Cardiac Troponin T and Troponin I in the General Population.

BACKGROUND: There is great interest in widening the use of high-sensitivity cardiac troponins for population cardiovascular disease (CVD) and heart failure screening. However, it is not clear whether cardiac troponin T (cTnT) and troponin I (cTnI) are equivalent measures of risk in this setting. We aimed to compare and contrast (1) the association of cTnT and cTnI with CVD and non-CVD outcomes, and (2) their determinants in a genome-wide association study. METHODS: High-sensitivity cTnT and cTnI were measured in serum from 19 501 individuals in Generation Scotland Scottish Family Health Study. Median follow-up was 7.8 years (quartile 1 to quartile 3, 7.1-9.2). Associations of each troponin with a composite CVD outcome (1177 events), CVD death (n=266), non-CVD death (n=374), and heart failure (n=216) were determined by using Cox models. A genome-wide association study was conducted using a standard approach developed for the cohort. RESULTS: Both cTnI and cTnT were strongly associated with CVD risk in unadjusted models. After adjusting for classical risk factors, the hazard ratio for a 1 SD increase in log transformed troponin was 1.24 (95% CI, 1.17-1.32) and 1.11 (1.04-1.19) for cTnI and cTnT, respectively; ratio of hazard ratios 1.12 (1.04-1.21). cTnI, but not cTnT, was associated with myocardial infarction and coronary heart disease. Both cTnI and cTnT had strong associations with CVD death and heart failure. By contrast, cTnT, but not cTnI, was associated with non-CVD death; ratio of hazard ratios 0.77 (0.67-0.88). We identified 5 loci (53 individual single-nucleotide polymorphisms) that had genome-wide significant associations with cTnI, and a different set of 4 loci (4 single-nucleotide polymorphisms) for cTnT. CONCLUSIONS: The upstream genetic causes of low-grade elevations in cTnI and cTnT appear distinct, and their associations with outcomes also differ. Elevations in cTnI are more strongly associated with some CVD outcomes, whereas cTnT is more strongly associated with the risk of non-CVD death. These findings help inform the selection of an optimal troponin assay for future clinical care and research in this setting.

To tolerate or to agree: A tutorial on tolerance intervals in method comparison studies with BivRegBLS R Package.

The well-known agreement interval by Bland and Altman is extensively applied in method comparison studies. Two clinical measurement methods are considered interchangeable if their differences are not clinically significant. The agreement interval is commonly applied to assess the spread of the differences. However, this interval is approximate (too narrow) and several authors propose calculating a confidence interval around each bound. This article demonstrates that this approach is misleading, awkward, and confusing. On the other hand, tolerance intervals are exact and can include a confidence level if needed. Tolerance intervals are also easier to calculate and to interpret. Real data sets are used to illustrate the tolerance intervals with the R package BivRegBLS under normal or log-normal assumptions. Furthermore, it is also explained how to assess the coverage probabilities of the tolerance intervals with simulations.

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment.

Background: Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2x10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA) whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk.

Comparison between High-Sensitivity Cardiac Troponin T and Cardiac Troponin I in a Large General Population Cohort.

BACKGROUND: Few data compare cardiac troponin T (cTnT) and cardiac troponin I (cTnI) in a general population. We sought to evaluate the distribution and association between cTnT, cTnI, and cardiovascular risk factors in a large general population cohort. METHODS: High-sensitivity cTnT and cTnI were measured in serum from 19501 individuals in the Generation Scotland Scottish Family Health Study. Associations with cardiovascular risk factors were compared using age- and sex-adjusted regression. Observed age- and sex-stratified 99th centiles were compared with 99th centiles for cTnT (men, 15.5 ng/L; women, 9.0 ng/L) and cTnI (men, 34.2 ng/L; women, 15.6 ng/L) used in clinical practice. RESULTS: cTnT and cTnI concentrations were detectable in 53.3% and 74.8% of participants, respectively, and were modestly correlated in unadjusted analyses (R 2 = 21.3%) and only weakly correlated after adjusting for age and sex (R 2 = 9.5%). Cardiovascular risk factors were associated with both troponins, but in age- and sex-adjusted analyses, cTnI was more strongly associated with age, male sex, body mass index, and systolic blood pressure (P < 0.0001 for all vs cTnT). cTnT was more strongly associated with diabetes (P < 0.0001 vs cTnI). The observed 99th centiles were broadly consistent with recommended 99th centiles in younger men and women. After the age of 60 years, observed 99th centiles increased substantially for cTnT, and beyond 70 years of age, the 99th centiles approximately doubled for both troponins. CONCLUSIONS: In the general population, cTnT and cTnI concentrations are weakly correlated and are differentially associated with cardiovascular risk factors. The 99th centiles currently in use are broadly appropriate for men and women up to but not beyond the age of 60 years.

Gaining an advantage by sitting an OSCE after your peers: A retrospective study.

Purpose: To investigate if final year medical students undertaking an OSCE station at a later stage during examination diet were advantaged over their peers who undertook the same station at an earlier stage, and whether any such effect varies by the student's relative academic standing. Methods: OSCE data from six consecutive final year cohorts totaling 1505 students was analyzed. Mixed effects logistic regression was used to model factors associated with the probability of passing each individual station (random effects for students and circuits; and fixed effects to assess the association with day of examination, time of day, gender and year). Results: Weaker students were more likely to pass if they took their OSCE later in the examination period. The odds of passing a station increased daily by 20%. Overall, the mean number of stations passed by each student increased over the 5 days. Conclusions: Students undertaking the same OSCE stations later in examination period statistically had higher chances of passing compared to their peers, and the weaker students appear to be particularly advantaged. These findings have major implications for OSCE design, to ensure students are not advantaged by examination timing, and weaker students are not "passing in error".

Feasibility of the Manchester Acute Coronary Syndromes (MACS) decision rule to safely reduce unnecessary hospital admissions: a pilot randomised controlled trial.

BACKGROUND: Observational studies suggest that the Manchester Acute Coronary Syndromes (MACS) decision rule can effectively 'rule out' and 'rule in' acute coronary syndromes (ACS) following a single blood test. In a pilot randomised controlled trial, we aimed to determine whether a large trial is feasible. METHODS: Patients presenting to two EDs with suspected cardiac chest pain were randomised to receive care guided by the MACS decision rule (intervention group) or standard care (controls). The primary efficacy outcome was a successful discharge from the ED, defined as a decision to discharge within 4 hours of arrival providing that the patient did not have a missed acute myocardial infarction (AMI) or develop a major adverse cardiac event (MACE: death, AMI or coronary revascularisation) within 30 days. Feasibility outcomes included recruitment and attrition rates. RESULTS: In total, 138 patients were included between October 2013 and October 2014, of whom 131 (95%) were randomised (66 to intervention and 65 controls). Nine (7%) patients had prevalent AMI and six (5%) had incident MACE within 30 days. All 131 patients completed 30-day follow-up and were included in the final analysis with no missing data for the primary analyses. Compared with standard care, a significantly greater proportion of patients whose care was guided by the MACS rule were successfully discharged within 4 hours (26% vs 8%, adjusted OR 5.45, 95% CI 1.73 to 17.11, p=0.004). No patients in either group who were discharged within 4 hours had a diagnosis of AMI or incident MACE within 30 days (0.0%, 95% CI 0% to 20.0% in the intervention group). CONCLUSIONS: In this pilot trial, use of the MACS rule led to a significant increase in safe discharges from the ED but a larger, fully powered trial remains necessary. Our findings seem to support the feasibility of that trial. TRIAL REGISTRATION NUMBER: ISRCTN 86818215. RESEARCH ETHICS COMMITTEE REFERENCE: 13/NW/0081. UKCRN REGISTRATION ID: 14334.

Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial.

BACKGROUND: Meta-analyses of previous randomised controlled trials concluded that the smooth muscle relaxant drugs tamsulosin and nifedipine assisted stone passage for people managed expectantly for ureteric colic, but emphasised the need for high-quality trials with wide inclusion criteria. We aimed to fulfil this need by testing effectiveness of these drugs in a standard clinical care setting. METHODS: For this multicentre, randomised, placebo-controlled trial, we recruited adults (aged 18-65 years) undergoing expectant management for a single ureteric stone identified by CT at 24 UK hospitals. Participants were randomly assigned by a remote randomisation system to tamsulosin 400 µg, nifedipine 30 mg, or placebo taken daily for up to 4 weeks, using an algorithm with centre, stone size (≤5 mm or >5 mm), and stone location (upper, mid, or lower ureter) as minimisation covariates. Participants, clinicians, and trial personnel were masked to treatment assignment. The primary outcome was the proportion of participants who did not need further intervention for stone clearance within 4 weeks of randomisation, analysed in a modified intention-to-treat population defined as all eligible patients for whom we had primary outcome data. This trial is registered with the European Clinical Trials Database, EudraCT number 2010-019469-26, and as an International Standard Randomised Controlled Trial, number 69423238. FINDINGS: Between Jan 11, 2011, and Dec 20, 2013, we randomly assigned 1167 participants, 1136 (97%) of whom were included in the primary analysis (17 were excluded because of ineligibility and 14 participants were lost to follow-up). 303 (80%) of 379 participants in the placebo group did not need further intervention by 4 weeks, compared with 307 (81%) of 378 in the tamsulosin group (adjusted risk difference 1·3% [95% CI -5·7 to 8·3]; p=0·73) and 304 (80%) of 379 in the nifedipine group (0·5% [-5·6 to 6·5]; p=0·88). No difference was noted between active treatment and placebo (p=0·78), or between tamsulosin and nifedipine (p=0·77). Serious adverse events were reported in three participants in the nifedipine group (one had right loin pain, diarrhoea, and vomiting; one had malaise, headache, and chest pain; and one had severe chest pain, difficulty breathing, and left arm pain) and in one participant in the placebo group (headache, dizziness, lightheadedness, and chronic abdominal pain). INTERPRETATION: Tamsulosin 400 µg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Can Automated Imaging for Optic Disc and Retinal Nerve Fiber Layer Analysis Aid Glaucoma Detection?

PURPOSE: To compare the diagnostic performance of automated imaging for glaucoma. DESIGN: Prospective, direct comparison study. PARTICIPANTS: Adults with suspected glaucoma or ocular hypertension referred to hospital eye services in the United Kingdom. METHODS: We evaluated 4 automated imaging test algorithms: the Heidelberg Retinal Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany) glaucoma probability score (GPS), the HRT Moorfields regression analysis (MRA), scanning laser polarimetry (GDx enhanced corneal compensation; Glaucoma Diagnostics (GDx), Carl Zeiss Meditec, Dublin, CA) nerve fiber indicator (NFI), and Spectralis optical coherence tomography (OCT; Heidelberg Engineering) retinal nerve fiber layer (RNFL) classification. We defined abnormal tests as an automated classification of outside normal limits for HRT and OCT or NFI ≥ 56 (GDx). We conducted a sensitivity analysis, using borderline abnormal image classifications. The reference standard was clinical diagnosis by a masked glaucoma expert including standardized clinical assessment and automated perimetry. We analyzed 1 eye per patient (the one with more advanced disease). We also evaluated the performance according to severity and using a combination of 2 technologies. MAIN OUTCOME MEASURES: Sensitivity and specificity, likelihood ratios, diagnostic, odds ratio, and proportion of indeterminate tests. RESULTS: We recruited 955 participants, and 943 were included in the analysis. The average age was 60.5 years (standard deviation, 13.8 years); 51.1% were women. Glaucoma was diagnosed in at least 1 eye in 16.8%; 32% of participants had no glaucoma-related findings. The HRT MRA had the highest sensitivity (87.0%; 95% confidence interval [CI], 80.2%-92.1%), but lowest specificity (63.9%; 95% CI, 60.2%-67.4%); GDx had the lowest sensitivity (35.1%; 95% CI, 27.0%-43.8%), but the highest specificity (97.2%; 95% CI, 95.6%-98.3%). The HRT GPS sensitivity was 81.5% (95% CI, 73.9%-87.6%), and specificity was 67.7% (95% CI, 64.2%-71.2%); OCT sensitivity was 76.9% (95% CI, 69.2%-83.4%), and specificity was 78.5% (95% CI, 75.4%-81.4%). Including only eyes with severe glaucoma, sensitivity increased: HRT MRA, HRT GPS, and OCT would miss 5% of eyes, and GDx would miss 21% of eyes. A combination of 2 different tests did not improve the accuracy substantially. CONCLUSIONS: Automated imaging technologies can aid clinicians in diagnosing glaucoma, but may not replace current strategies because they can miss some cases of severe glaucoma.

Vitrectomy with internal limiting membrane peeling versus no peeling for idiopathic full-thickness macular hole.

OBJECTIVE: To determine whether internal limiting membrane (ILM) peeling improves anatomic and functional outcomes of full-thickness macular hole (FTMH) surgery when compared with the no-peeling technique. DESIGN: Systematic review and individual participant data (IPD) meta-analysis undertaken under the auspices of the Cochrane Eyes and Vision Group. Only randomized controlled trials (RCTs) were included. PARTICIPANTS AND CONTROLS: Patients with idiopathic stage 2, 3, and 4 FTMH undergoing vitrectomy with or without ILM peeling. INTERVENTION: Macular hole surgery, including vitrectomy and gas endotamponade with or without ILM peeling. MAIN OUTCOME MEASURES: Primary outcome was best-corrected distance visual acuity (BCdVA) at 6 months postoperatively. Secondary outcomes were BCdVA at 3 and 12 months; best-corrected near visual acuity (BCnVA) at 3, 6, and 12 months; primary (after a single surgery) and final (after >1 surgery) macular hole closure; need for additional surgical interventions; intraoperative and postoperative complications; patient-reported outcomes (PROs) (EuroQol-5D and Vision Function Questionnaire-25 scores at 6 months); and cost-effectiveness. RESULTS: Four RCTs were identified and included in the review. All RCTs were included in the meta-analysis; IPD were obtained from 3 of the 4 RCTs. No evidence of a difference in BCdVA at 6 months was detected (mean difference, -0.04; 95% confidence interval [CI], -0.12 to 0.03; P=0.27); however, there was evidence of a difference in BCdVA at 3 months favoring ILM peeling (mean difference, -0.09; 95% CI, -0.17 to-0.02; P=0.02). There was evidence of an effect favoring ILM peeling with regard to primary (odds ratio [OR], 9.27; 95% CI, 4.98-17.24; P<0.00001) and final macular hole closure (OR, 3.99; 95% CI, 1.63-9.75; P=0.02) and less requirement for additional surgery (OR, 0.11; 95% CI, 0.05-0.23; P<0.00001), with no evidence of a difference between groups with regard to intraoperative or postoperative complications or PROs. The ILM peeling was found to be highly cost-effective. CONCLUSIONS: Available evidence supports ILM peeling as the treatment of choice for patients with idiopathic stage 2, 3, and 4 FTMH.

Choosing and using methodological search filters: searchers' views.

BACKGROUND: Search filters or hedges are search strategies developed to assist information specialists and librarians to retrieve different types of evidence from bibliographic databases. The objectives of this project were to learn about searchers' filter use, how searchers choose search filters and what information they would like to receive to inform their choices. METHODS: Interviews with information specialists working in, or for, the National Institute for Health and Care Excellence (NICE) were conducted. An online questionnaire survey was also conducted and advertised via a range of email lists. RESULTS: Sixteen interviews were undertaken and 90 completed questionnaires were received. The use of search filters tends to be linked to reducing a large amount of literature, introducing focus and assisting with searches that are based on a single study type. Respondents use numerous ways to identify search filters and can find choosing between different filters problematic because of knowledge gaps and lack of time. CONCLUSIONS: Search filters are used mainly for reducing large result sets (introducing focus) and assisting with searches focused on a single study type. Features that would help with choosing filters include making information about filters less technical, offering ratings and providing more detail about filter validation strategies and filter provenance.

Reporting methodological search filter performance comparisons: a literature review.

BACKGROUND: Methodological search filters are tools for retrieving database records reporting studies which use a specific research method. Choosing a filter is likely to be based on filter performance data. This review examines which measures are reported, and the way that filter performance is presented, in filter comparisons. METHODS: Studies were identified from the current content and pending update (2010) of a filter website. Eligible studies compared two or more methodological search filters designed to identify randomised controlled trials, diagnostic test accuracy studies, systematic reviews or economic evaluations. RESULTS: Eighteen studies met the inclusion criteria. The number of filters compared in a single study ranged from 2 to 38. The most commonly reported measures were sensitivity/recall and precision. All studies displayed results in tables and gave results as percentages or proportions. Two studies supplemented results tables with graphical displays of data: a bar graph of the proportion of retrieved and missed gold standard references per filter; a forest plot of the overall sensitivity and specificity of each filter. CONCLUSIONS: Sensitivity/recall and precision are the most frequently reported performance measures. This review highlights the potential for presenting results in novel and innovative ways to aid filter selection.

Antimicrobial catheters for reduction of symptomatic urinary tract infection in adults requiring short-term catheterisation in hospital: a multicentre randomised controlled trial.

BACKGROUND: Catheter-associated urinary tract infection (CAUTI) is a major preventable cause of harm for patients in hospital. We aimed to establish whether short-term routine use of antimicrobial catheters reduced risk of CAUTI compared with standard polytetrafluoroethylene (PTFE) catheterisation. METHODS: In our parallel, three group, multicentre, randomised controlled superiority trial, we enrolled adults (aged ≥16 years) requiring short-term (≤14 days) catheterisation at 24 hospitals in the UK. Participants were randomly allocated 1:1:1 with a remote computer allocation to receive a silver alloy-coated catheter, a nitrofural-impregnated catheter, or a PTFE-coated catheter (control group). Patients undergoing unplanned catheterisation were also included and consent for participation was obtained retrospectively. Participants and trial staff were unmasked to treatment assignment. Data were collected by trial staff and by patient-reported questionnaires for 6 weeks after randomisation. The primary outcome was incidence of symptomatic urinary tract infection for which an antibiotic was prescribed by 6 weeks. We postulated that a 3·3% absolute reduction in CAUTI would represent sufficient benefit to recommend routine use of antimicrobial catheters. This study is registered, number ISRCTN75198618. FINDINGS: 708 (10%) of 7102 randomly allocated participants were not catheterised, did not confirm consent, or withdrew, and were not included in the primary analyses. Compared with 271 (12·6%) of 2144 participants in the control group, 263 (12·5%) of 2097 participants allocated a silver alloy catheter had the primary outcome (difference -0·1% [95% CI -2·4 to 2·2]), as did 228 (10·6%) of 2153 participants allocated a nitrofural catheter (-2·1% [-4·2 to 0·1]). Rates of catheter-related discomfort were higher in the nitrofural group than they were in the other groups. INTERPRETATION: Silver alloy-coated catheters were not effective for reduction of incidence of symptomatic CAUTI. The reduction we noted in CAUTI associated with nitrofural-impregnated catheters was less than that regarded as clinically important. Routine use of antimicrobial-impregnated catheters is not supported by this trial. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Vitrectomy with internal limiting membrane (ILM) peeling versus vitrectomy with no peeling for idiopathic full-thickness macular hole (FTMH).

BACKGROUND: Several observational studies have suggested the potential benefit of internal limiting membrane (ILM) peeling to treat idiopathic full-thickness macular hole (FTMH). However, no strong evidence is available on the potential benefit(s) of this surgical manoeuvre and uncertainty remains among vitreoretinal surgeons about the indication for peeling the ILM, whether to use it in all cases or in long-standing and/or larger holes.  OBJECTIVES: To determine whether ILM peeling improves anatomical and functional outcomes of macular hole surgery compared with the no-peeling technique and to investigate the impact of different parameters such as presenting vision, stage/size of the hole and duration of symptoms in the success of the surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) which contains the Cochrane Eyes and Vision Group Trials Register (The Cochrane Library 2013, Issue 2), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to February 2013), EMBASE (January 1980 to February 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to February 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We searched the reference lists of included studies for any additional studies not identified by the electronic searches. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 February 2013.We searched reference lists of the studies included in the review for information about other studies on ILM peeling in macular hole surgery. We searched Proceedings for the following conferences up to February 2013: American Academy of Ophthalmology (AAO), Annual Meeting of the American Society of Retina Specialists (ASRS), Annual Meeting of the Retina Society, Congress of the Asia-Pacific Academy of Ophthalmology (APAO), European Association for Vision and Eye Research (EVER) Annual Congress, European Vitreoretinal Society (EVRS) Annual Meeting, Association for Research in Vision and Ophthalmology (ARVO) Meeting, International Vitreoretinal Meeting, and World Ophthalmology Congress. SELECTION CRITERIA: Only randomised controlled trials (RCTs) comparing ILM peeling with the no-peeling counterpart were included. DATA COLLECTION AND ANALYSIS: Two review authors (KSC and NL) independently assessed the titles and abstracts of all RCTs identified by electronic and manual searches.We obtained Individual patient data (IPD) from three of the four identified eligible trials. The fourth identified RCT had only been published in abstract form and no IPD were available; we included data from this published abstract for one outcome (macular hole closure).The primary outcome was distance visual acuity at six months. Secondary outcomes included distance and near  visual acuity at three and 12 months postoperatively, near visual acuity at six months postoperatively, primary (after a single surgery) and final (following more than one surgery) macular hole closure, need for additional surgical interventions, vision-related quality of life and intraoperative and postoperative complications.We performed meta-analysis using standard techniques (the Mantel-Haenszel odds ratio (OR) for binary outcomes, mean difference (MD) for continuous outcomes) using a fixed-effect model. For two outcomes we also used the IPD to perform adjusted analyses using regression methods. MAIN RESULTS: We identified and included four RCTs; these were conducted in Denmark, France, Hong Kong and the United Kingdom/Republic of Ireland and randomised 47, 80, 49 and 141 participants respectively.There was no evidence of a difference in the primary outcome (distance visual acuity at six months), nor in distance visual acuity at 12 months between randomised groups. However, there was evidence of improved best corrected distance visual acuity in the ILM peeling group at three months (WMD -0.09, 95% CI -0.17 to -0.02). We found no evidence for a difference in near vision between groups at any of the time points investigated.Overall, more participants in the ILM peeling group than in the no-peeling group had primary macular hole closure (OR 9.27, 95% CI 4.98 to 17.24); this held true when results were stratified by the stage of the macular hole. There was also evidence that those in the ILM peeling group were more likely to have final macular hole closure (OR 3.99, 95% CI 1.63 to 9.75). Fewer participants required further surgery in the ILM peeling group than in the no-peeling group (OR 0.11, 95% CI: 0.05 to 0.23).Rates of intraoperative and postoperative complications were similar in both groups.Based on the results of one study, there was no evidence that total VFQ-25 or EQ-5D scores differed between the groups at six months.  Based on this same study, ILM peeling is highly likely to be cost-effective. AUTHORS' CONCLUSIONS: Although we found no evidence of a benefit of ILM peeling in terms of the primary outcome (visual acuity at six months), ILM peeling appears to be superior to its no-peeling counterpart as it offers more favourable cost effectiveness by increasing the likelihood of primary anatomical closure and subsequently decreasing the likelihood of further surgery, with no differences in unwanted side-effects compared with no peeling. 

Urinary incontinence in men after formal one-to-one pelvic-floor muscle training following radical prostatectomy or transurethral resection of the prostate (MAPS): two parallel randomised controlled trials.

BACKGROUND: Urinary incontinence is common immediately after prostate surgery. Men are often advised to do pelvic-floor exercises, but evidence to support this is inconclusive. Our aim was to establish if formal one-to-one pelvic floor muscle training reduces incontinence. METHODS: We undertook two randomised trials in men in the UK who were incontinent 6 weeks after radical prostatectomy (trial 1) or transurethral resection of the prostate (TURP; trial 2) to compare four sessions with a therapist over 3 months with standard care and lifestyle advice only. Randomisation was by remote computer allocation. Our primary endpoints, collected via postal questionnaires, were participants' reports of urinary incontinence and incremental cost per quality-adjusted life year (QALY) after 12 months. Group assignment was masked from outcome assessors, but this masking was not possible for participants or caregivers. We used intention-to-treat analyses to compare the primary outcome at 12 months. This study is registered, number ISRCTN87696430. FINDINGS: In the intervention group in trial 1, the rate of urinary incontinence at 12 months (148 [76%] of 196) was not significantly different from the control group (151 [77%] of 195; absolute risk difference [RD] -1·9%, 95% CI -10 to 6). In trial 2, the difference in the rate of urinary incontinence at 12 months (126 [65%] of 194) from the control group was not significant (125 [62%] of 203; RD 3·4%, 95% CI -6 to 13). Adjusting for minimisation factors or doing treatment-received analyses did not change these results in either trial. No adverse effects were reported. In both trials, the intervention resulted in higher mean costs per patient (£180 and £209 respectively) but we did not identify evidence of an economically important difference in QALYs (0·002 [95% CI -0·027 to 0·023] and -0·00003 [-0·026 to 0·026]). INTERPRETATION: In settings where information about pelvic-floor exercise is widely available, one-to-one conservative physical therapy for men who are incontinent after prostate surgery is unlikely to be effective or cost effective. The high rates of persisting incontinence after 12 months suggest a substantial unrecognised and unmet need for management in these men. FUNDING: National Institute of Health Research, Health Technology Assessment (NIHR HTA) Programme.

Surveillance mammography for detecting ipsilateral breast tumour recurrence and metachronous contralateral breast cancer: a systematic review.

OBJECTIVES: To determine the diagnostic accuracy of surveillance mammography for detecting ipsilateral breast tumour recurrence and metachronous contralateral breast cancer in women previously treated for primary breast cancer. METHODS: A systematic review of surveillance mammography compared with ultrasound, magnetic resonance imaging (MRI), specialist-led clinical examination or unstructured primary care follow-up, using histopathological assessment for test positives and follow-up for test negatives as the reference standard. RESULTS: Nine studies met our inclusion criteria. Variations in study comparisons precluded meta-analysis. For routine ipsilateral breast tumour detection, surveillance mammography sensitivity ranged from 64-67% and specificity ranged from 85-97%. For MRI, sensitivity ranged from 86-100% and specificity was 93%. For non-routine ipsilateral breast tumour detection, sensitivity and specificity for surveillance mammography ranged from 50-83% and 57-75% and for MRI 93-100% and 88-96%. For routine metachronous contralateral breast cancer detection, one study reported sensitivity of 67% and specificity of 50% for both surveillance mammography and MRI. CONCLUSION: Although mammography is associated with high sensitivity and specificity, MRI is the most accurate test for detecting ipsilateral breast tumour recurrence and metachronous contralateral breast cancer in women previously treated for primary breast cancer. Results should be interpreted with caution because of the limited evidence base. Key Points • Surveillance mammography is associated with high sensitivity and specificity • Findings suggest that MRI is the most accurate test for detecting further breast cancer • Robust conclusions cannot be made due to the limited evidence base • Further research comparing surveillance mammography and other diagnostic tests is required.

Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: Systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to assess the test performance and clinical effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC) in people suspected of new or recurrent bladder cancer. METHODS: A systematic review was conducted of randomized controlled trials (RCTs), nonrandomized comparative studies, or diagnostic cross-sectional studies comparing PDD with WLC. Fifteen electronic databases and Web sites were searched (last searches April 2008). For clinical effectiveness, only RCTs were considered. RESULTS: Twenty-seven studies (2,949 participants) assessed test performance. PDD had higher sensitivity than WLC (92 percent, 95 percent confidence interval [CI], 80-100 percent versus 71 percent, 95 percent CI, 49-93 percent) but lower specificity (57 percent, 95 percent CI, 36-79 percent versus 72 percent, 95 percent CI, 47-96 percent). For detecting higher risk tumors, median range sensitivity of PDD (89 percent [6-100 percent]) was higher than WLC (56 percent [0-100 percent]) whereas for lower risk tumors it was broadly similar (92 percent [20-95 percent] versus 95 percent [8-100 percent]). Four RCTs (709 participants) using 5-aminolaevulinic acid (5-ALA) as the photosensitising agent reported clinical effectiveness. Using PDD at transurethral resection of bladder tumor (TURBT) resulted in fewer residual tumors at check cystoscopy (relative risk [RR], 0.37, 95 percent CI, 0.20-0.69) and longer recurrence-free survival (RR, 1.37, 95 percent CI, 1.18-1.59), compared with WLC. CONCLUSIONS: PDD detects more bladder tumors than WLC, including more high-risk tumors. Based on four RCTs reporting clinical effectiveness, 5-aminolaevulinic acid-mediated PDD at TURBT facilitates a more complete resection and prolongs recurrence-free survival.

Diagnostic accuracy of optical coherence tomography for diagnosing glaucoma: secondary analyses of the GATE study.

BACKGROUND/AIMS: To assess the diagnostic performance of retinal nerve fibre layer (RNFL) data of optical coherence tomography (OCT) for detecting glaucoma. METHODS: Secondary analyses of a prospective, multicentre diagnostic study (Glaucoma Automated Tests Evaluation (GATE)) referred to hospital eye services in the UK were conducted. We included data from 899 of 966 participants referred to hospital eye services with suspected glaucoma or ocular hypertension. We used both eyes' data and logistic regression-based receiver operator characteristics analysis to build a set of models to measure the sensitivity and specificity of the average and inferior quadrant RNFL thickness data of OCT. The reference standard was expert clinician examination including automated perimetry. The main outcome measures were sensitivity at 0.95 specificity and specificity at 0.95 sensitivity and the corresponding RNFL thickness thresholds. We explored the possibility of accuracy improvement by adding measures of within-eye and between-eye variation, scan quality, intraocular pressure (IOP) and age. RESULTS: Glaucoma was diagnosed in at least one eye in 17% of participants. Areas under the curve were between 0.83 and 0.88. When specificity was fixed at 0.95, the sensitivity was between 0.38 and 0.55, and the highest values were reached with models including the inferior quadrant rather than the average RNFL thickness. Fixing sensitivity at 0.95, the specificity was between 0.36 and 0.58. The addition of age, refractive error, IOP or within-subject variation did not improve the accuracy. CONCLUSION: RNFL thickness data of OCT can be used as a diagnostic test, but accuracy estimates remain moderate even in exploratory multivariable modelling of aiming to improve accuracy.

Nuclear magnetic resonance-based metabolomics identifies phenylalanine as a novel predictor of incident heart failure hospitalisation: results from PROSPER and FINRISK 1997.

AIMS: We investigated the association between quantified metabolite, lipid and lipoprotein measures and incident heart failure hospitalisation (HFH) in the elderly, and examined whether circulating metabolic measures improve HFH prediction. METHODS AND RESULTS: Overall, 80 metabolic measures from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial were measured by proton nuclear magnetic resonance spectroscopy (n = 5341; 182 HFH events during 2.7-year follow-up). We repeated the work in FINRISK 1997 (n = 7330; 133 HFH events during 5-year follow-up). In PROSPER, the circulating concentrations of 13 metabolic measures were found to be significantly different in those who were later hospitalised for heart failure after correction for multiple comparisons. These included creatinine, phenylalanine, glycoprotein acetyls, 3-hydroxybutyrate, and various high-density lipoprotein measures. In Cox models, two metabolites were associated with risk of HFH after adjustment for clinical risk factors and N-terminal pro-B-type natriuretic peptide (NT-proBNP): phenylalanine [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10-1.53; P = 0.002] and acetate (HR 0.81, 95% CI 0.68-0.98; P = 0.026). Both were retained in the final model after backward elimination. Compared to a model with established risk factors and NT-proBNP, this model did not improve the C-index but did improve the overall continuous net reclassification index (NRI 0.21; 95% CI 0.06-0.35; P = 0.007) due to improvement in classification of non-cases (NRI 0.14; 95% CI 0.12-0.17; P < 0.001). Phenylalanine was replicated as a predictor of HFH in FINRISK 1997 (HR 1.23, 95% CI 1.03-1.48; P = 0.023). CONCLUSION: Our findings identify phenylalanine as a novel predictor of incident HFH, although prediction gains are low. Further mechanistic studies appear warranted.