Search

Rationale: Interferon gamma (IFN-γ) release assays for latent tuberculosis infection result in a larger-than-expected number of conversions and reversions in occupational screening programs, and reproducibility of test results is a concern.Objectives: Knowledge of the relative contribution and extent of the individual sources of variability (immunological, preanalytical, or analytical) could help optimize testing protocols.Methods: We performed a systematic review of studies published by October 2013 on all potential sources of variability of commercial IFN-γ release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB). The included studies assessed test variability under identical conditions and under different conditions (the latter both overall and stratified by individual sources of variability). Linear mixed effects models were used to estimate within-subject SD.Measurements and Main Results: We identified a total of 26 articles, including 7 studies analyzing variability under the same conditions, 10 studies analyzing variability with repeat testing over time under different conditions, and 19 studies reporting individual sources of variability. Most data were on QuantiFERON (only three studies on T-SPOT.TB). A considerable number of conversions and reversions were seen around the manufacturer-recommended cut-point. The estimated range of variability of IFN-γ response in QuantiFERON under identical conditions was ±0.47 IU/ml (coefficient of variation, 13%) and ±0.26 IU/ml (30%) for individuals with an initial IFN-γ response in the borderline range (0.25-0.80 IU/ml). The estimated range of variability in noncontrolled settings was substantially larger (±1.4 IU/ml; 60%). Blood volume inoculated into QuantiFERON tubes and preanalytic delay were identified as key sources of variability.Conclusions: This systematic review shows substantial variability with repeat IFN-γ release assays testing even under identical conditions, suggesting that reversions and conversions around the existing cut-point should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Introduction: Interferon ? release assays (IGRAs) are increasingly used for tuberculosis (TB) infection, but their incremental value beyond patient demographics, clinical signs and conventional tests for active disease has not been evaluated in children. Methods: The incremental value of T-SPOT.TB was assessed in 491 smear-negative children from two hospitals in Cape Town, South Africa. Bayesian model averaging was used to select the optimal set of patient demographics and clinical signs for predicting culture-confirmed TB. The added value of T-SPOT.TB over and above patient characteristics and conventional tests was measured using statistics such as the difference in the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI). Results: Cough longer than 2 weeks, fever longer than 2 weeks, night sweats, malaise, history of household contact and HIV status were the most important predictors of culture-confirmed TB. Binary T-SPOT.TB results did not have incremental value when added to the baseline model with clinical predictors, chest radiography and the tuberculin skin test. The AUC difference was 3% (95% CI 0% to 7%). Using risk cut-offs of <10%, 10-30% and >30%, the NRI was 7% (95% CI -8% to 31%) but the CI included the null value. The IDI was 3% (95% CI 0% to 11%), meaning that the average predicted probability across all possible cut-offs improved marginally by 3%. Conclusions: In a high-burden setting, the T-SPOT.TB did not have added value beyond clinical data and conventional tests for diagnosis of TB disease in smear-negative children. [ABSTRACT FROM AUTHOR]

Abstract: Infections due to meticillin-resistant Staphylococcus aureus (MRSA) pose a serious health risk. Novel methods for assessing comparative effectiveness and safety may provide valuable insights into therapeutic choices. We did a systematic review searching electronic databases including the archives of FDA/CDER and performed a Bayesian network meta-analysis to compare parenteral antibiotics used for treating hospitalised adults with complicated skin and soft-tissue infections (cSSTIs) or hospital-acquired or ventilator-associated pneumonia (HAP/VAP). Models were adjusted for clinical heterogeneity due to between-arm differences in the proportion of patients with diabetes (for cSSTI) and in those requiring mechanical ventilation (for pneumonia). Treatments were ranked on efficacy, defined as clinical success in the modified intention-to-treat population (MITT) and in the MITT population with MRSA at baseline (MRSA m-MITT), on all-cause mortality (in pneumonia only), and on serious adverse events and withdrawals due to adverse events. We identified 24 randomised controlled trials (17 for cSSTI and 10 for HAP/VAP) comparing one of six antibiotics with vancomycin. The network meta-analysis indicated that vancomycin ranked third (of six antibiotics) in cSSTI and second (of four) in pneumonia on both efficacy and safety. However, direct pairwise meta-analyses remained inconclusive as evidenced by the adjusted median odds ratios (ORs) and their 95% credible intervals. In cSSTI, linezolid and ceftaroline were non-significantly more effective than vancomycin. Linezolid ORs were 1.15 (0.74–1.71) and 1.01 (0.42–2.14) and ceftaroline ORs were 1.12 (0.78–1.64) and 1.59 (0.68–3.74) in the MITT and MRSA m-MITT populations, respectively. For HAP/VAP, linezolid was non-significantly better than vancomycin, with ORs of 1.05 (0.72–1.57) and 1.32 (0.71–2.48) in the MITT and MRSA m-MITT populations, respectively. We suspect performance and detection bias in cSSTI trials involving linezolid, but regression methods could not adjust for this potential bias. In these clinical trials, the preferred agents for treating serious MRSA infections were ceftaroline (for cSSTI, not studied in HAP/VAP) and linezolid. However, translation of these findings into practice should consider the small size of the evidence networks and the consequent uncertainty associated with the parameter estimates, the lack of evidence for ceftaroline in patients with severe renal impairment, and the lower internal validity of some of the linezolid trials. [Copyright &y& Elsevier]

Absence of a perfect reference test is an acknowledged source of bias in diagnostic studies. In the case of tuberculous pleuritis, standard reference tests such as smear microscopy, culture and biopsy have poor sensitivity. Yet meta-analyses of new tests for this disease have always assumed the reference standard is perfect, leading to biased estimates of the new test's accuracy. We describe a method for joint meta-analysis of sensitivity and specificity of the diagnostic test under evaluation, while considering the imperfect nature of the reference standard. We use a Bayesian hierarchical model that takes into account within- and between-study variability. We show how to obtain pooled estimates of sensitivity and specificity, and how to plot a hierarchical summary receiver operating characteristic curve. We describe extensions of the model to situations where multiple reference tests are used, and where index and reference tests are conditionally dependent. The performance of the model is evaluated using simulations and illustrated using data from a meta-analysis of nucleic acid amplification tests (NAATs) for tuberculous pleuritis. The estimate of NAAT specificity was higher and the sensitivity lower compared to a model that assumed that the reference test was perfect. [ABSTRACT FROM AUTHOR]

The article discusses the typology of disease verification problems encountered in diagnostic accuracy studies as well as the solutions for associated biases. It says that the biases may be caused by the impossibility of disease verification using single reference standard. It tackles various diagnostic accuracy study situations which depict complete, partial, and differential verifications. It states that partial verification is associated with various types of biases such as work-up, partial verification, and referral biases. It explores the Bayesian correction method for differential bias adjustment and imperfect multiple reference tests. It recommends using correction methods even with small missing verification data rates which could still lead to biased accuracy index test estimates.

In studies of diagnostic accuracy, the performance of an index test is assessed by verifying its results against those of a reference standard. If verification of index-test results by the preferred reference standard can be performed only in a subset of subjects, an alternative reference test could be given to the remainder. The drawback of this so-called differential-verification design is that the second reference test is often of lesser quality, or defines the target condition in a different way. Incorrectly treating results of the 2 reference standards as equivalent will lead to differential-verification bias. The Bayesian methods presented in this paper use a single model to (1) acknowledge the different nature of the 2 reference standards and (2) make simultaneous inferences about the population prevalence and the sensitivity, specificity, and predictive values of the index test with respect to both reference tests, in relation to latent disease status. We illustrate this approach using data from a study on the accuracy of the elbow extension test for diagnosis of elbow fractures in patients with elbow injury, using either radiography or follow-up as reference standards. [ABSTRACT FROM AUTHOR]

Background: Multiple randomized controlled trials (RCTs) have examined the cardiovascular effects of omega-3 fatty acids and have provided unexplained conflicting results. A meta-analysis of these RCTs to estimate efficacy and safety and potential sources of heterogeneity may be helpful. Methods: The Cochrane library, MEDLINE, and EMBASE were systematically searched to identify all interventional trials of omega-3 fatty acids compared to placebo or usual diet in high-risk cardiovascular patients. The primary outcome was all-cause mortality and secondary outcomes were coronary restenosis following percutaneous coronary intervention and safety. Meta-analyses were carried out using Bayesian random-effects models, and heterogeneity was examined using meta-regression. Results: A total of 29 RCTs (n = 35,144) met our inclusion criteria, with 25 reporting mortality and 14 reporting restenosis. Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR] = 0.88, 95% Credible Interval [CrI] = 0.64, 1.03) or with restenosis prevention (RR = 0.89, 95% CrI = 0.72, 1.06), though the probability of some benefit remains high (0.93 and 0.90, respectively). However in meta-regressions, there was a >90% probability that larger studies and those with longer follow-up were associated with smaller benefits. No serious safety issues were identified. Conclusions: Although not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis. However, caution must be exercised in interpreting these benefits as results were attenuated in higher quality studies, suggesting that bias may be at least partially responsible. Additional high quality studies are required to clarify the role of omega-3 fatty acid supplementation for the secondary prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background Clopidogrel is an antiplatelet drug that is prescribed after percutaneous coronary intervention (PCI) to prevent stent thrombosis. Previous studies have suggested that some statins may inhibit the antiplatelet effects of clopidogrel via competitive metabolism of its activating enzyme cytochrome P450 3A4 (CYP3A4). Objectives To investigate a possible interaction between statins and clopidogrel after a PCI procedure in a population-based cohort study. Methods A population-based cohort study was carried out between January 2001 and December 2004 using the health insurance databases from Quebec, Canada. The primary endpoint was a composite of death from any cause, myocardial infarction (MI), unstable angina, repeat revascularization and cerebrovascular events. PCI patients ≥ 66 years of age were followed from their initial post-discharge clopidogrel prescription until the earliest of study endpoint occurrence, end of clopidogrel exposure or end of study (90 days post discharge). Time-dependent Cox regression analysis was performed. Results We identified 10 491 patients who were prescribed clopidogrel post-PCI and 43.5% were also prescribed statins at the baseline discharge. During 1793 patient years of follow-up, 623 composite endpoints were observed. Compared to the reference group (non-CYP3A4-metabolized statins), the co-prescription of CYP3A4-metabolized statins (hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.47), or no statin use (HR 1.22, 95%CI 0.93-1.59) were not statistically associated with an increase in adverse outcomes. Conclusions In this PCI cohort, the association of clopidogrel with CYP3A4-metabolized statins did not demonstrate an increased early risk of adverse cardiovascular events, although a small risk could not be completely excluded. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore whether a longitudinal comparison between reported and predicted health could be used as a method of identifying subjects who potentially experienced response shift. A response-shift model was developed using data from a longitudinal study of stroke in which measures of stroke impact were made at study entry and at 1, 3, 6, and 12 months post stroke. Residuals from a random effects model were centered and used to create trajectories. This model was tested against a data set from a study in which the then-test had been administered. Twenty simulated data sets were also generated to examine how much of response shift could be attributed to random error. Group-based trajectory analysis identified seven trajectory groups. The majority (67%) of the 387 persons showed no response shift over time, whereas 15% lowered and 13% raised their health over time, disproportionally to that predicted. Results of the validation studies were supportive that this methodology identifies response shift, but further research is required to compare results with other methodologies and other predictive models. [ABSTRACT FROM AUTHOR]

Background: Testing to determine HER2 status has come into focus since the approval of trastuzumab (Herceptin) for the treatment of HER2-positive breast cancer. We compared the cost-effectiveness of various strategies used to test HER2 status, an important first step toward evaluating the overall cost-effectiveness of trastuzumab therapy. Methods: We performed a systematic review of studies that evaluated concordance between immunohistochemistry and fluorescence in situ hybridization testing to determine HER2 status. We performed a meta-analysis to estimate the distribution of immunohistochemistry scores in each category (0, 1+, 2+, 3+) and the probability of receiving a positive result of fluorescence in situ hybridization (which we assumed to be the "gold-standard" test) for each category. We calculated the accuracy and incremental cost per accurate diagnosis for each testing strategy compared with the base strategy (immunohistochemistry testing, followed by confirmation of 2+ scores by fluorescence in situ hybridization). Results: The median percentage of patients in each category of immunohistochemistry score was: 0, 36.1%; 1+, 35.5%; 2+, 12.0%; and 3+, 16.2%. The median percentage of results of fluorescence in situ hybridization that were positive in each immunohistochemistry category was: 0, 1.6%; 1+, 4.9%; 2+, 29.8%; and 3+, 92.4%. The base strategy was expected to correctly determine the HER2 status of 96% of patients with breast cancer. Confirmation of the HER2 status by fluorescence in situ hybridization in cases that received a score of 3+ reduced the percentage of false-positive results to 0% and increased the percentage of accurately determined HER2 results to 97.6%. Compared with the base strategy, this strategy was associated with a median incremental cost-effectiveness ratio of $6175 per case of accurately determined HER2 status. The strategy of performing fluorescence in situ hybridization testing in all cases of breast cancer was associated with a median incremental cost-effectiveness ratio of $8401 per case of accurately determined HER2 status. Interpretation: The strategy with the lowest cost-effectiveness ratio involved screening all newly diagnosed cases of breast cancer with immunohistochemistry and confirming scores of 2+ or 3+ with fluorescence in situ hybridization testing. [ABSTRACT FROM AUTHOR]

Background: Drug-eluting stents have been seen as an attractive alternative to bare-metal stents for percutaneous coronary interventions (PCIs) because of the decreased need for revascularization. However, comparative clinical trials have shown no difference in patient outcomes, and drug-eluting stents are considerably more expensive than their bare-metal counterparts. We conducted a systematic review of all published comparative cost-effectiveness analyses to identify the factors contributing to the heterogeneity of their conclusions. Methods: We retrieved all articles published between Jan. 1, 2000, and July 31, 2006, in which the cost-effectiveness, from a third-party payer perspective, of drug-eluting stents was compared with that of bare-metal stents for PCI in unrestricted patient populations. Electronic databases, Web sites from health technology assessment groups and references of identified articles were searched. Our outcome variable was whether the study's conclusions favoured widespread use of drug-eluting stents, as assessed by 4 independent reviewers. Study characteristics such as quality, funding source, country and year of publication were extracted. Two-by-2 tables and Fisher's exact test were used to study the association between covariates and the outcome variable. A classification and regression tree (CART) model was used for multivariate analysis. Results: We identified 19 cost-effectiveness analyses. Ten were in favour of widespread use of drug-eluting stents, and 9 favoured more restrained use. Only 1 of 9 high-quality studies supported widespread use, as compared with 9 of 10 lower quality studies (p < 0.001). All of the 7 sponsored studies argued in favour of widespread use, as compared with 3 of the 12 studies without sponsorship (p = 0.003). Studies from the United States were more likely than those from other countries to endorse unlimited use (p = 0.032). A CART model with 2 covariates - study quality and sponsorship - provided the best fit (error rate 10.5%). Interpretation: Conclusions drawn by cost-effectiveness analyses of drug-eluting stents for PCI are associated with the study's quality, funding source and country of origin. Vigilance regarding these study characteristics is required when interpreting findings from cost-effectiveness analyses. [ABSTRACT FROM AUTHOR]

Background Major depression is a frequent and serious disorder in older medical inpatients. Because the condition goes undetected and untreated in most of these patients, we conducted a randomized clinical trial to evaluate the effectiveness of a strategy of systematic detection and multidisciplinary treatment of depression in this population. Methods Consecutive patients aged 65 years or more admitted to general medical services in a primary care hospital between October 1999 and November 2002 were screened for depression with the Diagnostic Interview Schedule (DIS) within 48 hours after admission. Patients found to have major depression were randomly allocated to receive the intervention or usual care. The intervention involved consultation and treatment by a psychiatrist and follow-up by a research nurse and the patient's family physician. Research assistants, blind to group allocation, collected data from the patients at enrolment and at 3 and 6 months later using the Hamilton Depression Rating Scale (HAMD), the Medical Outcomes 36-item Short Form (SF-36), the DIS, the Mini-Mental State Examination (MMSE), the Older Americans Resources and Services (OARS) questionnaire to assess basic and instrumental activities of daily living (OARS-ADL and OARS-IADL) and the Rating Scale for Side Effects. Data on the severity of illness, length of hospital stay, health services and medication use, mortality and process of care were also collected. The primary outcome measures were the HAMD and SF-36. Results Of 1500 eligible patients who were screened, 157 were found to have major depression and consented to participate (78 in the intervention group and 79 in the usual care group). At randomization, there were no clinically or statistically significant differences between the 2 groups. Sixty-four patients completed follow-up to 6 months, 57 withdrew, and 36 died. At 6 months, there were no clinically or statistically significant differences the 2 groups in HAMD or SF-36 scores or any of the secondary outcome measures. Interpretation We were unable to demonstrate that systematic detection and multidisciplinary care of depression was more beneficial than usual care for elderly medical inpatients. [ABSTRACT FROM AUTHOR]

During the past 10 years, medical diagnostic testing for sexually transmitted infections (STIs) has changed markedly as a result of the rapid expansion and marketing of nucleic acid amplification tests (NAATs). Among such new DNA/RNA-amplification techniques are the polymerase chain reaction (PCR), the ligase chain reaction (LCR), and the transcription-mediated amplification (TMA) tests. Regrettably, the test evaluation process undergone by these tests has not always been rigorous or scientifically sound. Here, we review the controversy surrounding the statistical evaluation of these NAATs. We also review some of the traditional and recent statistical methods developed to estimate test sensitivity and specificity parameters in the absence of reliable gold-standard tests. In particular, we review the traditional latent class modeling approach that requires the assumption of independence between diagnostic tests conditional on the true disease status, and the more recent procedures that relax the conditional independence assumption. Finally, we apply some of these statistical modeling techniques to real data to estimate the sensitivity and specificity of a NAAT for Chlamydia trachomatis. On the basis of the latent class modeling approach with a pessimistic prior for culture sensitivity, the NAAT specificity estimate was 97.6% and, on the basis of an optimistic prior, the specificity was 95.3%. Similarly, the sensitivity estimates ranged from 88.1% to 89.6%. [ABSTRACT FROM AUTHOR]

Preeclampsia (PrE) is a leading complication of pregnancy characterized by vascular dysfunction. Characterizing the longitudinal changes in vascular function prior to PrE onset is critical to the identification of optimal timepoints for vascular assessment and the development of effective early screening strategies. In this prospective longitudinal study of women with singleton high-risk pregnancies, arterial stiffness and wave reflection parameters were assessed using applanation tonometry at 10–13 weeks' gestation and repeated every 4 weeks throughout pregnancy. Changepoints in carotid-femoral pulse wave velocity (cfPWV), carotid-radial PWV (crPWV), augmentation index (AIx), time to wave reflection (T 1R), pulse pressure amplification (PPA), and subendocardial viability ratio (SEVR) were compared between women who did and did not subsequently develop PrE. A changepoint in cfPWV and crPWV was detected at 14–17 weeks' gestation. cfPWV then increased in women who went on to develop PrE but decreased in women who did not; a 1.2 m/s difference in cfPWV between the groups was observed at 22–25 weeks' gestation. Conversely, crPWV converged in the two groups from a baseline difference of 1.05 m/s (95% credible interval: 0.37, 1.72). Women who subsequently developed PrE demonstrated an increase in AIx at 18–21 weeks' gestation that was not seen in women who did not develop PrE until 30–33 weeks. No differences in T 1R , PPA, or SEVR were observed between the groups. Altered vascular adaptations were detected using measures of arterial stiffness and wave reflection in the early second trimester of pregnant women who developed PrE compared to those who did not. These findings demonstrate the potential clinical utility of arterial stiffness and wave reflection parameters as an early screening tool for PrE, which can be used to inform clinical management of high-risk pregnancies. • Altered vascular adaptations in women with PrE were noted early in the second trimester. • A changepoint in cfPWV was detected at 14–17 weeks. • cfPWV was higher by 1.2 m/s at 22–25 weeks in women who developed PrE. • AIx increased at 18–21 weeks in women with PrE, while at 30–33 weeks in those without. [ABSTRACT FROM AUTHOR]

Background Omalizumab is an anti-immunoglobulin E monoclonal antibody used to treat moderate to severe chronic idiopathic urticaria, asthma, and nasal polyps. Recent research suggested that omalizumab may enhance the innate antiviral response and have anti-inflammatory properties. Objective We aimed to investigate the efficacy and safety of omalizumab in adults hospitalized for coronavirus disease 2019 (COVID-19) pneumonia. Methods This was a phase II randomized, double blind, placebo-controlled trial comparing omalizumab with placebo (in addition to standard of care) in hospitalized patients with COVID-19. The primary endpoint was the composite of mechanical ventilation and/or death at day 14. Secondary endpoints included all-cause mortality at day 28, time to clinical improvement, and duration of hospitalization. Results Of 41 patients recruited, 40 were randomized (20 received the study drug and 20 placebo). The median age of the patients was 74 years and 55.0% were male. Omalizumab was associated with a 92.6% posterior probability of a reduction in mechanical ventilation and death on day 14 with an adjusted odds ratio of 0.11 (95% credible interval 0.002-2.05). Omalizumab was also associated with a 75.9% posterior probability of reduced all-cause mortality on day 28 with an adjusted odds ratio of 0.49 (95% credible interval, 0.06-3.90). No statistically significant differences were found for the time to clinical improvement and duration of hospitalization. Numerically fewer adverse events were reported in the omalizumab group and there were no drug-related serious adverse events. Conclusions These results suggest that omalizumab could prove protective against death and mechanical ventilation in hospitalized patients with COVID-19. This study could also support the development of a phase III trial program investigating the antiviral and anti-inflammatory effect of omalizumab for severe respiratory viral illnesses requiring hospital admission. ClinicalTrials.gov ID: NCT04720612 [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Serodiagnosis of Tuberculosis in Asian Elephants (Elephas maximus) in Southern India: A Latent Class Analysis." The correction addresses an issue with the ponceau loading control panels in Figure 1F and 1L, which appear more similar than expected. The original uncropped images are no longer available, but replicate data is provided. The authors also provide an updated version of Figure 1 with replicate image data and original uncropped images for Western blotting and ponceau staining. The raw data for Figure 1G and the summary results in Tables 1-3 are no longer available, but the original underlying data for all other results in the article and supporting information files are available. The authors apologize for the error. [Extracted from the article]

Background: Clinical and laboratory diagnosis of cutaneous leishmaniasis (CL) is hampered by under-ascertainment of direct microscopy. Methods: This study compared the diagnostic accuracy of qPCR on DNA extracted from filter paper to the accuracy of direct smear slide microscopy in participants presenting with a cutaneous lesion suspected of leishmaniasis to 16 rural healthcare centers in the Ecuadorian Amazon and Pacific regions, from January 2019 to June 2021. We used Bayesian latent class analysis to estimate test sensitivity, specificity, likelihood ratios (LR), and predictive values (PV) with their 95% credible intervals (95%CrI). The impact of sociodemographic and clinical characteristics on predictive values was assessed as a secondary objective. Results: Of 320 initially included participants, paired valid test results were available and included in the diagnostic accuracy analysis for 129 from the Amazon and 185 from the Pacific region. We estimated sensitivity of 68% (95%CrI 49% to 82%) and 73% (95%CrI 73% to 83%) for qPCR, and 51% (95%CrI 36% to 66%) and 76% (95%CrI 65% to 86%) for microscopy in the Amazon and Pacific region, respectively. In the Amazon, with an estimated disease prevalence among participants of 73%, negative PV for qPCR was 54% (95%CrI 5% to 77%) and 44% (95%CrI 4% to 65%) for microscopy. In the Pacific, (prevalence 88%) the negative PV was 34% (95%CrI 3% to 58%) and 37% (95%CrI 3% to 63%). The addition of qPCR parallel to microscopy in the Amazon increases the observed prevalence from 38% to 64% (+26 (95%CrI 19 to 34) percentage points). Conclusion: The accuracy of either qPCR on DNA extracted from filter paper or microscopy for CL diagnosis as a stand-alone test seems to be unsatisfactory and region-dependent. We recommend further studies to confirm the clinically relevant increment found in the diagnostic yield due to the addition of qPCR. Author summary: Cutaneous leishmaniasis is caused by the parasite Leishmania and is treated when a microscopy test confirms the presence of the parasite in a sample of the lesion. This test, however, is known to miss patients with cutaneous leishmaniasis. DNA diagnostic tests (like PCR) that detect the parasite's genetic material in the lesion, have been proposed to improve diagnosis. Filter paper preserves DNA at room temperature and allows samples to be transported from remote health centers to the PCR laboratory. The ability of microscopic and DNA testing to recognize leishmaniasis patients in real-life is complex to evaluate. We compared the performance of both tests using a statistical method that can evaluate both tests simultaneously without assuming that either test works perfectly. We found that PCR will be positive 68% of the time in a participant with leishmaniasis in the Amazon and 73% of the time in the Pacific region. In the Amazon, microscopy detects one out of every two cases, while it does in three out of every four cases in the Pacific. The addition of the PCR test can improve the number of participants with a diagnosis of leishmaniasis, mostly in the Amazon region. [ABSTRACT FROM AUTHOR]

Background Streptococcus pneumoniae (SP) pneumonia is often treated empirically as diagnosis is challenging because of the lack of a perfect test. Using BinaxNOW-SP, a urinary antigen test, as an add-on to standard cultures may not only increase diagnostic yield but also increase costs. Objective To estimate the sensitivity and specificity of BinaxNOW-SP and subsequently estimate the cost-effectiveness of adding BinaxNOW-SP to the diagnostic work-up. Design We fit a Bayesian latent-class meta-analysis model to obtain estimates of BinaxNOW-SP accuracy that adjust for the imperfect accuracy of culture. Meta-analysis results were combined with information on prevalence of SP pneumonia to estimate the number of patients who are correctly classified under competing diagnostic strategies. Taking into consideration the cost of antibiotics, we determined the incremental cost of adding BinaxNOW-SP to the work-up per case correctly diagnosed. Results The BinaxNOW-SP test had a pooled sensitivity of 0.74 (95% credible interval [CrI], 0.67-0.83) and a pooled specificity of 0.96 (95% CrI, 0.92-0.99). An overall increase in diagnostic accuracy of 6.2% due to the addition of BinaxNOW-SP corresponded to an incremental cost per case correctly classified of $582 Canadian dollars. Conclusions The methods we have described allow us to evaluate the accuracy and economic value of a new test in the absence of a perfect reference test using an evidence-based approach. [ABSTRACT FROM AUTHOR]

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 in <90 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 1&2 Direct Kit PCR. Real-time PCR assay. Two investigators independently extracted data, rated risk of bias, and assessed quality using QUADAS-2. 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. [ABSTRACT FROM AUTHOR]

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

Background: Confirmation of sepsis by standard blood cultures (STD) is often inconclusive due to slow growth and low positivity. Molecular diagnostics (MOL) are faster and may have higher positivity, but test performance can be inaccurately estimated if STD methods are used as comparators. Bayesian latent class models (LCMs) can evaluate diagnostic methods when there is no "gold standard." Intensive care unit studies that have used LCMs to combine and compare STD and MOL method performance and estimate the prevalence of sepsis have not been described. Patients and methods: Results from an ICU sepsis study that used both tests simultaneously were analyzed. Bayesian LCMs combined prior prevalence of sepsis, prior diagnostic characteristics of the two methods, and the study results to estimate the posterior prevalence and diagnostic characteristics. Sensitivity analyses were performed using objective (published studies) and subjective (expert opinion) prior parameters. Positive predictive values (PPVs) of the prevalence of sepsis were estimated for all combinations of test results. Results: The range of posterior estimates was: sepsis prevalence (0.38-0.88), sensitivities (STD: 0.2-0.35, MOL: 0.56-0.86), and specificities (STD: 0.87-0.99, MOL: 0.72-0.95). The PPV (sepsis) of both tests being positive was (0.72-0.99). Conclusion: LCMs combined two imperfect methods to estimate prevalence, PPV, and diagnostic characteristics. The posterior estimates (STD sensitivity < MOL and STD specificity > MOL) seem to reflect the clinical experience appropriately. The high PPV when both methods show positive results can be useful for ruling in disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

Highlights • Higher sensitivity and specificity of fecal culture compared to serum-ELISA. • Very low within herd paratuberculosis prevalence of participant herds. • The importance of assessing conditional dependence between the tests was illustrated. • Conditional dependence between fecal culture and serum-ELISA was observed among infected animals. Abstract A latent class model fit within a Bayesian framework was used to estimate the sensitivity and specificity of individual fecal culture (IFC) in liquid medium (Para TB culture liquid medium and BACTEC MGIT 960 system) for the detection of Mycobacterium avium subsp. paratuberculosis (MAP) infections in Québec dairy cows. As a secondary objective, the within-herd paratuberculosis prevalence was estimated. A dataset including 21 commercial Québec dairy herds participating in previous research projects was retrospectively analyzed. In total, 1386 adult cows on which both IFC and serum-ELISA were available were included. The selected latent class model assumed conditional dependence between the tests. Non-informative priors for IFC accuracy and paratuberculosis prevalence were used while informative priors, obtained from the literature, were used for serum-ELISA accuracy. The WinBUGS statistical freeware was used to obtain posterior estimates (medians and 95% Bayesian credibility intervals (95% BCI)) for each parameter. The sensitivity and specificity estimates for IFC were 34.4% (95% BCI: 20.3–66.1) and 99.5% (95% BCI: 98.6–100), respectively. Sensitivity and specificity for serum-ELISA were 27.3% (95% BCI: 18.1–38.3) and 97.4% (95% BCI: 96.6–98.0). Median paratuberculosis within herd prevalence was estimated to be 0.3% (0–3.3). In conclusion, a higher sensitivity of IFC compared to serum-ELISA was observed both in the unconditional and conditional dependent models. Since the sensitivity of both IFC and serum-ELISA was relatively low, conditional dependence between the tests is more likely in the true disease positive animals. We hypothesize that conditional dependence arises because an unmeasured covariate influences the performance of both tests among disease positive animals causing both tests to incorrectly misclassify the animal as negative. One limitation of this study was the very low within herd prevalence of the participant herds. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Rapid and accurate influenza diagnostics can improve patient care.Purpose: To summarize and compare accuracy of traditional rapid influenza diagnostic tests (RIDTs), digital immunoassays (DIAs), and rapid nucleic acid amplification tests (NAATs) in children and adults with suspected influenza.Data Sources: 6 databases from their inception through May 2017.Study Selection: Studies in English, French, or Spanish comparing commercialized rapid tests (that is, providing results in <30 minutes) with reverse transcriptase polymerase chain reaction reference standard for influenza diagnosis.Data Extraction: Data were extracted using a standardized form; quality was assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) criteria.Data Synthesis: 162 studies were included (130 of RIDTs, 19 of DIAs, and 13 of NAATs). Pooled sensitivities for detecting influenza A from Bayesian bivariate random-effects models were 54.4% (95% credible interval [CrI], 48.9% to 59.8%) for RIDTs, 80.0% (CrI, 73.4% to 85.6%) for DIAs, and 91.6% (CrI, 84.9% to 95.9%) for NAATs. Those for detecting influenza B were 53.2% (CrI, 41.7% to 64.4%) for RIDTs, 76.8% (CrI, 65.4% to 85.4%) for DIAs, and 95.4% (CrI, 87.3% to 98.7%) for NAATs. Pooled specificities were uniformly high (>98%). Forty-six influenza A and 24 influenza B studies presented pediatric-specific data; 35 influenza A and 16 influenza B studies presented adult-specific data. Pooled sensitivities were higher in children by 12.1 to 31.8 percentage points, except for influenza A by rapid NAATs (2.7 percentage points). Pooled sensitivities favored industry-sponsored studies by 6.2 to 34.0 percentage points. Incomplete reporting frequently led to unclear risk of bias.Limitations: Underreporting of clinical variables limited exploration of heterogeneity. Few NAAT studies reported adult-specific data, and none evaluated point-of-care testing. Many studies had unclear risk of bias.Conclusion: Novel DIAs and rapid NAATs had markedly higher sensitivities for influenza A and B in both children and adults than did traditional RIDTs, with equally high specificities.Primary Funding Source: Québec Health Research Fund and BD Diagnostic Systems. [ABSTRACT FROM AUTHOR]

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 45 days 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. [ABSTRACT FROM AUTHOR]

The Standards for the Reporting of Diagnostic Accuracy (STARD) statement, which was recently updated to the STARD2015 statement, was developed to encourage complete and transparent reporting of test accuracy studies. Although STARD principles apply broadly, the checklist is limited to studies designed to evaluate the accuracy of tests when the disease status is determined from a perfect reference procedure or an imperfect one with known measures of test accuracy. However, a reference standard does not always exist, especially in the case of infectious diseases with a long latent period. In such cases, a valid alternative to classical test evaluation involves the use of latent class models that do not require a priori knowledge of disease status. Latent class models have been successfully implemented in a Bayesian framework for over 20 years. The objective of this work was to identify the STARD items that require modification and develop a modified version of STARD for studies that use Bayesian latent class analysis to estimate diagnostic test accuracy in the absence of a reference standard. Examples and elaborations for each of the modified items are provided. The new guidelines, termed STARD-BLCM (Standards for Reporting of Diagnostic accuracy studies that use Bayesian Latent Class Models), will facilitate improved quality of reporting on the design, conduct and results of diagnostic accuracy studies that use Bayesian latent class models. [ABSTRACT FROM AUTHOR]

The prevailing lack of consensus about the comparative harms and benefits of cancer screening stems, in part, from the inappropriate calculations of the expected mortality impact of a sustained screening programme. There is an inherent, and often substantial, time lag from the time of screening until the resulting mortality reductions begin, reach their maximum and ultimately end. However, the cumulative mortality reduction reported in a randomised screening trial is typically calculated over an arbitrarily defined follow-up period, including follow-up time where the mortality impact is yet to realise or where it has already been exhausted. Because of this, the cumulative reduction cannot be used for projecting the mortality impact expected from a sustained screening programme. For this purpose, we propose a new measure, the time-specific probability of being helped by screening, given that the cancer would have proven fatal otherwise. This can be decomposed into round-specific impacts, which in turn can be parametrised and estimated from the trial data. This represents a major shift in quantifying the benefits due to a sustained screening programme, based on statistical evidence extracted from existing trial data. We illustrate our approach using data from screening trials in lung and colorectal cancers. [ABSTRACT FROM AUTHOR]

Background: Clostridium difficile infection is the leading cause of health care–associated diarrhea, and the bacterium can also be carried asymptomatically. The objective of this study was to identify host and bacterial factors associated with health care–associated acquisition of C. difficile infection and colonization. Methods: We conducted a 15-month prospective study in six Canadian hospitals in Quebec and Ontario. Demographic information, known risk factors, potential confounding factors, and weekly stool samples or rectal swabs were collected. Pulsed-field gel electrophoresis (PFGE) was performed on C. difficile isolates to determine the genotype. Levels of serum antibodies against C. difficile toxins A and B were measured. Results: A total of 4143 patients were included in the study; 117 (2.8%) and 123 (3.0%) had health care–associated C. difficile infection and colonization, respectively. Older age and use of antibiotics and proton-pump inhibitors were significantly associated with health care–associated C. difficile infection. Hospitalization in the previous 2 months; use of chemotherapy, proton-pump inhibitors, and H2 blockers; and antibodies against toxin B were associated with health care–associated C. difficile colonization. Among patients with health care–associated C. difficile infection and those with colonization, 62.7% and 36.1%, respectively, had the North American PFGE type 1 (NAP1) strain. Conclusions: In this study, health care–associated C. difficile infection and colonization were differentially associated with defined host and pathogen variables. The NAP1 strain was predominant among patients with C. difficile infection, whereas asymptomatic patients were more likely to be colonized with other strains. (Funded by the Consortium de Recherche sur le Clostridium difficile.) [ABSTRACT FROM PUBLISHER]