The future of dementia risk reduction research: barriers and solutions.

BACKGROUND: We examine why dementia prevention and risk reduction are relatively underfunded and suggest potential remediation strategies. The paper is aimed at researchers, funders and policy-makers, both within dementia and also the wider health prevention field. METHODS: A discussion-led workshop, attended by 58 academics, clinicians, funders and policy-makers. RESULTS: The key barriers identified were the gaps in understanding the basic science of dementia; the complex interplay between individual risk factors; variations in study methodology; disincentives to collaboration; a lack of research capacity and leadership and the broader stigma of the condition. Recommendations were made to encourage strategic leadership, provide greater support for grant applications, promote collaboration and support randomized control trials for the research field. CONCLUSION: Having identified the barriers, the key challenge is how to implement the potential solutions. This will require engagement with decision-makers within funding, policy and research to ensure that action takes place.

The transcription factors Egr1 and Egr2 have opposing influences on adipocyte differentiation.

The zinc finger-containing transcription factors Egr1 (Krox24) and Egr2 (Krox20) have been implicated in the proliferation and differentiation of many cell types. Egr2 has earlier been shown to play a positive role in adipocyte differentiation, but the function of Egr1 in this context is unknown. We compared the roles of Egr1 and Egr2 in the differentiation of murine 3T3-L1 adipocytes. Egr1 protein was rapidly induced after addition of differentiation cocktail, whereas Egr2 protein initially remained low before increasing on days 1 and 2, concomitant with the disappearance of Egr1. In marked contrast to the effects of Egr2, differentiation was inhibited by ectopic expression of Egr1 and potentiated by knockdown of Egr1. The pro-adipogenic effects of Egr1 knockdown were particularly notable when isobutylmethylxanthine (IBMX) was omitted from the differentiation medium. However, knockdown of Egr1 did not affect CCAAT/enhancer binding protein (C/EBP)beta protein expression or phosphorylation of CREB Ser133. Further, Egr1 did not directly affect the activity of promoters for the master adipogenic transcription factors, C/EBPalpha or peroxisome proliferator-activated receptor-gamma2, as assessed in luciferase reporter assays. These data indicate that Egr1 and Egr2 exert opposing influences on adipocyte differentiation and that the careful regulation of both is required for maintaining appropriate levels of adipogenesis. Further, the pro-differentiation effects of IBMX involve suppression of the inhibitory influence of Egr1.

Bed occupancy and incidence of Methicillin-resistant Staphylococcus aureus infection in an intensive care unit.

Methicillin-resistant Staphylococcus aureus (MRSA) incidence and workload as reflected by daily bed occupancy were assessed retrospectively over a 12-month period in a mixed adult ICU. All MRSA positive results were retrieved from the Microbiology Department; patients with MRSA were divided into those whose admission swabs were positive and those whose specimens subsequently became positive. There were 619 admissions, 48 of which had MRSA on admission (7.8% incidence) and 16 new MRSA infections in ICU (total incidence 10.3%). The frequency of MRSA acquisition was significantly higher on days when more than seven beds were occupied (0.0090 vs 0.0059 new acquisitions per patient per day, respectively, p = 0.015). In this well staffed but physically small unit local routes of infection transmission may be relevant.

Modelling patient flows as an aid to decision making for critical care capacities and organisation.

Using real data from a number of hospitals, we predicted the patient flows following a capacity or organisational change. Clinically recognisable patient groups obtained through classification and regression tree analysis were used to tune a simulation model for the flow of patients in critical care units. A tuned model which accurately reflected the base case of the flow of patients was used to predict alterations in service provision in a number of scenarios which included increases in bed numbers, alterations in patients' lengths of stay, fewer delayed discharges, caring for long stay patients outside the formal intensive care unit and amalgamating small units. Where available the predictions' accuracy was checked by comparison with real hospital data collected after an actual capacity change. The model takes variability and uncertainty properly into account and it provides the necessary information for making better decisions about critical care capacity and organisation.

Determinants of hospital costs associated with traumatic brain injury in England and Wales.

Using data from the Trauma Audit Research Network, we investigated the costs of acute care in patients > or = 18 years of age hospitalised for traumatic brain injury between January 2000 and December 2005 in England and Wales. Traumatic brain injury patients were defined and stratified using the Abbreviated Injury Scale. A total of 6484 traumatic brain injury patients were identified; 22.3% had an Abbreviated Injury Scale score of three, 38.0% of four and 39.7% of five. Median age (IQR) was 42 years (28-59) and 76.7% were men. Primary cause of injury was motor vehicle collisions (42.4%) followed by falls (38.0%). In total 23.7% of the patients died before discharge. Hospitalisation costs averaged 15,462 pounds sterling (SD 16,844 pounds sterling). Costs varied significantly by age, Glasgow Coma Score, Injury Severity Score, coexisting injuries of the thorax, spine and lower limb, hospital mortality, availability of neurosurgical services, and specialty of attendants seen in the Accident and Emergency department.

Drotrecogin alfa (activated): diffusion from clinical trials to clinical practice.

BACKGROUND AND OBJECTIVE: Although the PROWESS trial demonstrated a mortality benefit, subsequent studies in different patient populations have not reproduced the effect. As a result, concerns have been expressed about the clinical effectiveness of drotrecogin alfa (activated). Therefore the aim of this audit was to review the clinical impact of drotrecogin alfa (activated) when used outside clinical trials. METHODS: A retrospective review of ICU charts and medical records of patients who had received drotrecogin alfa (activated) in the five largest users of drotrecogin alfa (activated) in England. Patients characteristics details at ICU admission and vital status at hospital discharge were recorded. The severity of illness was assessed by the APACHE II score (using first 24 h admission data) and the number of organ dysfunctions. Adverse incidents were recorded and any sequence effect explored. RESULTS: In all, 351 patients received drotrecogin alfa (activated) between December 2002 and November 2005. Of those, 201 (57.2%) were male, and 177 (50.4%) were admitted after recent surgery. The patients' average age was 61.8 yr. The mean admission APACHE II score was 23.3 and the average number of dysfunctional organs on admission was 3.3. The hospital mortality was 46.7% (164 deaths). The expected number of deaths calculated by using the APACHE II risk of death was 173 (49.3%) and by number of sepsis induced organ failures 210 (59.7%). Overall, there were 33 (9.4%) adverse incidents. CONCLUSIONS: Expected mortality derived from both the APACHE II score and organ dysfunctions suggests that drotrecogin alfa (activated) does reduce mortality. Serious adverse incidents occurred in 5.1% patients; however, the direct contributing effect of drotrecogin alfa (activated) cannot be established from this type of audit.

Cost effectiveness of adult intensive care in the UK.

We wished to investigate whether intensive care represents good value for money to the National Health Service in the UK using cost-effectiveness analysis. We developed a cost-effectiveness model using secondary data sources to estimate the incremental cost per quality adjusted life year gained of treatment in intensive care vs non-intensive care treatment in adults. Estimates of hospital mortality with and without intensive care were obtained from seven published studies and from data published by the Intensive Care National Audit and Research Centre. Quality of life estimates were obtained from a literature review and NHS reference costs were used. Relative to non-intensive care treatment, the incremental cost per quality adjusted life year gained of treatment in intensive care is 7010 pounds. This figure is sensitive to the mortality risk reduction associated with intensive care. Despite the high daily cost of intensive care, its cost-effectiveness is excellent and compares favourably with other commonly used health interventions. Our findings suggest that adult intensive care represents good value for money.

Cost effectiveness of recombinant activated factor VII for the control of bleeding in patients with severe blunt trauma injuries in the United Kingdom.

The aim of this study was to assess the lifetime cost effectiveness of recombinant activated factor VII vs placebo as adjunctive therapy for control of bleeding in patients with severe blunt trauma in the UK. We developed a cost-effectiveness model based on patient level data from a 30-day international, randomised, placebo-controlled Phase II trial. The data were supplemented with secondary data from UK sources to estimate lifetime costs and benefits. The model produced a baseline estimate of the incremental cost per life year gained with recombinant activated factor VII relative to placebo of 12 613 UK pounds. The incremental cost per quality adjusted life year gained was 18 825 UK pounds. These estimates are sensitive to the choice of discount rate and health state utility values used. Preliminary results suggest that relative to placebo, recombinant activated factor VII may be a cost-effective therapy to the UK National Health Service.

Variation in end-of-life decision making between critical care consultants.

Considerable variation in end-of-life decision making is reported between intensive care units in the United Kingdom, possibly because of differences in casemix. Senior medical staff within any one unit should, however, be consistent in such decision making. We reviewed the medical records for a 4-year period to establish if there was consistency in our own unit. This revealed considerable variation in the apparent willingness of consultants to make end-of-life decisions, emphasising the subjective nature of these decisions. Personality typing (Myers-Briggs Type Indicator) of consultants revealed that those who had made more than the expected number of decisions had scores towards the judging end of the judging/perceiving domain.

UK guidance for non-heart-beating donation.

This guidance offers consensus opinion on the optimum management of non-heart-beating organ donation in adult critical care units. The guidance is not meant to dictate practice but rather to offer suggestions as to what might be considered reasonable practice. The following sections mainly relate to the medical aspects of non-heart-beating organ donation. Fuller guidance on other aspects of organ and tissue donation is available on the Society's website (www.ics.ac.uk). There are a number of parallel areas of work, such as the law on consent, the definition of death and revision of the original Code of Practice describing brainstem testing, which means that many aspects of organ donation are changing rapidly. This guidance is designed to help critical care practitioners while these issues are resolved.

Modelling the impact of an influenza pandemic on critical care services in England.

The UK Influenza Pandemic Contingency Plan does not consider the impact of a pandemic on critical care services. We modelled the demand for critical care beds in England with software developed by the Centers for Disease Control (Flusurge 1.0), using a range of attack rates and pandemic durations. Using inputs that have been employed in UK Department of Health scenarios (25% attack rate and 8-week pandemic duration) resulted in a demand for ventilatory support that exceeded 200% of present capacity. Demand remained unsustainably high even when more favourable scenarios were considered. Current critical care bed capacity in England would be unable to cope with the increased demand provided by an influenza pandemic. Appropriate contingency planning is essential.

Cost effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom.

Drotrecogin alfa (activated) is licensed in Europe for the treatment of severe sepsis in patients with multiple organ failure. We constructed a model to assess the cost effectiveness of drotrecogin alfa (activated) from the perspective of the UK National Health Service when used in adult intensive care units. Patient outcomes from a 28-day international clinical trial (PROWESS) and a subsequent follow-up study (EVBI) were supplemented with UK data. Cost effectiveness was assessed as incremental cost per life year and per quality adjusted life year saved compared to placebo alongside best usual care. Applying the 28-day mortality outcomes of the PROWESS study, the model produced a cost per life year saved of 4608 UK pounds and cost per quality adjusted life year saved of 6679 UK pounds. Equivalent results using actual hospital outcomes were 7625 UK pounds per life year and 11,051 UK pounds per quality adjusted life year. Drotrecogin alfa (activated) appears cost effective in treating severe sepsis in UK intensive care units.

Prescription errors in UK critical care units.

Drug prescription errors are a common cause of adverse incidents and may be largely preventable. The incidence of prescription errors in UK critical care units is unknown. The aim of this study was to collect data about prescription errors and so calculate the incidence and variation of errors nationally. Twenty-four critical care units took part in the study for a 4-week period. The total numbers of new and re-written prescriptions were recorded daily. Errors were classified according to the nature of the error. Over the 4-week period, 21,589 new prescriptions (or 15.3 new prescriptions per patient) were written. Eighty-five per cent (18,448 prescriptions) were error free, but 3141 (15%) prescriptions had one or more errors (2.2 erroneous prescriptions per patient, or 145.5 erroneous prescriptions per 1000 new prescriptions). The five most common incorrect prescriptions were for potassium chloride (10.2% errors), heparin (5.3%), magnesium sulphate (5.2%), paracetamol (3.2%) and propofol (3.1%). Most of the errors were minor or would have had no adverse effects but 618 (19.6%) errors were considered significant, serious or potentially life threatening. Four categories (not writing the order according to the British National Formulary recommendations, an ambiguous medication order, non-standard nomenclature and writing illegibly) accounted for 47.9% of all errors. Although prescription rates (and error rates) in critical care appear higher than elsewhere in hospital, the number of potentially serious errors is similar to other areas of high-risk practice.

Cardiac scoring systems--what is their value?

Estimating the peri-operative risk of major adverse cardiac events is one of the functions of cardiac risk scoring systems. Fortunately, peri-operative cardiac complications are relatively infrequent in most patients. Clinical algorithms use sequential screening tests to detect patients most at risk of cardiac complications. However, because the sensitivity and specificity of the tests used are low, the predictive performance of the commonly-used cardiac screening tests may not be completely satisfactory. The purpose of this review is to describe measures of performance of cardiac screening tests and illustrate their potential benefits and weaknesses.

A near fatal case of the dapsone hypersensitivity syndrome in a patient with urticarial vasculitis.

Dapsone (4,4'-diaminodiphenyl sulphone) is used for a variety of dermatological conditions including immunobullous diseases and urticarial vasculitis. Side-effects are common and include lethargy, headaches, methaemoglobinaemia and haemolysis. Severe adverse effects are rare but the dapsone hypersensitivity syndrome is well recognized. Symptoms include fever, haemolytic anaemia, lymphocytosis and hepatitis. We report a near fatal case of the dapsone hypersensitivity syndrome in a patient with urticarial vasculitis. This diagnosis should be remembered in any patient who becomes unwell whilst taking dapsone.

Long-term survival following intensive care: subgroup analysis and comparison with the general population.

This study aimed to compare the very long-term survival of critically ill patients with that of the general population, and examine the association among age, sex, admission diagnosis, APACHE II score and mortality. In a retrospective observational cohort study of prospectively gathered data, 2104 adult patients admitted to the intensive care unit (ICU) of a teaching hospital in Glasgow from 1985 to 1992, were followed until 1997. Vital status at five years was compared with that of an age- and sex-matched Scottish population. Five-year mortality for the ICU patients was 47.1%, 3.4 times higher than that of the general population. For those surviving intensive care the five-year mortality was 33.4%. Mortality was greater than that of the general population for four years following intensive care unit admission (95% confidence interval included 1.0 at four years). Multivariate analysis showed that risk factors for mortality in those admitted to ICU were age, APACHE II score on admission and diagnostic category. Mortality was higher for those admitted with haematological (87.5%) and neurological diseases (61.7%) and septic shock (62.9%). A risk score was produced: Risk Score = 10 (age hazard ratio + APACHE II hazard ratio + diagnosis hazard ratio). None of the patients with a risk score > 100 survived more than five years and for those who survived to five years the mean risk score was 57. Long-term survival following intensive care is not only related to age and severity of illness but also diagnostic category. The risk of mortality in survivors of critical illness matches that of the normal population after four years. Age, severity of illness and diagnosis can be combined to provide an estimate of five-year survival.