Detection and genome characterization of Middelburg virus strains isolated from CSF and whole blood samples of humans with neurological manifestations in South Africa.

BACKGROUND: The Old world Alphavirus, Middelburg virus (MIDV), is not well known and although a few cases associated with animal illness have previously been described from Southern Africa, there has been no investigation into the association of the virus with human illness. The current study aimed to investigate possible association of MIDV infection with febrile or neurological manifestations in hospitalized or symptomatic patients fromGauteng, South Africa. METHODS: This study is a descriptive retrospective and prospective laboratory based study. Archived cerebrospinal fluid (CSF) samples submitted to the National Health Laboratory Service (NHLS), Tshwane Academic division for viral investigation from public sector hospitals in Gauteng as well as EDTA (ethylenediaminetetraacetic acid) whole blood samples from ad hoc cases of veterinary students, presenting with neurological and febrile illness, were selected and screened for the presence of alphaviruses using real-time reverse transcription(rtRT) PCR.Virus isolations from rtRT-PCR positive samples were conducted in Vero cell culture and used to obtain full genome sequences. Basic descriptive statistical analysis was conducted using EpiInfo. RESULTS: MIDV was detected by rtRT-PCR in 3/187 retrospective CSF specimens obtained from the NHLS from hospitalised patients in the Tshwane region of Gauteng and 1/2 EDTA samples submitted in the same year (2017) from ad hoc query arbovirus cases from veterinary students from the Faculty of Veterinary Science University of Pretoria.Full genome sequences were obtained for virus isolates from two cases; one from an EDTA whole blood sample (ad hoc case) and another from a CSF sample (NHLS sample).Two of the four Middelburg virus positive cases,for which clinical information was available, had other comorbidities or infections at the time of infection. CONCLUSION: Detection of MIDV in CSF of patients with neurological manifestations suggests that the virus should be investigated as a human pathogen with the potential of causing or contributing to neurological signs in children and adults.

Impact of optimized PET imaging conditions on 18F-FDG uptake quantification in patients with apparently normal aortas.

BACKGROUND: The cardiovascular committee of the European Association of Nuclear Medicine (EANM) recently published recommendations on imaging conditions to be observed during 18F-FDG PET imaging of vascular inflammation. This study aimed to evaluate the impact of applying these optimized imaging conditions on PET quantification of arterial 18F-FDG uptake. METHODS AND RESULTS: Fifty-seven patients were prospectively recruited to undergo an early 18F-FDG PET/CT imaging at 60 minutes and repeat delayed imaging at ≥ 120 minutes post tracer injection. Routine oncologic 18F-FDG PET protocol was observed for early imaging, while delayed imaging parameters were optimized for vascular inflammation imaging as recommended by the EANM. Aortic SUVmax of the ascending aorta and SUVmean from the lumen of the superior vena cava (SVC SUVmean) were obtained on early and delayed imaging. Target-to-background ratio (TBR) was obtained for the early and delayed imaging. Aortic SUVmax increased by a mean of 70%, while SVC SUVmean decreased by a mean of 52% between early and delayed imaging (P < 0.001). TBR increased by 122% following delayed imaging. TBR increased, while SVC SUVmean declined across all time-points from 120 to > 180 minutes. Aortic SUVmax significantly increased at imaging time-points between 120 and 180 minutes. No significant improvement in aortic SUVmax was seen at imaging time-points beyond 180 minutes. CONCLUSIONS: 18F-FDG PET imaging conditions optimized for vascular inflammation imaging lead to an improved quantification through an increase in the quantified vascular tracer uptake and decrease in blood-pool background activity.

Auditory Brainstem Response Test at Different Stimulus Rates in Normal-Hearing Adults Living With HIV.

Purpose The study investigated whether the auditory brainstem response (ABR) at a baseline and at higher repetition rates can detect if neurodegeneration has occurred in adults living with HIV who present with normal behavioral pure-tone thresholds. Method An exploratory research design was used. Forty adults with HIV (80 ears, 57.5% female; M age = 26.3 years, SD = 3.68) and 20 adults without HIV participated. Phase 1 compared ABR absolute and interwave latencies at a baseline rate. Phase 2 examined the effect of HIV status and category of immunodeficiency on ABR absolute Wave V latency and Wave V latency shift at increased stimulus rates. Analysis included a two-way analysis of variance of the interaction between stimulus rate and HIV status and between CD4+ category and rate, and multiple regression analysis. Results In adults living with HIV, the baseline ABR yielded prolonged Wave III and V absolute latencies and interpeak prolongations in 22.5%. Interaural Wave V latency differences were present in 15% of participants. An additional 15% of ears presented with abnormal Wave V at increased rates. No significant interaction between HIV status and rate in either ear or between CD4+ category and rate was found in either ear (p > .05). Although rate and gender contributed significantly to the prediction of Wave V latency of the rate study (left and right, p < .001), HIV status did not (left and right, p > .05). Conclusions Although the interaction of HIV status and CD4+ with rate was not significant, more ears were identified with abnormal results at increased stimulus rates than with the baseline ABR alone. The ABR at increased rates may therefore be a valuable addition for the identification of individuals living with HIV with auditory neural deficiencies.

Exhaled Mycobacterium tuberculosis output and detection of subclinical disease by face-mask sampling: prospective observational studies.

BACKGROUND: Tuberculosis remains a global health challenge, with early diagnosis key to its reduction. Face-mask sampling detects exhaled Mycobacterium tuberculosis. We aimed to investigate bacillary output from patients with pulmonary tuberculosis and to assess the potential of face-mask sampling as a diagnostic method in active case-finding. METHODS: We did a 24-h longitudinal study in patients from three hospitals in Pretoria, South Africa, with microbiologically confirmed pulmonary tuberculosis. Patients underwent 1 h of face-mask sampling eight times over a 24-h period, with contemporaneous sputum sampling. M tuberculosis was detected by quantitative PCR. We also did an active case-finding pilot study in inhabitants of an informal settlement near Pretoria. We enrolled individuals with symptoms of tuberculosis on the WHO screening questionnaire. Participants provided sputum and face-mask samples that were tested with the molecular assay Xpert MTB/RIF Ultra. Sputum-negative and face-mask-positive individuals were followed up prospectively for 20 weeks by bronchoscopy, PET-CT, and further sputum analysis to validate the diagnosis. FINDINGS: Between Sept 22, 2015, and Dec 3, 2015, 78 patients with pulmonary tuberculosis were screened for the longitudinal study, of whom 24 completed the study (20 had HIV co-infection). M tuberculosis was detected in 166 (86%) of 192 face-mask samples and 38 (21%) of 184 assessable sputum samples obtained over a 24-h period. Exhaled M tuberculosis output showed no diurnal pattern and did not associate with cough frequency, sputum bacillary content, or chest radiographic disease severity. On May 16, 2018, 45 individuals were screened for the prospective active case-finding pilot study, of whom 20 had tuberculosis symptoms and were willing to take part. Eight participants were diagnosed prospectively with pulmonary tuberculosis, of whom six were exclusively face-mask positive at screening. Four of these participants (three of whom were HIV-positive) had normal findings on chest radiography but had treatment-responsive early tuberculosis-compatible lesions on PET-CT scans, with Xpert-positive sputum samples after 6 weeks. INTERPRETATION: Face-mask sampling offers a highly efficient and non-invasive method for detecting exhaled M tuberculosis, informing the presence of active infection both with greater consistency and at an earlier disease stage than with sputum samples. The approach shows potential for diagnosis and screening, particularly in difficult-to-reach communities. FUNDING: Wellcome Trust, CARA (Council for At-Risk Academics), University of Leicester, the UK Medical Research Council, and the National Institute for Health Research. VIDEO ABSTRACT.

Auditory, video head impulse test and vestibular evoked myogenic potentials findings in adults with human immunodeficiency virus.

OBJECTIVES: Even though there is an association between hearing loss and human immunodeficiency virus (HIV), particularly in low- and middle-income countries, further research is needed to investigate the nature of such hearing loss. Likewise, despite documented vestibular alterations in people with HIV, the true occurrence, presentation, and nature of these manifestations are yet to be established. Advances in technology for vestibular testing has allowed for objective site-of-lesion tests such as the video head impulse test (vHIT), cervical vestibular evoked myogenic potentials (cVEMPs) and ocular vestibular evoked myogenic potential (oVEMPs). The current study aimed to compare and describe auditory, vHIT, cVEMPs and oVEMPs findings in adults with and without HIV. METHODS: The current study included an HIV positive group (n = 30) and an HIV negative group (n = 30) who underwent an auditory assessment (tympanometry and pure tone audiometry) and objective vestibular assessments. RESULTS: The occurrence of hearing loss was 53.3% in the HIV positive group compared to 33.3% in the HIV negative group. A higher occurrence of vestibular involvement was documented in the HIV positive group (73.3%) compared to 13.3% in the HIV negative group. CONCLUSION: Auditory assessment and objective measures of vestibular end-organ function (vHIT and VEMPs) can be useful to detect sub-clinical alterations. The equipment is mobile and can be performed in any health care setting such as infectious disease clinics for surveillance and monitoring purposes.

Vertical transmission of HIV among pregnant women who initially had false-negative rapid HIV tests in four South African antenatal clinics.

INTRODUCTION: There is a risk of mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding. The aim of this study was to assess vertical transmission of HIV among pregnant women who initially had false-negative rapid HIV tests in South African antenatal care (ANC) clinics. METHODS: Pregnant participants were enrolled in a diagnostic study that used nucleic acid amplification testing (NAAT) to screen for early HIV infection among individuals who tested negative on rapid HIV tests used at the point-of-care (POC) facilities. Participants were enrolled from four ANC clinics in the Tshwane district of South Africa. All NAAT-positive participants were recalled to the clinics for further management. Vertical transmission was assessed among exposed infants whose HIV polymerase chain reaction (PCR) results were available. RESULTS: This study enrolled 8208 pregnant participants who tested negative on rapid HIV tests between 2013 and 2016. Their median age was 26 years (interquartile range [IQR]: 23-30). NAAT detected HIV infections in 0.6% (n = 49; 95% confidence interval {CI}: 0.5-0.8) of all study participants. The distribution of these infections among the four clinics ranged from 0.3%- 1.1%, but this was not statistically significant (p = 0.07). Forty-seven participants (95.9%) were successfully recalled and referred for antiretroviral treatment initiation as part of prevention of MTCT (PMTCT). Most women with newly diagnosed HIV infection presented for the first ANC visit in the second (61.9%, n = 26) and third (31.0%, n = 13) trimesters. HIV PCR results were available for thirty-two infants, three of whom tested positive (9.4%; 95% CI: 1.98-25.02). CONCLUSIONS: This study showed that supplemental HIV testing for pregnant women led to earlier linkage to the PMTCT programme. Inaccurate diagnosis of HIV infection at ANC clinics is likely to undermine the efforts of eliminating MTCT particularly in HIV-endemic settings.

Field performance of the INSTI HIV-1/-2 antibody test in two South African antenatal clinics.

This was a prospective study that assessed field performance of the INSTI HIV-1/-2 antibody test (INSTI test) in two antenatal clinics in South Africa (SA). INSTI test was evaluated against rapid tests used at these clinics, and pooled nucleic acid amplification testing (NAAT) performed for individuals with negative rapid tests. Three hundred and eighty-six pregnant women were enrolled; 334 (86.5%) with negative results on the screening rapid test, and 52 (13.5%; 95% confidence interval [CI]: 10.2-17.3%) with positive results on screening and confirmatory rapid tests. INSTI test yielded the same results as other rapid tests in all participants, thus showing a 100% sensitivity (95% CI: 93.2-100.0%) and specificity (95% CI: 98.9-100.0%). Pooled NAAT was performed for 290 participants who had negative rapid tests, and yielded negative results in all pools. These data show excellent field performance of the INSTI test, and highlight that this test can be implementedat SA clinics.

Monitoring Hearing in an Infectious Disease Clinic with mHealth Technologies.

BACKGROUND: Decentralized detection and monitoring of hearing loss can be supported by new mobile health technologies using automated testing that can be facilitated by minimally trained persons. These may prove particularly useful in an infectious disease (ID) clinic setting where the risk of hearing loss is high. PURPOSE: To evaluate the clinical utility of mobile and automated audiometry hearing health technology in an ID clinic setting. RESEARCH DESIGN: Smartphone-automated pure-tone audiometry (PTA) (hearTest™) and speech-in-noise testing (SA English digits-in-noise [DIN] test) were compared with manual audiometry (2, 4, and 8 kHz). Smartphone-automated PTA and the DIN test were repeated to determine the test-retest reliability. STUDY SAMPLE: Two hundred subjects (73% female and 27% male) were enrolled. Fifty participants were retested with the smartphone applications. Participants ranged from an age of 18 to 55 years with a mean age of 44.4 (8.7 standard deviation). DATA ANALYSIS: Threshold comparisons were made between smartphone audiometry testing and manual audiometry. Smartphone-automated PTA, manual audiometry, and test-retest measures were compared (Wilcoxon signed ranked test). Spearman rank correlation test was used to determine the relationship between the smartphone applications and manual audiometry, as well as for test-retest reliability. RESULTS: Within all participants, 88.2% of thresholds corresponded within 10 dB or less between smartphone audiometry and manual audiometry. There was a significant difference (p < 0.05) between the right ear at 4 and 8 kHz and in the left ear at 2 and 4 kHz between smartphone and manual audiometry, respectively. No significant difference was noted (p < 0.05) between test and retest measures of smartphone technology. CONCLUSIONS: Smartphone audiometry with calibrated headphones provides reliable results in an ID clinic setting and can be used as a baseline and monitoring tool at ID clinics.

Modeling the Airborne Infection Risk of Tuberculosis for a Research Facility in eMalahleni, South Africa.

A detailed mathematical modeling framework for the risk of airborne infectious disease transmission in indoor spaces was developed to enable mathematical analysis of experiments conducted at the Airborne Infections Research (AIR) facility, eMalahleni, South Africa. A model was built using this framework to explore possible causes of why an experiment at the AIR facility did not produce expected results. The experiment was conducted at the AIR facility from August 31, 2015 to December 4, 2015, in which the efficacy of upper room germicidal ultraviolet (GUV) irradiation as an environmental control was tested. However, the experiment did not produce the expected outcome of having fewer infections in the test animal room than the control room. The simulation results indicate that dynamic effects, caused by switching the GUV lights, power outages, or introduction of new patients, did not result in the unexpected outcomes. However, a sensitivity analysis highlights that significant uncertainty exists with risk of transmission predictions based on current measurement practices, due to the reliance on large viable literature ranges for parameters.

Radionuclide imaging of inflammation in atherosclerotic vascular disease among people living with HIV infection: current practice and future perspective.

People living with human immunodeficiency virus (HIV) infection have twice the risk of atherosclerotic vascular disease compared with non-infected individuals. Inflammation plays a critical role in the development and progression of atherosclerotic vascular disease. Therapies targeting inflammation irrespective of serum lipid levels have been shown to be effective in preventing the occurrence of CVD. Radionuclide imaging is a viable method for evaluating arterial inflammation. This evaluation is useful in quantifying CVD risk and for assessing the effectiveness of anti-inflammatory treatment. The most tested radionuclide method for quantifying arterial inflammation among people living with HIV infection has been with F-18 FDG PET/CT. The level of arterial uptake of F-18 FDG correlates with vascular inflammation and with the risk of development and progression of atherosclerotic disease. Several limitations exist to the use of F-18 FDG for PET quantification of arterial inflammation. Many targets expressed on macrophage, a significant player in arterial inflammation, have the potential for use in evaluating arterial inflammation among people living with HIV infection. The review describes the clinical utility of F-18 FDG PET/CT in assessing arterial inflammation as a risk for atherosclerotic disease among people living with HIV infection. It also outlines potential newer probes that may quantify arterial inflammation in the HIV-infected population by targeting different proteins expressed on macrophages.

Human skin volatiles: Passive sampling and GC × GC-ToFMS analysis as a tool to investigate the skin microbiome and interactions with anthropophilic mosquito disease vectors.

Volatile organic compounds (VOCs) emanating from the surfaces of human skin are of great interest to researchers in medical and forensic fields, as well as to biologists studying the ecology of blood-feeding insect vectors of human disease. Research involving the comparison of relative abundances of VOCs emanating from human skin is currently limited by the methodology used for sample collection and pre-concentration. The use of in-house developed silicone rubber (polydimethylsiloxane (PDMS)) passive sampling devices constructed in the form of bracelets and anklets was explored to address this need. The easy-to-use samplers were employed as non-invasive passive sampling devices for the non-targeted collection and concentration of volatile human skin emissions prior to thermal desorption thereof coupled with comprehensive gas chromatographic time-of-flight mass spectrometric (GC × GC-TOFMS) analysis. Compounds collected were from a wide range of compound classes. Several compounds, notably cyclic ketones, identified have not been previously reported in skin volatile literature. Comparison of normalized unique mass peak area signals has revealed relative quantitative differences and similarities between the samples collected from two individuals' wrists and as well as between an individual's wrist and ankle. The sampling method was evaluated based on its ability to provide many candidate compounds for potential biomarker discovery. The results show the ability of the new sampling method for augmenting the current knowledge on human skin volatile emissions. The samplers are both easy to use and economical. Applications explored include the study of the complex relationships between the human skin microbiome and the attractiveness of individuals to anthropophilic blood host seeking mosquitoes.

High risk exposure to HIV among sexually active individuals who tested negative on rapid HIV Tests in the Tshwane District of South Africa-The importance of behavioural prevention measures.

OBJECTIVE: To assess the prevalence of HIV risk behaviour among sexually active HIV sero-negative individuals in the Tshwane district of South Africa (SA). METHODS: Demographic and HIV risk behaviour data were collected on a questionnaire from participants of a cross-sectional study that screened for early HIV infection using pooled nucleic acid amplification testing (NAAT). The study enrolled individuals who tested negative on rapid HIV tests performed at five HIV counseling and testing (HCT) clinics, which included four antenatal clinics and one general HCT clinic. RESULTS: The study enrolled 9547 predominantly black participants (96.6%) with a median age of 27 years (interquartile range [IQR]: 23-31). There were 1661 non-pregnant and 7886 pregnant participants largely enrolled from the general and antenatal HCT clinics, respectively. NAAT detected HIV infection in 61 participants (0.6%; 95% confidence interval [CI]: 0.4-0.8) in the whole study. A high proportion of study participants, 62.8% and 63.0%, were unaware of their partner's HIV status; and also had high prevalence, 88.5% and 99.5%, of recent unprotected sex in the general and pregnant population, respectively. Consistent use of condoms was associated with protection against HIV infection in the general population. Trends of higher odds for HIV infection were observed with most demographic and HIV risk factors at univariate analysis, however, multivariate analysis did not show statistical significance for almost all these factors. A significantly lower risk of HIV infection was observed in circumcised men (p <0.001). CONCLUSIONS: These data show that a large segment of sexually active people in the Tshwane district of SA have high risk exposure to HIV. The detection of newly diagnosed HIV infections in all study clinics reflects a wide distribution of individuals who are capable of sustaining HIV transmission in the setting where HIV risk behaviour is highly prevalent. A questionnaire that captures HIV risk behaviour would be useful during HIV counselling and testing to ensure that there is a systematic way of identifying HIV risk factors and that counselling is optimised for each individual. HIV risk behaviour surveillance could be used to inform relevant HIV prevention interventions that could be implemented at a community or population level.

Detection of Acute and Early HIV-1 Infections in an HIV Hyper-Endemic Area with Limited Resources.

BACKGROUND: Two thirds of the world's new HIV infections are in sub-Saharan Africa. Acute HIV infection (AHI) is the time of virus acquisition until the appearance of HIV antibodies. Early HIV infection, which includes AHI, is the interval between virus acquisition and establishment of viral load set-point. This study aimed to detect acute and early HIV infections in a hyper-endemic setting. METHODS: This was a cross-sectional diagnostic study that enrolled individuals who had negative rapid HIV results in five clinics in South Africa. Pooled nucleic acid amplification testing (NAAT) was performed, followed by individual sample testing in positive pools. NAAT-positive participants were recalled to the clinics for confirmatory testing and appropriate management. HIV antibody, p24 antigen, Western Blot and avidity tests were performed for characterization of NAAT-positive samples. RESULTS: The study enrolled 6910 individuals with negative rapid HIV results. Median age was 27 years (interquartile range {IQR}: 23-31). NAAT was positive in 55 samples, resulting in 0.8% newly diagnosed HIV-infected individuals (95% confidence interval {CI}: 0.6-1.0). The negative predictive value for rapid HIV testing was 99.2% (95% CI: 99.0-99.4). Characterization of NAAT-positive samples revealed that 0.04% (95% CI: 0.000-0.001) had AHI, 0.3% (95% CI: 0.1-0.4) had early HIV infection, and 0.5% (95% CI: 0.5-0.7) had chronic HIV infection. Forty-seven (86%) of NAAT-positive participants returned for follow-up at a median of 4 weeks (IQR: 2-8). Follow-up rapid tests were positive in 96% of these participants. CONCLUSIONS: NAAT demonstrated that a substantial number of HIV-infected individuals are misdiagnosed at South African points-of-care. Follow-up rapid tests done within a 4 week interval detected early and chronic HIV infections initially missed by rapid HIV testing. This may be a practical and affordable strategy for earlier detection of these infections in resource-constrained settings. Newer molecular tests that can be used at the points-of-care should be evaluated for routine diagnosis of HIV in hyper-endemic settings.

Molecular analysis of genetic mutations among cross-resistant second-line injectable drugs reveals a new resistant mutation in Mycobacterium tuberculosis.

Mutations causing mono and cross-resistance among amikacin, kanamycin and capreomycin of second-line injectable drugs (SLIDs) namely are not well understood. We investigated 124 isolates of Mycobacterium tuberculosis for mutations within rrs, eis, tlyA and efflux pump (Rv1258c and Rv0194) genes involved in resistance towards SLIDs. The distribution of mutations across these genes were significantly different in strains with mono-resistance or cross-resistance. A new mutation G878A was found in rrs gene, among strains with capreomycin mono-resistant, or in strains with cross-resistance of capreomycin, kanamycin and amikacin. This mutation was associated with the Euro-American X3 lineage (P < 0.0001). Mutations in the two efflux genes Rv1258c and Rv0194 were confined to strains with only capreomycin/amikacin/kanamycin cross-resistance. We further investigated the minimum inhibitory concentration of capreomycin on isolates with new G878A mutation ranging from 8 µg/mL to 64 µg/mL. Inclusion of G878A on new molecular assays could increase the sensitivity of capreomycin resistance detection.

Mycolic acids, a promising mycobacterial ligand for targeting of nanoencapsulated drugs in tuberculosis.

The appearance of drug-resistant strains of Mycobacterium tuberculosis (Mtb) poses a great challenge to the development of novel treatment programmes to combat tuberculosis. Since innovative nanotechnologies might alleviate the limitations of current therapies, we have designed a new nanoformulation for use as an anti-TB drug delivery system. It consists of incorporating mycobacterial cell wall mycolic acids (MA) as targeting ligands into a drug-encapsulating Poly dl-lactic-co-glycolic acid polymer (PLGA), via a double emulsion solvent evaporation technique. Bone marrow-derived mouse macrophages, either uninfected or infected with different mycobacterial strains (Mycobacterium avium, Mycobacterium bovis BCG or Mtb), were exposed to encapsulated isoniazid-PLGA nanoparticles (NPs) using MA as a targeting ligand. The fate of the NPs was monitored by electron microscopy. Our study showed that i) the inclusion of MA in the nanoformulations resulted in their expression on the outer surface and a significant increase in phagocytic uptake of the NPs; ii) nanoparticle-containing phagosomes were rapidly processed into phagolysosomes, whether MA had been included or not; and iii) nanoparticle-containing phagolysosomes did not fuse with non-matured mycobacterium-containing phagosomes, but fusion events with mycobacterium-containing phagolysosomes were clearly observed.

The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro.

Polymyxins have previously been described to have activity against Mycobacterium tuberculosis (MTB), but further research was abandoned due to systemic toxicity concerns to achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well tolerated when inhaled directly into the lungs, resulting in high local concentrations. We report here for the first time, MIC and MBC data for CMS determined by the microtiter Alamar Blue assay (MABA). We also determined how the MIC would be affected by the presence of pulmonary surfactant (PS) and if any synergy with isoniazid (INH) and rifampicin (RIF) exists. The effect of CMS on the ultrastructure of MTB was also determined. The MIC for CMS was 16 mg/L, while the MBC was 256 mg/L. MIC for CMS in PS was antagonised by eight fold. For synergy, indifference was determined while time-kill assays revealed a greater killing effect when CMS was used together with INH. Ultrastructure analysis suggests that the disruption of the outer polysaccharide layer of MTB by CMS may lead to enhanced uptake of INH. Our findings may provide insight for further investigations of CMS against MTB.

Institutional Tuberculosis Transmission. Controlled Trial of Upper Room Ultraviolet Air Disinfection: A Basis for New Dosing Guidelines.

RATIONALE: Transmission is driving the global tuberculosis epidemic, especially in congregate settings. Worldwide, natural ventilation is the most common means of air disinfection, but it is inherently unreliable and of limited use in cold climates. Upper room germicidal ultraviolet (UV) air disinfection with air mixing has been shown to be highly effective, but improved evidence-based dosing guidelines are needed. OBJECTIVES: To test the efficacy of upper room germicidal air disinfection with air mixing to reduce tuberculosis transmission under real hospital conditions, and to define the application parameters responsible as a basis for proposed new dosing guidelines. METHODS: Over an exposure period of 7 months, 90 guinea pigs breathed only untreated exhaust ward air, and another 90 guinea pigs breathed only air from the same six-bed tuberculosis ward on alternate days when upper room germicidal air disinfection was turned on throughout the ward. MEASUREMENTS AND MAIN RESULTS: The tuberculin skin test conversion rates (>6 mm) of the two chambers were compared. The hazard ratio for guinea pigs in the control chamber converting their skin test to positive was 4.9 (95% confidence interval, 2.8-8.6), with an efficacy of approximately 80%. CONCLUSIONS: Upper room germicidal UV air disinfection with air mixing was highly effective in reducing tuberculosis transmission under hospital conditions. These data support using either a total fixture output (rather than electrical or UV lamp wattage) of 15-20 mW/m(3) total room volume, or an average whole-room UV irradiance (fluence rate) of 5-7 µW/cm(2), calculated by a lighting computer-assisted design program modified for UV use.

Rheumatic fever: a forgotten but still existing cause of fever of unknown origin detected on FDG PET/CT.

We present a case of heterogeneous and strongly increased myocardial and valvular 18F-FDG uptake on 18F-FDG PET/CT in an HIV-positive patient with productive cough, fever, weight loss, and progressive dyspnea for 6 months. Contrast-enhanced CT did not reveal the cause of fever, but hyperechogenic valvular lesions on echocardiography in combination with PET/CT findings are suggestive of endocarditis/myocarditis. Postmortem histology 3 weeks after PET/CT showed Aschoff bodies with Anitschkow cells, pathognomonic for rheumatic carditis. This case illustrates that rheumatic heart disease can be detected on 18F-FDG PET/CT and demonstrates the value of 18F-FDG PET/CT in patients with fever of unknown origin.

Cytomegalovirus viral load kinetics in patients with HIV/AIDS admitted to a medical intensive care unit: a case for pre-emptive therapy.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with severe diseases in immunosuppressed patients; however, there is a lack of data for pre-emptive therapy in patients with HIV/AIDS. METHOD: This was a retrospective study, which enrolled patients diagnosed with HIV/AIDS (CD4<200 cells/µl), who had detectable CMV viral load (VL) during their stay in an adult medical intensive care unit between 2009-2012. RESULTS: After screening 82 patients' records, 41 patients met the enrolment criteria. Their median age was 37 (interquartile range [IQR]: 31-46), and median CD4 count was 29 cells/µl (IQR: 5-55). Sixteen patients (39%) had serial measurements of CMV VL before treatment with ganciclovir. Patients whose baseline CMV VL values were between 1,000-3,000 copies/ml had significantly higher values (median of 14,650 copies/ml) on follow-up testing done 4-12 days later. Those with undetectable VLs at baseline testing had detectable VLs (median of 1,590 copies/ml) mostly within 20 days of follow-up testing. Patients who had VLs >1,000 copies/ml at baseline testing had significantly higher mortality compared to those who had <1,000 copies/ml {hazard ratio of 3.46, p = 0.003 [95% confidence interval (CI): 1.55-7.71]}. Analysis of the highest CMV VL per patient showed that patients who had VLs of >5,100 copies/ml and did not receive ganciclovir had 100% mortality compared to 58% mortality in those who received ganciclovir at VLs of >5,100 copies/ml, 50% mortality in those who were not treated and had low VLs of <5,100 copies/ml, and 44% mortality in those who had ganciclovir treatment at VLs of <5,100 copies/ml (p = 0.084, 0.046, 0.037, respectively). CONCLUSION: This study showed a significantly increased mortality in patients with HIV/AIDS who had high CMV VLs, and suggests that a threshold value of 1,000 copies/ml may be appropriate for pre-emptive treatment in this group.

A comparison of the pharmacokinetics of Aspen Ceftriaxone and Rocephin in community-acquired meningitis.

BACKGROUND: Community-acquired bacterial meningitis (CABM) is a life-threatening condition that is common among immunocompromised individuals. Intravenous ceftriaxone, of which Rocephin (ROC) is the originator brand, is recommended as first-line therapy in South Africa. Despite concerns regarding therapeutic equivalence with generic agents, this is the first study that has been conducted comparing clinical pharmacokinetics (PK) of a generic ceftriaxone formulation with the originator. OBJECTIVE: To compare the PK and safety of Aspen Ceftriaxone (AC) and ROC in the treatment of adult CABM.Methods. A total of 63 eligible patients were randomised 1:1 to receive 2 g of either medication twice daily for a duration based on the identity of the causative organism and their physician's clinical judgment. The primary endpoint of this study was the comparison of clinical PK, specifically the concentrations of each drug in the cerebrospinal fluid with corresponding paired plasma samples. While this study was underpowered to assess efficacy, safety could be evaluated on the basis of reported adverse events. RESULTS: The two patient groups were epidemiologically similar. There were no statistically significant differences in PK between either agent, nor any difference with regard to safety. CONCLUSION: AC can be considered as equivalent to ROC with regard to PK and safety in patients with CABM.