Xpert MTB/RIF Ultra assay for tuberculosis disease and rifampicin resistance in children

Background Every year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 of those children die. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)‐recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. We previously published a Cochrane Review 'Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for tuberculosis disease and rifampicin resistance in children'. The current review updates evidence on the diagnostic accuracy of Xpert Ultra in children presumed to have tuberculosis disease. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents. Objectives To assess the diagnostic accuracy of Xpert Ultra for detecting: pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance, in children with presumed tuberculosis. Secondary objectives To investigate potential sources of heterogeneity in accuracy estimates. For detection of tuberculosis, we considered age, comorbidity (HIV, severe pneumonia, and severe malnutrition), and specimen type as potential sources. To summarize the frequency of Xpert Ultra trace results. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, three other databases, and three trial registers without language restrictions to 9 March 2021. Selection criteria Cross‐sectional and cohort studies and randomized trials that evaluated Xpert Ultra in HIV‐positive and HIV‐negative children under 15 years of age. We included ongoing studies that helped us address the review objectives. We included studies evaluating sputum, gastric, stool, or nasopharyngeal specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), and fine needle aspirate or surgical biopsy tissue (lymph node tuberculosis). For detecting tuberculosis, reference standards were microbiological (culture) or composite reference standard; for stool, we also included Xpert Ultra performed on a routine respiratory specimen. For detecting rifampicin resistance, reference standards were drug susceptibility testing or MTBDRplus. Data collection and analysis Two review authors independently extracted data and, using QUADAS‐2, assessed methodological quality judging risk of bias separately for each target condition and reference standard. For each target condition, we used the bivariate model to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We summarized the frequency of Xpert Ultra trace results; trace represents detection of a very low quantity of Mycobacterium tuberculosis DNA. We assessed certainty of evidence using GRADE. Main results We identified 14 studies (11 new studies since the previous review). For detection of pulmonary tuberculosis, 335 data sets (25,937 participants) were available for analysis. We did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra for detection of rifampicin resistance. Ten studies (71%) took place in countries with a high tuberculosis burden based on WHO classification. Overall, risk of bias was low. Detection of pulmonary tuberculosis Sputum, 5 studies Xpert Ultra summary sensitivity verified by culture was 75.3% (95% CI 64.3 to 83.8; 127 participants; high‐certainty evidence), and specificity was 97.1% (95% CI 94.7 to 98.5; 1054 participants; high‐certainty evidence). Gastric aspirate, 7 studies Xpert Ultra summary sensitivity verified by culture was 70.4% (95% CI 53.9 to 82.9; 120 participants; moderate‐certainty evidence), and specificity was 94.1% (95% CI 84.8 to 97.8; 870 participants; moderate‐certainty evidence). Stool, 6 studies Xpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7; 200 participants; moderate‐certainty evidence), and specificity was 98.0% (95% CI 93.3 to 99.4; 1232 participants; high certainty‐evidence). Nasopharyngeal aspirate, 4 studies Xpert Ultra summary sensitivity verified by culture was 43.7% (95% CI 26.7 to 62.2; 46 participants; very low‐certainty evidence), and specificity was 97.5% (95% CI 93.6 to 99.0; 489 participants; high‐certainty evidence). Xpert Ultra sensitivity was lower against a composite than a culture reference standard for all specimen types other than nasopharyngeal aspirate, while specificity was similar against both reference standards. Interpretation of results In theory, for a population of 1000 children: • where 100 have pulmonary tuberculosis in sputum (by culture): ‐ 101 would be Xpert Ultra‐positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and ‐ 899 would be Xpert Ultra‐negative, and of these, 25 (3%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in gastric aspirate (by culture): ‐ 123 would be Xpert Ultra‐positive, and of these, 53 (43%) would not have pulmonary tuberculosis (false positive); and ‐ 877 would be Xpert Ultra‐negative, and of these, 30 (3%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in stool (by culture): ‐ 74 would be Xpert Ultra‐positive, and of these, 18 (24%) would not have pulmonary tuberculosis (false positive); and ‐ 926 would be Xpert Ultra‐negative, and of these, 44 (5%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in nasopharyngeal aspirate (by culture): ‐ 66 would be Xpert Ultra‐positive, and of these, 22 (33%) would not have pulmonary tuberculosis (false positive); and ‐ 934 would be Xpert Ultra‐negative, and of these, 56 (6%) would have tuberculosis (false negative). Detection of rifampicin resistance Xpert Ultra sensitivity was 100% (3 studies, 3 participants; very low‐certainty evidence), and specificity range was 97% to 100% (3 studies, 128 participants; low‐certainty evidence). Trace results Xpert Ultra trace results, regarded as positive in children by WHO standards, were common. Xpert Ultra specificity remained high in children, despite the frequency of trace results. Authors' conclusions We found Xpert Ultra sensitivity to vary by specimen type, with sputum having the highest sensitivity, followed by gastric aspirate and stool. Nasopharyngeal aspirate had the lowest sensitivity. Xpert Ultra specificity was high against both microbiological and composite reference standards. However, the evidence base is still limited, and findings may be imprecise and vary by study setting. Although we found Xpert Ultra accurate for detection of rifampicin resistance, results were based on a very small number of studies that included only three children with rifampicin resistance. Therefore, findings should be interpreted with caution. Our findings provide support for the use of Xpert Ultra as an initial rapid molecular diagnostic in children being evaluated for tuberculosis

Relaxin: Review of Biology and Potential Role in Treating Heart Failure

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells

Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NO(X)) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner from RBL-2H3 cells. Inhibition of NO production by CSS in AEC, A549, and NHTBE cells was also dose-dependent. In addition, CSS decreased expression of NOS mRNA and protein expression. The addition of NO inhibitors and scavengers did not, however, reverse the effects of CSS, nor did a NO donor (SNP) or nicotine mimic CSS. N-acetyl-cysteine, partially reversed the inhibition of beta-hexosaminidase release suggesting CSS may act via oxidative free radicals. Thus, some of the inhibitory effects of CSS appear to be via oxidative free radicals rather than a NO(X )-related negative feedback

Integrated Close Range Remote Sensing Techniques for Detecting, Documenting, and Interpreting Lost Medieval Settlements under Canopy: The Case of Altanum (RC, Italy)

This paper focuses on the potential of an integrated approach using aerial LiDAR, aerial and terrestrial photogrammetry, terrestrial laser scanning, and archaeological survey to detect the presence and configuration of lost medieval settlements under canopy. This approach was applied to the site of Altanum (Calabria, Italy), on the hill of Sant'Eusebio, completely covered by vegetation. Altanum was a large fortified settlement characterised by a long occupation, especially during the Byzantine and Norman-Swabian periods. The activity began by carrying out a LiDAR survey of the whole hill. The acquired LiDAR data were processed and filtered in order to obtain a DFM (Digital Feature Model) useful for the identification of features of archaeological interest. Several enhancement techniques were performed on DFM to increase the visibility of archaeological features. The features thus identified were subsequently surveyed through the use of terrestrial and aerial photogrammetry integrated with laser scanning to document the visible buildings. The most significant result of the study was to create a single GIS platform with the integration of all data in order to delineate the whole settlement layout, as well as to produce 2D and 3D datasets useful for the for knowledge and protection of the identified remains

Interstitial brachytherapy for eyelid carcinoma : Outcome analysis in 60 patients.

Background. Eyelid cancer is a therapeutic challenge due to the cosmetic and functional implications of this anatomical region and the objectives of therapy are tumor control, functional and cosmetic outcome. Aim. The present study was performed to analyze local control, toxicity, functional and cosmetic results in patients with eyelid carcinoma treated by interstitial brachytherapy. Material and methods. In this study 60 patients with eyelid carcinoma were treated by interstitial brachytherapy using iridium (192Ir) wires with a linear activity of 1.2\u20131.7 mCi/cm. The prescription dose was 51\u201370 Gy (mean 65 Gy, median 66 Gy). Results. Of the 60 patients 51 (85.0%) had received no prior treatment, 4 (6.7%) had received previous surgery with positive or close margins and 5 (8.3%) had suffered local recurrence after surgery. Of the tumors 52 (86.7%) were basal cell carcinoma, 7 (11.7%) squamous cell carcinoma and 1 (1.7%) Merkel cell carcinoma. Clinical stage of the 51 previously untreated tumors was 38 T1N0, 12 T2N0 and 1 T3N0. Mean follow\u2013up was 92 months (range 6\u2013253 months). Local control was maintained in 96.7% of patients. Late effects higher than grade 2 were observed in 3.0% of cases. Functional and cosmetic outcomes were optimal in 68.4% of patients. Conclusion. Interstitial brachytherapy for carcinoma of the eyelid can achieve local control, cosmetic and functional results comparable to those of surgery