Search

Background: The treatment of osteoarthritis with knee replacement aims to reduce pain and disability. However, some people experience chronic pain. Objectives: To improve outcomes for people with chronic pain after knee replacement by identifying post-surgical predictors and effective interventions, characterising patient pathways and resource use, developing and evaluating a new care pathway, and exploring non-use of services. Design: The programme comprised systematic reviews, national database analyses, a cohort study, intervention development, a randomised controlled trial, health economic analyses, qualitative studies and stakeholder engagement. Extensive and meaningful patient and public involvement underpinned all studies. Setting: NHS, secondary care, primary care. Participants: People with, or at risk of, chronic pain after knee replacement and health-care professionals involved in the care of people with pain. Interventions: A care pathway for the management of people with pain at 3 months after knee replacement. Main outcome measures: Patient-reported outcomes and cost-effectiveness over 12 months. Data sources: Literature databases, the National Joint Registry, Hospital Episode Statistics, patient- reported outcomes, the Clinical Practice Research Datalink, the Clinical Outcomes in Arthroplasty Study, the Support and Treatment After joint Replacement randomised trial, interviews with 90 patients and 14 health-care professionals, and stakeholder events. Review methods: Systematic reviews of cohort studies or randomised trials, using meta-analysis or narrative synthesis. Results: In the Clinical Outcomes in Arthroplasty Study cohort, 14% of people experienced chronic pain 1 year after knee replacement. By 5 years, 65% reported no pain, 31% fluctuated and 4% remained in chronic pain. People with chronic pain had a worse quality of life, higher primary care costs, and more frequent analgesia prescriptions, particularly for opioids, than those not in chronic pain. People with chronic pain after knee replacement who made little or no use of services often felt nothing more could be done, or that further treatments may have no benefit or cause harm. People described a feeling of disconnection from their replaced knee. Analysis of UK databases identified risk factors for chronic pain after knee replacement. Pre- operative predictors were mild knee pain, smoking, deprivation, body mass index between 35 and 40 kg/m2 and knee arthroscopy. Peri- and post-operative predictors were mechanical complications, infection, readmission, revision, extended hospital stay, manipulation under anaesthetic and use of opioids or antidepressants. In systematic reviews, pre-operative exercise and education showed no benefit in relation to chronic pain. Peri-operative interventions that merit further research were identified. Common peri- operative treatments were not associated with chronic pain. There was no strong evidence favouring specific post-operative physiotherapy content. We evaluated the Support and Treatment After joint Replacement care pathway in a multicentre randomised controlled trial. We randomised 363 people with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales. At 12 months’ follow-up, the intervention group had lower mean pain severity (adjusted difference –0.65, 95% confidence interval –1.17 to -0.13; p = 0.014) and pain interference (adjusted difference –0.68, 95% confidence interval –1.29 to -0.08; p = 0.026), as measured on the Brief Pain Inventory subscales (scale 0–10). People receiving the Support and Treatment After joint Replacement pathway had lower NHS and Personal Social Services costs (–£724, 95% confidence interval –£150 to £51) and higher quality-adjusted life-years (0.03, 95% confidence interval –0.008 to 0.06) than those with usual care. The Support and Treatment After joint Replacement pathway was cost-effective with an incremental net monetary benefit at the £20,000 per quality-adjusted life-year threshold of £1256 (95% confidence interval £164 to £2348), indicating a 98.79% probability that the intervention is the cost-effective option. Participants found the Support and Treatment After joint Replacement pathway acceptable, with opportunities to receive information and discuss concerns while ensuring further treatment and support. In systematic reviews considering treatments for chronic pain after surgery we identified some unifactorial interventions that merit further research after knee replacement. Health-care professionals delivering and implementing the Support and Treatment After joint Replacement pathway valued its focus on neuropathic pain and psychosocial issues, enhanced patient care, formalised referrals, and improved pain management. Stakeholders supported pathway implementation. Limitations: Database analyses were limited to factors recorded in data sets. Pain was only measured 6 months after surgery. However, analyses including large numbers of centres and patients should be generalisable across the NHS. In many studies found in systematic reviews, long-term pain was not a key outcome. Conclusions: The Support and Treatment After joint Replacement pathway is a clinically effective and cost-effective, acceptable intervention for the management of chronic pain after knee replacement. Unifactorial interventions merit further study before inclusion in patient care. People with pain should be empowered to seek health care, with the support of health-care professionals. Future work: Future work should include research relating to the implementation of the Support and Treatment After joint Replacement pathway into the NHS, an assessment of its long-term clinical effectiveness and cost-effectiveness and wider application, and an evaluation of new interventions for incorporation in the pathway. It will also be important to design and conduct research to improve communication between patients and health-care professionals before surgery; explore whether or not education and support can enable earlier recognition of chronic pain; consider research that may identify how to support people’s feelings of disconnectedness from their new knee; and design and evaluate a pre-surgical intervention based on risk factors. Study registration: All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The Support and Treatment After joint Replacement randomised trial was registered as ISRCTN92545361. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information.

BACKGROUND: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy. METHODS: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of longterm androgen-deprivation therapy (secondary outcomes). RESULTS: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P=0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis. CONCLUSIONS: After 15 years of follow-up, prostate cancer–specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Objective: To investigate the effectiveness of combining mirtazapine with Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) or Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants for patients in primary care who had not responded to an antidepressant.\ud \ud Design: A two parallel-group multi-centre, placebo controlled, randomised trial comparing the addition of mirtazapine to placebo for patients who had been adherent to an SSRI or SNRI for at least 6 weeks and were still depressed. Participants were stratified by centre and minimised by baseline Beck Depression Inventory score [BDI-II], gender and current psychological therapy. Participants, their General Practitioners (GPs), and the research team were blind to the allocation. Primary analyses compared the two groups as allocated without imputing missing data Setting: 106 general practices in 4 centres in the UK; Bristol, Exeter, Hull and North Staffordshire.\ud \ud Participants: Between August 2013 and October 2015, we recruited 480 participants aged over 17 years, 69.1% of whom were female. Participants scored >13 using the BDI-II and fulfilled International Classification of Diseases [ICD]-10 criteria for depression. Exclusion criteria included bipolar disorder, psychosis and major alcohol/substance abuse. 431 (89.8%) were included in the (primary) 12-week follow-up. \ud \ud Intervention: 241 participants were randomised to mirtazapine and 239 to placebo, both given in addition to their usual SSRI/SNRI medication. They were followed up at 12, 24 and 52 weeks. \ud Main outcome measures: Depressive symptoms at 12 weeks post-randomisation, measured using the BDI-II score as a continuous variable. Secondary outcomes include measures of anxiety, quality of life and adverse effects at 12, 24 and 52 weeks. \ud \ud Results: BDI-II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline BDI-II and minimisation/stratification variables, although the confidence interval included the null (mean (SD) BDI-II scores at 12 weeks: 18.0 (12.3) in the mirtazapine group; 19.7 (12.4) in the placebo group; adjusted difference between means -1.83 (95% confidence interval: -3.92 to 0.27, p=0.087)). Adverse effects were more frequent in the mirtazapine group and associated with stopping the trial medication.\ud \ud Conclusion: This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI antidepressant over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where there is limited evidence of effective treatment options.

Statistical Analysis Plan.

Purpose: To determine prevalence and predictors of persistent speech sound disorder (SSD) in children aged 8.Method: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used. Children were classified as having persistent SSD based on Percentage of Consonants Correct measures from connected speech samples. Multivariable logistic regression analyses were performed to identify predictors.Results: The estimated prevalence of persistent SSD was 3.6%. Children with persistent SSD were more likely to be male and from families who were not home-owners. Early childhood predictors identified as important were: weak sucking at 4 weeks; not often combining words at 24 months; limited use of word morphology at 38 months; and being unintelligible to strangers at age 38 months. School-age predictors identified as important were: maternal report of difficulty pronouncing certain sounds and hearing impairment at 7 years; tympanostomy tube insertion at any age up to 8 years; and a history of suspected coordination problems. The contribution of these findings to our understanding of risk factors for persistent SSD and the nature of the condition is considered. Conclusion: Variables identified as predictive of persistent SSD suggest that factors across motor, cognitive and linguistic processes may place a child at risk.

BACKGROUND: Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression. METHOD: A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses. RESULTS: At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) -0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (-0.29, 95% CI -3.04 to 2.46, p = 0.84) or the other mental health outcomes. CONCLUSIONS: There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.

BACKGROUND AND OBJECTIVE: Recruitment to randomized trials is often difficult, but few studies have investigated interventions to improve recruitment. In a randomized trial nested within a trial of treatments for localized prostate cancer, we investigated the comparative effectiveness and cost-effectiveness of nurses and surgeons in recruiting patients. METHODS: Men with localized prostate cancer were randomized to see a nurse or urologic surgeon for an "information appointment" in which they were asked to consent to the ProtecT treatment trial comparing surgery, radiotherapy, and active monitoring. Analysis was conducted by intention to treat using chi-square with 95% confidence intervals for proportions and differences between groups. An economic evaluation was performed using the duration of appointments and grade of recruitment staff. RESULTS: Case-finding identified 167 men with localized prostate cancer. One hundred fifty (90%) took part in the recruitment trial. There was a 4.0% difference between nurses and surgeons in recruitment rates (67% nurses, 71% urologists, 95% CI -10.8% to +18.8%, P=.60). Cost-minimization analysis showed that nurses spent longer times with patients but surgeon costs were higher and nurses often supported surgeon-led clinics. CONCLUSION: Nurses were as effective and more cost-effective recruiters than urologic surgeons. This suggests an increased role for nurses in recruiting patients to randomized trials.

Rationale: Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment. Objectives: To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment. Methods: Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation. Results: Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p = 0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p = 0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants. Conclusions: The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects. © 2014 The Author(s).

AIMS: To investigate the hypothesis that increasing alcohol consumption is accompanied by increasing use of acute, but decreasing use of preventative, medical services among the general population. DESIGN AND PARTICIPANTS: Health and life-style survey of 41,000 randomly-sampled adults in SE England who self-completed a validated questionnaire covering socio-demographics, alcohol and tobacco usage and use of acute (A&E department and general practitioner) and preventative (dental, optician, mammography and cervical cytology) services: the response rate was 60%. MEASUREMENTS: Comparative use of acute and preventative health care services by patients with varying consumption of alcoholic beverages. This was estimated by the odds ratio for service use, after correcting for the following confounding variables; age, social class, ethnic group, employment status, whether lives with children or with other adults, whether is a career, limiting long-term illness, depression status, smoking habit and use of private health insurance. FINDINGS: There was increased use of accident and emergency services by the harmful and intermediate drinking groups compared with the safe drinking group. Male abstainers attended their A&E departments more frequently than 'safe limit' drinkers. With respect to preventative services, both male and female abstainers and harmful drinkers used dental services less than safe limit drinkers. For females, mammography and cervical cytology services were less frequently used by abstainers and by harmful drinkers. CONCLUSIONS: This study supports the generally held view that heavy alcohol consumers are disproportionate users of acute medical services but they are relative under-users of preventative medical care services. Alcohol abstainers are also over-users of acute services, but under-users of preventative services. These latter observations are relevant to the claims that moderate alcohol consumers have lower apparent morbidity and mortality rates compared to abstainers.

In this paper we report the application of an extensive database of symptoms, signs, laboratory findings and illnesses, to the diagnosis of an historical figure. The medical diagnosis of Augustus d'Este (1794-1848) - widely held to be the first documented case of multiple sclerosis - is reviewed, using the detailed symptom diary, which he kept over many years, as clinical data. Some of the reported features prompted the competing claim that d'Este suffered from acute porphyria, which in turn was used in support of the hypothesis that his grandfather, King George III, also suffered from the disease. We find that multiple sclerosis is statistically the most likely diagnosis, with neuromyelitis optica a strong alternative possibility. The database did not support a diagnosis of any of the acute porphyrias.

Background: General practitioners with special interests (GPSIs) are increasingly being used to provide dermatology services in the U.K. Little is known about U.K. dermatology patient attitudes to proposed variations in secondary care service delivery or the values they attach to aspects of the care they receive. Objectives: To quantify preferences for different attributes of care within dermatology secondary care services. Methods: Attributes of care that are important to dermatology patients were derived using in-depth qualitative interviews with 19 patients at different points in the care pathway. A discrete choice experiment using 'best-worst scaling' was sent by post to 119 patients referred to secondary care dermatology services and suitable for GPSI care who had agreed to participate in research. Results: Four attributes were derived from the qualitative work: waiting, expertise, thorough care and convenience. For the discrete choice experiment, 99 patients returned questionnaires, 93 of which contained sufficient data for analysis. All attributes were found to be quantitatively important. The attribute of greatest importance was expertise of the doctor, while waiting time was of least importance. Respondents were willing to wait longer than the current 3 months maximum to receive care that was thorough, 2.1 months to see a team led by an expert and 1.3 months to attend a consultation that is easy to get to. Conclusions: Although the need to reduce outpatient waiting times is a key policy driver behind the expansion of GPSI services, this does not appear to be the most important issue for patients. The thoroughness with which the consultation is provided and the expertise of the clinician seen are higher priorities. © 2006 British Association of Dermatologists.

Statements like "quality of care is more highly valued than waiting time" can neither be supported nor refuted by comparisons of utility parameters from a traditional discrete choice experiment (DCE). Best-worst scaling can overcome this problem because it asks respondents to perform a different choice task. However, whilst the nature of the best-worst task is generally understood, there are a number of issues relating to the design and analysis of a best-worst choice experiment that require further exposition. This paper illustrates how to aggregate and analyse such data and using a quality of life pilot study demonstrates how richer insights can be drawn by the use of best-worst tasks. © 2006 Elsevier B.V. All rights reserved.

Background The advent of urine testing for Chlamydia trachomatis has raised the possibility of large-scale screening for this sexually transmitted infection, which is now the most common in the United Kingdom. The purpose of this study was to investigate the effect of an invitation to be screened for chlamydia and of receiving a negative result on levels of anxiety, depression and self-esteem. Methods 19,773 men and women aged 16 to 39 years, selected at random from 27 general practices in two large city areas (Bristol and Birmingham) were invited by post to send home-collected urine samples or vulvo-vaginal swabs for chlamydia testing. Questionnaires enquiring about anxiety, depression and self-esteem were sent to random samples of those offered screening: one month before the dispatch of invitations; when participants returned samples; and after receiving a negative result. Results Home screening was associated with an overall reduction in anxiety scores. An invitation to participate did not increase anxiety levels. Anxiety scores in men were lower after receiving the invitation than at baseline. Amongst women anxiety was reduced after receipt of negative test results. Neither depression nor self-esteem scores were affected by screening. Conclusion Postal screening for chlamydia does not appear to have a negative impact on overall psychological well-being and can lead to a decrease in anxiety levels among respondents. There is, however, a clear difference between men and women in when this reduction occurs.

Determination of cellular enzyme activities in washout preservation solution used in hypothermic liver graft storage may allow development of an index that could be clinically valuable in prediction of early post-transplant graft function. In the present study, we collected washed out preservation fluid at the time of graft rinsing from 53 liver recipients. Aspartate aminotransferase and, to a lesser extent, lactate dehydrogenase levels correlated with early postoperative graft viability as assessed by 1-month graft survival and standard biochemical indices of liver function. Those patients with the highest aspartate aminotransferase activity in the washout preservation solution experienced the highest levels of this enzyme postoperatively (area-under-the-curve day 1-3; 1340 vs. 788 IU/L), total bilirubin (area-under-the-curve day 1-5; 901 vs. 538 mumol/L), and rejection frequency (67% vs. 31%) (all P < 0.05), with a significantly lower 1-month graft survival rate compared with patients with low effluent levels (62% vs. 92%, P < 0.05). Two markers of endothelial cell damage, purine nucleoside phosphorylase and a creatine kinase isoenzyme, measured in the fluid did not correlate with early graft viability. It is suggested that assay of aspartate aminotransferase activities in preservation fluid washout samples is a clinically useful indicator of graft viability.