transformed (cubed) Staff Empathy for people with Challenging Behaviour Questionnaire score at the primary end point was 1073.2 (95% CI: -938.1 to 3084.5, P = 0.296) in favour of the intervention group (effect size Cohen's d = .19). CONCLUSIONS: This is the first large-scale RCT of a co-produced training course delivered by people with ID. Findings indicated a small positive (but statistically non-significant) effect on increased staff empathy at 20 weeks, and small to moderate effects for staff reported secondary outcomes in favour of the intervention group.

Fish Oil Supplementation Increases Event-Related Posterior Cingulate Activation in Older Adults with Subjective Memory Impairment.

OBJECTIVES: To determine the effects of long-chain omega-3 (LCn-3) fatty acids found in fish oil, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on cortical blood oxygen level-dependent (BOLD) activity during a working memory task in older adults with subjective memory impairment. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Academic medical center. PARTICIPANTS: Healthy older adults (62-80 years) with subjective memory impairment, but not meeting criteria for mild cognitive impairment or dementia. INTERVENTION: Fish oil (EPA+DHA: 2.4 g/d, n=11) or placebo (corn oil, n=10) for 24 weeks. MEASUREMENTS: Cortical BOLD response patterns during performance of a sequential letter n-back working memory task were determined at baseline and week 24 by functional magnetic resonance imaging (fMRI). RESULTS: At 24 weeks erythrocyte membrane EPA+DHA composition increased significantly from baseline in participants receiving fish oil (+31%, p ≤ 0.0001) but not placebo (-17%, p=0.06). Multivariate modeling of fMRI data identified a significant interaction among treatment, visit, and memory loading in the right cingulate (BA 23/24), and in the right sensorimotor area (BA 3/4). In the fish oil group, BOLD increases at 24 weeks were observed in the right posterior cingulate and left superior frontal regions during memory loading. A region-of-interest analysis indicated that the baseline to endpoint change in posterior cingulate cortex BOLD activity signal was significantly greater in the fish oil group compared with the placebo group during the 1-back (p=0.0003) and 2-back (p=0.0005) conditions. Among all participants, the change in erythrocyte EPA+DHA during the intervention was associated with performance in the 2-back working memory task (p = 0.01), and with cingulate BOLD signal during the 1-back (p = 0.005) with a trend during the 2-back (p = 0.09). Further, cingulate BOLD activity was related to performance in the 2-back condition. CONCLUSION: Dietary fish oil supplementation increases red blood cell omega-3 content, working memory performance, and BOLD signal in the posterior cingulate cortex during greater working memory load in older adults with subjective memory impairment suggesting enhanced neuronal response to working memory challenge.

New hazards in paediatric poisoning presentations.

Accidental ingestion is an important preventable cause of childhood morbidity. All accidental ingestion presentations (n = 478) to a tertiary paediatric ED from January 2010 to December 2011 were analysed. These results were compared with a similar study in the same institution ten years previously in 2001 and showed that while accidental ingestions constituted a higher proportion of presentations (0.5% in this study v 0.45% in 2001), fewer had investigations performed (21% v 35%) and fewer were admitted (7% v 20%). Accidental ingestions account for 0.5% of presentations and are an important focus of home safety information for parents and guardians. Paracetamol (n = 67, 14%) and liquid detergent capsules (n = 44, 9.2%) were the two most common substances implicated in these presentations, and have the potential to cause severe morbidity and mortality.

Predictors of treatment response in young people at ultra-high risk for psychosis who received long-chain omega-3 fatty acids.

Previous efforts in the prospective evaluation of individuals who experience attenuated psychotic symptoms have attempted to isolate mechanisms underlying the onset of full-threshold psychotic illness. In contrast, there has been little research investigating specific predictors of positive outcomes. In this study, we sought to determine biological and clinical factors associated with treatment response, here indexed by functional improvement in a pre-post examination of a 12-week randomized controlled intervention in individuals at ultra-high risk (UHR) for psychosis. Participants received either long-chain omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) or placebo. To allow the determination of factors specifically relevant to each intervention, and to be able to contrast them, both treatment groups were investigated in parallel. Univariate linear regression analysis indicated that higher levels of erythrocyte membrane α-linolenic acid (ALA; the parent fatty acid of the ω-3 family) and more severe negative symptoms at baseline predicted subsequent functional improvement in the treatment group, whereas less severe positive symptoms and lower functioning at baseline were predictive in the placebo group. A multivariate machine learning analysis, known as Gaussian Process Classification (GPC), confirmed that baseline fatty acids predicted response to treatment in the ω-3 PUFA group with high levels of sensitivity, specificity and accuracy. In addition, GPC revealed that baseline fatty acids were predictive in the placebo group. In conclusion, our investigation indicates that UHR patients with higher levels of ALA may specifically benefit from ω-3 PUFA supplementation. In addition, multivariate machine learning analysis suggests that fatty acids could potentially be used to inform prognostic evaluations and treatment decisions at the level of the individual. Notably, multiple statistical analyses were conducted in a relatively small sample, limiting the conclusions that can be drawn from what we believe to be a first-of-its-kind study. Additional studies with larger samples are therefore needed to evaluate the generalizability of these findings.

International comparisons of the management of patients with non-ST segment elevation acute myocardial infarction in the United Kingdom, Sweden, and the United States: The MINAP/NICOR, SWEDEHEART/RIKS-HIA, and ACTION Registry-GWTG/NCDR registries.

OBJECTIVES: To compare management of patients with acute non-ST segment elevation myocardial infarction (NSTEMI) in three developed countries with national ongoing registries. BACKGROUND: Results from clinical trials suggest significant variation in care across the world. However, international comparisons in "real world" registries are limited. METHODS: We compared the use of in-hospital procedures and discharge medications for patients admitted with NSTEMI from 2007 to 2010 using the unselective MINAP/NICOR [England and Wales (UK); n=137,009], the unselective SWEDEHEART/RIKS-HIA (Sweden; n=45,069), and the selective ACTION Registry-GWTG/NCDR [United States (US); n=147,438] clinical registries. RESULTS: Patients enrolled among the three registries were generally similar except those in the US who were younger but had higher rates of smoking, diabetes, hypertension, prior heart failure, and prior MI than in Sweden or in UK. Angiography and percutaneous coronary intervention (PCI) were performed more often in the US (76% and 44%) and Sweden (65% and 42%) relative to the UK (32% and 22%). Discharge betablockers were also prescribed more often in the US (89%) and Sweden (89%) than in the UK (76%). In contrast, discharge statins, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), and dual antiplatelet agents (among those not receiving PCI) were higher in the UK (92%, 79%, and 71%) than in the US (85%, 65%, 41%) and Sweden (81%, 69%, and 49%). CONCLUSIONS: The care for patients with NSTEMI differed substantially among the three countries. These differences in care among countries provide an opportunity for future comparative effectiveness research as well as identify opportunities for global quality improvement.

Use of lean principals to improve flow of patients with fractured neck of femur--the HOPE study.

We describe the implementation of a care pathway for patients with fractured neck of femur (NOF) using Lean and Six Sigma principles. After introduction of the Lean pathway, 32 patients out a total of 86 (37%) with fractured NOF were admitted to the Trauma Ward within 4 hours of presentation to the hospital; prior to implementation this was 16 patients out of a total of 59 (27%). Post-Lean an earlier mean theatre start time of 8.40am was achieved, resulting in a 38 minute increase in daily theatre time. An additional 52 patients (12%) received surgery within 24 hours of admission, resulting in 1 night length of stay reduction. Lean methodology proved an effective method to guide change resulting in an improved journey for the patient and significant workflow gains.

Epidemiology of high falls from windows in children.

Falls from a height result in significant morbidity and mortality worldwide. Targeted prevention strategies in the US combined data collection, publicity campaigns and building regulation and reduced high falls in New York by 93%. This retrospective cohort study describes children who fell from a height presenting or referred to Children's University Hospital Temple St. over a 2 year period. Case ascertainment was through the Emergency Department Symphony registration system and the Trauma Area Research Network (TARN) database. Forty five falls were identified, 33 falls (73.3%) were in children less than 5 with boys being three times more likely to fall. Forty four falls were from windows, 31 from < 12 feet and 7 were witnessed. Injury severity Scores (ISS) correlated to height of fall; both deaths fells from > 24ft. A publicity campaign is warranted to highlight the frequency of injury following falls from windows. Building legislation is required to safeguard high windows and balconies. A post fall questionnaire would enable the collection of unbiased forensic data.

Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and related psychostimulants: mechanisms and mediators.

Concomitant consumption of caffeine with recreational psychostimulant drugs of abuse can provoke severe acute adverse reactions in addition to longer term consequences. The mechanisms by which caffeine increases the toxicity of psychostimulants include changes in body temperature regulation, cardiotoxicity and lowering of the seizure threshold. Caffeine also influences the stimulatory, discriminative and reinforcing effects of psychostimulant drugs. In this review, we consider our current understanding of such caffeine-related drug interactions, placing a particular emphasis on an adverse interaction between caffeine and the substituted amphetamine, 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'), which has been most recently described and characterized. Co-administration of caffeine profoundly enhances the acute toxicity of MDMA in rats, as manifested by high core body temperature, tachycardia and increased mortality. In addition, co-administration of caffeine enhances the long-term serotonergic neurotoxicity induced by MDMA. Observations to date support an interactive model of drug-induced toxicity comprising MDMA-related enhancement of dopamine release coupled to a caffeine-mediated antagonism of adenosine receptors in addition to inhibition of PDE. These experiments are reviewed together with reports of caffeine-related drug interactions with cocaine, d-amphetamine and ephedrine where similar mechanisms are implicated. Understanding the underlying mechanisms will guide appropriate intervention strategies for the management of severe reactions and potential for increased drug-related toxicity, resulting from concomitant caffeine consumption.

Development and evaluation by a cluster randomised trial of a psychosocial intervention in children and teenagers experiencing diabetes: the DEPICTED study.

OBJECTIVE: To develop and evaluate a health-care communication training programme to help diabetes health-care professionals (HCPs) counsel their patients more skilfully, particularly in relation to behaviour change. DESIGN: The HCP training was assessed using a pragmatic, cluster randomised controlled trial. The primary and secondary analyses were intention-to-treat comparisons of outcomes using multilevel modelling to allow for cluster (service) and individual effects, and involved two-level linear models. SETTING: Twenty-six UK paediatric diabetes services. PARTICIPANTS: The training was delivered to HCPs (doctors, nurses, dietitians and psychologists) working in paediatric diabetes services and the effectiveness of this training was measured in 693 children aged 4-15 years and families after 1 year (95.3% follow-up). INTERVENTIONS: A blended learning programme was informed by a systematic review of the literature, telephone and questionnaire surveys of professional practice, focus groups with children and parents, experimental consultations and three developmental workshops involving a stakeholder group. The programme focused on agenda-setting, flexible styles of communication (particularly guiding) and a menu of strategies using web-based training and practical workshops. MAIN OUTCOME MEASURES: The primary trial outcome was a change in glycosylated haemoglobin (HbA1c) levels between the start and finish of a 12-month study period. Secondary trial outcomes included change in quality of life, other clinical [including body mass index (BMI)] and psychosocial measures (assessed at participant level as listed above) and cost (assessed at service level). In addition, patient details (HbA1c levels, height, weight, BMI, insulin regimen), health service contacts and patient-borne costs were recorded at each clinic visit, along with details of who patients consulted with, for how long, and whether or not patients consulted on their own at each visit. Patients and carers were also asked to complete an interim questionnaire assessing patient enablement (or feelings towards clinic visit for younger patients aged 7-10 years) at their first clinic visit following the start of the trial. The cost of the intervention included the cost of training intervention teams. RESULTS: Trained staff showed better skills than control subjects in agenda-setting and consultation strategies, which waned from 4 to 12 months. There was no effect on HbA1c levels (p = 0.5). Patients in intervention clinics experienced a loss of confidence in their ability to manage diabetes, whereas controls showed surprisingly reduced barriers (p = 0.03) and improved adherence (p = 0.05). Patients in intervention clinics reported short-term increased ability (p = 0.04) to cope with diabetes. Parents in the intervention arm experienced greater excitement (p = 0.03) about clinic visits and improved continuity of care (p = 0.01) without the adverse effects seen in their offspring. The mean cost of training was £13,145 per site or £2163 per trainee. There was no significant difference in total NHS costs (including training) between groups (p = 0.1). CONCLUSIONS: Diabetes HCPs can be trained to improve consultation skills, but these skills need reinforcing. Over 1 year, no benefits were seen in children, unlike parents, who may be better placed to support their offspring. Further modification of this training is required to improve outcomes that may need to be measured over a longer time to see effects. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61568050. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 29. See the HTA programme website for further project information.