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Background: There is a lack of consensus related to the collection of standardized data for individuals with vitiligo enrolled in clinical trials and registries as well as those seen in clinical practice which causes difficulty in accurately interpreting, comparing, and pooling of data. Several years ago, efforts to initiate work on developing core outcome sets were performed and a consensus was reached in 2015 on the first core domain set for vitiligo clinical trials., Methods/design: This project aims to further develop a core outcome set for vitiligo clinical trials as well as create internationally agreed-upon core outcome sets for registries and clinical practice. These core outcome sets will include a core domain set and a core measurement instruments set and will be supplemented by contextual factors, including baseline and treatment-related characteristics. In a preparatory exercise, the 2015 core domain set will be re-evaluated and will serve as the basis for the list of outcome domains used to initiate the consensus process. This project will consist of two parts. Part 1 will focus on the selection of a core domain set, or "what to measure" and contextual factors, for each setting based on electronic surveys (e-Delphi technique) and a conclusive consensus meeting by a large group of international stakeholders. Part 2 will include selection of core measurement instruments, or "how to measure," and measurement details (e.g., scale and timing) for the core domain sets and contextual factors agreed upon in part 1. Part 2 will be based on consensus meetings with stakeholders involved in part 1 and will be guided by C3 (CHORD-COUSIN Collaboration), Harmonising Outcome Measures for Eczema (HOME), COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), and Outcome Measures in Rheumatology (OMERACT) recommendations including information on measurement properties of available instruments (systematic review and expert/patient opinion). At the end of part 2, all stakeholders involved will be invited to participate in a final meeting in which the ultimate core data sets (core outcome sets and contextual factors) will be presented and the dissemination plan and implementation goals will be defined., Discussion: This project will harmonize data collection between clinical trials, registries, and clinical practices, facilitating new insights in vitiligo., Trial Registration: This study is registered in the Core Outcome Measures for Effectiveness Trials (COMET) database and on the C3 (CHORD-COUSIN Collaboration) website., (© 2022. The Author(s).)

Background: Robotic radical prostatectomy (RARP) is a first-line curative treatment option for localized prostate cancer. Postoperative erectile dysfunction and urinary incontinence are common associated adverse side effects that can negatively impact patients' quality of life. Preserving the lateral neurovascular bundles (NS) during RARP improves functional outcomes. However, selecting men for NS may be difficult when there is concern about incurring in positive surgical margin (PSM) which in turn risks adverse oncological outcomes. The NeuroSAFE technique (intra-operative frozen section examination of the neurovascular structure adjacent prostate margin) can provide real-time pathological consult to promote optimal NS whilst avoiding PSM., Methods: NeuroSAFE PROOF is a single-blinded, multi-centre, randomised controlled trial (RCT) in which men are randomly allocated 1:1 to either NeuroSAFE RARP or standard RARP. Men electing for RARP as primary treatment, who are continent and have good baseline erectile function (EF), defined by International Index of Erectile Function (IIEF-5) score > 21, are eligible. NS in the intervention arm is guided by the NeuroSAFE technique. NS in the standard arm is based on standard of care, i.e. a pre-operative image-based planning meeting, patient-specific clinical information, and digital rectal examination. The primary outcome is assessment of EF at 12 months. The primary endpoint is the proportion of men who achieve IIEF-5 score ≥ 21. A sample size of 404 was calculated to give a power of 90% to detect a difference of 14% between groups based on a feasibility study. Oncological outcomes are continuously monitored by an independent Data Monitoring Committee. Key secondary outcomes include urinary continence at 3 months assessed by the international consultation on incontinence questionnaire, rate of biochemical recurrence, EF recovery at 24 months, and difference in quality of life., Discussion: NeuroSAFE PROOF is the first RCT of intra-operative frozen section during radical prostatectomy in the world. It is properly powered to evaluate a difference in the recovery of EF for men undergoing RARP assessed by patient-reported outcome measures. It will provide evidence to guide the use of the NeuroSAFE technique around the world., Trial Registration: NCT03317990 (23 October 2017). Regional Ethics Committee; reference 17/LO/1978., (© 2022. The Author(s).)

Objectives: To evaluate interobserver variability for diagnosis of disease presence and extent of small bowel and colonic Crohn's disease using MR enterography (MRE)., Methods: Data from the first 73 consecutive patients (mean age 32, 33F, 28 new diagnosis, 45 suspected relapse) recruited to a multicentre, prospective diagnostic accuracy trial evaluating MRE for small bowel Crohn's disease were each read independently by three (from a pool of 20) radiologists. Radiologists documented presence and segmental location of small bowel Crohn's disease and recorded morphological mural/extramural parameters for involved segments. Per patient percentage agreement for disease presence and extent were calculated against an outcome-based construct reference standard (averaged between pairs of readers). Prevalence-adjusted bias-adjusted κ (PABAK) was calculated., Results: Agreement for small bowel disease presence for new diagnosis/relapsed patients was 68%(κ = 0.36)/ 78% (κ = 0.56) and 43%(κ = 0.14)/ 53% for disease extent (κ = 0.07), respectively. For disease presence, all three radiologists agreed correctly with the reference standard in 41/59 (69%) of patients with small bowel involvement, and in 8/14 (57%) cases of without small bowel disease. Agreement was highest for multisegment disease, greater than 5 cm in length, with mural thickness>6 mm, and increased mural T2 signal. Agreement for colonic disease presence was 61% (κ = 0.21 fair agreement) for new diagnosis/ 60% (κ = 0.20, slight agreement) for relapsed patients., Conclusion: There is a reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed Crohn's disease, and patients with suspected relapse, respectively. Agreement is lower for disease extent., Advances in Knowledge: There is reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed (68%) Crohn's disease, and patients with suspected relapse (78%). Agreement is lower for disease extent (43% new diagnosis and 53% suspected relapse).

The biochemical heterogeneity of food items often yields tradeoffs as each bite of food tends to contain some nutrients in surplus and others in deficit, as well as other less palatable or even toxic compounds. These multidimensional nutritional challenges are likely to be compounded when foraged foods are used to provision others (e.g., offspring or symbionts) with different physiological needs and tolerances. We explored these challenges in free-ranging colonies of leafcutter ants that navigate a diverse tropical forest to collect plant fragments they use to provision a co-evolved fungal cultivar. We tested the prediction that leafcutter farmers face provisioning tradeoffs between the nutritional quality and concentration of toxic tannins in foraged plant fragments. Chemical analyses of plant fragments sampled from the mandibles of Panamanian Atta colombica leafcutter ants provided little support for a nutrient-tannin foraging tradeoff. First, colonies foraged for plant fragments that ranged widely in tannin concentration. Second, high tannin levels did not appear to restrict colonies from selecting plant fragments with blends of protein and carbohydrates that maximized cultivar performance when measured with in vitro experiments. We also tested whether tannins expand the realized nutritional niche selected by leafcutter ants into high-protein dimensions as: (1) tannins can bind proteins and reduce their accessibility during digestion, and (2) in vitro experiments have shown that excess protein provisioning reduces cultivar performance. Contrary to this hypothesis, the most protein-rich plant fragments did not have highest tannin levels. More generally, the approach developed here can be used to test how multidimensional interactions between nutrients and toxins shape the costs and benefits of providing care to offspring or symbionts., (© 2022 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Introduction: Chronic liver disease is a growing cause of morbidity and mortality in the UK. Acute presentation with advanced disease is common and prioritisation of resources to those at highest risk at earlier disease stages is essential to improving patient outcomes. Existing prognostic tools are of limited accuracy and to date no imaging-based tools are used in clinical practice, despite multiple anatomical imaging features that worsen with disease severity.In this paper, we outline our scoping review protocol that aims to provide an overview of existing prognostic factors and models that link anatomical imaging features with clinical endpoints in chronic liver disease. This will provide a summary of the number, type and methods used by existing imaging feature-based prognostic studies and indicate if there are sufficient studies to justify future systematic reviews., Methods and Analysis: The protocol was developed in accordance with existing scoping review guidelines. Searches of MEDLINE and Embase will be conducted using titles, abstracts and Medical Subject Headings restricted to publications after 1980 to ensure imaging method relevance on OvidSP. Initial screening will be undertaken by two independent reviewers. Full-text data extraction will be undertaken by three pretrained reviewers who have participated in a group data extraction session to ensure reviewer consensus and reduce inter-rater variability. Where needed, data extraction queries will be resolved by reviewer team discussion. Reporting of results will be based on grouping of related factors and their cumulative frequencies. Prognostic anatomical imaging features and clinical endpoints will be reported using descriptive statistics to summarise the number of studies, study characteristics and the statistical methods used., Ethics and Dissemination: Ethical approval is not required as this study is based on previously published work. Findings will be disseminated by peer-reviewed publication and/or conference presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Most radiologists reporting CT colonography (CTC) do not undergo compulsory performance accreditation, potentially lowering diagnostic sensitivity. Purpose To determine whether 1-day individualized training in CTC reporting improves diagnostic sensitivity of experienced radiologists for 6-mm or larger lesions, the durability of any improvement, and any associated factors. Materials and Methods This prospective, multicenter cluster-randomized controlled trial was performed in National Health Service hospitals in England and Wales between April 2017 and January 2020. CTC services were cluster randomized into intervention (1-day training plus feedback) or control (no training or feedback) arms. Radiologists in the intervention arm attended a 1-day workshop focusing on CTC reporting pitfalls with individualized feedback. Radiologists in the control group received no training. Sensitivity for 6-mm or larger lesions was tested at baseline and 1, 6, and 12 months thereafter via interpretation of 10 CTC scans at each time point. The primary outcome was the mean difference in per-lesion sensitivity between arms at 1 month, analyzed using multilevel regression after adjustment for baseline sensitivity. Secondary outcomes included per-lesion sensitivity at 6- and 12-month follow-up, sensitivity for flat neoplasia, and effect of prior CTC experience. Results A total of 69 hospitals were randomly assigned to the intervention (31 clusters, 80 radiologists) or control (38 clusters, 59 radiologists) arm. Radiologists were experienced (median, 500-999 CTC scans interpreted) and reported CTC scans routinely (median, 151-200 scans per year). One-month sensitivity improved after intervention (66.4% [659 of 992]) compared with sensitivity in the control group (42.4% [278 of 655]; difference = 20.8%; 95% CI: 14.6, 27.0; P < .001). Improvements were maintained at 6 (66.4% [572 of 861] vs 50.5% [283 of 560]; difference = 13.0%; 95% CI: 7.4, 18.5; P < .001) and 12 (63.7% [310 of 487] vs 44.4% [187 of 421]; difference = 16.7%; 95% CI: 10.3, 23.1; P < .001) months. This beneficial effect applied to flat lesions (difference = 22.7%; 95% CI: 15.5, 29.9; P < .001) and was independent of career experience (≥1500 CTC scans: odds ratio = 1.09; 95% CI: 0.88, 1.36; P = .22). Conclusion For radiologists evaluating CT colonography studies, a 1-day training intervention yielded sustained improvement in detection of clinically relevant colorectal neoplasia, independent of previous career experience. Clinical trial registration no. NCT02892721 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Pickhardt in this issue. An earlier incorrect version appeared online and in print. This article was corrected on February 28, 2022.

Background: Coeliac disease (CD) affects approximately 1% of the population, although only a fraction of patients are diagnosed. Our objective was to develop diagnostic prediction models to help decide who should be offered testing for CD in primary care., Methods: Logistic regression models were developed in Clinical Practice Research Datalink (CPRD) GOLD (between Sep 9, 1987 and Apr 4, 2021, n=107,075) and externally validated in CPRD Aurum (between Jan 1, 1995 and Jan 15, 2021, n=227,915), two UK primary care databases, using (and controlling for) 1:4 nested case-control designs. Candidate predictors included symptoms and chronic conditions identified in current guidelines and using a systematic review of the literature. We used elastic-net regression to further refine the models., Findings: The prediction model included 24, 24, and 21 predictors for children, women, and men, respectively. For children, the strongest predictors were type 1 diabetes, Turner syndrome, IgA deficiency, or first-degree relatives with CD. For women and men, these were anaemia and first-degree relatives. In the development dataset, the models showed good discrimination with a c -statistic of 0·84 (95% CI 0·83-0·84) in children, 0·77 (0·77-0·78) in women, and 0·81 (0·81-0·82) in men. External validation discrimination was lower, potentially because 'first-degree relative' was not recorded in the dataset used for validation. Model calibration was poor, tending to overestimate CD risk in all three groups in both datasets., Interpretation: These prediction models could help identify individuals with an increased risk of CD in relatively low prevalence populations such as primary care. Offering a serological test to these patients could increase case finding for CD. However, this involves offering tests to more people than is currently done. Further work is needed in prospective cohorts to refine and confirm the models and assess clinical and cost effectiveness., Funding: National Institute for Health Research Health Technology Assessment Programme (grant number NIHR129020)., Competing Interests: All authors report funding from the National Institute for Health Research (NIHR) Health Technology Assessment Programme grant (NIHR129020). This publication presents independent research funded by the NIHR. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Sue Mallett receives funding from the NIHR UCL/UCLH Biomedical Research Centre., (© 2022 The Authors.)

Background: 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., Objectives: To estimate the diagnostic accuracy of POC tests to detect high viral load levels in PLHIV attending healthcare facilities., Search Methods: 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., Selection Criteria: 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., Data Collection and Analysis: 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., Main Results: 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., Authors' Conclusions: 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., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Goal-directed fluid therapy (GDFT) has been shown to reduce the complications following a variety of major surgical procedures, possibly mediated by improved organ perfusion and function. We have shown that it is feasible to randomise patients to GDFT or standard fluid management following liver transplant in the cardiac-output optimisation following liver transplantation (COLT) trial. The current study compares end organ function in patients from the COLT trial who received GDFT in comparison to those receiving standard care (SC) following liver transplant., Methods: Adult patients with liver cirrhosis undergoing liver transplantation were randomised to GDFT or SC for the first 12 h following surgery as detailed in a published trial protocol. GDFT protocol was based on stroke volume (SV) optimisation using 250 ml crystalloid boluses. Total fluid administration and time to extubation were recorded. Hourly SV and cardiac output (CO) readings were recorded from the non-invasive cardiac output monitoring (NICOM) device in both groups. Pulmonary function was assessed by arterial blood gas (ABG) and ventilatory parameters. Lung injury was assessed using PaO 2 :FiO 2 ratios and calculated pulmonary compliance. The KDIGO score was used for determining acute kidney injury. Renal and liver graft function were assessed during the post-operative period and at 3 months and 1-year., Results: 60 patients were randomised to GDFT (n = 30) or SC (n = 30). All patients completed the 12 h intervention period. GDFT group received a significantly higher total volume of fluid during the 12 h trial intervention period (GDFT 5317 (2335) vs. SC 3807 (1345) ml, p = 0.003); in particular crystalloids (GDFT 3968 (2073) vs. SC 2510 (1027) ml, p = 0.002). There was no evidence of significant difference between the groups in SV or CO during the assessment periods. Time to extubation, PaO2: FIO 2 ratios, pulmonary compliance, ventilatory or blood gas measurements were similar in both groups. There was a significant rise in serum creatinine from baseline (77 μmol/L) compared to first (87 μmol/L, p = 0.039) and second (107 μmol/L, p = 0.001) post-operative days. There was no difference between GDFT and SC in the highest KDIGO scores for the first 7 days post-LT. At 1-year follow-up, there was no difference in need for renal replacement therapy or graft function., Conclusions: In this randomised trial of fluid therapy post liver transplant, GDFT was associated with an increased volume of crystalloids administered but did not alter early post-operative pulmonary or renal function when compared with standard care., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

(1) Background: There is currently limited evidence on the diagnostic accuracy of abbreviated biparametric MRI (a-bpMRI) protocols for prostate cancer (PCa) detection and screening. In the present study, we aim to investigate the performance of a-bpMRI among multiple readers and its potential application to an imaging-based screening setting. (2) Methods: A total of 151 men who underwent 3T multiparametric MRI (mpMRI) of the prostate and transperineal template prostate mapping biopsies were retrospectively selected. Corresponding bpMRI (multiplanar T2WI, DWI, ADC maps) and a-bpMRI (axial T2WI and b 2000 s/mm 2 DWI only) dataset were derived from mpMRI. Three experienced radiologists scored a-bpMRI, standard biparametric MRI (bpMRI) and mpMRI in separate sessions. Diagnostic accuracy and interreader agreement of a-bpMRI was tested for different positivity thresholds and compared to bpMRI and mpMRI. Predictive values of a-bpMRI were computed for lower levels of PCa prevalence to simulate a screening setting. The primary definition of clinically significant PCa (csPCa) was Gleason ≥ 4 + 3, or cancer core length ≥ 6 mm. (3) Results: The median age was 62 years, the median PSA was 6.8 ng/mL, and the csPCa prevalence was 40%. Using a cut off of MRI score ≥ 3, the sensitivity and specificity of a-bpMRI were 92% and 48%, respectively. There was no significant difference in sensitivity compared to bpMRI and mpMRI. Interreader agreement of a-bpMRI was moderate (AC1 0.58). For a low prevalence of csPCa (e.g., <10%), higher cut offs (MRI score ≥ 4) yield a more favourable balance between the predictive values and positivity rate of MRI. (4) Conclusion: Abbreviated bpMRI protocols could match the diagnostic accuracy of bpMRI and mpMRI for the detection of csPCa. If a-bpMRI is used in low-prevalence settings, higher cut-offs for MRI positivity should be prioritised.

Introduction: Bystander cardiopulmonary resuscitation (BCPR) is strongly advocated by resuscitation councils for paediatric out-of-hospital cardiac arrests (OHCAs). However, there are limited reports on rates of BCPR in children and its relationship with return of spontaneous circulation (ROSC) or survival outcomes., Objective: We describe the rate of BCPR and its association with any ROSC and survival- to- hospital-discharge., Methods: We conducted retrospective analysis of prospectively collected paediatric (<18 years of age) OHCA cases in England; we included specialist registry patients treated by emergency medical services (EMS) with known BCPR status and outcome between January 2014 and November 2018. Data included patient demographics, aetiology, witness status, initial rhythm, EMS, season, time of day and bystander status. Associations between BCPR, and any ROSC and survival-to-hospital-discharge outcomes were explored using multivariable logistic regression., Results: There were 2363 paediatric OHCAs treated across 11 EMS regions. BCPR was performed in 69.6% (1646/2363) of the cases overall (range 57.7% (206/367) to 83.7% (139/166) across EMS regions). Only 34.9% (550/1572) of BCPR cases were witnessed. Overall, any ROSC was achieved in 22.8% (523/2289) and survival to hospital discharge in 10.8% (225/2066). Adjusted odds ratio (aOR) for any ROSC was significantly improved following BCPR compared to no BCPR (aOR 1.37, 95% CI 1.03-1.81), but adjusted odds ratio for survival-to-hospital-discharge were similar (aOR 1.01, 95% CI 0.66-1.55)., Conclusions: BCPR was associated with improved rates of any ROSC but not survival-to-hospital-discharge. Variations in EMS BCPR rates may indicate opportunities for regional targeted increase in public BCPR education., Competing Interests: Declaration of Competing Interest Dr Scholefield is funded by a National Institute for Health Research, United Kingdom (NIHR-CS-2015-15-016) Fellowship award. However, this project was not funded by the National Institute for Health Research. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health and Social Care. Gavin Perkins is GDP is Director of the OHCAO Registry which is funded by the Resuscitation Council UK and British Heart Foundation and an Editor for Resuscitation. This research is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Sarah Berhane is funded by NIHR Biomedical Research Centre (NIHR BRC) grant. However, NIHR BRC did not fund this project., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This review explains in simple terms, accessible to the non-statistician, general principles regarding the correct research methods to develop and then evaluate imaging biomarkers in a clinical setting, including radiomic biomarkers. The distinction between diagnostic and prognostic biomarkers is made and emphasis placed on the need to assess clinical utility within the context of a multivariable model. Such models should not be restricted to imaging biomarkers and must include relevant disease and patient characteristics likely to be clinically useful. Biomarker utility is based on whether its addition to the basic clinical model improves diagnosis or prediction. Approaches to both model development and evaluation are explained and the need for adequate amounts of representative data stressed so as to avoid underpowering and overfitting. Advice is provided regarding how to report the research correctly. KEY POINTS: • Imaging biomarker research is common but methodological errors are encountered frequently that may mean the research is not clinically useful. • The clinical utility of imaging biomarkers is best assessed by their additive effect on multivariable models based on clinical factors known to be important. • The data used to develop such models should be sufficient for the number of variables investigated and the model should be evaluated, preferably using data unrelated to development., (© 2021. The Author(s).)

Comparative diagnostic test accuracy studies assess and compare the accuracy of 2 or more tests in the same study. Although these studies have the potential to yield reliable evidence regarding comparative accuracy, shortcomings in the design, conduct, and analysis may bias their results. The currently recommended quality assessment tool for diagnostic test accuracy studies, QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), is not designed for the assessment of test comparisons. The QUADAS-C (Quality Assessment of Diagnostic Accuracy Studies-Comparative) tool was developed as an extension of QUADAS-2 to assess the risk of bias in comparative diagnostic test accuracy studies. Through a 4-round Delphi study involving 24 international experts in test evaluation and a face-to-face consensus meeting, an initial version of the tool was developed that was revised and finalized following a pilot study among potential users. The QUADAS-C tool retains the same 4-domain structure of QUADAS-2 (Patient Selection, Index Test, Reference Standard, and Flow and Timing) and comprises additional questions to each QUADAS-2 domain. A risk-of-bias judgment for comparative accuracy requires a risk-of-bias judgment for the accuracy of each test (resulting from QUADAS-2) and additional criteria specific to test comparisons. Examples of such additional criteria include whether participants either received all index tests or were randomly assigned to index tests, and whether index tests were interpreted with blinding to the results of other index tests. The QUADAS-C tool will be useful for systematic reviews of diagnostic test accuracy addressing comparative questions. Furthermore, researchers may use this tool to identify and avoid risk of bias when designing a comparative diagnostic test accuracy study.

Background: The prevalence of coeliac disease (CD) is around 1%, but diagnosis is challenged by varied presentation and non-specific symptoms and signs. This study aimed to identify diagnostic indicators that may help identify patients at a higher risk of CD in whom further testing is warranted., Methods: International guidance for systematic review methods were followed and the review was registered at PROSPERO (CRD42020170766). Six databases were searched until April 2021. Studies investigating diagnostic indicators, such as symptoms or risk conditions, in people with and without CD were eligible for inclusion. Risk of bias was assessed using the QUADAS-2 tool. Summary sensitivity, specificity, and positive predictive values were estimated for each diagnostic indicator by fitting bivariate random effects meta-analyses., Findings: 191 studies reporting on 26 diagnostic indicators were included in the meta-analyses. We found large variation in diagnostic accuracy estimates between studies and most studies were at high risk of bias. We found strong evidence that people with dermatitis herpetiformis, migraine, family history of CD, HLA DQ2/8 risk genotype, anaemia, type 1 diabetes, osteoporosis, or chronic liver disease are more likely than the general population to have CD. Symptoms, psoriasis, epilepsy, inflammatory bowel disease, systemic lupus erythematosus, fractures, type 2 diabetes, and multiple sclerosis showed poor diagnostic ability. A sensitivity analysis revealed a 3-fold higher risk of CD in first-degree relatives of CD patients., Conclusions: Targeted testing of individuals with dermatitis herpetiformis, migraine, family history of CD, HLA DQ2/8 risk genotype, anaemia, type 1 diabetes, osteoporosis, or chronic liver disease could improve case-finding for CD, therefore expediting appropriate treatment and reducing adverse consequences. Migraine and chronic liver disease are not yet included as a risk factor in all CD guidelines, but it may be appropriate for these to be added. Future research should establish the diagnostic value of combining indicators., Competing Interests: The authors have declared that no competing interests exist.

Background: Primary and incisional ventral hernia trials collect unstandardized inconsistent data, limiting data interpretation and comparison. This study aimed to create two minimum data sets for primary and incisional ventral hernia interventional trials to standardize data collection and improve trial comparison. To support these data sets, standardized patient-reported outcome measures and trial methodology criteria were created., Methods: To construct these data sets, nominal group technique methodology was employed, involving 15 internationally recognized abdominal wall surgeons and two patient representatives. Initially a maximum data set was created from previous systematic and panellist reviews. Thereafter, three stages of voting took place: stage 1, selection of the number of variables for data set inclusion; stage 2, selection of variables to be included; and stage 3, selection of variable definitions and detection methods. A steering committee interpreted and analysed the data., Results: The maximum data set contained 245 variables. The three stages of voting commenced in October 2019 and had been completed by July 2020. The final primary ventral hernia data set included 32 variables, the incisional ventral hernia data set included 40 variables, the patient-reported outcome measures tool contained 25 questions, and 40 methodological criteria were chosen. The best known variable definitions were selected for accurate variable description. CT was selected as the optimal preoperative descriptor of hernia morphology. Standardized follow-up at 30 days, 1 year, and 5 years was selected., Conclusion: These minimum data sets, patient-reported outcome measures, and methodological criteria have allowed creation of a manual for investigators aiming to undertake primary ventral hernia or incisional ventral hernia interventional trials. Adopting these data sets will improve trial methods and comparisons., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Computer-aided diagnosis (CAD) of prostate cancer on multiparametric magnetic resonance imaging (mpMRI), using artificial intelligence (AI), may reduce missed cancers and unnecessary biopsies, increase inter-observer agreement between radiologists, and alleviate pressures caused by rising case incidence and a shortage of specialist radiologists to read prostate mpMRI. However, well-designed evaluation studies are required to prove efficacy above current clinical practice. A systematic search of the MEDLINE, EMBASE, and arXiv electronic databases was conducted for studies that compared CAD for prostate cancer detection or classification on MRI against radiologist interpretation and a histopathological reference standard, in treatment-naïve men with a clinical suspicion of prostate cancer. Twenty-seven studies were included in the final analysis. Due to substantial heterogeneities in the included studies, a narrative synthesis is presented. Several studies reported superior diagnostic accuracy for CAD over radiologist interpretation on small, internal patient datasets, though this was not observed in the few studies that performed evaluation using external patient data. Our review found insufficient evidence to suggest the clinical deployment of artificial intelligence algorithms at present. Further work is needed to develop and enforce methodological standards, promote access to large diverse datasets, and conduct prospective evaluations before clinical adoption can be considered.

Background: Identification of biomarkers that predict severe Crohn's disease is an urgent unmet research need, but existing research is piecemeal and haphazard., Objective: To identify biomarkers that are potentially able to predict the development of subsequent severe Crohn's disease., Design: This was a prognostic systematic review with meta-analysis reserved for those potential predictors with sufficient existing research (defined as five or more primary studies)., Data Sources: PubMed and EMBASE searched from inception to 1 January 2016, updated to 1 January 2018., Review Methods: Eligible studies were studies that compared biomarkers in patients who did or did not subsequently develop severe Crohn's disease. We excluded biomarkers that had insufficient research evidence. A clinician and two statisticians independently extracted data relating to predictors, severe disease definitions, event numbers and outcomes, including odds/hazard ratios. We assessed risk of bias. We searched for associations with subsequent severe disease rather than precise estimates of strength. A random-effects meta-analysis was performed separately for odds ratios., Results: In total, 29,950 abstracts yielded just 71 individual studies, reporting 56 non-overlapping cohorts. Five clinical biomarkers (Montreal behaviour, age, disease duration, disease location and smoking), two serological biomarkers (anti- Saccharomyces cerevisiae antibodies and anti-flagellin antibodies) and one genetic biomarker (nucleotide-binding oligomerisation domain-containing protein 2) displayed statistically significant prognostic potential. Overall, the strongest association with subsequent severe disease was identified for Montreal B2 and B3 categories (odds ratio 4.09 and 6.25, respectively)., Limitations: Definitions of severe disease varied widely, and some studies confounded diagnosis and prognosis. Risk of bias was rated as 'high' in 92% of studies overall. Some biomarkers that are used regularly in daily practice, for example C-reactive protein, were studied too infrequently for meta-analysis., Conclusions: Research for individual biomarkers to predict severe Crohn's disease is scant, heterogeneous and at a high risk of bias. Despite a large amount of potential research, we encountered relatively few biomarkers with data sufficient for meta-analysis, identifying only eight biomarkers with potential predictive capability., Future Work: We will use existing data sets to develop and then validate a predictive model based on the potential predictors identified by this systematic review. Contingent on the outcome of that research, a prospective external validation may prove clinically desirable., Study Registration: This study is registered as PROSPERO CRD42016029363., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 45. See the NIHR Journals Library website for further project information.

Background: Severe asthma is associated with a broad range of phenotypes and clinical characteristics. This analysis assessed whether select baseline patient characteristics could prognosticate mepolizumab efficacy in severe eosinophilic asthma., Methods: This was a post hoc meta-analysis of data from the Phase III MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862) studies. Patients aged ≥ 12 years with severe eosinophilic asthma and a history of exacerbations were randomised to receive placebo (MENSA/MUSCA), mepolizumab 75 mg intravenously (MENSA) or 100 mg subcutaneously (SC) (MENSA/MUSCA) every 4 weeks for 32 (MENSA) or 24 (MUSCA) weeks. The primary endpoint was the annual rate of clinically significant exacerbations; other outcomes included the proportion of patients with no exacerbations and changes from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV 1 ), St George's Respiratory Questionnaire (SGRQ) total score and Asthma Control Questionnaire (ACQ)-5 score. Analyses were performed by baseline age of asthma onset (< 18 years; 18-40 years; ≥ 40 years); lung function (% predicted FEV 1  ≤ 60; 60-80; > 80); airway reversibility (reversible [≥ 12% change in FEV 1 ]; non-reversible [< 12% change in FEV 1 ]); perennial and/or seasonal allergen sensitivity (yes/no); asthma control (uncontrolled [ACQ-5 score ≥ 1.5]; partial/complete control [ACQ-5 score < 1.5])., Results: Overall, 936 patients received mepolizumab 100 mg SC or placebo. Across age at asthma onset, lung function and airway reversibility subgroups, mepolizumab reduced the rate of clinically significant exacerbations by 49-63% versus placebo. Improvements in lung function, SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across most age and lung function subgroups. Clinically significant exacerbations were reduced with mepolizumab versus placebo irrespective of season or allergen sensitivity; SGRQ total and ACQ-5 scores were generally improved across seasons., Conclusions: Mepolizumab efficacy was consistent for patients with varying age at asthma onset, lung function, airway reversibility and allergen sensitivities at baseline. Our results indicate that mepolizumab is likely to be beneficial for patients with severe eosinophilic asthma with a broad range of baseline clinical characteristics; large-scale real-world studies are needed to confirm the external validity of these findings. Trial registration Post hoc meta-analysis of data from MENSA (NCT01691521/MEA115588) and MUSCA (NCT02281318/200862).

Purpose: Improved understanding of characteristics that may influence treatment response across phenotypes may help guide treatment decisions., Patients and Methods: This was a post hoc analysis of MENSA, a multicenter, randomized, double-blind, placebo-controlled trial (NCT01691521). Patients aged ≥12 years with severe eosinophilic asthma received mepolizumab (75 mg intravenously or 100 mg subcutaneously) or placebo, plus standard of care, every 4 weeks for 32 weeks. Outcomes assessed were the annualized rate of clinically significant exacerbations and change from baseline in Asthma Control Questionnaire (ACQ)-5 score. Subgroup analyses were performed by baseline blood eosinophil count (<150, ≥150-300, ≥300 cells/μL) within atopic subgroups (non-atopic [specific immunoglobulin E <0.35 kU/L], atopic [≥0.35-17.5 kU/L], strongly atopic [>17.5 kU/L]), and by house dust mite (HDM) sensitivity., Results: Of 576 patients analyzed, 272 were non-atopic, 181 were atopic and 94 were strongly atopic; 29 had missing atopy data. In patients with blood eosinophil counts ≥300 cells/µL, mepolizumab versus placebo reduced clinically significant exacerbations by 74%, 43% and 25% in the non-atopic, atopic and strongly atopic subgroups. Similar reductions were observed in all atopic subgroups in other blood eosinophil count categories where there were sufficient patient numbers for analysis, except for non-atopic patients with baseline blood eosinophil counts of <150 cells/μL. Improvements in ACQ-5 scores of -0.75, -0.73 and -0.78 with mepolizumab versus placebo were observed in non-atopic, atopic and strongly atopic patients with blood eosinophil counts ≥300 cells/µL; consistent improvements in ACQ-5 were not observed in patients with blood eosinophil counts <150 or ≥150-300 cells/μL. Reductions in clinically significant exacerbations with mepolizumab versus placebo were also observed irrespective of sensitivity to HDMs., Conclusion: Mepolizumab was associated with a trend for reductions in clinically significant exacerbations and improved asthma control versus placebo in patients with severe eosinophilic asthma, irrespective of atopic status or HDM sensitivity., Competing Interests: CMP, SM and SWY are all employees and shareholders of GSK. FCA is a former employee of GSK, holds GSK stocks/shares and is currently employed by Avillion US, Inc. MI has received fees from Actelion, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, Grifols, GSK, MSD, Novartis and Teva. JAD has received personal fees from AstraZeneca, GSK, Novartis and Sanofi-Aventis, has been an investigator for AstraZeneca, GSK, Novartis, Sanofi-Aventis, Grifols, BioCryst, CSL Ltd and Equilium, and holds shares in CSL Ltd. AB has received fees from GSK, Regeneron, Chiesi, AstraZeneca, Teva, Novartis and Boehringer Ingelheim and been an investigator for Novartis and AstraZeneca. The authors report no other conflicts of interest in this work., (© 2021 Prazma et al.)

Background: Ventra hernias are increasing in prevalence and many recur despite attempted repair. To date, much of the literature is underpowered and divergent. As a result there is limited high quality evidence to inform surgeons succinctly which perioperative variables influence postoperative recurrence. This systematic review aimed to identify predictors of ventral hernia recurrence., Methods: PubMed was searched for studies reporting prognostic data of ventral hernia recurrence between 1 January 1995 and 1 January 2018. Extracted data described hernia type (primary/incisional), definitions of recurrence, methods used to detect recurrence, duration of follow-up, and co-morbidity. Data were extracted for all potential predictors, estimates and thresholds described. Random-effects meta-analysis was used. Bias was assessed with a modified PROBAST (Prediction model Risk Of Bias ASsessment Tool)., Results: Screening of 18 214 abstracts yielded 274 individual studies for inclusion. Hernia recurrence was defined in 66 studies (24.1 per cent), using 41 different unstandardized definitions. Three patient variables (female sex, age 65 years or less, and BMI greater than 25, 30, 35 or 40 kg/m2), five patient co-morbidities (smoking, diabetes, chronic obstructive pulmonary disease, ASA grade III-IV, steroid use), two hernia-related variables (incisional/primary, recurrent/primary), six intraoperative variables (biological mesh, bridged repair, open versus laparoscopic surgery, suture versus mesh repair, onlay/retrorectus, intraperitoneal/retrorectus), and six postoperative variables (any complication, surgical-site occurrence, wound infection, seroma, haematoma, wound dehiscence) were identified as significant prognostic factors for hernia recurrence., Conclusion: This study summarized the current evidence base for predicting ventral hernia recurrence. Results should inform best practice and future research., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

INTRODUCTION: Our psychiatric emergency room (ER) averages 18 patient-to-staff physical assaults annually, with some incidents resulting in multiple injuries. AIMS: The purpose of this performance improvement project was to develop, implement, and evaluate a multifaceted approach to reducing the number of physical assaults on staff. METHODS: We assessed the impact of these bundled interventions on staff assault rate: (1) increasing behavioral response team drills, (2) implementing shift doses, (3) screening for patients' risk for violence, (4) posting signage to communicate patients' violence propensity (Golden Hand), (5) implementing mitigating countermeasure interventions, (6) conducting postassault debriefing, and (7) providing postassault support. Psychiatric ER nurses completed questionnaires measuring their perceived self-efficacy in managing patients with a propensity for violence before, during, and after the bundled interventions. Physical assaults on staff were recorded and tracked monthly from May 2016 to September 2018 through a retrospective review of the hospital's online incident report system. RESULTS: Staff perceived self-efficacy increased from 78% to 95% after attending at least two behavioral response team drills. The Golden Hand signage was rated useful as it flagged and communicated the presence of high-risk patients. Shift dose was evaluated as an informative tool and manageable at ≤5 minutes. The violence-screening tool was considered more accurate in identifying patients with violent tendencies than standard assaultive precautions. Physical assaults on staff by patients decreased to zero in our psychiatric ER, which was sustained for a year. CONCLUSIONS: This innovative, multifaceted, bundled approach provides an opportunity for nurse leaders to promote workplace safety while improving staff engagement and empowerment.

Humanitarian aid and development is a multibillion-dollar sector, representing millions of organisations, with hundreds of millions of employees and volunteers operating worldwide. The community is, by its very nature, drawn towards danger, supporting vulnerable parties in high-risk areas. In the face of complex global health emergencies, natural disasters and deteriorating security conditions, the imperative for individuals to deploy to, or work in, increasingly fragile and hostile environments is growing. At the same time, expectations regarding the sector's duty of care are mounting, and employees, families, donors and governments are holding organisations increasingly accountable for their actions. Where an organisation fails - or is perceived to have failed - the people it is supposed to protect, it can face catastrophic litigation and reputational harm. Hostile environment awareness training is part of the duty-of-care strategy for those working in, or travelling to, high to extreme-risk environments. It addresses tactical-level risks by raising the awareness and competency of the individual in identifying, controlling and reacting to security and safety risks. In doing so, it concurrently reduces enterprise-level risks to the organisation. This paper discusses what drives the increasing need for hostile environment awareness training (HEAT), the value it brings in terms of duty of care and organisational resilience, what technical content and immersive learning should be included within a HEAT curriculum, and the challenges organisations face when implementing instruction programme at the global and multicultural level.

Introduction: Test evaluation trials present different challenges for trial managers compared to intervention trials. There has been very little research on the management of test evaluation trials and how this impacts on trial success, in comparison with intervention trials. Evaluations of medical tests present specific challenges, because they are a pivot point bridging the complexities of pathways prompting testing with treatment decision-making. We systematically explored key differences in the trial design and management of test evaluation trials compared to intervention trials at the different stages of study design and delivery. We identified challenges in test evaluation trials that were more pronounced than in intervention trials, based on experience from 10 test evaluation trials., Methods: We formed a focus group of 7 trial managers and a statistician who had been involved in the day-to-day management of both test evaluation trials and intervention trials. We used discussion and content analysis to group challenges from 10 trials into a structured thematic format. The trials covered a range of medical conditions, diagnostic tests, clinical pathways and conditions including chronic kidney disease, chronic pelvic pain, colitis, detrusor over-activity, group B streptococcal colonisation, tuberculosis and colorectal, lung, ovarian and thyroid cancers., Results: We identified 10 common themes underlying challenges that are more pronounced in test evaluation compared to intervention trials. We illustrate these themes with examples from 10 trials, including with 31 specific challenges we experienced. The themes were ethics/governance; accessing patient populations; recruitment; patient preference; test processes, clinical pathways and samples storage; uncertainty of diagnostic results; verifying diagnosis (reference standard); follow-up; adverse effects; and diagnostic impact., Conclusion: We present 10 common themes, including 31 challenges, in test evaluation trials that will be helpful to others designing and managing future test evaluation trials. Proactive identification of potential challenges at the design and planning stages of test evaluation trials will enable strategies to improve trial design and management that may be different from standard strategies used for intervention trials. Future work could extend this topic to include challenges for other trial stakeholders including participants, clinicians, statisticians and funders., Trial Registration: All trials reviewed in this project were registered and are provided in Table 1.

Background: Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral ribonucleic acid (RNA) using reverse transcription polymerase chain reaction (RT-PCR) are pivotal to detecting current coronavirus disease (COVID-19) and duration of detectable virus indicating potential for infectivity., Methods: We conducted an individual participant data (IPD) systematic review of longitudinal studies of RT-PCR test results in symptomatic SARS-CoV-2. We searched PubMed, LitCOVID, medRxiv, and COVID-19 Living Evidence databases. We assessed risk of bias using a QUADAS-2 adaptation. Outcomes were the percentage of positive test results by time and the duration of detectable virus, by anatomical sampling sites., Results: Of 5078 studies screened, we included 32 studies with 1023 SARS-CoV-2 infected participants and 1619 test results, from - 6 to 66 days post-symptom onset and hospitalisation. The highest percentage virus detection was from nasopharyngeal sampling between 0 and 4 days post-symptom onset at 89% (95% confidence interval (CI) 83 to 93) dropping to 54% (95% CI 47 to 61) after 10 to 14 days. On average, duration of detectable virus was longer with lower respiratory tract (LRT) sampling than upper respiratory tract (URT). Duration of faecal and respiratory tract virus detection varied greatly within individual participants. In some participants, virus was still detectable at 46 days post-symptom onset., Conclusions: RT-PCR misses detection of people with SARS-CoV-2 infection; early sampling minimises false negative diagnoses. Beyond 10 days post-symptom onset, lower RT or faecal testing may be preferred sampling sites. The included studies are open to substantial risk of bias, so the positivity rates are probably overestimated.

Introduction: Coeliac disease (CD) is a systemic immune-mediated disorder triggered by gluten in genetically predisposed individuals. CD is diagnosed using a combination of serology tests and endoscopic biopsy of the small intestine. However, because of non-specific symptoms and heterogeneous clinical presentation, diagnosing CD is challenging. Early detection of CD through improved case-finding strategies can improve the response to a gluten-free diet, patients' quality of life and potentially reduce the risk of complications. However, there is a lack of consensus in which groups may benefit from active case-finding., Methods and Analysis: We will perform a systematic review to determine the accuracy of diagnostic indicators (such as symptoms and risk factors) for CD in adults and children, and thus can help identify patients who should be offered CD testing. MEDLINE, Embase, Cochrane Library and Web of Science will be searched from 1997 until 2020. Screening will be performed in duplicate. Data extraction will be performed by one and checked by a second reviewer. Disagreements will be resolved through discussion or referral to a third reviewer. We will produce a narrative summary of identified prediction models. Studies, where 2×2 data can be extracted or reconstructed, will be treated as diagnostic accuracy studies, that is, the diagnostic indicators are the index tests and CD serology and/or biopsy is the reference standard. For each diagnostic indicator, we will perform a bivariate random-effects meta-analysis of the sensitivity and specificity., Ethics and Dissemination: Results will be reported in peer-reviewed journals, academic and public presentations and social media. We will convene an implementation panel to advise on the optimum strategy for enhanced dissemination. We will discuss findings with Coeliac UK to help with dissemination to patients. Ethical approval is not applicable, as this is a systematic review and no research participants will be involved., Prospero Registration Number: CRD42020170766., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Purpose: To prospectively evaluate interobserver agreement for small bowel ultrasound (SBUS) in newly diagnosed and relapsing Crohn's disease., Methods: A subset of patients recruited to a prospective trial comparing the diagnostic accuracy of MR enterography and SBUS underwent a second SBUS performed by one of a pool of six practitioners, who recorded the presence, activity and location of small bowel and colonic disease. Detailed segmental mural and extra-mural observations were also scored. Interobserver variability was expressed as percentage agreement with a construct reference standard, split by patient cohort, grouping disease as present or absent. Prevalence adjusted bias adjusted kappa (PABAK), and simple percentage agreement between practitioners, irrespective of the reference standard, were calculated., Results: Thirty-eight patients (11 new diagnosis, 27 relapse) were recruited from two sites. Overall percentage agreement for small bowel disease presence against the consensus reference was 82% (52-95% (95%CI)), kappa coefficient (κ) 0.64, (substantial agreement) for new diagnosis and 81%, κ 0.63 (substantial agreement) for the relapsing cohort. Agreement for colonic disease presence was 64%, κ 0.27 (fair agreement) in new diagnosis and 78%,κ 0.56 (moderate agreement) in the relapsing cohort. Simple agreement between practitioners was 84% and 87% for small bowel and colonic disease presence respectively. Practitioners agreed on small bowel disease activity in 24/27 (89%) where both identified disease. Kappa agreement for detailed mural observations ranged from κ 0.00 to 1.00., Conclusion: There is substantial practitioner agreement for small bowel disease presence in newly diagnosed and relapsing CD patients, supporting wider dissemination of enteric US.

Background: Perioperative goal directed fluid therapy (GDFT) has been shown to reduce postoperative complications following major surgery; this intervention has not been formally evaluated in the setting of liver transplantation., Methods: We conducted a prospective trial of GDFT following liver transplantation randomising patients with liver cirrhosis to either 12 h of GDFT using non-invasive cardiac output monitoring or standard care (SC). The primary outcome was feasibility. Secondary outcomes included survival, postoperative complications (Clavien-Dindo), quality of life (by EQ-5D-5L) and resource use. Trial specific follow up occurred at 90 and 180 days after surgery., Results: The study was feasible. Of 224 eligible patients, 122 were approached, 114 consented to participate and 60 were enrolled into the trial. The mean (SD) volume of IV crystalloid administered to the GDFT group during the 12-h study period was 3968 (2073) ml for the GDFT group and 2510 (1026) ml for the SC group. As regards secondary outcomes there was no difference in survival or overall complication rates. There was no significant difference in quality of life scores and resource use between the groups., Conclusion: A randomised study of GDFT following liver transplantation is feasible. A post-trial stakeholder meeting supported proceeding with a full multi-centre trial., (Copyright © 2019. Published by Elsevier Ltd.)

This review identifies and examines terms used to describe a radiological research "study" or "trial". A taxonomy of clinical research descriptions is explained with reference to medical imaging examples. Because many descriptive terms have precise methodological implications, it is important that these terms are understood by readers and used correctly by researchers, so that the reader is not misled. KEY POINTS: • Multiple different terms are being used to describe radiological research "studies" and "trials", and many of these terms have precise methodological implications. • Radiological researchers sometimes use titles that describe their research incorrectly. This can mislead the reader as to what was actually done. • It is important that readers and researchers understand the correct taxonomy of clinical research and that researchers adopt the correct description for their work.

Many systematic reviews and meta-analyses concern the effect of a healthcare intervention on a binary outcome i.e . occurrence (or not) of a particular event. Usually, the overall effect, pooled across all studies included in the meta-analysis, is summarised using the odds ratio (OR) or the relative risk (RR). Under most circumstances, it is obvious how to identify what should be considered as the event of interest-for example, death or a clinically important side-effect. However, on occasion it may not be clear in which "direction" the event should be specified-such as attendance ( vs non-attendance) at cancer screening. Usually, this choice is not critical to the overall conclusion of the meta-analysis, but occasionally it can lead to differences in how the included studies are pooled, ultimately affecting the overall meta-analytic result, particularly when using RRs rather than ORs. In this commentary, we will explain this phenomenon in more detail using examples from the literature, and explore how analysts and readers can avoid some potential pitfalls.

Background: Transvaginal ultrasound and serum CA125 are routinely used for differential diagnosis of pelvic adnexal mass. Use of human epididymis 4 was approved in the United States in 2011. However, there is scarcity of studies evaluating the additional value of human epididymis 4., Objective: The objective of the study was to evaluate the performance characteristics of transvaginal ultrasound, CA125, and human epididymis 4 for differential diagnosis of ovarian cancer in postmenopausal women with adnexal masses., Study Design: This was a cohort study nested within the screen arms of the multicenter randomized controlled trial, United Kingdom Collaborative Trial of Ovarian Cancer Screening, based in England, Wales, and Northern Ireland. In United Kingdom Collaborative Trial of Ovarian Cancer Screening, 48,230 women randomized to transvaginal ultrasound screening and 50,078 to multimodal screening (serum CA125 interpreted by Risk of Ovarian Cancer Algorithm with second line transvaginal ultrasound) underwent the first (prevalence) screen. Women with adnexal lesions and/or persistently elevated risk were clinically assessed and underwent surgery or follow-up for a median of 10.9 years. Banked samples taken within 6 months of transvaginal ultrasound from all clinically assessed women were assayed for human epididymis 4 and CA125. Area under the curve and sensitivity for diagnosing ovarian cancer of multiple penalized logistic regression models incorporating logCA125, log human epididymis 4, age, and simple ultrasound features of the adnexal mass were compared., Results: Of 1590 (158 multimodal, 1432 ultrasound) women with adnexal masses, 78 were diagnosed with ovarian cancer (48 invasive epithelial ovarian, 14 type I, 34 type II; 24 borderline epithelial; 6 nonepithelial) within 1 year of scan. The area under the curve (0.893 vs 0.896; P = .453) and sensitivity (74.4% vs 75.6% ;P = .564) at fixed specificity of 90% of the model incorporating age, ultrasound, and CA125 were similar to that also including human epididymis 4. Both models had high sensitivity for invasive epithelial ovarian (89.6%) and type II (>91%) cancers., Conclusion: Our population cohort study suggests that human epididymis 4 adds little value to concurrent use of CA125 and transvaginal ultrasound in the differential diagnosis of adnexal masses in postmenopausal women., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The implications of a serious disease outbreak extend well beyond the disease itself. The levels of sickness and mortality, while important, can be quickly overshadowed by cascading risk implications that affect the global economy, threaten societal confidence, weaken the rule of law, present a risk to food security, and can lead to inter- and intra-state conflict. When multiple countries are concurrently impacted, the provision of life-saving and time-sensitive aid and humanitarian assistance can also be affected, leading to isolation and a domino effect of collapsing societies. When nations start from a low baseline level of resilience, then the speed of government and infrastructure failure may be swift. Resilience across every facet of government, community and business is critical if the disruptive effects of the disease and the more far-reaching effects of the fear the unseen enemy creates are to be controlled. This article describes the interconnected risks and impacts found within a pandemic crisis and how COVID-19 can impact every facet of society and business - providing the backdrop against which risk practitioners can contextualise how their respective organisations can plan for, respond to, manage, and ultimately recover from a pandemic crisis.

Background: Risk assessment informs decisions around admission to and discharge from secure psychiatric hospital and contributes to treatment and supervision. There are advantages to using brief, scalable, free online tools with similar accuracy to instruments currently used. We undertook a study of one such risk assessment, the Forensic Psychiatry and Violence Oxford (FoVOx) tool, examining its acceptability, feasibility, and practicality. Methods: We completed the FoVOx tool on all discharges from six secure psychiatric hospitals in one region in England over two years. We interviewed 11 senior forensic psychiatrists regarding each discharge using a standardized questionnaire. Their patient's FoVOx score was compared to clinical risk assessment, and the senior clinicians were asked if they considered FoVOx scores accurate and useful. A modified thematic analysis was conducted, and clinicians were surveyed about current risk assessment practice on discharge. Results: Of 90 consecutive discharges, 84 were included in the final analysis. The median FoVOx probability score was 11% risk of violent recidivism in two years after discharge. We estimated that 12 (14%) individuals reoffended since discharge; all were in the medium or high risk FoVOx categories. Clinical assessment of risk agreed with the FoVOx categories in around half the cases. Clinicians were more likely to provide lower risk categories compared with FoVOx ones. FoVOx was considered to be an accurate representation of risk in 67% of cases; clinicians revised their view on some patient's risk assessment after being informed of their FoVOx scores. Completing FoVOx was reported to be helpful in the majority of cases. Reasons included improved communication with other agencies, reassurance to clinical teams, and identifying additional factors not fully considered. 10 of the 11 respondents reported that FoVOx was practical, and seven of 11 reported that they would use it in the future, highlighting its brevity and speed of use compared to existing risk assessment tools. Conclusions: Senior clinicians in this regional forensic psychiatric service found the FoVOx risk assessment tool feasible, practical, and easy to use. Its use addressed a lack of consistency around risk assessment at the point of discharge and, if used routinely, could assist in clinical decision-making., (Copyright © 2019 Cornish, Lewis, Parry, Ciobanasu, Mallett and Fazel.)

Background: Whole-body magnetic resonance imaging is advocated as an alternative to standard pathways for staging cancer., Objectives: The objectives were to compare diagnostic accuracy, efficiency, patient acceptability, observer variability and cost-effectiveness of whole-body magnetic resonance imaging and standard pathways in staging newly diagnosed non-small-cell lung cancer (Streamline L) and colorectal cancer (Streamline C)., Design: The design was a prospective multicentre cohort study., Setting: The setting was 16 NHS hospitals., Participants: Consecutive patients aged ≥ 18 years with histologically proven or suspected colorectal (Streamline C) or non-small-cell lung cancer (Streamline L)., Interventions: Whole-body magnetic resonance imaging. Standard staging investigations (e.g. computed tomography and positron emission tomography-computed tomography)., Reference Standard: Consensus panel decision using 12-month follow-up data., Main Outcome Measures: The primary outcome was per-patient sensitivity difference between whole-body magnetic resonance imaging and standard staging pathways for metastasis. Secondary outcomes included differences in specificity, the nature of the first major treatment decision, time and number of tests to complete staging, patient experience and cost-effectiveness., Results: Streamline C - 299 participants were included. Per-patient sensitivity for metastatic disease was 67% (95% confidence interval 56% to 78%) and 63% (95% confidence interval 51% to 74%) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference in sensitivity of 4% (95% confidence interval -5% to 13%; p  = 0.51). Specificity was 95% (95% confidence interval 92% to 97%) and 93% (95% confidence interval 90% to 96%) respectively, a difference of 2% (95% confidence interval -2% to 6%). Pathway treatment decisions agreed with the multidisciplinary team treatment decision in 96% and 95% of cases, respectively, a difference of 1% (95% confidence interval -2% to 4%). Time for staging was 8 days (95% confidence interval 6 to 9 days) and 13 days (95% confidence interval 11 to 15 days) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference of 5 days (95% confidence interval 3 to 7 days). The whole-body magnetic resonance imaging pathway was cheaper than the standard staging pathway: £216 (95% confidence interval £211 to £221) versus £285 (95% confidence interval £260 to £310). Streamline L - 187 participants were included. Per-patient sensitivity for metastatic disease was 50% (95% confidence interval 37% to 63%) and 54% (95% confidence interval 41% to 67%) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference in sensitivity of 4% (95% confidence interval -7% to 15%; p  = 0.73). Specificity was 93% (95% confidence interval 88% to 96%) and 95% (95% confidence interval 91% to 98%), respectively, a difference of 2% (95% confidence interval -2% to 7%). Pathway treatment decisions agreed with the multidisciplinary team treatment decision in 98% and 99% of cases, respectively, a difference of 1% (95% confidence interval -2% to 4%). Time for staging was 13 days (95% confidence interval 12 to 14 days) and 19 days (95% confidence interval 17 to 21 days) for whole-body magnetic resonance imaging and standard pathways, respectively, a difference of 6 days (95% confidence interval 4 to 8 days). The whole-body magnetic resonance imaging pathway was cheaper than the standard staging pathway: £317 (95% confidence interval £273 to £361) versus £620 (95% confidence interval £574 to £666). Participants generally found whole-body magnetic resonance imaging more burdensome than standard imaging but most participants preferred the whole-body magnetic resonance imaging staging pathway if it reduced time to staging and/or number of tests., Limitations: Whole-body magnetic resonance imaging was interpreted by practitioners blinded to other clinical data, which may not fully reflect how it is used in clinical practice., Conclusions: In colorectal and non-small-cell lung cancer, the whole-body magnetic resonance imaging staging pathway has similar accuracy to standard staging pathways, is generally preferred by patients, improves staging efficiency and has lower staging costs. Future work should address the utility of whole-body magnetic resonance imaging for treatment response assessment., Trial Registration: Current Controlled Trials ISRCTN43958015 and ISRCTN50436483., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 66. See the NIHR Journals Library website for further project information., Competing Interests: Stuart A Taylor reports personal fees from Robarts Clinical Trials Inc. (London, ON, Canada) outside the submitted work. Andrea Rockall reports personal fees from Guerbet (Paris, France) outside the submitted work. Vicky Goh and Anwar Padhani report grants from Siemens AG (Erlangen, Germany) outside the submitted work. Steve Halligan reports non-financial support from iCad Inc. (Nashua, NH, USA) outside the submitted work and was a member of the Health Technology Assessment (HTA) commissioning board (2008–14). Stephen Morris declares past membership of the National Institute for Health Research (NIHR) HTA Clinical Evaluation and Trials Board (2007–9), HTA Commissioning Board (2009–13), Public Health Research Board (2011–17), Health Services and Delivery Research (HSDR) Commissioning Board (2014–16) and HSDR Board (2014–18), and current membership of the NIHR Programme Grants for Applied Research expert subpanel (2015–present) and HSDR Evidence Synthesis Sub Board (2016–present).

Background: Ventral hernias (VHs) often recur after surgical repair and subsequent attempts at repair are especially challenging. Rigorous research to reduce recurrence is required but such studies must be well-designed and report representative and comprehensive outcomes., Objective: We aimed to assesses methodological quality of non-randomised interventional studies of VH repair by systematic review., Methods: We searched the indexed literature for non-randomised studies of interventions for VH repair, January 1995 to December 2017 inclusive. Each prospective study was coupled with a corresponding retrospective study using pre-specified criteria to provide matched, comparable groups. We applied a bespoke methodological tool for hernia trials by combining relevant items from existing published tools. Study introduction and rationale, design, participant inclusion criteria, reported outcomes, and statistical methods were assessed., Results: Fifty studies (17,608 patients) were identified: 25 prospective and 25 retrospective. Overall, prospective studies scored marginally higher than retrospective studies for methodological quality, median score 17 (IQR: 14-18) versus 15 (IQR 12-18), respectively. For the sub-categories investigated, prospective studies achieved higher median scores for their, 'introduction', 'study design' and 'participants'. Surprisingly, no study stated that a protocol had been written in advance. Only 18 (36%) studies defined a primary outcome, and only 2 studies (4%) described a power calculation. No study referenced a standardised definition for VH recurrence and detection methods for recurrence varied widely. Methodological quality did not improve with publication year or increasing journal impact factor., Conclusion: Currently, non-randomised interventional studies of VH repair are methodologically poor. Clear outcome definitions and a standardised minimum dataset are needed.

Background: Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared., Objective: To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease., Design: Prospective multicentre cohort study., Setting: Eight NHS hospitals., Participants: Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse., Interventions: Magnetic resonance enterography and ultrasonography., Main Outcome Measures: The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness., Results: Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%; p  = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests., Limitations: Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice., Conclusions: Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease., Trial Registration: Current Controlled Trials ISRCTN03982913., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 42. See the NIHR Journals Library website for further project information., Competing Interests: Stuart A Taylor reports personal fees from Robarts Clinical Trials Inc. (London, ON, Canada) outside the submitted work. Simon Travis reports receiving fees for consultancy work and/or speaking engagements from the following: AbbVie Inc. (Chicago, IL, USA), Centocor Inc. (Horsham, PA, USA), Schering-Plough (Kenilworth, NJ, USA), Bristol-Myers Squibb (New York, NY, USA), Chemocentryx Inc. (Mountain View, CA, USA), Cosmo Pharmaceuticals (Dublin, Ireland), Elan Pharma Inc. (Dublin, Ireland), Genentech Inc. (San Francisco, CA, USA), Giuliani SpA (Milan, Italy), Merck & Co. Inc. (Kenilworth, NJ, USA), Takeda UK Ltd (Woodburn Green, Buckinghamshire, UK), Otsuka Pharmaceuticals (Tokyo, Japan), PDL BioPharma (Nevada, NV, USA), Pfizer Inc. (San Francisco, CA, USA), Shire Pharmaceuticals UK (St Helier, Jersey), Glenmark Pharmaceuticals (Maharashtra, India), Synthon Biopharmaceuticals (Nijmegen, the Netherlands), NPS Pharmaceuticals (Bedminster, NJ, USA), Eli Lilly and Company (Indiana, IN, USA), Warner Chilcott Ltd, Proximagen Group Ltd (London, UK), VHsquared Ltd (Cambridge, UK), Topivert Pharma Ltd (London, UK), Ferring Pharmaceuticals (Saint-Prex, Switzerland), Celgene Corporation (Summit, NJ, USA), GlaxoSmithKline plc (Brentford, UK), Amgen Inc. (Thousand Oaks, CA, USA), Biogen Inc. (Cambridge, MA, USA), Enterome SA (Paris, France), Immunocore Ltd (Oxford, UK), Immunometabolism/Third Rock Ventures (Boston, MA, USA), Bioclinica Inc. (Newtown, PA, USA), Boehringer Ingelheim GmBH (Ingelheim am Rhein, Germany), Gilead Sciences Inc. (Foster City, CA, USA), Grunenthal Ltd (Aachen, Germany), Janssen Pharmaceutica (Beerse, Belgium), Novartis AG (Basel, Switzerland), Receptos Inc. (San Diego, CA, USA), Pharm-Olam International UK Ltd (Bracknell, UK), Sigmoid Pharma (Dublin, Ireland), Theravance Biopharma Inc. (Dublin, Ireland), Given Imaging Ltd (Yokneam Illit, Israel), UCB Pharma SA (Brussels, Belgium), Tillotts Pharma AG (Rheinfelden, Switzerland), Sanofi Aventis SA (Paris, France), Vifor Pharma (St Gallen, Switzerland), Abbott Laboratories Ltd (Chicago, IL, USA) and Procter and Gamble Ltd (Cincinnati, OH, USA). Simon Travis reports directorships of charities IBD2020 (Barnet, UK; UK 09762150), Cure Crohn’s Colitis (Sydney, Australia; ABN 85 154 588 717) and the Truelove Foundation (London, UK; UK 11056711). Simon Travis also reports receiving fees from the following for expert testimony work and/or royalties: Santarus Inc. (San Diego, CA, USA), Cosmo Technologies Ltd (Dublin, Ireland), Tillotts Pharma AG, Wiley-Blackwell Inc. (Hoboken, NJ, USA), Elsevier Ltd (Amsterdam, the Netherlands) and Oxford University Press (Oxford, UK). Simon Travis has received research grants from the following: AbbVie Inc., the International Organization for the Study of Inflammatory Bowel Disease, Eli Lilly and Company, UCB Inc. (Brussels, Belgium), Vifor Pharma, Norman Collisson Foundation (Bicester, UK), Ferring Pharmaceuticals, Schering-Plough, Merck Sharpe & Dohme Corp. (Kenilworth, NJ, USA), Procter and Gamble Ltd, Warner Chilcott Ltd, Abbott Laboratories Ltd, PDL BioPharma Inc. (Incline Village, NV, USA), Takeda UK Ltd and the International Consortium for Health Care Outcomes Measurement. Ailsa Hart reports personal fees from AbbVie Inc., Atlantic Healthcare Ltd (Saffron Walden, UK), Bristol-Myers Squibb, Celltrion Inc. (Incheon, South Korea), Dr Falk Pharma UK Ltd (Bourne End, UK), Ferring Pharmaceuticals, Janssen Pharmaceuticals, Merck Sharpe & Dohme Corp., Napp Pharmaceuticals Ltd (Cambridge, UK), Pfizer Inc., Pharmacosmos A/S (Holbæk, Denmark), Shire Pharmaceuticals UK and Takeda UK Ltd, and non-financial support from Genentech Inc. Alastair Windsor reports personal fees from Takeda, grants from Allergan Inc. (Dublin, Ireland), personal fees from Allergan, personal fees from Cook Medical Inc. (Bloomington, IN, USA) and grants and personal fees from Bard Ltd (Crawley, UK) outside the submitted work. Andrew Plumb reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme outside the submitted work, grants from the NIHR Fellowships programme during the conduct of the study and honoraria for educational lectures delivered at events arranged by Acelity Inc. (Crawley, UK), Actavis Pharma Inc. (Parsippany-Troy Hills, NJ, USA), Dr Falk Pharma UK Ltd, Janssen-Cilag Ltd (High Wycombe, UK) and Takeda UK Ltd on the subject of inflammatory bowel disease. Ilan Jacobs reports share ownership in General Electric Company (Boston, MA, USA), which manufacturers and sells magnetic resonance imaging equipment. Charles D Murray reports personal fees from AbbVie Inc., Merck Sharpe & Dohme Corp. and Janssen Pharmaceutica outside the submitted work. Antony Higginson reports personal fees from Toshiba Corporation (Tokyo, Japan) outside the submitted work. Steve Halligan reports non-financial support from iCAD Inc. (Nashua, NH, USA) outside the submitted work, and sat on the HTA commissioning board (2008–14). Stephen Morris reports Health Services and Delivery Research (HSDR) Board membership (2014–18), HSDR Evidence Synthesis Sub Board membership (2016), HTA Commissioning Board membership (2009–13) and Public Health Research Board membership (2011–17).

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p < 0.001) . Eighty-nine percent of the patients in the severe BDI-II category had poorly controlled asthma (ACQ-5 score ≥ 1.5) compared with 63% in the minimal category (p < 0.001) . Conclusion: Increased severity of depressive symptoms was associated with worse respiratory-related quality of life and asthma control in the patients with severe eosinophilic asthma. These findings highlight the need for a multidimensional approach for the management of uncontrolled asthma, including timely identification of depressive symptoms. Additional research is needed to further explore the interactions between the two common conditions.Clinical trials NCT01691521 and NCT01619508, www.clinicaltrials.gov.

Background: Whole-body MRI (WB-MRI) could be an alternative to multimodality staging of colorectal cancer, but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in colorectal cancer., Methods: The Streamline C trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed colorectal cancer. Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or polyp cancer. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs), and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN43958015, and is complete., Findings: Between March 26, 2013, and Aug 19, 2016, 1020 patients were screened for eligibility. 370 patients were recruited, 299 of whom completed the trial; 68 (23%) had metastasis at baseline. Pathway sensitivity was 67% (95% CI 56 to 78) for WB-MRI and 63% (51 to 74) for standard pathways, a difference in sensitivity of 4% (-5 to 13, p=0·51). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (95% [95% CI 92-97]) and standard pathways (93% [90-96], p=0·48). Agreement with the multidisciplinary team's final treatment decision was 96% for WB-MRI and 95% for the standard pathway. Time to complete staging was shorter for WB-MRI (median, 8 days [IQR 6-9]) than for the standard pathway (13 days [11-15]); a 5-day (3-7) difference. WB-MRI required fewer tests (median, one [95% CI 1 to 1]) than did standard pathways (two [2 to 2]), a difference of one (1 to 1). Mean per-patient staging costs were £216 (95% CI 211-221) for WB-MRI and £285 (260-310) for standard pathways., Interpretation: WB-MRI staging pathways have similar accuracy to standard pathways and reduce the number of tests needed, staging time, and cost., Funding: UK National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Whole-body magnetic resonance imaging (WB-MRI) could be an alternative to multi-modality staging of non-small-cell lung cancer (NSCLC), but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in NSCLC., Methods: The Streamline L trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed NSCLC that was potentially radically treatable on diagnostic chest CT (defined as stage IIIb or less). Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or histologies other than NSCLC. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs) and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN50436483, and is complete., Findings: Between Feb 26, 2013, and Sept 5, 2016, 976 patients were screened for eligibility. 353 patients were recruited, 187 of whom completed the trial; 52 (28%) had metastasis at baseline. Pathway sensitivity was 50% (95% CI 37-63) for WB-MRI and 54% (41-67) for standard pathways, a difference of 4% (-7 to 15, p=0·73). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (93% [88-96]) and standard pathways (95% [91-98], p=0·45). Agreement with the multidisciplinary team's final treatment decision was 98% for WB-MRI and 99% for the standard pathway. Time to complete staging was shorter for WB-MRI (13 days [12-14]) than for the standard pathway (19 days [17-21]); a 6-day (4-8) difference. The number of tests required was similar WB-MRI (one [1-1]) and standard pathways (one [1-2]). Mean per-patient costs were £317 (273-361) for WBI-MRI and £620 (574-666) for standard pathways., Interpretation: WB-MRI staging pathways have similar accuracy to standard pathways, and reduce the staging time and costs., Funding: UK National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission., Objective: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses., Methods: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/μL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg., Results: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/μL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395)., Conclusion: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Acute Kidney Injury, a common complication of liver transplant, is associated with a significant increase in the risk of morbidity, mortality and graft loss. Current diagnostic criteria leaves a delay in diagnosis allowing further potential irreversible damage. Early biomarkers of renal injury are of clinical importance and Neutrophil Gelatinase Associated Lipocalins (NGALs) and Syndecan-1 were investigated., Methods: AKI was defined according to the Acute Kidney Injury Network criteria. Urine and blood samples were collected pre-operatively, immediately post-op and 24 h post reperfusion to allow measurement of NGAL and Syndecan-1 levels., Results: 13 of 27 patients developed an AKI. Patients who developed AKI had significantly higher peak transaminases. Urinary NGAL, plasma NGAL and Syndecan-1 levels were significantly elevated in all patients post reperfusion. Urinary NGAL levels immediately post-op were significantly higher in patients who developed an AKI than those that didn't [1319 ng/ml vs 46.56 ng/ml, p ≤ 0.001]. ROC curves were performed and urinary NGAL levels immediately post-op were an excellent biomarker for AKI with an area under the curve of 0.948 (0.847-1.00)., Conclusions: Urinary NGAL levels measured immediately post-op accurately predict the development of AKI and their incorporation into clinical practise could allow early protocols to be developed to treat post transplant AKI., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)