Aluminum salts such as aluminum oxyhydroxide and aluminum hydroxyphosphate are commonly used human vaccine adjuvants. In an effort to improve the adjuvant activity of aluminum salts, we previously showed that the adjuvant activity of aluminum oxyhydroxide nanoparticles is significantly more potent than that of aluminum oxyhydroxide microparticles. The present study was designed to i) understand the mechanism underlying the potent adjuvant activity of aluminum oxyhydroxide nanoparticles, relative to microparticles, and ii) to test whether aluminum hydroxyphosphate nanoparticles have a more potent adjuvant activity than aluminum hydroxyphosphate microparticles as well. In human THP-1 myeloid cells, wild-type and NLRP3-deficient, both aluminum oxyhydroxide nanoparticles and microparticles stimulate the secretion of proinflammatory cytokine IL-1β by activating NLRP3 inflammasome, although aluminum oxyhydroxide nanoparticles are more potent than microparticles, likely related to the higher uptake of the nanoparticles by the THP-1 cells than the microparticles. Aluminum hydroxyphosphate nanoparticles also have a more potent adjuvant activity than microparticles in helping a model antigen lysozyme to stimulate specific antibody response, again likely related to their stronger ability to activate the NLRP3 inflammasome.

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IMPORTANCEThere are an increasing number of veterans in the United States, and the current delay and wait times prevent Veterans Affairs institutions from fully meeting the needs of current and former service members. Concrete strategies to improve throughput at these facilities have been sparse. OBJECTIVE To identify whether lean processes can be used to improve wait times for surgical procedures in Veterans Affairs hospitals. DESIGN, SETTING, AND PARTICIPANTS Databases in the Veterans Integrated Service Network 11 Data Warehouse, Veterans Health Administration Support Service Center, and Veterans Information Systems and Technology Architecture/Dynamic Host Configuration Protocol were queried to assess changes in wait times for elective general surgical procedures and clinical volume before, during, and after implementation of lean processes over 3 fiscal years (FYs) at a tertiary care Veterans Affairs medical center. All patients evaluated by the general surgery department through outpatient clinics, clinical video teleconferencing, and e-consultations from October 2011 through September 2014 were included. Patients evaluated through the emergency department or as inpatient consults were excluded.EXPOSURES The surgery service and systems redesign service held a value stream analysis in FY 2013, culminating in multiple rapid process improvement workshops. Multidisciplinary teams identified systemic inefficiencies and strategies to improve interdepartmental and patient communication to reduce canceled consultations and cases, diagnostic rework, and no-shows. High-priority triage with enhanced operating room flexibility was instituted to reduce scheduling wait times. General surgery department pilot projects were then implemented mid-FY 2013. MAIN OUTCOMES AND MEASURESPlanned outcome measures included wait time, clinic and telehealth volume, number of no-shows, and operative volume. Paired t tests were used to identify differences in outcome measures after the institution of reforms. CONCLUSIONS AND RELEVANCE Improvement in the overall surgical patient experience can stem from multidisciplinary collaboration among systems redesign personnel, clinicians, and surgical staff to reduce systemic inefficiencies. Monitoring and follow-up of system efficiency measures and the employment of lean practices and process improvements can have positive short-and long-term effects on wait times, clinical throughput, and patient care and satisfaction.

The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108 - 109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery.