Background-Tuberculosis is a common complication and leading cause of death in HIV infection. Antiretroviral therapy (ART) lowers the risk of tuberculosis, but may not be sufficient to control HIV-related tuberculosis. Isoniazid preventive therapy (IPT) reduces tuberculosis incidence significantly, but is not widely used.

Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.

Diabetes mellitus (DM) is an emerging chronic health condition of developed and developing countries. We conducted a retrospective cohort study of patients with active, culture-confirmed tuberculosis (TB) in Maryland to determine the impact of DM on TB treatment outcomes. Of 297 TB patients, 42 (14%) had DM. Patients with diabetes had 2.0 times higher odds of death than patients without diabetes (95% confidence interval [CI] 0.74-5.2, P = 0.18). Adjusting for human immunodeficiency virus (HIV), age, weight, and foreign birth, the odds of death were 6.5 times higher in patients with diabetes than patients without diabetes (95% CI 1.1-38.0, P = 0.039). In pulmonary TB patients, time to sputum culture conversion was longer in patients with diabetes than patients without diabetes (median 49 versus 39 days, P = 0.09). Two-month culture conversion proportions were similar (70% and 69%). Treatment failure occurred in 4.1% of patients without diabetes and 6.7% of patients with diabetes (P = 0.51). In conclusion, DM was a risk factor for death in Maryland TB patients. There was a trend toward increased time to culture conversion; two-month culture conversion proportions, however, were similar.

Background The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa. Methods Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk. Results Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78). Conclusion Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.

Practitioners as well as scholars of European integration have for decades debated why it takes so long for the European Union (EU) to adopt legislation and how to improve decision-making efficiency. Four studies have investigated decision-making speed using survival analysis, a particularly appropriate quantitative technique. In this paper I show that all four studies suffer from serious methodological problems that render their conclusions unreliable. I then outline where work in this area should focus, and take an initial step in this direction by fitting a methodologically more appropriate survival model to my 2002 EU decision-making data set (Golub, 2002). Substantively, the results indicate that throughout the EU's history, for the most important types of legislation, qualified majority voting (QMV) and EU enlargement have increased decision-making speed, whereas empowerment of the European Parliament and extreme preference heterogeneity amongst decision-makers have decreased it. Theoretically, formal approaches — spatial models and especially coalition theory — do a better job of explaining these results than do perspectives that privilege informal norms

The importance of high-incidence "hotspots" to population-level tuberculosis (TB) incidence remains poorly understood. TB incidence varies widely across countries, but within smaller geographic areas (e.g., cities), TB transmission may be more homogeneous than other infectious diseases. We constructed a steady-state compartmental model of TB in Rio de Janeiro, replicating nine epidemiological variables (e.g., TB incidence) within 1% of their observed values. We estimated the proportion of TB transmission originating from a high-incidence hotspot (6.0% of the city's population, 16.5% of TB incidence) and the relative impact of TB control measures targeting the hotspot vs. the general community. If each case of active TB in the hotspot caused 0.5 secondary transmissions in the general community for each within-hotspot transmission, the 6.0% of people living in the hotspot accounted for 35.3% of city-wide TB transmission. Reducing the TB transmission rate (i.e., number of secondary infections per infectious case) in the hotspot to that in the general community reduced city-wide TB incidence by 9.8% in year 5, and 29.7% in year 50-an effect similar to halving time to diagnosis for the remaining 94% of the community. The importance of the hotspot to city-wide TB control depended strongly on the extent of TB transmission from the hotspot to the general community. High-incidence hotspots may play an important role in propagating TB epidemics. Achieving TB control targets in a hotspot containing 6% of a city's population can have similar impact on citywide TB incidence as achieving the same targets throughout the remaining community.infectious disease transmission | theoretical models | urban population | epidemiology | communicable disease control T uberculosis (TB) remains a leading infectious cause of morbidity and mortality, with over 8.8 million cases and 1.4 million deaths annually worldwide (1). TB is known to cluster in hyperendemic "hotspots" often characterized by crowding (2), poverty (3), HIV infection (4), and other social determinants (5). However, compared with other infectious diseases [e.g., sexually transmitted diseases (6) and vector-borne diseases (7)], where 20% of the population may generate 80% of transmission (7), TB transmission appears relatively more homogeneous. As a result, though spatial targeting is often advocated as an efficient method for achieving control of diseases such as malaria (8), the degree to which hotspots contribute to community-wide transmission of TB remains uncertain. The concept of geographically defined hotspots driving TB transmission has biological plausibility. Preventing TB cases in high-transmission areas (e.g., crowded urban slums, poorly ventilated hospitals) may avert many more secondary transmissions than similar efforts in low-transmission areas. Similarly, cases in high-transmission areas are more likely to represent recent infection (which is more amenable to intervention) than reactivation of latent disease (9). Prior explorations of heterogeneity in TB tra...

Scholarship on the European Community (EC) focuses particular attention on how formal voting rules and institutional reform condition decision-making outcomes. The predominant view of EC history holds that decision making remained paralyzed until institutional reforms in 1987 and 1992 restored and expanded adherence to majority voting rules, which in turn unblocked and expedited EC legislative efforts. In this study I challenge these fundamental assumptions using comprehensive data for 1974–95 and a series of quantitative assessments, including event history analysis. I show that decision making in the 1970s was anything but paralyzed, that the impact of the Luxembourg Compromise has been greatly overstated, that institutional reforms actually encumbered rather than eased the EC legislative process, and that institutional effects are mediated by the underlying distribution of member state preferences. The findings have important implications for our understanding of the history and future trajectory of European integration and highlight the applicability of standard political science theories and methods to the study of the EC.

Background Effective tuberculosis (TB) control in HIV-prevalent settings is hindered by absence of accurate, rapid TB diagnostic tests. We evaluated the accuracy of a urine lipoarabinomannan (LAM) test for TB diagnosis in South Africa. Methods Hospitalized adults with signs and/or symptoms of active TB were enrolled. Sputum smear microscopy and mycobacterial culture, mycobacterial blood culture, and HIV testing were performed. A spot urine specimen was tested for LAM. Results 499 participants were enrolled; 422 (84.6%) were HIV-infected. In microbiologically-confirmed TB patients, the LAM test was positive in 114/193 (sensitivity 59%, [95% CI 52, 66]), including 112/167 (67% [59, 74]) who were HIV-infected. Among individuals classified as “not TB”, the LAM test was negative in 117/122 (specificity 96% [91, 99]), including 83/88 (94% [87, 98]) who were HIV-infected. In confirmed TB patients, the LAM test was more sensitive than sputum smear microscopy (42%, 82/193, p<0.001) and detected 56% (62/111) of those who were sputum smear-negative. HIV-infection (AOR 13.4), mycobacteremia (AOR 3.21), and positive sputum smear (AOR 2.42) were risk factors for a positive LAM test. Conclusions The urine LAM test detected a subset of HIV-infected patients with severe TB in whom sputum smear microscopy had suboptimal sensitivity. The combination of urine LAM testing and sputum smear microscopy is attractive for use in settings with high HIV burden.