Lipoarabinomannan in sputum to detect bacterial load and treatment response in patients with pulmonary tuberculosis: Analytic validation and evaluation in two cohorts.

BACKGROUND: Lipoarabinomannan (LAM) is a major antigen of Mycobacterium tuberculosis (MTB). In this report, we evaluated the ability of a novel immunoassay to measure concentrations of LAM in sputum as a biomarker of bacterial load prior to and during treatment in pulmonary tuberculosis (TB) patients. METHODS AND FINDINGS: Phage display technology was used to isolate monoclonal antibodies binding to epitopes unique in LAM from MTB and slow-growing nontuberculous mycobacteria (NTM). Using these antibodies, a sandwich enzyme-linked immunosorbent assay (LAM-ELISA) was developed to quantitate LAM concentration. The LAM-ELISA had a lower limit of quantification of 15 pg/mL LAM, corresponding to 121 colony-forming units (CFUs)/mL of MTB strain H37Rv. It detected slow-growing NTMs but without cross-reacting to common oral bacteria. Two clinical studies were performed between the years 2013 and 2016 in Manila, Philippines, in patients without known human immunodeficiency virus (HIV) coinfection. In a case-control cohort diagnostic study, sputum specimens were collected from 308 patients (aged 17-69 years; 62% male) diagnosed as having pulmonary TB diseases or non-TB diseases, but who could expectorate sputum, and were then evaluated by smear microscopy, BACTEC MGIT 960 Mycobacterial Detection System (MGIT) and Lowenstein-Jensen (LJ) culture, and LAM-ELISA. Some sputum specimens were also examined by Xpert MTB/RIF. The LAM-ELISA detected all smear- and MTB-culture-positive samples (n = 70) and 50% (n = 29) of smear-negative but culture-positive samples (n = 58) (versus 79.3%; 46 positive cases by the Xpert MTB/RIF), but none from non-TB patients (n = 56). Among both LAM and MGIT MTB-culture-positive samples, log10-transformed LAM concentration and MGIT time to detection (TTD) showed a good inverse relationship (r = -0.803, p < 0.0001). In a prospective longitudinal cohort study, 40 drug-susceptible pulmonary TB patients (aged 18-69 years; 60% male) were enrolled during the first 56 days of the standard 4-drug therapy. Declines in sputum LAM concentrations correlated with increases of MGIT TTD in individual patients. There was a 1.29 log10 decrease of sputum LAM concentration, corresponding to an increase of 221 hours for MGIT TTD during the first 14 days of treatment, a treatment duration often used in early bactericidal activity (EBA) trials. Major limitations of this study include a relatively small number of patients, treatment duration up to only 56 days, lack of quantitative sputum culture CFU count data, and no examination of the correlation of sputum LAM to clinical cure. CONCLUSIONS: These results indicate that the LAM-ELISA can determine LAM concentration in sputum, and sputum LAM measured by the assay may be used as a biomarker of bacterial load prior to and during TB treatment. Additional studies are needed to examine the predictive value of this novel biomarker on treatment outcomes.

A thermal stress treadmill walk for clinic evaluation of candidates for hazardous materials (HazMat) duty.

UNLABELLED: U.S. guidance for examining hazmat workers recommends stress testing be considered when heat stress is expected. However, the most common stress test-Bruce protocol treadmill electrocardiography (BPTE) wearing gym clothes-creates little thermal stress. OBJECTIVE: Evaluate a novel thermal stress treadmill walk (TSTW). METHODS: Body temperatures and heart rates during BPTE in 93 current and potential hazmat workers wearing gym clothes were compared with later values in 35 of these subjects while they were wearing thermally-restrictive "sauna suits" during a 45-min TSTW. Physiological strain index (PSI) was calculated from temperature and heart rate changes and compared with PSI values from hazmat simulations and climatic chamber exercises. RESULTS: Tympanic temperature (TT) rose 0.5°C (SD 0.5) during BPTE lasting 12.4 min (SD 2.9). PSI reached 6.0 (SD 1.3). TT rose 1.0°C (SD 0.5) during TSTW, p < .01. PSI averaged 6.6 (SD 1.9) in 29 subjects who completed TSTW, versus 5.7 (SD 5.7) in the 6 subjects who did not. Ingested thermistor temperatures increased more than did TT during TSTW, yielding PSI of 7.0 (SD 1.5), equal to PSI values from climatic chamber exercises, i.e., 7.0 (SD 1.0). CONCLUSION: TSTW increased body temperature and PSI in 29 of the 35 subjects who completed it to levels matching those of operational simulations in climatic chambers and during hazmat exercises. This TSTW may be useful for evaluating candidates for hazmat duty.

Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study.

BACKGROUND: The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA, USA) can detect tuberculosis and its multidrug-resistant form with very high sensitivity and specificity in controlled studies, but no performance data exist from district and subdistrict health facilities in tuberculosis-endemic countries. We aimed to assess operational feasibility, accuracy, and effectiveness of implementation in such settings. METHODS: We assessed adults (≥18 years) with suspected tuberculosis or multidrug-resistant tuberculosis consecutively presenting with cough lasting at least 2 weeks to urban health centres in South Africa, Peru, and India, drug-resistance screening facilities in Azerbaijan and the Philippines, and an emergency room in Uganda. Patients were excluded from the main analyses if their second sputum sample was collected more than 1 week after the first sample, or if no valid reference standard or MTB/RIF test was available. We compared one-off direct MTB/RIF testing in nine microscopy laboratories adjacent to study sites with 2-3 sputum smears and 1-3 cultures, dependent on site, and drug-susceptibility testing. We assessed indicators of robustness including indeterminate rate and between-site performance, and compared time to detection, reporting, and treatment, and patient dropouts for the techniques used. FINDINGS: We enrolled 6648 participants between Aug 11, 2009, and June 26, 2010. One-off MTB/RIF testing detected 933 (90·3%) of 1033 culture-confirmed cases of tuberculosis, compared with 699 (67·1%) of 1041 for microscopy. MTB/RIF test sensitivity was 76·9% in smear-negative, culture-positive patients (296 of 385 samples), and 99·0% specific (2846 of 2876 non-tuberculosis samples). MTB/RIF test sensitivity for rifampicin resistance was 94·4% (236 of 250) and specificity was 98·3% (796 of 810). Unlike microscopy, MTB/RIF test sensitivity was not significantly lower in patients with HIV co-infection. Median time to detection of tuberculosis for the MTB/RIF test was 0 days (IQR 0-1), compared with 1 day (0-1) for microscopy, 30 days (23-43) for solid culture, and 16 days (13-21) for liquid culture. Median time to detection of resistance was 20 days (10-26) for line-probe assay and 106 days (30-124) for conventional drug-susceptibility testing. Use of the MTB/RIF test reduced median time to treatment for smear-negative tuberculosis from 56 days (39-81) to 5 days (2-8). The indeterminate rate of MTB/RIF testing was 2·4% (126 of 5321 samples) compared with 4·6% (441 of 9690) for cultures. INTERPRETATION: The MTB/RIF test can effectively be used in low-resource settings to simplify patients' access to early and accurate diagnosis, thereby potentially decreasing morbidity associated with diagnostic delay, dropout and mistreatment. FUNDING: Foundation for Innovative New Diagnostics, Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership (TA2007.40200.009), Wellcome Trust (085251/B/08/Z), and UK Department for International Development.

Prolonged respiratory illness after single overnight continuous positive airway pressure humidification: endotoxin as the suspect.

A patient developed a prolonged respiratory illness after a single overnight use of tap water to humidify air supplied by a constant positive airway pressure (CPAP) device, which she had previously used for six years without difficulty. During those years, she used only distilled water for this purpose, as instructed by her sleep specialist. Analysis of the well water supplying her home showed no microorganisms, metals or other analytes likely to have caused her illness, but endotoxin was found at concentrations well above that recommended by the U.S. Pharmacopeia, as a maximum in water which may be inhaled as an aerosol.

Preventing Diabetes in the Workplace: Effects of Coaching and Monetary Incentives.

OBJECTIVE: Prevention of diabetes demonstrated in the diabetes prevention program has not been thoroughly evaluated in workplace settings. METHODS: Glycemic control was assessed by glycated hemoglobin (HbA1c) and its impact on 5-year incidence of diabetes and prediabetes prevalence, in wellness program participants (WPP) of (Group A, with) or (Group B, without) health coaching and monetary incentives. RESULTS: HbA1c fell in Group A WPP (5.52 ±â€Š0.60 vs 5.58 ±â€Š0.36 SD, P = 0.04) as did prediabetes. Incident diabetes was less than expected (24 vs 74, P < 0.001). HbA1c increased in Group B WPP (5.37 ±â€Š0.40 SD vs 5.58 ±â€Š0.54, P < 0.001) and prediabetes increased from 28 to 36 (P < 0.001). CONCLUSIONS: Health coaching and monetary incentives improved glycemic control over 5 years, an improvement not observed in WPP without these interventions.

Inguinal phlegmon and positive serology for syphilis after penile bite laceration: true, true and unrelated.

Among many causes of penile injury, sexual activity is infrequently reported. The present case involved delay in recognition, which led to development of a phlegmon near major vascular structures. Positive serologic evidence of syphilis was an incidental finding.

Preliminary inter-rater reliability of the wheelchair components questionnaire for condition.

PURPOSE: The Wheelchair Components Questionnaire for Condition (WCQ-C) enables the collection of data on wheelchair maintenance condition and durability in resource-limited environments. It can be used in large studies to indicate typical patterns of wear at a location, or for a type of wheelchair. It can also be used in clinical settings as an evidence based indication that a wheelchair may need repair or replacement. This type of data can enable effective use of limited funds by wheelchair providers, manufacturers and users. The goal of this study was to investigate the inter-rater reliability of the WCQ-C. METHODS: Two therapists from North America who have worked extensively in low-resource areas used the WCQ-C to independently evaluate 46 wheelchairs at a primary school for children with disabilities in Kenya. RESULTS: Mean scores of ratings for each wheelchair by the two raters were used to calculate a two-way random interclass correlation coefficient. A value of 0.82 with a 95% confidence interval of 0.67-0.89 indicated good preliminary reliability. CONCLUSION: Preliminary results indicate that the WCQ-C is a reliable method of assessment. Additional studies are needed with larger and more diverse groups of raters. Because WCQ-C findings are specific to wheelchair wear and maintenance at each location, studies at other locations are also needed. Implications for rehabilitation The importance of inter-rater reliability testing in confirming the reliability of an assessment tool such as the WCQ-C. The use of the WCQ-C to monitor wheelchair condition in low-resource settings and other field settings. If used at regular interval can produce data that can be used to describe typical changes over time at each individual setting. This could enable proactive planning at that setting to avoid typical breakdowns and the injuries or clinical complications that could result. The use of the WCQ-C to monitor the condition of groups of wheelchairs of the same type. It can describe typical patterns of wear and failure in a way that enables responsive change by manufacturers and designers. This enables more effective use of limited funds. On an individual basis, the use of the WCQ-C to alert users and health professionals of a need for repair or replacement. This could minimize the clinical problems and accidents that can result from wheelchair breakdown. Assessment of a wheelchair using the WCQ-C could provide evidence based data to insurance companies or wheelchair providers which indicates a need for wheelchair repair or replacement.

Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial.

PURPOSES: Study a tumor necrosis factor receptor antagonist (etanercept) in the treatment of chronic ocular sarcoidosis. SUBJECTS AND METHODS: Eighteen patients with ocular sarcoidosis and ongoing inflammation in the eyes. All patients had received at least 6 months of therapy with methotrexate and were currently receiving corticosteroids. Patients were randomized to receive either etanercept, 25 mg subcutaneously twice a week, or placebo in a double-blind randomized trial. Treatment for ocular inflammation with systemic and local corticosteroids at the beginning and end of 6 months of treatment was noted. All patients underwent an ocular examination at the beginning and the end of the study by one ophthalmologist who was unaware of what treatment the patient was receiving. RESULTS: Three of the patients treated with etanercept and one treated with placebo were being treated with lower doses of corticosteroids by the end of the study. However, three of the etanercept patients and one of the placebo patients required larger doses of corticosteroids by the end of the study. The ophthalmology global assessment improved for two of the etanercept-treated patients and three of the placebo-treated patients. CONCLUSION: For most patients, therapy with etanercept was not associated with a significant improvement in their chronic ocular disease.

Stress testing in the medical evaluation for hazardous materials duty: results and consequences in three groups of candidates.

OBJECTIVE: The objective of this study was to determine the yield of exercise stress testing (GXT) and other methods for evaluating candidates for HAZMAT duty. METHODS: The authors conducted an analysis of prior and current records of GXTs, medical examinations, blood tests, chest radiographs, spirometry, and audiometry in 190 candidates. The authors also conducted scrutiny of GXT results, using Duke Treadmill Score (DTS), Chronotropic Index (CI), and Heart Rate Recovery (HRR). RESULTS: Seven candidates were disapproved by history and/or physical examination. Twenty-one others were deferred for GXT-induced, marked hypertension, and/or ST depression >/=2 mm. The latter appeared to be false-positive indications of ischemia, low risks confirmed by DTS, CI, and HRR. Heat stress was not induced in 26 subjects so evaluated. CONCLUSIONS: GXT identified marked hypertension in 12 HAZMAT candidates and ischemic ST changes in 10, the latter appearing to be false-positives. Other testing yielded useful baselines, rarely disqualifying.

A benefit-cost analysis of a worksite nurse practitioner program: first impressions.

OBJECTIVE: This study aimed to assess the initial impact of an on-site nurse practitioner (NP) initiative on the health care costs (HCC) among 4,284 employees and their dependents. METHODS: The authors analyzed HCC by two methods. First, they compared annualized actual values for the first 6 months of the startup year (2004) with those projected for 2004 on the basis of claims paid in 2002 and 2003. Both aggregate and per-individual HCC were used as the basis for comparison. The difference in HCC between projected and observed values for 2004 was defined as the benefit of the NP program. In a second analysis, HCC were calculated using 2003 paid claims for major diagnostic categories (MDC). These HCC were compared with those that would have been incurred had off-site care been used for the (annualized) number of such patients cared for by the NP in 2004 with the same MDC. The cost of the NP program was used as the denominator in calculating the benefit-to-cost ratio using the savings in HCC estimated by the two previously mentioned methods. RESULTS: Annualized cost of the NP program was 82,716 dollars. Savings in HCC using the first method were 1,313,756 dollars per year, yielding a benefit-to-cost ratio of 15 to 1. Using the MDC analysis, the ratio was 2.4 to 1. This difference in ratios between the two estimates may partly be attributable to effects of other initiatives such as the wellness program and the Nurse Health Line. The latter was begun 10 weeks before the NP program, is available at all times, and is intended to minimize the need for workers and families to seek high-cost care at hospital emergency departments. CONCLUSIONS: The first 6 months of a new NP initiative yielded substantial reductions in HCC that warrant further analysis over longer periods of observation. However, the initial estimates may understate the aggregate value of the program because it may also reduce on-site injury and illness patterns and improve productivity, end points that were not assessed in this initial snapshot.