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Introduction Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. Methods/Design S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. Discussion This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels. Trial registration: NCT02410772 . Registered 8 April 2015, https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1

BackgroundPersons with diabetes mellitus (DM) have a 3-fold increased risk of tuberculosis (TB). Atypical radiographic findings and differences in bacteriologic response during anti-TB treatment have been reported in earlier studies; however, the findings have varied. We evaluated the effect of DM on manifestations and response to treatment in adults with pulmonary TB in Qatar.MethodsThe impact of DM on the clinical and radiographic presentations of pulmonary TB and bacteriologic response during anti-TB treatment was evaluated between January 2007 and December 2011, comparing patients with and without DM. This is a retrospective unmatched case-control study conducted at a large national hospital. Cases and controls were randomly selected from patients diagnosed with pulmonary TB over a 5-year period. Sputum culture conversion was assessed after 2 months of anti-TB treatment.ResultsClinical symptoms were similar between patients with and without DM. Patients with DM had a higher initial sputum acid-fast bacillus (AFB) smear grade and were less likely to have cavitary lesions on initial chest radiographs than patients without DM. Of 134 adults with DM and TB, 71 (53%) remained sputum culture positive after 2 months of anti-TB treatment, compared with 36 (27%) patients without DM.ConclusionsDM was associated with atypical radiographic findings and delayed sputum culture conversion at 2 months in adults with pulmonary TB in Qatar. Increased health education of patients with DM about symptoms of TB, low thresholds for evaluation for active TB, and close monitoring of bacteriologic response to treatment among patients with TB and DM are warranted.

Introduction Readmission following revision orthopedic surgery imposes tremendous costs due to the increased length of stay, procedure complexity, and revision surgery. Following revision total hip arthroplasty, as many as one in five patients are readmitted postoperatively. Readmissions cost the federal government $17.4 billion annually. The purpose of this study was to identify risk factors for unplanned readmission following revision total hip arthroplasty. Methods This was a retrospective case series review of randomized revision total hip arthroplasties (THA) patients between 2008 and 2018. Exclusions were as follows: outside hospital revisions, staged revisions, revisions for infection, and bilateral revisions. Data were collected by manual chart review. Readmissions were tracked from discharge until the final follow-up. Results A total of 61 patients and 85 revision THAs were analyzed. Nineteen patients (31.1%) were readmitted; 31.6% of the readmitted patients had a coronary artery disease compared to 6.5% of non-readmitted patients. Readmission was also associated with obesity, former smokers, and hypertension. Also, the mean duration of follow-up was 26.5 months for readmitted patients as compared to 8.96 for non-readmitted patients. Conclusion Obesity, former tobacco use, younger age, coronary artery disease (CAD), and hypertension were associated with readmission. The medical optimization of patients with these risk factors prior to surgery could significantly lower costs relative to revision THA.

Category: Other Introduction/Purpose: The tourniquet is commonly used in orthopedic surgeries on the upper and lower extremities to reduce blood loss, improve visualization, and expedite the surgical procedure. However, tourniquets have been associated with multiple local and systemic complications, including postoperative pain. Guidelines vary regarding ideal tourniquet pressure and duration, while the practice of fixed, high tourniquet pressures remains common. The relationship between tourniquet pressure, duration, and postoperative pain has been studied in various orthopaedic procedures, but these relationships remain unknown in foot and ankle surgery. The purpose of this study was to assess for correlation between excessive tourniquet pressure and duration and the increased incidence of tourniquet pain in foot and ankle surgery patients. Methods: Retrospective chart review was performed for 132 adult patients who underwent foot and ankle surgery with concomitant use of intraoperative tourniquet at a single institution between August and December of 2015. Patients with history of daily opioid use of 30 or more morphine oral equivalents for greater than 30 days, patients who underwent foot and ankle surgery without regional nerve block, patients deemed to have failed regional nerve block, and patients who underwent foot and ankle surgery without tourniquet use were excluded. Patient’s baseline systolic blood pressure, tourniquet pressure and duration, tourniquet deflation time, tourniquet reinflation pressure and duration, intraoperative blood pressure and heart rate changes, intra-operative opioid consumption, PACU pain scores, PACU opioid consumption, and PACU length of stay were collected. Statistical correlation between tourniquet pressure and duration and postoperative pain scores, pain location, narcotic use, and length of stay in PACU was assessed using linear regression in SPSS. Results: Average age of patients was 47.6 years (Range: 16 - 79). Tourniquet pressure was 280 mmHg in 90.6% of patients (Range: 250-300 mmHg). Only 3.8% percent of patients had tourniquet pressures 100-150 mmHg above systolic blood pressure. Mean tourniquet time was 106.2 ± 40.1 min. Tourniquet time showed significant positive correlation with morphine equivalents used in the perioperative period (N = 121; r = 0.406; p < 0.001). Long tourniquet times (= 90 minutes) were associated with greater intraoperative opioid use than short tourniquet times (= 90 minutes) (19 mg ± 22 mg vs. 5 mg ± 11.6 mg; p Conclusion: The majority of cases of foot and ankle surgery at our institution did not adhere to current tourniquet use guidelines, which recommend tourniquet pressure between 100 and 150 mmHg above patient’s systolic blood pressure. Prolonged tourniquet times at high pressures not based on limb occlusion pressure, as observed in our study, lead to increased pain and opioid use and prolonged time in PACU. Basing tourniquet pressures on limb occlusion pressures could likely improve the safety margin of tourniquets, however randomized studies need to be completed to confirm this.

BACKGROUND: Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment. METHODS: Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01–009 study (validation cohort). RESULTS: In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P

Background: When using a dorsal approach for Morton’s neuroma excision, the most common complication is recurrent Morton’s neuroma. The present cadaveric study demonstrates how far proximally the nerve is resected during a dorsal approach and examines both the laminar spreader and Gelpiretractor to determine which instrument facilitates maximal proximal resection of the nerve. Methods: This study involved 12 fresh-frozen cadaver specimens, each of which underwent a dorsal approach to the interdigital nerve with proximal resection. Either a laminar spreader or a Gelpi retractor was used to improve visualization of the intermetatarsal space. The interdigital nerve was then resected, and the lengths of the cut nerves were compared based on the retractor employed. Results: The mean length of proximal resection in the second intermetatarsal space was 2.42 cm when using the laminar spreader and 1.93 cm when using the Gelpi retractor (P = .252). In the third intermetatarsal space, the mean length of proximal resection was 2.14 cm when using the Laminar spreader and 1.48 cm when using the Gelpi retractor (P = .166). Conclusion: This study demonstrates how far proximal the interdigital nerve is resected during a dorsal approach to Morton’s neuroma and shows no statistically significant difference between the Laminar spreader and the Gelpi retractor. Levels of Evidence: Level V: Cadaver study

Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase approved for the treatment of B-cell malignancies. There is growing concern about the risk of opportunistic infections following ibrutinib therapy. Herein, we describe the first case of Mycobacterium chelonae skin and soft tissue infection in a patient receiving ibrutinib and recount the challenges in treating this infection.

Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase approved for the treatment of B-cell malignancies. There is growing concern about the risk of opportunistic infections following ibrutinib therapy. Herein, we describe the first case of Mycobacterium chelonae skin and soft tissue infection in a patient receiving ibrutinib and recount the challenges in treating this infection.

Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis . However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United States enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated by analysis of covariance (ANCOVA) on moxifloxacin exposure and the peak (maximum) concentration ( C max ). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) and C max were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g.−11187G>A in the SLCO1B1 gene (rs4149015) but not by geographic region. The median moxifloxacin AUC 0–24 was 46% higher and the median C max was 30% higher in 4 (8%) participants who had the SLCO1B1 g.−11187 AG genotype than in 45 participants who had the wild-type GG genotype (median AUC 0–24 from the model, 34.4 versus 23.6 μg · h/ml [ P = 0.005, ANCOVA]; median C max from the model, 3.5 versus 2.7 μg/ml [ P = 0.009, ANCOVA]). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate the risk associated with the SLCO1B1 g.−11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.)

Non-infectious soft tissue lesions of the foot and ankle are relatively rare clinically. These include benign and malignant neoplasms, as well as non-neoplastic or pseudotumoral lesions such as ganglionic, synovial and epidermoid cysts, intermetatarsal and adventitious bursitis, inflammatory lesions like gouty tophi and rheumatoid nodules, Morton's neuroma, and granuloma annulare. A 48-year-old male with a history of medically treated tophaceous gout presented with left foot neuropathic pain and paresthesia, in the setting of a well-circumscribed soft tissue lesion of the second intermetatarsal space, suspected to be a Morton's neuroma. Magnetic resonance imaging (MRI) showed a 4.1 x 2.7 x 2.6 cm heterogeneous soft tissue mass containing multiple cystic areas. Excisional biopsy was performed and histologic examination revealed well-circumscribed nodules of amorphous material containing needle-shaped clefts, rimmed by histiocytes, and multinucleated giant cells consistent with a gouty tophus. This is the first case reported in the literature of an intermetatarsal gouty tophus causing neuropathic pain and paresthesia. While Morton's neuroma is the most common cause of this presentation, this case illustrates that other pseudotumoral lesions, such as a gouty tophus, may present similarly, and should be considered in the differential diagnosis. While most cases of tophaceous gout can be adequately treated with urate-lowering therapy, surgery may be indicated for tophi that do not resolve with medical treatment based upon symptom severity, compression of nearby structures, and functional impairment.

The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimum dose is uncertain. Current strategies are not informed by clinical pharmacokinetic (PK)/pharmacodynamic (PD) data; we aimed to address this gap.We defined linezolid PK/PD targets for efficacy (fAUC0-24:MIC119 mg/L/h) and safety (fCmin1.38 mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC0-24 and fCmin for published doses. Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment.The efficacy target was attained in all simulated individuals at 300 mg q12h and 600 mg q12h, but only 20.7% missed the safety target at 300 mg q12h versus 98.5% at 600 mg q12h. Although suggesting 300 mg q12h should be used preferentially, these data were reliant on a single centre. Efficacy and safety targets were missed by 41.0% and 24.2%, respectively, at 300 mg q24h and by 44.6% and 27.5%, respectively, at 600 mg q24h. However, the confounding effect of between-study heterogeneity on target attainment for q24h regimens was considerable.Linezolid dosing at 300 mg q12h may retain the efficacy of the 600 mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300 mg q24h and 600 mg q24h doses are limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug-resistant TB treatment are required.

A model for densification based on the master sintering curve concept is applied to solid-state sintering of W and Mo and to liquid-phase sintering of W–10Cu and Mo–18Cu. The effects of small additions of Ni, Co, Fe, and Pd to W–10Cu and Mo–18Cu are investigated. Separate grain growth models for solid-state and liquid-phase sintering are also applied to these systems. The model predictions are compared to experimental results to determine the effects of the activators on densification and grain growth mechanisms. Ni and Pd additions only slightly reduce the activation energy for densification, while Co and Fe have a much larger effect. The effects of Co and Fe additions on grain growth rate constants are not adequately described by consideration of their effects on the solubility of W and Mo in the liquid phase. The experimental results with Co and Fe additions are better described by a solid-state grain growth model. The effects of Co and Fe additions on densification and grain growth are consistent with enhanced diffusion through a segregated solid phase during liquid-phase sintering.

A long-standing question in immunology has been to understand how transcription factors (TF) determine cell-type-specific transcription programs. Traditionally, investigating TFs in immune cells has been limited to measuring the effect of a single TF on a limited number of gene targets. The advent of next generation sequencing methods makes it possible to measure the effects of multiple transcription factors on a genome-wide scale. This holistic approach gives us a better understanding of the influence that multiple TFs have on cell-specific programs. In this issue of European Journal of Immunology, Fang et al. [Eur. J. Immunol. 2015. 45: 3150-3157] show that genomic regions cooccupied with two or more TFs show increased epigenetic histone marks of active enhancers, which correspond to increased transcriptional activity.

Great progress has been made in understanding immunity to viral infection. However, infection can occur in the context of co-infection by unrelated pathogens that modulate immune responses and/or disease. We have studied immunity and disease during co-infection with two unrelated viruses: Ectromelia virus (ECTV) and Lymphocytic Choriomeningitis virus (LCMV). ECTV infection can be a lethal in mice due in part to the blockade of Type I Interferons (IFN-I). We show that ECTV/LCMV co-infection results in decreased ECTV viral load and amelioration of ECTV-induced disease, likely due to IFN-I induction by LCMV, as rescue is not observed in IFN-I receptor deficient mice. However, immune responses to LCMV in ECTV co-infected mice were also lower compared to mice infected with LCMV alone and potentially biased toward effector-memory cell generation. Thus, we provide evidence for bi-directional effects of viral co-infection that modulate disease and immunity.

Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time (

AZD-5847 is a new oxazolidinone derivative under development for the treatment of tuberculosis (TB). Here we describe the population pharmacokinetics (PK) of AZD-5847 in patients with tuberculosis based on a recently completed phase II study. The study included 60 patients with drug-susceptible TB. Patients were randomized to four dosages (500 mg once daily, 1,200 mg once daily, 500 mg twice daily, and 800 mg twice daily). Patients were intensively sampled on days 1 and 14. AZD-5847 pharmacokinetics were best described with a two-compartment model with lag time ( T lag ) for absorption. AZD-5847 bioavailability was nonlinear and plateaued at 800 mg. We performed deterministic simulation to compare the PK/pharmacodynamics (PD) of AZD-5847, linezolid, and sutezolid. AZD-5847 PK/PD in terms of both area under the concentration-time curve for the free, unbound fraction ( f AUC)/MIC and time the free concentration was above the MIC ( f T>MIC) were less favorable than those for linezolid and sutezolid. This could help explain the poor bactericidal activity of AZD-5847 in the recent phase II study.

Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis. However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United States enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated by analysis of covariance (ANCOVA) on moxifloxacin exposure and the peak (maximum) concentration (Cmax). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0–24) and Cmax were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g.−11187G>A in the SLCO1B1 gene (rs4149015) but not by geographic region. The median moxifloxacin AUC0–24 was 46% higher and the median Cmax was 30% higher in 4 (8%) participants who had the SLCO1B1 g.−11187 AG genotype than in 45 participants who had the wild-type GG genotype (median AUC0–24 from the model, 34.4 versus 23.6 μg · h/ml [P = 0.005, ANCOVA]; median Cmax from the model, 3.5 versus 2.7 μg/ml [P = 0.009, ANCOVA]). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate the risk associated with the SLCO1B1 g.−11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.)

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

Phase 2 clinical trials for tuberculosis (TB) treatment require reliable culture methods to determine presence or absence of Mycobacterium tuberculosis (Mtb) over the course of therapy, as these trials are based primarily on bacteriological endpoints. We evaluate which of 5 solid media is most reliable: Lowenstein-Jensen (LJ) egg-based medium and 4 Middlebrook agar media (nonselective 7H10 and 7H11 and selective 7H10 and 7H11). We analyze 393 specimens from 50 HIV-negative Ugandan adults with newly-diagnosed, pulmonary TB and high acid-fast bacillus smear grade. Specimens were collected every 2–4 weeks during the first 12 weeks of therapy. We compare the results for each culture to 2 composite reference standards—one that was deemed positive if any solid culture was positive for Mtb and another based on latent class analysis. Both reference standards established that the 2 selective Middlebrook media most reliably determine the presence or absence of Mtb (P

Background T-cell interferon-γ release assays (IGRAs) are used in the diagnosis of Mycobacterium tuberculosis infection and could be useful biomarkers of response to treatment of latent TB infection for clinical trials, infection control units, and TB programs. Methods This investigation was a prospective, controlled substudy of IGRA responses in 82 healthy South African adults with HIV seronegative and positive tuberculin skin test results randomly assigned to treatment with 6 months of daily isoniazid preventive therapy (IPT) or observation before Bacillus Calmette-Guerin revaccination in a clinical trial. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was used to measure interferon-γ (IFN-γ) response to mycobacterial antigens at baseline and after IPT or observation. Results IFN-γ levels declined between baseline and the end of IPT (signed rank test P ≤ .0001) and between baseline and a similar period of observation without IPT (signed rank test P = .03). The rate of decrease in IFN-γ responses over time did not differ between the groups (Mann-Whitney-Wilcoxon test P = .31). QFT-GIT test results in two subjects (5%) in the IPT group and two subjects (5%) in the observation group reverted from positive to negative during follow-up. No significant difference was found between the groups with respect to baseline positivity or the proportion of patients whose tests reverted to negative. Conclusions IPT had no effect on changes in QFT-GIT readouts during short-term follow-up of adults with positive tuberculin skin tests in a high TB incidence setting. QFT-GIT is unlikely to be a useful biomarker of response to treatment of latent TB infection. Trial registry ClinicalTrials.gov ; No.: NCT01119521; URL: www.clinicaltrials.gov

Background The epidemiology of disseminated Mycobacterium avium complex (DMAC) infection in the United States is changing. Previously most DMAC occurred in adults with advanced AIDS. Since the development of effective antiretroviral therapy, the incidence of DMAC in AIDS has fallen more than 10-fold. Malignancy, immunosuppression, and tumor necrosis factor inhibitors are known risk factors for DMAC. We sought to describe the epidemiology of DMAC disease in HIV seronegative patients in the United States. Methods We performed a retrospective analysis of a commercial database (Explorys Inc., Cleveland, OH). This database contains an aggregate of Electronic Health Record data from 26 major integrated healthcare systems in the United States from 1999 to present. Explorys contains de-identified information from over 50 million patients, 360 hospitals, and over 317,000 providers. We identified a total of 571 persons diagnosed with DMAC, based on Systemized Nomenclature of Medicine-Clinical Terms. We excluded 80 HIV-infected and identified association of the infection with known risk factors. Results Of 570 patients, 491 HIV-uninfected patients with DMAC were studied. Underlying structural pulmonary diseases were COPD and bronchiectasis (51% and 47%, respectively). Two hundred ten patients had concomitant malignancy of which lung cancer was the most frequent (43%). Seventy-nine percent were receiving corticosteroids and 10 patients (2%) were on TNF inhibitors (2%). Conclusion In this study, majority of patients with DMAC are HIV-uninfected. Larger studies should focus on identifying the prevalence and risk factors of DMAC in the post-AIDS era. Table: Distribution of the Sample According to Associated Conditions N = 490 (%) Age, years Senior (>65) 330 (67%) Adult (18–65) 160 (33%) Female 310 (63) Smoking history 420 (86) Bronchiectasis 230 (47) Previous pulmonary tuberculosis 40 (8) COPD 250 (51) HTN 310 (63) Diabetes mellitus 130 (27) Chronic kidney disease 110 (22) Interstitial lung disease 90 (18) Inflammatory bowel disease 20 (4) Concomitant malignancy 210 (43) Lung 60 (28) GI 50 (23) Head and neck 40 (19) Hematological 40 (19) Renal 30 (14) Chronic oral corticosteroid treatment 390 (79) Tumor necrosis factor alpha inhibitor therapy 10 (2) COPD; chronic obstructive pulmonary disease, HTN; hypertension, GI gastrointestinal. Disclosures All authors: No reported disclosures.

Objective: To explore simple inexpensive non-culture based predictors of recurrent pulmonary tuberculosis (PTB). Setting and study population: HIV-infected and uninfected adults with the first episode of smear positive, culture-confirmed pulmonary tuberculosis in a high tuberculosis burden country. Design: A nested prospective cohort study of participants with pulmonary tuberculosis (PTB) presenting to a hospital out-patient clinic. Results: A total of 630 TB culture confirmed participants were followed up for eighteen months of which 57 (9%) developed recurrent recurrent TB. On univariate analysis,4.7% low grade(1+) pre-treatment sputum smear participants developed recurrent tuberculosis Vs 8.8% with high grade(3+) smears (OR=0.31,95%CI: 0.10-0.93, p=0.037).On multivariate analysis:participants with extensive fibro-cavitation had a high risk of recurrent TB Vs minimal end of treatment fibro-cavitation (18%Vs12%,OR=2.3,95%CI:1.09-4.68, p=0.03).Weight gain with HIV infection was assosciated with a high risk of recurrent TB Vs weight gain with no HIV infection(18%Vs 6%,OR=6.8,95%CI:165-27.83,p=0.008) where as weight gain with a low pre-treatment high bacillary burden was assosciated with a low risk of recurrent TB Vs weight gain with a high pre-treatmentbacillary burden(6.5%Vs7.9%,OR=0.2,95%CI:0.05-0.79,p=0.02). Conclusion: Extensive end of treatment pulmonary fibro-cavitation, high pre-treatment bacillary burden with no weight gain and HIV infection could be reliable predictors of recurrent tuberculosis. Keywords: Grade, fibrosis, cavities, weight.

Whether conventional dendritic cells (cDC) acquire subset identity under direction of regenerative glycoproteins is unknown. We demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is necessary and sufficient for pre-cDC1 BM specification. CD11c-restricted Wnt4 deficiency reduced mature cDC1 numbers in BM, spleen, lung, and intestine and Wnt4 directly induced of pJNK activation and cDC1 commitment. CD11cCreWnt4flox/flox mice lacked IRF8/cJun complex stabilization and had increased basal numbers of cDC2, group 2 innate lymphoid cells ILC2 and increased resistance to the parasite Nippostrongylus brasiliensis compared to CD11cCre controls. These data reveal a novel role for Wnt4 in DC commitment and pathogen-specific immunity.

T-cell exhaustion is a hallmark of immunologic failure in chronic infections and cancer. Blocking immune inhibitory receptors such as programmed death-1 (PD-1) can re-invigorate exhausted T-cells (Tex), but many patients fail to achieve durable disease control. Thus, a deeper understanding of molecular pathways underlying reversal of T-cell exhaustion is needed. Little is known about “reprogramming” of Tex into recovered T-cells (Trecov) with better functionality and durable memory properties following cure of chronic disease. Here, we aim to determine the molecular program and underlying mechanisms of Trecov. We used the well-defined LCMV mouse model of T-cell exhaustion. To achieve “cure” of chronic infection, we adoptively transferred Tex from mice chronically infected with LCMV clone 13 into antigen-free mice and interrogated changes in Tex as they recovered, including testing the recall capacity of Trecov, a quintessential memory T-cell (Tmem) property. These studies revealed some recovery of phenotypic markers of T-cell memory, but also demonstrated that “scars” of chronic infection persisted. For example, although expression of the IL-7R was increased and PD-1 expression was lower, consistent with differentiation toward memory, the frequency of IL-7R+ cells was lower and PD-1 expression was still higher when compared to bona fide memory T-cells. These changes were accompanied by partial recovery from dysfunction, where Trecov displayed a moderate improvement in effector function. Consistent with this partial recovery, single-cell RNA sequencing (scRNAseq) indicated that the gene-expression profile of Trecov resembles Tmem in some respects, but other features were still more similar to Tex cells. To test how this collection of changes impacted a key property of Tmem, the ability to mount a recall response, we designed a series of challenge experiments. These studies revealed that although Trecov responded better than Tex, recall capacity was still inferior on a per cell basis compared to true Tmem. Together, these results suggest that following elimination of persistent antigenic stimulation and inflammation, previously exhausted T-cells are able to recover some properties of Tmem, while other aspects remain “scarred” from their history of exhaustion. These studies will enhance our understanding of immunologic and molecular mechanisms of Tex recovery, and have the potential to identify novel therapeutic strategies for recovery of more durable functional T-cells in the treatment of cancer and chronic infection. Citation Format: Mohamed S. Abdel-Hakeem, Jean-Christophe Beltra, Zeyu Chen, John Johnson, Saskinath Manne, Mohammed-Alkhatim Ali, E. John Wherry. Reprogramming of exhausted T-cells following cure of chronic viral infection [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A166.

We retrospectively analyzed time to detection of 3747 positive MGIT sputum cultures at a laboratory in a country with heavy burden of tuberculosis. Ninety-nine percent of diagnostic cultures turned positive within 28 days, suggesting that physicians may consider alternative diagnoses if sputum cultures remain negative after 4 weeks of incubation.

Alternatives to culture are needed in high burden countries to assess whether response to treatment of multidrug-resistant-tuberculosis (MDR-TB) is satisfactory. The objective was to assess the association of weight gain and treatment outcome. The methods included analysis of clinical, bacteriologic, and weight from 439 MDR-TB patients in the Philippines. Odds ratios (ORs) were calculated to determine whether 5% weight gain during the first 6 months of treatment was associated with outcome. Three hundred and ten (71%) patients were cured and 129 (29%) had poor outcomes (death, defaulted, or failed treatment). Fifty-three percent were underweight (body mass index [BMI] < 18.5 kg/m(2)) before treatment. Five percent weight gain after completing 3 months of treatment was associated with good outcome among patients who were underweight before treatment (OR 2.1; 95% confidence interval [CI], 1.05 to 4.4). Baseline weight and degree of weight change during the first 6 months of treatment can help identify persons who are more likely to have poor outcomes and require other interventions.

SUMMARY SETTING: Patients with smear-positive, newly diagnosed pulmonary tuberculosis (TB) presenting to the out- patient TB clinic in Kampala, Uganda. OBJECTIVE: To compare colony-forming unit (cfu) counting and time to positive (TTP) in Mycobacteria Growth Indicator Tube (MGIT) culture as measures of early bactericidal activity (EBA). DESIGN: Patients were enrolled in an EBA feasibility study of standard TB chemotherapy. Sixteen-hour over- night sputum collections were obtained before and on days 2, 4, 7, 10, 12 and 14 of treatment for quantitative culture on selective Middlebrook 7H11 agar media and TTP in the MGIT liquid culture system. RESULTS: Log cfu and TTP were correlated over all time points (rs = −0.71, P < 0.001). Within-subject (day to day) variation as a percentage of total variation was very similar between the two measures: 25.7% for cfu and 25% for TTP. Mean EBA 0-14, 0-2 and 2-14 mea- sured by TTP were similar to those previously reported. CONCLUSION: TTP measured by an automated, stan- dardized, commercially available culture system corre- lates with cfu determinations. EBA measured by TTP provides similar information to cfu counting, and is re- producible across sites and in different patient popula- tions. These findings support replacing cfu counting with TTP as the primary measurement in EBA studies.

The densification behavior of 88W–8.4Ni–3.6Fe, 88W–8.4Ni–3.6Cu, and W–15Cu during heating is compared using the master sintering curve (MSC) approach. The MSC parameters, such as the work of sintering, activation energy, and densification ratio, are calculated from dilatometry tests, based on which the densification is classified into three regions with different sintering mechanisms. This approach enables contrast and comparison of the densification sensitivity to solubility, temperature, and heating rate. The master sintering curves are combined into a master sintering surface that includes integral work and the solubility of tungsten in the liquid phase.

TOBACCO USE is among the leading preventable causes of death worldwide,1 and is a major contributor to respiratory diseases, including tuberculosis (TB).2 Smoking reduces normal mucociliary clearance of tracheobronchial secretions and impairs alveolar macrophage function against Mycobacterium tuberculosis.3 Culture conversion to negative after the first 2 months of treatment is a widely used measure of bacteriologic response to therapy in anti-tuberculosis treatment trials, and is associated with long-term cure.4 Delayed sputum conversion prolongs the time during which patients are infectious and capable of transmitting TB to others in their community. Several studies have examined the impact of smoking on sputum smear and culture conversion and outcomes of TB treatment.2 Smoking did not affect smear conversion in a study from Kuwait,5 whereas smoking and bilateral cavitary disease increased the risk of culture positivity two fold after the first 2 months of treatment in a cohort of non-human immunodeficiency virus (HIV) infected patients with drug-susceptible TB in Spain.6 Batista et al. recently reported that smoking was associated with a 2.5-fold increased risk of relapse after treatment in 754 patients in Brazil.7 However, most earlier studies did not control for confounding by other factors associated with delayed response to treatment, such as non-adherence to treatment, alcohol use and cavitary disease.8 To further examine the impact of smoking and other factors on bacillary clearance and response to anti-tuberculosis treatment, we analyzed sputum culture status during the first 2 months of treatment in adults with non-cavitary pulmonary TB participating in a TB treatment trial.

The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials.To evaluate the association between symptoms and microbiological response to tuberculosis treatment.We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures. Two trials (studies 22 and 23) followed participants to identify recurrent tuberculosis; participants in studies 27 and 28 were only followed to treatment completion.This analysis included 1,978 participants; 39 (2.0%) had culture-confirmed treatment failure, and 75 (3.9%) had culture-confirmed recurrence. Productive cough was associated with indices of increased mycobacterial burden at diagnosis (acid-fast smear grade, severity of radiographic abnormalities). Fever and sweats improved rapidly with treatment, whereas productive cough decreased more slowly and was present in 20% of visits after treatment completion. During treatment, study participants with productive cough more often had concurrent culture positivity compared with those without productive cough (studies 22 and 23: adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.33-2.44). Finally, symptoms during the latter part of treatment and follow-up were associated with culture-confirmed treatment failure and recurrence in studies 22 and 23 (for cough: adjusted hazard ratio, 2.07; 95% CI, 1.23-3.49; for fever: adjusted hazard ratio, 5.05; 95% CI, 2.76-9.19).There are consistent relationships between symptoms and microbiological indices of tuberculosis, including measures of mycobacterial burden at baseline, culture positivity during treatment, and time to culture-confirmed treatment failure and recurrence.

AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis . The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log 10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log 10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (−0.163 log 10 CFU/ml sputum/day; 95% confidence interval [CI], −0.193, −0.133 log 10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (−0.039; 95% CI, −0.069, −0.009; P = 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, −0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, −0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, −0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.)

Setting Chest radiographs (CXRs) are widely used for diagnosing pulmonary TB and assessing response to therapy. The Timika X-ray score has been proposed as a tool for measuring disease severity and predicting treatment outcome. Objective To evaluate inter- and intra-reader agreement of Timika scores and assess the ability of the score to predict microbiologic outcome at 2 months. Design Analytical validation study. Disease severity was measured by two readers using pretreatment radiographs and follow-up films taken at 2, 6 and 12 months after the start of treatment among 110 human immunodeficiency virus negative adults with pulmonary TB. One fourth of the films were reread to assess intra-reader agreement. Results The two-component Timika score had high inter- and intra-reader agreement (intraclass correlation (ICC)inter = 75%, ICCintra > 0.81). Baseline Timika score was associated with positive month 2 smear (P = 0.0004) and culture status (P = 0.03). The average Timika score declined significantly over the course of successful treatment. Conclusion The Timika score showed good inter- and intra-reader agreement and a significant association with microbiological outcomes after 2 months of treatment. The results of this study strengthen the evidence supporting the use of the Timika score for measuring disease severity on CXR.

This article briefly discusses the annealing practices for refractory metals such as tungsten, molybdenum, niobium, tantalum, and rhenium and their alloys. It also presents the applications and properties of these metals and their alloys.

The activation of immune responses relies on variations of a common rule where immune cells that are able to sense infections produce one set of cytokines to induce lymphocytes to produce another set of cytokines, which in turn activate the appropriate effector responses. This multitiered immune response is in fact a remarkable showcase of different ways the same genome can be used to facilitate cellular communications. Here, we review next-generation sequencing methods enabling us to map the differential usage of our genome in primary immune cells.

Background Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment. Methods In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase. Results Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79). Conclusions The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted. Clinical trials registration NCT00694629.

Standard methods to monitor tuberculosis (TB) treatment response rely on sputum microscopy and culture conversion. Alternatives to these methods are needed for those patients whose sputum tests are smear or culture negative. Here, we examine anti-phospholipid IgM antibody level changes as a biomarker for treatment response in smear positive TB patients. Serum samples were obtained from 40 pulmonary TB patients at the start and end of the intensive phase treatment (IPT) from the CDC-TB Trials Consortium randomized clinical trial in Kampala, Uganda. Samples were screened by ELISA for IgM levels against five phospholipids found in Mycobacterium tuberculosis and host cells. Lipid antigens included cardiolipin (CL), phosphatidyl inositol (PI), phosphatidyl ethanolamine (PE), phosphatidyl choline (PTC), and sphingolipid (SL). Levels of IgM against all phospholipids significantly decreased (p = 0.034, 0.001, 0.008 0.008, 0.040, respectively) following anti-TB drug treatment in patients without lung cavitary disease at baseline. The mean sensitivity of this test in these patients was 83% when the IgM response to a single lipid antigen was used; it was >90% when responses to 2 or more lipids were assessed. In contrast, cavitary TB patients showed an overall IgM increase, with a significant rise against PE (p = 0.025). There was no significant difference in the change in antibody levels between patients who remained culture-positive and those who culture-converted after 40 doses of drug therapy. The measurement of IgM anti-phospholipid antibodies may be a useful biomarker to monitor treatment response in non-cavitary TB patients.

New drugs and drug combinations are urgently needed for shorter, more effective TB treatment. Standard regimens require treatment for at least 6 months and are difficult to complete in resource-constrained settings. Resistance to first- and second-line drugs is increasing in many areas and therefore drugs with new mechanisms of action are needed. These issues complicate clinical trials of new anti-TB drugs, which continue to require prolonged follow-up of 1 to 2 years after therapy and rely heavily on end points based on mycobacterial culture. Significant barriers to accelerated testing include the development and validation of biomarkers that can be used as surrogate end points to reliably predict long-term clinical outcomes in Phase II and III trials, designing trials to evaluate new drugs for drug-resistant TB, better approaches for selecting, optimizing and testing combination regimens, and expanding the infrastructure and sites to support registration trials in high-burden countries.

X-Linked intellectual disability accounts for a significant fraction of males with cognitive impairment. Many of these males present with a non-syndromic phenotype and presently mutations in 17 X-linked genes are associated with these patients. Mutations in IL1RAPL1 have been found in multiple families with non-syndromic X-linked intellectual disability. All of the published mutations predict loss of function of the protein. We have identified an additional two families with deletions of a portion of the gene that give rise to cognitive impairment, as well as some behavioral problems and mild dysmorphism. Our clinical findings better delineate the phenotypic spectrum associated with IL1RAPL1 mutations.

Background Persons with diabetes mellitus (DM) have a 3-fold increased risk of TB. Vitamin D deficiency also is associated with a 4-fold increase in risk of progression of TB from latent TB infection to active TB. Qatar is an oil rich country with high prevalence of diabetes, obesity, and vitamin D deficiency. We aimed to evaluate the effect of diabetes mellitus on manifestations and response to treatment in adults with DM and TB. Methods Retrospective national hospital-based study of adult from January 2007 to December 2011, comparing TB-infected patients with and without DM. Results Of 134 adults with DM and TB, 62 (47%) became culture negative after 8 weeks of anti-TB treatment compared with 84 (72%) patients without DM. Patients with DM had more frequent lower lobe disease (28% vs. 17%, P = 0.03). Week 8 sputum culture conversion did not differ between patients by the degree of dysglyemia at time of diagnosis and onset of anti-TB treatment (70% vs. 46%, P = 0.09). Conclusion Diabetes mellitus was associated with delayed sputum culture conversion at two month and atypical radiological findings in adults with pulmonary TB in Qatar. Glycemic control had no effect on week-8 sputum culture conversion. Disclosures All authors: No reported disclosures.

Rifampin has concentration-dependent activity against Mycobacterium tuberculosis . However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1 , SLCO1B3 , and MDR1 . Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] of 40.2 versus 40.9 μg·h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC 0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC 0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC 0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC 0-24 values was observed, but the mean values of the AUC 0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.

Liquid-phase sintering of high-purity, submicron, co-reduced W-15Cu powders at temperatures of 1463 to 1623 K (1190 to 1350 °C) produces W grain sizes ranging from 0.6 to 1.2 μm while maintaining less than 2 pct porosity. Measured thermal conductivities of 185 to 221 W/(m·K) are related to the grain size and contiguity, which ranged from 0.51 to 0.62. The effects of composition and microstructure on thermal conductivity are further investigated with a model based on a computational cell that allows adjustment of the grain shape to produce selected matrix volume fractions and contiguities. The model considers porosity, the effects of transition metal impurities on the thermal conductivities of the W and Cu phases, and the role of an interfacial resistance between W grains. The effects of grain size and contiguity on thermal conductivity are shown for thermal boundary conductances ranging from 0 to 1.7 × 1010 W/(m2·K). Comparison of the model predictions with those of prior models, the experimental results, and previously reported thermal conductivities shows that impurities are highly detrimental to the thermal conductivity, but the thermal boundary conductance is a significant factor for high-purity W-Cu.

OBJECTIVE: To compare tuberculosis cure rates among patients supervised by household members or health care workers. METHODS: Prospective cohort study of 171 patients treated by the program in Vitoria, Southeastern Brazil, from 2004 to 2007. Each patient was followed-up for six months until the end of the treatment. Of the patients studied, a household member supervised 59 patients and healthcare workers supervised 112 patients. Patients' sociodemographic and clinic data were analyzed. Differences between groups were assessed using chi-square test or Student's t-test. Significance level was set at 5%. RESULTS: Most patients had smear positive, culture confirmed pulmonary tuberculosis. Two patients were HIV-positive. There were more illiterate patients in the healthcare-supervised group, in comparison to those supervised by their families (p=0.01). All patients supervised by a household member were cured compared to 90% of the patients supervised by health care workers (p = 0.024). CONCLUSIONS: Successful tuberculosis treatment was more frequent when supervised by household members.OBJETIVO: Comparar los resultados de cura por tuberculosis entre pacientes supervisados por ele miembro familiar y por el profesional de salud. MÉTODOS: Estudio de cohorte prospectivo de 171 pacientes de Vitória, sureste de Brasil, en el período de 2004 a 2007. Cada paciente fue acompañado por seis meses hasta la finalización del tratamiento. De los pacientes estudiados, 59 pacientes tratados eran supervisados por un miembro familiar y 112 por los profesionales de salud. Fueron evaluados datos sociodemográficos y clínicos de los pacientes. Diferencias entre los grupos de estudio fueron evaluadas utilizando la prueba Chi-cuadrado o prueba t de Student al nivel de significancia de 5%. RESULTADOS: La mayoría de los sujetos de estudio presentaron bacioscopia positiva y cultivo confirmado para tuberculosis. Dos pacientes tenían serología positiva para HIV. Un número mayor de pacientes en el grupo supervisado por profesionales de salud no eran alfabetizados, comparado con aquellos pacientes del grupo supervisado por miembros familiares (p=0,01). Todos los pacientes supervisados por un familiar fueron curados, frente a 90% de los pacientes supervisados por los profesionales de salud (p=0,024). CONCLUSIONES: El éxito del tratamiento de tuberculosis fue mayor cuando se supervisó por un familiar.OBJETIVO: Comparar os resultados de cura por tuberculose entre pacientes supervisionados pelo membro familiar e pelo profissional de saúde. MÉTODOS: Estudo de coorte prospectiva de 171 pacientes de Vitória, ES, no período de 2004 a 2007. Cada paciente foi acompanhado por seis meses até a finalização do tratamento. Dos pacientes estudados, 59 pacientes tratados eram supervisionados por um membro familiar e 112 pelos profissionais de saúde. Foram avaliados dados sociodemográficos e clínicos dos pacientes. Diferenças entre os grupos de estudo foram avaliadas utilizando o teste qui-quadrado ou teste t de Student ao nivel de significância de 5%. RESULTADOS: A maioria dos sujeitos do estudo apresentaram bacioscopia positiva e cultura confirmada para tuberculose. Dois pacientes tinham sorologia positiva para HIV. Um número maior de pacientes no grupo supervisionado por profissionais de saúde não eram alfabetizados, comparado com aqueles pacientes do grupo supervisionado por membros familiares (p = 0,01). Todos os pacientes supervisionados por um familiar foram curados, frente a 90% dos pacientes supervisionados pelos profissionais de saúde (p=0,024). CONCLUSÕES: O sucesso do tratamento de tuberculose foi maior quando supervisionado por um familiar.