Real-time gait analysis with accelerometer-based smart shoes.

In this paper, we present the evaluation of a new smart shoe capable of performing gait analysis in real time. The system is exclusively based on accelerometers which minimizes the power consumption. The estimated parameters are activity class (rest/walk/run), step cadence, ground contact time, foot impact (zone, strength, and balance), forward distance, and speed. The different parameters have been validated with a customized database of 26 subjects on a treadmill and video data labeled manually. Key measures for running analysis such as the cadence is retrieved with a maximum error of 2%, and the ground contact time with an average error of 3.25%. The classification of the foot impact zone achieves a precision between 72% and 91% depending of the running style. The presented algorithm has been licensed to ICON Health & Fitness Inc. for their line of wearables under the brand iFit.

Real-time monitoring of swimming performance.

This article presents the performance results of a novel algorithm for swimming analysis in real-time within a low-power wrist-worn device. The estimated parameters are: lap count, stroke count, time in lap, total swimming time, pace/speed per lap, total swam distance, and swimming efficiency (SWOLF). In addition, several swimming styles are automatically detected. Results were obtained using a database composed of 13 different swimmers spanning 646 laps and 858.78 min of total swam time. The final precision achieved in lap detection ranges between 99.7% and 100%, and the classification of the different swimming styles reached a sensitivity and specificity above 98%. We demonstrate that a swimmers performance can be fully analyzed with the smart bracelet containing the novel algorithm. The presented algorithm has been licensed to ICON Health & Fitness Inc. for their line of wearables under the brand iFit.

Structured Frameworks to Increase the Transparency of the Assessment of Benefits and Risks of Medicines: Current Status and Possible Future Directions.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.

Managing Injuries of the Neck Trial (MINT): a randomised controlled trial of treatments for whiplash injuries.

OBJECTIVES: To examine the clinical effectiveness of a stepped care approach over a 12-month period after an acute whiplash injury; to estimate the costs and cost-effectiveness of each strategy including treatments and subsequent health-care costs; and to gain participants' perspective on experiencing whiplash injury, NHS treatment, and recovery within the context of the Managing Injuries of the Neck Trial (MINT). DESIGN: Two linked, pragmatic, randomised controlled trials. In Step 1, emergency departments (EDs) were cluster randomised to usual care advice (UCA) or The Whiplash Book advice (WBA)/active management advice. In Step 2, participants were individually randomised to either a single session of advice from a physiotherapist or a physiotherapy package of up to six sessions. An economic evaluation and qualitative study were run in parallel with the trial. SETTING: Twelve NHS trusts in England comprising 15 EDs. PARTICIPANTS: People who attended EDs with an acute whiplash injury of whiplash-associated disorder grades I-III were eligible for Step 1. People who had attended EDs with whiplash injuries and had persistent symptoms 3 weeks after ED attendance were eligible for Step 2. INTERVENTIONS: In Step 1, the control intervention was UCA and the experimental intervention was a psycho-educational intervention (WBA/active management advice). In Step 2 the control treatment was reinforcement of the advice provided in Step 1 and the experimental intervention was a package of up to six physiotherapy treatments. MAIN OUTCOME: The primary outcome was the Neck Disability Index (NDI), which measures severity and frequency of pain and symptoms, and a range of activities including self-care, driving, reading, sleeping and recreation. Secondary outcomes included the mental and physical health-related quality-of-life (HRQoL) subscales of the Short Form questionnaire-12 items (SF-12) and the number of work days lost. RESULTS: A total of 3851 patients were recruited to Step 1 of the trial. 1598 patients attending EDs were randomised to UCA, and 2253 were randomised to WBA/active management. Outcome data were obtained at 12 months for 70% and 80% of participants at Step 1 and Step 2, respectively. The majority of people recovered from the injury. Eighteen per cent of the Step 1 cohort had late whiplash syndrome. There was no statistically or clinically significant difference observed in any of the outcomes for participants attending EDs randomised to UCA or active management advice [difference in NDI 0.5, 95% confidence interval (CI) -1.8 to 2.8]. In Step 2 the physiotherapy package resulted in improvements in neck disability at 4 months compared with a single advice session, but these effects were small at the population level (difference in NDI -3.2, 95% CI -5.8 to -0.7). The physiotherapy package was accompanied by a significant reduction in the number of work days lost at 4-month follow-up (difference -40.2, 95% CI -44.3 to -35.8). CONCLUSIONS: MINT suggests that enhanced psycho-educational interventions in EDs are no more effective than UCA in reducing the burden of acute whiplash injuries. A physiotherapy package provided to people who have persisting symptoms within the first 6 weeks of injury produced additional short-term benefits in neck disability compared with a single physiotherapy advice session. However, from a health-care perspective, the physiotherapy package was not cost-effective at current levels of willingness to pay. Both experimental treatments were associated with increased cost with no discernible gain in health-related quality of life. However, an important benefit of the physiotherapy package was a reduction in work days lost; consequently, the intervention may prove cost-effective at the societal level. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33302125. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 49. See the HTA programme website for further project information.

Development of a novel immunoassay for the iron regulatory peptide hepcidin.

To date there have been few published immunoassays for the important iron regulator hepcidin. This study describes a novel competitive radioimmunoassay (RIA) for the bioactive hepcidin peptide. A rabbit anti-hepcidin polyclonal antibody was produced using synthetic hepcidin radiolabelled with 125I to produce a competitive RIA. Normal patient (n=47) samples were collected and assayed for hepcidin to determine a reference range. Other patient groups collected were ulcerative colitis (UC; n=40), iron deficiency anaemia (IDA; n=15), chronic kidney disease not requiring dialysis (CKD; n=45) and chronic kidney disease requiring dialysis (HCKD; n=94). Detection limit of the assay was determined as 0.6 ng/mL. Intra-assay precision was 5 ng/mL (7.2%) and 50 ng/mL (5.8%), interassay precision was 5 ng/mL (7.6%) and 50 ng/mL (6.7%). Analytical recovery was 98% (5 ng/mL), 94% (10 ng/mL) and 97% (50 ng/mL). The assay was linear up to 200 ng/mL. No demonstrable cross-reactivity with human insulin, glucagon I, angiotensinogen I, beta-defensin 1-4, alpha-defensin-1 and plectasin was observed. There was significant correlation (r=0.96, P < or = 0.0001) between the hepcidin RIA and an established hepcidin SELDI-TOF-MS method. Analysis of the normal human samples gave a reference range of 1.1-55 ng/mL for hepcidin. Further statistical evaluation revealed a significant difference between male and female hepcidin levels. There was significant correlation between hepcidin and ferritin in the control group (r=0.6, P < or = 0.0001). There was also a significant difference between the normal and disease groups (P < or = 0.0001). Healthy volunteers (n=10) showed a diurnal increase in plasma hepcidin at 4.00 pm compared to 8.00 am. A robust and optimised immunoassay for bioactive hepcidin has been produced and the patient sample results obtained further validates the important role of hepcidin in iron regulation, and will allow further investigation of this important peptide and its role in iron homeostasis.

Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

OBJECTIVES: To determine whether GPs should advise their older patients with chronic knee pain to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs). DESIGN: An equivalence study was designed to compare the effect of advice to use preferentially oral or topical ibuprofen (an NSAID) on knee pain and disability, NSAID-related adverse effects and NHS/societal costs, using a randomised controlled trial (RCT) and a patient preference study (PPS). Reasons for patient preferences for topical or oral preparations, and attitudes to adverse effects, were explored in a qualitative study. SETTING: Twenty-six general practices in the UK. PARTICIPANTS: Participants comprised 585 people with knee pain, aged 50 years or over; 44% were male, mean age 64 years. The RCT had 282 participants: 144 in the oral group and 138 in the topical group. The PPS had 303 participants: 79 in the oral group and 224 in the topical group. INTERVENTIONS: Advice to use preferentially oral or topical NSAIDs for knee pain. OUTCOME MEASURES: The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcome measures were the Short Form with 36 Items (SF-36), perceived troublesomeness of knee pain, satisfaction with health status, major adverse effects (unplanned hospital admissions and deaths) and minor adverse events over 12 months. The health economic analysis measured the comparative cost per quality-adjusted life-year (QALY) from both an NHS and a societal perspective over 1 and 2 years. RESULTS: Changes in the global WOMAC score at 12-months were equivalent in both studies: topical - oral, RCT difference=2 [95% confidence interval (CI) -2 to 6], PPS difference=1 (95% CI -4 to 6). There were no differences in the secondary outcomes, except for a suggestion, in the RCT, that those in the topical group were more likely to have more severe overall pain and disability as measured by the chronic pain grade, and more likely to report changing treatment because of inadequate pain relief. There were no differences in the rate of major adverse effects but some differences in the number of minor ones. In the RCT, 17% and 10% in the oral and the topical group, respectively, had a defined respiratory adverse effect (95% CI of difference -17% to -2.0%); after 12 months, the change in serum creatinine was 3.7 mmol/l (95% CI 0.9 to 6.5) less favourable in the oral than in the topical group, and 11% of those in the oral group reported changing treatment because of adverse effects compared with 1% in the topical group (p=0.02). None of these differences were seen in the PPS. Oral NSAIDs cost the NHS 191 pounds and 72 pounds more per participant over 1 year in the RCT and PPS respectively. In the RCT the cost per QALY in the oral group, from an NHS perspective, was in the range 9000-12,000 pounds. In the PPS it was 2564 pounds over 1 year, but over 2 years the oral route was more cost-effective. Patient preference for medication type was affected by previous experience of medication (including adverse reactions), other illness, pain elsewhere, anecdotes, convenience, severity of pain and perceived degree of degeneration. Lack of understanding about knee pain and the action of medication led to increased tolerance of symptoms. Potentially important symptoms may inadvertently have been disregarded, increasing participants' risk of suffering a major adverse effect. CONCLUSIONS: Advice to use either oral or topical preparations has an equivalent effect on knee pain, but oral NSAIDs appear to produce more minor adverse effects than topical NSAIDs. Generally, these results support advising older people with knee pain to use topical rather than oral NSAIDS. However, for patients who prefer oral NSAID preparations rather than a topical NSAID, particularly those with more widespread or severe pain, the oral route is a reasonable treatment option, provided that patients are aware of the risks of potentially serious adverse effects from oral medication. Further research is needed into strategies to change prescribing behaviour and ensure that older patients are aware of the potential risks and benefits of using NSAIDs. Observational studies are needed to estimate rates of different predefined minor adverse effects associated with the use of oral NSAIDs in older people as are long-term studies of topical NSAIDs in those for whom oral NSAIDs are not appropriate.

Chronic forearm pain presents as a transient and indistinct pain site in a community setting: results from a UK population survey.

OBJECTIVES: To investigate the prevalence of chronic forearm pain in a non-occupational community setting over a 2-year period. METHOD: A longitudinal community-based postal questionnaire survey conducted in the south-eastern quadrant of England. RESULTS: We received 2493/4172 (60%) responses at baseline and we followed up 429 of these 2 years later: 252 responded (59%). Forearm pain prevalence was 4% at baseline and 5% at follow-up. Over 95% of those with forearm pain had pain in other areas [odds ratio 1.5 (95% confidence interval 1.3-1.7)] and it was most commonly associated with elbow and wrist pain. Seventy-six per cent of those with forearm pain at baseline recovered. At follow-up, 78% of those with chronic forearm pain had new-onset forearm pain. CONCLUSIONS: Persistent forearm pain (pain for over 2 years) was rare and the capacity for recovery was good (76%). Isolated forearm pain as a diagnostic category is of little utility. Treating and managing forearm pain in a site-specific manner is unlikely to be successful owing to its strong association with pain in other areas. In the community, forearm pain laterality was not evident; our findings suggest that forearm pain in the workplace is influenced by different factors to those in a community setting.

Aqueous microsolvation of mercury halide species.

The effects of aqueous solvation on the thermochemistry of reactions between mercury and small halogen molecules has been investigated by the microsolvation approach using ab initio and density functional theory (DFT) calculations. The structures, vibrational frequencies, and binding energies of 1, 2, and 3 water molecules with mercury-halide (HgBr2, HgBrCl, HgCl2, HgBr, and HgCl) and related mercury and halogen species (Br2, BrCl, Cl2, Cl, Hg, and Br) have been computed with second order Møller-Plesset perturbation theory (MP2) and the B3LYP density functional method. Accurate incremental water binding energies have been obtained at the complete basis set (CBS) limit using sequences of correlation consistent basis sets, including higher order correlation effects estimated from coupled cluster calculations. The resulting energetics were used to calculate the influence of water molecules on the thermochemistry of a number of reactions between mercury and small halogen-containing molecules. In general, the presence of water favors the formation of oxidized mercury halide species.

Chronic musculoskeletal pain rarely presents in a single body site: results from a UK population study.

OBJECTIVE: To investigate the frequency and health impact of chronic multi-site musculoskeletal pain, in a representative UK sample. METHOD: Population postal questionnaire survey, using 16 general practices in the southeast of England, nationally representative urban/rural, ethnic and socioeconomic mix. A random selection of 4049 registered patients, aged 18 or over, were sent a questionnaire. The main outcome measures were chronic pain location, identified using a pain drawing; distress, pain intensity and disability as measured by the GHQ12 and the Chronic Pain Grade. RESULTS: A total of 2445 patients (60%) responded to the survey (44% male, mean age 52 yrs); 45% had chronic musculoskeletal pain. Of those with chronic pain, three quarters had pain in multiple sites (two or more sites). Variables significantly predicting this were: age under 55, [odds ratio (OR) 0.5, 95% confidence interval (CI) 0.4, 0.6]; psychological distress (OR 1.8, CI at 95% 1.4, 2.2) and high pain intensity (OR 5.2, CI at 95% 4.1, 6.7). Only 33% of multi-site pain distributions conformed to the American College of Rheumatology definition of chronic widespread pain. CONCLUSIONS: Multi-site chronic pain is more common than single-site chronic pain and is commonly associated with other problems. Indiscriminate targeting of research and care for chronic musculoskeletal pain on single sites may often be inappropriate.

Recent progress in PYY research--an update report for 8th NPY meeting.

UNLABELLED: PYY(3-36) is a gut regulatory peptide which has recently been found to reduce appetite. Variability of this effect across different experimental conditions has led to confusion and polarization of opinion on its potential as an anti-obesity treatment. This review summarizes recent progress in this area. The basic anorexigenic effect leading to weight loss in rodents has now been confirmed by several groups. Anorexia has also been confirmed in human studies although optimal route and dosing remain to be defined. Gastric bypass causes PYY levels to rise, which may in part mediate the weight loss occurring after this surgery, and levels have been found to be normal or low in obese people. The straightforward ARC model of mechanism, involving inhibition and activation, respectively, of NPY and POMC neurons, is giving way to a more complicated system involving vagal afferent signals. CONCLUSION: It works, but not how we thought it did.

Orthodontic treatment for posterior crossbites.

BACKGROUND: 'Posterior crossbite' occurs when the top back teeth bite inside the bottom back teeth. When it affects one side of the mouth the lower jaw may have to move to one side to allow the back teeth to meet together. It is unclear what causes posterior crossbites and they may develop or improve at any time from when the baby teeth come into the mouth to when the adult teeth come through. Several treatments have been recommended to correct this problem. Some treatments widen the upper teeth whilst others are directed at treating the cause of the posterior crossbite e.g. breathing problems or sucking habits. Most treatments have been used at each stage of dental development. OBJECTIVES: The aim of this review was to evaluate orthodontic treatments used to expand the maxillary dentition and correct posterior crossbites. SEARCH STRATEGY: All randomised and controlled clinical trials identified from the Cochrane Controlled Trials Register according to the Oral Health Group Search Strategy and stored in the Cochrane Collaboration Oral Health Group Database of Clinical Trials, a MEDLINE search using the Mesh term Palatal Expansion Technique and relevant free text words, hand searching the British, European and American journals of orthodontics and Angle Orthodontist, and the bibliographies of papers and review articles which reported the outcome of orthodontic treatment to expand the maxillary dentition and/or correct a posterior crossbite that were published as abstracts or papers between 1970 and 1999. SELECTION CRITERIA: All randomised and controlled clinical trials published as full papers or abstracts which reported quantitative data on the outcomes crossbite correction, molar and/or canine expansion, signs and symptoms of temporomandibular joint dysfunction or respiratory disease. DATA COLLECTION AND ANALYSIS: Data were extracted without blinding to the authors, treatments used or results obtained. The first named authors of randomised and controlled clinical trials were written to in an attempt to establish the method of randomisation / allocation and identify unpublished studies. Odds ratio, relative risk, relative risk reduction, absolute risk reduction, the number need to treat and corresponding 95% confidence intervals, were calculated for event data. The weighted mean difference and 95% confidence intervals were calculated for continuous data. MAIN RESULTS: Using the search strategy seven randomised and five controlled clinical trials were identified but following correspondence with the authors, three of the randomised and one of the controlled clinical trials were reclassified giving five randomised and seven controlled clinical trials for inclusion in the review. For the update an additional CCT was found giving five RCTs and eight CCTs for inclusion in this update. Trials comparing occlusal grinding in the primary dentition with/without an upper removable expansion appliance in the mixed dentition versus no treatment, banded versus bonded and two point versus four point rapid maxillary expansion, banded versus bonded slow maxillary expansion, transpalatal arch with/without buccal root torque, an upper removable expansion appliance versus quad-helix were identified. Occlusal grinding in the primary dentition with/without the addition of an upper removable expansion plate, in the mixed dentition for those children who did not respond to grinding, was shown to be effective in preventing a posterior crossbite in the primary dentition from being perpetuated to the mixed and permanent dentitions. No evidence of a difference in treatment effect (molar and canine expansion) between the test and control intervention was found in the trials which compared banded versus bonded and two point versus four point rapid maxillary expansion, banded versus bonded slow maxillary expansion, transpalatal arch with/without buccal root torque, or upper removable expansion appliance versus quad-helix. Insufficient data were provided in the paper comparing two point versus four point rapid maxillary expansion to allow a formal analysis. REVIEWER'S CONCLUSIONS: The evidence from the trials reported by Lindner (1989); Thilander (1984) suggests that removal of premature contacts of the baby teeth is effective in preventing a posterior crossbite from being perpetuated to the mixed dentition and adult teeth. When grinding alone is not effective, using an upper removable expansion plate to expand the top teeth will decrease the risk of a posterior crossbite from being perpetuated to the permanent dentition. The comparisons of treatments made in the trials reported by Asanza (1997); Sandikçioglu (1997); Mossaz-Joëlson (1989); Ingervall (1995); Schneidman (1990) were inconclusive so recommendations for clinical practice can not be made based on the results of these trials. (ABSTRACT TRUNCATED)

Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression.

The degree of immune recovery achievable with anti-human immunodeficiency virus (HIV) therapy remains to be established. The effects of potent antiretroviral therapy, including ritonavir and saquinavir, on immune function were studied for a prolonged period in 41 patients. After 96 weeks, 88% of patients had plasma HIV RNA levels below the limit of quantitation. There were continuous increases in CD4 lymphocyte counts and in CD4:CD8 ratios over time. About half the patients developed lymphoproliferative responses to HIV p24 antigen, and nearly all developed responses to phytohemagglutinin. This occurred in parallel with increases in interleukin-12 production and expression of CD28 on CD8 lymphocytes, despite potential antiproliferative effects of protease inhibitors. Transient increases in virus load were temporally associated with loss of proliferative responses. The improved immune function, including HIV-specific immunity in many subjects, demonstrates the potential reversibility of HIV-induced immunodeficiency and does not identify a limit to immune recovery.

Lack of effect of serum amyloid A (SAA) on the ability of high-density lipoproteins to inhibit endothelial cell adhesion molecule expression.

Studies have been conducted to determine whether the ability of high density lipoproteins (HDL) to inhibit the cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells is altered by the presence in HDL of the acute phase reactant, serum amyloid-A (SAA). Preparations of HDL(3) were isolated on two separate occasions from the plasma of each of 19 patients: the first was collected before and the second 3 days after undergoing coronary artery bypass graft surgery. Whereas the preoperative HDL(3) sample contained no SAA, in the postoperative sample SAA accounted for an average of 42% of the HDL(3) protein. The preoperative HDL(3) and postoperative, SAA-enriched HDL(3) were identical in terms of their ability to inhibit the tumour necrosis factor-alpha (TNF-alpha)-induced expression of VCAM-1 in human umbilical vein endothelial cells (HUVECs). To assess the effect of having an even greater SAA enrichment of HDL(3), samples of HDL(3) were incubated with purified SAA, which displaced almost all of the apoAI and about 40% of the apoAII from the HDL(3). This in vitro SAA-enriched HDL(3) inhibited the TNF-alpha-induced expression of VCAM-1 in HUVECs in a concentration dependent manner, which was identical to that of the unmodified HDL(3). The presence of SAA did not alter the cell-surface binding of HDL(3) to endothelial cells. It has been concluded that the presence of SAA in HDL has no effect on the ability of these lipoproteins either to inhibit the expression of VCAM-1 in endothelial cells or to bind to proteins on the endothelial cell surface.

Carboxymethylation of the PP2A catalytic subunit in Saccharomyces cerevisiae is required for efficient interaction with the B-type subunits Cdc55p and Rts1p.

Protein phosphatase 2A (PP2A) is an essential eukaryotic serine/threonine phosphatase known to play important roles in cell cycle regulation. Association of different B-type targeting subunits with the heterodimeric core (A/C) enzyme is known to be an important mechanism of regulating PP2A activity, substrate specificity, and localization. However, how the binding of these targeting subunits to the A/C heterodimer might be regulated is unknown. We have used the budding yeast Saccharomyces cerevisiae as a model system to investigate the hypothesis that covalent modification of the C subunit (Pph21p/Pph22p) carboxyl terminus modulates PP2A complex formation. Two approaches were taken. First, S. cerevisiae cells were generated whose survival depended on the expression of different carboxyl-terminal Pph21p mutants. Second, the major S. cerevisiae methyltransferase (Ppm1p) that catalyzes the methylation of the PP2A C subunit carboxyl-terminal leucine was identified, and cells deleted for this methyltransferase were utilized for our studies. Our results demonstrate that binding of the yeast B subunit, Cdc55p, to Pph21p was disrupted by either acidic substitution of potential carboxyl-terminal phosphorylation sites on Pph21p or by deletion of the gene for Ppm1p. Loss of Cdc55p association was accompanied in each case by a large reduction in binding of the yeast A subunit, Tpd3p, to Pph21p. Moreover, decreased Cdc55p and Tpd3p binding invariably resulted in nocodazole sensitivity, a known phenotype of CDC55 or TPD3 deletion. Furthermore, loss of methylation also greatly reduced the association of another yeast B-type subunit, Rts1p. Thus, methylation of Pph21p is important for formation of PP2A trimeric and dimeric complexes, and consequently, for PP2A function. Taken together, our results indicate that methylation and phosphorylation may be mechanisms by which the cell dynamically regulates PP2A complex formation and function.

Radiocontrast-induced acute renal failure: allocations and outcomes.

Radiocontrast-induced nephropathy causes significant morbidity and mortality with increase in hospital length of stay and costs. It can be largely prevented by identifying the patients at risk before the procedure. Once the at-risk patient is identified, ways to prevent the development of acute renal failure are: avoiding volume depletion, aggressive saline hydration with the aim of keeping the urine output over 150 mL/hour, and the use of low-osmolality contrast agents, with as little volume used as possible. There is theoretical potential for the dopamine DA1 agonist fenoldopam as a preventive agent, and this is currently being tested in randomized trials.

Evidence-based medicine as Bayesian decision-making.

We review two recent trends: the emergence of evidence-based medicine and the growing use of Bayesian statistics in medical applications. Evidence-based medicine requires an integrated assessment of the available evidence, and associated uncertainty, but there is also an emphasis on decision-making, for individual patients, or at other points in the health-care system. This demands consideration of the values and costs associated with potential outcomes. We argue that the natural statistical framework for evidence-based medicine is a Bayesian approach to decision-making that incorporates an integrated summary of the available evidence and associated uncertainty with assessment of utilities. We outline a practical agenda for further development.