A longitudinal view of successful aging with HIV: role of resilience and environmental factors.

PURPOSE: The purpose of this study is to estimate the extent to which people aging with HIV meet criteria for successful aging as operationalized through HRQL and maintain this status over time. A second objective is to identify factors that place people at promise for continued successful aging, including environmental and resilience factors. METHODS: Participants were members of the Positive Brain Health Now (BHN) cohort. People ≥ 50 years (n = 513) were classified as aging successfully if they were at or above norms on 7 or 8 of 8 health-related quality of life domains from the RAND-36. Group-based trajectory analysis, regression tree analysis, a form of machine learning, and logistic regression were applied to identify factors predicting successful aging. RESULTS: 73 (14·2%) met criteria for successful aging at entry and did not change status over time. The most influential factor was loneliness which split the sample into two groups with the prevalence of successful aging 28·4% in the "almost never" lonely compared to 4·6% in the "sometimes/often" lonely group. Other influential factors were feeling safe, social network, motivation, stigma, and socioeconomic status. These factors identified 17 sub-groups with at least 30 members with the proportions classified as aging successfully ranging from 0 to 79·4%. The nine variables important to classifying successful aging had a predictive accuracy of 0.862. Self-reported cognition but not cognitive test performance improved this accuracy to 0.895. The two groups defined by successful aging status did not differ on age, sex or viral load, nadir and current. CONCLUSION: The results indicate the important role of social determinants of health in successful aging among people living with HIV.

Antimicrobial Stewardship in Bronchiolitis: A Retrospective Cohort Study of Three PICUs in Canada.

OBJECTIVES: To determine the association between the implementation of an antimicrobial stewardship program at a local PICU and to determine the association between the presence of an antimicrobial stewardship programs and antimicrobial use across three Canadian PICUs, among critically ill children with bronchiolitis. DESIGN: A multicenter retrospective cohort study. SETTING: Three Canadian PICUs over two winter seasons. INTERVENTIONS: An antimicrobial stewardship program was implemented at PICU 1 at the end of season 1. PATIENTS: Patients less than or equal to 2 years old admitted with bronchiolitis. MEASUREMENTS AND MAIN RESULTS: We used regression models with an interaction term between site (PICU 1 and PICU 2) and season (1 and 2) as the primary analysis to determine the association between implementation of an antimicrobial stewardship program at PICU 1 and 1) the proportion of antimicrobials discontinued 72 hours after hospital admission (logistic regression), 2) antimicrobial treatment duration (negative binomial regression), and 3) antimicrobial prescriptions within 48 hours of hospital admission (logistic regression). As a secondary analysis, we determined the association between having an antimicrobial stewardship program present and the aforementioned outcomes across the three PICUs. A total of 372 patients were included. During seasons 1 and 2, median age was 2.2 months (interquartile range, 1.2-6.2 mo) and 2.1 months (interquartile range, 1.3-6.8 mo), respectively. Among patients with viral bronchiolitis, implementation of an antimicrobial stewardship program at PICU 1 was associated with increased odds of discontinuing antimicrobials (odds ratio, 25.63; 95% CI, 2.86-326.29), but not with antimicrobial duration (odds ratio, 0.56; 95% CI, 0.31-1.02) or antimicrobial prescriptions (odds ratio, 0.33; 95% CI, 0.10-1.04). The presence of an antimicrobial stewardship program was similarly associated with antimicrobial discontinuation among patients with viral bronchiolitis (odds ratio, 20.79; 95% CI, 2.46-244.92), but not with antimicrobial duration (odds ratio, 0.57; 95% CI, 0.32-1.03) or antimicrobial prescriptions (odds ratio, 0.37; 95% CI, 0.12-1.11). CONCLUSIONS: Antimicrobial stewardship programs were associated with increased likelihood of discontinuing antimicrobial treatments in the PICU patients with viral bronchiolitis. However, larger studies are needed to further determine the role of an antimicrobial stewardship programs in reducing unnecessary antimicrobial use in this patient population.

Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms.

BACKGROUND: Tuberculosis is a leading cause of infectious disease-related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends the use of specific rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for the detection of tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one-third of all active tuberculosis cases go undiagnosed and unreported. We were interested in whether a single test, Xpert MTB/RIF or Xpert Ultra, could be useful as a screening test to close this diagnostic gap and improve tuberculosis case detection. OBJECTIVES: To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for pulmonary tuberculosis in adults, irrespective of signs or symptoms of pulmonary tuberculosis in high-risk groups and in the general population. Screening "irrespective of signs or symptoms" refers to screening of people who have not been assessed for the presence of tuberculosis symptoms (e.g. cough). To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for detecting rifampicin resistance in adults screened for tuberculosis, irrespective of signs and symptoms of pulmonary tuberculosis in high-risk groups and in the general population. SEARCH METHODS: We searched 12 databases including the Cochrane Infectious Diseases Group Specialized Register, MEDLINE and Embase, on 19 March 2020 without language restrictions. We also reviewed reference lists of included articles and related Cochrane Reviews, and contacted researchers in the field to identify additional studies. SELECTION CRITERIA: Cross-sectional and cohort studies in which adults (15 years and older) in high-risk groups (e.g. people living with HIV, household contacts of people with tuberculosis) or in the general population were screened for pulmonary tuberculosis using Xpert MTB/RIF or Xpert Ultra. For tuberculosis detection, the reference standard was culture. For rifampicin resistance detection, the reference standards were culture-based drug susceptibility testing and line probe assays. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardized form and assessed risk of bias and applicability using QUADAS-2. We used a bivariate random-effects model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs) separately for tuberculosis detection and rifampicin resistance detection. We estimated all models using a Bayesian approach. For tuberculosis detection, we first estimated screening accuracy in distinct high-risk groups, including people living with HIV, household contacts, people residing in prisons, and miners, and then in several high-risk groups combined. MAIN RESULTS: We included a total of 21 studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. Fifteen studies (75%) were conducted in high tuberculosis burden and 16 (80%) in high TB/HIV-burden countries. We judged most studies to have low risk of bias in all four QUADAS-2 domains and low concern for applicability. Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis In people living with HIV (12 studies), Xpert MTB/RIF pooled sensitivity and specificity (95% CrI) were 61.8% (53.6 to 69.9) (602 participants; moderate-certainty evidence) and 98.8% (98.0 to 99.4) (4173 participants; high-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 40 would be Xpert MTB/RIF-positive; of these, 9 (22%) would not have tuberculosis (false-positives); and 960 would be Xpert MTB/RIF-negative; of these, 19 (2%) would have tuberculosis (false-negatives). In people living with HIV (1 study), Xpert Ultra sensitivity and specificity (95% CI) were 69% (57 to 80) (68 participants; very low-certainty evidence) and 98% (97 to 99) (503 participants; moderate-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 53 would be Xpert Ultra-positive; of these, 19 (36%) would not have tuberculosis (false-positives); and 947 would be Xpert Ultra-negative; of these, 16 (2%) would have tuberculosis (false-negatives). In non-hospitalized people in high-risk groups (5 studies), Xpert MTB/RIF pooled sensitivity and specificity were 69.4% (47.7 to 86.2) (337 participants, low-certainty evidence) and 98.8% (97.2 to 99.5) (8619 participants, moderate-certainty evidence). Of 1000 people where 10 have tuberculosis on culture, 19 would be Xpert MTB/RIF-positive; of these, 12 (63%) would not have tuberculosis (false-positives); and 981 would be Xpert MTB/RIF-negative; of these, 3 (0%) would have tuberculosis (false-negatives). We did not identify any studies using Xpert MTB/RIF or Xpert Ultra for screening in the general population. Xpert MTB/RIF as a screening test for rifampicin resistance Xpert MTB/RIF sensitivity was 81% and 100% (2 studies, 20 participants; very low-certainty evidence), and specificity was 94% to 100%, (3 studies, 139 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Of the high-risks groups evaluated, Xpert MTB/RIF applied as a screening test was accurate for tuberculosis in high tuberculosis burden settings. Sensitivity and specificity were similar in people living with HIV and non-hospitalized people in high-risk groups. In people living with HIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar. As there was only one study of Xpert Ultra in this analysis, results should be interpreted with caution. There were no studies that evaluated the tests in people with diabetes mellitus and other groups considered at high-risk for tuberculosis, or in the general population.

Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults.

BACKGROUND: Xpert MTB/RIF Ultra (Xpert Ultra) and Xpert MTB/RIF are World Health Organization (WHO)-recommended rapid nucleic acid amplification tests (NAATs) widely used for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum. To extend our previous review on extrapulmonary tuberculosis (Kohli 2018), we performed this update to inform updated WHO policy (WHO Consolidated Guidelines (Module 3) 2020). OBJECTIVES: To estimate diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for extrapulmonary tuberculosis and rifampicin resistance in adults with presumptive extrapulmonary tuberculosis. SEARCH METHODS: Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, 2 August 2019 and 28 January 2020 (Xpert Ultra studies), without language restriction. SELECTION CRITERIA: Cross-sectional and cohort studies using non-respiratory specimens. Forms of extrapulmonary tuberculosis: tuberculous meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, disseminated tuberculosis. Reference standards were culture and a study-defined composite reference standard (tuberculosis detection); phenotypic drug susceptibility testing and line probe assays (rifampicin resistance detection). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias and applicability using QUADAS-2. For tuberculosis detection, we performed separate analyses by specimen type and reference standard using the bivariate model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs). We applied a latent class meta-analysis model to three forms of extrapulmonary tuberculosis. We assessed certainty of evidence using GRADE. MAIN RESULTS: 69 studies: 67 evaluated Xpert MTB/RIF and 11 evaluated Xpert Ultra, of which nine evaluated both tests. Most studies were conducted in China, India, South Africa, and Uganda. Overall, risk of bias was low for patient selection, index test, and flow and timing domains, and low (49%) or unclear (43%) for the reference standard domain. Applicability for the patient selection domain was unclear for most studies because we were unsure of the clinical settings. Cerebrospinal fluid Xpert Ultra (6 studies) Xpert Ultra pooled sensitivity and specificity (95% CrI) against culture were 89.4% (79.1 to 95.6) (89 participants; low-certainty evidence) and 91.2% (83.2 to 95.7) (386 participants; moderate-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 168 would be Xpert Ultra-positive: of these, 79 (47%) would not have tuberculosis (false-positives) and 832 would be Xpert Ultra-negative: of these, 11 (1%) would have tuberculosis (false-negatives). Xpert MTB/RIF (30 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 71.1% (62.8 to 79.1) (571 participants; moderate-certainty evidence) and 96.9% (95.4 to 98.0) (2824 participants; high-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 99 would be Xpert MTB/RIF-positive: of these, 28 (28%) would not have tuberculosis; and 901 would be Xpert MTB/RIF-negative: of these, 29 (3%) would have tuberculosis. Pleural fluid Xpert Ultra (4 studies) Xpert Ultra pooled sensitivity and specificity against culture were 75.0% (58.0 to 86.4) (158 participants; very low-certainty evidence) and 87.0% (63.1 to 97.9) (240 participants; very low-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 192 would be Xpert Ultra-positive: of these, 117 (61%) would not have tuberculosis; and 808 would be Xpert Ultra-negative: of these, 25 (3%) would have tuberculosis. Xpert MTB/RIF (25 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 49.5% (39.8 to 59.9) (644 participants; low-certainty evidence) and 98.9% (97.6 to 99.7) (2421 participants; high-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 60 would be Xpert MTB/RIF-positive: of these, 10 (17%) would not have tuberculosis; and 940 would be Xpert MTB/RIF-negative: of these, 50 (5%) would have tuberculosis. Lymph node aspirate Xpert Ultra (1 study) Xpert Ultra sensitivity and specificity (95% confidence interval) against composite reference standard were 70% (51 to 85) (30 participants; very low-certainty evidence) and 100% (92 to 100) (43 participants; low-certainty evidence). Of 1000 people where 100 have lymph node tuberculosis, 70 would be Xpert Ultra-positive and 0 (0%) would not have tuberculosis; 930 would be Xpert Ultra-negative and 30 (3%) would have tuberculosis. Xpert MTB/RIF (4 studies) Xpert MTB/RIF pooled sensitivity and specificity against composite reference standard were 81.6% (61.9 to 93.3) (377 participants; low-certainty evidence) and 96.4% (91.3 to 98.6) (302 participants; low-certainty evidence). Of 1000 people where 100 have lymph node tuberculosis, 118 would be Xpert MTB/RIF-positive and 37 (31%) would not have tuberculosis; 882 would be Xpert MTB/RIF-negative and 19 (2%) would have tuberculosis. In lymph node aspirate, Xpert MTB/RIF pooled specificity against culture was 86.2% (78.0 to 92.3), lower than that against a composite reference standard. Using the latent class model, Xpert MTB/RIF pooled specificity was 99.5% (99.1 to 99.7), similar to that observed with a composite reference standard. Rifampicin resistance Xpert Ultra (4 studies) Xpert Ultra pooled sensitivity and specificity were 100.0% (95.1 to 100.0), (24 participants; low-certainty evidence) and 100.0% (99.0 to 100.0) (105 participants; moderate-certainty evidence). Of 1000 people where 100 have rifampicin resistance, 100 would be Xpert Ultra-positive (resistant): of these, zero (0%) would not have rifampicin resistance; and 900 would be Xpert Ultra-negative (susceptible): of these, zero (0%) would have rifampicin resistance. Xpert MTB/RIF (19 studies) Xpert MTB/RIF pooled sensitivity and specificity were 96.5% (91.9 to 98.8) (148 participants; high-certainty evidence) and 99.1% (98.0 to 99.7) (822 participants; high-certainty evidence). Of 1000 people where 100 have rifampicin resistance, 105 would be Xpert MTB/RIF-positive (resistant): of these, 8 (8%) would not have rifampicin resistance; and 895 would be Xpert MTB/RIF-negative (susceptible): of these, 3 (0.3%) would have rifampicin resistance. AUTHORS' CONCLUSIONS: Xpert Ultra and Xpert MTB/RIF may be helpful in diagnosing extrapulmonary tuberculosis. Sensitivity varies across different extrapulmonary specimens: while for most specimens specificity is high, the tests rarely yield a positive result for people without tuberculosis. For tuberculous meningitis, Xpert Ultra had higher sensitivity and lower specificity than Xpert MTB/RIF against culture. Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity for rifampicin resistance. Future research should acknowledge the concern associated with culture as a reference standard in paucibacillary specimens and consider ways to address this limitation.

Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis.

BACKGROUND: Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy. OBJECTIVES: To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction. SELECTION CRITERIA: We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results. MAIN RESULTS: We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace-positive results. Rifampicin resistance detection Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high-certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high-certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at -0.3% (-6.9 to 5.7) for sensitivity and 0.3% (-1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF. We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1). AUTHORS' CONCLUSIONS: Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.

Blood Cultures and Molecular Diagnostics in Intensive Care Units to Diagnose Sepsis: A Bayesian Latent Class Model Analysis.

BACKGROUND: Confirmation of sepsis by standard blood cultures (STD) is often inconclusive due to slow growth and low positivity. Molecular diagnostics (MOL) are faster and may have higher positivity, but test performance can be inaccurately estimated if STD methods are used as comparators. Bayesian latent class models (LCMs) can evaluate diagnostic methods when there is no "gold standard." Intensive care unit studies that have used LCMs to combine and compare STD and MOL method performance and estimate the prevalence of sepsis have not been described. PATIENTS AND METHODS: Results from an ICU sepsis study that used both tests simultaneously were analyzed. Bayesian LCMs combined prior prevalence of sepsis, prior diagnostic characteristics of the two methods, and the study results to estimate the posterior prevalence and diagnostic characteristics. Sensitivity analyses were performed using objective (published studies) and subjective (expert opinion) prior parameters. Positive predictive values (PPVs) of the prevalence of sepsis were estimated for all combinations of test results. RESULTS: The range of posterior estimates was: sepsis prevalence (0.38-0.88), sensitivities (STD: 0.2-0.35, MOL: 0.56-0.86), and specificities (STD: 0.87-0.99, MOL: 0.72-0.95). The PPV (sepsis) of both tests being positive was (0.72-0.99). CONCLUSION: LCMs combined two imperfect methods to estimate prevalence, PPV, and diagnostic characteristics. The posterior estimates (STD sensitivity < MOL and STD specificity > MOL) seem to reflect the clinical experience appropriately. The high PPV when both methods show positive results can be useful for ruling in disease. HOW TO CITE THIS ARTICLE: Sampath S, Baby J, Krishna B, Dendukuri N, Thomas T. Blood Cultures and Molecular Diagnostics in Intensive Care Units to Diagnose Sepsis: A Bayesian Latent Class Model Analysis. Indian J Crit Care Med 2021;25(12):1402-1407.

Interventional Therapy Versus Medical Therapy for Secundum Atrial Septal Defect: A Systematic Review (Part 2) for the 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

Secundum atrial septal defect (ASD) is the most common adult congenital heart defect and can present with wide variation in clinical findings. With the intention of preventing morbidity and mortality associated with late presentation of ASD, consensus guidelines have recommended surgical or percutaneous ASD closure in adults with right heart enlargement, with or without symptoms. The aim of the present analysis was to determine if the protective effect of secundum ASD closure in adults could be qualified by pooling data from published studies. A systematic review and meta-analysis were performed by using EMBASE, MEDLINE (through PubMed), and the Cochrane Library databases to assess the effect of secundum ASD percutaneous or surgical closure in unoperated adults ≥18 years of age. Data were pooled across studies with the DerSimonian-Laird random-effects model or a Bayesian meta-analysis model. Between-study heterogeneity was assessed with Cochran's Q test. Bias assessment was performed with the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool, and statistical risk of bias was assessed with Begg and Mazumdar's test and Egger's test. A total of 11 nonrandomized studies met the inclusion criteria, contributing 603 patients. Pooled analysis showed a protective effect of ASD closure on New York Heart Association functional class and on right ventricular systolic pressure, volumes, and dimensions. Two additional studies comprising 652 patients were reviewed separately for mortality outcome and primary outcome of interest because they did not meet the inclusion criteria. Those studies showed that ASD closure was associated with a weak protective effect on adjusted mortality rate but no significant impact on atrial arrhythmias in patients >50 years of age. Across all studies, there was significant heterogeneity between studies for nearly all clinical outcomes. The overall body of evidence was limited to observational cohort studies, the limitations of which make for low-strength evidence. Even within the parameters of the included studies, quality of evidence was further diminished by the lack of well-defined clinical outcomes. In conclusion, pooled data analysis on the impact of secundum ASD closure in adults was notably limited because of the lack of randomized controlled trials in patients with only secundum ASD. The few cohort studies in this population demonstrated improvement in functional status and right ventricular size and function as shown by echocardiogram. However, our findings suggest that at the time of this publication, insufficient data are available to determine the impact of ASD repair on mortality rate in adults.

Medical Therapy for Systemic Right Ventricles: A Systematic Review (Part 1) for the 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

Patients with systemic morphological right ventricles (RVs), including congenitally corrected transposition of the great arteries and dextro-transposition of the great arteries with a Mustard or Senning atrial baffle repair, have a high likelihood of developing systemic ventricular dysfunction. Unfortunately, there are a limited number of clinical studies on the efficacy of medical therapy for systemic RV dysfunction. We performed a systematic review and meta-analysis to assess the effect of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), beta blockers, and aldosterone antagonists in adults with systemic RVs. The inclusion criteria included age ≥18 years, systemic RVs, and at least 3 months of treatment with ACE inhibitor, ARB, beta blocker, or aldosterone antagonist. The outcomes included RV end-diastolic and end-systolic dimensions, RV ejection fraction, functional class, and exercise capacity. EMBASE, PubMed, and Cochrane databases were searched. The selected data were pooled and analyzed with the DerSimonian-Laird random-effects meta-analysis model. Between-study heterogeneity was assessed with Cochran's Q test. A Bayesian meta-analysis model was also used in the event that heterogeneity was low. Bias assessment was performed with the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool, and statistical risk of bias was assessed with Begg and Mazumdar's test and Egger's test. Six studies met the inclusion criteria, contributing a total of 187 patients; treatment with beta blocker was the intervention that could not be analyzed because of the small number of patients and diversity of outcomes reported. After at least 3 months of treatment with ACE inhibitors, ARBs, or aldosterone antagonists, there was no statistically significant change in mean ejection fraction, ventricular dimensions, or peak ventilatory equivalent of oxygen. The methodological quality of the majority of included studies was low, mainly because of a lack of a randomized and controlled design, small sample size, and incomplete follow-up. In conclusion, pooled results across the limited available studies did not provide conclusive evidence with regard to a beneficial effect of medical therapy in adults with systemic RV dysfunction. Randomized controlled trials or comparative-effectiveness studies that are sufficiently powered to demonstrate effect are needed to elucidate the efficacy of ACE inhibitors, ARBs, beta blockers, and aldosterone antagonists in patients with systemic RVs.

Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.

BACKGROUND: In clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50-60%. OBJECTIVE: To observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response. METHODS: In four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs. RESULTS: Suboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology. CONCLUSION: A significant number of patients who meet currently approved indications for anti-IL5 mAbs show suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.

Impact of decreasing cerebrospinal fluid enterovirus PCR turnaround time on costs and management of children with suspected enterovirus meningitis.

To estimate the impact of implementing in-hospital enterovirus (EV) polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) with same-day turn-around-time (TAT) on length-of-stay (LOS), antibiotic use and on cost per patient with suspected EV meningitis, compared with testing at an outside reference laboratory. A model-based analysis using a retrospective cohort of all hospitalized children with CSF EV PCR testing done between November 2013 and 2017. The primary outcome measured was the potential date of discharge if the EV PCR result had been available on the same day. Patients with positive EV PCR were considered for potential earlier discharge once clinically stable with no reason for hospitalization other than intravenous antibiotics. Descriptive statistics and cost-sensitivity analyses were performed. CSF EV PCR testing was done on 153 patients, of which 44 (29%) had a positive result. Median test TAT was 5.3 days (IQR 3.9-7.6). Median hospital LOS was 5 days (IQR 3-12). Most (86%) patients received intravenous antibiotics with mean duration of 5.72 ± 6.51 days. No patients with positive EV PCR had a serious bacterial infection. We found that same-day test TAT would reduce LOS and duration of intravenous antibiotics by 0.50 days (95%CI 0.33-0.68) and 0.67 days (95%CI 0.42-0.91), respectively. Same-day test TAT was associated with a cost reduction of 342.83CAD (95%CI 178.14-517.00) per patient with suspected EV meningitis. Compared with sending specimens to a reference laboratory, performing CSF EV PCR in-hospital with same-day TAT was associated with decreased LOS, antibiotic therapy, and cost per patient.

Association between cognitive reserve and cognitive performance in people with HIV: a systematic review and meta-analysis.

Cognitive reserve is a potential explanation for the disparity between brain pathology and its clinical manifestations. The main objective of this study was to estimate, based on published studies, the strength of the association between cognitive reserve and cognitive performance in individuals with HIV. A systematic literature search using Ovid MEDLINE, PsychINFO, and EMBASE was performed to identify studies published between 1990 and 2016 that quantified the association between cognitive reserve and cognitive performance in HIV. A random-effects meta-analysis was used to compute a summary estimate (Cohen's d) with 95% confidence intervals (CI) and 95% prediction intervals (PI). The risk of bias and quality of reporting in the studies were indicated by the Appraisal tool for Cross-Sectional Studies (AXIS). Ten observational studies were deemed eligible. The pooled effect size was 0.9 (95% CI: 0.7-1.0; 95% PI: 0.4-1.4) with marked heterogeneity studies [Cochran's Q (df = 9) = 28.0, p = .0009; I2 statistic = 67.4%]. Risk-of-bias appraisal showed that non-response bias was never addressed and the items associated with selection bias were only partially met. The association between cognitive reserve and cognitive performance suggests that building reserve through non-pharmacological interventions could be a potentially effective way of combating cognitive impairment in people with HIV.

International Survey on Determinants of Antibiotic Duration and Discontinuation in Pediatric Critically Ill Patients.

OBJECTIVES: We hypothesized that antibiotic use in PICUs is based on criteria not always supported by evidence. We aimed to describe determinants of empiric antibiotic use in PICUs in eight different countries. DESIGN: Cross-sectional survey. SETTING: PICUs in Canada, the United States, France, Italy, Saudi Arabia, Japan, Thailand, and Brazil. SUBJECTS: Pediatric intensivists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used literature review and focus groups to develop the survey and its clinical scenarios (pneumonia, septic shock, meningitis, and intra-abdominal infections) in which cultures were unreliable due to antibiotic pretreatment. Data analyses included descriptive statistics and linear regression with bootstrapped SEs. Overall response rate was 39% (482/1,251), with individual country response rates ranging from 25% to 76%. Respondents in all countries prolonged antibiotic duration based on patient characteristics, disease severity, pathogens, and radiologic findings (from a median increase of 1.8 d [95% CI, 0.5-4.0 d] to 9.5 d [95% CI, 8.5-10.5 d]). Younger age, severe disease, and ventilator-associated pneumonia prolonged antibiotic treatment duration despite a lack of evidence for such practices. No variables were reported to shorten treatment duration for all countries. Importantly, more than 39% of respondents would use greater than or equal to 7 days of antibiotics for patients with a positive viral polymerase chain reaction test in all scenarios, except in France for pneumonia (29%), septic shock (13%), and meningitis (6%). The use of elevated levels of inflammatory markers to prolong antibiotic treatment duration varied among different countries. CONCLUSIONS: Antibiotic-related decisions are complex and may be influenced by cultural and contextual factors. Evidence-based criteria are necessary to guide antibiotic duration and ensure the rational use of antibiotics in PICUs.

Clostridium difficile: Investigating Transmission Patterns Between Infected and Colonized Patients Using Whole Genome Sequencing.

Background: Whole genome sequencing (WGS) studies can enhance our understanding of the role of patients with asymptomatic Clostridium difficile colonization in transmission. Methods: Isolates obtained from patients with Clostridium difficile infection (CDI) and colonization identified in a study conducted during 2006-2007 at 6 Canadian hospitals underwent typing by pulsed-field gel electrophoresis, multilocus sequence typing, and WGS. Isolates from incident CDI cases not in the initial study were also sequenced where possible. Ward movement and typing data were combined to identify plausible donors for each CDI case, as defined by shared time and space within predefined limits. Proportions of plausible donors for CDI cases that were colonized, infected, or both were examined. Results: Five hundred fifty-four isolates were sequenced successfully, 353 from colonized patients and 201 from CDI cases. The NAP1/027/ST1 strain was the most common strain, found in 124 (62%) of infected and 92 (26%) of colonized patients. A donor with a plausible ward link was found for 81 CDI cases (40%) using WGS with a threshold of ≤2 single nucleotide polymorphisms to determine relatedness. Sixty-five (32%) CDI cases could be linked to both infected and colonized donors. Exclusive linkages to infected and colonized donors were found for 28 (14%) and 12 (6%) CDI cases, respectively. Conclusions: Colonized patients contribute to transmission, but CDI cases are more likely linked to other infected patients than colonized patients in this cohort with high rates of the NAP1/027/ST1 strain, highlighting the importance of local prevalence of virulent strains in determining transmission dynamics.

Predictors of discordant latent tuberculosis infection test results amongst South African health care workers.

BACKGROUND: The tuberculin skin test (TST) and interferon-gamma-release-assays (IGRAs) are utilized in screening programmes for presumed latent tuberculosis infection (LTBI) in health care workers (HCWs). However, inter-test comparison yields high rates of discordance, which is poorly understood. The aim of the study was therefore to identify factors associated with discordance amongst HCWs in a TB and HIV endemic setting. METHODS: 505 HCWs were screened for LTBI in South Africa using the TST and two IGRA assays (QuantiFERON-TB-Gold-In-Tube (QFT-GIT) and TSPOT.TB). Factors associated with discordance were analyzed using a multinomial logistic regression model. RESULTS: TST-IGRA discordance was negatively associated with longer duration of employment for both TSPOT.TB (OR = 0.92; 95% confidence interval (CI) 0.85-0.99) and QFT-GIT (OR = 0.90; 95% CI 0.84-0.96). Marked test discordance occurred in HIV-infected individuals who were more likely to have TSPOT.TB + ve / TST-ve discordance (OR 4.44; 95% CI 1.14-17.27) or TSPOT.TB + ve / QFT-GIT-ve test discordance (OR 5.72; 95% CI 1.95-16.78). Those engaged in home care were less likely to have QFT-GIT + ve/TSPOT.TB -ve / discordance (OR 0.32; 95% CI 0.10-0.95). CONCLUSION: The marked TST-IGRA and IGRA-IGRA discordance in HIV-infected individuals suggest greater sensitivity of TSPOT.TB in immunocompromised persons or potential greater reactivity of TSPOT.TB in this population.

Incidence and predictors of prolonged postoperative ileus after colorectal surgery in the context of an enhanced recovery pathway.

BACKGROUND: Prolonged postoperative ileus (PPOI) is common after colorectal surgery but has not been widely studied in the context of enhanced recovery pathways (ERPs) that include interventions aimed to accelerate gastrointestinal recovery. The aim of this study is to estimate the incidence and predictors of PPOI in the context of an ERP for colorectal surgery. METHODS: We analyzed data from an institutional colorectal surgery ERP registry. Incidence of PPOI was estimated according to a definition adapted from Vather (intolerance of solid food and absence of flatus or bowel movement for ≥ 4 days) and compared to other definitions in the literature. Potential risk factors for PPOI were identified from previous studies, and their predictive ability was evaluated using Bayesian model averaging (BMA). Results are presented as posterior effect probability (PEP). Evidence of association was categorized as: no evidence (PEP < 50%), weak evidence (50-75%), positive evidence (75-95%), strong evidence (95-99%), and very strong evidence (> 99%). RESULTS: There were 323 patients analyzed (mean age 63.5 years, 51% males, 74% laparoscopic, 33% rectal resection). The incidence of PPOI was 19% according to the primary definition, but varied between 11 and 59% when using other definitions. On BMA analysis, intraoperative blood loss (PEP 99%; very strong evidence), administration of any intravenous opioids in the first 48 h (PEP 94%; strong evidence), postoperative epidural analgesia (PEP 56%; weak evidence), and non-compliance with intra-operative fluid management protocols (3 ml/kg/h for laparoscopic and 5 ml/kg/h for open; PEP 55%, weak evidence) were predictors of PPOI. CONCLUSIONS: The incidence of PPOI after colorectal surgery is high even within an established ERP and varied considerably by diagnostic criteria, highlighting the need for a consensus definition. The use of intravenous opioids is a modifiable strong predictor of PPOI within an ERP, while the role of epidural analgesia and intraoperative fluid management should be further evaluated.

Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults.

BACKGROUND: Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review. OBJECTIVES: To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin-resistant tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction. SELECTION CRITERIA: Randomized trials, cross-sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture-based drug susceptibility testing or MTBDRplus for rifampicin resistance. DATA COLLECTION AND ANALYSIS: Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS-2 and performed meta-analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random-effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing. MAIN RESULTS: We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen.Tuberculosis detectionOf the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias.Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high-certainty evidence). We found similar accuracy when we included all studies.For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF-positive and 18 (17%) would not have tuberculosis (false-positives); 897 would be Xpert MTB/RIF-negative and 15 (2%) would have tuberculosis (false-negatives).Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate-certainty evidence).Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear-positive and 67% (62% to 72%) in smear-negative, culture-positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV-negative and 81% (75% to 86%) in HIV-positive participants; specificities were similar 98% (97% to 99%), (14 studies).Rifampicin resistance detectionXpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high-certainty evidence).For a population of 1000 people where 100 have rifampicin-resistant tuberculosis, 114 would be positive for rifampicin-resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false-positives); 886 would be would be negative for rifampicin-resistant tuberculosis and four (0.4%) would have rifampicin resistance (false-negatives).Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear-positive than smear-negative participants and HIV-negative than HIV-positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug-resistant tuberculosis.

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV.

BACKGROUND: The lateral flow urine lipoarabinomannan (LF-LAM) assay Alere Determine™ TB LAM Ag is recommended by the World Health Organization (WHO) to help detect active tuberculosis in HIV-positive people with severe HIV disease. This review update asks the question, "does new evidence justify the use of LF-LAM in a broader group of people?", and is part of the WHO process for updating guidance on the use of LF-LAM. OBJECTIVES: To assess the accuracy of LF-LAM for the diagnosis of active tuberculosis among HIV-positive adults with signs and symptoms of tuberculosis (symptomatic participants) and among HIV-positive adults irrespective of signs and symptoms of tuberculosis (unselected participants not assessed for tuberculosis signs and symptoms).The proposed role for LF-LAM is as an add on to clinical judgement and with other tests to assist in diagnosing tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, without language restriction to 11 May 2018. SELECTION CRITERIA: Randomized trials, cross-sectional, and observational cohort studies that evaluated LF-LAM for active tuberculosis (pulmonary and extrapulmonary) in HIV-positive adults. We included studies that used the manufacturer's recommended threshold for test positivity, either the updated reference card with four bands (grade 1 of 4) or the corresponding prior reference card grade with five bands (grade 2 of 5). The reference standard was culture or nucleic acid amplification test from any body site (microbiological). We considered a higher quality reference standard to be one in which two or more specimen types were evaluated for tuberculosis diagnosis and a lower quality reference standard to be one in which only one specimen type was evaluated. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardized form and REDCap electronic data capture tools. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and performed meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and a Bayesian approach. We analyzed studies enrolling strictly symptomatic participants separately from those enrolling unselected participants. We investigated pre-defined sources of heterogeneity including the influence of CD4 count and clinical setting on the accuracy estimates. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 15 unique studies (nine new studies and six studies from the original review that met the inclusion criteria): eight studies among symptomatic adults and seven studies among unselected adults. All studies were conducted in low- or middle-income countries. Risk of bias was high in the patient selection and reference standard domains, mainly because studies excluded participants unable to produce sputum and used a lower quality reference standard.Participants with tuberculosis symptomsLF-LAM pooled sensitivity (95% credible interval (CrI) ) was 42% (31% to 55%) (moderate-certainty evidence) and pooled specificity was 91% (85% to 95%) (very low-certainty evidence), (8 studies, 3449 participants, 37% with tuberculosis).For a population of 1000 people where 300 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 189 to be LF-LAM positive: of these, 63 (33%) would not have tuberculosis (false-positives); and 811 to be LF-LAM negative: of these, 174 (21%) would have tuberculosis (false-negatives).By clinical setting, pooled sensitivity was 52% (40% to 64%) among inpatients versus 29% (17% to 47%) among outpatients; and pooled specificity was 87% (78% to 93%) among inpatients versus 96% (91% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count.Unselected participants not assessed for signs and symptoms of tuberculosisLF-LAM pooled sensitivity was 35% (22% to 50%), (moderate-certainty evidence) and pooled specificity was 95% (89% to 96%), (low-certainty evidence), (7 studies, 3365 participants, 13% with tuberculosis).For a population of 1000 people where 100 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 80 to be LF-LAM positive: of these, 45 (56%) would not have tuberculosis (false-positives); and 920 to be LF-LAM negative: of these, 65 (7%) would have tuberculosis (false-negatives).By clinical setting, pooled sensitivity was 62% (41% to 83%) among inpatients versus 31% (18% to 47%) among outpatients; pooled specificity was 84% (48% to 96%) among inpatients versus 95% (87% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count. AUTHORS' CONCLUSIONS: We found that LF-LAM has a sensitivity of 42% to diagnose tuberculosis in HIV-positive individuals with tuberculosis symptoms and 35% in HIV-positive individuals not assessed for tuberculosis symptoms, consistent with findings reported previously. Regardless of how people are enrolled, sensitivity is higher in inpatients and those with lower CD4 cell, but a concomitant lower specificity. As a simple point-of-care test that does not depend upon sputum evaluation, LF-LAM may assist with the diagnosis of tuberculosis, particularly when a sputum specimen cannot be produced.

A Framework for Aiding the Translation of Scientific Evidence into Policy: The Experience of a Hospital-Based Technology Assessment Unit.

OBJECTIVES: Very few practical frameworks exist to guide the formulation of recommendations at hospital-based health technology assessment (HTA) units. The objectives of our study were: (i) to identify decision criteria specific to the context of hospital-based health technologies and interventions, (ii) to estimate the extent to which the expert community agrees on the importance of the identified criteria, (iii) to incorporate the identified criteria into a decision-aid tool, and (iv) to illustrate the application of a prototype decision-aid tool. METHODS: Relevant decision criteria were identified using existing frameworks for HTA recommendations, our past experience, a literature search, and feedback from a survey of diverse stakeholders. RESULTS: Based on the survey results, twenty-three decision criteria were incorporated into the final framework. We defined an approach that eschewed a scoring system, but instead relied on a visual means for arriving at a final recommendation, by juxtaposing the importance rating for each criterion against the results of the health technology assessment. For a technology to be approved, a majority of criteria considered important should also have received favorable findings. CONCLUSIONS: We created a simple and practical decision-aid tool that incorporates all decision criteria relevant to a hospital-based HTA unit. With its ease of use and accessibility, our tool renders the subjective decision-making process more structured and transparent.

Accuracy of Administrative Health Data for Surveillance of Traumatic Brain Injury: A Bayesian Latent Class Analysis.

BACKGROUND: Traumatic brain injury surveillance provides information for allocating resources to prevention efforts. Administrative data are widely available and inexpensive but may underestimate traumatic brain injury burden by misclassifying cases. Moreover, previous studies evaluating the accuracy of administrative data surveillance case definitions were at risk of bias by using imperfect diagnostic definitions as reference standards. We assessed the accuracy (sensitivity/specificity) of traumatic brain injury surveillance case definitions in administrative data, without using a reference standard, to estimate incidence accurately. METHODS: We used administrative data from a 25% random sample of Montreal residents from 2000 to 2014. We used hierarchical Bayesian latent class models to estimate the accuracy of widely used traumatic brain injury case definitions based on the International Classification of Diseases, or on head radiologic examinations, covering the full injury spectrum in children, adults, and the elderly. We estimated measurement error-adjusted age- and severity-specific incidence. RESULTS: The adjusted traumatic brain injury incidence was 76 (95% CrI = 68, 85) per 10,000 person-years (underestimated as 54 [95% CrI = 54, 55] per 10,000 without adjustment). The most sensitive case definitions were radiologic examination claims in adults/elderly (0.48; 95% CrI = 0.43, 0.55 and 0.66; 95% CrI = 0.54, 0.79) and emergency department claims in children (0.45; 95% CrI = 0.39, 0.52). The most specific case definitions were inpatient claims and discharge abstracts (0.99; 95% CrI = 0.99, 1.00). We noted strong secular trends in case definition accuracy. CONCLUSIONS: Administrative data remain a useful tool for conducting traumatic brain injury surveillance and epidemiologic research when measurement error is adjusted for.

Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance.

BACKGROUND: Tuberculosis (TB) is the world's leading infectious cause of death. Extrapulmonary TB accounts for 15% of TB cases, but the proportion is increasing, and over half a million people were newly diagnosed with rifampicin-resistant TB in 2016. Xpert® MTB/RIF (Xpert) is a World Health Organization (WHO)-recommended, rapid, automated, nucleic acid amplification assay that is used widely for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum specimens. This Cochrane Review assessed the accuracy of Xpert in extrapulmonary specimens. OBJECTIVES: To determine the diagnostic accuracy of Xpert a) for extrapulmonary TB by site of disease in people presumed to have extrapulmonary TB; and b) for rifampicin resistance in people presumed to have extrapulmonary TB. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature (LILACS), Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number (ISRCTN) Registry, and ProQuest up to 7 August 2017 without language restriction. SELECTION CRITERIA: We included diagnostic accuracy studies of Xpert in people presumed to have extrapulmonary TB. We included TB meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB. We used culture as the reference standard. For pleural TB, we also included a composite reference standard, which defined a positive result as the presence of granulomatous inflammation or a positive culture result. For rifampicin resistance, we used culture-based drug susceptibility testing or MTBDRplus as the reference standard. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed risk of bias and applicability using the QUADAS-2 tool. We determined pooled predicted sensitivity and specificity for TB, grouped by type of extrapulmonary specimen, and for rifampicin resistance. For TB detection, we used a bivariate random-effects model. Recognizing that use of culture may lead to misclassification of cases of extrapulmonary TB as 'not TB' owing to the paucibacillary nature of the disease, we adjusted accuracy estimates by applying a latent class meta-analysis model. For rifampicin resistance detection, we performed univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. We used theoretical populations with an assumed prevalence to provide illustrative numbers of patients with false positive and false negative results. MAIN RESULTS: We included 66 unique studies that evaluated 16,213 specimens for detection of extrapulmonary TB and rifampicin resistance. We identified only one study that evaluated the newest test version, Xpert MTB/RIF Ultra (Ultra), for TB meningitis. Fifty studies (76%) took place in low- or middle-income countries. Risk of bias was low for patient selection, index test, and flow and timing domains and was high or unclear for the reference standard domain (most of these studies decontaminated sterile specimens before culture inoculation). Regarding applicability, in the patient selection domain, we scored high or unclear concern for most studies because either patients were evaluated exclusively as inpatients at tertiary care centres, or we were not sure about the clinical settings.Pooled Xpert sensitivity (defined by culture) varied across different types of specimens (31% in pleural tissue to 97% in bone or joint fluid); Xpert sensitivity was > 80% in urine and bone or joint fluid and tissue. Pooled Xpert specificity (defined by culture) varied less than sensitivity (82% in bone or joint tissue to 99% in pleural fluid and urine). Xpert specificity was ≥ 98% in cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid.Xpert testing in cerebrospinal fluidXpert pooled sensitivity and specificity (95% credible interval (CrI)) against culture were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%), respectively (29 studies, 3774 specimens; moderate-certainty evidence).For a population of 1000 people where 100 have TB meningitis on culture, 89 would be Xpert-positive: of these, 18 (20%) would not have TB (false-positives); and 911 would be Xpert-negative: of these, 29 (3%) would have TB (false-negatives).For TB meningitis, ultra sensitivity and specificity against culture (95% confidence interval (CI)) were 90% (55% to 100%) and 90% (83% to 95%), respectively (one study, 129 participants).Xpert testing in pleural fluidXpert pooled sensitivity and specificity (95% CrI) against culture were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%), respectively (27 studies, 4006 specimens; low-certainty evidence).For a population of 1000 people where 150 have pleural TB on culture, 83 would be Xpert-positive: of these, seven (8%) would not have TB (false-positives); and 917 would be Xpert-negative: of these, 74 (8%) would have TB (false-negatives).Xpert testing in urineXpert pooled sensitivity and specificity (95% CrI) against culture were 82.7% (69.6% to 91.1%) and 98.7% (94.8% to 99.7%), respectively (13 studies, 1199 specimens; moderate-certainty evidence).For a population of 1000 people where 70 have genitourinary TB on culture, 70 would be Xpert-positive: of these, 12 (17%) would not have TB (false-positives); and 930 would be Xpert-negative: of these, 12 (1%) would have TB (false-negatives).Xpert testing for rifampicin resistanceXpert pooled sensitivity (20 studies, 148 specimens) and specificity (39 studies, 1088 specimens) were 95.0% (89.7% to 97.9%) and 98.7% (97.8% to 99.4%), respectively (high-certainty evidence).For a population of 1000 people where 120 have rifampicin-resistant TB, 125 would be positive for rifampicin-resistant TB: of these, 11 (9%) would not have rifampicin resistance (false-positives); and 875 would be negative for rifampicin-resistant TB: of these, 6 (1%) would have rifampicin resistance (false-negatives).For lymph node TB, the accuracy of culture, the reference standard used, presented a greater concern for bias than in other forms of extrapulmonary TB. AUTHORS' CONCLUSIONS: In people presumed to have extrapulmonary TB, Xpert may be helpful in confirming the diagnosis. Xpert sensitivity varies across different extrapulmonary specimens, while for most specimens, specificity is high, the test rarely yielding a positive result for people without TB (defined by culture). Xpert is accurate for detection of rifampicin resistance. For people with presumed TB meningitis, treatment should be based on clinical judgement, and not withheld solely on an Xpert result, as is common practice when culture results are negative.