Objectives To assess the clinical effectiveness, effect on waiting times, and patient acceptability of PhysioDirect services in patients with musculoskeletal problems, compared with usual care.Design Pragmatic randomised controlled trial to assess equivalence in clinical effectiveness. Patients were individually randomised in a 2:1 ratio to PhysioDirect or usual care.Setting Four physiotherapy services in England.Participants Adults (aged ≥18 years) referred by general practitioners or self referred for musculoskeletal physiotherapy.Interventions PhysioDirect services invited patients to telephone a physiotherapist for initial assessment and advice, followed by face-to-face physiotherapy if necessary. Usual care involved patients joining a waiting list for face-to-face treatment.Main outcome measures Numbers of appointments, waiting time for treatment, and non-attendance rates. Primary outcome was physical health (SF-36v2 physical component score) at six months. Secondary outcomes included four other measures of health outcome, mental component score and scales from the SF-36v2, time lost from work, and patient satisfaction and preference. Participants were not blind to allocation, but outcome data were collected blind to allocation.Results Of 1506 patients allocated to PhysioDirect and 743 to usual care, 85% provided primary outcome data at six months (1283 and 629 patients, respectively). PhysioDirect patients had fewer face-to-face appointments than usual care patients (mean 1.91 v 3.11; incidence rate ratio 0.59 (95% confidence interval 0.53 to 0.65)), a shorter waiting time (median 7 days v 34 days; arm time ratio 0.32 (0.29 to 0.35)), and lower rates of non-attendance (incidence rate ratio 0.55 (0.41 to 0.73)). After six months’ follow-up, the SF-36v2 physical component score was equivalent between groups (adjusted difference in means −0.01 (−0.80 to 0.79)). Health outcome measures suggested a trend towards slightly greater improvement in the PhysioDirect arm at six week follow-up and no difference at six months. There was no difference in time lost from work. PhysioDirect patients were no more satisfied with access to physiotherapy than usual care patients, but had slightly lower satisfaction overall at six months (difference in satisfaction −3.8% (−7.3% to −0.3%); P=0.031). PhysioDirect patients were more likely than usual care patients to prefer PhysioDirect in future. No adverse events were detected.Conclusions PhysioDirect is equally clinically effective compared with usual care, provides faster access to physiotherapy, and seems to be safe. However, it could be associated with slightly lower patient satisfaction.Trial registration Current Controlled Trials ISRCTN55666618.

The GeneQuiz system is publicly available for analysis of protein sequences through a Web server at http://www.sander.ebi.ac. uk/gqsrv/submit

Multi-arm trials (trials with more than two arms) are particularly valuable forms of evidence for network meta-analysis (NMA). Trial results are available either as arm-level summaries, where effect measures are reported for each arm, or as contrast-level summaries, where the differences in effect between arms compare with the control arm chosen for the trial. We show that likelihood-based inference in both contrast-level and arm-level formats is identical if there are only two-arm trials, but that if there are multi-arm trials, results from the contrast-level format will be incorrect unless correlations are accounted for in the likelihood. We review Bayesian and frequentist software for NMA with multi-arm trials that can account for this correlation and give an illustrative example of the difference in estimates that can be introduced if the correlations are not incorporated. We discuss methods of imputing correlations when they cannot be derived from the reported results and urge trialists to report the standard error for the control arm even if only contrast-level summaries are reported. Copyright © 2012 John Wiley & Sons, Ltd.

BackgroundWe have conducted a population-based study of pleural mesothelioma patients with occupational histories and measured asbestos lung burdens in occupationally exposed workers and in the general population. The relationship between lung burden and risk, particularly at environmental exposure levels, will enable future mesothelioma rates in people born after 1965 who never installed asbestos to be predicted from their asbestos lung burdens.MethodsFollowing personal interview asbestos fibres longer than 5 µm were counted by transmission electron microscopy in lung samples obtained from 133 patients with mesothelioma and 262 patients with lung cancer. ORs for mesothelioma were converted to lifetime risks.ResultsLifetime mesothelioma risk is approximately 0.02% per 1000 amphibole fibres per gram of dry lung tissue over a more than 100-fold range, from 1 to 4 in the most heavily exposed building workers to less than 1 in 500 in most of the population. The asbestos fibres counted were amosite (75%), crocidolite (18%), other amphiboles (5%) and chrysotile (2%).ConclusionsThe approximate linearity of the dose–response together with lung burden measurements in younger people will provide reasonably reliable predictions of future mesothelioma rates in those born since 1965 whose risks cannot yet be seen in national rates. Burdens in those born more recently will indicate the continuing occupational and environmental hazards under current asbestos control regulations. Our results confirm the major contribution of amosite to UK mesothelioma incidence and the substantial contribution of non-occupational exposure, particularly in women.

ObjectivesTo compare the cost-effectiveness of PhysioDirect with usual physiotherapy care for patients with musculoskeletal problems.Design(1) Cost-consequences comparing cost to the National Health Service (NHS), to patients, and the value of lost productivity with a range of outcomes. (2) Cost-utility analysis comparing cost to the NHS with Quality-Adjusted Life Years (QALYs).SettingFour physiotherapy services in England.ParticipantsAdults (18+) referred by their general practitioner or self-referred for physiotherapy.InterventionsPhysioDirect involved telephone assessment and advice followed by face-to-face care if needed. Usual care patients were placed on a waiting list for face-to-face care.Primary and secondary outcomesPrimary clinical outcome: physical component summary from the SF-36v2 at 6 months. Also included in the cost-consequences: Measure Yourself Medical Outcomes Profile; a Global Improvement Score; response to treatment; patient satisfaction; waiting time. Outcome for the cost-utility analysis: QALYs.Results2249 patients took part (1506 PhysioDirect; 743 usual care). (1) Cost-consequences: there was no evidence of a difference between the two groups in the cost of physiotherapy, other NHS services, personal costs or value of time off work. Outcomes were also similar. (2) Cost-utility analysis based on complete cases (n=1272). Total NHS costs, including the cost of physiotherapy were higher in the PhysioDirect group by £19.30 (95% CI −£37.60 to £76.19) and there was a QALY gain of 0.007 (95% CI −0.003 to 0.016). The incremental cost-effectiveness ratio was £2889 and the net monetary benefit at λ=£20 000 was £117 (95% CI −£86 to £310).ConclusionsPhysioDirect may be a cost-effective alternative to usual physiotherapy care, though only with careful management of staff time. Physiotherapists providing the service must be more fully occupied than was possible under trial conditions: consideration should be given to the scale of operation, opening times of the service and flexibility in the methods used to contact patients.

This report should be referenced as follows: Salisbury C, Foster NE, Hopper C, Bishop A, Hollinghurst S, Coast J, et al. A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of 'PhysioDirect' telephone assessment and advice services for physiotherapy. Health Technol Assess 2013;17(2). This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). Health Technology Assessment is indexed and abstracted inEditorial contact: nihredit@southampton.ac.ukThe full HTA archive is freely available to view online at http://www.hta.ac.uk/project/htapubs.asp. Print copies can be purchased from the individual report pages. Criteria for inclusion in the Health Technology Assessment journalReports are published in Health Technology Assessment (HTA) if (1) they have resulted from work for the HTA programme or, originally commissioned by the Medical Research Council (MRC) and now managed by the Efficacy and Mechanism Evaluation programme which is funded by the MRC and NIHR, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors.Reviews in Health Technology Assessment are termed 'systematic' when the account of the search appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. HTA programmeThe HTA programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA programme findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the 'National Knowledge Service'.For more information about the HTA programme please visit the website: http://www.hta.ac.uk/ This reportThis issue of Health Technology Assessment contains a project originally commissioned by the MRC but managed by the Efficacy and Mechanism Evaluation Programme. The EME programme was created as part of the National Institute for Health Research (NIHR) and the Medical Research Council (MRC) coordinated strategy for clinical trials. The EME programme is funded by the MRC and NIHR, with contributions from the CSO in Scotland and NISCHR in Wales and the HSC R&D, Public Health Agency in Northern Ireland. It is managed by the NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) based at the University of Southampton.The authors have been wholly responsible for all data collection, analysis and interpretation, and for w...

Hepatitis C virus (HCV) infection is a dynamic process during which molecular variants are continously selected as the result of virus adaptation to the host. Understanding the nature of HCV genetic variation is central to current theories of pathogenesis and immune response. We prospectively studied hypervariable region 1 (HVR1) variation in the E2 gene of 36 hepatitis C patients, including 10 asymptomatic carriers, followed up for 1 to 2 years. Sequence changes in single and consecutive serum samples were assessed and correlated with clinical and virological parameters of liver disease. A region of the E1 gene was sequenced for comparison in 3 subjects. HVR1 heterogeneity at single time points widely varied in individual patients, did not increase cumulatively over the follow-up period, and did not correlate with HVR1 evolutionary rates. Conversely, the process of HVR1 sequence diversification, although differed considerably among patients, was stable over time and directly correlated with infections by HCV type 2, lower alanine aminotransferase (ALT) levels, and absence of cirrhosis. HCV carriers showed the highest HVR1 variation rates. Our findings indicate that HVR1 variation has an adaptive significance and is associated with favorable features of liver disease and suggest that prospective, rather than static, observations are required to model the process of HCV variation. (HEPATOLOGY 1998;27:1678-1686.)Hepatitis C virus (HCV) shares with other eukaryotic RNA viruses considerable sequence diversity both among isolates from unrelated individuals and within the same individual, 1 in which the virus is not present as a single molecular species, but as a variable population of closely related genomes, 2 according to the model of the viral quasispecies. 3,4 HCV sequence diversity observed among isolates is relevant to the process of viral evolution as it occurred during the history of human populations 1 ; therefore, it has been largely exploited to classify viral variants showing different epidemiologic and pathogenetic features. 5 Conversely, genetic diversity within individuals is more pertinent to the long-term adaptation of the virus to the host and reflects the dynamics of viral populations and the selective mechanisms operating during the course of the infection. 4 Sequence diversity is unevenly distributed throughout the viral genome being highly concentrated at the N-terminus of the E2 envelope glycoprotein, in which an hypervariable region (HVR1) of 31 aminoacids has been identified. 6 This suggests that sequence changes within HVR1 do not simply reflect the intrinsic mutation rates of the virus, but rather indicates that viral variants are actively selected and that genetic variation in this region may have an adaptive significance. [7][8][9][10] The quasispecies nature of the RNA virus populations represents a formidable obstacle to the study of genetic variation; this is a problem further compounded by the lack of structural constraints within protein domains, such as the hypervariable regions of ...

Objective: To systematically review temporal changes in perioperative safety of carotid endarterectomy (CEA) in asymptomatic individuals in trial and registry studies. Methods:The MEDLINE and EMBASE databases were searched using the terms "carotid" and "endarterectomy" and "asymptomatic" from 1947 to August 23, 2014. Articles dealing with 50%-99% stenosis in asymptomatic individuals were included and low-volume studies were excluded. The primary endpoint was 30-day stroke or death and the secondary endpoint was 30-day all-cause mortality. Statistical analysis was performed using random-effects metaregression for registry data and for trial data graphical interpretation alone was used.Results: Six trials (n 5 4,431 procedures) and 47 community registries (n 5 204,622 procedures) reported data between 1983 and 2013. Registry data showed a significant decrease in postoperative stroke or death incidence over the period 1991-2010, equivalent to a 6% average proportional annual reduction (95% credible interval [CrI] 4%-7%; p , 0.001). Considering postoperative all-cause mortality, registry data showed a significant 5% average proportional annual reduction (95% CrI 3%-9%; p , 0.001). Trial data showed a similar visual trend.Conclusions: CEA is safer than ever before and high-volume registry results closely mirror the results of trials. New benchmarks for CEA are a stroke or death risk of 1.2% and a mortality risk of 0.4%. This information will prove useful for quality improvement programs, for health care funders, and for those re-examining the long-term benefits of asymptomatic revascularization in future trials. Carotid endarterectomy (CEA) in asymptomatic individuals was introduced in the 1970s for long-term prevention of ipsilateral stroke 1 and now comprises the bulk of those undergoing endarterectomy in the United States.2 However, the 10-year absolute risk reduction in stroke or death risk in the largest and most recent trial, the Asymptomatic Carotid Surgery Trial 1 (ACST-1), was only 4.6%, demonstrating small absolute benefit of CEA. 3,4On modern medical therapy, ipsilateral ischemic stroke rates have fallen, 5 with 3 recent cohort studies demonstrating annual ipsilateral ischemic stroke risks in patients with 50%-99% asymptomatic stenosis of 0.3%-0.8%, 6-8 less than the 0.96% risk in ACST. 4 If CEA is to prove effective in the future, one of the prerequisites is that perioperative outcomes must become safer not only in trials, but in wider clinical practice.The aim of this systematic review was to examine temporal trends in perioperative safety of CEA in asymptomatic individuals with 50%-99% internal carotid artery stenosis. When compared with symptomatic patients, 9 the benefits of asymptomatic revascularization are less pronounced, and without marked improvements in operative safety, asymptomatic revascularization faces becoming a historical footnote. This analysis will provide valuable information for From the Academic Section of Vascular Surgery (A.B.M., M.I.Q., A.T.,