Model-based economic evaluation of the effectiveness of "'Hypos' can strike twice", a leaflet-based ambulance clinician referral intervention to prevent recurrent hypoglycaemia.

"'Hypos' can strike twice" (HS2) is a pragmatic, leaflet-based referral intervention designed for administration by clinicians of the emergency medical services (EMS) to people they have attended and successfully treated for hypoglycaemia. Its main purpose is to encourage the recipient to engage with their general practitioner or diabetic nurse in order that improvements in medical management of their diabetes may be made, thereby reducing their risk of recurrent hypoglycaemia. Herein we build a de novo economic model for purposes of incremental analyses to compare, in 2018-19 prices, HS2 against standard care for recurrent hypoglycaemia in the fortnight following the initial attack from the perspective of the UK National Health Service (NHS). We found that per patient NHS costs incurred by people receiving the HS2 intervention over the fortnight following an initial hypoglycaemia average £49.79, and under standard care costs average £40.50. Target patient benefit assessed over that same period finds the probability of no recurrence of hypoglycaemia averaging 42.4% under HS2 and 39.4% under standard care, a 7.6% reduction in relative risk. We find that implementing HS2 will cost the NHS an additional £309.36 per episode of recurrent hypoglycaemia avoided. Contrary to the favourable support offered in Botan et al., we conclude that in its current form the HS2 intervention is not a cost-effective use of NHS resources when compared to standard NHS care in reducing the risk of hypoglycaemia recurring within a fortnight of an initial attack that was resolved at-scene by EMS ambulance clinicians.

"It's like a swan, all nice and serene on top, and paddling like hell underneath": community first responders' practices in attending patients and contributions to rapid emergency response in rural England, United Kingdom-a qualitative interview study.

BACKGROUND: Community First Responder (CFR) schemes are a long-established service supplementing ambulance trusts in their local community in the United Kingdom. CFRs are community members who volunteer to respond to people with life-threatening conditions. Previous studies highlighted the motivations for becoming CFRs, their training, community (un)awareness and implications of their work on themselves and others. The practices of CFRs in prehospital care remain underexplored. Therefore, we aimed to explore real-world practice of Community First Responders and their contribution to prehospital emergency care. METHODS: We conducted 47 interviews with CFRs (21), CFR leads (15), ambulance clinicians (4), commissioners (2) and patients and relatives (5) from six ambulance services and regions of England, United Kingdom. Thematic analysis enabled identification of themes and subthemes, with subsequent interpretation built on the theory of practice wisdom. RESULTS: Our analysis revealed the embeddedness of the concept of doing the right thing at the right time in CFR practice. CFRs' work consisted of a series of sequential and interconnected activities which included: identifying patients' signs, symptoms and problems; information sharing with the ambulance control room on the patient's condition; providing a rapid emergency response including assessment and care; and engaging with ambulance clinicians for patient transfer. The patient care sequence began with recognising patients' signs and symptoms, and validation of patient information provided by the ambulance control room. The CFRs shared patient information with ambulance control who in turn notified the ambulance crew en-route. The practices of CFRs also included delivery of emergency care before ambulance clinicians arrived. Following the delivery of a rapid emergency response, CFRs engaged with the ambulance crew to facilitate patient transfer to the nearest medical facility. CONCLUSION: The sequential CFR practices supported ambulance services in delivering prehospital and emergency care in rural areas. CFR practices were founded on the principle of practice wisdom where CFRs constructed their practice decisions based on the patient's condition, their training, availability of equipment and medications and their scope of practice.

Community First Responders' Contribution to Emergency Medical Service Provision in the United Kingdom.

STUDY OBJECTIVE: We aimed to investigate community first responders' contribution to emergency care provision in terms of number, rate, type, and location of calls and characteristics of patients attended. METHODS: We used a retrospective observational design analyzing routine data from electronic clinical records from 6 of 10 ambulance services in the United Kingdom during 2019. Descriptive statistics, including numbers and frequencies, were used to illustrate characteristics of incidents and patients that the community first responders attended first in both rural and urban areas. RESULTS: The data included 4.5 million incidents during 1 year. The community first responders first attended a higher proportion of calls in rural areas compared with those in urban areas (3.90% versus 1.48 %). In rural areas, the community first responders also first attended a higher percentage of the most urgent call categories, 1 and 2. The community first responders first attended more than 9% of the total number of category 1 calls and almost 5% of category 2 calls. The community first responders also attended a higher percentage of the total number of cardiorespiratory and neurological/endocrine conditions. They first attended 6.5% of the total number of neurological/endocrine conditions and 5.9% of the total number of cardiorespiratory conditions. Regarding arrival times in rural areas, the community first responders attended higher percentages (more than 6%) of the total number of calls that had arrival times of less than 7 minutes or more than 60 minutes. CONCLUSION: In the United Kingdom, community first responders contribute to the delivery of emergency medical services, particularly in rural areas and especially for more urgent calls. The work of community first responders has expanded from their original purpose-to attend to out-of-hospital cardiac arrests. The future development of community first responders' schemes should prioritize training for a range of conditions, and further research is needed to explore the contribution and potential future role of the community first responders from the perspective of service users, community first responders' schemes, ambulance services, and commissioners.

Evaluation of the effectiveness and costs of inhaled methoxyflurane versus usual analgesia for prehospital injury and trauma: non-randomised clinical study.

BACKGROUND: We aimed to investigate clinical benefits and economic costs of inhaled methoxyflurane when used by ambulance staff for prehospital emergency patients with trauma. Comparison is to usual analgesic practice (UAP) in the UK in which patient records were selected if treatment had been with Entonox® or intravenous morphine or intravenous paracetamol. METHODS: Over a 12-month evaluation period, verbal numerical pain scores (VNPS) were gathered from adults with moderate to severe trauma pain attended by ambulance staff trained in administering and supplied with methoxyflurane. Control VNPS were obtained from ambulance database records of UAP in similar patients for the same period. Statistical modelling enabled comparisons of methoxyflurane to UAP, where we employed an Ordered Probit panel regression model for pain, linked by observational rules to VNPS. RESULTS: Overall, 96 trained paramedics and technicians from the East Midlands Ambulance Service NHS Trust (EMAS) prepared 510 doses of methoxyflurane for administration to a total of 483 patients. Comparison data extracted from the EMAS database of UAP episodes involved: 753 patients using Entonox®, 802 patients using intravenous morphine, and 278 patients using intravenous paracetamol. Modelling results included demonstration of faster pain relief with inhaled methoxyflurane (all p-values < 0.001). Methoxyflurane's time to achieve maximum pain relief was estimated to be significantly shorter: 26.4 min (95%CI 25.0-27.8) versus Entonox® 44.4 min (95%CI 39.5-49.3); 26.5 min (95%CI 25.0-27.9) versus intravenous morphine 41.8 min (95%CI 38.9-44.7); 26.5 min (95%CI 25.1-28.0) versus intravenous paracetamol 40.8 (95%CI 34.7-46.9). Scenario analyses showed that durations spent in severe pain were significantly less for methoxyflurane. Costing scenarios showed the added benefits of methoxyflurane were achieved at higher cost, eg versus Entonox® the additional cost per treated patient was estimated to be £12.30. CONCLUSION: When administered to adults with moderate or severe pain due to trauma inhaled methoxyflurane reduced pain more rapidly and to a greater extent than Entonox® and parenteral analgesics. Inclusion of inhaled methoxyflurane to the suite of prehospital analgesics provides a clinically useful addition, but one that is costlier per treated patient.

People with diabetes and ambulance staff perceptions of a booklet-based intervention for diabetic hypoglycaemia, "Hypos can strike twice": a mixed methods process evaluation.

BACKGROUND: Hypoglycaemia is a potentially serious condition, characterised by lower-than-normal blood glucose levels, common in people with diabetes (PWD). It can be prevented and self-managed if expert support, such as education on lifestyle and treatment, is provided. Our aim was to conduct a process evaluation to investigate how ambulance staff and PWD perceived the "Hypos can strike twice" booklet-based ambulance clinician intervention, including acceptability, understandability, usefulness, positive or negative effects, and facilitators or barriers to implementation. METHODS: We used an explanatory sequential design with a self-administered questionnaire study followed by interviews of people with diabetes and ambulance staff. We followed the Medical Research Council framework for process evaluations of complex interventions to guide data collection and analysis. Following descriptive analysis (PWD and staff surveys), exploratory factor analysis was conducted to identify staff questionnaire subscales and multiple regression models were fitted to identify demographic predictors of overall and subscale scores. RESULTS: 113 ambulance staff members and 46 PWD completed the survey. We conducted interviews with four ambulance staff members and five PWD who had been attended by an ambulance for a hypoglycaemic event. Based on surveys and interviews, there were positive attitudes to the intervention from both ambulance staff and PWD. Although the intervention was not always implemented, most staff members and PWD found the booklet informative, easy to read and to use or explain. PWD who completed the survey reported that receiving the booklet reminded and/or encouraged them to test their blood glucose more often, adjust their diet, and have a discussion/check up with their diabetes consultant. Interviewed PWD felt that the booklet intervention would be more valuable to less experienced patients or those who cannot manage their diabetes well. Overall, participants felt that the intervention could be beneficial, but were uncertain about whether it might help prevent a second hypoglycaemic event and/or reduce the number of repeat ambulance attendances. CONCLUSIONS: The 'Hypos may strike twice' intervention, which had demonstrable reductions in repeat attendances, was found to be feasible, acceptable to PWD and staff, prompting reported behaviour change and help-seeking from primary care. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT04243200 on 27 January 2020.

Recruitment to a large scale randomised controlled clinical trial in primary care: the Helicobacter Eradication Aspirin Trial (HEAT).

BACKGROUND: The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter (H.) pylori eradication reduces hospitalisation for peptic ulcer bleeding. Recruited participants were aged 60 and over and taking aspirin (≤325 mg daily) for at least four months prior to consent. Based on results of a pilot study, a sample size calculation predicted 6600 H. pylori-positive randomised participants would be required, from 33,000 volunteers, recruited from 170,000 invited patients. Methodology was therefore designed for recruitment of large numbers of patients from primary care using a novel electronic search tool, automated mail-out and electronic follow-up. Recruitment started in 2012 and completed in 2017. METHODS: All participants were recruited from GP practices, with assistance from the UK Clinical Research Network (UKCRN). H. pylori-positive participants were randomised to one week of eradication treatment or placebo. Recruitment was managed using a bespoke web-based database that communicated directly with a programmed search tool downloaded at participating practices. The primary endpoint is hospitalisation due to peptic ulcer bleeding. The trial will end when 87 adjudicated events have occurred, identified from searches of GP databases, review of secondary care admission data and mortality data, and reported events from randomised participants and GPs. RESULTS: HEAT has recruited participants from 1208 GP practices across the UK. Of the 188,875 invitation letters sent, 38,771 returned expressions of interest. Of these, 30,166 patients were consented to the trial, of whom 5355 H. pylori-positive participants (17.8% of those consented) were randomised. Mean age at consent was 73.1 ± 6.9 (SD) years and 72.2% of participants were male. Of the randomised (H. pylori-positive) participants, 531 have died (as of 17 Sep 2020); none of the deaths was due to trial treatment. CONCLUSION: The HEAT trial methodology has demonstrated that recruitment of large numbers of patients from primary care is attainable, with the assistance of the UKCRN, and could be applied to other clinical outcomes studies. TRIAL REGISTRATION: ClinicalTrials.gov ; registration number NCT01506986 . Registered on 10 Jan 2012.

Patient-maintained versus anaesthetist-controlled propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia: a randomised controlled trial.

BACKGROUND: Patient-maintained propofol TCI sedation (PMPS) allows patients to titrate their own target-controlled infusion (TCI) delivery of propofol sedation using a handheld button. The aim of this RCT was to compare PMPS with anaesthetist-controlled propofol TCI sedation (ACPS) in patients undergoing elective primary lower-limb arthroplasty surgery under spinal anaesthesia. METHODS: In this single-centre open-label investigator-led study, adult patients were randomly assigned to either PMPS or ACPS during their surgery. Both sedation regimes used Schnider effect-site TCI modelling. The primary outcome measure was infusion rate adjusted for weight (expressed as mg kg-1 h-1). Secondary outcomes measures included depth of sedation, occurrence of sedation-related adverse events and time to medical readiness for discharge from the postanaesthsia care unit (PACU). RESULTS: Eighty patients (48 female) were randomised. Subjects using PMPS used 39.3% less propofol during the sedation period compared with subjects in group ACPS (1.56 [0.57] vs 2.57 [1.33] mg kg-1 h-1; P<0.001), experienced fewer discrete episodes of deep sedation (0 vs 6; P=0.0256), fewer airway/breathing adverse events (odds ratio [95% confidence interval]: 2.94 [1.31-6.64]; P=0.009) and were ready for discharge from PACU more quickly (8.94 [5.5] vs 13.51 [7.2] min; P=0.0027). CONCLUSIONS: Patient-maintained propofol sedation during lower-limb arthroplasty under spinal anaesthesia results in reduced drug exposure and fewer episodes of sedation-related adverse events compared with anaesthetist-controlled propofol TCI sedation. To facilitate further investigation of this procedural sedation technique, PMPS-capable TCI infusion devices should be submitted for regulatory approval for clinical use. CLINICAL TRIAL REGISTRATION: ISRCTN29129799.

Clinical effectiveness and costs of pre-hospital inhaled methoxyflurane for acute pain in trauma in adults: non-randomised control group study.

AIMS: Inhaled methoxyflurane, newly licensed in Europe for acute trauma pain in adults, has limited evidence of effectiveness in the pre-hospital setting. We aimed to investigate the clinical effectiveness and costs of methoxyflurane delivered when administered by ambulance staff compared with usual analgesic practice (UAP) for adults with trauma. METHODS: A non-randomised control group design was used to compare methoxyflurane versus Entonox® or parenteral analgesics. Verbal numerical pain scores (VNPS) were gathered over time in adults with moderate to severe trauma pain attended by ambulance staff trained in administering and supplied with methoxyflurane. Comparator VNPS were obtained from database records of UAP in similar patients. Clinical efficacy was tested using an Ordered Probit panel regression model of pain intensity linked by observational rules to VNPS. Scenario analyses were used to compare durations under analgesia spent in severe pain, and costs. RESULTS: Over the 12-month evaluation period, 96 trained paramedics and technicians prepared 510 doses of methoxyflurane for administration to a grand total of 483 patients. Thirty-two patients reported side effects, 19 of whom discontinued early. Thirteen patients, 10 aged over 75 years, were nonadherent to instructions given on inhaler use. Modelling results included demonstration of statistically significant clinical effectiveness of methoxyflurane over each comparator (all p-values <0.001). Methoxyflurane's time to achieve maximum pain relief was significantly faster (all p-values <0.001): 25.7 mins (95%CI 24.4-27.0) versus Entonox® 44.4 (39.5-49.3); 25.8 (24.5-27.1) versus IV paracetamol 40.7 (34.6-46.9); 25.7 (24.4-27.0) versus IV morphine sulfate 41.9 (38.9-44.8). Scenario analyses of time spent in severe pain (VNPS on administration just scoring 10 reducing to a score of 7) were significantly less for methoxyflurane (all difference p-values <0.001): 7.6 mins (95%CI 6.5-8.7) versus Entonox® 24.6 (20.1-29.0); 6.7 (5.6-7.7) versus IV paracetamol 23.0 (17.9-28.0); 6.9 (5.9-7.9) versus IV morphine sulfate 14.9 (13.3-16.6). Costing scenarios compared single-dose use of methoxyflurane versus Entonox® and versus parenteral analgesics (80-20% weighted episode mix of morphine sulfate and paracetamol). In both scenarios, the benefits of methoxyflurane were achieved at higher cost: the additional cost per treated patient was £8.77 versus Entonox® and £9.69 versus parenteral analgesics. The BNF list price for one vial containing a 3 mL dose of methoxyflurane for vaporisation in a Penthrox® inhaler is £17.89 per pack. CONCLUSION: Methoxyflurane administered by ambulance clinicians reduced moderate or severe pain due to trauma in adults more rapidly compared to Entonox® or parenteral drugs. Methoxyflurane provides a useful addition to pre-hospital analgesia.

The effects of a leaflet-based intervention, 'Hypos can strike twice', on recurrent hypoglycaemic attendances by ambulance services: A non-randomised stepped wedge study.

AIMS: We aimed to investigate the effect of an intervention in which ambulance personnel provided advice supported by a booklet-'Hypos can strike twice'-issued following a hypoglycaemic event to prevent future ambulance attendances. METHODS: We used a non-randomised stepped wedge-controlled design. The intervention was introduced at different times (steps) in different areas (clusters) of operation within East Midlands Ambulance Service NHS Trust (EMAS). During the first step (T0), no clusters were exposed to the intervention, and during the last step (T3), all clusters were exposed. Data were analysed using a general linear mixed model (GLMM) and an interrupted-time series analysis (ITSA). RESULTS: The study included 4825 patients (mean age 65.42 years, SD 19.42; 2,166 females) experiencing hypoglycaemic events attended by EMAS. GLMM indicated a reduction in the number of unsuccessful attendances (i.e., attendance followed by a repeat attendance) in the final step of the intervention when compared to the first (odds ratio OR: 0.50, 95%CI: 0.33-0.76, p = 0.001). ITSA indicated a significant decrease in repeat ambulance attendances for hypoglycaemia-relative to the pre-intervention trend (p = 0.008). Furthermore, the hypoglycaemia care bundle was delivered in 66% of attendances during the intervention period, demonstrating a significant level of practice change (p < 0.001). CONCLUSION: The 'Hypos can strike twice' intervention had a positive effect on reducing numbers of repeat attendances for hypoglycaemia and in achieving the care bundle. The study supports the use of information booklets by ambulance clinicians to prevent future attendances for recurrent hypoglycaemic events.

Anaesthetist-controlled versus patient-maintained effect-site targeted propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia (ACCEPTS): study protocol for a parallel-group randomised comparison trial.

BACKGROUND: The clinical efficacy of effect-site targeted patient-maintained propofol sedation (PMPS) compared to anaesthetist-controlled propofol sedation (ACPS) for patients undergoing awake joint replacement surgery is currently unknown. There is no commercially available medical device capable of delivering PMPS so we have designed and built such a device. We plan a clinical trial to compare PMPS to ACPS and to collect data relating to the safety of our prototype device in delivering sedation. METHODS: The trial is an open-label, randomised, controlled superiority trial recruiting adults who are undergoing elective primary lower-limb arthroplasty with sedation by propofol infusion by effect-site targeting into two equal-sized parallel arms: PMPS and ACPS. The primary research objective is to compare the body-weight-normalised rate of propofol consumption when sedation for surgery on adults undergoing elective primary lower-limb arthroplasty under spinal anaesthesia is patient-maintained versus when it is anaesthetist-controlled. The study primary null hypothesis is that there is no difference in the rate of propofol consumption when sedation is patient-maintained versus anaesthetist-controlled. DISCUSSION: This is the first trial to test the superiority of effect-site-targeted patient-maintained propofol sedation versus anaesthetist-controlled propofol sedation in terms of total propofol consumption during the sedation period. The results of this trial will help inform clinicians and device manufacturers of the clinical efficacy and safety of patient-maintained propofol sedation applied to a common operative setting. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Registry, ISRCTN29129799 . Prospectively registered on 12 June 2018.

Biosimilar uptake by British local formularies: a cross sectional study.

Background Biological medicines are starting to lose their patent protection, so similar, inexact copies (biosimilars) are being developed and licensed. The high acquisition costs of biologics for healthcare providers could be reduced by switching to biosimilars, thus alleviating budgetary pressures and increasing patient access. Therefore, the acceptance of biosimilars by prescribers in Great Britain (GB; England, Scotland, Wales) needs to be described and understood. Objective To determine uptake of the first wave of biosimilars (somatropin, epoetin, filgrastim) by local formularies (lists of preferred medicines for prescribing in local healthcare settings). Settings This study targeted local formularies in GB. Method In November 2014, local formularies (medicines formularies of Acute Trusts and Health Boards in GB) were screened for their approach to listing of biologics and their biosimilars as well as recommendations on usage of these pharmaceuticals. Main Outcomes Measures Listing frequencies of biosimilars. Results One hundred and forty-six British local formularies were screened. Amongst the 80% of formularies in which brand names were specified, biosimilar filgrastim was the most frequently listed when compared to the other targeted biosimilars. Biosimilars were listed in preference to reference biologic medicine in 49% of local formularies for filgrastim, 11% for somatropin and in only 6% for epoetin. Conclusion Although the market for biosimilars can act in parallel to the generic market, their uptake measured using local British formularies was less than what is expected given that the British market for medicines has a strong focus on generics. Finally, geographical variability within GB requires further investigation.

The Helicobacter Eradication Aspirin Trial (HEAT): A Large Simple Randomised Controlled Trial Using Novel Methodology in Primary Care.

BACKGROUND: Clinical trials measuring the effect of an intervention on clinical outcomes are more influential than those investigating surrogate measures but are costly. We developed methods to reduce costs substantially by using existing data in primary care systems, to ask whether Helicobacter pylori eradication would reduce the incidence of hospitalisation for ulcer bleeding in aspirin users. METHODS: The Helicobacter Eradication Aspirin Trial (HEAT) is a National Institute of Health Research-funded, double-blind placebo controlled randomised trial of the effects of H. pylori eradication on subsequent ulcer bleeding in infected individuals taking aspirin daily, conducted in practices across the whole of England, Wales and Northern Ireland. A bespoke web-based trial management system developed for the trial (and housed within the secure NHS Data Network) communicates directly with the HEAT Toolkit software downloaded at participating practices, which issues queries searching entry criteria (≥ 60 years, on chronic aspirin ≤ 325 mg daily, not on anti-ulcer therapy or non-steroidal anti-inflammatory drugs) for GP review of eligibility. Trial participation is invited using a highly secure automated online mail management system. Interested patients are seen once for consent and breath testing. Those with a positive test are randomised to eradication treatment (lansoprazole, clarithromycin, metronidazole) or placebo, with drug sent by post. Events are tracked by upload of accumulating information in the GP database, patient contact, review of National Hospital Episode Statistics and Office of National Statistics data. RESULTS: HEAT is the largest Clinical Research Network-supported drug trial, with 115,660 invitation letters sent from 850 practices, 22,922 volunteers, and 3038 H. pylori positive patients randomised to active or placebo treatment after 2.5 years of recruitment. 178 practices have performed their first follow-up data search to identify 21 potential endpoints to date. DISCUSSION: HEAT is important medically, because aspirin is so widely used, and methodologically, as a successful trial would show that large-scale studies of important clinical outcomes can be conducted at a fraction of the cost of those conducted by industry, which in turn will help to ensure that trials of primarily medical rather than commercial interest can be conducted successfully in the UK.

Assessment of the feasibility and clinical value of further research to evaluate the management options for children with Down syndrome and otitis media with effusion: a feasibility study.

BACKGROUND: There is clinical uncertainty of the benefits and costs of different treatment options for children with Down syndrome who have glue ear. This study was designed to assess the extent of this lack of knowledge and determine if pursuing further information would be practical, beneficial and cost-effective. OBJECTIVES: To assess the level and practical effect of current uncertainty around treatment options for children with Down syndrome and glue ear. To assess the feasibility of studying the options for management of glue ear in children with Down syndrome via a randomised controlled trial (RCT) or multicentre prospective cohort study by evaluating the willingness of (1) parents to agree to randomisation for their children and (2) clinicians to recruit participants to a definitive study. To undertake value of information analyses to demonstrate the potential economic benefit from undertaking further research. DESIGN: A feasibility study exploring the views of parents of children with Down syndrome and professionals who have responsibility for the health and education of children with Down syndrome, on the participation in, and value of, future research into interventions for glue ear. Data were collected from parents via self-completed questionnaires, face-to-face interviews and focus groups and from professionals via online questionnaires and a Delphi review exercise. Development of economic models to represent clinical pathways of care and a RCT informed a value of information (VOI) analysis. SETTING: UK (professionals); East Midlands region of the UK (parents). PARTICIPANTS: Parents of children aged 1-11 years with Down syndrome (n = 156). Professionals including audiologists, ear, nose and throat surgeons, audiological physicians, speech and language therapists, and teachers of the deaf (n = 128). MAIN OUTCOME MEASURES: Quantitative and qualitative data on parental views and experiences of glue ear and its effects; interventions and treatment received; taking part in research and factors that would encourage or discourage participation; and the importance of various outcome domains to them and for their children. For professionals: information on caseloads; approaches to clinical management; opinions on frequency and significance of the consequences of glue ear for this population; importance of different outcome measures; opinions of interventions and their role in future research; views on health research; facilitators and barriers to recruitment, and participation in research involving RCTs. RESULTS: The complexity of the experience and individual characteristics of children with Down syndrome poses challenges for the design of any future research but these challenges were not considered by professionals to raise sufficient barriers to prevent it being undertaken. Parents were generally supportive of the need for, and value of, research but identified practical and emotional issues that would need addressing. Glue ear was considered to impact more on speech, language and communication than on hearing. Outcome measures for future research would need to evaluate these elements but measures should be designed specifically for the population. Parents and professionals identified randomisation as a significant barrier to participation. The VOI analyses identified lack of data as problematic but concluded that a future trial involving surgical intervention would be feasible at costs of < £650,000. CONCLUSIONS: Future research into the benefits of interventions for glue ear in children with Down syndrome would be feasible and could be cost-effective but should be carefully designed to facilitate and maximise participation from parents and professionals responsible for recruitment. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Adherence to inhaled corticosteroids by asthmatic patients: measurement and modelling.

BACKGROUND: Poor adherence to inhaled corticosteroids (ICS) is known as the main cause for therapeutic failure in asthma treatment and associated morbidity. To improve adherence, targetted and effective interventions need to be developed ideally based on using longitudinal follow-up of a large study cohort to establish patterns and influences on adherence. OBJECTIVE: To develop an annual measure of asthma patients' adherence to ICS using primary care prescribing data over consecutive annual intervals, and to statistically model ICS adherence controlling for a range of patient factors. SETTING: A retrospective cohort study between 1997 and 2010 using United Kingdom general practice prescribing data on asthma patients aged between 12 and 65 years, without a diagnosis of chronic obstructive pulmonary disease. METHOD: Patient's ICS prescriptions are used to calculate the 'number of days prescribed during calendar year' divided by 'number of days in the interval' to form an annual prescription possession ratio (PPR) for each patient. Several definitions of PPR are considered and compared when calculating numerator and denominator. Adherence, measured by the preferred PPR, is then modelled to estimate the effect of asthma exacerbation, severity, control and other patient factors on adherence. MAIN OUTCOME MEASURE: PPR, being a proxy measure for adherence. RESULTS: Annual PPR by all strategies gave a similar frequency profile. ICS were either over- or under-prescribed for over half of the follow-up time. Adherence was lower in younger patients, those newer to the study timeframe, those with less severe asthma, those with good control, with lower previous adherence, and who had not previously experienced an exacerbation. CONCLUSION: The chosen PPR simulated clinical use of ICS most closely; including overlapping days, excess days passed to the next interval, considering gaps in the denominator, with censoring at 100 %. The PPR is a useful measure for signalling or measuring adherence changes over time. The modelling results identified many characteristics which would indicate which asthma patients and at what points in their treatment cycle they would be at increased risk of low adherence.

Modelling the participation decision and duration of sporting activity in Scotland.

Motivating individuals to actively engage in physical activity due to its beneficial health effects has been an integral part of Scotland's health policy agenda. The current Scottish guidelines recommend individuals participate in physical activity of moderate vigour for 30 min at least five times per week. For an individual contemplating the recommendation, decisions have to be made in regard of participation, intensity, duration and multiplicity. For the policy maker, understanding the determinants of each decision will assist in designing an intervention to effect the recommended policy. With secondary data sourced from the 2003 Scottish Health Survey (SHeS) we statistically model the combined decisions process, employing a copula approach to model specification. In taking this approach the model flexibly accounts for any statistical associations that may exist between the component decisions. Thus, we model the endogenous relationship between the decision of individuals to participate in sporting activities and, amongst those who participate, the duration of time spent undertaking their chosen activities. The main focus is to establish whether dependence exists between the two random variables assuming the vigour with which sporting activity is performed to be independent of the participation and duration decision. We allow for a variety of controls including demographic factors such as age and gender, economic factors such as income and educational attainment, lifestyle factors such as smoking, alcohol consumption, healthy eating and medical history. We use the model to compare the effect of interventions designed to increase the vigour with which individuals undertake their sport, relating it to obesity as a health outcome.

Predictive biomarkers for personalised anti-cancer drug use: discovery to clinical implementation.

A priority translational research objective in cancer medicine is the discovery of novel therapeutic targets for solid tumours. Ideally, co-discovery of predictive biomarkers occurs in parallel to facilitate clinical development of agents and ultimately personalise clinical use. However, the identification of clinically useful predictive biomarkers for solid tumours has proven challenging with many initially promising biomarkers failing to translate into clinically useful applications. In particular, the 'failure' of a predictive biomarker has often only become apparent at a relatively late stage in investigation. Recently, the field has recognised the need to develop a robust clinical biomarker development methodology to facilitate the process. This review discusses the recent progress in this area focusing on the key stages in the biomarker development process: discovery, validation, qualification and implementation. Concentrating on predictive biomarkers for selecting systemic therapies for individual patients in the clinic, the advances and progress in each of these stages in biomarker development are outlined and the key remaining challenges are discussed. Specific examples are discussed to illustrate the challenges identified and how they have been addressed. Overall, we find that significant progress has been made towards a formalised biomarker developmental process. This holds considerable promise for facilitating the translation of predictive biomarkers from discovery to clinical implementation. Further enhancements could eventually be found through alignment with regulatory processes.

Infant mortality and child nutrition in Bangladesh.

The excess female infant mortality observed in South Asia has typically been attributed to gender discrimination in the intra-household allocation of food and medical care. However, studies on child nutrition find no evidence of gender differences. A natural explanation could be that in environments of high infant mortality of females, the surviving children are healthier, so that child nutrition cannot be studied independently of mortality. In this paper, we use data from the 2004 Bangladesh Demographic Health Survey to investigate if there are any gender differences in survival probabilities and whether this leads to differences in child nutrition. We argue the importance of establishing whether or not there exists a dependence relationship between the two random variables--infant mortality and child nutrition--and in order to detect this we employ a copula approach to model specification. The results suggest, for example, that while male children have a significantly lower likelihood of surviving their first year relative to female children, should they survive they have significantly better height-for-age Z-scores. From a policy perspective, household wealth and public health interventions such as vaccinations are found to be important predictors of better nutritional outcomes.