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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.

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%.

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.

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.

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.

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.

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.

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.

What's known on the subject? and What does the study add? The history of The Urological Society of Australasia was written by Sally Wilde and published by Hyland House in 1999.Whilst this documented geographical and numerical growth along with some structural changes, it did not discuss the change in and development of organisational structure. This paper describes how the growth of an organisation can at times proceed at a rate not matched by concurrent growth in organisational skill. The need for review of structure and the mechanism to affect change that matches and facilitates growth, together with some of the consequences are discussed. • A review of the history and development of the Urological Society of Australasia now the Urological Society of Australia and New Zealand

Good Clinical Practices (GCPs) are international ethical and quality standards for the design, conduct, performance, monitoring, auditing, analysis, recording, reporting, and regulation of clinical investigations. Clinical investigations are experiments in which a medical product such as a drug is administered or dispensed to, or used involving, one or more human subjects. These standards provide assurance that the rights and confidentiality of the trial subjects are protected and that the data and reported results are credible and accurate. Keywords: sponsor; monitor; compliance; documentation; inspections

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.

This study examined the ability of the HRindex model to accurately predict maximal oxygen uptake ([Formula: see text]O2max) across a variety of incremental exercise protocols. Ten men completed five incremental protocols to volitional exhaustion. Protocols included three treadmill (Bruce, UCLA running, Wellness Fitness Initiative [WFI]), one cycle, and one field (shuttle) test. The HRindex prediction equation (METs = 6 × HRindex - 5, where HRindex = HRmax/HRrest) was used to generate estimates of energy expenditure, which were converted to body mass-specific estimates of [Formula: see text]O2max. Estimated [Formula: see text]O2max was compared with measured [Formula: see text]O2max. Across all protocols, the HRindex model significantly underestimated [Formula: see text]O2max by 5.1 mL·kg(-1)·min(-1) (95% CI: -7.4, -2.7) and the standard error of the estimate (SEE) was 6.7 mL·kg(-1)·min(-1). Accuracy of the model was protocol-dependent, with [Formula: see text]O2max significantly underestimated for the Bruce and WFI protocols but not the UCLA, Cycle, or Shuttle protocols. Although no significant differences in [Formula: see text]O2max estimates were identified for these three protocols, predictive accuracy among them was not high, with root mean squared errors and SEEs ranging from 7.6 to 10.3 mL·kg(-1)·min(-1) and from 4.5 to 8.0 mL·kg(-1)·min(-1), respectively. Correlations between measured and predicted [Formula: see text]O2max were between 0.27 and 0.53. Individual prediction errors indicated that prediction accuracy varied considerably within protocols and among participants. In conclusion, across various protocols the HRindex model significantly underestimated [Formula: see text]O2max in a group of aerobically fit young men. Estimates generated using the model did not differ from measured [Formula: see text]O2max for three of the five protocols studied; nevertheless, some individual prediction errors were large. The lack of precision among estimates may limit the utility of the HRindex model; however, further investigation to establish the model's predictive accuracy is warranted.

The benefits of non-invasive ventilation (NIV) in patients with type 2 respiratory failure secondary to exacerbations of COPD are widely acknowledged [1], but its efficacy in respiratory failure of other aetiologies is less clear. We describe use of NIV (bilevel and/ or continuous positive airway pressure modes) in the subgroup of patients with a clinical diagnosis of pneumonia in a 35-bed adult critical care unit (ACCU).

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 (p0.01). 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.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.

Summary We describe five individuals in whom extra-pulmonary tuberculosis appeared to localise at a site of previous blunt injury. We review other similar case reports where preceding trauma was blunt and non-penetrating, and discuss a possible mechanism involving transport of mycobacteria in monocytes to sites of injury during "latent" tuberculosis infection. This challenges the conventional model proposed for mycobacteria dissemination in tuberculosis disease.

Despite increasing use, limited data has been published comparing safety of different outpatient parenteral antimicrobial therapy (OPAT) models. Potential risks of self-administration at home include venous access device infection and other line complications. This study aims to investigate rates and predictors of intravenous access device complications in a large OPAT cohort. This is a retrospective cohort study of all uses of midlines, peripherally inserted central catheters (PICCs) and tunnelled central venous catheters (TCVCs) with univariate and multivariate (logistic regression) analysis of factors associated with line infections (LIs) and with other line events (OLEs). On univariate analysis, line infections were associated with length of line use, female sex and TCVC lines (compared to midlines). Patients self-administering OPAT in the home had a non-significantly lower rate of LIs. On multivariate analysis only duration of line use was a significant predictor of LIs-OR 1.012 (95%CI 1.001-1.023). For OLEs, multivariate analysis suggested that only line type and use of flucloxacillin were significant explanatory variables. In this cohort, there is no evidence that self-administration of OPAT is associated with higher rates of venous access device complications after controlling for confounding variables.

Background More than 30 years since it was developed for clinical use, the third-generation cephalosporin ceftriaxone remains the most commonly used agent for outpatient parental antimicrobial therapy (OPAT). Recent antimicrobial stewardship programmes have tended to restrict ceftriaxone use in hospitals to control antibiotic resistance and outbreaks of Clostridium difficle infection (CDI). Considering the expansion of OPAT programmes both in the UK and worldwide, revisiting the role of ceftriaxone in OPAT in the context of changing antimicrobial prescribing practices is timely. Aim of the review To identify the evidence base for OPAT, review current and historical data on indications for, and safety of ceftriaxone within the OPAT setting, and to provide some perspectives on the future role of ceftriaxone. Method We searched PubMed and Scopus for articles published in English, and hand searched reference lists. We also conducted a complementary descriptive analysis of prospectively acquired data on the use of ceftriaxone in more than 1,300 OPAT episodes over a 10-year period in our UK centre. Results Ceftriaxone has an excellent safety profile in the OPAT setting, and its broad spectrum of activity makes it an established agent in a wide range of clinical infection syndromes, such as skin and soft-tissue infection, bone and joint infection, streptococcal endocarditis and several others. Intriguingly, in contrast to the inpatient setting, liberal use of ceftriaxone in OPAT has not been strongly linked to CDI, suggesting additional patient and environmental factors may be important in mediating CDI risk.

Excerpt Over two years have elapsed since Astwood1first reported his observations on the use of thiouracil in a patient with thyrotoxicosis. It is now well known that the drug has a remarkable effe...

The mechanism for the production of hydroxyl radical by lignin peroxidase from the white rot fungus Phanerochaete chrysosporium was investigated. Ferric iron reduction was demonstrated in reaction mixtures containing lignin peroxidase isozyme H2 (LiPH2), H2O2, veratryl alcohol, oxalate, ferric chloride, and 1,10-phenanthroline. The rate of iron reduction was dependent on the concentration of oxalate and was inhibited by the addition of superoxide dismutase. The addition of ferric iron inhibited oxygen consumption in reaction mixtures containing LiPH2, H2O2, veratryl alcohol, and oxalate. Thus, the reduction of ferric iron was thought to be dependent on the LiPH2-catalyzed production of superoxide in which veratryl alcohol and oxalate serve as electron mediators. Oxalate production and degradation in nutrient nitrogen-limited cultures of P. chrysosporium was also studied. The concentration of oxalate in these cultures decreased during the period in which maximum lignin peroxidase activity (veratryl alcohol oxidation) was detected. Electron spin resonance studies using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide were used to obtain evidence for the production of the hydroxyl radical in reaction mixtures containing LiPH2, H2O2, veratryl alcohol, EDTA, and ferric chloride. It was concluded that the white rot fungus might produce hydroxyl radical via a mechanism that includes the secondary metabolites veratryl alcohol and oxalate. Such a mechanism may contribute to the ability of this fungus to degrade environmental pollutants.

In 1977 powers to charge those not 'ordinarily resident' in the UK for NHS care were first introduced, and rules governing eligibility for free NHS care have become increasingly complex since. In this issue (p. 156), Dubrey et al present an interpretation of the current regulations and express concern that the treatment of ineligible patients presents a threat to the UK health system. Here we suggest the opposite: increasing attempts to restrict the access of vulnerable humans to health care present a threat both to individual and public health. We challenge all clinicians to provide immediately necessary care and to protect public health.

Firefighting is a hazardous profession which has claimed on average the lives of 105 US firefighters per year for the past decade. The leading cause of line-of-duty mortality is sudden cardiac death, which accounts for approximately 45% of all firefighter duty-related fatalities. Strenuous physical activity, emotional stress, and environmental pollutants all strain the cardiovascular system, and each can increase the risk of sudden cardiac events in susceptible individuals. Sudden cardiac death is more likely to occur during or shortly after emergency duties such as fire suppression, despite the fact that these duties comprise a relatively small proportion of firefighters' annual duties. Additionally, cardiac events are more likely to occur in firefighters who possess an excess of traditional risk factors for cardiovascular disease along with underlying atherosclerosis and/or structural heart disease. In this review, we propose a theoretical model for the interaction between underlying cardiovascular disease in firefighters and the multifactorial physiological strain of firefighting.

In a recent QJM editorial,1 Daniels began by stating that medicine and politics are inextricably intertwined, yet concluded that medical journals should publish less ‘political’ material in favour of a more technical agenda. If journals adopt this approach, they are failing doctors, patients and wider society. Many of the issues that influence both health and the practice of medicine are deemed political; it is therefore appropriate for medical journals to inform health professionals about these issues. Even the best evidence-based technical medical intervention will be unsuccessful if the political solutions that allow it to be implemented are not identified. Jones et al . estimate that the implementation of a limited range of interventions could prevent 63% of the worldwide 10 million deaths per year in the under-5 age group.2 The interventions considered in this analysis were selected based on their evidence and feasibility for high coverage in low-income settings. If the objective is to improve global health, we have to look beyond the randomized control trial to what is really impeding progress, even if this leads us into slightly less comfortable ‘political’ areas. Technical matters are far from being a refuge from politics. Even the most seemingly apolitical and technical medical article profoundly reflects its political environment. As Taracena states, …

The peroxidase isozymes secreted by the white rot fungus Phanerochaete chrysosporium include lignin peroxidases and manganese-dependent peroxidases. The major isozymes, called lignin peroxidases, are thought to oxidize chemicals directly. The manganese-dependent peroxidases (H3, H4, H5, and H9) are relatively minor, making up only a fraction of the total peroxidase protein. However, we have found that lignin peroxidases will also catalyze the H2O2-dependent oxidation of Mn2+ to Mn3+. We have used lignin peroxidase isozyme H2 (LiPH2) to characterize the manganese peroxidase activity of lignin peroxidases. Transient state kinetic studies were used to obtain a second-order rate constant of 4.2 x 10(4) M-1 S-1 for the reaction of LiPH2-compound I with free or chelated Mn2+ at pH 6.0. This reaction was too fast to monitor at pH 4.5. Only chelated Mn2+ could reduce LiPH2-compound II to ferric enzyme. The Mn(2+)-chelate (oxalate) first bound LiPH2-compound II with a Kd of (1.5 +/- 0.3) x 10(-5) M and then reduced LiPH2-compound II to ferric enzyme with a first order rate constant of 215 +/- 6 S-1. Steady-state kinetic studies on LiPH2 were performed by directly monitoring the formation of Mn(3+)-oxalate. These results show that oxidation of Mn2+ by a lignin peroxidase does not occur through free radical mediation as proposed previously [Popp et al. (1990) Biochemistry 29, 10475-10480). Electron spin resonance and oxygen evolution studies also indicate that Mn2+ is directly oxidized by LiPH2.(ABSTRACT TRUNCATED AT 250 WORDS)

When is a disaster not a disaster? In the male medical ward of this ex-mission hospital 400 km north and inland of Durban—right in the heart of Zululand—the answer is easy to find. It is defined by the disaster management posters on the wall: a disaster is a fire, explosion, bomb, war, flood, earthquake, volcanic eruption, tornado, mass food poisoning, hysteria. More recently these posters have been joined by elaborate swine flu protocols. Strictest standards of barrier nursing and high dependency care are advocated. The hospital management has described swine flu as “a crisis, a disaster.” In total there has been one suspected, unconfirmed, case in these wards. In contrast here in KwaZulu, as the HIV pandemic has taken off, admissions to medical wards have increased 300% in the last 15 years. Average age of patient, length of stay, and survival to discharge have all plummeted. National life expectancy has fallen from 62 years in 1992 to 50.5 years in 2007. Statistics South Africa1 indicate that all cause mortality in adults aged 25-49 has increased from …

In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV); these guidelines were updated in 1997 and 1999. This fourth edition of the guidelines, made available on the Internet in 2001, is intended for clinicians and other health-care providers who care for HIV-infected persons. The goal of these guidelines is to provide evidence-based guidelines for preventing OIs among HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or infected children. Nineteen OIs, or groups of OIs, are addressed, and recommendations are included for preventing exposure to opportunistic pathogens, preventing first episodes of disease by chemoprophylaxis or vaccination (primary prophylaxis), and preventing disease recurrence (secondary prophylaxis). Major changes since the last edition of the guidelines include 1) updated recommendations for discontinuing primary and secondary OI prophylaxis among persons whose CD4+ T lymphocyte counts have increased in response to antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for infection with hepatitis C virus; 3) new information regarding transmission of human herpesvirus 8 infection; 4) new information regarding drug interactions, chiefly related to rifamycins and antiretroviral drugs; and 5) revised recommendations for immunizing HIV-infected adults and adolescents and HIV-exposed or infected children.

EDITOR—Kent has around 4000 asylum seekers, many of whom are not registered with a general practitioner. The local medical committee recently wrote to all the members of parliament (MPs) in Kent seeking separate central funding to provide adequate services for refugees and asylum seekers. The committee was concerned that an effective service was unlikely to be provided unless funds were separately identified and also that funds for general medical services would be used to provide a service that takes money from the population as a …

SUMMARY The availability of an increasing number of antiretroviral agents and the rapid evolution of new information has introduced extraordinary complexity into the treatment of HIV-infected persons. In 1996, the Department of Health and Human Services and the Henry J. Kaiser Family Foundation convened the Panel on Clinical Practices for the Treatment of HIV to develop guidelines for the clinical management of HIV-infected adults and adolescents. This report recommends that care should be supervised by an expert, and makes recommendations for laboratory monitoring including plasma HIV RNA, CD4 cell counts and HIV drug resistance testing. The report also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special considerations are provided for adolescents and pregnant women. As with treatment of other chronic conditions, therapeutic decisions require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Antiretroviral regimens are complex, have major side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance due to non-adherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic

Propagation of an array of cracks, due to cooling of a body and crack surfaces has many important applications; e.g. it could greatly increase the rate at which heat can be extracted from a Hot Dry Rock geothermal system. A procedure and numerical program are presented for determining the stresses associated with such a crack array, assuming it is propagating under steady state conditions. The technique employs superposition of the stress fields associated with constant-velocity heat sinks and dislocation distributions can be used to simulate resulting cracking, as described in Part I of the paper.

Inoculation of neonatal CD-1 mice by multiple routes with an amyocarditic temperature-sensitive ( ts ) mutant ( ts 1) derived from a myocarditic parent variant of coxsackievirus B3 (CVB3 m ) resulted in approximately half of the neonates surviving to adolescence. Challenge of the ts 1 survivors with CVB3 m did not induce myocarditis, as assessed by histological examination of heart tissues. Virus was not detected in heart tissues of adolescent ts 1 survivors, but inoculation of these mice with CVB3 m resulted in virus concentrations similar in titers to those found in CVB3 m -inoculated normal adolescent mice. The ts 1 survivors did not contain detectable levels of anti-CVB3 m neutralizing antibody, but upon challenge with CVB3 m they produced antibody more rapidly and to higher titers than did normal CD-1 adolescents after primary inoculation with CVB3 m . Cell-mediated immunity in ts 1 survivors was compared with that of normal mice after challenge with CVB3 m . The capacity for production of migration inhibitory factor was assessed by the agarose droplet cell migration inhibition assay, using peritoneal exudate cells and a CVB3 m cell lysate or KCl-extracted antigens from heart tissues of CVB3 m -inoculated mice. Migration inhibitory factor activity was not detected in cultures of splenic leukocytes from ts 1 survivors of CVB3 m -inoculated ts 1 survivors, but it was readily detected in cultures of splenic leukocytes from CVB3 m -inoculated normal adolescent mice. The [ 3 H]thymidine stimulation assay, performed with splenic lymphoid cells and purified CVB3 m particles, revealed that lymphocytes from normal mice, whether inoculated with CVB3 m or not, were not stimulated by CVB3 m particle antigens, whereas lymphoid cells from a significantly higher proportion of ts 1 survivors, whether inoculated with CVB3 m or not, responded with a stimulation index ≥2.0. The cells responding with positive stimulation were T lymphocytes. A higher proportion of normal mice and ts 1 survivors, both inoculated with CVB3 m , contained splenic cytotoxic T lymphocytes with higher reactivity against CVB3 m -infected neonatal skin fibroblasts than against normal skin fibroblasts, as assessed by a 51 Cr release assay. The group of uninoculated ts 1 survivors present as a high proportion of individuals with cytotoxic T-lymphocyte reactivity against both uninoculated and CVB3 m -inoculated skin fibroblasts. However, ts 1 survivors and normal mice possessed the same proportions of splenic lymphocytes carrying either allele for Lyt 1 and Lyt 2 surface markers. The results suggest two mechanisms by which ts 1 survivors exhibit resistance to CVB3 m induction of myocarditis, namely, the rapid production of high-titered anti-CVB3 m neutralizing antibody in response to CVB3 m inoculation and altered cell-mediated immune responses against CVB3 m -induced viral or novel cellular antigens. The data are compatible with the notion that an immune deviation mechanism, thought to be controlled through a mechanism requiring suppressor cell activity which inhibits macrophage activation in ts 1 survivors, protects these mice from induction of myocarditis.

(1979). General Implications of Noise-Induced Hearing Loss: End Organ and Non-End Organ Effects. Australian Journal of Human Communication Disorders: Vol. 7, No. 1, pp. 52-57.