GC-072: A Novel Therapeutic Candidate for Oral Treatment of Melioidosis and Infections Caused by Select Biothreat Pathogens.

Burkholderia pseudomallei (B. pseudomallei), the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from B. pseudomallei varies depending on the type of infection and extent of available health care, but in the case of septicemia left untreated it can range from 50 - 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for two weeks or longer, followed by oral eradication-phase treatment lasting several months. An effective oral therapeutic for outpatient treatment of acute-phase melioidosis is needed. GC-072 is a potent, 4-oxoquinolizine antibiotic with selective inhibitory activity against bacterial topoisomerases. GC-072 has demonstrated in vitro potency against susceptible and drug-resistant strains of B. pseudomallei and is also active against Burkholderia mallei, Bacillus anthracis, Yersinia pestis, and Francisella tularensis GC-072 is bactericidal both extra- and intracellularly, with rapid killing noted within a few hours and reduced development of resistance compared to ceftazidime. GC-072, delivered intragastrically to mimic oral administration, promoted dose-dependent survival in mice using lethal inhalational models of B. pseudomallei infection following exposure to a 24 or 339 LD50 challenge with B. pseudomallei strain 1026b. Overall, GC-072 appears to be a strong candidate for first-line, oral treatment of melioidosis.

Continuous Medication Monitoring (CoMM): A foundational model to support the clinical work of community pharmacists.

BACKGROUND: Under the Continuous Medication Monitoring (CoMM) approach, community pharmacists prevent, identify, resolve, and document drug therapy problems during the dispensing process. OBJECTIVE: To describe the patients receiving CoMM interventions and the pattern of delivery of CoMM interventions. METHODS: Pharmacy dispensing and clinical records were reviewed for patients filling at least one prescription and receiving at least one continuous medication monitoring intervention at a community pharmacy from April 2014 through March 2015. The proportion of patients receiving an intervention type and the number of interventions per patient were computed. RESULTS: Nearly 2500 patients received 16,986 continuous medication monitoring interventions over the year. The average age of the patients receiving the interventions was 59.1 years, and they filled an average of 8.0 unique medications. An average of 6.8 interventions was delivered to each patient. About half (49.7%) of interventions addressed drug therapy problems. The pharmacists delivered 3.0 patient counseling and education and 3.4 drug therapy problem interventions per patient on average. CONCLUSION: There are many opportunities to improve patients' medication use that can be identified and addressed under a Continuous Medication Monitoring model. Movement to this model of practice is desirable, but changes are needed to facilitate the shift.

Maternal resolution of child diagnosis: stability and relations with child attachment across the toddler to preschooler transition.

In this longitudinal study, the authors investigated individual differences in how families adapt to a child's congenital disorder. Family impact, maternal grief resolution, and child attachment were assessed among 74 mothers and their toddlers with a neurological disorder or disfigurement. Fifty dyads were reevaluated 16 months later. For children with neurological compared with disfigurement diagnoses, there was a greater likelihood of negative impact on family, unresolved maternal grief, and insecure attachment at Time 1. Children classified as secure were significantly more likely to have mothers classified as resolved regarding their reactions to their children's diagnosis. Maternal grief resolution was significantly stable (77%) over time and mediated the relation between type of diagnosis and child security. With time, negative impact of child condition on the family decreased and percentage of children classified as secure increased, suggesting that on average families improved. Results suggest that helping parents come to terms emotionally and cognitively with their child's condition may be a useful focus for intervention.

Measurement of aggregate cohesion by tissue surface tensiometry.

Rigorous measurement of intercellular binding energy can only be made using methods grounded in thermodynamic principles in systems at equilibrium. We have developed tissue surface tensiometry (TST) specifically to measure the surface free energy of interaction between cells. The biophysical concepts underlying TST have been previously described in detail. The method is based on the observation that mutually cohesive cells, if maintained in shaking culture, will spontaneously assemble into clusters. Over time, these clusters will round up to form spheres. This rounding-up behavior mimics the behavior characteristic of liquid systems. Intercellular binding energy is measured by compressing spherical aggregates between parallel plates in a custom-designed tissue surface tensiometer. The same mathematical equation used to measure the surface tension of a liquid droplet is used to measure surface tension of 3D tissue-like spherical aggregates. The cellular equivalent of liquid surface tension is intercellular binding energy, or more generally, tissue cohesivity. Previous studies from our laboratory have shown that tissue surface tension (1) predicts how two groups of embryonic cells will interact with one another, (2) can strongly influence the ability of tissues to interact with biomaterials, (3) can be altered not only through direct manipulation of cadherin-based intercellular cohesion, but also by manipulation of key ECM molecules such as FN and 4) correlates with invasive potential of lung cancer, fibrosarcoma, brain tumor and prostate tumor cell lines. In this article we will describe the apparatus, detail the steps required to generate spheroids, to load the spheroids into the tensiometer chamber, to initiate aggregate compression, and to analyze and validate the tissue surface tension measurements generated.