Publications by authors named "David J Horne"

52 Publications

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

Tuberc Res Treat 2022 30;2022:9947068. Epub 2022 Jun 30.

University of Washington, Department of Medicine, Seattle, USA.

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. 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.
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http://dx.doi.org/10.1155/2022/9947068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274229PMC
June 2022

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

AIDS 2022 08 25;36(10):1363-1371. Epub 2022 May 25.

Department of Medicine, University of Washington, Seattle, Washington.

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.
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http://dx.doi.org/10.1097/QAD.0000000000003262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329226PMC
August 2022

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.

Zootaxa 2022 Feb 9;5098(1):1-84. Epub 2022 Feb 9.

Senckenberg Forschungsinstitut Frankfurt, Senckenberganlage 25, D-60325 Frankfurt-am-Main, Germany..

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).
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http://dx.doi.org/10.11646/zootaxa.5098.1.1DOI Listing
February 2022

Accidental monstrosities: Taxonomic chimeras in Ostracoda (Crustacea).

Zootaxa 2022 Mar 18;5116(2):151-199. Epub 2022 Mar 18.

School of Geography, Queen Mary University of London, Mile End Road, London E1 4NS, UK.

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.
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http://dx.doi.org/10.11646/zootaxa.5116.2.1DOI Listing
March 2022

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

Lancet Infect Dis 2022 04 17;22(4):507-518. Epub 2021 Nov 17.

Johns Hopkins University Center for Tuberculosis Research, Baltimore, MD, USA.

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/m), 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.
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http://dx.doi.org/10.1016/S1473-3099(21)00387-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942858PMC
April 2022

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

Drugs Aging 2021 09 5;38(9):807-815. Epub 2021 Jul 5.

TB Control Program, Public Health-Seattle & King county, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1007/s40266-021-00880-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256198PMC
September 2021

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

J Clin Microbiol 2021 07 19;59(8):e0007421. Epub 2021 Jul 19.

Department of Bioengineering, University of Washington, Seattle, Washington, USA.

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.
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http://dx.doi.org/10.1128/JCM.00074-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373247PMC
July 2021

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

Cochrane Database Syst Rev 2021 03 23;3:CD013694. Epub 2021 Mar 23.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Firland Northwest TB Center, University of Washington, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1002/14651858.CD013694.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437892PMC
March 2021

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

BMC Infect Dis 2021 Feb 25;21(1):218. Epub 2021 Feb 25.

Department of Global Health, University of Washington, 325 9th Ave, Box 359762, Seattle, WA, 98102, USA.

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.
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http://dx.doi.org/10.1186/s12879-021-05916-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908695PMC
February 2021

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

Cochrane Database Syst Rev 2021 02 22;2:CD009593. Epub 2021 Feb 22.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Firland Northwest TB Center, University of Washington, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1002/14651858.CD009593.pub5DOI Listing
February 2021

New record of podocopid ostracods from Cretaceous amber.

PeerJ 2020 26;8:e10134. Epub 2020 Oct 26.

School of Geography, Queen Mary University of London, London, United Kingdom.

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.
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http://dx.doi.org/10.7717/peerj.10134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594633PMC
October 2020

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

Proc Biol Sci 2020 09 16;287(1935):20201661. Epub 2020 Sep 16.

State Key Laboratory of Palaeobiology and Stratigraphy, Nanjing Institute of Geology and Palaeontology and Center for Excellence in Life and Paleoenvironment, Chinese Academy of Sciences, 39 East Beijing Road, Nanjing 210008, People's Republic of China.

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, gen. et sp. nov., exhibiting an ontogenetic sequence from juveniles to adults (male and female). Seven individuals are assigned to sp. (Cypridoidea, Candonidae, Paracypridinae) and one to 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.
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http://dx.doi.org/10.1098/rspb.2020.1661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542813PMC
September 2020

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

Clin Infect Dis 2021 10;73(7):e2278-e2284

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

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.
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http://dx.doi.org/10.1093/cid/ciaa1135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678585PMC
October 2021

Contrasting subsurface denitrification characteristics under temperate pasture lands and its implications for nutrient management in agricultural catchments.

J Environ Manage 2020 Oct 28;272:111067. Epub 2020 Jul 28.

Environmental Science, School of Agriculture and Environment, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand.

Subsurface denitrification plays a key role in the reduction or 'attenuation' of nitrate contamination of groundwater and surface waters. We investigated subsurface denitrification characteristics in the vadose zone and shallow groundwater at four sites under pastoral farming in the Manawatū River catchment, located in the lower part of North Island, New Zealand. The denitrification potential of the vadose zone was determined by the laboratory incubation assays measuring the denitrifying enzyme activity (DEA) in soil samples collected from different soil horizons (up to 2.1 m below ground surface), whereas denitrification rates in shallow groundwaters were measured in situ by single-well, push-pull tests conducted in piezometers installed at multiple depths at the study sites. Soils and underlying geology, defining hydrogeologic settings, appear to influence the spatial variability of subsurface denitrification characteristics at the study sites. Where the vadose zone is thin and composed of coarse-textured soils, percolation of nitrate was evident in observed high nitrate-nitrogen concentrations (>5 mg L) in oxic and young shallow groundwaters, but low nitrate-nitrogen concentrations (<0.05 mg L) were observed in the reduced shallow groundwater found underneath the fine textured soils and/or a thick vadose zone. This was confirmed by the push-pull tests measuring denitrification rates from 0.08 to 1.07 mg N L h in the reduced shallow groundwaters (dissolved oxygen or DO < 0.5 mg L), while negligible in the oxic groundwaters (DO > 5 mg L) found at the study sites. These contrasting subsurface denitrification characteristics determine the ultimate delivery of nitrate losses from agricultural soils to receiving waters, where the fine textured thick vadose zone and reducing groundwater conditions offer nitrate reduction in the subsurface environment.
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http://dx.doi.org/10.1016/j.jenvman.2020.111067DOI Listing
October 2020

Crustacean remains from the Yuka mammoth raise questions about non-analogue freshwater communities in the Beringian region during the Pleistocene.

Sci Rep 2020 01 21;10(1):859. Epub 2020 Jan 21.

A.N. Severtsov Institute of Ecology and Evolution, Leninsky Prt. 33, Moscow, 119071, Russia.

Frozen permafrost Pleistocene mammal carcasses with soft tissue remains are subject to intensive study and help elucidate the palaeoenvironment where these animals lived. Here we present an inventory of the freshwater fauna and flora found in a sediment sample from the mummified Woolly Mammoth carcass found in August 2010, from the Oyogos Yar coast near the Kondratievo River in the Laptev Sea region, Sakha (Yakutia) Republic, NE Russia. Our study demonstrates that the waterbody where the carcass was buried could be characterized as a shallow pond or lake inhabited mainly by taxa which are present in this area today, but additionally by some branchiopod crustacean taxa currently absent or unusual in the region although they exist in the arid zone of Eurasia (steppes and semi-deserts). These findings suggest that some "non-analogue" crustacean communities co-existed with the "Mammoth fauna". Our findings raise questions about the nature of the waterbodies that existed in Beringia during the MIS3 climatic optimum when the mammoth was alive.
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http://dx.doi.org/10.1038/s41598-020-57604-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972846PMC
January 2020

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

Cochrane Database Syst Rev 2019 06 7;6:CD009593. Epub 2019 Jun 7.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Firland Northwest TB Center, University of Washington, Seattle, WA, USA.

Background: Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review.

Objectives: To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin-resistant tuberculosis.

Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction.

Selection Criteria: Randomized trials, cross-sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture-based drug susceptibility testing or MTBDRplus for rifampicin resistance.

Data Collection And Analysis: Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS-2 and performed meta-analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random-effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing.

Main Results: We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen.Tuberculosis detectionOf the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias.Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high-certainty evidence). We found similar accuracy when we included all studies.For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF-positive and 18 (17%) would not have tuberculosis (false-positives); 897 would be Xpert MTB/RIF-negative and 15 (2%) would have tuberculosis (false-negatives).Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate-certainty evidence).Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear-positive and 67% (62% to 72%) in smear-negative, culture-positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV-negative and 81% (75% to 86%) in HIV-positive participants; specificities were similar 98% (97% to 99%), (14 studies).Rifampicin resistance detectionXpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high-certainty evidence).For a population of 1000 people where 100 have rifampicin-resistant tuberculosis, 114 would be positive for rifampicin-resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false-positives); 886 would be would be negative for rifampicin-resistant tuberculosis and four (0.4%) would have rifampicin resistance (false-negatives).Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate-certainty evidence).

Authors' Conclusions: We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear-positive than smear-negative participants and HIV-negative than HIV-positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug-resistant tuberculosis.
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http://dx.doi.org/10.1002/14651858.CD009593.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555588PMC
June 2019

Nontuberculous Mycobacteria and Heterologous Immunity to Tuberculosis.

J Infect Dis 2019 08;220(7):1091-1098

Tuberculosis Research and Training Center, Department of Medicine, University of Washington, Seattle.

Development of an improved tuberculosis (TB) vaccine is a high worldwide public health priority. Bacillus Calmette-Guerin (BCG), the only licensed TB vaccine, provides variable efficacy against adult pulmonary TB, but why this protection varies is unclear. Humans are regularly exposed to non-tuberculous mycobacteria (NTM) that live in soil and water reservoirs and vary in different geographic regions around the world. Immunologic cross-reactivity may explain disparate outcomes of BCG vaccination and susceptibility to TB disease. Evidence supporting this hypothesis is increasing but challenging to obtain due to a lack of reliable research tools. In this review, we describe the progress and bottlenecks in research on NTM epidemiology, immunology and heterologous immunity to Mtb. With ongoing efforts to develop new vaccines for TB, understanding the effect of NTM on vaccine efficacy may be a critical determinant of success.
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http://dx.doi.org/10.1093/infdis/jiz285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736075PMC
August 2019

Tuberculosis in Older Adults: Seattle and King County, Washington.

Clin Infect Dis 2020 03;70(6):1202-1207

Tuberculosis Control Program, Public Health-Seattle and King County.

Background: In the United States, tuberculosis (TB) incidence rates are highest among adults aged ≥65 years. We performed this study to evaluate outcomes of older patients undergoing treatment for TB disease, including the frequency of adverse events related to TB treatment.

Methods: This study evaluated adult patients who were diagnosed with pulmonary TB from 2009 to 2014 in King County, Washington. Patient characteristics, manifestation of TB, and treatment outcomes in different age groups were compared. Frequency and type of adverse events that resulted in treatment interruption were evaluated and patients aged ≥65 years were compared with selected younger patients.

Results: There were 403 patients who met the study criteria, 111 of whom were aged ≥65 years. Older patients were significantly less likely to have cavitation on chest radiographs. Patients aged ≥65 years were less likely to complete TB treatment (76.6% vs 94.9%, P < .0001) and were more likely to die during treatment (18.9% vs 2.1%, P < .0001). The difference in these outcomes was heightened for those aged ≥75 years compared with those aged <75 years. Those aged ≥75 years were also more likely to have an adverse event attributable to TB medication and were more likely to have an adverse event later in therapy. Regardless of age, pyrazinamide was responsible for the majority of adverse reactions.

Conclusions: Adults aged ≥65 years with pulmonary TB had less-advanced disease but a higher risk of complications during treatment such as death or adverse events. This effect was most pronounced among those aged ≥75 years.
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http://dx.doi.org/10.1093/cid/ciz306DOI Listing
March 2020

Clot Analysis in Acute Ischemic Stroke.

Stroke 2019 04;50(4):e106-e109

Division of Allergy and Infectious Diseases (M.A.C.), Department of Medicine, University of Washington School of Medicine, Seattle.

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http://dx.doi.org/10.1161/STROKEAHA.118.023700DOI Listing
April 2019

Remembering the Host in Tuberculosis Drug Development.

J Infect Dis 2019 04;219(10):1518-1524

Stop TB Partnership Working Group on New Drugs, New York, New York.

New therapeutics to augment current approaches and shorten treatment duration are of critical importance for combating tuberculosis (TB), especially those with novel mechanisms of action to counter the emergence of drug-resistant TB. Host-directed therapy (HDT) offers a novel strategy with mechanisms that include activating immune defense mechanisms or ameliorating tissue damage. These and related concepts will be discussed along with issues that emerged from the workshop organized by the Stop TB Working Group on New Drugs, held at the Gordon Research Conference for Tuberculosis Drug Development in Lucca, Italy in June 2017, titled "Strategic Discussion on Repurposing Drugs & Host Directed Therapies for TB." In this review, we will highlight recent data regarding drugs, pathways, and concepts that are important for successful development of HDTs for TB.
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http://dx.doi.org/10.1093/infdis/jiy712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562157PMC
April 2019

Symptom screening for active tuberculosis in pregnant women living with HIV.

Cochrane Database Syst Rev 2018 24;2018(1). Epub 2018 Jan 24.

Department of Medicine, Division of Infectious Diseases, Center for Global Health, Weill Cornell Medical College, New York, USA.

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To assess the accuracy of the four-symptom screen (cough, fever, night sweats, or weight loss) for identifying active TB in pregnant PLHIV who are screened in an outpatient or community setting. To investigate potential sources of heterogeneity of the accuracy of the four-symptom screen between studies including: ART status, CD4 cell count, gestational age, pregnancy stage (pregnancy vs. postpartum), screening test definition of cough (any cough vs. cough greater than 2 weeks).To describe the accuracy of single symptoms included within the four-symptom screen, additioal symptoms or symptom combinations, for identifying active TB in pregnant PLHIV. For example, additional symptoms may include failure to gain weight or fatigue.
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http://dx.doi.org/10.1002/14651858.CD012934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997280PMC
July 2019

Correlation between investment in sexual traits and valve sexual dimorphism in Cyprideis species (Ostracoda).

PLoS One 2017 5;12(7):e0177791. Epub 2017 Jul 5.

School of Geography, Queen Mary University of London, London, United Kingdom.

Assessing the long-term macroevolutionary consequences of sexual selection has been hampered by the difficulty of studying this process in the fossil record. Cytheroid ostracodes offer an excellent system to explore sexual selection in the fossil record because their readily fossilized carapaces are sexually dimorphic. Specifically, males are relatively more elongate than females in this superfamily. This sexual shape difference is thought to arise so that males carapaces can accommodate their very large copulatory apparatus, which can account for up to one-third of body volume. Here we test this widely held explanation for sexual dimorphism in cytheroid ostracodes by correlating investment in male genitalia, a trait in which sexual selection is seen as the main evolutionary driver, with sexual dimorphism of carapace in the genus Cyprideis. We analyzed specimens collected in the field (C. salebrosa, USA; C. torosa, UK) and from collections of the National Museum of Natural History, Washington, DC (C. mexicana). We digitized valve outlines in lateral view to obtain measures of size (valve area) and shape (elongation, measured as length to height ratio), and obtained several dimensions from two components of the hemipenis: the muscular basal capsule, which functions as a sperm pump, and the section that includes the intromittent organ (terminal extension). In addition to the assessment of this primary sexual trait, we also quantified two dimensions of the male secondary sexual trait-where the transformed right walking leg functions as a clasping organ during mating. We also measured linear dimensions from four limbs as indicators of overall (soft-part) body size, and assessed allometry of the soft anatomy. We observed significant correlations in males between valve size, but not elongation, and distinct structural parts of the hemipenis, even after accounting for their shared correlation with overall body size. We also found weak but significant positive correlation between valve elongation and the degree of sexual dimorphism of the walking leg, but only in C. torosa. The correlation between the hemipenis parts, especially basal capsule size and male valve size dimorphism suggests that sexual selection on sperm size, quantity, and/or efficiency of transfer may drive sexual size dimorphism in these species, although we cannot exclude other aspects of sexual and natural selection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177791PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497955PMC
October 2017

Incidence of influenza virus infection among pregnant women: a systematic review.

BMC Pregnancy Childbirth 2017 May 30;17(1):155. Epub 2017 May 30.

Better Outcomes Registry & Network (BORN), CHEO Research Institute, Ottawa, Canada.

Background: The World Health Organization (WHO) considers pregnant women to be a risk group for severe influenza disease. We conducted a systematic review to evaluate influenza disease incidence in pregnant women in order to inform estimates of influenza vaccine impact for low-resource countries.

Methods: We performed electronic literature searches, targeting studies on the following outcomes in pregnant women: attack rate, hospitalization rate, intensive care unit admission rate, mortality rate, and disability-adjusted life years lost. Only original studies published in peer-reviewed journals that had laboratory confirmation for influenza virus infection and included population-based incidence rates with denominator data were included. We summarized study characteristics in descriptive tables and outcome-specific Forest plots. We generated summary incidence rates using random effects models and assessed statistical heterogeneity by visual examination of Forest plots, and by χ and I tests.

Results: We identified 1543 articles, of which nine articles met the study inclusion criteria. Five were case series, three were cohort studies, and one was a randomized controlled trial. Eight studies were from high-income countries, and one was from an upper middle-income country. Six studies reported results for pandemic influenza, and three reported seasonal influenza. Statistical heterogeneity was high for all outcomes, and methodologies and duration of surveillance varied considerably among studies; therefore, we did not perform meta-analyses.

Conclusions: Study quality was very low according to GRADE criteria. More data on influenza disease incidence in pregnant women, particularly in low- and middle-income countries and for seasonal influenza disease, are needed to inform public health decision-making.
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http://dx.doi.org/10.1186/s12884-017-1333-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450114PMC
May 2017

A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis.

Am J Respir Crit Care Med 2017 08;196(4):502-511

1 University of Washington School of Medicine, Seattle, Washington.

Rationale: The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood.

Objectives: To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis.

Methods: We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection.

Measurements And Main Results: We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2 CD4 T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection.

Conclusions: TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.
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http://dx.doi.org/10.1164/rccm.201611-2346OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564674PMC
August 2017

The SIGLEC14 null allele is associated with Mycobacterium tuberculosis- and BCG-induced clinical and immunologic outcomes.

Tuberculosis (Edinb) 2017 05 21;104:38-45. Epub 2017 Feb 21.

Univ. of Washington, Seattle, WA, USA.

Humans exposed to Mycobacterium tuberculosis (Mtb) have variable susceptibility to tuberculosis (TB) and its outcomes. Siglec-5 and Siglec-14 are members of the sialic-acid binding lectin family that regulate immune responses to pathogens through inhibitory (Siglec-5) and activating (Siglec-14) domains. The SIGLEC14 coding sequence is deleted in a high proportion of individuals, placing a SIGLEC5-like gene under the expression of the SIGLEC14 promoter (the SIGLEC14 null allele) and causing expression of a Siglec-5 like protein in monocytes and macrophages. We hypothesized that the SIGLEC14 null allele was associated with Mtb replication in monocytes, T-cell responses to the BCG vaccine, and clinical susceptibility to TB. The SIGLEC14 null allele was associated with protection from TB meningitis in Vietnamese adults but not with pediatric TB in South Africa. The null allele was associated with increased IL-2 and IL-17 production following ex-vivo BCG stimulation of blood from 10 week-old South African infants vaccinated with BCG at birth. Mtb replication was increased in THP-1 cells overexpressing either Siglec-5 or Siglec-14 relative to controls. To our knowledge, this is the first study to demonstrate an association between SIGLEC expression and clinical TB, Mtb replication, or BCG-specific T-cell cytokines.
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http://dx.doi.org/10.1016/j.tube.2017.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289319PMC
May 2017

Species-Specific Risk Factors, Treatment Decisions, and Clinical Outcomes for Laboratory Isolates of Less Common Nontuberculous Mycobacteria in Washington State.

Ann Am Thorac Soc 2017 Jul;14(7):1129-1138

1 Department of Medicine, School of Medicine and.

Rationale: Nontuberculous mycobacteria (NTM) are a diverse group of environmental organisms that infrequently cause human disease. Understanding of the epidemiologic and clinical characteristics associated with NTM disease is needed to refine diagnostic and treatment strategies, particularly among the less commonly isolated species.

Objectives: To improve knowledge of geographic variance of NTM species, to correlate detailed clinical information with isolation of specific NTM, and to examine the decision to treat and outcomes for specific NTM.

Methods: Mycobacterial cultures submitted to the University of Washington mycobacterial laboratory from 1998 to 2011 were examined. We report isolation frequency and demographic information from all samples with clinical variables. We also examined treatment decisions and outcomes in a subset of patients with Mycobacterium abscessus complex, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium gordonae, Mycobacterium kansasii, Mycobacterium lentiflavum, Mycobacterium porcinum, and Mycobacterium xenopi.

Results: Cultures of NTM were available from 3,470 patients, 937 of whom had clinical data available. When we compared patients born within or outside Washington State, we found that the mycobacterial species frequency varied. Among 168 patients with one of the studied environmental mycobacteria, 72% had major comorbid conditions. Bronchiectasis was common among patients with pulmonary isolation of any NTM, including those with nonpathogenic M. gordonae. Although mortality was high (37%), few deaths were directly attributable to mycobacterial infection. Among 56 patients who met American Thoracic Society criteria for NTM lung disease, 22 were treated, and 19 of those had M. abscessus complex and M. kansasii. The treatment regimens used tended to follow published guidelines.

Conclusions: Isolation of NTM varied by geographic region of origin and location within Washington State. Several clinical risk factors were specific to individual species. Comorbid conditions were common in patients with and without mycobacterial disease. Among patients with one of the studied organisms, there was a high mortality rate more frequently related to comorbid conditions than to mycobacterial disease.
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http://dx.doi.org/10.1513/AnnalsATS.201609-731OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566289PMC
July 2017

Effect of Pregnancy on Interferon Gamma Release Assay and Tuberculin Skin Test Detection of Latent TB Infection Among HIV-Infected Women in a High Burden Setting.

J Acquir Immune Defic Syndr 2017 05;75(1):128-136

*Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA; †Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA; Departments of ‡Research and Programs; §Reproductive Health, Kenyatta National Hospital, Nairobi, Kenya; Departments of ‖Global Health; ¶Biostatistics, University of Washington, Seattle, WA; #Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington Harborview Medical Center, Seattle, WA; **Firland Northwest TB Center, Seattle, WA; and Departments of ††Pediatrics; ‡‡Epidemiology, University of Washington, Seattle, WA.

Background: Peripartum immunologic changes may affect latent tuberculosis infection (LTBI) diagnostic performance among HIV-infected women.

Methods: HIV-infected women were serially tested with tuberculin skin test (TST) and interferon gamma release assay [QuantiFERON TB Gold In-tube (QFT)] in pregnancy and 6 weeks postpartum in Kenya. Prevalence, sensitivity and agreement, and correlates of QFT/TST positivity were assessed. Quantitative QFT mitogen and Mycobacterium tuberculosis antigen (Mtb-Ag) responses were compared by peripartum stage. Incidence of test conversion at 6 weeks postpartum was evaluated in baseline TST-/QFT- women.

Results: Among 100 HIV-infected women, median age was 26 years, median CD4 was 555 cells per cubic millimeter, and 88% were on antiretrovirals. More women were QFT+ than TST+ in both pregnancy (35.4% vs. 13.5%, P = 0.001) and postpartum (29.6% vs. 14.8%, P < 0.001). Among 18 consistently QFT+ women, 8 (44%) converted from TST- to TST+, with improved test agreement postpartum (56.9%, κ = 0.20 to 82.4%, κ = 0.60). Three initially QFT-/TST- women had test conversion (TST+ and/or QFT+), suggesting new infection (incidence 13.4/100 person-years). Mean QFT mitogen (4.46 vs. 7.64 IU/mL, P < 0.001) and Mtb-Ag (1.03 vs. 1.54 IU/mL, P = 0.03) responses were lower among all women retested in pregnancy vs. postpartum, and specifically among persistently QFT+ women (Mtb-Ag: 3.46 vs. 4.48 IU/mL, P = 0.007). QFT indeterminate rate was higher in pregnancy (16%) compared with postpartum (0%) because of lower mitogen response.

Conclusions: QFT identified >2-fold more women with LTBI compared with TST in pregnancy and postpartum. Lower QFT Mtb-Ag and mitogen responses in pregnancy compared with postpartum suggest that pregnancy-associated immunologic changes may influence LTBI test performance.
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http://dx.doi.org/10.1097/QAI.0000000000001298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388595PMC
May 2017

Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection.

J Infect Dis 2016 10 2;214(8):1260-7. Epub 2016 Aug 2.

Department of Medicine, University of Washington School of Medicine.

Background: Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI.

Methods: We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication.

Results: In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy.

Conclusions: These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes.
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http://dx.doi.org/10.1093/infdis/jiw347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034956PMC
October 2016

Latent Tuberculosis Infection Test Agreement in the National Health and Nutrition Examination Survey.

Am J Respir Crit Care Med 2016 08;194(4):493-500

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine.

Rationale: Latent tuberculosis infection (LTBI) test discordance is poorly understood.

Objectives: To determine the frequency and predictors of tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFT) discordance in the U.S.

Methods: We analyzed data from a representative sample of the U.S. population ages 6 years and older who participated in the 2011-2012 National Health and Nutrition Examination Survey. We determined prevalence estimates of test positivity, calculated test agreement and kappa statistics, and performed multivariable logistic regression to determine predictors of discordance.

Measurements And Main Results: LTBI prevalence among the U.S. born ranged from 0.6% to 2.8%, depending on how LTBI was defined, with test agreement 97.0% and kappa 0.27 (95% confidence interval, 0.18-0.36). Prevalence among the foreign born ranged from 9.1% to 20.3%, depending on how LTBI was defined, with test agreement 81.6% and kappa 0.38 (95% confidence interval, 0.33-0.44). TST(+)/QFT(-) discordance was associated with age, male sex, black race, Mexican-American ethnicity, previous TB exposure, and past LTBI treatment in U.S.-born participants, but only with higher lymphocyte count in foreign-born participants. TST(-)/QFT(+) discordance was associated with older age, previous TB exposure, and past LTBI treatment in U.S.-born participants and with older age, male sex, and past LTBI treatment in foreign-born participants.

Conclusions: In the largest population-based sample of concurrently performed TST and QFT tests in a low tuberculosis incidence population, prevalence estimates depended heavily on how LTBI was defined and test agreement was only fair. We identified several predictors of discordance warranting further study.
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http://dx.doi.org/10.1164/rccm.201508-1560OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003328PMC
August 2016
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