Interpreter usage and associations with latent tuberculosis infection treatment acceptance and completion in the USA among non-U.S.-born persons, 2012-2017.

BACKGROUND: Latent tuberculosis infection (LTBI) screening and treatment interventions that are tailored to optimize acceptance among the non-U.S.-born population are essential for U.S. tuberculosis elimination. We investigated the impact of medical interpreter use on LTBI treatment acceptance and completion among non-U.S.-born persons in a multisite study. METHODS: The Tuberculosis Epidemiologic Studies Consortium was a prospective cohort study that enrolled participants at high risk for LTBI at ten U.S. sites with 18 affiliated clinics from 2012 to 2017. Non-U.S.-born participants with at least one positive tuberculosis infection test result were included in analyses. Characteristics associated with LTBI treatment offer, acceptance, and completion were evaluated using multivariable logistic regression with random intercepts to account for clustering by enrollment site. Our primary outcomes were whether use of an interpreter was associated with LTBI treatment acceptance and completion. We also evaluated whether interpreter usage was associated treatment offer and whether interpreter type was associated with treatment offer, acceptance, or completion. RESULTS: Among 8,761 non-U.S.-born participants, those who used an interpreter during the initial interview had a significantly greater odds of accepting LTBI treatment than those who did not use an interpreter. There was no association between use of an interpreter and a clinician's decision to offer treatment or treatment completion once accepted. Characteristics associated with lower odds of treatment being offered included experiencing homelessness and identifying as Pacific Islander persons. Lower treatment acceptance was observed in Black and Latino persons and lower treatment completion by participants experiencing homelessness. Successful treatment completion was associated with use of shorter rifamycin-based regimens. Interpreter type was not associated with LTBI treatment offer, acceptance, or completion. CONCLUSIONS: We found greater LTBI treatment acceptance was associated with interpreter use among non-U.S.-born individuals.

TBscreen: A passive cough classifier for tuberculosis screening with a controlled dataset.

Recent respiratory disease screening studies suggest promising performance of cough classifiers, but potential biases in model training and dataset quality preclude robust conclusions. To examine tuberculosis (TB) cough diagnostic features, we enrolled subjects with pulmonary TB (N = 149) and controls with other respiratory illnesses (N = 46) in Nairobi. We collected a dataset with 33,000 passive coughs and 1600 forced coughs in a controlled setting with similar demographics. We trained a ResNet18-based cough classifier using images of passive cough scalogram as input and obtained a fivefold cross-validation sensitivity of 0.70 (±0.11 SD). The smartphone-based model had better performance in subjects with higher bacterial load {receiver operating characteristic-area under the curve (ROC-AUC): 0.87 [95% confidence interval (CI): 0.87 to 0.88], P < 0.001} or lung cavities [ROC-AUC: 0.89 (95% CI: 0.88 to 0.89), P < 0.001]. Overall, our data suggest that passive cough features distinguish TB from non-TB subjects and are associated with bacterial burden and disease severity.

Perspectives About Racism and Patient-Clinician Communication Among Black Adults With Serious Illness.

Importance: Black patients with serious illness experience higher-intensity care at the end of life. Little research has used critical, race-conscious approaches to examine factors associated with these outcomes. Objective: To investigate the lived experiences of Black patients with serious illness and how various factors may be associated with patient-clinician communication and medical decision-making. Design, Setting, and Participants: In this qualitative study, one-on-one, semistructured interviews were conducted with 25 Black patients with serious illness hospitalized at an urban academic medical center in Washington State between January 2021 and February 2023. Patients were asked to discuss experiences with racism, how those experiences affected the way they communicated with clinicians, and how racism impacted medical decision-making. Public Health Critical Race Praxis was used as framework and process. Main Outcomes and Measures: The experience and of racism and its association, as described by Black patients who had serious illness, with patient-clinician communication and medical decision-making within a racialized health care setting. Results: A total of 25 Black patients (mean [SD] age, 62.0 [10.3] years; 20 males [80.0%]) with serious illness were interviewed. Participants had substantial socioeconomic disadvantage, with low levels of wealth (10 patients with 0 assets [40.0%]), income (annual income <$25 000 among 19 of 24 patients with income data [79.2%]), educational attainment (mean [SD] 13.4 [2.7] years of schooling), and health literacy (mean [SD] score in the Rapid Estimate of Adult Literacy in Medicine-Short Form, 5.8 [2.0]). Participants reported high levels of medical mistrust and high frequency of discrimination and microaggressions experienced in health care settings. Participants reported epistemic injustice as the most common manifestation of racism: silencing of their own knowledge and lived experiences about their bodies and illness by health care workers. Participants reported that these experiences made them feel isolated and devalued, especially if they had intersecting, marginalized identities, such as being underinsured or unhoused. These experiences were associated with exacerbation of existing medical mistrust and poor patient-clinician communication. Participants described various mechanisms of self-advocacy and medical decision-making based on prior experiences with mistreatment from health care workers and medical trauma. Conclusions and Relevance: This study found that Black patients' experiences with racism, specifically epistemic injustice, were associated with their perspectives on medical care and decision-making during serious illness and end of life. These findings suggest that race-conscious, intersectional approaches may be needed to improve patient-clinician communication and support Black patients with serious illness to alleviate the distress and trauma of racism as these patients near the end of life.

Trends in tuberculosis clinicians' adoption of short-course regimens for latent tuberculosis infection.

Objective: Little is known about regimen choice for latent tuberculosis infection in the United States. Since 2011, the Centers for Disease Control and Prevention has recommended shorter regimens-12 weeks of isoniazid and rifapentine or 4 months of rifampin-because they have similar efficacy, better tolerability, and higher treatment completion than 6-9 months of isoniazid. The objective of this analysis is to describe frequencies of latent tuberculosis infection regimens prescribed in the United States and assess changes over time. Methods: Persons at high risk for latent tuberculosis infection or progression to tuberculosis disease were enrolled into an observational cohort study from September 2012-May 2017, tested for tuberculosis infection, and followed for 24 months. This analysis included those with at least one positive test who started treatment. Results: Frequencies of latent tuberculosis infection regimens and 95% confidence intervals were calculated overall and by important risk groups. Changes in the frequencies of regimens by quarter were assessed using the Mann-Kendall statistic. Of 20,220 participants, 4,068 had at least one positive test and started treatment: 95% non-U.S.-born, 46% female, 12% <15 years old. Most received 4 months of rifampin (49%), 6-9 months of isoniazid (32%), or 12 weeks of isoniazid and rifapentine (13%). Selection of short-course regimens increased from 55% in 2013 to 81% in late 2016 (p < 0.001). Conclusions: Our study identified a trend towards adoption of shorter regimens. Future studies should assess the impact of updated treatment guidelines, which have added 3 months of daily isoniazid and rifampin to recommended regimens.

Reconciling diagnostic traits in living and fossil taxa: The taxonomy and evolution of the genus Microceratina (Crustacea, Ostracoda, Cytheruridae).

The original diagnosis of the genus Microceratina Swanson is re-examined with the aim of elucidating the evolutionary history of this living and fossil genus. The different systematic placements of this genus in one of three alternative suprageneric taxa, family Bythocytheridae Sars, family Cytheruridae G.W. Müller (subfamily Eucytherurinae Puri, emend. Maddocks & Steineck) and/or family Loxoconchidae Sars are reviewed. We provide details of a special type of tiny pores, named Loophole Sieve-type Pore Canals, and show how their morphology and position on the valve differ from the typical Sieve-type Pore Canals present in other superfamily Cytheroidea groups, especially members of the Loxoconchidae. A comparative analysis of the valve ornamentation, especially the structure of the anterior peripheral area, and posterior margin morphology, between selected taxa of the three subfamilies of the Cytheruridae (Cytherurinae, Cytheropterinae, Eucytherurinae) demonstrates that Microceratina species belong to a special phylogenetic lineage of Eucytherurinae, which differs from another lineage represented by the genus Xylocythere Maddocks & Steineck. This proposal is strengthened by examination of the limb traits of Microceratina martensi Namiotko et al., currently the only living species of the genus for which both valves and limbs are described; the description is extended herein. Key diagnostic traits of the genus Microceratina are presented, a new Early Jurassic age species is described, and two new combinations are proposed. The homeomorphic valve shapes of M. andreui sp. nov., M. amfibola and ?S. rectum (Loxoconchidae) support the value of the approach adopted herein: analysis of subtle morphological details with high-resolution microscopy.

T-cell deficiency and hyperinflammatory monocyte responses associate with Mycobacterium avium complex lung disease.

Immunological mechanisms of susceptibility to nontuberculous mycobacterial (NTM) disease are poorly understood. To understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in asymptomatic individuals with a previous history of MAC lung disease (MACDZ). We hypothesized that Mav-specific immune responses are associated with susceptibility to MAC lung disease. We measured MAC-, NTM-, or MAC/Mtb-specific T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mycobacterium avium-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls. We were unable to detect increased T-cell responses against MAC-specific reagents in MACDZ compared to controls, while the responses to non-mycobacteria derived antigens were preserved. MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. In addition, MACDZ subjects had lower transcriptional responses in PBMCs stimulated with a mycobacterial peptide pool (MTB300). By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and M. avium-infected monocytes, i.e. a hyperinflammatory in vitro response, derived from MACDZ subjects compared to controls. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation which persists years after completion of treatment.

Yield and Coverage of Active Case Finding Interventions for Tuberculosis Control:A Systematic Review and Meta-analysis.

Background: Active case finding (ACF) for tuberculosis (TB) is a key strategy to reduce diagnostic delays, expedite treatment, and prevent transmission. Objective: Our objective was to identify the populations, settings, screening and diagnostic approaches that optimize coverage (proportion of those targeted who were screened) and yield (proportion of those screened who had active TB) in ACF programs. Methods: We performed a comprehensive search to identify studies published from 1980-2016 that reported the coverage and yield of different ACF approaches. For each outcome, we conducted meta-analyses of single proportions to produce estimates across studies, followed by meta-regression to identify predictors. Findings. Of 3,972 publications identified, 224 met criteria after full-text review. Most individuals who were targeted successfully completed screening, for a pooled coverage estimate of 93.5%. The pooled yield of active TB across studies was 3.2%. Settings with the highest yield were internally-displaced persons camps (15.6%) and healthcare facilities (6.9%). When compared to symptom screening as the reference standard, studies that screened individuals regardless of symptoms using microscopy, culture, or GeneXpert®MTB/RIF (Xpert) had 3.7% higher case yield. In particular, microbiological screening (usually microscopy) as the initial test, followed by culture or Xpert for diagnosis had 3.6% higher yield than symptom screening followed by microscopy for diagnosis. In a model adjusted for use of Xpert testing, approaches targeting persons living with HIV (PLWH) had a 4.9% higher yield than those targeting the general population. In all models, studies targeting children had higher yield (4.8%-5.7%) than those targeting adults. Conclusion: ACF activities can be implemented successfully in various populations and settings. Screening yield was highest in internally-displaced person and healthcare settings, and among PLWH and children. In high-prevalence settings, ACF approaches that screen individuals with laboratory tests regardless of symptoms have higher yield than approaches focused on symptomatic individuals.

Isoniazid preventive therapy and tuberculosis transcriptional signatures in people with HIV.

OBJECTIVES: To examine the association between isoniazid preventive therapy (IPT) or nontuberculous mycobacteria (NTM) sputum culture positivity and tuberculosis (TB) transcriptional signatures in people with HIV. DESIGN: Cross-sectional study. METHODS: We enrolled adults living with HIV who were IPT-naive or had completed IPT more than 6 months prior at HIV care clinics in western Kenya. We calculated TB signatures using gene expression data from qRT-PCR. We used multivariable linear regression to analyze the association between prior receipt of IPT or NTM sputum culture positivity with a transcriptional TB risk score, RISK6 (range 0-1). In secondary analyses, we explored the association between IPT or NTM positivity and four other TB transcriptional signatures. RESULTS: Among 381 participants, 99.7% were receiving antiretroviral therapy and 86.6% had received IPT (completed median of 1.1 years prior). RISK6 scores were lower (mean difference 0.10; 95% confidence interval (CI): 0.06-0.15; P  < 0.001) among participants who received IPT than those who did not. In a model that adjusted for age, sex, duration of ART, and plasma HIV RNA, the RISK6 score was 52.8% lower in those with a history of IPT ( P  < 0.001). No significant association between year of IPT receipt and RISK6 scores was detected. There was no association between NTM sputum culture positivity and RISK6 scores. CONCLUSION: In people with HIV, IPT was associated with significantly lower RISK6 scores compared with persons who did not receive IPT. These data support investigations of its performance as a TB preventive therapy response biomarker.

Accidental monstrosities: Taxonomic chimeras in Ostracoda (Crustacea).

Taxonomic chimeras, artificial taxa created unintentionally by amalgamation of morphological traits belonging to different taxonomic units, can be found in 19th century to present day scientific literature. We recognise two types of such artefacts in Ostracoda. Chimera Type 1 is represented by species defined by morphological traits belonging to two (or more) different valid taxa at the rank of species. A thorough comparative analysis of carapace and limb characteristics of Fabaeformiscandona balatonica (Daday) sensu Bronshtein (1947) allows us to conclude that it is a chimera comprising F. balatonica and F. levanderi (Hirschmann), for which we provide new, expanded diagnoses. Chimera Type 2 refers to a genus defined by juvenile morphological traits that also occur in other genera. Analysis of Candoniella Schneider, 1956 shows it to be an artefact based on morphological traits belonging to juveniles of at least three genera: Pseudocandona Kaufmann, 1900, Fabaeformiscandona Krsti, 1972 and Neglecandona Krsti, 2006. Elimination of taxonomic artefacts is necessary to improve not only taxonomy but also adjacent domains of investigation like the ecology and geographical distribution of confused taxa. Considered in historical contexts, the creation and perpetuation of such accidental monstrosities may be attributed to social motivations as well as limitations of material, literature and communication.

Non-marine Ostracoda (Crustacea) of the Early Cretaceous Pre-Salt sediments of Brazil: An illustrated catalogue of the type specimens of Wicher, Krmmelbein, Krmmelbein amp; Weber, and Bate.

Type material of 10 genera, one subgenus, 110 species and 28 subspecies described by Wicher (1959), Krmmelbein (1961, 1962, 1963, 1964a,b, 1965a,b), Krmmelbein Weber (1971) and Bate (1972, 1994) are re-illustrated using optical digital technology in order to provide a standard reference for future systematic work and its biostratigraphical and palaeoenvironmental application. The genera are: Brasacypris, Coriacina, Hourcqia, Ilhasina, Looneyellopsis, Pattersoncypris, Petrobrasia, Reconcavona, Salvadoriella, and Tucanocypris, and subgenus Cypridea (Sebastianites).

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BACKGROUND: The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population. METHODS: In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895. FINDINGS: We identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (<10 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively. INTERPRETATION: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications. FUNDING: World Health Organization.

Ilyocyprisleptolinea Wang & Zhai, sp. nov., an ostracod (Ostracoda, Crustacea) from the late Quaternary of Inner Mongolia, northern China.

Ilyocyprisleptolinea Wang & Zhai, sp. nov. is described from late Quaternary sediments in central-eastern Inner Mongolia, northern China. The new species, which has a carapace shape and pitted surface typical of the genus, is characterised by double rows of fine, densely arranged marginal ripplets, separated by an inner list, along both anterior and posterior calcified inner lamellae in the left valve. Outline analysis and Principal Component Analysis indicate that its morpho-space overlaps with I.bradyi Sars, 1890, I.japonica Okubo, 1990, and I.mongolica Martens, 1991, which have living or fossil representatives in Inner Mongolia, but it is clearly discriminated from I.innermongolica Zhai & Xiao, 2013. Judging from the relatively coarse lithology dominated by silt and sand, and the lack of accompanying brackish-water ostracods, I.leptolinea Wang & Zhai, sp. nov. may have lived in a relatively shallow freshwater lake. It perhaps can be added to the list of species that went extinct during the Quaternary, but the timing and process of extinction await further investigation.

Pulmonary Tuberculosis in Older Adults: Increased Mortality Related to Tuberculosis Within Two Months of Treatment Initiation.

BACKGROUND: The proportion of tuberculosis (TB) patients who are older adults is increasing worldwide. Nearly 60% of TB patients in Japan are 70 years or older, and the TB incidence rate in Japan is one of the highest among high-income countries. The previous TB treatment guidelines prior to 2018 in Japan recommended excluding pyrazinamide (PZA) from the initial regimen for patients aged over 80 years. OBJECTIVES: We aimed to examine differences in TB treatment outcomes among different age groups, and between those who received PZA and those who did not. METHODS: We performed a retrospective cohort study of patients with pulmonary TB who were managed at a single medical center in Japan. We compared treatment outcomes and adverse events that resulted in treatment interruption across the age groups. RESULTS: Of 246 patients, 117 (48%) were aged 75 years or older. Compared with patients aged < 74 years, those ≥ 75 years were less likely to have PZA in the initial regimen (53.0% vs 89.9%; p < 0.0001), more likely to die during treatment (38.5% vs 6.2%; p < 0.0001), and more likely to experience adverse events (30.8% vs 19.4%; p < 0.05). The mortality rate related to TB at 2 months after TB treatment initiation was 28% in those aged ≥ 84 years. Furthermore, among patients aged ≥ 84 years, those who did not receive PZA were significantly more likely to die than those who did (65.8% vs 36.8%; p < 0.05). CONCLUSIONS: Patients aged ≥ 75 years with pulmonary TB experienced increased mortality related to TB during treatment and more frequent adverse events than younger patients, even though PZA was often avoided among older patients.

Diagnosing Pulmonary Tuberculosis by Using Sequence-Specific Purification of Urine Cell-Free DNA.

Transrenal urine cell-free DNA (cfDNA) is a promising tuberculosis (TB) biomarker, but is challenging to detect because of the short length (<100 bp) and low concentration of TB-specific fragments. We aimed to improve the diagnostic sensitivity of TB urine cfDNA by increasing recovery of short fragments during sample preparation. We developed a highly sensitive sequence-specific purification method that uses hybridization probes immobilized on magnetic beads to capture short TB cfDNA (50 bp) with 91.8% average efficiency. Combined with short-target PCR, the assay limit of detection was ≤5 copies of cfDNA in 10 ml urine. In a clinical cohort study in South Africa, our urine cfDNA assay had 83.7% sensitivity (95% CI: 71.0 to 91.5%) and 100% specificity (95% CI: 86.2 to 100%) for diagnosis of active pulmonary TB when using sputum Xpert MTB/RIF as the reference standard. The detected cfDNA concentration was 0.14 to 2,804 copies/ml (median 14.6 copies/ml) and was inversely correlated with CD4 count and days to culture positivity. Sensitivity was nonsignificantly higher in HIV-positive (88.2%) compared to HIV-negative patients (73.3%), and was not dependent on CD4 count. Sensitivity remained high in sputum smear-negative (76.0%) and urine lipoarabinomannan (LAM)-negative (76.5%) patients. With improved sample preparation, urine cfDNA is a viable biomarker for TB diagnosis. Our assay has the highest reported accuracy of any TB urine cfDNA test to date and has the potential to enable rapid non-sputum-based TB diagnosis across key underserved patient populations.

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

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

Pulmonary tuberculosis screening in anti-retroviral treated adults living with HIV in Kenya.

BACKGROUND: People living with HIV (PLHIV) who reside in high tuberculosis burden settings remain at risk for tuberculosis disease despite treatment with anti-retroviral therapy and isoniazid preventive therapy (IPT). The performance of the World Health Organization (WHO) symptom screen for tuberculosis in PLHIV receiving anti-retroviral therapy is sub-optimal and alternative screening strategies are needed. METHODS: We enrolled HIV-positive adults into a prospective study in western Kenya. Individuals who were IPT-naïve or had completed IPT > 6 months prior to enrollment were eligible. We evaluated tuberculosis prevalence overall and by IPT status. We assessed the accuracy of the WHO symptom screen, GeneXpert MTB/RIF (Xpert), and candidate biomarkers including C-reactive protein (CRP), hemoglobin, erythrocyte sedimentation rate (ESR), and monocyte-to-lymphocyte ratio for identifying pulmonary tuberculosis. Some participants were evaluated at 6 months post-enrollment for tuberculosis. RESULTS: The study included 383 PLHIV, of whom > 99% were on antiretrovirals and 88% had received IPT, completed a median of 1.1 years (IQR 0.8-1.55) prior to enrollment. The prevalence of pulmonary tuberculosis at enrollment was 1.3% (n = 5, 95% CI 0.4-3.0%): 4.3% (0.5-14.5%) among IPT-naïve and 0.9% (0.2-2.6%) among IPT-treated participants. The sensitivity of the WHO symptom screen was 0% (0-52%) and specificity 87% (83-90%). Xpert and candidate biomarkers had poor to moderate sensitivity; the most accurate biomarker was CRP ≥ 3.3 mg/L (sensitivity 80% (28-100) and specificity 72% (67-77)). Six months after enrollment, the incidence rate of pulmonary tuberculosis following IPT completion was 0.84 per 100 person-years (95% CI, 0.31-2.23). CONCLUSIONS: In Kenyan PLHIV treated with IPT, tuberculosis prevalence was low at a median of 1.4 years after IPT completion. WHO symptoms screening, Xpert, and candidate biomarkers were insensitive for identifying pulmonary tuberculosis in antiretroviral-treated PLHIV.

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

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

Optimal Testing Choice and Diagnostic Strategies for Latent Tuberculosis Infection Among US-Born People Living with Human Immunodeficiency Virus (HIV).

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/mm3), 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.

New record of podocopid ostracods from Cretaceous amber.

Burmese Cretaceous amber (∼99 Ma, Myanmar) is famous for the preservation of a wide range of fauna and flora, including representatives of marine, freshwater and terrestrial groups. Here, we report on three ostracod specimens, that came visible as syninclusions to an aquatic isopod. The three specimens represent three different taxa, that were found preserved in a single piece of amber. One of the described specimens was studied using µCT scanning data. On the basis of general carapace morphology we assign all three to the group Podocopida, and (tentatively) its ingroup Cypridocopina. A lack of visibility of more particular diagnostic features such as adductor muscle scars and details of the marginal zone precludes a further identification, but we discuss possible affinities with either the marine-brackish group Pontocypridoidea or the non-marine group Cypridoidea. The taphonomy indicates that the studied ostracods had been subject to limited (if any) post-mortem transport, which could be consistent with marginal marine environments.

Exceptional preservation of reproductive organs and giant sperm in Cretaceous ostracods.

The bivalved crustacean ostracods have the richest fossil record of any arthropod group and display complex reproductive strategies contributing to their evolutionary success. Sexual reproduction involving giant sperm, shared by three superfamilies of living ostracod crustaceans, is among the most fascinating behaviours. However, the origin and evolution of this reproductive mechanism has remained largely unexplored because fossil preservation of such features is extremely rare. Here, we report exceptionally preserved ostracods with soft parts (appendages and reproductive organs) in a single piece of mid-Cretaceous Kachin amber (approximately 100 Myr old). The ostracod assemblage is composed of 39 individuals. Thirty-one individuals belong to a new species and genus, Myanmarcypris hui gen. et sp. nov., exhibiting an ontogenetic sequence from juveniles to adults (male and female). Seven individuals are assigned to Thalassocypria sp. (Cypridoidea, Candonidae, Paracypridinae) and one to Sanyuania sp. (Cytheroidea, Loxoconchidae). Our micro-CT reconstruction provides direct evidence of the male clasper, sperm pumps (Zenker organs), hemipenes, eggs and female seminal receptacles with giant sperm. Our results reveal that the reproduction behavioural repertoire, which is associated with considerable morphological adaptations, has remained unchanged over at least 100 million years-a paramount example of evolutionary stasis. These results also double the age of the oldest unequivocal fossil animal sperm. This discovery highlights the capacity of amber to document invertebrate soft parts that are rarely recorded by other depositional environments.