THE TREATMENT OF COCCIDIOIDOMYCOSIS

SUMMARYTherapy of coccidioidomycosis continues to evolve. For primary pulmonary disease, antifungal therapy is frequently not required while prolonged courses of antifungals are generally needed for those in whom extrathoracic disseminated has occurred. Intravenous amphotericin B should be reserved for those with severe disease. Oral triazole antifungals have had a great impact on the management of coccidioidomycosis. Both fluconazole and itraconazole at 400 mg daily have been effective for various forms of coccidioidomycosis, including meningitis, although relapse after therapy is discontinued is a problem. Individuals with suppressed cellular immunity are at increased risk for symptomatic coccidioidomycosis and they include those with HIV infection, those on immunosuppressive medications, and those who have received a solid organ transplant. Pregnant women and African-American men have been identified as two other groups who are at an increased risk for symptomatic and severe infection

Mobility patterns of persons at risk for drug-resistant tuberculosis in Mumbai, India.

SettingTuberculosis (TB) hospital in Mumbai, India.ObjectiveTo describe the mobility patterns of persons with suspected drug-resistant tuberculosis (DR-TB) and to assess whether there were significant differences in demographic or risk characteristics based on mobility.DesignObservational cohort study of TB clinic patients at risk for DR-TB.ResultsAmong 602 participants, 37% had ever moved from their place of birth; 14% were local movers (within state), and 23% were distant movers, between states or countries. Univariate multinomial logistic regression models showed that distant movers were more likely than non-movers to have lower income, less education, a greater number of previous TB episodes, and to have ever smoked. Compared to non-movers, local movers were more likely to have lower income and were more likely to have seen a doctor in the past 2 years. Clinical outcomes, including DR-TB, diabetes, and human immunodeficiency virus (HIV), did not differ between the three mobility groups.ConclusionMobility was common among patients at risk for DR-TB in Mumbai. TB programs should consider the implications of mobility on the protracted treatment for DR-TB in India

Phenotypic and genotypic diversity in a multinational sample of drug-resistant Mycobacterium tuberculosis isolates.

ObjectiveTo develop and evaluate rapid, molecular-based drug susceptibility testing (DST) for extensively drug-resistant tuberculosis (XDR-TB), we assembled a phenotypically and genotypically diverse collection of Mycobacterium tuberculosis isolates from patients evaluated for drug resistance in four high-burden countries.MethodsM. tuberculosis isolates from India (n = 111), Moldova (n = 90), the Philippines (n = 96), and South Africa (n = 103) were selected from existing regional and national repositories to maximize phenotypic diversity for resistance to isoniazid, rifampin (RMP), moxifloxacin, ofloxacin, amikacin, kanamycin, and capreomycin. MGIT™ 960 was performed on viable isolates in one laboratory using standardized procedures and drug concentrations. Genetic diversity within drug resistance phenotypes was assessed.ResultsNineteen distinct phenotypes were observed among 400 isolates with complete DST results. Diversity was greatest in the Philippines (14 phenotypes), and least in South Africa (9 phenotypes). Nearly all phenotypes included multiple genotypes. All sites provided isolates resistant to injectables but susceptible to fluoroquinolones. Many patients were taking drugs to which their disease was resistant.DiscussionDiverse phenotypes for XDR-TB-defining drugs, including resistance to fluoroquinolones and/or injectable drugs in RMP-susceptible isolates, indicate that RMP susceptibility does not ensure effectiveness of a standard four-drug regimen. Rapid, low-cost DST assays for first- and second-line drugs are thus needed

Evaluation of recorded video-observed therapy for anti-tuberculosis treatment.

BACKGROUND: Asynchronous video directly observed therapy (VDOT) may reduce tuberculosis (TB) program costs and the burden on patients. We compared VDOT performance across three cities in the United States, each of which have TB incidence rates above the national average.METHODS: Patients aged ≥18 years who are currently receiving directly observed anti-TB treatment were invited to use VDOT for monitoring treatment. Pre- and post-treatment interviews and medical records were used to assess site differences in treatment adherence and patient characteristics and perceptions.RESULTS: Participants were enrolled in New York City, NY (n = 48), San Diego, CA (n = 52) and San Francisco, CA, USA (n = 49). Overall, the mean age was 41 years (range 18-87); 59% were male; most were Asian (45%) or Hispanic/Latino (30%); and 77% were foreign-born. The median fraction of expected doses observed (FEDO) was 88% (IQR 76-96). At follow-up, 97% thought VDOT was "very or somewhat easy to use" and 95% would recommend VDOT to other TB patients. Age, race/ethnicity, annual income, and country of birth differed by city (P < 0.05), but FEDO and VDOT perceptions did not.CONCLUSIONS: TB programs in three large US cities observed a high FEDO using VDOT while minimizing staff time and travel. Similar findings across sites support VDOT adoption by other large, urban TB programs

The excitation of solar-like oscillations in a δ Sct star by efficient envelope convection

Delta Scuti (delta Sct) stars are opacity-driven pulsators with masses of 1.5-2.5M$_{\odot}$, their pulsations resulting from the varying ionization of helium. In less massive stars such as the Sun, convection transports mass and energy through the outer 30 per cent of the star and excites a rich spectrum of resonant acoustic modes. Based on the solar example, with no firm theoretical basis, models predict that the convective envelope in delta Sct stars extends only about 1 per cent of the radius, but with sufficient energy to excite solar-like oscillations. This was not observed before the Kepler mission, so the presence of a convective envelope in the models has been questioned. Here we report the detection of solar-like oscillations in the delta Sct star HD 187547, implying that surface convection operates efficiently in stars about twice as massive as the Sun, as the ad hoc models predicted.Comment: to appear as a Letter to Natur

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism

Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood