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BACKGROUND: Ovarian cancer (OC) has the highest case fatality rate of all gynaecological cancers. Diagnostic delays are caused by non-specific symptoms. Existing systematic reviews have not comprehensively covered tests in current practice, not estimated accuracy separately in pre- and postmenopausal women, or used inappropriate meta-analytic methods. OBJECTIVES: To establish the accuracy of combinations of menopausal status, ultrasound scan (USS) and biomarkers for the diagnosis of ovarian cancer in pre- and postmenopausal women and compare the accuracy of different test combinations. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), five other databases and three trial registries from 1991 to 2015 and MEDLINE (Ovid) and Embase (Ovid) form June 2015 to June 2019. We also searched conference proceedings from the European Society of Gynaecological Oncology, International Gynecologic Cancer Society, American Society of Clinical Oncology and Society of Gynecologic Oncology, ZETOC and Conference Proceedings Citation Index (Web of Knowledge). We searched reference lists of included studies and published systematic reviews. SELECTION CRITERIA: We included cross-sectional diagnostic test accuracy studies evaluating single tests or comparing two or more tests, randomised trials comparing two or more tests, and studies validating multivariable models for the diagnosis of OC investigating test combinations, compared with a reference standard of histological confirmation or clinical follow-up in women with a pelvic mass (detected clinically or through USS) suspicious for OC. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using QUADAS-2. We used the bivariate hierarchical model to indirectly compare tests at commonly reported thresholds in pre- and postmenopausal women separately. We indirectly compared tests across all thresholds and estimated sensitivity at fixed specificities of 80% and 90% by fitting hierarchical summary receiver operating characteristic (HSROC) models in pre- and postmenopausal women separately. MAIN RESULTS: We included 59 studies (32,059 women, 9545 cases of OC). Two tests evaluated the accuracy of a combination of menopausal status and USS findings (IOTA Logistic Regression Model 2 (LR2) and the Assessment of Different NEoplasias in the adneXa model (ADNEX)); one test evaluated the accuracy of a combination of menopausal status, USS findings and serum biomarker CA125 (Risk of Malignancy Index (RMI)); and one test evaluated the accuracy of a combination of menopausal status and two serum biomarkers (CA125 and HE4) (Risk of Ovarian Malignancy Algorithm (ROMA)). Most studies were at high or unclear risk of bias in participant, reference standard, and flow and timing domains. All studies were in hospital settings. Prevalence was 16% (RMI, ROMA), 22% (LR2) and 27% (ADNEX) in premenopausal women and 38% (RMI), 45% (ROMA), 52% (LR2) and 55% (ADNEX) in postmenopausal women. The prevalence of OC in the studies was considerably higher than would be expected in symptomatic women presenting in community-based settings, or in women referred from the community to hospital with a suspicion of OC. Studies were at high or unclear applicability because presenting features were not reported, or USS was performed by experienced ultrasonographers for RMI, LR2 and ADNEX. The higher sensitivity and lower specificity observed in postmenopausal compared to premenopausal women across all index tests and at all thresholds may reflect highly selected patient cohorts in the included studies. In premenopausal women, ROMA at a threshold of 13.1 (± 2), LR2 at a threshold to achieve a post-test probability of OC of 10% and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 77.4%, 95% CI 72.7% to 81.5%; LR2: 83.3%, 95% CI 74.7% to 89.5%; ADNEX: 95.5%, 95% CI 91.0% to 97.8%) compared to RMI (57.2%, 95% CI 50.3% to 63.8%). The specificity of ROMA and ADNEX were lower in premenopausal women (ROMA: 84.3%, 95% CI 81.2% to 87.0%; ADNEX: 77.8%, 95% CI 67.4% to 85.5%) compared to RMI 92.5% (95% CI 90.3% to 94.2%). The specificity of LR2 was comparable to RMI (90.4%, 95% CI 84.6% to 94.1%). In postmenopausal women, ROMA at a threshold of 27.7 (± 2), LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 90.3%, 95% CI 87.5% to 92.6%; LR2: 94.8%, 95% CI 92.3% to 96.6%; ADNEX: 97.6%, 95% CI 95.6% to 98.7%) compared to RMI (78.4%, 95% CI 74.6% to 81.7%). Specificity of ROMA at a threshold of 27.7 (± 2) (81.5, 95% CI 76.5% to 85.5%) was comparable to RMI (85.4%, 95% CI 82.0% to 88.2%), whereas for LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) specificity was lower (LR2: 60.6%, 95% CI 50.5% to 69.9%; ADNEX: 55.0%, 95% CI 42.8% to 66.6%). AUTHORS' CONCLUSIONS: In specialist healthcare settings in both premenopausal and postmenopausal women, RMI has poor sensitivity. In premenopausal women, ROMA, LR2 and ADNEX offer better sensitivity (fewer missed cancers), but for ROMA and ADNEX this is off-set by a decrease in specificity and increase in false positives. In postmenopausal women, ROMA demonstrates a higher sensitivity and comparable specificity to RMI. ADNEX has the highest sensitivity in postmenopausal women, but reduced specificity. The prevalence of OC in included studies is representative of a highly selected referred population, rather than a population in whom referral is being considered. The comparative accuracy of tests observed here may not be transferable to non-specialist settings. Ultimately health systems need to balance accuracy and resource implications to identify the most suitable test.

IntroductionProstate MRI is a well-established tool for the diagnostic work-up for men with suspected prostate cancer (PCa). Current recommendations advocate the use of multiparametric MRI (mpMRI), which is composed of three sequences: T2-weighted sequence (T2W), diffusion-weighted sequence (DWI) and dynamic contrast-enhanced sequence (DCE). Prior studies suggest that a biparametric MRI (bpMRI) approach, omitting the DCE sequences, may not compromise clinically significant cancer detection, though there are limitations to these studies, and it is not known how this may affect treatment eligibility. A bpMRI approach will reduce scanning time, may be more cost-effective and, at a population level, will allow more men to gain access to an MRI than an mpMRI approach.MethodsProstate Imaging Using MRI±Contrast Enhancement (PRIME) is a prospective, international, multicentre, within-patient diagnostic yield trial assessing whether bpMRI is non-inferior to mpMRI in the diagnosis of clinically significant PCa. Patients will undergo the full mpMRI scan. Radiologists will be blinded to the DCE and will initially report the MRI using only the bpMRI (T2W and DWI) sequences. They will then be unblinded to the DCE sequence and will then re-report the MRI using the mpMRI sequences (T2W, DWI and DCE). Men with suspicious lesions on either bpMRI or mpMRI will undergo prostate biopsy. The main inclusion criteria are men with suspected PCa, with a serum PSA of ≤20 ng/mL and without prior prostate biopsy. The primary outcome is the proportion of men with clinically significant PCa detected (Gleason score ≥3+4 or Gleason grade group ≥2). A sample size of at least 500 patients is required. Key secondary outcomes include the proportion of clinically insignificant PCa detected and treatment decision.Ethics and disseminationEthical approval was obtained from the National Research Ethics Committee West Midlands, Nottingham (21/WM/0091). Results of this trial will be disseminated through peer-reviewed publications. Participants and relevant patient support groups will be informed about the results of the trial.Trial registration numberNCT04571840.

Background: Worldwide, many countries have adopted colorectal cancer (CRC) screening programmes, often based on faecal occult blood tests (FOBTs). CRC screening aims to detect advanced neoplasia (AN), which is defined as CRC or advanced adenomas. FOBTs fall into two categories based on detection technique and the detected blood component: qualitative guaiac-based FOBTs (gFOBTs) and faecal immunochemical tests (FITs), which can be qualitative and quantitative. Screening with gFOBTs reduces CRC-related mortality. Objectives: To compare the diagnostic test accuracy of gFOBT and FIT screening for detecting advanced colorectal neoplasia in average-risk individuals. Search methods: We searched CENTRAL, MEDLINE, Embase, BIOSIS Citation Index, Science Citation Index Expanded, and Google Scholar. We searched the reference lists and PubMed-related articles of included studies to identify additional studies. Selection criteria: We included prospective and retrospective studies that provided the number of true positives, false positives, false negatives, and true negatives for gFOBTs, FITs, or both, with colonoscopy as reference standard. We excluded case-control studies. We included studies in which all participants underwent both index test and reference standard ("reference standard: all"), and studies in which only participants with a positive index test underwent the reference standard while participants with a negative test were followed for at least one year for development of interval carcinomas ("reference standard: positive"). The target population consisted of asymptomatic, average-risk individuals undergoing CRC screening. The target conditions were CRC and advanced neoplasia (advanced adenomas and CRC combined). Data collection and analysis: Two review authors independently screened and selected studies for inclusion. In case of disagreement, a third review author made the final decision. We used the Rutter and Gatsonis hierarchical summary receiver operating characteristic model to explore differences between tests and identify potential sources of heterogeneity, and the bivariate hierarchical model to estimate sensitivity and specificity at common thresholds: 10 µg haemoglobin (Hb)/g faeces and 20 µg Hb/g faeces. We performed indirect comparisons of the accuracy of the two tests and direct comparisons when both index tests were evaluated in the same population. Main results: We ran the initial search on 25 June 2019, which yielded 63 studies for inclusion. We ran a top-up search on 14 September 2021, which yielded one potentially eligible study, currently awaiting classification. We included a total of 33 "reference standard: all" published articles involving 104,640 participants. Six studies evaluated only gFOBTs, 23 studies evaluated only FITs, and four studies included both gFOBTs and FITs. The cut-off for positivity of FITs varied between 2.4 μg and 50 µg Hb/g faeces. For each Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability than gFOBTs for AN (P < 0.001) and CRC (P = 0.004). For the detection of AN, the summary sensitivity of gFOBTs was 15% (95% confidence interval (CI) 12% to 20%), which was significantly lower than FITs at both 10 μg and 20 μg Hb/g cut-offs with summary sensitivities of 33% (95% CI 27% to 40%; P < 0.001) and 26% (95% CI 21% to 31%, P = 0.002), respectively. Results were simulated in a hypothetical cohort of 10,000 screening participants with 1% CRC prevalence and 10% AN prevalence. Out of 1000 participants with AN, gFOBTs missed 850, while FITs missed 670 (10 μg Hb/g cut-off) and 740 (20 μg Hb/g cut-off). No significant differences in summary specificity for AN detection were found between gFOBTs (94%; 95% CI 92% to 96%), and FITs at 10 μg Hb/g cut-off (93%; 95% CI 90% to 95%) and at 20 μg Hb/g cut-off (97%; 95% CI 95% to 98%). So, among 9000 participants without AN, 540 were offered (unnecessary) colonoscopy with gFOBTs compared to 630 (10 μg Hb/g) and 270 (20 μg Hb/g) with FITs. Similarly, for the detection of CRC, the summary sensitivity of gFOBTs, 39% (95% CI 25% to 55%), was significantly lower than FITs at 10 μg and 20 μg Hb/g cut-offs: 76% (95% CI 57% to 88%: P = 0.001) and 65% (95% CI 46% to 80%; P = 0.035), respectively. So, out of 100 participants with CRC, gFOBTs missed 61, and FITs missed 24 (10 μg Hb/g) and 35 (20 μg Hb/g). No significant differences in summary specificity for CRC were found between gFOBTs (94%; 95% CI 91% to 96%), and FITs at the 10 μg Hb/g cut-off (94%; 95% CI 87% to 97%) and 20 μg Hb/g cut-off (96%; 95% CI 91% to 98%). So, out of 9900 participants without CRC, 594 were offered (unnecessary) colonoscopy with gFOBTs versus 594 (10 μg Hb/g) and 396 (20 μg Hb/g) with FITs. In five studies that compared FITs and gFOBTs in the same population, FITs showed a higher discriminative ability for AN than gFOBTs (P = 0.003). We included a total of 30 "reference standard: positive" studies involving 3,664,934 participants. Of these, eight were gFOBT-only studies, 18 were FIT-only studies, and four studies combined both gFOBTs and FITs. The cut-off for positivity of FITs varied between 5 µg to 250 µg Hb/g faeces. For each QUADAS-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability for detecting CRC than gFOBTs (P < 0.001). The summary sensitivity for CRC of gFOBTs, 59% (95% CI 55% to 64%), was significantly lower than FITs at the 10 μg Hb/g cut-off, 89% (95% CI 80% to 95%; P < 0.001) and the 20 μg Hb/g cut-off, 89% (95% CI 85% to 92%; P < 0.001). So, in the hypothetical cohort with 100 participants with CRC, gFOBTs missed 41, while FITs missed 11 (10 μg Hb/g) and 11 (20 μg Hb/g). The summary specificity of gFOBTs was 98% (95% CI 98% to 99%), which was higher than FITs at both 10 μg and 20 μg Hb/g cut-offs: 94% (95% CI 92% to 95%; P < 0.001) and 95% (95% CI 94% to 96%; P < 0.001), respectively. So, out of 9900 participants without CRC, 198 were offered (unnecessary) colonoscopy with gFOBTs compared to 594 (10 μg Hb/g) and 495 (20 μg Hb/g) with FITs. At a specificity of 90% and 95%, FITs had a higher sensitivity than gFOBTs. Authors' conclusions: FITs are superior to gFOBTs in detecting AN and CRC in average-risk individuals. Specificity of both tests was similar in "reference standard: all" studies, whereas specificity was significantly higher for gFOBTs than FITs in "reference standard: positive" studies. However, at pre-specified specificities, the sensitivity of FITs was significantly higher than gFOBTs.

ObjectiveTo investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping.DesignObservational controlled interrupted time series study.SettingUK primary and secondary care.Participants515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping.InterventionFetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure.Main outcome measuresThe primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally.ResultsProphylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years.ConclusionsThis study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section.

Viral load (VL) testing in people living with HIV (PLHIV) helps to monitor antiretroviral therapy (ART). VL is still largely tested using central laboratory-based platforms, which have long test turnaround times and involve sophisticated equipment. VL tests with point-of-care (POC) platforms capable of being used near the patient are potentially easy to use, give quick results, are cost-effective, and could replace central or reference VL testing platforms.To estimate the diagnostic accuracy of POC tests to detect high viral load levels in PLHIV attending healthcare facilities.We searched eight electronic databases using standard, extensive Cochrane search methods, and did not use any language, document type, or publication status limitations. We also searched the reference lists of included studies and relevant systematic reviews, and consulted an expert in the field from the World Health Organization (WHO) HIV Department for potentially relevant studies. The latest search was 23 November 2020.We included any primary study that compared the results of a VL test with a POC platform to that of a central laboratory-based reference test to detect high viral load in PLHIV on HIV/AIDS care or follow-up. We included all forms of POC tests for VL as defined by study authors, regardless of the healthcare facility in which the test was conducted. We excluded diagnostic case-control studies with healthy controls and studies that did not provide sufficient data to create the 2 × 2 tables to calculate sensitivity and specificity. We did not limit our study inclusion to age, gender, or geographical setting.Two review authors independently screened the titles, abstracts, and full texts of the search results to identify eligible articles. They also independently extracted data using a standardized data extraction form and conducted risk of bias assessment using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Using participants as the unit of analysis, we fitted simplified univariable models for sensitivity and specificity separately, employing a random-effects model to estimate the summary sensitivity and specificity at the current and commonly reported World Health Organization (WHO) threshold (≥ 1000 copies/mL). The bivariate models did not converge to give a model estimate.We identified 18 studies (24 evaluations, 10,034 participants) defining high viral loads at main thresholds ≥ 1000 copies/mL (n = 20), ≥ 5000 copies/mL (n = 1), and ≥ 40 copies/mL (n = 3). All evaluations were done on samples from PLHIV retrieved from routine HIV/AIDS care centres or health facilities. For clinical applicability, we included 14 studies (20 evaluations, 8659 participants) assessing high viral load at the clinical threshold of ≥ 1000 copies/mL in the meta-analyses. Of these, sub-Saharan Africa, Europe, and Asia contributed 16, three, and one evaluation respectively. All included participants were on ART in only nine evaluations; in the other 11 evaluations the proportion of participants on ART was either partial or not clearly stated. Thirteen evaluations included adults only (n = 13), five mixed populations of adults and children, whilst in the remaining two the age of included populations was not clearly stated. The majority of evaluations included commercially available tests (n = 18). Ten evaluations were POC VL tests conducted near the patient in a peripheral or onsite laboratory, whilst the other 10 were evaluations of POC VL tests in a central or reference laboratory setting. The test types evaluated as POC VL tests included Xpert HIV-1 Viral Load test (n = 8), SAMBA HIV-1 Semi-Q Test (n = 9), Alere Q NAT prototype assay for HIV-1 (n = 2) and m-PIMA HIV-1/2 Viral Load test (n = 1). The majority of evaluations (n = 17) used plasma samples, whilst the rest (n = 3) utilized whole blood samples. Pooled sensitivity (95% confidence interval (CI)) of POC VL at a threshold of ≥ 1000 copies/mL was 96.6% (94.8 to 97.8) (20 evaluations, 2522 participants), and pooled specificity (95% CI) was 95.7% (90.8 to 98.0) (20 evaluations, 6137 participants). Median prevalence for high viral load (≥ 1000 copies/mL) (n = 20) was 33.4% (range 6.9% to 88.5%). Limitations The risk of bias was mostly assessed as unclear across the four domains due to incomplete reporting.We found POC VL to have high sensitivity and high specificity for the diagnosis of high HIV viral load in PLHIV attending healthcare facilities at a clinical threshold of ≥ 1000 copies/mL.

GBS2 was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (13/82/04). The funder had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. JJD is supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. KSK is a Distinguished Investigator funded by the Beatriz Galindo (senor modality) Program grant given to the University of Granada by the Ministry of Science, Innovation, and Universities of the Spanish Government., Background: Mother-to-baby transmission of group B Streptococcus (GBS) is the main cause of early-onset infection. We evaluated whether, in women with clinical risk factors for early neonatal infection, the use of point-ofcare rapid intrapartum test to detect maternal GBS colonisation reduces maternal antibiotic exposure compared with usual care, where antibiotics are administered due to those risk factors. We assessed the accuracy of the rapid test in diagnosing maternal GBS colonisation, against the reference standard of selective enrichment culture. Methods: We undertook a parallel-group cluster randomised trial, with nested test accuracy study and microbiological sub-study. UK maternity units were randomised to a strategy of rapid test (GeneXpert GBS system, Cepheid) or usual care. Within units assigned to rapid testing, vaginal-rectal swabs were taken from women with risk factors for vertical GBS transmission in established term labour. The trial primary outcome was the proportion of women receiving intrapartum antibiotics to prevent neonatal early-onset GBS infection. The accuracy of the rapid test was compared against the standard of selective enrichment culture in diagnosing maternal GBS colonisation. Antibiotic resistance profiles were determined in paired maternal and infant samples. Results: Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units; 906 mothers (951 babies) were in usual care units. There was no evidence of a difference in the rates of intrapartum antibiotic prophylaxis (relative risk 1.16, 95% CI 0.83 to 1.64) between the rapid test (41%, 297/716) and usual care (36%, 328/906) units. No serious adverse events were reported. The sensitivity and specificity measures of the rapid test were 86% (95% CI 81 to 91%) and 89% (95% CI 85 to 92%), respectively. Babies born to mothers who carried antibiotic-resistant Escherichia coli were more likely to be colonised with antibiotic-resistant strains than those born to mothers with antibiotic-susceptible E. coli. Conclusion: The use of intrapartum rapid test to diagnose maternal GBS colonisation did not reduce the rates of antibiotics administered for preventing neonatal early-onset GBS infection than usual care, although with considerable uncertainty. The accuracy of the rapid test is within acceptable limits., National Institute for Health Research (NIHR) 13/82/04, NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust University of Birmingham, Beatriz Galindo (senor modality) Program

Introduction Patients with atrial fibrillation frequently suffer from heart failure despite having a normal ejection fraction. There is no proven therapy to improve physical capacity and quality of life in patients with permanent atrial fibrillation with preserved cardiac contractility. Objective The IMproved exercise tolerance in heart failure with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation (IMPRESS-AF) trial addressed whether or not 2 years of treatment with spironolactone, as compared with placebo, improves exercise tolerance, quality of life and diastolic function in patients with permanent atrial fibrillation and preserved left ventricular ejection fraction. Design A randomised, single-centre, double-blind, placebo-controlled trial. Setting Two hundred and fifty ambulatory patients [mean age 72.3 years (standard deviation 7.4 years); 23.6% female] with permanent atrial fibrillation and left ventricular ejection fraction ≥ 55% [mean 60.5% (standard deviation 5.5%)]. Interventions Treatment with either 25 mg of spironolactone (n = 125) or placebo (n = 125) daily. Main outcome measures The primary efficacy end point was exercise tolerance at 2 years as measured by peak oxygen consumption (VO2) on cardiopulmonary exercise testing. Secondary end points were quality of life, the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E′) (E/E′; a marker of diastolic dysfunction), all-cause hospital admissions and spontaneous return to sinus rhythm. Treatment effects were estimated by adjusting for baseline values. Study ethics The study was approved by the National Research and Ethics Committee West Midlands – Coventry and Warwickshire (reference 14/WM/1211). All patients provided informed written consent. Results There was no difference in the peak oxygen consumption at 2 years between the spironolactone group [analysed, n = 103; mean VO2 14.03 ml/minute/kg (standard deviation 5.38 ml/minute/kg)] and the placebo group [analysed, n = 106; mean VO2 14.45 ml/minute/kg (standard deviation 5.14 ml/minute/kg)] (adjusted treatment effect –0.28 ml/minute/kg, 95% confidence interval –1.27 to 0.71 ml/minute/kg; p = 0.58). The findings were consistent across all sensitivity analyses. For secondary efficacy end points, there was no significant change in the mean 6-minute walking distance (treatment effect –8.47 m, 95% confidence interval –31.87 to 14.93 m; p = 0.48). This also held true for the mean ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E′) (i.e. E/E′), a measure of left ventricular diastolic function (treatment effect –0.64, 95% confidence interval –1.48 to 0.20; p = 0.13). The study treatment was also not associated with a significant treatment effect for quality-of-life scores [p = 0.67 for the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), questionnaire and p = 0.84 for the Minnesota Living with Heart Failure (MLWHF) questionnaire at 2 years]. The findings remained consistent after adjustment for age, sex and body mass index. Spontaneous return to sinus rhythm on electrocardiography, performed at 2 years, was uncommon in both study groups [4% (standard deviation 3.8%) in the placebo group and 8% (standard deviation 7.9%) in the spironolactone group; p = 0.21]. At least one hospitalisation for any reason was required by 15.3% of patients in the spironolactone group and 22.8% in the placebo group (p = 0.15; after adjustment for age, sex and body mass index, p = 0.12). The estimated glomerular filtration rate was reduced by 6 ml/minute/1.73 m2 at 2 years in patients allocated to spironolactone (with no reduction in those receiving placebo, resulting in a reduction in the p-value of the difference in the estimated glomerular filtration rate between patients in the spironolactone group and those in the placebo group of Limitations This was a relatively small study. Conclusions Spironolactone therapy does not improve exercise capacity, cardiac function or quality of life in patients with atrial fibrillation and preserved ejection fraction. Future work Further testing of spironolactone in patients with atrial fibrillation and preserved ejection fraction would be difficult to justify. Trial registration Current Controlled Trials ISRCTN10259346, European Union Clinical Trials Register 2014-003702-33 and ClinicalTrials.gov NCT02673463. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 4. See the NIHR Journals Library website for further project information. This project received support from the NIHR Clinical Research Network.

Objective The objective of this study was to examine methodological and reporting characteristics of systematic reviews and meta-analyses which compare diagnostic test accuracy (DTA) of multiple index tests, identify good practice, and develop guidance for better reporting. Study Design and Setting Methodological survey of 127 comparative or multiple tests reviews published in 74 different general medical and specialist journals. We summarized methods and reporting characteristics that are likely to differ between reviews of a single test and comparative reviews. We then developed guidance to enhance reporting of test comparisons in DTA reviews. Results Of 127 reviews, 16 (13%) reviews restricted study selection and test comparisons to comparative accuracy studies while the remaining 111 (87%) reviews included any study type. Fifty-three reviews (42%) statistically compared test accuracy with only 18 (34%) of these using recommended methods. Reporting of several items—in particular the role of the index tests, test comparison strategy, and limitations of indirect comparisons (i.e., comparisons involving any study type)—was deficient in many reviews. Five reviews with exemplary methods and reporting were identified. Conclusion Reporting quality of reviews which evaluate and compare multiple tests is poor. The guidance developed, complemented with the exemplars, can assist review authors in producing better quality comparative reviews.

Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

BackgroundThe success of case isolation and contact tracing for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS), i.e. fever, cough and loss or change in smell or taste, could improve case definitions and accelerate case identification in SARS-CoV-2 contacts.MethodsTwo prospective longitudinal London (UK)-based cohorts of community SARS-CoV-2 contacts, recruited within 5 days of exposure, provided independent training and test datasets. Infected and uninfected contacts completed daily symptom diaries from the earliest possible time-points. Diagnostic information gained by adding symptoms to the CS was quantified using likelihood ratios and area under the receiver operating characteristic curve. Improvements in sensitivity and time to detection were compared with penalties in terms of specificity and number needed to test.ResultsOf 529 contacts within two cohorts, 164 (31%) developed PCR-confirmed infection and 365 (69%) remained uninfected. In the training dataset (n=168), 29% of infected contacts did not report the CS. Four symptoms (sore throat, muscle aches, headache and appetite loss) were identified as early-predictors (EP) which added diagnostic value to the CS. The broadened symptom criterion “≥1 of the CS, or ≥2 of the EP” identified PCR-positive contacts in the test dataset on average 2 days earlier after exposure (p=0.07) than “≥1 of the CS”, with only modest reduction in specificity (5.7%).ConclusionsBroadening symptom criteria to include individuals with at least two of muscle aches, headache, appetite loss and sore throat identifies more infections and reduces time to detection, providing greater opportunities to prevent SARS-CoV-2 transmission.

ObjectivesThis is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the accuracy of routine blood-based laboratory tests to predict mortality and deterioration to severe or critical (from mild or moderate) COVID-19 in people with SARS-CoV-2 infection.Secondary objectivesWhere data are available, we will investigate whether prognostic accuracy varies according to a specific measurement or test, reference standard, timing of outcome verification, sample type, study design, and setting, including prevalence of the target condition (either by stratified analysis or meta-regression).

Background Although the pharmacological approach may help with motor symptoms in Parkinson's disease (PD), they are clearly not the complete solution. Thus, for the treatment of PD motor symptoms, physical activity has been proposed as an effective intervention. Methods A systematic search in MEDLINE, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials databases was conducted to identify randomized controlled trials testing the effectiveness of exercise interventions on motor symptoms of PD. Physical exercise interventions were divided into 9 categories: endurance, resistance, combined, balance, dance, alternative exercises, body weight supported, sensorimotor interventions including endurance exercise, and sensorimotor interventions not including endurance exercise. A pairwise meta-analysis for direct and indirect comparisons between intervention and control/nonintervention groups was carried out. Results Fifty-six studies met the inclusion criteria, including 2740 participants, aged between 57.6 and 77.7 years. Results of our analyses showed that sensorimotor training including endurance (effect size [ES]-1.09; 95% confidence interval [CI], -1.68 to -0.50), resistance (ES-0.82; 95% CI, -1.23 to -0.41), and dance (ES-0.64; 95% CI, -1.24 to -0.05) were the most effective physical activity interventions for mitigating PD motor symptoms. Conclusion Physical activity interventions are an effective strategy for the management of motor symptoms in patients with PD. Among the different exercise intervention programs, those including more complex and demanding activities (sensorimotor training including endurance, resistance, and dance) seem to be the most effective physical activity interventions.

Background The standard method of diagnosing HIV in infants and children less than 18 months is with a nucleic acid amplification test reverse transcriptase polymerase chain reaction test (NAT RT‐PCR) detecting viral ribonucleic acid (RNA). Laboratory testing using the RT‐PCR platform for HIV infection is limited by poor access, logistical support, and delays in relaying test results and initiating therapy in low‐resource settings. The use of rapid diagnostic tests at or near the point‐of‐care (POC) can increase access to early diagnosis of HIV infection in infants and children less than 18 months of age and timely initiation of antiretroviral therapy (ART). Objectives To summarize the diagnostic accuracy of point‐of‐care nucleic acid‐based testing (POC NAT) to detect HIV‐1/HIV‐2 infection in infants and children aged 18 months or less exposed to HIV infection. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (until 2 February 2021), MEDLINE and Embase (until 1 February 2021), and LILACS and Web of Science (until 2 February 2021) with no language or publication status restriction. We also searched conference websites and clinical trial registries, tracked reference lists of included studies and relevant systematic reviews, and consulted experts for potentially eligible studies. Selection criteria We defined POC tests as rapid diagnostic tests conducted at or near the patient site. We included any primary study that compared the results of a POC NAT to a reference standard of laboratory NAT RT‐PCR or total nucleic acid testing to detect the presence or absence of HIV infection denoted by HIV viral nucleic acids in infants and children aged 18 months or less who were exposed to HIV‐1/HIV‐2 infection. We included cross‐sectional, prospective, and retrospective study designs and those that provided sufficient data to create the 2 × 2 table to calculate sensitivity and specificity. We excluded diagnostic case control studies with healthy controls. Data collection and analysis We extracted information on study characteristics using a pretested standardized data extraction form. We used the QUADAS‐2 (Quality Assessment of Diagnostic Accuracy Studies) tool to assess the risk of bias and applicability concerns of the included studies. Two review authors independently selected and assessed the included studies, resolving any disagreements by consensus. The unit of analysis was the participant. We first conducted preliminary exploratory analyses by plotting estimates of sensitivity and specificity from each study on forest plots and in receiver operating characteristic (ROC) space. For the overall meta‐analyses, we pooled estimates of sensitivity and specificity using the bivariate meta‐analysis model at a common threshold (presence or absence of infection). Main results We identified a total of 12 studies (15 evaluations, 15,120 participants). All studies were conducted in sub‐Saharan Africa. The ages of included infants and children in the evaluations were as follows: at birth (n = 6), ≤ 12 months (n = 3), ≤ 18 months (n = 5), and ≤ 24 months (n = 1). Ten evaluations were field evaluations of the POC NAT test at the point of care, and five were laboratory evaluations of the POC NAT tests.The POC NAT tests evaluated included Alere q HIV‐1/2 Detect qualitative test (recently renamed m‐PIMA q HIV‐1/2 Detect qualitative test) (n = 6), Xpert HIV‐1 qualitative test (n = 6), and SAMBA HIV‐1 qualitative test (n = 3). POC NAT pooled sensitivity and specificity (95% confidence interval (CI)) against laboratory reference standard tests were 98.6% (96.1 to 99.5) (15 evaluations, 1728 participants) and 99.9% (99.7 to 99.9) (15 evaluations, 13,392 participants) in infants and children ≤ 18 months. Risk of bias in the included studies was mostly low or unclear due to poor reporting. Five evaluations had some concerns for applicability for the index test, as they were POC tests evaluated in a laboratory setting, but there was no difference detected between settings in sensitivity (−1.3% (95% CI −4.1 to 1.5)); and specificity results were similar. Authors' conclusions For the diagnosis of HIV‐1/HIV‐2 infection, we found the sensitivity and specificity of POC NAT tests to be high in infants and children aged 18 months or less who were exposed to HIV infection., Plain language summary Point‐of‐care tests for detecting HIV viral molecules in infants and children aged 18 months or less Why is improving the diagnosis of HIV infection important? It is estimated that 1.5 million infants are still exposed to HIV every year. If left untreated, about 50% to 60% of HIV‐infected infants will die by the age of two years. Children infected before birth are especially at high risk of death. HIV is incurable; however, there are medications that suppress HIV, known as antiretroviral drugs (ART). When HIV is detected early, severe illness and death from HIV‐related infections can be prevented by taking this medication. A test that detects HIV viral genetic molecules quickly and accurately at or near the patient's side (point‐of‐care) therefore can increase access to early appropriate treatment and minimize missing treatments in those whose HIV remains undetected. What is the aim of this review? To determine the accuracy of molecular point‐of‐care tests for detecting the main types of HIV infection (HIV‐1/HIV‐2) in infants and children aged 18 months or less. What was studied in this review? Published reports of molecular point‐of‐care tests with results measured against laboratory viral‐based tests (benchmark). What are the main results of this review? Twelve studies which completed 15 evaluations involving 15,120 participants compared molecular point‐of‐care tests for diagnosing HIV infection. What are the strengths and limitations of this review? The review included sufficient studies and participants. All studies were conducted in sub‐Saharan Africa, making the results highly applicable for use in communities where the disease is regularly found and where disease control programmes are often targeted. However, one in three included evaluations of the molecular point‐of‐care tests were conducted in a laboratory setting and not near the patient but there was no difference in the test accuracy between settings. To whom do the results of this review apply? Infants and children aged 18 months or less who were exposed to HIV infection. What are the implications of this review? In theory, for a population of 1000 children aged 18 months or less where 100 have HIV infection, 100 children will be positive with the molecular point‐of‐care test, of which one will not have the infection (false‐positive result), and 900 will be negative with the molecular point‐of‐care test, of which one will indeed have the infection (false‐negative result). How up‐to‐date is this review? The evidence is current to 2 February 2021.

It is essential that studies of the accuracy of lateral flow antigen tests (LFTs) to detect SARS-CoV-2 are accurately and completely reported and that data are widely available and freely shared to ensure public and health policy are properly informed [1]. The FDA have raised concerns on the evidence for the Innova LFT [2]. Peto report key studies from Porton Down and the University of Oxford which form the evidence base for use of Innova and its rebranded version (the NHS Test-and-Trace LFT) [3]. We highly commend the authors for kindly sharing their data [4] with our Cochrane team for inclusion in our systematic review of the accuracy of rapid antigen tests [5]. However, we have observed discrepancies between the report of these studies in this journal, information presented in their preprint [6], and the data the investigators provided to our team. We request clarification from the authors. 1) The paper computes specificity by combining data on 6954 Innova tests across studies from “negative samples” (Table 2) [3]. This implies all 6954 samples were verified by a reference standard which returned a negative result (anticipated to be RT-PCR, but no reference standard is described). The preliminary report indicated none of the 3985 participants in the school studies contributing to the estimate of specificity received RT-PCR or any other test to verify their disease status [4], and the data sent to the Cochrane team indicated that the 17 participants in the school studies who tested positive on the Innova assay were parallel-tested with RT-PCR [5]. Can the authors clarify which students received a reference standard, and if so, what test was used and when it was done? If full verification of disease status was not performed, computing specificity using a sample size of 6954 (rather than 2969) is not correct. Notably only 1852 of these samples appear to have been tested using dry swabs in line with manufacturer's instructions, so the relevant sample size is likely even smaller. 2) Of the 17 school samples reported to the Cochrane team as Innova positive, 14 were false positives as the RT-PCR test was reported negative [5]. Whilst unable to compute sensitivity or specificity from these studies, knowing the numbers of test positives and false positives allows computation of a positive predictive value of 18% (95% confidence interval 4 to 43%). This important result is not reported in the publication or preprint. (The publication suggests 16 false positives and higher total numbers tested [3], so the exact value may slightly differ). The positive predictive value of school testing has been an important debate [7], particularly given school testing was originally introduced without RT-PCR confirmatory testing, thus its omission from this report is of relevance. Can the authors clarify that this result is correct and explain why it has been excluded from this report? 3) The authors report a specificity of 100% but no sensitivity value for the Armed Forces cohort. A full 2 × 2 table for this study was provided to and included in the Cochrane review – Innova was positive in 13 out of 46 who were PCR positive (sensitivity 28, 95% confidence interval (16 to 43%)) [5]. Why has this result not been reported? The STARD reporting guideline, adopted by the Lancet journals, aims to assist authors, peer reviewers and editors in ensuring that the methods and results of test accuracy studies are fully reported [8]. The reporting criteria have not been fully adhered to by this article. Regarding the evaluation in schools, if only LFD positive results were verified, the study can only estimate test failure rates, the feasibility of testing, and the positive predictive value. Such a design falls short of what is expected from field evaluations of a diagnostic test [1], particularly given that this was the first large scale evaluation of testing asymptomatic individuals. Testing in schools was introduced in the UK without evidence of the sensitivity of the test to detect cases in this population, which these studies could have easily addressed should verification been done [7]. Whilst we have observed large, well reported trials of vaccines and drugs following established methodology during the pandemic, the same level of methodological rigour has not been applied to test evaluations. We have great concern that the evidence supporting the use of Innova for mass testing has not been obtained and reported with adequate attention to the scientific method required to provide a sound evidence base for policy-making. Yours Jonathan J Deeks PhD CStat FMedSci, Professor of Biostatistics, University of Birmingham, UK Jacqueline Dinnes PhD, Senior Researcher, University of Birmingham, UK Clare Davenport MBChB, PhD, FFPH, Clinical Senior Lecturer, University of Birmingham, UK Yemisi Takwoingi DVM, PhD, Professor of Test Evaluation and Evidence Synthesis, University of Birmingham, UK Matthew McInnes Professor of Radiology and Epidemiology, University of Ottawa, Canada Mariska M. G. Leeflang, PhD, Associate professor, University of Amsterdam, Netherlands Jane Cunningham MD, Medical Officer, World Health Organisation, Switzerland on behalf of the Cochrane COVID-19 Diagnostic Test Accuracy Group.

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs

Objectives: This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:. To assess the diagnostic test accuracy of eNoses to screen for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in public places, such as airports. To assess the diagnostic test accuracy of sniffer animals, and more specifically dogs, to screen for SARS-CoV-2 infection in public places, such as airports. To assess the diagnostic test accuracy of eNoses for SARS-CoV-2 infection or COVID-19 in symptomatic people presenting in the community, or in secondary care. To assess the diagnostic test accuracy of sniffer animals, and more specifically dogs, for SARS-CoV-2 infection or COVID-19 in symptomatic people presenting in the community, or in secondary care. Secondary objectives If sufficient data are available, we will investigate the accuracy (either by stratified analysis, or by subgroup analysis) according to specific eNose technology or animal, and according to whether those who are tested are symptomatic or not. We will also investigate whether eNose brand, reference standard, and healthcare setting are associated with differences in diagnostic test accuracy.

Background Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown. Methods Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry. Results All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA−CCR7−CD127− IFNγ −IL-2−TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90–97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects. Conclusions Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.

Lateral flow devices (LFDs) are quickly being implemented for use in large-scale population surveillance programs for SARS-CoV-2 infection in the United Kingdom. These programs have been piloted in city-wide screening in the city of Liverpool and are now being rolled out to support care home visits and the return home of University students for the Christmas break. Here, we present data on the performance of LFDs to test almost 8,000 students at the University of Birmingham between December 2 and December 9, 2020. The performance is validated against almost 800 samples using PCR performed in the University Pillar 2 testing lab and theoretically validated on thousands of Pillar 2 PCR testing results performed on low-prevalence care home testing samples. Our data show that LFDs do not detect infections presenting with PCR Ct values over 29 to 30 as determined using the Thermo Fisher TaqPath asssay. This may be of particular importance in detecting individuals that are either at the early, or late stages of infection, and reinforces the need for frequent, recurrent testing., Antigen-detecting lateral flow tests are faster than PCR tests in detecting SARS-CoV-2 infection and are being implemented for use in large-scale population surveillance in the UK. An evaluation of the performance of the lateral flow devices, validated using PCR, concludes that lateral flow devices do not detect infections presenting with higher PCR Ct values, reinforcing the need for frequent, recurrent testing.

Purpose: Intratumoral hypoxia and immunity have been correlated with patient outcome in various tumor settings. However, these factors are not currently considered for treatment selection in head and neck cancer (HNC) due to lack of validated biomarkers. Here we sought to develop a hypoxia-immune classifier with potential application in patient prognostication and prediction of response to targeted therapy. Experimental Design: A 54-gene hypoxia-immune signature was constructed on the basis of literature review. Gene expression was analyzed in silico using the The Cancer Genome Atlas (TCGA) HNC dataset (n = 275) and validated using two independent cohorts (n = 130 and 123). IHC was used to investigate the utility of a simplified protein signature. The spatial distribution of hypoxia and immune markers was examined using multiplex immunofluorescence staining. Results: Unsupervised hierarchical clustering of TCGA dataset (development cohort) identified three patient subgroups with distinct hypoxia-immune phenotypes and survival profiles: hypoxialow/immunehigh, hypoxiahigh/immunelow, and mixed, with 5-year overall survival (OS) rates of 71%, 51%, and 49%, respectively (P = 0.0015). The prognostic relevance of the hypoxia-immune gene signature was replicated in two independent validation cohorts. Only PD-L1 and intratumoral CD3 protein expression were associated with improved OS on multivariate analysis. Hypoxialow/immunehigh and hypoxiahigh/immunelow tumors were overrepresented in “inflamed” and “immune-desert” microenvironmental profiles, respectively. Multiplex staining demonstrated an inverse correlation between CA-IX expression and prevalence of intratumoral CD3+ T cells (r = −0.5464; P = 0.0377), further corroborating the transcription-based classification. Conclusions: We developed and validated a hypoxia-immune prognostic transcriptional classifier, which may have clinical application to guide the use of hypoxia modification and targeted immunotherapies for the treatment of HNC.

Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-TB) may be an alternative to systematic biopsy for diagnosing prostate cancer.The primary aims of this systematic review and meta-analysis were to compare the detection rates of clinically significant and clinically insignificant cancer by MRI-TB with those by systematic biopsy in men undergoing prostate biopsy to identify prostate cancer.A literature search was conducted using the PubMed, Embase, Web of Science, Cochrane library, and Clinicaltrials.gov databases. We included prospective and retrospective paired studies where the index test was MRI-TB and the comparator test was systematic biopsy. We also included randomised controlled trials (RCTs) if one arm included MRI-TB and another arm included systematic biopsy. The risk of bias was assessed using a modified Quality Assessment of Diagnostic Accuracy Studies-2 checklist. In addition, the Cochrane risk of bias 2.0 tool was used for RCTs.We included 68 studies with a paired design and eight RCTs, comprising a total of 14709 men who either received both MRI-TB and systematic biopsy, or were randomised to receive one of the tests. MRI-TB detected more men with clinically significant cancer than systematic biopsy (detection ratio [DR] 1.16 [95% confidence interval {CI} 1.09-1.24], p0.0001) and fewer men with clinically insignificant cancer than systematic biopsy (DR 0.66 [95% CI 0.57-0.76], p0.0001). The proportion of cores positive for cancer was greater for MRI-TB than for systematic biopsy (relative risk 3.17 [95% CI 2.82-3.56], p0.0001).MRI-TB is an attractive alternative diagnostic strategy to systematic biopsy.We evaluated the published literature, comparing two methods of diagnosing prostate cancer. We found that biopsies targeted to suspicious areas on magnetic resonance imaging were better at detecting prostate cancer that needs to be treated and avoiding the diagnosis of disease that does not need treatment than the traditional systematic biopsy.

Background Atrial fibrillation (AF) is the arrhythmia most commonly diagnosed in clinical practice. It is associated with significant morbidity and mortality. Prevalence of AF and complications of AF, estimated by hospitalisations, have increased dramatically in the last decade. Being able to predict AF would allow tailoring of management strategies and a focus on primary or secondary prevention. Models predicting recurrent AF would have particular clinical use for the selection of rhythm control therapy. There are existing prognostic models which combine several predictors or risk factors to generate an individualised estimate of risk of AF. The aim of this systematic review is to summarise and compare model performance measures and predictive accuracy across different models and populations at risk of developing incident or recurrent AF. Methods Methods tailored to systematic reviews of prognostic models will be used for study identification, risk of bias assessment and synthesis. Studies will be eligible for inclusion where they report an internally or externally validated model. The quality of studies reporting a prognostic model will be assessed using the Prediction Study Risk Of Bias Assessment Tool (PROBAST). Studies will be narratively described and included variables and predictive accuracy compared across different models and populations. Meta-analysis of model performance measures for models validated in similar populations will be considered where possible. Discussion To the best of our knowledge, this will be the first systematic review to collate evidence from all studies reporting on validated prognostic models, or on the impact of such models, in any population at risk of incident or recurrent AF. The review may identify models which are suitable for impact assessment in clinical practice. Should gaps in the evidence be identified, research recommendations relating to model development, validation or impact assessment will be made. Findings will be considered in the context of any models already used in clinical practice, and the extent to which these have been validated. Systematic review registration PROSPERO (CRD42018111649).

Background Multivariate meta-analysis (MVMA) jointly synthesizes effects for multiple correlated outcomes. The MVMA model is potentially more difficult and time-consuming to apply than univariate models, so if its use makes little difference to parameter estimates, it could be argued that it is redundant. Methods We assessed the applicability and impact of MVMA in Cochrane Pregnancy and Childbirth (CPCB) systematic reviews. We applied MVMA to CPCB reviews published between 2011 and 2013 with two or more binary outcomes with at least three studies and compared findings with results of univariate meta-analyses. Univariate random effects meta-analysis models were fitted using restricted maximum likelihood estimation (REML). Results Eighty CPCB reviews were published. MVMA could not be applied in 70 of these reviews. MVMA was not feasible in three of the remaining 10 reviews because the appropriate models failed to converge. Estimates from MVMA agreed with those of univariate analyses in most of the other seven reviews. Statistical significance changed in two reviews: In one, this was due to a very small change in P value; in the other, the MVMA result for one outcome suggested that previous univariate results may be vulnerable to small-study effects and that the certainty of clinical conclusions needs consideration. Conclusions MVMA methods can be applied only in a minority of reviews of interventions in pregnancy and childbirth and can be difficult to apply because of missing correlations or lack of convergence. Nevertheless, clinical and/or statistical conclusions from MVMA may occasionally differ from those from univariate analyses.

Objectives Linked evidence models are recommended to predict health benefits and cost-effectiveness of diagnostic tests. We considered how published models accounted for changes in patient pathways that occur with point of care tests (POCTs) and their impact on patient health and costs. Study Design and Setting Model-based evaluations of diagnostic POCTs published from 2004 to 2017 were identified from searching six databases. For each model, we assessed the outcomes considered, and whether reduced time to diagnosis and increased access to testing affected patient health and costs. Results Seventy-four model-based evaluations were included: 95% incorporated evidence on test accuracy, but 34% only assessed intermediate outcomes such as rates of correct diagnosis. Of 54 models where POCTs reduced testing time, 39% addressed the economic and 37% addressed the health benefits of faster diagnosis. No model considered differences in access to tests. Conclusion Many models fail to capture the effects of POCTs in increasing access, advancing speed of diagnosis and treatment, and reducing anxiety and the associated costs. Many only consider the impact of testing from changes in accuracy. Ensuring models incorporate changes in patient pathways from faster and more accessible testing will lead to economic evaluations that better reflect the impact of POCTs.