Association of computed tomography-derived body composition and complications after colorectal cancer surgery: A systematic review and meta-analysis.

The prediction of the risk of developing complications after colorectal surgery for colorectal carcinoma remains imprecise. Body composition measurements on a computed tomography (CT) scan can potentially contribute to a better preoperative risk assessment. The aim of this systematic review is to evaluate the evidence for the use of body composition measurements on CT scans to predict short-term complications after colorectal cancer surgery. A literature search (in PubMed, Embase and Web of Science) was performed up to 1 August 2022. Two researchers independently screened the articles, extracted data and assessed the quality of the studies using the Quality in Prognosis Studies tool. The primary outcome measure was the occurrence of complications within 30 days after surgery. Meta-analysis was conducted using a random-effects model to synthesize a pooled odds ratio (OR). The study protocol was registered in PROSPERO (CRD42021281010). Forty-five articles with a total of 16 537 patients were included. In total, 26 body composition measures were investigated: 8 muscle-related measures, 11 adipose tissue measures, 4 combined muscle and adipose tissue measures, and 3 other measures. These were investigated as potential predictors for more than 50 differently defined postoperative complications. Meta-analysis was only possible for two measurements and showed that higher amounts of visceral fat increase the risk of developing overall complications (OR: 2.52 [1.58-4.00], P < 0.0001) and anastomotic leakage (OR: 1.76 [1.17-2.65], P = 0.006). A wide variety of body composition measurements on preoperative CT scans have been investigated as a predictive factor for postoperative complications. Visceral fat appeared to be associated with overall complications and anastomotic leakage; however, the association is weak, and its clinical relevance or applicability is questionable. The current evidence is limited by methodological heterogeneity and the risk of bias. To improve comparability of results across studies and improve decision-making, future studies should use standardized methods for measuring body composition on CT scans, outcome definitions and statistical analyses.

Benefit-Harm Analysis for Informed Decision Making on Participating in Colorectal Cancer Screening: A Modeling Study.

OBJECTIVES: To facilitate informed decision making on participating in colorectal cancer (CRC) screening, we assessed the benefit-harm balance of CRC screening for a wide range of subgroups over different time horizons. METHODS: The study combined incidence proportions of benefits and harms of (not) participating in CRC screening estimated by the Adenoma and Serrated pathway to CAncer microsimulation model, a preference eliciting survey, and benefit-harm balance modeling combining all outcomes to determine the net health benefit of CRC screening over 10, 20, and 30 years. Probability of net health benefit was estimated for 210 different subgroups based on age, sex, previous participation in CRC screening, and lifestyle. RESULTS: CRC screening was net beneficial in 183 of 210 subgroups over 30 years (median probability [MP] of 0.79, interquartile range [IQR] of 0.69-0.85) across subgroups. Net health benefit was greater for men (MP 0.82; IQR 0.69-0.89) than women (MP 0.76; IQR 0.67-0.83) and for those without history of participation in previous screenings (MP 0.84; IQR 0.80-0.89) compared with those with (MP 0.69; IQR 0.59-0.75). Net health benefit decreased with increasing age, from MP of 0.84 (IQR 0.80-0.86) at age 55 to 0.61 (IQR 0.56-0.71) at age 75. Shorter time horizons led to lower benefit, with MP of 0.70 (IQR 0.62-0.80) over 20 years and 0.54 (IQR 0.48-0.67) over 10 years. CONCLUSIONS: Our benefit-harm analysis provides information about net health benefit of screening participation, based on important characteristics and preferences of individuals, which could assist screening invitees in making informed decisions on screening participation.

Perceived Importance of the Benefits and Harms of Colorectal Cancer Screening: A Best-Worst Scaling Study.

OBJECTIVES: To elicit the relative importance of the benefits and harms of colorectal cancer (CRC) screening among potential screening participants in the Dutch population. METHODS: In a consensus meeting with 11 experts, risk reduction of CRC and CRC deaths (benefits) and complications from colonoscopy, stress of receiving positive fecal immunological test (FIT) results, as well as false-positive and false-negative FIT results (harms) were selected as determinant end points to consider during decision making. We conducted an online best-worst scaling survey among adults aged 55 to 75 years from the Dutch Health Care Consumer Panel of The Netherlands Institute for Health Services Research to elicit preference values for these outcomes. The preference values were estimated using conditional logit regression. RESULTS: Of 265 participants, 234 (89%) had ever participated in CRC screening. Compared with the stress of receiving a positive FIT result, the outcome perceived most important was the risk of CRC death (odds ratio [OR] 4.5; 95% confidence interval [CI] 3.9-5.1), followed by risk of CRC (OR 4.1; 95% CI 3.6-4.7), a false-negative FIT result (OR 3.1; 95% CI 2.7-3.5), colonoscopy complications (OR 1.6; 95% CI 1.4-1.8), and a false-positive FIT result (OR 1.4; 95% CI 1.3-1.6). The magnitude of these differences in perceived importance varied according to age, educational level, ethnic background, and whether the individual had previously participated in CRC screening. CONCLUSION: Dutch men and women eligible for FIT-based CRC screening perceive the benefits of screening to be more important than the harms.

Diagnostic Accuracy of MRI for Solid Renal Masses: A Systematic Review and Meta-analysis.

BACKGROUND: Biparametric (bp)-MRI and multiparametric (mp)-MRI may improve the diagnostic accuracy of renal mass histology. PURPOSE: To evaluate the available evidence on the diagnostic accuracy of bp-MRI and mp-MRI for solid renal masses in differentiating malignant from benign, aggressive from indolent, and clear cell renal cell carcinoma (ccRCC) from other histology. STUDY TYPE: Systematic review. POPULATION: MEDLINE, EMBASE, and CENTRAL up to January 11, 2022 were searched. FIELD STRENGTH/SEQUENCE: 1.5 or 3 Tesla. ASSESSMENT: Eligible studies evaluated the accuracy of MRI (with at least two sequences: T2, T1, dynamic contrast and diffusion-weighted imaging) for diagnosis of solid renal masses in adult patients, using histology as reference standard. Risk of bias and applicability were assessed using QUADAS-2. STATISTICAL TESTS: Meta-analysis using a bivariate logitnormal random effects model. RESULTS: We included 10 studies (1239 masses from approximately 1200 patients). The risk of bias was high in three studies, unclear in five studies and low in two studies. The diagnostic accuracy of malignant (vs. benign) masses was assessed in five studies (64% [179/281] malignant). The summary estimate of sensitivity was 95% (95% confidence interval [CI]: 77%-99%), and specificity was 63% (95% CI: 46%-77%). No study assessed aggressive (vs. indolent) masses. The diagnostic accuracy of ccRCC (vs. other subtypes) was evaluated in six studies (47% [455/971] ccRCC): the summary estimate of sensitivity was 85% (95% CI: 77%-90%) and specificity was 77% (95% CI: 73%-81%). DATA CONCLUSION: Our study reveals deficits in the available evidence on MRI for diagnosis of renal mass histology. The number of studies was limited, at unclear/high risk of bias, with heterogeneous definitions of solid masses, imaging techniques, diagnostic criteria, and outcome measures. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Diagnostic accuracy and added value of blood-based protein biomarkers for pancreatic cancer: A meta-analysis of aggregate and individual participant data.

Background: Novel blood-based protein biomarkers may be of value for efficient, accurate, and non-invasive diagnosis of pancreatic cancer. This study assesses the diagnostic accuracy of newly recognized blood-based protein biomarkers for detecting pancreatic cancer, and investigates their added value to CA19-9, the common blood-based biomarker in clinical use for pancreatic cancer. Methods: PubMed, Embase, Web of Science, and the Wiley/Cochrane Library were systematically searched from inception until June 2022. A meta-analysis of aggregate and individual participant data was conducted using frequentist and Bayesian hierarchical random-effects models. The added clinical utility of protein biomarkers was investigated using bootstrap bias-corrected decision curve analyses. Findings: Aggregate data from 28 primary studies (6127 participants) were included, of which 8 studies (1790 participants) provided individual participant data. CA19-9 was significantly more accurate than MIC-1 for distinguishing pancreatic cancer from benign disease (AUC, 0.83 vs 0.74; relative diagnostic odds ratio [rDOR], 2.10 [95% CI, 0.98-4.48]; p = 0.002), THBS2 (AUC, 0.87 vs 0.69; rDOR, 4.53 [2.16-9.39]; p < 0.0001), TIMP-1 (AUC, 0.91 vs 0.70; rDOR, 8.00 [3.81-16.9]; p < 0.0001), OPN (AUC, 0.89 vs 0.74; rDOR, 4.22 [1.13-15.6]; p < 0.0001), ICAM-1 (AUC, 0.91 vs 0.68; rDOR 9.30 [0.87-99.5]; p < 0.0001), and IGFBP2 (AUC, 0.91 vs 0.68; rDOR, 4.48 [0.78-24.3]; p < 0.0001). The addition of these novel protein biomarkers to CA19-9 did not significantly improve the AUC, and resulted in minor increases or limited decreases in clinical utility. Interpretation: Novel protein biomarkers have moderate diagnostic accuracy, do not outperform CA19-9 in differentiating pancreatic cancer from benign disease, and show limited added clinical value to CA19-9. We propose recommendations to aid the development of minimally invasive diagnostic tests with sufficient clinical utility to improve the management of patients with suspected pancreatic cancer. Funding: Bennink Foundation, Dutch Cancer Foundation (KWF Kankerbestrijding), and AIRC.

Symptom- and chest-radiography screening for active pulmonary tuberculosis in HIV-negative adults and adults with unknown HIV status.

BACKGROUND: Systematic screening in high-burden settings is recommended as a strategy for early detection of pulmonary tuberculosis disease, reducing mortality, morbidity and transmission, and improving equity in access to care. Questioning for symptoms and chest radiography (CXR) have historically been the most widely available tools to screen for tuberculosis disease. Their accuracy is important for the design of tuberculosis screening programmes and determines, in combination with the accuracy of confirmatory diagnostic tests, the yield of a screening programme and the burden on individuals and the health service. OBJECTIVES: To assess the sensitivity and specificity of questioning for the presence of one or more tuberculosis symptoms or symptom combinations, CXR, and combinations of these as screening tools for detecting bacteriologically confirmed pulmonary tuberculosis disease in HIV-negative adults and adults with unknown HIV status who are considered eligible for systematic screening for tuberculosis disease. Second, to investigate sources of heterogeneity, especially in relation to regional, epidemiological, and demographic characteristics of the study populations. SEARCH METHODS: We searched the MEDLINE, Embase, LILACS, and HTA (Health Technology Assessment) databases using pre-specified search terms and consulted experts for unpublished reports, for the period 1992 to 2018. The search date was 10 December 2018. This search was repeated on 2 July 2021. SELECTION CRITERIA: Studies were eligible if participants were screened for tuberculosis disease using symptom questions, or abnormalities on CXR, or both, and were offered confirmatory testing with a reference standard. We included studies if diagnostic two-by-two tables could be generated for one or more index tests, even if not all participants were subjected to a microbacteriological reference standard. We excluded studies evaluating self-reporting of symptoms. DATA COLLECTION AND ANALYSIS: We categorized symptom and CXR index tests according to commonly used definitions. We assessed the methodological quality of included studies using the QUADAS-2 instrument. We examined the forest plots and receiver operating characteristic plots visually for heterogeneity. We estimated summary sensitivities and specificities (and 95% confidence intervals (CI)) for each index test using bivariate random-effects methods. We analyzed potential sources of heterogeneity in a hierarchical mixed-model. MAIN RESULTS: The electronic database search identified 9473 titles and abstracts. Through expert consultation, we identified 31 reports on national tuberculosis prevalence surveys as eligible (of which eight were already captured in the search of the electronic databases), and we identified 957 potentially relevant articles through reference checking. After removal of duplicates, we assessed 10,415 titles and abstracts, of which we identified 430 (4%) for full text review, whereafter we excluded 364 articles. In total, 66 articles provided data on 59 studies. We assessed the 2 July 2021 search results; seven studies were potentially eligible but would make no material difference to the review findings or grading of the evidence, and were not added in this edition of the review. We judged most studies at high risk of bias in one or more domains, most commonly because of incorporation bias and verification bias. We judged applicability concerns low in more than 80% of studies in all three domains. The three most common symptom index tests, cough for two or more weeks (41 studies), any cough (21 studies), and any tuberculosis symptom (29 studies), showed a summary sensitivity of 42.1% (95% CI 36.6% to 47.7%), 51.3% (95% CI 42.8% to 59.7%), and 70.6% (95% CI 61.7% to 78.2%, all very low-certainty evidence), and a specificity of 94.4% (95% CI 92.6% to 95.8%, high-certainty evidence), 87.6% (95% CI 81.6% to 91.8%, low-certainty evidence), and 65.1% (95% CI 53.3% to 75.4%, low-certainty evidence), respectively. The data on symptom index tests were more heterogenous than those for CXR. The studies on any tuberculosis symptom were the most heterogeneous, but had the lowest number of variables explaining this variation. Symptom index tests also showed regional variation. The summary sensitivity of any CXR abnormality (23 studies) was 94.7% (95% CI 92.2% to 96.4%, very low-certainty evidence) and 84.8% (95% CI 76.7% to 90.4%, low-certainty evidence) for CXR abnormalities suggestive of tuberculosis (19 studies), and specificity was 89.1% (95% CI 85.6% to 91.8%, low-certainty evidence) and 95.6% (95% CI 92.6% to 97.4%, high-certainty evidence), respectively. Sensitivity was more heterogenous than specificity, and could be explained by regional variation. The addition of cough for two or more weeks, whether to any (pulmonary) CXR abnormality or to CXR abnormalities suggestive of tuberculosis, resulted in a summary sensitivity and specificity of 99.2% (95% CI 96.8% to 99.8%) and 84.9% (95% CI 81.2% to 88.1%) (15 studies; certainty of evidence not assessed). AUTHORS' CONCLUSIONS: The summary estimates of the symptom and CXR index tests may inform the choice of screening and diagnostic algorithms in any given setting or country where screening for tuberculosis is being implemented. The high sensitivity of CXR index tests, with or without symptom questions in parallel, suggests a high yield of persons with tuberculosis disease. However, additional considerations will determine the design of screening and diagnostic algorithms, such as the availability and accessibility of CXR facilities or the resources to fund them, and the need for more or fewer diagnostic tests to confirm the diagnosis (depending on screening test specificity), which also has resource implications. These review findings should be interpreted with caution due to methodological limitations in the included studies and regional variation in sensitivity and specificity. The sensitivity and specificity of an index test in a specific setting cannot be predicted with great precision due to heterogeneity. This should be borne in mind when planning for and implementing tuberculosis screening programmes.

Haploidentical Allogeneic Stem Cell Transplantation in Sickle Cell Disease: A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic stem cell transplantation (SCT) is the sole established curative treatment option for patients with sickle cell disease (SCD). However, a lack of HLA-identical sibling donors is a limiting factor. Haploidentical related donors are a promising donor pool, potentially extending SCT as a curative treatment option to a larger group of patients with no other meaningful treatment options for their severe SCD. In the present study, we aimed to systematically review the results of haploidentical SCT in patients with SCD. A comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data were extracted by 2 reviewers independently, and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Fourteen studies met our inclusion criteria. To provide an overview of the results of haploidentical SCT, we grouped the studies into myeloablative conditioning versus nonmyeloablative conditioning as well as into in vitro versus in vivo (ie, with post-transplantation cyclophosphamide) T cell depletion with a subgroup meta-analysis of proportions. All the included studies were observational cohort studies. Only 3 of these studies reported data for both matched sibling donor (MSD) SCT and haploidentical SCT. Based on a comparative meta-analysis of the 3 studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio, 5.3; 95% confidence interval [CI], 1.0 to 27.6). Overall survival was not significantly different between the groups. A subgroup meta-analysis of the results of haploidentical SCT showed relatively low overall pooled proportions of graft failure (7%; 95% CI, 2% to 20%), acute graft-versus-host disease (GVHD) (4%; 95% CI, 2% to 12%), and chronic GVHD (11%; 95% CI, 7% to 16%). Overall survival (OS) was high in all the included studies (91%; 95% CI, 85% to 94%). Adjustments to the conditioning regimens, robust pretransplantation and post-transplantation T cell depletion, and improved supportive care have resulted in reduced graft failure and improved OS following haploidentical SCT in patients with SCD. We conclude that the safety of haploidentical SCT in SCD patients has improved significantly, and that this should be considered as a curative option in patients with severe SCD.

Routine laboratory testing to determine if a patient has COVID-19.

BACKGROUND: Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C-reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID-19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. OBJECTIVES: To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. SEARCH METHODS: On 4 May 2020 we undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. SELECTION CRITERIA: We included both case-control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. The reference standard could be reverse transcriptase polymerase chain reaction (RT-PCR) alone; RT-PCR plus clinical expertise or and imaging; repeated RT-PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS-2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta-analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta-analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. MAIN RESULTS: We included 21 studies in this review, including 14,126 COVID-19 patients and 56,585 non-COVID-19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID-19, the included studies used detection of SARS-CoV-2 infection through RT-PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin-6, increase in C-reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low-certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low-certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low-certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low-certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low-certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low-certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low-certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low-certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low-certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low-certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low-certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low-certainty evidence). The summary sensitivity of an increase in IL-6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low-certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low-certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low-certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low-certainty evidence). AUTHORS' CONCLUSIONS: Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID-19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non-hospital settings to evaluate how these tests would perform in people with milder symptoms.

Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children.

BACKGROUND: In children with urinary tract infection (UTI), only those with pyelonephritis (and not cystitis) are at risk for developing long-term renal sequelae. If non-invasive biomarkers could accurately differentiate children with cystitis from children with pyelonephritis, treatment and follow-up could potentially be individualized. This is an update of a review first published in 2015. OBJECTIVES: The objectives of this review were to 1) determine whether procalcitonin (PCT), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) can replace the acute DMSA scan in the diagnostic evaluation of children with UTI; 2) assess the influence of patient and study characteristics on the diagnostic accuracy of these tests, and 3) compare the performance of the three tests to each other. SEARCH METHODS: We searched MEDLINE, EMBASE, DARE, Web of Science, and BIOSIS Previews through to 17th December 2019 for this review. The reference lists of all included articles and relevant systematic reviews were searched to identify additional studies not found through the electronic search. SELECTION CRITERIA: We only considered published studies that evaluated the results of an index test (PCT, CRP, ESR) against the results of an acute-phase 99Tc-dimercaptosuccinic acid (DMSA) scan (conducted within 30 days of the UTI) in children aged 0 to 18 years with a culture-confirmed episode of UTI. The following cut-off values were used for the primary analysis: 0.5 ng/mL for procalcitonin, 20 mg/L for CRP and 30 mm/hour for ESR. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria to all citations and independently abstracted data. We used the bivariate model to calculate pooled random-effects pooled sensitivity and specificity values. MAIN RESULTS: A total of 36 studies met our inclusion criteria. Twenty-five studies provided data for the primary analysis: 12 studies (1000 children) included data on PCT, 16 studies (1895 children) included data on CRP, and eight studies (1910 children) included data on ESR (some studies had data on more than one test). The summary sensitivity estimates (95% CI) for the PCT, CRP, ESR tests at the aforementioned cut-offs were 0.81 (0.67 to 0.90), 0.93 (0.86 to 0.96), and 0.83 (0.71 to 0.91), respectively. The summary specificity values for PCT, CRP, and ESR tests at these cut-offs were 0.76 (0.66 to 0.84), 0.37 (0.24 to 0.53), and 0.57 (0.41 to 0.72), respectively. AUTHORS' CONCLUSIONS: The ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. A low CRP value (< 20 mg/L) appears to be somewhat useful in ruling out pyelonephritis (decreasing the probability of pyelonephritis to < 20%), but unexplained heterogeneity in the data prevents us from making recommendations at this time. The procalcitonin test seems better suited for ruling in pyelonephritis, but the limited number of studies and the marked heterogeneity between studies prevents us from reaching definitive conclusions. Thus, at present, we do not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.

Diagnostic accuracy of cardiac MRI, FDG-PET, and myocardial biopsy for the diagnosis of cardiac sarcoidosis: a protocol for a systematic review and meta-analysis.

BACKGROUND: CS constitutes a rare but potentially underdiagnosed and fatal disease. Its diagnosis remains difficult owing to the infrequent and indistinguishable symptoms and the lack of formal diagnostic criteria dependent upon the diagnostic techniques used. Early diagnosis and treatment, however, may help to counter its poor prognosis.We aim to characterize and compare the diagnostic accuracy of cardiac MRI, FDG-PET and myocardial biopsy for the diagnosis of cardiac sarcoidosis and to advance and compare methods for complex diagnostic test accuracy reviews and meta-analysis. METHODS: Following a systematic review on DTA studies on the aforementioned topic, a four-part approach to meta-analysis will be used: (1) direct comparison of index tests with clinical reference standard, (2) indirect comparison of index tests with clinical reference standard, (3) addition of an alternative test to that indirect comparison (4) and Bayesian meta-analysis using results of part 3 as informative prior for comparisons analogous to part 1 and 2. DISCUSSION: The most widely recognized diagnostic algorithm for cardiac sarcoidosis is considered out of date, as it precedes the introduction of imaging techniques in diagnostic pathways. These novel imaging techniques, like CMR and FDG-PET scan, have emerged as promising diagnostic tools which may fill the current diagnostic gap. Thus, a systematic review and evaluation of CS diagnosis are much needed. Such an attempt is anticipated to alter the current diagnostic guidelines for CS by shedding more light on the role of sophisticated imaging techniques on prompt CS therapy and follow-up. TRIAL REGISTRATION: PROSPERO, CRD42019047126.

Measuring the impact of screening automation on meta-analyses of diagnostic test accuracy.

BACKGROUND: The large and increasing number of new studies published each year is making literature identification in systematic reviews ever more time-consuming and costly. Technological assistance has been suggested as an alternative to the conventional, manual study identification to mitigate the cost, but previous literature has mainly evaluated methods in terms of recall (search sensitivity) and workload reduction. There is a need to also evaluate whether screening prioritization methods leads to the same results and conclusions as exhaustive manual screening. In this study, we examined the impact of one screening prioritization method based on active learning on sensitivity and specificity estimates in systematic reviews of diagnostic test accuracy. METHODS: We simulated the screening process in 48 Cochrane reviews of diagnostic test accuracy and re-run 400 meta-analyses based on a least 3 studies. We compared screening prioritization (with technological assistance) and screening in randomized order (standard practice without technology assistance). We examined if the screening could have been stopped before identifying all relevant studies while still producing reliable summary estimates. For all meta-analyses, we also examined the relationship between the number of relevant studies and the reliability of the final estimates. RESULTS: The main meta-analysis in each systematic review could have been performed after screening an average of 30% of the candidate articles (range 0.07 to 100%). No systematic review would have required screening more than 2308 studies, whereas manual screening would have required screening up to 43,363 studies. Despite an average 70% recall, the estimation error would have been 1.3% on average, compared to an average 2% estimation error expected when replicating summary estimate calculations. CONCLUSION: Screening prioritization coupled with stopping criteria in diagnostic test accuracy reviews can reliably detect when the screening process has identified a sufficient number of studies to perform the main meta-analysis with an accuracy within pre-specified tolerance limits. However, many of the systematic reviews did not identify a sufficient number of studies that the meta-analyses were accurate within a 2% limit even with exhaustive manual screening, i.e., using current practice.

Upper Tract Urothelial Carcinoma Grade Prediction Based on the Ureteroscopic Appearance: Caution Should be Taken.

OBJECTIVES: To investigate the diagnostic accuracy, inter-rater and intrarater agreement of grade predictions based on the visual appearance of papillary upper tract urothelial carcinoma (UTUC) during digital ureteroscopy. METHODS: Nine urologists predicted the histopathologic grade of 64 papillary UTUC (low-grade vs high-grade) by assessing the visual appearance of the tumors in videos from digital ureteroscopy. The diagnostic accuracy was estimated by comparing the grade predictions with the histopathology from colocalized biopsies. Inter-rater agreement was assessed by pairwise inter-rater percentage agreement and Fleiss Kappa analysis. The videos were rated in a random order again 30 days after the first assessment to evaluate the intrarater percentage agreement. RESULTS: Low-grade tumors were predicted correctly in 37%-85% of the cases with a median concordance of 59% for questionnaire 1 and 66% for questionnaire 2. High-grade tumors were predicted correctly in 26%-91% of the cases with a median concordance of 52% and 61% for each questionnaire. The median pairwise inter-rater percentage agreement was 66% for both questionnaires with a Fleiss Kappa of 0.29 and 0.38, respectively. The median intrarater percentage agreement was 81%. CONCLUSION: The histopathologic grade of UTUC is essential to the risk-stratification for treatment selection. Predictions of the histopathologic grade based on the visual appearance of papillary UTUC with digital ureteroscopy are often incorrect in comparison with biopsy results and yield low inter-rater agreement. Urologists must be aware of these limitations in the assessment of the tumor grade during digital ureteroscopy to warrant good clinical practice.

The Accuracy of Anal Swab-Based Tests to Detect High-Grade Anal Intraepithelial Neoplasia in HIV-Infected Patients: A Systematic Review and Meta-analysis.

BACKGROUND: The incidence of high-risk human papillomavirus (HR-HPV)-induced anal cancer is increasingly problematic among HIV-positive patients. Anal cancer is preceded by precursor lesions, anal intraepithelial neoplasia (AIN). AIN detection requires high-resolution anoscopy, a cumbersome and time-consuming procedure. We aggregated evidence on anal swab-based tests to detect AIN in HIV-positive patients. METHODS: We searched MEDLINE and EMBASE for cross-sectional studies on AIN detection with anal cytology, HR-HPV DNA detection, HPV E6/E7 mRNA analysis, and P16INK4a and Ki-67 immunostaining. Summary estimates of sensitivity and specificity were calculated using bivariate logistic regression. Cytology was reported using the terms squamous intra-epithelial lesion (SIL) for AIN and high-grade SIL (HSIL) for high-grade AIN (HGAIN). RESULTS: We included 22 studies. Using cytology with a cutoff of any SIL to detect HGAIN, we detected a sensitivity of 82% (95% CI, 74%-87%) and specificity of 45% (95% CI, 44%-66%); with the cutoff of HSIL, the sensitivity was 44% (95% CI, 45%-67%) and the specificity was 79% (95% CI, 69%-87%). The sensitivity of HPV DNA to detect HGAIN was 91% (95% CI, 82%-95%) and the specificity was 27% (95% CI, 21%-33%). For MSM, the positive predictive value (PPV) of cytology with a cutoff of any SIL was 36% (95% CI, 23%-50%) and the negative predictive value (NPV) was 87% (95% CI, 78%-93%), whereas cytology with a cutoff of HSIL had a PPV of 62% (95% CI, 50%-73%) and an NPV of 78% (95% CI, 65%-87%). The PPV of HR-HPV DNA detection was 37% (95% CI, 20%-57%) and the NPV was 87% (95% CI, 79%-93%). CONCLUSIONS: Given its sensitivity, cytology with a cutoff of any SIL could be considered as a triaging method, whereas cytology with a cutoff of HSIL had better specificity and could be used for quality assurance. HR-HPV DNA detection had poor specificity and PPV, making it unsuitable for triage.

Galactomannan detection in broncho-alveolar lavage fluid for invasive aspergillosis in immunocompromised patients.

BACKGROUND: Invasive aspergillosis (IA) is a life-threatening opportunistic mycosis that occurs in some people with a compromised immune system. The serum galactomannan enzyme-linked immunosorbent assay (ELISA) rapidly gained widespread acceptance as part of the diagnostic work-up of a patient suspected of IA. Due to its non-invasive nature, it can be used as a routine screening test. The ELISA can also be performed on bronchoalveolar lavage (BAL), allowing sampling of the immediate vicinity of the infection. The invasive nature of acquiring BAL, however, changes the role of the galactomannan test significantly, for example by precluding its use as a routine screening test. OBJECTIVES: To assess the diagnostic accuracy of galactomannan detection in BAL for the diagnosis of IA in people who are immunocompromised, at different cut-off values for test positivity, in accordance with the Cochrane Diagnostic Test Accuracy Handbook. SEARCH METHODS: We searched three bibliographic databases including MEDLINE on 9 September 2016 for aspergillosis and galactomannan as text words and subject headings where appropriate. We checked reference lists of included studies for additional studies. SELECTION CRITERIA: We included cohort studies that examined the accuracy of BAL galactomannan for the diagnosis of IA in immunocompromised patients if they used the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) classification as reference standard. DATA COLLECTION AND ANALYSIS: Two review authors assessed study quality and extracted data. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used for quality assessment. MAIN RESULTS: We included 17 studies in our review. All studies except one had a high risk of bias in two or more domains. The diagnostic performance of an optical density index (ODI) of 0.5 as cut-off value was reported in 12 studies (with 1123 patients). The estimated sensitivity was 0.88 (95% confidence interval (CI) 0.75 to 1.00) and specificity 0.81 (95% CI 0.71 to 0.91). The performance of an ODI of 1.0 as cut-off value could be determined in 11 studies (with 648 patients). The sensitivity was 0.78 (95% CI 0.61 to 0.95) and specificity 0.93 (95% CI 0.87 to 0.98). At a cut-off ODI of 1.5 or higher, the heterogeneity in specificity decreased significantly and was invariably >90%. AUTHORS' CONCLUSIONS: The optimal cut-off value depends on the local incidence and clinical pathway. At a prevalence of 12% a hypothetical population of 1000 patients will consist of 120 patients with IA. At a cut-off value of 0.5 14 patients with IA will be missed and there will be 167 patients incorrectly diagnosed with IA. If we use the test at a cut-off value of 1.0, we will miss 26 patients with IA. And there will be 62 patients incorrectly diagnosed with invasive aspergillosis. The populations and results were very heterogeneous. Therefore, interpretation and extrapolation of these results has to be performed with caution. A test result of 1.5 ODI or higher appears a strong indicator of IA.

Laparoscopy for diagnosing resectability of disease in women with advanced ovarian cancer.

BACKGROUND: This is an update of a Cochrane Review that was originally published in 2014, Issue 2.The presence of residual disease after primary debulking surgery is a highly significant prognostic factor in women with advanced ovarian cancer. In up to 60% of women, residual tumour of > 1 cm is left behind after primary debulking surgery (defined as suboptimal debulking). These women might have benefited from neoadjuvant chemotherapy (NACT) prior to interval debulking surgery instead of primary debulking surgery followed by chemotherapy. It is therefore important to select accurately those women who would best be treated with primary debulking surgery followed by chemotherapy from those who would benefit from NACT prior to surgery. OBJECTIVES: To determine if performing a laparoscopy, in addition to conventional diagnostic work-up, in women suspected of advanced ovarian cancer is accurate in predicting the resectability of disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library; MEDLINE via Ovid, Embase via Ovid, MEDION and Science Citation Index and Conference Proceedings Citation Index (ISI Web of Science) to July 2018. We also checked references of identified primary studies and review articles. SELECTION CRITERIA: We included studies that evaluated the diagnostic accuracy of laparoscopy to determine the resectability of disease in women who are suspected of advanced ovarian cancer and planned to receive primary debulking surgery. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently assessed the quality of included studies using QUADAS-2 and extracted data on study and participant characteristics, index test, target condition and reference standard. We extracted data for two-by-two tables and summarised these graphically. We calculated sensitivity and specificity and negative predictive values. MAIN RESULTS: We included 18 studies, reporting on 14 cohorts of women (including 1563 participants), of which one was a randomised controlled trial (RCT). Laparoscopic assessment suggested that disease was suitable for optimal debulking surgery (no macroscopic residual disease or residual disease < 1 cm (negative predictive values)) in 54% to 96% of women who had macroscopic complete debulking surgery (no visible disease at end of laparotomy) and in 69% to 100% of women who had optimal debulking surgery (residual tumour < 1 cm at end of laparotomy).Only two studies avoided partial verification bias by operating on all women independent of laparoscopic findings, and provided data to calculate sensitivity and specificity. These two studies had no false positive laparoscopies (i.e. no women had a laparoscopy indicating unresectable disease and then went on to have optimal debulking surgery (no disease > 1 cm remaining)).Due to the large heterogeneity pooling of the data was not possible for meta-analysis. AUTHORS' CONCLUSIONS: Laparoscopy may be a useful tool to identify those women who have unresectable disease, as no women were inappropriately unexplored. However, some women had suboptimal primary debulking surgery, despite laparoscopy predicting optimal debulking and data are at high risk of verification bias as only two studies performed the reference standard (debulking laparotomy) in test (laparoscopy)-positive women. Using a prediction model does not increase the sensitivity and will result in more unnecessarily explored women, due to a lower specificity.

GRADE guidelines: 22. The GRADE approach for tests and strategies-from test accuracy to patient-important outcomes and recommendations.

OBJECTIVES: This article describes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group's framework of moving from test accuracy to patient or population-important outcomes. We focus on the common scenario when studies directly evaluating the effect of diagnostic and other tests or strategies on health outcomes are not available or are not providing the best available evidence. STUDY DESIGN AND SETTING: Using practical examples, we explored how guideline developers and other decision makers can use information from test accuracy to develop a recommendation by linking evidence that addresses downstream consequences. Guideline panels should develop an analytic framework that summarizes the actions that follow from applying a test and the consequences. RESULTS: We describe GRADE's current thinking about the overall certainty of the evidence (also known as quality of the evidence or confidence in the estimates) arising from consideration of the often complex pathways that involve multiple tests and management options. Each link in the evidence can-and often does-lower the overall certainty of the evidence required to formulate recommendations and make decisions about tests. The frequency with which an outcome occurs and its importance will influence whether or not a particular step in the linked evidence is critical to decision-making. CONCLUSIONS: Overall certainty may be expressed by the weakest critical step in the linked evidence. The linked approach to addressing optimal testing will often require the use of decision analytic approaches. We present an example that involves decision modeling in a GRADE Evidence to Decision framework for cervical cancer screening. However, because resources and time of guideline developers may be limited, we describe alternative, pragmatic strategies for developing recommendations addressing test use.

Facilitating healthcare decisions by assessing the certainty in the evidence from preclinical animal studies.

Laboratory animal studies are used in a wide range of human health related research areas, such as basic biomedical research, drug research, experimental surgery and environmental health. The results of these studies can be used to inform decisions regarding clinical research in humans, for example the decision to proceed to clinical trials. If the research question relates to potential harms with no expectation of benefit (e.g., toxicology), studies in experimental animals may provide the only relevant or controlled data and directly inform clinical management decisions. Systematic reviews and meta-analyses are important tools to provide robust and informative evidence summaries of these animal studies. Rating how certain we are about the evidence could provide important information about the translational probability of findings in experimental animal studies to clinical practice and probably improve it. Evidence summaries and certainty in the evidence ratings could also be used (1) to support selection of interventions with best therapeutic potential to be tested in clinical trials, (2) to justify a regulatory decision limiting human exposure (to drug or toxin), or to (3) support decisions on the utility of further animal experiments. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach is the most widely used framework to rate the certainty in the evidence and strength of health care recommendations. Here we present how the GRADE approach could be used to rate the certainty in the evidence of preclinical animal studies in the context of therapeutic interventions. We also discuss the methodological challenges that we identified, and for which further work is needed. Examples are defining the importance of consistency within and across animal species and using GRADE's indirectness domain as a tool to predict translation from animal models to humans.

Three-dimensional saline infusion sonography compared to two-dimensional saline infusion sonography for the diagnosis of focal intracavitary lesions.

BACKGROUND: Focal abnormalities most commonly acquired within the uterine cavity include endometrial polyps (arising from the endometrium) and submucous fibroids (arising from the myometrium). These benign abnormalities can cause several problems, including abnormal uterine bleeding (AUB) and subfertility. Two-dimensional saline infusion sonography (2D SIS) is a minimally invasive test that can be used to diagnose these pathologies, but it is less accurate than hysteroscopy, which is a more invasive procedure by which an endoscope allows direct visualisation of the uterine cavity. Three-dimensional (3D) SIS appears to enhance sonographic visualisation within the uterine cavity, thereby offering a potentially more accurate minimally invasive diagnostic test. OBJECTIVES: Primary objectives • To evaluate the diagnostic accuracy of 3D SIS (index test 1) compared with 2D SIS for the diagnosis of focally growing lesions (presence or not) in women with AUB or subfertility, with hysteroscopy performed as the reference test. • To evaluate the diagnostic accuracy of 2D+3D SIS (index test 2) compared with 2D SIS for the diagnosis of focally growing lesions (presence or not) in women with AUB or subfertility, with hysteroscopy performed as the reference test. In this case, any abnormality on either modality was regarded as a positive result ('OR' approach). Secondary objectives • To evaluate the diagnostic accuracy of 3D SIS (index test 1) compared with 2D SIS according to type of abnormality and discrimination between uterine polyps and submucous fibroids in women with AUB or subfertility, with hysteroscopy and histology used as the reference.• To evaluate the diagnostic accuracy of 2D+3D SIS (index test 2) compared with 2D SIS according to type of abnormality and discrimination between uterine polyps and submucous fibroids in women with AUB or subfertility, with hysteroscopy and histology used as the reference. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PubMed, Cochrane Gynaecology and Fertility Group (CGF) Specialised Register and CGFG Diagnostic Test Accuracy (DTA) Specialised Register, clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Screening reference lists of appropriate studies was also performed. We screened for eligibility all studies identified from inception until March 2016. We performed searches with no date or language restrictions. SELECTION CRITERIA: The population of interest consisted of premenopausal women with AUB or subfertility and postmenopausal women with AUB. Diagnostic test accuracy studies, randomised controlled trials (RCTs) and prospective cohort studies were eligible for inclusion if they evaluated the accuracy of both 2D SIS and 3D SIS for the diagnosis of acquired intracavitary abnormalities with hysteroscopy used as the reference standard. In light of the lack of data for 3D SIS, we also included studies that evaluated the accuracy of 3D SIS alone. DATA COLLECTION AND ANALYSIS: Two review authors read all potentially eligible references after performing a first screening by title and abstract (LLN and FJRH). They independently extracted data to construct 2×2 tables from eligible studies and assessed studies for methodological quality using the QUADAS-2 tool (revised tool for quality assessment of diagnostic accuracy studies). To describe and visually present results, we produced in RevMan forest plots showing pairs of sensitivity and specificity together with 95% confidence intervals from each study, as well as raw receiver operating characteristic (ROC) plots. We displayed paired analyses in an ROC plot by linking sensitivity-specificity pairs from each study by using a dashed line. To compare 3D SIS versus 2D SIS, we restricted analyses to studies that provided 2×2 tables for both tests and used the bivariate meta-analysis of sensitivity and specificity. MAIN RESULTS: Thirteen studies (1053 women) reported the accuracy of 3D SIS for focal uterine abnormalities; 11 of these (846 women) were suitable for meta-analysis, and eight reported accuracy according to the type of focal abnormality. The design of the included studies seems applicable. The main problem involving the quality of included studies is insufficient reporting of study methods, resulting in unclear risk of bias for several of the quality domains assessed. Therefore, we considered the overall quality of the evidence as low. The summary estimate (11 studies reporting absence or presence of abnormality at 3D SIS) for sensitivity was 94.5% (95% confidence interval (CI) 90.6% to 96.9%) and for specificity 99.4% (95% CI 96.2% to 99.9%). Meta-analysis of the eight studies (N = 716) directly comparing 2D SIS versus 3D SIS showed summary sensitivity of 96.9% (95% CI 91.9% to 98.8%) and summary specificity of 99.5% (95% CI 96.1% to 100%) for 3D SIS. For 2D SIS, summary sensitivity was 90.9% (95% CI 81.2% to 95.8%) and summary specificity was 96.3% (95% CI 86.1% to 99.1%). The difference in accuracy between 2D SIS and 3D SIS was non-significant (P values of 0.07 for sensitivity and 0.10 for specificity). AUTHORS' CONCLUSIONS: Low-quality evidence suggests that 3D SIS may be very accurate in detecting intracavitary abnormalities. Meta-analysis revealed no statistically significant differences between 2D SIS and 3D SIS. Summary sensitivity and summary specificity are higher for 3D SIS, but margins of improvement are limited because 2D SIS is already very accurate. When the technology and appropriate expertise are available, 3D SIS offers an alternative to 2D SIS. Both 2D SIS and 3D SIS should be considered alternatives to diagnostic hysteroscopy when intracavitary pathology is suspected in subfertile women and in those with abnormal uterine bleeding.

Galactomannan detection for invasive aspergillosis in immunocompromised patients.

BACKGROUND: Invasive aspergillosis is the most common life-threatening opportunistic invasive mycosis in immunocompromised patients. A test for invasive aspergillosis should neither be too invasive nor too great a burden for the already weakened patient. The serum galactomannan enzyme-linked immunosorbent assay (ELISA) seems to have the potential to meet both requirements. OBJECTIVES: To obtain summary estimates of the diagnostic accuracy of galactomannan detection in serum for the diagnosis of invasive aspergillosis. SEARCH METHODS: We searched MEDLINE, EMBASE and Web of Science with both MeSH terms and text words for both aspergillosis and the sandwich ELISA. We checked the reference lists of included studies and review articles for additional studies. We conducted the searches in February 2014. SELECTION CRITERIA: We included cross-sectional studies, case-control designs and consecutive series of patients assessing the diagnostic accuracy of galactomannan detection for the diagnosis of invasive aspergillosis in patients with neutropenia or patients whose neutrophils are functionally compromised. The reference standard was composed of the criteria given by the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed quality and extracted data. We carried out meta-analysis using the bivariate method. We investigated sources of heterogeneity by adding potential sources of heterogeneity to the model as covariates. MAIN RESULTS: We included 54 studies in the review (50 in the meta-analyses), containing 5660 patients, of whom 586 had proven or probable invasive aspergillosis. When using an optical density index (ODI) of 0.5 as a cut-off value, the sensitivity of the test was 82% (73% to 90%) and the specificity was 81% (72% to 90%). At a cut-off value of 1.0 ODI, the sensitivity was 72% (65% to 80%) and the specificity was 88% (84% to 92%). At a cut-off value of 1.5 ODI, the sensitivity was 61% (47% to 75%) and the specificity was 93% (89% to 97%). None of the potential sources of heterogeneity had a statistically significant effect on either sensitivity or specificity. AUTHORS' CONCLUSIONS: If we used the test at a cut-off value of 0.5 ODI in a population of 100 patients with a disease prevalence of 9% (overall median prevalence), two patients who have invasive aspergillosis would be missed (sensitivity 82%, 18% false negatives), and 17 patients would be treated unnecessarily or referred unnecessarily for further testing (specificity 81%, 19% false negatives). If we used the test at a cut-off value of 1.5 in the same population, that would mean that four invasive aspergillosis patients would be missed (sensitivity 61%, 39% false negatives), and six patients would be treated or referred for further testing unnecessarily (specificity 93%, 7% false negatives). These numbers should, however, be interpreted with caution because the results were very heterogeneous.