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PURPOSE Childhood cancer survivors (CCS) are at risk of developing subsequent malignant neoplasms (SMNs) resulting from exposure to prior therapies. CCS with underlying cancer predisposition syndromes are at additional genetic risk of SMN development. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) tool identifies children with cancer at increased likelihood of having a cancer predisposition syndrome, guiding clinicians through a series of Yes or No questions that generate a recommendation for or against genetic evaluation. We evaluated MIPOGG's ability to predict SMN development in CCS. METHODS Using the provincial cancer registry (Ontario, Canada), and adopting a nested case-control approach, we identified CCS diagnosed and/or treated for a primary malignancy before age 18 years (1986-2015). CCS who developed an SMN (cases) were matched, by primary cancer and year of diagnosis, with CCS who did not develop an SMN (controls) over the same period (1:5 ratio). Potential predictors for SMN development (chemotherapy, radiation, and MIPOGG output) were applied retrospectively using clinical data pertaining to the first malignancy. Conditional logistic regression models estimated hazard ratios and 95% CIs associated with each covariate, alone and in combination, for SMN development. RESULTS Of 13,367 children with a primary cancer, 317 (2.4%) developed an SMN and were matched to 1,569 controls. A MIPOGG output recommending evaluation was significantly associated with SMN development (hazard ratio 1.53; 95% CI, 1.06 to 2.19) in a multivariable model that included primary cancer therapy exposures. MIPOGG was predictive of SMN development, showing value in nonhematologic malignancies and in CCS not exposed to radiation. CONCLUSION MIPOGG has additional value for SMN prediction beyond treatment exposures and may be beneficial in decision making for enhanced individualized SMN surveillance strategies for CCS.

Background: As a result of the COVID-19 pandemic first wave, reductions in ST-elevation myocardial infarction (STEMI) invasive care, ranging from 23% to 76%, have been reported from various countries. Whether this change had any impact on coronary angiography (CA) volume or on mechanical support device use for STEMI and post-STEMI mechanical complications in Canada is unknown. Methods: We administered a Canada-wide survey to all cardiac catheterization laboratory directors, seeking the volume of CA use for STEMI performed during the period from March 1 2020 to May 31, 2020 (pandemic period), and during 2 control periods (March 1, 2019 to May 31, 2019 and March 1, 2018 to May 31, 2018). The number of left ventricular support devices used, as well as the number of ventricular septal defects and papillary muscle rupture cases diagnosed, was also recorded. We also assessed whether the number of COVID-19 cases recorded in each province was associated with STEMI-related CA volume. Results: A total of 41 of 42 Canadian catheterization laboratories (98%) provided data. There was a modest but statistically significant 16% reduction (incidence rate ratio [IRR] 0.84; 95% confidence interval 0.80-0.87) in CA for STEMI during the first wave of the pandemic, compared to control periods. IRR was not associated with provincial COVID-19 caseload. We observed a 26% reduction (IRR 0.74; 95% confidence interval 0.61-0.89) in the use of intra-aortic balloon pump use for STEMI. Use of an Impella pump and mechanical complications from STEMI were exceedingly rare. Conclusions: We observed a modest 16% decrease in use of CA for STEMI during the pandemic first wave in Canada, lower than the level reported in other countries. Provincial COVID-19 caseload did not influence this reduction. Résumé: Introduction: Après la première vague de la pandémie de COVID-19, de nombreux pays ont déclaré une réduction de 23 % à 76 % des soins invasifs de l'infarctus du myocarde avec élévation du segment ST (STEMI). On ignore si ce changement a entraîné des répercussions sur le volume d'angiographies coronariennes (AC) ou sur l'utilisation des dispositifs d'assistance mécanique lors de STEMI et des complications mécaniques post-STEMI au Canada. Méthodes: Nous avons réalisé un sondage pancanadien auprès de tous les directeurs de laboratoire de cathétérisme cardiaque pour obtenir le volume d'utilisation des AC lors des STEMI réalisées durant la période du 1er mars 2020 au 31 mai 2020 (période de pandémie) et durant 2 périodes témoins (1er mars 2019 au 31 mai 2019 et 1er mars 2018 au 31 mai 2018). Le nombre de dispositifs d'assistance ventriculaire gauche utilisés et le nombre de cas de communications interventriculaires et de ruptures du muscle papillaire diagnostiqués ont également été enregistrés. Nous avons aussi évalué si le nombre de cas de COVID-19 enregistrés dans chaque province était associé au volume d'AC liées aux STEMI. Résultats: Au total, 41 des 42 laboratoires canadiens de cathétérisme (98 %) ont fourni des données. Lors de la comparaison de la première vague de la pandémie aux périodes témoins, nous avons noté une réduction modeste, mais significative, sur le plan statistique de 16 % (ratio du taux d'incidence [RTI] 0,84; intervalle de confiance à 95 % 0,80-0,87) des AC lors de STEMI. Le RTI n’était pas associé au nombre provincial de cas de COVID-19. Nous avons observé une réduction de 26 % (RTI 0,74; intervalle de confiance à 95 % 0,61-0,89) de l'utilisation de pompes à ballonnet intra-aortique lors de STEMI. L'utilisation d'une pompe Impella et les complications mécaniques après les STEMI étaient extrêmement rares. Conclusions: Nous avons observé une diminution modeste de 16 % de l'utilisation des AC lors de STEMI durant la première vague de la pandémie au Canada, soit une diminution plus faible que ce que les autres pays ont signalé. Le nombre provincial de cas de COVID-19 n'a pas influencé cette réduction.

Studying existing health systems with variable living donor kidney transplantation (LDKT) performance and understanding factors that drive these differences can inform comprehensive system-level approaches to improve LDKT. We aimed to quantify previously identified barriers and estimate their association with LDKT performance.We conducted a cross-sectional survey of health professionals (HPs). Statements, rated on a Likert scale of "strongly disagree" to "strongly agree", captured themes related to communication; role perception; HP's education, training and comfort; attitudes; referral process; patient; as well as resources and infrastructure. The percentage who agreed with these statements was analyzed and compared by LDKT performance (living donation rates higher or lower than the national average) and participant characteristics.We obtained 353 complete responses. Themes related to poor communication, poor role perception, and HPs education or training or comfort emerged as barriers to LDKT. When compared with HPs from high-performing provinces, those from low-performing provinces had lower odds of agreeing that their province promoted LDKT (adjusted odd ratio [aOR] = 0.27, 95% confidence interval [CI]: 0.16-0.48). They also had lower odds of initiating discussions about LDKT (aOR = 0.30, 95% CI: 0.17-0.55), and higher odds of agreeing that the transplant team is best suited to discuss LDKT (aOR = 2.64, 95% CI: 1.60-4.33) and that more resources would increase LDKT discussions (aOR = 2.06, 95% CI: 1.25-3.40). Nonphysician role and less than 10 years of experience were associated with the level of agreement across several themes. Creating guidelines, streamlining evaluations, and improving communication were ranked as priorities to increase LDKT.There are system-level barriers to LDKT and some were more prevalent in low-performing provinces. Interventions to eliminate them should be implemented in conjunction with patient-level interventions as part of a comprehensive system-level approach to increase LDKT.

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.

Rapid and accurate diagnosis of herpes simplex virus (HSV)-1 and -2 (HSV1/2) in cerebrospinal fluid (CSF) is important for patient management.Summarize the diagnostic accuracy of commercial rapid sample-to-answer PCR assays (results in90 minutes, without a separate nucleic acid extraction step) for HSV1/2 detection in CSF.Four databases (MEDLINE, EMBASE, Scopus, and CENTRAL) and five conference abstract datasets from January 2012 to March 2022.Eligible diagnostic accuracy studies provided sufficient data for the construction of a standard diagnostic accuracy two-by-two table.Patients with suspected meningitis and/or encephalitis.FilmArray Meningitis-Encephalitis Panel and Simplexa HSV 12 Direct Kit PCR.Real-time PCR assay.Two investigators independently extracted data, rated risk of bias, and assessed quality using QUADAS-2. METHODS OF DATA SYNTHESIS: Accuracy estimates were pooled using Bayesian random effects models.Thirty-one studies were included (27 FilmArray; 4 Simplexa), comprising 9924 samples, with 95 HSV-1 and 247 HSV-2 infections. Pooled FilmArray sensitivities were 84.3% (95% credible interval, 72.3-93.0) and 92.9% (95% credible interval (CrI), 82.0-98.5) for HSV-1 and HSV-2, respectively; specificities were 99.8% (95% CrI, 99.6-99.9) and 99.9% (95% CrI, 99.9-100). Pooled Simplexa sensitivities were 97.1% (95% CrI, 88.1-99.6) and 97.9% (95% CrI, 89.6-99.9), respectively; specificities were 98.9% (95% CrI, 96.8-99.7) and 98.9% (95% CrI, 97.1-99.7). Pooled FilmArray sensitivities favoured industry-sponsored studies by 10.0 and 13.0 percentage points for HSV-1 and HSV-2, respectively. Incomplete reporting frequently led to unclear risk of bias. Several FilmArray studies did not fully report true negative data leading to their exclusion.Our results suggest Simplexa is accurate for HSV1/2 detection in CSF. Moderate FilmArray sensitivity for HSV-1 suggests additional testing and/or repeat CSF sampling is required for suspected HSV encephalitis when the HSV-1 result is negative. Low prevalence of HSV-1 infections limited summary estimates' precision. Underreporting of covariates limited exploration of heterogeneity.

Importance Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. Objective To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. Design, Setting, and Participants In this international, multicenter diagnostic accuracy study, 1071 pediatric (

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.

Background Evaluating the accuracy of extrapulmonary tuberculosis (TB) tests is challenging due to lack of a gold standard. Latent class analysis (LCA), a statistical modeling approach, can adjust for reference tests’ imperfect accuracies to produce less biased test accuracy estimates than those produced by commonly used methods like composite reference standards (CRSs). Our objective is to illustrate how Bayesian LCA can address the problem of an unavailable gold standard and demonstrate how it compares to using CRSs for extrapulmonary TB tests. Methods We re-analyzed a dataset of presumptive extrapulmonary TB cases in New Delhi, India, for three forms of extrapulmonary TB. Results were available for culture, smear microscopy, Xpert MTB/RIF, and a non-microbiological test, cytopathology/histopathology, or adenosine deaminase (ADA). A diagram was used to define assumed relationships between observed tests and underlying latent variables in the Bayesian LCA with input from an inter-disciplinary team. We compared the results to estimates obtained from a sequence of CRSs defined by increasing numbers of positive reference tests necessary for positive disease status. Results Data were available from 298, 388, and 230 individuals with presumptive TB lymphadenitis, meningitis, and pleuritis, respectively. Using Bayesian LCA, estimates were obtained for accuracy of all tests and for extrapulmonary TB prevalence. Xpert sensitivity neared that of culture for TB lymphadenitis and meningitis but was lower for TB pleuritis, and specificities of all microbiological tests approached 100%. Non-microbiological tests’ sensitivities were high, but specificities were only moderate, preventing disease rule-in. CRSs’ only provided estimates of Xpert and these varied widely per CRS definition. Accuracy of the CRSs also varied by definition, and no CRS was 100% accurate. Conclusion Unlike CRSs, Bayesian LCA takes into account known information about test performance resulting in accuracy estimates that are easier to interpret. LCA should receive greater consideration for evaluating extrapulmonary TB diagnostic tests.

OBJECTIVES Antivirals are recommended for children hospitalized with influenza but are underutilized. We describe antiviral prescribing during influenza admissions in Canadian pediatric centers and identify factors associated with antiviral use. METHODS We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from 2010–2011 to 2018–2019. Logistic regression analyses were used to identify factors associated with antiviral use. RESULTS Among 7545 patients, 57.4% were male; median age was 3 years (interquartile range: 1.1–6.3). Overall, 41.3% received antiviral agents; 72.8% received antibiotics. Antiviral use varied across sites (range, 10.2% to 81.1%) and influenza season (range, 19.9% to 59.6%) and was more frequent in children with ≥1 chronic health condition (52.7% vs 36.7%; P < .001). On multivariable analysis, factors associated with antiviral use included older age (adjusted odds ratio [aOR] 1.04 [95% confidence interval (CI), 1.02–1.05]), more recent season (highest aOR 9.18 [95% CI, 6.70–12.57] for 2018–2019), admission during peak influenza period (aOR 1.37 [95% CI, 1.19–1.58]), availability of local treatment guideline (aOR 1.54 [95% CI, 1.17–2.02]), timing of laboratory confirmation (highest aOR 2.67 [95% CI, 1.97–3.61] for result available before admission), presence of chronic health conditions (highest aOR 4.81 [95% CI, 3.61–6.40] for cancer), radiographically confirmed pneumonia (aOR 1.39 [95% CI, 1.20–1.60]), antibiotic treatment (aOR 1.51 [95% CI, 1.30–1.76]), respiratory support (1.57 [95% CI, 1.19–2.08]), and ICU admission (aOR 3.62 [95% CI, 2.88–4.56]). CONCLUSIONS Influenza antiviral agents were underused in Canadian pediatric hospitals, including among children with high-risk chronic health conditions. Prescribing varied considerably across sites, increased over time, and was associated with patient and hospital-level characteristics. Multifaceted hospital-based interventions are warranted to strengthen adherence to influenza treatment guidelines and antimicrobial stewardship practices.

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

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.

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.

ObjectivesVery 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.MethodsRelevant decision criteria were identified using existing frameworks for HTA recommendations, our past experience, a literature search, and feedback from a survey of diverse stakeholders.ResultsBased 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.ConclusionsWe 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.

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., Plain language summary How accurate are sputum Xpert tests for screening for active pulmonary tuberculosis and rifampicin resistance in adults whether or not they have tuberculosis symptoms? Why is using Xpert tests to screen for pulmonary tuberculosis important? Tuberculosis is the leading cause of infectious disease‐related death and one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends using specific rapid tests as initial tests for diagnosing 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. Not recognizing tuberculosis when it is present (a false negative test result) may result in illness and death and an increased risk of infecting others. An incorrect diagnosis of tuberculosis (false‐positive result) may mean that people are given antibiotics when there is no benefit to be gained. What is the aim of this review? To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis and rifampicin resistance in adults whether or not they have tuberculosis symptoms (such as cough, fever, weight loss, and night sweats). We were interested in how the tests worked in groups at high risk for tuberculosis, including people living with HIV (PLHIV), household contacts of people with tuberculosis, miners, people residing in prisons, people with diabetes, and in the general public. What was studied in this review? Xpert MTB/RIF and Xpert Ultra are rapid tests for simultaneously diagnosing tuberculosis and rifampicin resistance. We combined study results to determine: ‐ sensitivity: people with tuberculosis (rifampicin resistance) correctly diagnosed as having the condition. ‐ specificity: people without tuberculosis (rifampicin resistance) correctly identified as not having the condition. The closer sensitivity and specificity are to 100%, the better the test. What are the main results in this review? Twenty‐one 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. For every 1000 people tested, if 50 had tuberculosis according to the reference standard: PLHIV ‐ Xpert MTB/RIF (12 studies): · 40 people would test positive, including 9 without tuberculosis (62% sensitivity) · 960 people would test negative, including 19 with tuberculosis (99% specificity) ‐ Xpert Ultra (1 study): · 53 people would test positive, including 19 without tuberculosis (69% sensitivity) · 947 people would test negative, including 16 with tuberculosis (98% specificity) For every 1000 people tested, if 10 had tuberculosis according to the reference standard: Other high‐risk groups combined ‐ Xpert MTB/RIF (5 studies): · 19 people would test positive, including 12 without tuberculosis (69% sensitivity) · 981 people would test negative, including 3 with tuberculosis (99% specificity) For detection of rifampicin resistance, Xpert MTB/RIF sensitivity was 81% and 100% (2 studies) and specificity was 94% to 100% (3 studies). How reliable are the results of the studies in this review? In the included studies, the reference standards for diagnosing pulmonary tuberculosis (culture) and rifampicin resistance (drug susceptibility testing) are likely to have been reliable methods for deciding whether patients really had the conditions. We were fairly confident in the results for Xpert MTB/RIF in PLHIV, and less so for other high‐risk groups. Not enough people have been studied to be confident about the results for Xpert Ultra or for detection of rifampicin resistance. Who do the results of this review apply to? Studies were mainly performed in high tuberculosis and high HIV burden settings. No studies evaluated the tests in people with diabetes mellitus or the general population. What are the implications of this review? In PLHIV, Xpert MTB/RIF as a screening test was accurate for tuberculosis in high tuberculosis burden settings. In high‐risk groups, Xpert MTB/RIF may assist in identifying tuberculosis, but the certainty of evidence is low. In PLHIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar based on one study. There were few studies and few people tested for rifampicin resistance and no studies that evaluated the tests in people with diabetes or in the general population. How up‐to‐date is this review? 19 March 2020.

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.

Importance Nasopharyngeal swab nucleic acid amplification testing (NAAT) is the noninvasive criterion standard for diagnosis of coronavirus disease 2019 (COVID-19). However, it requires trained personnel, limiting its availability. Saliva NAAT represents an attractive alternative, but its diagnostic performance is unclear. Objective To assess the diagnostic accuracy of saliva NAAT for COVID-19. Data Sources In this systematic review, a search of the MEDLINE and medRxiv databases was conducted on August 29, 2020, to find studies of diagnostic test accuracy. The final meta-analysis was performed on November 17, 2020. Study Selection Studies needed to provide enough data to measure salivary NAAT sensitivity and specificity compared with imperfect nasopharyngeal swab NAAT as a reference test. An imperfect reference test does not perfectly reflect the truth (ie, it can give false results). Studies were excluded if the sample contained fewer than 20 participants or was neither random nor consecutive. The Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to assess the risk of bias. Data Extraction and Synthesis Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed for the systematic review, with multiple authors involved at each stage of the review. To account for the imperfect reference test sensitivity, we used a bayesian latent class bivariate model for the meta-analysis. Main Outcomes and Measures The primary outcome was pooled sensitivity and specificity. Two secondary analyses were performed: one restricted to peer-reviewed studies, and a post hoc analysis limited to ambulatory settings. Results The search strategy yielded 385 references, and 16 unique studies were identified for quantitative synthesis. Eight peer-reviewed studies and 8 preprints were included in the meta-analyses (5922 unique patients). There was significant variability in patient selection, study design, and stage of illness at which patients were enrolled. Fifteen studies included ambulatory patients, and 9 exclusively enrolled from an outpatient population with mild or no symptoms. In the primary analysis, the saliva NAAT pooled sensitivity was 83.2% (95% credible interval [CrI], 74.7%-91.4%) and the pooled specificity was 99.2% (95% CrI, 98.2%-99.8%). The nasopharyngeal swab NAAT had a sensitivity of 84.8% (95% CrI, 76.8%-92.4%) and a specificity of 98.9% (95% CrI, 97.4%-99.8%). Results were similar in secondary analyses. Conclusions and Relevance These results suggest that saliva NAAT diagnostic accuracy is similar to that of nasopharyngeal swab NAAT, especially in the ambulatory setting. These findings support larger-scale research on the use of saliva NAAT as an alternative to nasopharyngeal swabs.

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.

Background: Much attention is paid to the negative aspects of aging with HIV. Less is known about those doing well, yet much could be learned from those aging successfully. Objective: The purpose of this study is to estimate the extent to which people aging with HIV met criteria for successful aging and maintained this status over time. A second objective was to identify factors that placed people at promise for successful aging. Methods: Participants were members of the Positive Brain Health Now (BHN) cohort which recruited from five Canadian sites (2014-2016) with prospective follow-up over 27 months. People ≥50 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. Promise factors covered socio-demographic, HIV, co-morbidity, lifestyle, resilience, and environmental domains. Group-based Trajectory Analysis, logistic regression and regression tree analysis, a form of machine learning, were applied. Results: Of the 513 people age ≥50 at study entry, 73 (14·2%) met criteria for successful aging at entry and over time. The most influential factor was loneliness: splitting the sample into two groups with the prevalence of successful aging 28·4% in the not-lonely compared to 4·6% in the lonely. 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%. Conclusion: The results indicate the important role of social determinants of health in successful aging in people with HIV. Funding Statement: This project was supported by grants from the Canadian Institutes of Health Research (LKF,MJB, NM, TCO-125272), the CIHR Canadian HIV Trials Network (CTN 273), and salary support from the Fonds de Recherche Sante du Quebec (LKF) and the Research Institute of the McGill University Health Centre (MJB). Declaration of Interests: Authors declare that they have no conflicts of interest. Ethics Approval Statement: All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The project was approved by the Research Ethics Board of each of the participating institutions. All participants provided informed consent.

Background. To assess the diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for the detection of Shigella from stool samples from children. Methods. Consecutive stool samples from children aged Results. Amongst the 374 stool samples tested, 291 samples were positive by LAMP and 213 were positive by the composite reference standard. The sensitivity of LAMP was 100 % (98.3–100 %) and its specificity was 51.6 % (43.6–59.5 %) with a disease prevalence of 57 %. The sensitivity and specificity of LAMP improved to 99.3 % (94.2–100) and 98.2 % (94.5–99.9), respectively, using latent class analysis, while assuming that genomic sequencing has perfect specificity. Discussion. The authors have standardized the LAMP procedure for direct application to clinical stool samples. LAMP is a sensitive and specific method for the diagnosis of Shigella from stool samples of children as compared to both culture and conventional PCR.

Objectives\ud This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:\ud \ud To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for tuberculosis in adults irrespective of signs or symptoms of pulmonary tuberculosis in the general population (i.e. low‐risk population).\ud \ud To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for screening of pulmonary tuberculosis in adults in the following high‐risk groups.\ud \ud People living with HIV.\ud \ud Household contacts of people with tuberculosis.\ud \ud Patients residing in high‐tuberculosis‐burden settings attending primary health facilities.\ud \ud Homeless people.\ud \ud Miners.\ud \ud People with diabetes mellitus.\ud \ud People who abuse alcohol.\ud \ud Smokers.\ud \ud People residing in prisons.\ud \ud Healthcare workers.\ud \ud To determine the accuracy of Xpert MTB/RIF and Xpert Ultra for the detection of rifampicin resistance in the general population and in the high‐risk groups and settings described above.\ud \ud Secondary objectives\ud To compare the accuracy of Xpert MTB/RIF and Xpert Ultra in the above high‐risk groups and settings.\ud \ud To investigate potential sources of heterogeneity in accuracy estimates, including the percentage of participants with tuberculosis symptoms, tuberculosis burden, tuberculosis/HIV burden, and MDR‐TB burden.

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.

Background To assess the diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for the detection of Shigella from stool samples from children. Methods Consecutive stool samples from children aged

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 which have used LCMs to combine and compare STD and MOL method performance, and estimate prevalence of sepsis have not been described. Methods: Results from an ICU sepsis study which used both tests were analyzed. Bayesian LCMs combined prior prevalences of sepsis, diagnostic characteristics of the two methods ,and the study results to estimate posterior prevalence and diagnostic characteristics.Sensitivity analyses were performed by using varying objective and subjective prior parameters. Positive predictive values(PPVs) of the prevalence of sepsis were estimated for all combinations of test results. Finding: Posterior estimates were: 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). Interpretation: LCMs combined two imperfect methods to estimate prevalence,PPV, and diagnostic characteristics. The posterior estimates (STD sensitivity and STD specificity) seem to reflect clinical experience appropriately. The high PPV when both methods show positive results can be useful for ruling in disease. Funding Statement: This study has not received any funding from any source. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This study had recruited patients from the ICU of St John’s Medical College, Bangalore from April 2010 to September 2010 after Institutional Ethical Committee approval (IEC: Ref-188/2008). Further consent for performance of this study was also obtained (IEC: Ref-002/2020).

Background: Stents immediately implanted in thrombus-laden arteries cause embolization, which paradoxically impairs myocardial reperfusion and function. Methods: We conducted a Bayesian open-label randomized trial across 15 centres in France and Canada. Patients with acute ST-elevation myocardial infarction (STEMI) and reperfused by thrombectomy or small-size balloon angioplasty were randomly assigned to immediate stenting or to a bridging anti-thrombin therapy and delayed stenting between 18h to 48h after reperfusion. Using a hierarchical Bayesian analysis, we borrowed data from exchangeable twin trials to form a posterior probability of the risk ratio (RR) for the combined occurrence of cardiovascular death, heart failure, non-fatal myocardial infarction (MI), or target-vessel revascularisation (TVR) over 9 months in the intent-to-treat populations. Findings: Between April 2014 and September 2017, 305 participants were randomly assigned to delayed (n = 152) or immediate stenting (n = 153). In parallel, four similar RCTs were reported that satisfied exchangeability requirements, leading to 1,873 participants, including 930 assigned to delayed and 943 assigned to immediate stenting. The primary endpoint occurred in 167 participants (18.1%) assigned to delayed stenting compared to 194 participants (20.6%) assigned to immediate stenting (RR, 0.91; 95% credible interval [95%CrI], 0.76 to 1.09; probability of superiority, 89%). Delayed stenting led to a meaningful increase in unplanned target revascularization acutely (RR, 1.54; 95% CrI, 0.98 to 2.41, probability of inferiority, 99%). At long term, delayed stenting reduced the combined occurrence of CV death or heart failure (RR, 0.83; 95% CrI, 0.67 to 1.02, probability of superiority, 99%). Interpretation: In patients with STEMI, delayed stenting did not reduce the occurrence of cardiovascular death, non-fatal MI, heart failure and unplanned TVR compared to the immediate stenting. There is a high probability that delayed stenting substantially reduces cardiovascular death and heart failure in the longer-term. Trial Registration: ClinicalTrials.gov identifier: NCT01542385. Funding Statement: The trial was supported by an operating grant from the peer-reviewed, publically funded Canadian Institute of Health Research (CIHR), through the Industry-Partnered Collaborative Research program (grant #298937), in collaboration with Boston Scientific and AstraZeneca (unrestricted grants support). The industry partners played no role in the conduct and oversight of the study. Declaration of Interests: The investigators disclose the following relationships: E. Marc Jolicoeur: Advisory Board: Institut National d’Excellence en Sante et Services Sociaux du Quebec, Servier, Imbria Pharmaceutical, Carre technology; Board of Directors, Societe de Sciences Vasculaires du Quebec; Data Safety Monitoring Board: XyloCor; Research grants; Boston Scientific, AstraZeneca; The University of Glasgow (employer, C Berry) holds research and/or consultancy agreements with AstraZeneca, Abbott Vascular, Boehringer Ingelheim, GSK, HeartFlow, Novartis and Siemens Healthcare; Francois Roubille: Advisory Board: Abbott, Air liquide, Research grants; Boston Scientific, AstraZeneca. Consultancy agreements with AstraZeneca, Abbott Vascular, Air liquide, Amgen, Boehringer Ingelheim, GSK, MSD, Novartis, Sanofi, Novartis, Novonordisk, Vifor; Geraud Souteyrand: Consultancy agreements; Medtronic, Abbott, and Terumo; Guillaume Cayla: Consultancy agreements; Astra Zeneca, Amgen, Abbot Vascular, BMS, Boston, Biotronik, Medtronic, Pfizer, and Sanofi; Nicolas Delarche: Advisory board: Novartis; Samer Mansour: Consultant/Advisory board/Speaker’s Bureau: Abbott vascular, Soundbite, Boehringer Ingelheim, AstraZeneca, Bayer, BMS-Pfizer Alliance, Medtronic, Amgen, Sanofi, Servier, Gilead and Novartis; Erick Schampaert: Consultant/Advisory board/Speaker’s Bureau: Abbott, AstraZeneca, Bayer, BMS-Pfizer Alliance, Medtronic, Philips-Volcano, Servier; Loic Belle: Research Grant: AstraZeneca, Medtronic, Biotronic, Boston Scientific, Abbott Vascular, Terumo Ethics Approval Statement: The protocol complied with the Declaration of Helsinki and was approved by IRB at each participating centers. The trial was coordinated by the Montreal Health Innovation Coordinating Centre under the direction of the executive committee, which was responsible for trial conduct, the integrity of the data analysis, and the reporting of results.

Background Primary percutaneous coronary intervention is used to restore blood flow in the infarct-related coronary artery, followed by immediate stenting to prevent reocclusion. Stents implanted in thrombus-laden arteries cause distal embolization, which paradoxically impairs myocardial reperfusion and ventricular function. Whether a strategy of delayed stenting improves outcomes in patients with acute ST-elevation myocardial infarction (STEMI) is uncertain. Methods The Primary Reperfusion Secondary Stenting (PRIMACY) is a Bayesian prospective, randomized, open-label, blinded end point trial in which delayed vs immediate stenting in patients with STEMI were compared for prevention of cardiovascular death, nonfatal myocardial infarction, heart failure, or unplanned target vessel revascularization at 9 months. All participants were immediately reperfused, but those assigned to the delayed arm underwent stenting after an interval of 24 to 48 hours. This interval was bridged with antithrombin therapy to reduce thrombus burden. In the principal Bayesian hierarchical random effects analysis, data from exchangeable trials will be combined into a study prior and updated with PRIMACY into a posterior probability of efficacy. Results A total of 305 participants were randomized across 15 centres in France and Canada between April 2014 and September 2017. At baseline, the median age of participants was 59 years, 81% were male, and 3% had a history of percutaneous coronary intervention. Results from PRIMACY will be updated from the patient-level data of 1568 participants enrolled in the Deferred Stent Trial in STEMI (DEFER; United Kingdom), Minimalist Immediate Mechanical Intervention (MIMI; France), Danish Trial in Acute Myocardial Infarction-3 (DANAMI-3; Denmark), and Impact of Immediate Stent Implantation Versus Deferred Stent Implantation on Infarct Size and Microvascular Perfusion in Patients With ST Segment–Elevation Myocardial Infarction (INNOVATION, South Korea) trials. Conclusions We expect to clarify whether delayed stenting can safely reduce the occurrence of adverse cardiovascular end points compared with immediate stenting in patients with STEMI.

Background Respiratory tract infections are frequent causes of hospitalization and initiation of empirical antimicrobial therapy. Testing for a broad panel of respiratory viruses has been advocated as a useful tool for antibiotic stewardship. We conducted a prospective observational study to assess the impact of rapid viral test results on antimicrobial prescriptions and clinical outcomes among hospitalized adults. Methods Eight hundred patients admitted with respiratory symptoms were tested by a 12-virus respiratory panel (RVP) during 3 consecutive winters in Montreal, Canada. The primary outcome measure was change in antimicrobial prescriptions (ie, de-escalation of empirical antimicrobial therapy or commencement of new antimicrobial therapy) after RVP results were available. Clinical outcomes were also assessed. Results Influenza virus was identified in 53% of individuals in the study population, and other viruses were identified in 10%. Influenza virus positivity was associated with shorter duration of hospitalization and appropriate antiviral management. Antibiotic management was most significantly correlated with radiographic suspicion of pneumonia and less so with results of the RVP. Positivity for viruses other than influenza virus was not correlated with significantly different outcomes. Conclusions Physicians respond to results of testing for influenza virus when managing hospitalized adult patients but respond less to test results for other viruses. These data can inform the design of stewardship interventions and the selection of viral testing panels for hospitalized patients.

Using a milk sample for pregnancy diagnosis in dairy cattle is extremely convenient due to the low technical inputs required for collection of biological materials. Determining accuracy of a novel pregnancy diagnostic test that relies on a milk sample is, however, difficult since no gold standard test is available for comparison. The objective of the current study was to estimate diagnostic accuracy of the milk PAG-based ELISA and of transrectal ultrasonographic (TUS) exam for determining pregnancy status of individual dairy cows using a methodology suited for test validation in the absence of gold standard. Secondary objectives were to evaluate whether test accuracy varies with cow's characteristics and to identify the optimal ELISA optical density threshold for PAG test interpretation. Cows (n=519) from 18 commercial dairies tested with both TUS and PAG between 28 and 45days following breeding were included in the study. Other covariates (number of days since breeding, parity, and daily milk production) hypothesized to affect TUS or PAG test accuracy were measured. A Bayesian hierarchical latent class model (LCM) methodology assuming conditional independence between tests was used to obtain estimates of tests' sensitivities (Se) and specificities (Sp), to evaluate impact of covariates on these, and to compute misclassification costs across a range of ELISA thresholds. Very little disagreement was observed between tests with only 23 cows yielding discordant results. Using the LCM model with non-informative priors for tests accuracy parameters, median (95% credibility intervals [CI]) TUS Se and Sp estimates of 0.96 (0.91, 1.00) and 0.99 (0.97, 1.0) were obtained. For the PAG test, median (95% CI) Se of 0.99 (0.98, 1.00) and Sp of 0.95 (0.89, 1.0) were observed. The impact of adjusting for conditional dependence between tests was negligible. Test accuracy of the PAG test varied slightly by parity number. When assuming false negative to false positive costs ratio≥3:1, the optimal ELISA optical density threshold allowing minimization of misclassification costs was 0.25. In conclusion, both TUS and PAG showed excellent accuracy for pregnancy diagnosis in dairy cows. When using the PAG test, a threshold of 0.25 could be used for test interpretation.

BACKGROUND: Increased risk of progression from latent tuberculosis infection (LTBI) to tuberculosis (TB) disease among people living with human immunodeficiency virus (HIV; PLWH) prioritizes them for LTBI testing and treatment. Studies comparing the performance of interferon gamma release assays (IGRAs) and the tuberculin skin test (TST) among PLWH are lacking. METHODS: We used Bayesian latent class analysis to estimate the prevalence of LTBI and diagnostic characteristics of the TST, QuantiFERON Gold In-Tube (QFT), and T.SPOT-TB (TSPOT) among a prospective, multicenter cohort of US-born PLWH ≥5 years old with valid results for all 3 LTBI tests using standard US cutoffs (≥5 mm TST, ≥0.35 IU/mL QFT, ≥8 spots TSPOT). We also explored the performance of varying LTBI test cutoffs. RESULTS: Among 1510 PLWH (median CD4+ count 532 cells/mm(3)), estimated LTBI prevalence was 4.7%. TSPOT was significantly more specific (99.7%) and had a significantly higher positive predictive value (90.0%, PPV) than QFT (96.5% specificity, 50.7% PPV) and TST (96.8% specificity, 45.4% PPV). QFT was significantly more sensitive (72.2%) than TST (54.2%) and TSPOT (51.9%); negative predictive value of all tests was high (TST 97.7%, QFT 98.6%, TSPOT 97.6%). Even at the highest cutoffs evaluated (15 mm TST, ≥1.00 IU/mL QFT, ≥8 spots TSPOT), TST and QFT specificity was significantly lower than TSPOT. CONCLUSIONS: LTBI prevalence among this cohort of US-born PLWH was low compared to non-US born persons. TSPOT’s higher PPV may make it preferable for testing US-born PLWH at low risk for TB exposure and with high CD4+ counts.

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 symptoms LF‐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 tuberculosis LF‐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., Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV Why is improving the diagnosis of tuberculosis important? Tuberculosis causes more deaths in people living with HIV than any other disease. The lateral flow urine lipoarabinomannan assay (LF‐LAM, Alere Determine™ TB LAM Ag assay) is a World Health Organization‐recommended rapid test to assist in detection of active tuberculosis in HIV‐positive people with severe HIV disease. Rapid and early tuberculosis diagnosis may allow for prompt treatment and alleviate severe illness and death. An incorrect tuberculosis diagnosis may result in anxiety and unnecessary treatment. What is the aim of this review? To find out how accurate LF‐LAM is for diagnosing tuberculosis in HIV‐positive people with tuberculosis symptoms (symptomatic participants) and those not assessed for tuberculosis symptoms (unselected participants). This is an update of the 2016 Cochrane Review. What was studied in this review? LF‐LAM is a commercially available point‐of‐care test that detects lipoarabinomannan (LAM), a component of the bacterial cell walls, present in some people with active tuberculosis. The test is simple and shows results in 25 minutes. LF‐LAM results were measured against culture or molecular tests (benchmark). What are the main results of this review? Fifteen studies: eight studies evaluated LF‐LAM for tuberculosis among symptomatic participants and seven studies among unselected participants. All studies were conducted in low‐ or middle‐income countries. Tuberculosis diagnosis among symptomatic participants: LF‐LAM registered positive in 42% (sensitivity) of people who actually had tuberculosis and did not register positive in 91% of people who were actually negative (specificity). Tuberculosis diagnosis among unselected participants: LF‐LAM sensitivity was 35% and specificity 95%. How confident are we in the review’s results? Several studies excluded participants who could not produce sputum and most studies relied on a lower quality benchmark. Few studies and participants were included in some analyses and only one study was conducted outside of sub‐Saharan Africa. Results should be interpreted with caution. What do the results mean? Among symptomatic participants, in theory, 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). Among unselected participants, in theory, 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). Who do the review’s results apply to? HIV‐positive people with tuberculosis symptoms and those not assessed for tuberculosis symptoms. What are the implications of this review? LF‐LAM has sensitivity around 40% to detect tuberculosis. As the test does not require sputum collection, LF‐LAM may be the only way to diagnose tuberculosis when sputum cannot be produced. How up‐to‐date is this review? To 11 May 2018.

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 detection Of 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 detection Xpert 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., Xpert MTB/RIF and Xpert Ultra for diagnosing pulmonary tuberculosis and rifampicin resistance in adults Why is improving the diagnosis of pulmonary tuberculosis important? Tuberculosis causes more deaths globally than any other infectious disease. When detected early and effectively treated, tuberculosis is largely curable, but in 2017, around 1.6 million people died of tuberculosis. Xpert MTB/RIF and Xpert Ultra, the newest version, are World Health Organization‐recommended tests that simultaneously detect tuberculosis and rifampicin resistance in persons with tuberculosis symptoms. Rifampicin is an important anti‐tuberculosis drug. Not recognizing tuberculosis early may result in delayed diagnosis and treatment, severe illness, and death. An incorrect tuberculosis diagnosis may result in anxiety and unnecessary treatment. What is the aim of this review? To determine how accurate Xpert MTB/RIF and Xpert Ultra are for diagnosing pulmonary tuberculosis (PTB) and rifampicin resistance in adults. This is an update of the 2014 Cochrane Review. What was studied in this review? Xpert MTB/RIF and Xpert Ultra, with results measured against culture (benchmark). What are the main results in this review? 95 studies: 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis; 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert Ultra and Xpert MTB/RIF. For PTB, Xpert MTB/RIF was sensitive (85%), registering positive in people who actually had tuberculosis, and specific (98%), i.e. it did not register positive in people who were actually negative. Xpert Ultra had higher sensitivity than Xpert MTB/RIF (88% versus 83%) in one study. For rifampicin resistance, Xpert MTB/RIF was highly sensitive (96%) and specific (98%). Xpert Ultra gave similar results. Xpert MTB/RIF was better for diagnosing tuberculosis in HIV‐negative than in HIV‐positive people. How confident are we in the results of this review? Confident. We included many studies and used the best reference standards. Who do the results of this review apply to? People with presumed PTB or rifampicin resistance. What are the implications of this review? In theory, among 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). Among 1000 people where 100 have rifampicin resistance, 114 would be positive for rifampicin resistance and 18 (16%) would not have rifampicin resistance (false‐positives); 886 would be negative for rifampicin resistance and four (0.4%) would have rifampicin resistance (false‐negatives). How up‐to‐date is this review? To 11 October 2018.

Paratuberculosis is a worldwide infectious disease caused by Mycobacterium avium ssp. paratuberculosis (MAP). Various ruminant species can be affected by the disease, and the diagnosis of the disease is challenging in the absence of a gold standard test. The aim of this systematic review protocol is to determine the accuracy of the direct and indirect diagnostic tests for MAP infection with a special focus on sheep and goats.

BACKGROUND To address patient-level barriers to living-donor kidney transplantation (LDKT), centers have implemented educational interventions. Recently, some have highlighted several gaps in knowledge and lack of evidence of efficacy of these interventions. No review has synthesized the available data. METHODS We conducted a systematic review and meta-analysis of studies conducted to increase measures of LDKT. Outcomes of interest were LDKT rates, donor evaluation, donor contact/inquiry, total transplantation rates, and change in knowledge scores and pursuit behaviors. A literature search was conducted across 7 databases from inception until 2017. Educational interventions were a decision/teaching aid alone or with personalized sessions. Comparator was another intervention or nonspecific education. Random effects meta-analysis was performed to pool risk ratios (RRs) across studies. RESULTS Of the 1813 references, 15 met the inclusion criteria; 9 were randomized control trials. When compared with nonspecific education, interventions increased LDKT rates (RR = 2.54; 95% confidence interval [CI], 1.49-4.35), donor evaluation (RR = 3.82; 95% CI, 1.91-7.64), and donor inquiry/contact (RR = 2.41; 95% CI, 1.53-3.80), but not total transplants (RR = 1.24; 95% CI, 0.96-1.61). Significant increased mean knowledge scores postintervention was noted, and most showed favorable trends in pursuit behaviors. Quality across the studies was mixed and sometimes difficult to assess. The biggest limitations were small sample size, selection bias, and short follow-ups. CONCLUSIONS Educational interventions improve measures of LDKT activity; however, current literature is heterogeneous and at risk of selection bias. Prospective studies with diverse patient populations, longer follow-ups, and robust outcomes are needed to inform clinical practice.

Importance Cannabis is the most commonly used drug of abuse by adolescents in the world. While the impact of adolescent cannabis use on the development of psychosis has been investigated in depth, little is known about the impact of cannabis use on mood and suicidality in young adulthood. Objective To provide a summary estimate of the extent to which cannabis use during adolescence is associated with the risk of developing subsequent major depression, anxiety, and suicidal behavior. Data Sources Medline, Embase, CINAHL, PsycInfo, and Proquest Dissertations and Theses were searched from inception to January 2017. Study Selection Longitudinal and prospective studies, assessing cannabis use in adolescents younger than 18 years (at least 1 assessment point) and then ascertaining development of depression in young adulthood (age 18 to 32 years) were selected, and odds ratios (OR) adjusted for the presence of baseline depression and/or anxiety and/or suicidality were extracted. Data Extraction and Synthesis Study quality was assessed using the Research Triangle Institute item bank on risk of bias and precision of observational studies. Two reviewers conducted all review stages independently. Selected data were pooled using random-effects meta-analysis. Main Outcomes and Measures The studies assessing cannabis use and depression at different points from adolescence to young adulthood and reporting the corresponding OR were included. In the studies selected, depression was diagnosed according to the third or fourth editions of Diagnostic and Statistical Manual of Mental Disorders or by using scales with predetermined cutoff points. Results After screening 3142 articles, 269 articles were selected for full-text review, 35 were selected for further review, and 11 studies comprising 23 317 individuals were included in the quantitative analysis. The OR of developing depression for cannabis users in young adulthood compared with nonusers was 1.37 (95% CI, 1.16-1.62; I2 = 0%). The pooled OR for anxiety was not statistically significant: 1.18 (95% CI, 0.84-1.67; I2 = 42%). The pooled OR for suicidal ideation was 1.50 (95% CI, 1.11-2.03; I2 = 0%), and for suicidal attempt was 3.46 (95% CI, 1.53-7.84, I2 = 61.3%). Conclusions and Relevance Although individual-level risk remains moderate to low and results from this study should be confirmed in future adequately powered prospective studies, the high prevalence of adolescents consuming cannabis generates a large number of young people who could develop depression and suicidality attributable to cannabis. This is an important public health problem and concern, which should be properly addressed by health care policy.

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.