Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis. The synergy between tuberculosis and the AIDS epidemic, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrugresistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.

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This article proposes Bayesian analysis of mediation effects. Compared to conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate prior information into the mediation analysis, thus potentially improving the efficiency of estimates. Second, under the Bayesian mediation analysis, inference is straightforward and exact, which makes it appealing for studies with small samples. Third, the Bayesian approach is conceptually simpler for multilevel mediation analysis. Simulation studies and analysis of two datasets are used to illustrate the proposed methods. KeywordsSingle-level mediation; Multilevel Mediation; Bayesian inference; Credible Interval Mediation analysis is a statistical method that help researchers understand the mechanisms underlying the phenomena they study. It has wide applications in psychology, prevention research, and other social sciences. The basic mediation framework involves a three variable system in which an independent variable causes a mediating variable, which, in turn, causes a dependent variable (Baron & Kenny, 1986;MacKinnon, 2008). The aim of mediation analysis is to determine whether the relation between the independent variable and the dependent variable is due, wholly or in part, to the mediating variable.Considerable research has been conducted in mediation analysis, including that of Judd and Kenny (1981), James and Brett (1984), Baron and Kenny (1986), Dwyer (1993), Collins, Graham andFlaherty (1998) (2002), among others. These works mainly focus on the single-level mediation model that is suitable for analyzing independent data. Recently, there is emerging interest in multilevel mediation analysis that is useful for analyzing hierarchical and repeated measures data. See, for example, the work of Kenny, Kashy, and Bolger (1998), MacKinnon (1999, 2001), Raudenbush and Sampson (1999), Kenny, Korchmaros and Bolger (2003), and Bauer, Preacher and Gil (2006). Comprehensive reviews on mediation analysis can be found in publications by MacKinnon, Fairchild and Fritz (2006) and MacKinnon (2008). In this growing literature, no research has yet focused on mediation analysis from the Bayesian perspective.This article proposes Bayesian analysis of mediation effects in both single-level and multilevel models. Compared to conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate available prior information into the mediation analysis. This is a useful way of incorporating the information psychologists usually have before conducting experiments to test a mediation process. Such prior information arises from pilot studies or other related studies, and often includes information about limits (or distribution) on values of regression coefficients between the independent variable, the NIH Public Access

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In phase I trials, effectively treating patients and minimizing the chance of exposing them to subtherapeutic and overly toxic doses are clinicians' top priority. Motived by this practical consideration, we propose Bayesian optimal interval (BOIN) designs to find the maximum tolerated dose and to minimize the probability of inappropriate dose assignments for patients. We show, both theoretically and numerically, that the BOIN design not only has superior finite and large sample properties but also can be easily implemented in a simple way similar to the traditional '3+3' design. Compared with the well-known continual reassessment method, the BOIN design yields comparable average performance to select the maximum tolerated dose but has a substantially lower risk of assigning patients to subtherapeutic and overly toxic doses. We apply the BOIN design to two cancer clinical trials.

The majority of active tuberculosis cases arise as a result of reactivation of latent organisms which are quiescent within the host. The ability of mycobacteria to survive extended periods without active replication is a complex process whose details await elucidation. We used two-dimensional gel electrophoresis to examine both steady-state protein composition and time-dependent protein synthetic profiles in aging cultures of virulent Mycobacterium tuberculosis. At least seven proteins were maximally synthesized 1 to 2 weeks following the end of log-phase growth. One of these proteins accumulated to become a predominant stationary-phase protein. N-terminal amino acid sequencing and immunoreactivity identified this protein as the 16-kDa ␣-crystallin-like small heat shock protein. The gene for this protein was shown to be limited to the slowly growing M. tuberculosis complex of organisms as assessed by Southern blotting. Overexpression of this protein in wild-type M. tuberculosis resulted in a slower decline in viability following the end of log-phase growth. Accumulation of this protein was observed in log-phase cultures following a shift to oxygen-limiting conditions but not by other external stimuli. The protein was purified to homogeneity from overexpressing M. smegmatis in two steps and shown to have a significant ability to suppress the thermal denaturation of alcohol dehydrogenase. Collectively, these results suggest that the mycobacterial ␣-crystallin protein may play a role in enhancing long-term protein stability and therefore long-term survival of M. tuberculosis.More than 40 years after the introduction of effective chemotherapy, tuberculosis remains the single largest infectious cause of human mortality, resulting in about five deaths every minute (13). The failure to eradicate this disease is intimately linked to the pathogenesis of the organism. Initial infection with Mycobacterium tuberculosis only rarely leads to disease. Instead, infection is typically controlled by the host's immune system, and most viable bacilli are cleared. Not all bacteria are removed, however, and the remainder are capable of becoming inactive for decades before reactivating to cause clinical disease (37). The AIDS epidemic has exacerbated this problem. Patients latently infected with M. tuberculosis stand a 0.2% annual risk of reactivation, compared with the 5 to 10% annual risk borne by the human immunodeficiency virus-M. tuberculosis coinfected (13). The majority of the tuberculosis cases reported in the United States are the result of reactivation, not initial infection, and as many as 10 million to 15 million Americans have such latent infections (3). Worldwide the problem is even more serious: fully one-third of the entire human population may be latently infected with dormant bacilli (31). Clearly this delay in appearance of the active disease only complicates an already difficult problem, and new strategies which will allow the eradication of latent organisms are required. Such strategies will arise only through an ...

Although the 16-kDa ␣-crystallin homologue of Mycobacterium tuberculosis (MTB) is the dominant protein produced by stationary phase cultures in vitro, it is undetectable in logarithmically growing cultures. By growing bacilli at defined oxygen concentrations, acr transcription was shown to be strongly induced by mildly hypoxic conditions. Acr expression also was found to be induced during the course of in vitro infection of macrophages. The acr gene was replaced with a hygromycin resistance cassette by allelic exchange in MTB H37Rv. The resulting ⌬acr::hpt strain was shown to be equivalent to wild-type H37Rv in in vitro growth rate and infectivity but was significantly impaired for growth in both mouse bone marrow derived macrophages and THP-1 cells. In addition to its proposed role in maintenance of long-term viability during latent, asymptomatic infections, these results establish a role for the Acr protein in replication during initial MTB infection.

BACKGROUND After treatment for prostate cancer, multidisciplinary sexual rehabilitation involving couples appears more promising than traditional urologic treatment for erectile dysfunction (ED). We conducted a randomized trial comparing traditional or internet-based sexual counseling with a waitlist control. METHODS Couples were adaptively randomized to a 3-month waitlist (WL), a 3-session face-to-face format (FF), or an internet-based format with email contact with the therapist (WEB1). A second internet-based group (WEB2) was added to further examine the relationship between web site usage and outcomes. At baseline, post-waitlist, post-treatment, and at 3-, 6-, and 12-month follow-ups participants completed the International Index of Erectile Function (IIEF), the Female Sexual Function Index (FSFI), the Brief Symptom Inventory-18 to measure emotional distress, and the abbreviated Dyadic Adjustment Scale. RESULTS Outcomes did not change during the waitlist period. Of 115 couples entering the randomized trial and 71 entering the WEB2 group, 33% dropped out. However, a linear mixed model analysis including all participants confirmed improvements in IIEF scores that remained significant at 1-year follow-up (P<0.001). Women with abnormal FSFI scores initially also improved significantly (P=0.0255). Finding an effective medical treatment for ED and normal female sexual function at baseline, but not treatment format, were associated with better outcomes. In the WEB groups, only men completing more than 75% of the intervention had significant improvements in IIEF scores. CONCLUSIONS An internet-based sexual counseling program for couples is as effective as a brief, traditional sex therapy format in producing enduring improvements in men’s sexual outcomes after prostate cancer.