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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/m(2)), 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.

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

Objectives Diagnostic tests for SARS-CoV-2 are important for epidemiology, clinical management, and infection control. Limitations of oro-nasopharyngeal real-time PCR sensitivity have been described based on comparisons of single tests with repeated sampling. We assessed SARS-CoV-2 PCR clinical sensitivity using a clinical and radiological reference standard. Methods Between March-May 2020, 2060 patients underwent thoracic imaging and SARS-CoV-2 PCR testing. Imaging was independently double- or triple-reported (if discordance) by blinded radiologists according to radiological criteria for COVID-19. We excluded asymptomatic patients and those with alternative diagnoses that could explain imaging findings. Associations with PCR-positivity were assessed with binomial logistic regression. Results 901 patients had possible/probable imaging features and clinical symptoms of COVID-19 and 429 patients met the clinical and radiological reference case definition. SARS-CoV-2 PCR sensitivity was 68% (95% confidence interval 64–73), was highest 7-8 days after symptom onset (78% (68–88)) and was lower among current smokers (adjusted odds ratio 0.23 (0.12–0.42) p Conclusions In patients with clinical and imaging features of COVID-19, PCR test sensitivity was 68%, and was lower among smokers; a finding that could explain observations of lower disease incidence and that warrants further validation. PCR tests should be interpreted considering imaging, symptom duration and smoking status.

BackgroundSince 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.MethodsWe 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).FindingsOf 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 (2), 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.InterpretationThe 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%.FundingWorld Health Organization.

AIMS Patients hospitalized at the time of human immunodeficiency virus-associated tuberculosis (HIV-TB) diagnosis have high early mortality. We hypothesized that compared to outpatients, there would be lower anti-TB drug exposure in hospitalized HIV-TB patients, and amongst hospitalized patients exposure would be lower in patients who die or have high lactate (a sepsis marker). METHODS We performed pharmacokinetic sampling in hospitalized HIV-TB patients and outpatients. Plasma rifampicin, isoniazid and pyrazinamide concentrations were measured in samples collected predose and at 1, 2.5, 4, 6 and 8 hours on the third day of standard anti-TB therapy. Twelve-week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed. RESULTS Pharmacokinetic data were collected in 59 hospitalized HIV-TB patients and 48 outpatients. Inpatient 12-week mortality was 11/59 (19%). Rifampicin, isoniazid and pyrazinamide exposure was similar between hospitalized and outpatients (maximum concentration [Cmax ]: 7.4 vs 8.3 μg mL-1 , P = .223; 3.6 vs 3.5 μg mL-1 , P = .569; 50.1 vs 46.8 μg mL-1 , P = .081; area under the concentration-time curve from 0 to 8 hours: 41.0 vs 43.8 mg h L-1 , P = 0.290; 13.5 vs 12.4 mg h L-1 , P = .630; 316.5 vs 292.2 mg h L-1 , P = .164, respectively) and not lower in inpatients who died. Rifampicin and isoniazid Cmax were below recommended ranges in 61% and 39% of inpatients and 44% and 35% of outpatients. Rifampicin exposure was higher in patients with lactate >2.2 mmol L-1 . CONCLUSION Mortality in hospitalized HIV-TB patients was high. Early anti-TB drug exposure was similar to outpatients and not lower in inpatients who died. Rifampicin and isoniazid Cmax were suboptimal in 61% and 39% of inpatients and rifampicin exposure was higher in patients with high lactate. Treatment strategies need to be optimized to improve survival.

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%.

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.

The title diradical was synthesized and investigated by ESR and UV-vis spectroscopy. It was found to have a lifetime of weeks even in the presence of oxygen, and even survives brief heating in toluene up to about 60 °C. In the UV-vis spectrum, the diradical showed reversible thermochromic behavior in the -10 to 50 °C range. In the ESR spectrum, hyperfine analysis showed nearly isolated behavior by the phenoxyl and nitroxide spin carrying units. Upon warming, additional, broad lines appeared at the expense of the lower temperature lines. This temperature behavior was reversible over the 0 to 50 °C range, so long as the raised temperatures were not maintained for long time periods. The spectral behavior is interpreted as being due to temperature-dependent conformational effects on the exchange coupling between the spin carrying units, i.e.

Summary 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.

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 (2), 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.

Background: Mycobacterium tuberculosis bloodstream infection (MTBBSI) is a leading cause of death in people living with HIV. Tools to rapidly identify and quantify MTBBSI could facilitate both diagnosis and research for this critical condition. Methods: We developed a method to detect M. tuberculosis in blood using lysis-wash steps and the Xpert MTB/RIF Ultra platform, testing it on biobanked blood from participants hospitalized with HIV-associated TB. 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. 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, and prognostic value compared to other tuberculosis biomarkers models to predict 12-week mortality. Findings: Of 582 participants, 447 (77%) had tuberculosis; 165 out of 447 were blood Xpert-Ultra positive giving diagnostic yield 0·37 (95%CI 0·32 to 0·42). Diagnostic yield increased with lower CD4 cell count or haemoglobin, and outperformed urine lipoarabinomannan testing in participants with elevated venous lactate. Quantitative blood Xpert-Ultra results predicted mortality better than other tuberculosis biomarkers including blood culture, and urine lipoarabinomannan or urine-Xpert. Both blood Xpert-Ultra positivity and cycle threshold were strongly associated with a principal component of clinical phenotype capturing markers of inflammation, tissue damage and organ dysfunction. 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 MTBBSI bacillary load is causally related to outcomes. Funding Information: Wellcome Trust, Fogarty International Center, South African MRC, NIHR(UK), National Research Foundation of South Africa. Declaration of Interests: All authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the University of Cape Town Human Research Ethics Committee (HREC 057/2013).

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.

Violence is a pervasive theme of the Apocalypse, rooted in the very nature of the genre, which envisions a cosmic conflict between God and the forces of evil. John draws on two ancient symbols to tell this story: Holy War and the Exodus plagues. The violence he pictures pervades not only the plot but also the images and language used. This imagery is excessive; indeed, it seems beyond the bounds of civility, raising serious ethical issues. For some readers, these issues are so problematic that they would reject the work; others seek to explain (or explain away) the violence, either by showing that the violence is symbolic of some nonviolent alternative or by subsuming the violence under some overarching value such as justice. Neither approach is entirely satisfactory, and the reader is left to wrestle with the paradox of a story of justice told in actions and images that are inescapably unjust.

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 .

BackgroundDespite increasing numbers of human immunodeficiency virus (HIV)–infected South Africans receiving antiretroviral therapy (ART), tuberculosis (TB) remains the leading cause of mortality. Approximately 25% of patients treated for TB have microbiologically unconfirmed diagnoses. We assessed whether elevated Kaposi’s sarcoma–associated herpesvirus (KSHV) viral load (VL) contributes to mortality in hospitalized HIV-infected patients investigated for TB.MethodsSix hundred eighty-two HIV-infected patients admitted to Khayelitsha Hospital, South Africa, were recruited, investigated for TB, and followed for 12 weeks. KSHV serostatus, peripheral blood KSHV-VL, and KSHV-associated clinical correlates were evaluated.ResultsMedian CD4 count was 62 (range, 0–526) cells/μL; KSHV seropositivity was 30.7% (95% confidence interval [CI], 27%–34%); 5.8% had detectable KSHV-VL (median, 199.1 [range, 13.4–2.2 × 106] copies/106 cells); 22% died. Elevated KSHV-VL was associated with mortality (adjusted odds ratio, 6.5 [95% CI, 1.3–32.4]) in patients without TB or other microbiologically confirmed coinfections (n = 159). Six patients had “possible KSHV-inflammatory cytokine syndrome” (KICS): 5 died, representing significantly worse survival (P < .0001), and 1 patient was diagnosed with KSHV-associated multicentric Castleman disease at autopsy.ConclusionsGiven the association of mortality with elevated KSHV-VL in critically ill HIV-infected patients with suspected but not microbiologically confirmed TB, KSHV-VL and KICS criteria may guide diagnostic and therapeutic evaluation.

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.For this purpose, 108 hot flushes were objectively assessed in a laboratory setting in 72 symptomatic postmenopausal women (aged 45.8 ± 5.1 years; body mass index 25.9 ± 4.5 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).In the 20 minutes before a spontaneous hot flush, core temperature increased by 0.03 ± 0.12C (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 ± 0.2 vs 36.8 ± 0.3°C; P = 0.06).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.

The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degrees of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wave front sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of 1 nm/Hz at Fourier frequencies above 100 mHz. © 2019 authors. Published by the American Physical Society.

Background In high-burden settings, case fatality rates are reported to be between 11% and 32% in hospitalized patients with HIV-associated tuberculosis, yet the underlying causes of mortality remain poorly characterized. Understanding causes of mortality could inform the development of novel management strategies to improve survival. We aimed to assess clinical and microbiologic determinants of mortality and to characterize the pathophysiological processes underlying death by evaluating host soluble inflammatory mediators and determined the relationship between these mediators and death as well as biomarkers of disseminated tuberculosis. Methods and findings Adult patients with HIV hospitalized with a new diagnosis of HIV-associated tuberculosis were enrolled in Cape Town between 2014 and 2016. Detailed tuberculosis diagnostic testing was performed. Biomarkers of tuberculosis dissemination and host soluble inflammatory mediators at baseline were assessed. Of 682 enrolled participants, 576 with tuberculosis (487/576, 84.5% microbiologically confirmed) were included in analyses. The median age was 37 years (IQR = 31–43), 51.2% were female, and the patients had advanced HIV with a median cluster of differentiation 4 (CD4) count of 58 cells/L (IQR = 21–120) and a median HIV viral load of 5.1 log10 copies/mL (IQR = 3.3–5.7). Antituberculosis therapy was initiated in 566/576 (98.3%) and 487/576 (84.5%) started therapy within 48 hours of enrolment. Twelve-week mortality was 124/576 (21.5%), with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Clinical and microbiologic determinants of mortality included disseminated tuberculosis (positive urine lipoarabinomannan [LAM], urine Xpert MTB/RIF, or tuberculosis blood culture in 79.6% of deaths versus 60.7% of survivors, p = 0.001), sepsis syndrome (high lactate in 50.8% of deaths versus 28.9% of survivors, p < 0.001), and rifampicin-resistant tuberculosis (16.9% of deaths versus 7.2% of survivors, p = 0.002). Using non-supervised two-way hierarchical cluster and principal components analyses, we describe an immune profile dominated by mediators of the innate immune system and chemotactic signaling (interleukin-1 receptor antagonist [IL-1Ra], IL-6, IL-8, macrophage inflammatory protein-1 beta [MIP-1β]/C-C motif chemokine ligand 4 [CCL4], interferon gamma-induced protein-10 [IP-10]/C-X-C motif chemokine ligand 10 [CXCL10], MIP-1 alpha [MIP-1α]/CCL3), which segregated participants who died from those who survived. This immune profile was associated with mortality in a Cox proportional hazards model (adjusted hazard ratio [aHR] = 2.2, 95%CI = 1.9–2.7, p < 0.001) and with detection of biomarkers of disseminated tuberculosis. Clinicians attributing causes of death identified tuberculosis as a cause or one of the major causes of death in 89.5% of cases. We did not perform longitudinal sampling and did not have autopsy-confirmed causes of death. Conclusions In this study, we did not identify a major contribution from coinfections to these deaths. Disseminated tuberculosis, sepsis syndrome, and rifampicin resistance were associated with mortality. An immune profile dominated by mediators of the innate immune system and chemotactic signaling was associated with both tuberculosis dissemination and mortality. These findings provide pathophysiologic insights into underlying causes of mortality and could be used to inform the development of novel treatment strategies and to develop methods to risk stratify patients to appropriately target novel interventions. Causal relationships cannot be established from this study., In a prospective cohort study, Charlotte Schutz and colleagues identify biomarkers and clinical characteristics associated with tuberculosis dissemination and death in patients with HIV and TB., Author summary Why was this study done? Patients with HIV who are hospitalized with new tuberculosis are at high risk of death even after starting on standard antituberculosis treatment, and the reasons for this are not well understood. To facilitate the development of novel treatment strategies that improve survival, a better understanding of the cause of these deaths is required. What did the researchers do and find? We enrolled 576 patients with HIV hospitalized with a new diagnosis of tuberculosis and followed them up for 12 weeks. We systematically performed diagnostic tests for tuberculosis in blood and urine as a measure of tuberculosis dissemination (the spread of tuberculosis through the body via the bloodstream). We characterized the immune response in blood of these patients and compared these measures in patients who died with those who survived. In our study, 22% of patients died within 12 weeks, and those who had a greater number of positive measures for tuberculosis dissemination were more likely to die. An immune profile characterized by increased markers of the innate immune response and proteins that attract innate cells to tissue was associated with mortality, and this profile was also associated with more disseminated tuberculosis. What do these findings mean? Our findings provide novel insights into the immune response associated with death in patients with HIV who are severely ill with tuberculosis. This knowledge can be used to design, evaluate, and monitor new treatment strategies, including immune-based therapies. Our study evaluated immune responses at a single time point prior to treatment, and future studies should evaluate these responses longitudinally on antituberculosis treatment.

Background: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis blood stream infection (MTB-BSI) is incompletely understood. We hypothesised that MTB-BSI prevalence has been underestimated, that MTB-BSI independently predicts death, and sputum Xpert has suboptimal diagnostic yield for MTB-BSI. Methods: We conducted a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood-culture (TBBC), including HIV-positive adults aged ≥13-years with suspected tuberculosis. Predicted probabilities of MTB-BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum (Xpert or culture if Xpert unavailable) and urinelipoarabinomannan for MTB-BSI were obtained by two-level random-effect meta-analysis, mortality hazard of MTB-BSI by mixed-effect Cox proportional-hazard modelling, and effect of treatment delay with propensity-score analysis. Findings 5751 patients met inclusion criteria. Predicted probability of MTB-BSI was 45% (95%CI 38-52%) for danger-sign positive tuberculosis inpatients with cohort median CD4 count of 76 cells/μL. Diagnostic yield of sputum was 77% (95%CI 63–87%), rising to 89% (95%CI 80-94%) when combined with urinelipoarabinomannan testing. MTB-BSI increased hazard of death before 30-days (aHR2·5, 95%CI 2·1–3·1). In a propensity-score matched cohort (n=630), mortality increased with treatment delay >4 days in MTB-BSI (OR 3·2, 95%CI 1·1–10·3). Interpretation: In critically-ill adults with HIV-tuberculosis, MTB-BSI is a very frequent manifestation of tuberculosis and strongly predicts mortality. Better diagnostic yield in patients with MTB-BSI can be achieved by parallel use of sputum-Xpert and urine-LAM. Treatment delay may increase mortality hazard. Funding Statement: This study was supported by Wellcome fellowships 109105z/15/a, 105165/Z14/A. Charlotte Schutz was funded by the South African Medical Research Council under the National Health Scholars Programme. Moshi, Tanzania research was supported by an International Studies on AIDS Associated Co-infections (ISAAC) award, a program funded by the US National Institutes of Health (NIH) (U01 AI062563). John A. Crump receives support from US NIH R01AI121378. Elizabeth L. Corbett is supported by a Wellcome trust senior fellowship in clinical science (WT200901). Gary Maartens was supported in part by National Research Fund incentive funding (UID: 85810). Susan E. Dorman was supported by contract #HHSN2722000900050C and grant K24AI104830 (to SED), both from the US National Institutes of Health. Douglas Wilson was supported by BMS Secure the Future. Graeme Meintjes was supported by the Wellcome Trust (098316 and 203135/Z/16/Z), the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787), NRF incentive funding (UID: 85858) and the South African Medical Research Council through its TB and HIV Collaborating Centres Programme with funds received from the National Department of Health (RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014). Declaration of Interests: David Alland is on the Scientific Advisory Board of Specific Technologies and receives a portion of the licensing income paid by Cepheid to Rutgers University for sales of the Xpert Ultra assay. Neil Martinson has received institutional grants for collection of specimens for Roche and Becton Dickinson, and from Pfizer for assessing incident pneumonia. All other authors declare no competing interests. Ethics Approval Statement: PROSPERO registration: CRD42016050022.

BACKGROUND Many modern anesthetic machines offer automated control of anesthetic vapor. The user simply sets a desired end-tidal concentration and the machine will manipulate the vaporizer and gas flow rates to obtain and maintain the preset target. Greater efficiency, and more accurate delivery of anesthetic vapor have been documented across multiple machines within the adult setting however, there is little evidence for their use in children. AIMS The aim of this study was to compare the consumption of sevoflurane using the Maquet Flow-i anesthesia machine (Maquet, Solna, Sweden) in automatic gas control mode vs manual mode in pediatric anesthesia. The primary outcome measure is rate of sevoflurane use. METHOD Data logs were collected from our three Maquet Flow-i anesthesia machines over a 4-week period. We compared the rate of sevoflurane use when in manual mode vs cases where the automatic gas control mode was used. We also examined each automatic gas control case to determine whether percentage of anesthesia time in this mode correlated significantly with average rate of sevoflurane consumption. RESULTS Sevoflurane was the primary anesthetic used in 220 cases, comprising over 230 hours of anesthesia time. Of these, 36 cases were identified as automatic gas control cases and 184 as manual cases. Consumption of sevoflurane liquid in mL/min was significantly lower in automatic gas control cases (median 0.46, IQR 0.32-0.72 mL/min for automatic gas control; median 0.82, IQR 0.62-1.17 mL/min for manual; P

Background: Most tuberculosis-related deaths in people living with HIV (PLHIV) could be prevented with earlier diagnosis and treatment. The only commercially available tuberculosis point-of-care test (Alere DetermineTM TB LAM Ag (AlereLAM)) has suboptimal sensitivity which restricts its use in clinical practice. The novel Fujifilm SILVAMP TB LAM (FujiLAM) test was designed to achieve superior diagnostic accuracy. Methods: We performed a blinded assessment of FujiLAM on biobanked urine samples from three independent prospective cohort studies of hospitalized PLHIV at two South African district hospitals. Diagnostic accuracy was determined against both microbiological (MRS) and composite reference standards (CRS, including clinical diagnoses), in comparison with AlereLAM. Findings: A total of 968 newly admitted PLHIV were included. The prevalence of microbiologically-confirmed TB was 62% and the median CD4 count 86 cells/µl. In a meta-analysis, the estimated sensitivity of the FujiLAM was superior at 70·4% (95%CI: 53·0-83·1) over that of AlereLAM at 42·3% (31·7-51·8), against the MRS, with a difference of 28.1% (21.5-34.4). Specificities were 90·8% (86·0-94·4) and 95·0% (87·7-98·8) for the FujiLAM and AlereLAM against the MRS, respectively, with a non-significant difference of -4.2% (-12.7-4.4). Against the CRS, specificities of both assays were higher (FujiLAM 95·7% and AlereLAM 98·2%) but sensitivities were lower (FujiLAM 64·9% and AlereLAM 38·2%). In the subgroup of patients with CD4 ≤100 cells/µl, the sensitivity of FujiLAM was 84·2% (71·4-91·4) versus 57·3% (42·2-69·6) for AlereLAM. Interpretation: In comparison to AlereLAM, FujiLAM offers superior diagnostic sensitivity, while maintaining specificity, and has the potential to transform rapid point-of-care tuberculosis diagnosis for hospitalized PLHIV. FujiLAM's suitability for settings of intended use needs to be assessed in a prospective evaluation. Funding: GHIT Fund, UK DFID, Dutch MoFA, BMGF, Australian DFAT, German BMBF through KfW, Wellcome Trust, DST/ NRF of South Africa, and South African MRC. Declaration of Interest: TB, EI, AM, SO, CCB, and CMD are 384 employed by FIND. FIND is a not for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND’s independence and neutrality vis-a-vis the companies whose products get evaluated and describe roles and responsibilities. AP and TB report patents in the field of lipoarabinomannan detection. All other authors declare no competing interests. Ethical Approval: All study-related activities were approved by the Human Research Ethics Committee (HREC) of the University of Cape Town (UCT). Written informed consent was obtained from patients, as per study protocols. Study participation did not affect standard of care. Reporting followed STARD guidelines.12 167 Retrospective urine LAM testing was supervised by the sponsor, FIND, and was performed at UCT in April 2018.

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.

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

It is recommended that venous thromboembolism (VTE) prophylaxis be considered for patients receiving outpatient parenteral antimicrobial therapy (OPAT), but there is no published data to quantify VTE risk in this patient group.The aim of this retrospective cohort study was to establish VTE incidence in patients managed through an OPAT service and assess utility of a common VTE prediction score normally used for inpatients. Consecutive episodes of OPAT between May 2009 and May 2012 were included. Patients on long-term anti-coagulants, those with an established indication for extended, outpatient VTE prophylaxis (i.e. patients referred to OPAT following hip or knee arthroplasty) were excluded. The Padua VTE Prediction Score was retrospectively applied to the cohort. The primary outcome was incidence of symptomatic VTE during or up to 90 days after completion of OPAT treatment.There were 780 included patient episodes; 105 (13.5%) patients had a Padua VTE risk score3; no patients received pharmacological VTE prophylaxis during OPAT treatment. During or up to 90 days following OPAT, two proximal lower limb DVTs were diagnosed, giving VTE incidence of 2/780 (0.26%, 95% CI: 0.03-0.92%), and there were eight deaths of which none were suspected to be related to VTE. There was one intracranial haemorrhage associated death.This retrospective cohort study found a low incidence of VTE in OPAT patients, and does not support routine application of inpatient VTE prophylaxis algorithms to patients treated for infection in the community.

Outpatient parenteral antimicrobial therapy (OPAT) refers to outpatient or community-based management of an infection via the administration of an intravenous (IV) antimicrobial without an overnight hospital stay. Patients may be managed without admission or may transition to OPAT following hospitalisation. By minimising hospital stay, OPAT is increasingly recognised as a cost-efficient and acceptable management strategy for a variety of selected patients requiring either short- or medium-to long-term parenteral therapy in the UK (Table ​(Table11).1–5 This short article outlines good practice recommendations and highlights OPAT management of infections commonly encountered by physicians with acute medical duties. Table 1. Characteristics of recently published UK OPAT service cohorts.

Outpatient parenteral antimicrobial therapy (OPAT) refers to the administration of a parenteral antimicrobial in a non inpatient or ambulatory setting with the explicit aim of facilitating admission avoidance or early discharge. Whilst OPAT has predominantly been the domain of the infection specialist, the internal medicine specialist has a key role in service development and delivery as a component of broader ambulatory care initiatives such as "hospital at home". Main drivers for OPAT are patient welfare, reduction of risk of health care associated infection and cost-effective use of hospital resources. The safe practice of OPAT is dependent on a team approach with careful patient selection and antimicrobial management with programmed and adaptable clinical monitoring and assessment of outcome. Gram-positive infections, including cellulitis, bone and joint infection, bacteraemia and endocarditis are key infections potentially amenable to OPAT whilst resistant Gram-negative infections are of increasing importance. Ceftriaxone, teicoplanin, daptomycin and ertapenem lend themselves well to OPAT due to daily (or less frequent) bolus administration, although any antimicrobial may be administered if the patient is trained to administer and/or an appropriate infusion device is employed. Clinical experience from NHS Greater Glasgow and Clyde is presented to illustrate the key principles of OPAT as practised in the UK. Increasingly complex patients with multiple medical needs, the relative scarcity of inpatient resources and the broader challenge of ambulatory care and "hospital at home" will ensure the internal medicine specialist will have a key role in the future development of OPAT.

This paper focuses on the design, development and assessment of a novel, 2 degrees-of-freedom magnetic pipe inspection robot. It consists of 4 mecanum wheels, with the diagonals functionally coupled and the system rotation constrained by the surface geometry, maintaining full translational mobility with reduced control and actuation requirements. The system uses positional encoding that is decoupled from the transmission system to overcome the main sources of positional/positioning errors when using mecanum wheels. The kinematic and dynamic models of the system are derived and integrated within the controller. The prototype robot is then tested and shown to follow a scan path at 20mm/s within ±1.5mm whilst correcting for gravitational drift and slip events.

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.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 (p0.001) during rehabilitation. Initial vital signs and changes in vital signs during recovery were highly variable.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.

Use of outpatient parenteral antimicrobial therapy (OPAT) is increasing in settings with advanced healthcare systems internationally. This study describes a large OPAT service cohort developed in the west of Scotland and includes trends over a 10-year period of this service. Data were retrieved from a prospectively maintained electronic case database. Patient and logistic variables were collated for all OPAT episodes (n=2638, resulting in 39035 days of patient care over 10 years). Skin and soft-tissue infections and bone and joint infections accounted for 77% of OPAT cases, but a wide range of other conditions have been treated in this cohort. Outcome variables were evaluated for all first OPAT attendances (n=2233), amongst which a successful outcome (cure or improvement) was found for 2063 (92.4%). Unplanned admission was observed in 9.1% of patients (6.3 events per 1000 OPAT patient days). Healthcare-associated infection rates were low: amongst first OPAT attendances, 14 intravenous line infections were observed (0.4 per 1000 OPAT patient days). Statistically significant trends over time included: a decrease in OPAT treatment time; increased referrals from non-local and secondary care sources; increased rate of co-morbidity of OPAT referrals; and increased self/carer administration of antimicrobials. Outcome proportions (success and adverse events) did not vary over time. This cohort study adds to the increasing observational data suggesting that OPAT is safe, effective and acceptable for treating a wide variety of infections. Observed trends over a 10-year period suggest that this model of infection management is adaptable and sustainable.

Summary Substantial changes are needed to achieve a more targeted and strategic approach to investment in the response to the HIV/AIDS epidemic that will yield long-term dividends. Until now, advocacy for resources has been done on the basis of a commodity approach that encouraged scaling up of numerous strategies in parallel, irrespective of their relative effects. We propose a strategic investment framework that is intended to support better management of national and international HIV/AIDS responses than exists with the present system. Our framework incorporates major efficiency gains through community mobilisation, synergies between programme elements, and benefits of the extension of antiretroviral therapy for prevention of HIV transmission. It proposes three categories of investment, consisting of six basic programmatic activities, interventions that create an enabling environment to achieve maximum effectiveness, and programmatic efforts in other health and development sectors related to HIV/AIDS. The yearly cost of achievement of universal access to HIV prevention, treatment, care, and support by 2015 is estimated at no less than US$22 billion. Implementation of the new investment framework would avert 12·2 million new HIV infections and 7·4 million deaths from AIDS between 2011 and 2020 compared with continuation of present approaches, and result in 29·4 million life-years gained. The framework is cost effective at $1060 per life-year gained, and the additional investment proposed would be largely offset from savings in treatment costs alone.

Johns Revelation wrestles with the question of how Jesus' followers were to live under the imperial domination of Rome. While some see John as establishing an alternative imperial system, attention to the irony with which the story is told reveals a more compelling critique of power.

The book of Revelation is neither a guide to the end of the world nor a handbook of theology. It is a narrative in which John recounts what happened to him on Patmos, describes what he saw and heard when he ascended into the sky/heaven, and recounts the cosmic conflict between the forces of good and evil—an ultimate Holy War. It is thus a complicated narrative, recounting both John’s actions (what happened to him) and the actions he recounts in the stories he tells (what he saw and heard). He functions as both the narrator and as a character in the story. This article explores various techniques used to tell the story, including its genre, structure and plot, temporal and spatial distortions, narrative performance and characterizations, and narrative rhetoric.

BACKGROUND The Wellness-Fitness Initiative submaximal treadmill exercise test (WFI-TM) is recommended by the US National Fire Protection Agency to assess aerobic capacity (VO2 max) in firefighters. However, predicting VO2 max from submaximal tests can result in errors leading to erroneous conclusions about fitness. AIMS To investigate the level of agreement between VO2 max predicted from the WFI-TM against its direct measurement using exhaled gas analysis. METHODS The WFI-TM was performed to volitional fatigue. Differences between estimated VO2 max (derived from the WFI-TM equation) and direct measurement (exhaled gas analysis) were compared by paired t-test and agreement was determined using Pearson Product-Moment correlation and Bland-Altman analysis. Statistical significance was set at P < 0.05. RESULTS Fifty-nine men performed the WFI-TM. Mean (standard deviation) values for estimated and measured VO2 max were 44.6 (3.4) and 43.6 (7.9) ml/kg/min, respectively (P < 0.01). The mean bias by which WFI-TM overestimated VO2 max was 0.9ml/kg/min with a 95% prediction interval of ±13.1. Prediction errors for 22% of subjects were within ±5%; 36% had errors greater than or equal to ±15% and 7% had greater than ±30% errors. The correlation between predicted and measured VO2 max was r = 0.55 (standard error of the estimate = 2.8ml/kg/min). CONCLUSIONS WFI-TM predicts VO2 max with 11% error. There is a tendency to overestimate aerobic capacity in less fit individuals and to underestimate it in more fit individuals leading to a clustering of values around 42ml/kg/min, a criterion used by some fire departments to assess fitness for duty.

In this paper we model expected risks and returns on government bonds, allowing for partial integration of national and world bond markets. Using a conditional asset pricing model that permits variation in the price of, and exposure to, risk, we find strong evidence that national markets are only partially integrated into world markets. Around one quarter of total expected excess returns is related to local market risk; the remainder being due to world bond market risk. A range of parameter stability tests rejects the hypothesis of time-variation in the level of integration.

Life on the outside The European economic and monetary union (EMU) is now over 4 years old. In this paper we assess whether monetary union has begun to have significant economic effects by comparing countries in EMU with the EU countries outside. We focus principally on trade creation between EMU member countries, using a methodology that controls for the fact that the decision to join the monetary union was not random but was more likely to be taken by countries whose prospects of trading with other EMU members were already high. We find that the trade effects of monetary union are significant. We estimate that had the UK been inside EMU the sum of its imports and exports could have been substantially greater. For comparative purposes, we also make preliminary estimates of the effect of monetary union on three other dimensions of economic performance: foreign direct investment, the development of financial markets and overall macroeconomic performance, though we recognize that our ability to control for other factors is more limited in respect of these other indicators. The evidence suggests that inward investment in the countries outside would have been greater had they joined EMU, but that the impact of this on GDP would be no more than 0.3% of GDP per annum for the UK and less than that for the other ‘outs’. Financial market activity shows no clear sign of having been affected by EMU, and London’s position as Europe’s financial centre remains, as yet, largely unchallenged. On standard measures of aggregate performance – inflation, unemployment and output – no clear pattern of EMU effects has yet emerged. — David Barr, Francis Breedon and David Miles