Publications

The application of recently developed sensitive, specific, culture-independent tools for identification of microbes is transforming concepts of microbial ecology, including concepts of the relationships between the vast complex populations of microbes associated with ourselves and with states of health and disease. Although most work initially focused on the community of microbes (microbiome) in the gastrointestinal tract and its relationship to gastrointestinal disease, interest has expanded to include study of the relationships of the airway microbiome to asthma and its phenotypes and to the relationships between the gastrointestinal microbiome, development of immune function, and predisposition to allergic sensitization and asthma. Here we provide our perspective on the findings of studies of differences in the airway microbiome between asthmatic patients and healthy subjects and of studies of relationships between environmental microbiota, gut microbiota, immune function, and asthma development. In addition, we provide our perspective on how these findings suggest the broad outline of a rationale for approaches involving directed manipulation of the gut and airway microbiome for the treatment and prevention of allergic asthma.

Beta-lactam antibiotics target penicillin-binding proteins including several enzyme classes essential for bacterial cell-wall homeostasis. To better understand the functional and inhibitor-binding specificities of penicillin-binding proteins from the pathogen, Mycobacterium tuberculosis, we carried out structural and phylogenetic analysis of two predicted D,D-carboxypeptidases, Rv2911 and Rv3330. Optimization of Rv2911 for crystallization using directed evolution and the GFP folding reporter method yielded a soluble quadruple mutant. Structures of optimized Rv2911 bound to phenylmethylsulfonyl fluoride and Rv3330 bound to meropenem show that, in contrast to the nonspecific inhibitor, meropenem forms an extended interaction with the enzyme along a conserved surface. Phylogenetic analysis shows that Rv2911 and Rv3330 belong to different clades that emerged in Actinobacteria and are not represented in model organisms such as Escherichia coli and Bacillus subtilis. Clade-specific adaptations allow these enzymes to fulfill distinct physiological roles despite strict conservation of core catalytic residues. The characteristic differences include potential protein-protein interaction surfaces and specificity-determining residues surrounding the catalytic site. Overall, these structural insights lay the groundwork to develop improved beta-lactam therapeutics for tuberculosis.

BACKGROUND

Few data exist on the use of text messaging as a tool to promote retention in HIV care and virologic suppression at the clinic level in the United States. We describe the protocol for a study designed to investigate whether a text messaging intervention that supports healthy behaviors, encourages consistent engagement with care, and promotes antiretroviral persistence can improve retention in care and virologic suppression among patients in an urban safety-net HIV clinic in San Francisco.

METHODS/DESIGN

Connect4Care (C4C) is a single-site, randomized year-long study of text message appointment reminders vs. text message appointment reminders plus thrice-weekly supportive, informational, and motivational text messages. Eligible consenting patients are allocated 1:1 to the two arms within strata defined by HIV diagnosis within the past 12 months (i.e. "newly diagnosed") vs. earlier. Study participants must receive primary care at the San Francisco General Hospital HIV clinic, speak English, possess a cell phone and be willing to send/receive up to 25 text messages per month, a have viral load >200 copies/μL, and be either new to the clinic or have a history of poor retention. The primary efficacy outcome is virologic suppression at 12 months and the key secondary outcome, which will also be examined as a mediator of the primary outcome, is retention in HIV care, as operationalized by kept and missed primary care visits. Process outcomes include text message response rate and percent of time in study without cell phone service. Generalized estimating equation log-binomial models will be used for intent to treat, per protocol, and mediation analyses. An assessment of the cost and cost-effectiveness of the intervention is planned along with a qualitative evaluation of the intervention.

DISCUSSION

Findings from this study will provide valuable information about the use of behavioral-theory based text messaging to promote retention in HIV care and virologic suppression, further elucidate the challenges of using texting technology with marginalized urban populations, and help guide the development of new mobile health strategies to improve HIV care cascade outcomes.

TRIAL REGISTRATION

NCT01917994.

This paper investigates the dynamics of an SIR model of childhood vaccination under the assumption that the vaccination uptake rate depends on past values of disease prevalence. The delay kernel is a high order Erlang function, which allows no instantaneous feedback between prevalence at time t and vaccinations at time t. Multiple types of endemic equilibria are found, as are stable and unstable equilibria, periodic orbits, dependence on initial conditions, and apparent chaos.