Genetic analyses of the parasitic nematode, Parelaphostrongylus tenuis, in Missouri and Kentucky reveal unexpected levels of diversity and population differentiation.

Wildlife translocations, which involve the introduction of naive hosts into new environments with novel pathogens, invariably pose an increased risk of disease. The meningeal worm Parelaphostrongylus tenuis is a nematode parasite of the white-tailed deer (Odocoileus virginianus), which serves as its primary host and rarely suffers adverse effects from infection. Attempts to restore elk (Cervus canadensis) to the eastern US have been hampered by disease caused by this parasite. Using DNA sequence data from mitochondrial and nuclear genes, we examined the hypothesis that elk translocated within the eastern US could be exposed to novel genetic variants of P. tenuis by detailing the genetic structure among P. tenuis taken from white-tailed deer and elk at a source (Kentucky) and a release site (Missouri). We found high levels of diversity at both mitochondrial and nuclear DNA in Missouri and Kentucky and a high level of differentiation between states. Our results highlight the importance of considering the potential for increased disease risk from exposure to novel strains of parasites in the decision-making process of a reintroduction or restoration.

The nucleosome acidic patch directly interacts with subunits of the Paf1 and FACT complexes and controls chromatin architecture in vivo.

The nucleosome core regulates DNA-templated processes through the highly conserved nucleosome acidic patch. While structural and biochemical studies have shown that the acidic patch controls chromatin factor binding and activity, few studies have elucidated its functions in vivo. We employed site-specific crosslinking to identify proteins that directly bind the acidic patch in Saccharomyces cerevisiae and demonstrated crosslinking of histone H2A to Paf1 complex subunit Rtf1 and FACT subunit Spt16. Rtf1 bound to nucleosomes through its histone modification domain, supporting its role as a cofactor in H2B K123 ubiquitylation. An acidic patch mutant showed defects in nucleosome positioning and occupancy genome-wide. Our results provide new information on the chromatin engagement of two central players in transcription elongation and emphasize the importance of the nucleosome core as a hub for proteins that regulate chromatin during transcription.

The nucleosome DNA entry-exit site is important for transcription termination and prevention of pervasive transcription.

Compared to other stages in the RNA polymerase II transcription cycle, the role of chromatin in transcription termination is poorly understood. We performed a genetic screen in Saccharomyces cerevisiae to identify histone mutants that exhibit transcriptional readthrough of terminators. Amino acid substitutions identified by the screen map to the nucleosome DNA entry-exit site. The strongest H3 mutants revealed widespread genomic changes, including increased sense-strand transcription upstream and downstream of genes, increased antisense transcription overlapping gene bodies, and reduced nucleosome occupancy particularly at the 3' ends of genes. Replacement of the native sequence downstream of a gene with a sequence that increases nucleosome occupancy in vivo reduced readthrough transcription and suppressed the effect of a DNA entry-exit site substitution. Our results suggest that nucleosomes can facilitate termination by serving as a barrier to transcription and highlight the importance of the DNA entry-exit site in broadly maintaining the integrity of the transcriptome.

Swallowing problems in Parkinson disease: frequency and clinical correlates.

BACKGROUND: Changes to the efficiency and integrity of swallowing mechanisms are inevitable in Parkinson disease (PD); however, it remains unclear how many people with PD are at risk of dysphagia. The aim of this study was to establish the frequency of impaired swallowing in people with PD and the relationship between swallowing performance and indicators of disease progression. METHODS: A community-based and hospital-based cohort of 137 individuals with PD were asked to drink 150 ml of water as quickly as possible while in an 'off drug' state. RESULTS: Thirty-one (23%) patients could not completely drink the full 150 ml. Swallowing rate (ml/sec) fell to more than 1 SD below published norms for 115 (84%) patients and to more than 2SD below for 44 (32%) individuals. There were moderate correlations between rate of swallowing and disease severity, depression and cognition, but not between swallowing speed and disease duration. There was poor correlation between subjective reports of dysphagia and performance on the water swallow test. CONCLUSIONS: Swallowing problems are frequent in PD. Self-report of 'no difficulty' is not a reliable indicator of swallowing ability. Studies employing more-objective assessment of aspiration risk to compare with water swallow test performance are advocated.

Can we perceptually rate alaryngeal voice? Developing the Sunderland Tracheoesophageal Voice Perceptual Scale.

OBJECTIVE: To investigate the inter and intra reliability of raters (in relation to both profession and expertise) when judging two alaryngeal voice parameters: 'Overall Grade' and 'Neoglottal Tonicity'. Reliable perceptual assessment is essential for surgical and therapeutic outcome measurement but has been minimally researched to date. DESIGN: Test of inter and intra rater agreement from audio recordings of 55 tracheoesophageal speakers. SETTING: Cancer Unit. PARTICIPANTS: Twelve speech and language therapists and ten Ear, Nose and Throat surgeons. MAIN OUTCOME MEASURES: Perceptual voice parameters of 'Overall Grade' rated with a 0-3 equally appearing interval scale and 'Neoglottal Tonicity' with an 11-point bipolar semantic scale. RESULTS: All raters achieved 'good' agreement for 'Overall Grade' with mean weighted kappa coefficients of 0.78 for intra and 0.70 for inter-rater agreement. All raters achieved 'good' intra-rater agreement for 'Neoglottal Tonicity' (0.64) but inter-rater agreement was only 'moderate' (0.40). However, the expert speech and language therapists sub-group attained 'good' inter-rater agreement with this parameter (0.63). The effect of 'Neoglottal Tonicity' on 'Overall Grade' was examined utilising only expert speech and language therapists data. Linear regression analysis resulted in an r-squared coefficient of 0.67. Analysis of the perceptual impression of hypotonicity and hypertonicity in relation to mean 'Overall Grade' score demonstrated neither tone was linked to a more favourable grade (P = 0.42). CONCLUSIONS: Expert speech and language therapist raters may be the optimal judges for tracheoesophageal voice assessment. Tonicity appears to be a good predictor of 'Overall Grade'. These scales have clinical applicability to investigate techniques that facilitate optotonic neoglottal voice quality.

Entry site neovascularization and vitreous cavity hemorrhage after diabetic vitrectomy. The predictive value of inner sclerostomy site ultrasonography.

OBJECTIVE: To assess the incidence of neovascularization of the inner sclerostomy wound and occurrence of postoperative vitreous cavity hemorrhage (POVCH) after vitrectomy for proliferative diabetic retinopathy (PDR). DESIGN: Consecutive prospective longitudinal clinical study. PARTICIPANTS: Seventy-three eyes (58 patients) undergoing primary vitrectomy for PDR. METHODS: Twenty-megahertz (MHz) high-resolution anterior segment ultrasonography was performed on all sclerostomy sites 2 months postoperatively and repeated at the time of any POVCH. The appearance of the inner sclerostomy wound was divided into 4 classes (normal, spheroidal, tent, and trapezoidal, representing entry site neovascularization). The occurrence, degree, and duration of POVCH and need for revision surgery with vitreous cavity washout (VCW) were recorded. Postoperative vitreous cavity hemorrhage was divided into 3 groups-namely, mild, moderate, and major. MAIN OUTCOME MEASURES: Inner sclerostomy wound appearance on ultrasonography, degree and timing of POVCH, and need for VCW. RESULTS: There were 15 eyes in total with POVCH (20%): one patient had a persistent POVCH that required VCW. Fourteen other eyes (19%) had recurrent POVCH. Four (28%) of these 14 eyes with recurrent POVCH were classified as mild and 3 (21%) moderate: all cleared spontaneously with no further intervention needed. None of these had a trapezoidal image. Seven of the 14 eyes with recurrent POVCH were classified as major. Five of these 7 eyes had a trapezoidal image at 2 months postoperatively, and 4 required VCW (5.5% of total no. of eyes in study). All patients with a trapezoidal image experienced some degree of recurrent vitreous cavity hemorrhage (P = 0.0000024). The odds ratio was approximately 330:1. There was a significant correlation between the severity of POVCH and entry site appearance on ultrasound. In the first year of follow-up, all patients requiring VCW after recurrent POVCH had a trapezoidal image present at 2 months postoperatively (P = 0.009). CONCLUSION: The appearance of a trapezoidal image on 20-MHz high-resolution anterior segment ultrasonography at a sclerostomy site after vitrectomy for PDR was highly correlated with the occurrence of nonclearing POVCH and need for VCW. Conversely, the absence of a trapezoidal image in patients with POVCH was associated with spontaneous hemorrhage clearance.

A randomised controlled trial of early versus delayed oxytocin augmentation to treat primary dysfunctional labour in nulliparous women.

BACKGROUND: Oxytocin is widely used to speed up slow labour, especially in nulliparous women, but randomised trials, apart from one reported only in abstract, have been too small to exclude important effects. OBJECTIVE: To test the hypothesis that early use of oxytocin reduces the need for caesarean delivery. DESIGN: A randomised controlled trial. SETTING: Twelve obstetric units within the Northern and Yorkshire regions in the North East of England. PARTICIPANTS: A total of 412 low-risk nulliparous women in spontaneous labour at term, who had been diagnosed with primary dysfunctional labour were recruited from January 1999 to December 2001. INTERVENTION: Immediate oxytocin administration (active group) or oxytocin withheld for up to 8 hours (conservative group). MAIN OUTCOME MEASURES: Caesarean section and operative vaginal delivery rates. The length of labour measured from the time of randomisation to delivery. The rate of maternal Edinburgh Postnatal Depression Scale (EPDS) greater than 12 (major depression) within 48 hours of delivery. RESULTS: The caesarean section rates were 13.5% active versus 13.7% controls (OR 0.98, 95% CI 0.6-1.7). Operative delivery, 24.5% versus 30.9% (OR 0.73, 95% CI 0.5-1.1). The median (interquartile range) randomisation to delivery interval in the active group was 5 hours 52 minutes (3:57-8:28) and in the conservative group 9 hours 8 minutes (5:06-13:16) (P < 0.001). The rate of EPDS >12 was 20% in the active arm versus 15% among controls (OR 1.26, 95% CI 0.7-2.2). There was one perinatal death in each group and no major differences in perinatal outcomes. CONCLUSIONS: Among nulliparous women with primary dysfunctional labour, early use of oxytocin does not reduce caesarean section or short-term postnatal depression. However, it shortens labour considerably and may reduce operative vaginal deliveries.

Morbid obesity and intra-partum care.

Obesity is a major health problem in the developed world and is beginning to have an impact on pregnancy (CEMACH 2004). We aimed to examine the differences in the intra-partum care of morbidly obese women compared with those of normal weight women. Intra-partum variables of labour monitoring as well as anaesthetic and neonatal variables were compared between 50 morbidly obese and 50 normal weight women. The morbidly obese group was observed to be significantly more prone to invasive fetal monitoring (27% vs 0%, p

Measuring symptom load in Idiopathic Parkinson's disease.

This study evaluated the symptom burden experienced by patients with Idiopathic Parkinson's Disease (IPD) by using a standard palliative care assessment tool (PACA) and comparing it with the Unified Parkinson's Disease Rating Scale (UPDRS). These tools together with the Mini-Mental State Examination, Beck Depression Inventory and the Schedule for the Evaluation of Individual Quality of Life were used in 123 IPD patients. The PACA demonstrated broad coverage of both motor and non motor symptoms (mean=14.3 symptoms per patient) whereas the UPDRS predominantly assessed motor symptoms. Implications for symptom assessment and palliative care provision in IPD are discussed.

A transcriptional switch controls meiosis.

A key protein involved in the segregation of meiotic chromosomes is produced 'just in time' by the regulated expression of two mRNA isoforms.

Double masked randomised controlled trial to assess the effectiveness of paracetamol in reducing pain in panretinal photocoagulation.

AIM: To assess the effectiveness of pre-emptive analgesia with paracetamol in reducing pain associated with panretinal photocoagulation (PRP) in a prospective, double masked, randomised controlled trial. METHOD: 60 patients undergoing PRP for the first time were enrolled and randomised to paracetamol or placebo, taken for 2 days starting 24 hours before the laser treatment. The laser treatment was performed following a standardised protocol. Pain during and after treatment was assessed using the McGill pain questionnaire (MPQ) and visual analogue scales (VAS). RESULTS: The statistical analysis looked for differences between the two study groups immediately after the laser surgery and 24 hours later. There was no statistically significant difference in the primary outcome measure of perception of pain during and 24 hours after PRP, between the paracetamol and placebo group. However, none of the patients in the paracetamol group reported increased total pain at 24 hours, whereas six patients in the placebo group reported increased pain; this difference (21%) was significant to p = 0.01. CONCLUSIONS: Pre-emptive analgesia with paracetamol did not significantly reduce pain associated with PRP. This study has described for the first time the type of pain associated with PRP, which is perceived mainly as a discomfort. The main attributes of the pain that patients described, were sharp, flashing, tiring, intense, piercing, intermittent, and brief.

Reducing waiting times for GU medicine appointments: the impact of a new appointment system.

Our objective was to reduce the 'did not attend' (DNA) rates and waiting times by introducing a new confirmatory appointment system prior to their attendance at both Hartlepool and Middlesbrough genitourinary (GU) medicine departments. In Middlesbrough it was previous day appointment confirmation, whereas at Hartlepool it was 10 days. Both systems achieved significant attendance rates of 83.4% and 79.1% at Hartlepool and Middlesbrough, in comparison to 68.7% and 75.0% prior to the new system. The new system will improve the departmental capacity.

The Comorbidity Symptom Scale: a combined disease inventory and assessment of symptom severity.

OBJECTIVES: To develop and evaluate a scale to quantify the presence and severity of symptoms arising from comorbid diseases in older people. DESIGN: A validation cohort study of hospital inpatients and outpatients aged 65 years and older. SETTING: A Hospital and community in Northeast England. PARTICIPANTS: Development of the Comorbidity Symptom Scale-Convenience sample of 50 hospital inpatients and outpatients aged 65 years and older. Evaluation of the Comorbidity Symptom Scale- Convenience sample of 183 patients aged 65 years and older either awaiting cataract surgery or attending a geriatric day hospital. MEASUREMENTS: For development of the Comorbidity Symptom Scale, 22 comorbid conditions were identified and incorporated into a questionnaire (the CmSS). Evaluation of the Comorbidity Symptom Scale-Assessments included the CmSS, activities of daily living, perceived health status, and anxiety and depression. RESULTS: A 23-item scale was developed. Reliability of the CmSS was demonstrated by a test-retest correlation coefficient for the total instrument score of r = 0. 87 (P < .001). The CmSS scores correlated with assessments of activities of daily living, perceived health status, and anxiety and depression. CONCLUSIONS: The CmSS is a simple interviewer-administered tool for use in older people and provides an objective measure of the presence of comorbid disease and the patient's perception of severity of associated symptoms.

Measuring visual symptoms in British cataract patients: the cataract symptom scale.

AIMS: To develop and validate a scale for the measurement of visual symptoms and functional disability due to cataract in older UK residents. METHODS: In depth semistructured interviews were undertaken with 44 consecutive patients awaiting cataract surgery. Patients were asked to describe visual symptoms and problems with social functioning which were then incorporated into a questionnaire, the cataract symptom scale (CSS). The CSS was further examined in a cohort of 118 consecutive cataract patients awaiting surgery. Further assessments in these patients included visual acuity, visual function using an existing scale (the VF-14), activities of daily living, perceived health status, anxiety and depression, and a global assessment of how much patients felt their visual symptoms affected their daily life. RESULTS: A 15 item scale was derived which was simple to administer to older patients and had a high internal consistency. The test-retest correlation coefficient for the total instrument score was r = 0.91 (p<0.0001). The CSS correlated well with the VF-14 and to a lesser extent with visual acuity in the better eye, activities of daily living, perceived health status, anxiety and depression, and the patients' global assessment of visual symptoms. CONCLUSION: The CSS provides information regarding the symptomatic and functional status of older cataract patients resident in the UK which cannot be obtained by measurement of visual acuity alone.

Asthma in the elderly: underperceived, underdiagnosed and undertreated; a community survey.

Bronchial asthma is now increasingly recognized in the elderly and is associated with significant morbidity and mortality. The aims of this study were two-fold: first, to assess the prevalence and, second, to evaluate diagnostic awareness, therapeutic management and patient perception of bronchial asthma among elderly patients in the community. From the age-sex register of an urban general practice in NE England, 2004 patients aged > 65 years were eligible for inclusion. Response to an initial screening questionnaire on respiratory symptomatology was 68% (n = 1362). Of these, 869 patients had respiratory symptoms: 390 voluntarily agreed to be evaluated further including assessment of airway physiology. In this group 369/390 had obstructive spirometry and, of these, 95 patients fulfilled clinical and physiological criteria of bronchial asthma. Prevalence of asthma within this age cohort was minimally and rather crudely assigned at 4.5% (95/2004). Among the 95 patients so-defined patients with asthma [age 70 +/- 8 years (mean +/- SD), FEV1 = 0.96 +/- 0.41, 33 male, 75 life-long non-smokers], subjective awareness, perception and attribution of pulmonary symptoms were poor. Further, despite tangible evidence of reversible and significant airflow limitation, only 21 were receiving inhaled glucocorticoid therapy (median daily dose 400 micrograms). Asthma in the elderly remains poorly perceived, poorly recognized and suboptimally treated. These findings are particularly apposite in the light of current epidemiological trends in asthma mortality and morbidity in elderly age cohorts.

Meningococcal carriage: prevalence and sex-related risk factors.

A retrospective analysis was done to examine whether sexual behaviour was associated with meningococcal carriage. Over the 4 month period from January to April 1994, 136 (27.4%) of the 496 consecutive new/re-registered genito-urinary medicine clinic attenders showed meningococcal carriage. Two (15.4%) of 13 homosexual men compared with 134 (27.7%) of 484 heterosexual men and women had evidence of meningococcal carriage. Relative risk (RR) of meningococcal carriage was 1.8 with > 10 lifetime partners and 1.2 with 3-10 partners (P < 0.007). RR with age group of 16-25 was 4.2 and for 26-35 it was 3.5. There was no relationship with meningococcal carriage and pharyngeal symptoms, sexual orientation, intravenous drug use, number of partners per month and orogenital sex. Further longitudinal studies may be of value in order to determine whether a high number of sexual partners is a marker for meningococcal carriage. In addition, further study may show whether there is an increased risk of meningococcal carriage and disease in those who live with meningococcal carriers.

Quality of life in laryngectomees: a post-treatment comparison of laryngectomy alone versus combined therapy.

Patients with advanced and recurrent laryngeal and hypopharyngeal cancer often need combined therapy, which is associated with greater morbidity than single modality treatment. The aim of this study was to assess the quality of life in laryngectomees and to assess whether differences exist between the irradiated and the non-irradiated patients. The University of Michigan Head and Neck Quality of Life questionnaire, a validated instrument for assessing the head and neck cancer related functional status and well-being, was used for this purpose. Subjects for the study included patients who had undergone total laryngectomy for laryngeal or hypophyarngeal squamous cancer. No significant difference between the groups was evident in the various domain scores, although a trend towards higher scores was seen in the combined therapy group. This study suggests that long-term side effects induced by radiotherapy do not adversely affect the quality of life in laryngectomised patients.

Surgical accuracy in Le Fort I maxillary osteotomies.

UNLABELLED: The surgical outcome of planned movements of Le Fort I osteotomies is dependent on the surgeon's ability to achieve such movements intraoperatively. Our aim was to assess the surgical accuracy achieved for 30 consecutive patients undergoing Le Fort I osteotomies treated by one maxillofacial surgeon and his team. METHOD: Intraoperative control of the mobilized maxilla vertically was achieved by a combination of a nasion screw as the external reference point and bony marks above and below the osteotomy cuts intraorally. Movements horizontally and transversely were controlled with occlusal wafers. The surgical accuracy of maxillary movements vertically and horizontally (anteroposteriorly) were assessed by standard lateral cephalometric tracings of radiographs taken within two weeks prior to operation and 48 hours afterwards. Audit targets were arbitrarily set to be satisfactory when the difference between planned movements and actual movements as measured on the cephalometric tracings were 2 mm or less. RESULTS: The mean (SD) difference from planned vertical movements of the anterior maxilla was 0.37 mm (SD 0.64) and horizontal movements 0.85 mm (SD 0.91). Ninety-seven percent (29/30) of anterior maxillary movements in the vertical dimension, 90% (27/30) of anterior maxillary movements in the horizontal dimension and 87% (26/30) of movements in both dimensions had a difference of 2 mm or less. These results were comparable with the reported 'gold standard'. CONCLUSION: Good surgical accuracy in positioning the mobilized maxilla in Le Fort I osteotomies can be achieved with the use of external and internal reference points.

Intermaxillary fixation is not usually necessary to reduce mandibular fractures.

We undertook a retrospective study of all isolated mandibular fractures which had required active management over a 1-year period at the Maxillofacial Unit at Newcastle General Hospital. Patients with single or multiple fractures of the mandible were included in the study, if there were other simultaneous fractures of the facial skeleton, those patients were excluded. All case notes and radiographs were reviewed by a single operator. A total of 202 cases of fractured mandible were identified of which 115 fulfilled the selection criteria of: isolated fracture, no previous facial fracture, treatment by open reduction and internal fixation using titanium osteosynthesis miniplates, and all case notes and radiographs available to study. Sixty-six patients had their fractures reduced manually to obtain anatomical reduction without the use of peroperative intermaxillary fixation (IMF). Forty-nine were treated conventionally using peroperative IMF. The two groups were broadly similar in severity and type of fracture, and the method of reduction seemed to be decided by the operator according to their preference. IMF was not used routinely postoperatively. Overall there were significantly fewer occlusal discrepancies in the early postoperative period in those patients treated by anatomical reduction (6/66 compared with 16/49, P = 0.002) but there was no difference in the final outcome of the occlusion between the two methods of reduction. Avoidance of the use of peroperative IMF is more economical in time and cost, is safer for the operator, and more comfortable for the patient. As this technique produces comparable results in the long term with fewer early complications, we conclude that IMF is not usually necessary to reduce fractures confined to the mandibular bone.

An evidence synthesis of qualitative and quantitative research on component intervention techniques, effectiveness, cost-effectiveness, equity and acceptability of different versions of health-related lifestyle advisor role in improving health.

BACKGROUND: There is a need to identify and analyse the range of models developed to date for delivering health-related lifestyle advice (HRLA), or training, for effectiveness and cost-effectiveness in improving the health and well-being of individuals and communities in the UK, with particular reference to the reduction of inequalities. OBJECTIVES: To identify the component intervention techniques of lifestyle advisors (LAs) in the UK and similar contexts, and the outcomes of HRLA interventions. DATA SOURCES: Stakeholder views, secondary analysis of the National Survey of Health Trainer Activity, telephone survey of health trainer leads/coordinators. A search of a range of electronic databases was undertaken [including the Applied Social Sciences Index and Abstracts (ASSIA), EMBASE, NHS Economic Evaluation Database (NHS EED), MEDLINE, Psyc INFO, etc.], as well searching relevant journals and reference lists, conducted from inception to September 2008. REVIEW METHODS: Identified studies were scanned by two reviewers and those meeting the following criteria were included: studies carrying out an evaluation of HRLA; those taking place in developed countries similar to the UK context; those looking at adult groups; interventions with the explicit aim of health improvement; interventions that involved paid or voluntary work with an individual or group of peers acting in an advisory role; advice delivered by post, online or electronically; training, support or counselling delivered to patients, communities or members of the public. After quality assessment, studies were selected for inclusion in the review. Data were abstracted from each study according to an agreed procedure and narrative, and realist and economic approaches were used to synthesise the data. Cost-effectiveness analysis of interventions was undertaken. RESULTS: In total, 269 studies were identified but 243 were excluded. The 26 included studies addressing chronic care, mental health, breastfeeding, smoking, diet and physical activity, screening and human immunodeficiency virus (HIV) infection prevention. Overall, there was insufficient evidence to either support or refute the use of LAs to promote health and improve quality of life (QoL), and thus uncertainty about the interventions' cost-effectiveness. However, the economic analysis showed that LA interventions were cost-effective in chronic care and smoking cessation, inconclusive for breastfeeding and mental health and not cost-effective for screening uptake and diet/physical activity. LA interventions for HIV prevention were cost-effective, but not in a UK context. LIMITATIONS: The wide variety of LA models, delivery settings and target populations prevented the reviewers from establishing firm causal relationships between intervention mode and study outcomes. CONCLUSIONS: Evidence was variable, giving only limited support to LAs having a positive impact on health knowledge, behaviours and outcomes. Levels of acceptability appeared to be high. LAs acted as translational agents, sometimes removing barriers to prescribed behaviour or helping to create facilitative social environments. Reporting of processes of accessing or capitalising on indigenous knowledge was limited. Ambiguity was apparent with respect to the role and impact of lay and peer characteristics of the interventions. A future programme of research on HRLA could benefit from further emphasis on identification of needs, the broadening of population focus and intervention aims, the measurement of outcomes and the reviewing of evidence. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute for Health Research.