"SILVAMP TB LAM" Rapid Urine Tuberculosis Test Predicts Mortality in Patients Hospitalized With Human Immunodeficiency Virus in South Africa.

Reducing diagnostic delay is key toward decreasing tuberculosis-associated deaths in people living with human immunodeficiency virus. In tuberculosis patients with retrospective urine testing, the point-of-care Fujifilm SILVAMP TB LAM (FujiLAM) could have rapidly diagnosed tuberculosis in up to 89% who died. In FujiLAM negative patients, the probability of 12-week survival was 86-97%.

HIV-Associated Mycobacterium tuberculosis Bloodstream Infection Is Underdiagnosed by Single Blood Culture.

We assessed the additional diagnostic yield for Mycobacterium tuberculosis bloodstream infection (BSI) by doing more than one tuberculosis (TB) blood culture from HIV-infected inpatients. In a retrospective analysis of two cohorts based in Cape Town, South Africa, 72/99 (73%) patients with M. tuberculosis BSI were identified by the first of two blood cultures during the same admission, with 27/99 (27%; 95% confidence interval [CI], 18 to 36%) testing negative on the first culture but positive on the second. In a prospective evaluation of up to 6 blood cultures over 24 h, 9 of 14 (65%) patients with M. tuberculosis BSI had M. tuberculosis grow on their first blood culture; 3 more patients (21%) were identified by a second independent blood culture at the same time point, and the remaining 2 were diagnosed only on the 4th and 6th blood cultures. Additional blood cultures increase the yield for M. tuberculosis BSI, similar to what is reported for nonmycobacterial BSI.

Medical Monitoring During Firefighter Incident Scene Rehabilitation.

OBJECTIVE: The objective of this study was to retrospectively investigate aspects of medical monitoring, including medical complaints, vital signs at entry, and vital sign recovery, in firefighters during rehabilitation following operational firefighting duties. RESULTS: Incident scene rehabilitation logs obtained over a 5-year span that included 53 incidents, approximately 40 fire departments, and more than 530 firefighters were reviewed. Only 13 of 694 cases involved a firefighter reporting a medical complaint. In most cases, vital signs were similar between firefighters who registered a complaint and those who did not. On average, heart rate was 104 ± 23 beats·min(-1), systolic blood pressure was 132 ± 17 mmHg, diastolic blood pressure was 81 ± 12 mmHg, and respiratory rate was 19 ± 3 breaths·min(-1) upon entry into rehabilitation. At least two measurements of heart rate, systolic blood pressure, diastolic blood pressure, and respiratory rate were obtained for 365, 383, 376, and 160 cases, respectively. Heart rate, systolic and diastolic blood pressures, and respiratory rate decreased significantly (p < 0.001) during rehabilitation. Initial vital signs and changes in vital signs during recovery were highly variable. CONCLUSIONS: Data from this study indicated that most firefighters recovered from the physiological stress of firefighting without any medical complaint or symptoms. Furthermore, vital signs were within fire service suggested guidelines for release within 10 or 20 minutes of rehabilitation. The data suggested that vital signs of firefighters with medical symptoms were not significantly different from vital signs of firefighters who had an unremarkable recovery.

Assessment of bone mineral density in tenofovir-treated patients with chronic hepatitis B: can the fracture risk assessment tool identify those at greatest risk?

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is an established nucleotide analogue in the treatment of chronic hepatitis B. Bone mineral density loss has been described in TDF-treated patients with human immunodeficiency virus infection, but limited data exist for patients with chronic hepatitis B. Dual X-ray absorptiometry (DEXA) was used to determine bone mineral density changes in TDF-exposed patients. We evaluated the accuracy of the Fracture Risk Assessment Tool (FRAX) as an alternative to DEXA in clinical practice. METHODS: A total of 170 patients were studied: 122 were exposed to TDF, and 48 were controls. All patients underwent DEXA, and demographic details were recorded. FRAX scores (before and after DEXA) were calculated. RESULTS: TDF was associated with a lower hip T score (P = .02). On univariate and multivariate analysis, advancing age, smoking, lower body mass index, and TDF exposure were independent predictors of low bone mineral density. In addition, the pre-DEXA FRAX score was an accurate predictor of the post-DEXA FRAX treatment recommendation (100% sensitivity and 83% specificity), area under the curve 0.93 (95% CI, .87-.97, P < .001). CONCLUSIONS: TDF-treated patients with chronic hepatitis B have reduced bone mineral density, but the reduction is limited to 1 anatomical site. Age and advanced liver disease are additional contributing factors, underlining the importance of multifactorial fracture risk assessment. FRAX can accurately identify those at greatest risk of osteoporotic fracture.

Risk factors for failure of outpatient parenteral antibiotic therapy (OPAT) in infective endocarditis.

OBJECTIVES: To identify risk factors for failure of outpatient antibiotic therapy (OPAT) in infective endocarditis (IE). PATIENTS AND METHODS: We identified IE cases managed at a single centre over 12 years from a prospectively maintained database. 'OPAT failure' was defined as unplanned readmission or antibiotic switch due to adverse drug reaction or antibiotic resistance. We analysed patient and disease-related risk factors for OPAT failure by univariate and multivariate logistic regression. We also retrospectively collected follow-up data on adverse disease outcome (defined as IE-related death or relapse) and performed Kaplan-Meier survival analysis up to 36 months following OPAT. RESULTS: We identified 80 episodes of OPAT in IE. Failure occurred in 25/80 episodes (31.3%). On multivariate analysis, cardiac or renal failure [pooled OR 7.39 (95% CI 1.84-29.66), P=0.005] and teicoplanin therapy [OR 8.69 (95% CI 2.01-37.47), P=0.004] were independently associated with increased OPAT failure. OPAT failure with teicoplanin occurred despite therapeutic plasma levels. OPAT failure predicted adverse disease outcome up to 36 months (P=0.016 log-rank test). CONCLUSIONS: These data caution against selecting patients with endocarditis for OPAT in the presence of cardiac or renal failure and suggest teicoplanin therapy may be associated with suboptimal OPAT outcomes. Alternative regimens to teicoplanin in the OPAT setting should be further investigated.

Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction models for pulmonary tuberculosis screening among outpatients living with HIV: an individual participant data meta-analysis.

BACKGROUND: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg·L-1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs). METHODS: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal-external cross-validation to evaluate performance. RESULTS: We pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg·L-1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg·L-1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively. CONCLUSIONS: CRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg·L-1 cut-off or in a CPM depends on available resources.

Clinicopathological correlates in HIV seropositive tuberculosis cases presenting with jaundice after initiating antiretroviral therapy with a structured review of the literature.

BACKGROUND: The development of jaundice after initiation of HAART in HIV-TB co-infected patients is a challenging presentation in resource constrained settings, and is often attributed to drug induced liver injury (DILI).Some investigators have described hepatic tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) as a cause of liver disease in patients initiating HAART, which could also cause jaundice. CASE PRESENTATIONS: We report the clinical and histopathological features of five HIV-TB co-infected patients presenting with a syndrome of jaundice, tender hepatomegaly, bile canalicular enzyme rise and return of constitutional symptoms within 8 weeks of initiation of highly active antiretroviral therapy (HAART) for advanced HIV infection at a rural clinic in KwaZulu Natal, South Africa.All five patients had been diagnosed with tuberculosis infection prior to HAART initiation and were on antituberculous medication at time of developing jaundice. There was evidence of multiple aetiologies of liver injury in all patients. However, based on clinical course and pathological findings, predominant hepatic injury was thought to be drug induced in one case and hepatic tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in the other four.In these later 4 patients, liver biopsy findings included necrotising and non-necrotising granulomatous inflammation in the lobules and portal tracts. The granulomas demonstrated - in addition to epithelioid histiocytes and Langhans giant cells - neutrophils, plasma cells and large numbers of lymphocytes, which are not features of a conventional untreated tuberculous response. CONCLUSION: In this high TB prevalent, low resource setting, TB-IRIS may be an important cause of jaundice post-HAART initiation. Clinicopathological correlation is essential for optimal diagnosis. Further multi-organ based histopathological studies in the context of immune reconstitution would be useful to clinicians in low resource settings dealing with this challenging presentation.

Firefighter's personal protective equipment and the chronotropic index.

The purpose of this study was to investigate the effects of personal protective equipment (PPE) on cardiovascular and metabolic responses during incremental exercise, and to determine if PPE affects the relationship between heart rate (HR) and oxygen uptake when expressed as the chronotropic index (CI). Ten male participants performed graded exercise tests under three conditions: control (CON), (PPE) and weighted vest (WV) (same weight as PPE). Time to exhaustion was significantly longer in the CON compared to the other conditions (p < 0.01). Submaximal oxygen uptake and HR were significantly lower in the CON compared to the PPE and WV conditions. The CI (CON, 32.2 ± 4.5; PPE, 31.7 ± 5.7; WV, 32.6 ± 4.9) was similar in all three conditions. This study has shown that additional weight and encapsulating clothing leads to elevations in HR and oxygen uptake compared to a control condition, however, the CI remains unaffected. PRACTITIONER SUMMARY: Firefighters wear personal protective equipment that is designed to protect the wearer; however it also imposes a physiological burden. It is known that work in firefighting PPE increases cardiovascular and metabolic strain. This study has shown that PPE does not alter the relationship between heart rate and oxygen uptake.

Xpert Ultra testing of blood in severe HIV-associated tuberculosis to detect and measure Mycobacterium tuberculosis blood stream infection: a diagnostic and disease biomarker cohort study.

BACKGROUND: Mycobacterium tuberculosis bloodstream infection is a leading cause of death in people living with HIV and disseminated bacillary load might be a key driver of disease severity. We aimed to assess Xpert MTB/RIF Ultra (Xpert Ultra) testing of blood as a diagnostic for M tuberculosis bloodstream infection and investigate cycle threshold as a quantitative disease biomarker. METHODS: In this cohort study, we obtained biobanked blood samples from a large and well characterised cohort of adult patients admitted to hospital in Western Cape, South Africa with suspected HIV-associated tuberculosis and a CD4 count less than 350 cells per µL. Patients already receiving antituberculosis therapy were excluded. Samples were obtained on recruitment within 72 h of admission to hospital, and patients were followed up for 12 weeks to determine survival. We tested the biobanked blood samples using the Xpert Ultra platform after lysis and wash processing of the blood. We assessed diagnostic yield (proportion of cases detected, with unavailable test results coded as negative) against a microbiological reference, both as a function of markers of critical-illness and compared with other rapid diagnostics (urine lipoarabinomannan and sputum Xpert). Quantitative blood Xpert Ultra results were evaluated as a disease biomarker by assessing association with disease phenotype defined by principal component analysis of 32 host-response markers. Prognostic value compared to other tuberculosis biomarkers was assessed using likelihood ratio testing of nested models predicting 12-week mortality. FINDINGS: Between Jan 16, 2014, and Oct 19, 2016, of the 659 participants recruited to the parent study, 582 had an available biobanked blood sample. 447 (77%) of 582 met the microbiological reference standard for tuberculosis diagnosis. Median CD4 count was 62 (IQR 221-33) cells per µL, and 123 (21%) of participants died by 12-weeks follow-up. Blood Xpert Ultra was positive in 165 (37%) of 447 participants with confirmed tuberculosis by the microbiological reference standard, with a diagnostic yield of 0·37 (95% CI 0·32-0·42). Diagnostic yield increased with lower CD4 count or haemoglobin, and outperformed urine lipoarabinomannan testing in participants with elevated venous lactate. Quantitative blood Xpert Ultra results were more closely associated with mortality than other tuberculosis biomarkers including blood culture, and urine lipoarabinomannan, or urine Xpert (all p<0·05). A principal component of clinical phenotype capturing markers of inflammation, tissue damage, and organ dysfunction was strongly associated with both blood Xpert-Ultra positivity (associated with a SD increase of 1·1 in PC score, p<0·0001) and cycle threshold (r= -0·5; p<0·0001). INTERPRETATION: Xpert Ultra testing of pre-processed blood could be used as a rapid diagnostic test in critically ill patients with suspected HIV-associated tuberculosis, while also giving additional prognostic information compared with other available markers. A dose-response relationship between quantitative blood Xpert Ultra results, host-response phenotype, and mortality risk adds to evidence that suggests M tuberculosis bloodstream infection bacillary load is causally related to outcomes. FUNDING: Wellcome Trust, National Institute of Health Fogarty International Center, South African MRC, UK National Institute of Health Research, National Research Foundation of South Africa. TRANSLATIONS: For the Xhosa and Afrikaans translations of the abstract see Supplementary Materials section.

Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis.

BACKGROUND: Despite being highly prevalent in hospitalised patients with severe HIV-associated tuberculosis (TB) and sepsis, little is known about the mycobacteriology of Mycobacterium tuberculosis bloodstream infection (MTBBSI). We developed methods to serially measure bacillary load in blood and used these to characterise MTBBSI response to anti-TB therapy (ATT) and relationship with mortality. METHODS: We established a microscopy method for direct visualisation of M. tuberculosis bacilli in blood using a novel lysis-concentration protocol and the fluorescent probe, 4-N,N-dimethylaminonaphthalimide-trehalose (DMN-Tre). We tested blood using GeneXpert® MTB/RIF-Ultra (Xpert-ultra) and Myco/F lytic culture after processing blood through lysis-wash steps to remove PCR inhibitors and anti-microbial drug carry-over. HIV-positive patients predicted to have MTBBSI gave blood samples 0, 4, 24, 48 and 72 h after ATT initiation. Bacillary loads were quantified using microscopy, Xpert-ultra cycle threshold, and culture time-to-positivity. Pharmacodynamics were modelled using these measures combined on an ordinal scale, including association with 12-week mortality. FINDINGS: M. tuberculosis was detected in 27 of 28 recruited participants; 25 (89%) by blood Xpert-ultra, 22 (79%) by DMN-Tre microscopy, and 21 (75%) by Myco/F lytic blood culture. Eight (29%) participants died by 12-week follow-up. In a combined pharmacodynamic model, predicted probabilities of negative DMN-Tre microscopy, blood Xpert-ultra, or blood culture after 72 h treatment were 0·64, 0·27, and 0·94, respectively, in those who survived, compared with 0·23, 0·06, and 0·71 in those who died (posterior probability of slower clearance of MTBBSI in those that died >0·99). DMN-Tre microscopy of blood demonstrated heterogenous bacillary morphologies, including microcolonies and clumps. Bacillary cell-length varied significantly with ATT exposure (mean cell-length increase 0·13 log-µm/day; 95%CrI 0·10-0·16). INTERPRETATION: Pharmacodynamics of MTBBSI treatment can be captured using DMN-Tre microscopy, blood Xpert-ultra and culture. This could facilitate interventional trials in severe HIV-associated TB. FUNDING: Wellcome Trust, NIH Fogarty International Center, South African MRC, NIHR(UK), National Research Foundation of South Africa.

Diagnostic accuracy of WHO screening criteria to guide lateral-flow lipoarabinomannan testing among HIV-positive inpatients: A systematic review and individual participant data meta-analysis.

BACKGROUND: WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria followed by AlereLAM if screen positive) with AlereLAM and FujiLAM (a novel LF-LAM test) testing in all HIV-positive inpatients. METHODS: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were (1) AlereLAM or FujiLAM for screening tests/strategies and (2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM testing in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively. FINDINGS: We obtained data from all 5 identified studies (n = 3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/µL) had high sensitivities but low specificities; cough (≥2 weeks), hemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 88% and 96%, respectively. In 2 studies that collected sputum and non-sputum samples for Xpert and/or culture, diagnostic yield of sputum Xpert was 40-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 61%, 81%, and 92% of all cases, respectively. INTERPRETATION: WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis. FUNDING: None.

Tuberculosis screening among HIV-positive inpatients: a systematic review and individual participant data meta-analysis.

BACKGROUND: Since 2011, WHO has recommended that HIV-positive inpatients be routinely screened for tuberculosis with the WHO four-symptom screen (W4SS) and, if screened positive, receive a molecular WHO-recommended rapid diagnostic test (eg, Xpert MTB/RIF [Xpert] assay). To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm (ie, W4SS followed by Xpert) with Xpert for all HIV-positive inpatients. METHODS: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011, to March 1, 2020, for studies of adult and adolescent HIV-positive inpatients enrolled regardless of tuberculosis signs and symptoms. The separate reference standards were culture and Xpert. Xpert was selected since it is most likely to be the confirmatory test used in practice. We assessed the proportion of inpatients eligible for Xpert testing using the WHO algorithm; assessed the accuracy of W4SS and alternative screening tests or strategies to guide diagnostic testing; and compared the accuracy of the WHO Xpert algorithm (W4SS followed by Xpert) with Xpert for all. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy by fitting random-effects bivariate models, and assessed diagnostic yield descriptively. This systematic review has been registered on PROSPERO (CRD42020155895). FINDINGS: Of 6162 potentially eligible publications, six were eligible and we obtained data for all of the six publications (n=3660 participants). The pooled proportion of inpatients eligible for an Xpert was 90% (95% CI 89-91; n=3658). Among screening tests to guide diagnostic testing, W4SS and C-reactive protein (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin concentration (<8 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had higher specificities (61-90%) but suboptimal sensitivities (12-57%). The WHO Xpert algorithm (W4SS followed by Xpert) had a sensitivity of 76% (95% CI 67-84) and specificity of 93% (88-96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (95% CI 69-85) and specificity was 93% (87-96; n=639). In two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of sputum Xpert was 41-70% and 61-64% for urine Xpert. INTERPRETATION: The W4SS and other potential screening tests to guide Xpert testing have suboptimal accuracy in HIV-positive inpatients. On the basis of these findings, WHO now strongly recommends molecular rapid diagnostic testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10%. FUNDING: World Health Organization.

Flow cytometry method for absolute counting and single-cell phenotyping of mycobacteria.

Detection and accurate quantitation of viable Mycobacterium tuberculosis is fundamental to understanding mycobacterial pathogenicity, tuberculosis (TB) disease progression and outcomes; TB transmission; drug action, efficacy and drug resistance. Despite this importance, methods for determining numbers of viable bacilli are limited in accuracy and precision owing to inherent characteristics of mycobacterial cell biology-including the tendency to clump, and "differential" culturability-and technical challenges consequent on handling an infectious pathogen under biosafe conditions. We developed an absolute counting method for mycobacteria in liquid cultures using a bench-top flow cytometer, and the low-cost fluorescent dyes Calcein-AM (CA) and SYBR-gold (SG). During exponential growth CA + cell counts are highly correlated with CFU counts and can be used as a real-time alternative to simplify the accurate standardisation of inocula for experiments. In contrast to CFU counting, this method can detect and enumerate cell aggregates in samples, which we show are a potential source of variance and bias when using established methods. We show that CFUs comprise a sub-population of intact, metabolically active mycobacterial cells in liquid cultures, with CFU-proportion varying by growth conditions. A pharmacodynamic application of the flow cytometry method, exploring kinetics of fluorescent probe defined subpopulations compared to CFU is demonstrated. Flow cytometry derived Mycobacterium bovis bacillus Calmette-Guérin (BCG) time-kill curves differ for rifampicin and kanamycin versus isoniazid and ethambutol, as do the relative dynamics of discrete morphologically-distinct subpopulations of bacilli revealed by this high-throughput single-cell technique.

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

Is core temperature the trigger of a menopausal hot flush?

OBJECTIVE: Menopausal hot flushes negatively impact quality of life and may be a biomarker of cardiovascular and metabolic disease risk; therefore understanding the physiology of hot flushes is important. Current thinking is that a small elevation (∼0.03-0.05C) in core temperature surpasses a sweating threshold (that is reduced in the menopause), sweating is activated, and a hot flush ensues. Nevertheless, more recent studies examining thermoregulatory control question whether core temperature per se can explain the trigger for a hot flush. The primary aim of this study was to assess the contribution of increases in core temperature on the occurrence of menopausal hot flushes. METHODS: For this purpose, 108 hot flushes were objectively assessed in a laboratory setting in 72 symptomatic postmenopausal women (aged 45.8 ±â€Š5.1 years; body mass index 25.9 ±â€Š4.5 kg/m) from five previously reported studies. Women rested, wearing a tube-lined suit (or trousers), which was perfused with 34C water. A subset then underwent mild heat stress (48°C water). Sweat rate, skin blood flow, blood pressure, heart rate, skin, and core temperature were measured continuously throughout. A hot flush was objectively identified during rest (spontaneous hot flush) or mild heating as an abrupt increase in sternal sweat rate. Further, a subset of symptomatic postmenopausal women (n = 22) underwent whole-body passive heating for 60 minutes to identify core temperature thresholds and sensitivities for sweat rate and cutaneous vasodilation, which were compared to a subset of premenopausal women (n = 18). Data were analyzed using t tests and/or general linear modeling, and are presented as mean (95% confidence interval). RESULTS: In the 20 minutes before a spontaneous hot flush, core temperature increased by 0.03 ±â€Š0.12C (P < 0.05), but only 51% of hot flushes were preceded by an increase in core temperature. During mild heating, 76% of hot flushes were preceded by an increase in core temperature. The temperature thresholds for sweating were similar, but the vasodilatory threshold was higher in postmenopausal compared with premenopausal women (37.1 ±â€Š0.2 vs 36.8 ±â€Š0.3°C; P = 0.06). CONCLUSION: We provide new evidence that menopausal hot flushes are unlikely triggered by an increase in core temperature. These findings provide important information about the physiology of hot flushes that have implications for treatment and management options for menopausal hot flushes.

Novel lipoarabinomannan point-of-care tuberculosis test for people with HIV: a diagnostic accuracy study.

BACKGROUND: Most tuberculosis-related deaths in people with HIV could be prevented with earlier diagnosis and treatment. The only commercially available tuberculosis point-of-care test (Alere Determine TB LAM Ag [AlereLAM]) has suboptimal sensitivity, which restricts its use in clinical practice. The novel Fujifilm SILVAMP TB LAM (FujiLAM) assay has been developed to improve the sensitivity of AlereLAM. We assessed the diagnostic accuracy of the FujiLAM assay for the detection of tuberculosis in hospital inpatients with HIV compared with the AlereLAM assay. METHODS: For this diagnostic accuracy study, we assessed biobanked urine samples obtained from the FIND Specimen Bank and the University of Cape Town Biobank, which had been collected from hospital inpatients (aged ≥18 years) with HIV during three independent prospective cohort studies done at two South African hospitals. Urine samples were tested using FujiLAM and AlereLAM assays. The conduct and reporting of each test was done blind to other test results. The primary objective was to assess the diagnostic accuracy of FujiLAM compared with AlereLAM, against microbiological and composite reference standards (including clinical diagnoses). FINDINGS: Between April 18, 2018, and May 3, 2018, urine samples from 968 hospital inpatients with HIV were evaluated. The prevalence of microbiologically-confirmed tuberculosis was 62% and the median CD4 count was 86 cells per µL. Using the microbiological reference standard, the estimated sensitivity of FujiLAM was 70·4% (95% CI 53·0 to 83·1) compared with 42·3% (31·7 to 51·8) for AlereLAM (difference 28·1%) and the estimated specificity of FujiLAM was 90·8% (86·0 to 94·4) and 95·0% (87·7-98·8) for AlereLAM (difference -4·2%). Against the composite reference standard, the specificity of both assays was higher (95·7% [92·0 to 98·0] for FujiLAM vs 98·2% [95·7 to 99·6] for AlereLAM; difference -2·5%), but the sensitivity of both assays was lower (64·9% [50·1 to 76·7] for FujiLAM vs 38·2% [28·1 to 47·3] for AlereLAM; difference 26·7%). INTERPRETATION: In comparison to AlereLAM, FujiLAM offers superior diagnostic sensitivity, while maintaining specificity, and could transform rapid point-of-care tuberculosis diagnosis for hospital inpatients with HIV. The applicability of FujiLAM for settings of intended use requires prospective assessment. FUNDING: Global Health Innovative Technology Fund, UK Department for International Development, Dutch Ministry of Foreign Affairs, Bill & Melinda Gates Foundation, German Federal Ministry of Education and Research, Australian Department of Foreign Affairs and Trade, Wellcome Trust, Department of Science and Technology and National Research Foundation of South Africa, and South African Medical Research Council.

Disseminated tuberculosis among hospitalised HIV patients in South Africa: a common condition that can be rapidly diagnosed using urine-based assays.

HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood-culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3-6.4; and 2.4, 95%CI = 1.3-4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials.

Serial image analysis of Mycobacterium tuberculosis colony growth reveals a persistent subpopulation in sputum during treatment of pulmonary TB.

Faster elimination of drug tolerant 'persister' bacteria may shorten treatment of tuberculosis (TB) but no method exists to quantify persisters in clinical samples. We used automated image analysis to assess whether studying growth characteristics of individual Mycobacterium tuberculosis colonies from sputum on solid media during early TB treatment facilitates 'persister' phenotyping. As Time to Detection (TTD) in liquid culture inversely correlates with total bacterial load we also evaluated the relationship between individual colony growth parameters and TTD. Sputum from TB patients in Malawi was prepared for solid and liquid culture after 0, 2 and 4 weeks of treatment. Serial photography of agar plates was used to measure time to appearance (lag time) and radial growth rate for each colony. Mixed-effects modelling was used to analyse changing growth characteristics from serial samples. 20 patients had colony measurements recorded at ≥1 time-point. Overall lag time increased by 6.5 days between baseline and two weeks (p = 0.0001). Total colony count/ml showed typical biphasic elimination, but long lag time colonies (>20days) had slower, monophasic decline. TTD was associated with minimum lag time (time to appearance of first colony1). Slower elimination of long lag time colonies suggests that these may represent a persister subpopulation of bacilli.