The automated harm trigger system revealed not only more harm but a broader scope of harm and led to a deeper understanding of patient safety vulnerabilities.

No abstract

The year 2016 will mark an important milestone - the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) including Highly Active Antiretroviral Therapy (HAART) drug regimens is widely considered to be one of the greatest achievements in therapeutic drug research having transformed HIV infection into a chronically managed disease. Unfortunately, the lack of widespread preventive measures and the inability to eradicate HIV from infected cells highlight the significant challenges remaining today. Moving forward there are at least three high priority goals for anti-HIV drug delivery (DD) research: (1) to prevent new HIV infections from occurring, (2) to facilitate a functional cure, i.e., when HIV is present but the body controls it without drugs and (3) to eradicate established infection. Pre-exposure Prophylaxis (PrEP) represents a significant step forward in preventing the establishment of chronic HIV infection. However, the ultimate success of PrEP will depend on achieving sustained antiretroviral (ARV) tissue concentrations and will require strict patient adherence to the regimen. While first generation long acting/extended release (LA/ER) DDS currently in development show considerable promise, significant DD treatment and prevention challenges persist. First, there is a critical need to improve cell specificity through targeting in order to selectively achieve efficacious drug concentrations in HIV reservoir sites to control/eradicate HIV as well as mitigate systemic side effects. In addition, approaches for reducing cellular efflux and metabolism of ARV drugs to prolong effective concentrations in target cells need to be developed. Finally, given the current understanding of HIV pathogenesis, next generation anti-HIV DDS need to address selective DD to the gut mucosa and lymph nodes. The current review focuses on the DDS technologies, critical challenges, opportunities, strategies, and approaches by which novel delivery systems will help iterate towards prevention, functional cure and eventually the eradication of HIV infection.

Objectives: An adverse event (AE) is a physical harm experienced by a patient due to health care, requiring intervention. Describing and categorizing AEs is important for quality and safety assessment and identifying areas for improvement. Safety science suggests that improvement efforts should focus on preventing and mitigating harm rather than on error, which is commonplace but infrequently leads to AEs. Most taxonomies fail to describe harm experienced by patients (e.g., hypoxia, hemorrhage, anaphylaxis), focusing instead on errors, and use categorizations that are too broad to be useful (e.g., "communication error"). We set out to create a patient-centered, emergency department (ED)specific framework for describing AEs and near misses to advance quality and safety in the acute care setting. Methods:We performed a critical review of existing taxonomies of harm, evaluating their applicability to the ED.We identified and adopted a classification framework and developed a taxonomy using an iterative process categorizing approximately 600 previously identified AEs and near misses. We reviewed this taxonomy with collaborators at four medical centers, receiving feedback and providing clarification. We then disseminated a set of representative scenarios for these safety experts to categorize independently using the taxonomy. We calculated interrater reliability and performance compared to our criterion standard.Results: Our search identified candidate taxonomies for detailed review. We selected the Adventist Health Systems AE taxonomy and modified this for use in the ED, adopting a framework of categories, subcategories, and up to three modifiers to further describe events. On testing, overall reviewer agreement with the criterion standard was 92% at the category level and 88% at the subcategory level. Three of the four raters concurred in 55 of 59 scenarios (93%) and all four concurred in 46 of 59 scenarios (78%). At the subcategory level, there was complete agreement in 40 of 59 (68%) scenarios and majority agreement in 55 of 59 instances (93%). Performance of individual raters ranged from very good (88%, 52/59) to near perfect (98%, 58/59) at the main category level. Conclusions:We developed a taxonomy of AEs and near misses for the ED, modified from an existing framework. Testing of the tool with minimal training yielded high performance and good inter-rater reliability. This taxonomy can be adapted and modified by EDs seeking to enhance their quality and safety reviews and characterize harm occurring in their EDs for quality improvement purposes.From the

Local delivery of anti-HIV drugs to the colorectal mucosa, a major site of HIV replication, and their retention within mucosal tissue would allow for a reduction in dose administered, reduced dosing frequency and minimal systemic exposure. The current report describes a mucosal Pre-Exposure Prophylaxis (mPrEP) strategy that utilizes nanocarrier conjugates (NC) consisting of poly(ethylene glycol) (PEG), amprenavir (APV) and a cell penetrating peptide (CPP; namely Bac7, a fragment derived from bactenecin 7). APV-PEG NCs with linear PEGs (2, 5, 10, and 30 kDa) exhibited reduced (52 – 21%) anti-HIV-1 protease (PR) activity as compared to free APV in an enzyme-based FRET assay. In MT-2 T-cells, APV-PEG3.4kDa-FITC (APF) anti-HIV-1 activity was significantly reduced (160-fold, IC50 = 8.064 µM) due to poor cell uptake whereas it was restored (IC50 = 78.29 nM) and similar to APV (IC50 = 50.29 nM) with the addition of Bac7 to the NC (i.e., APV-PEG3.4kDa-Bac7, APB). Flow cytometry and confocal microscopy demonstrated Bac7-PEG3.4kDa-FITC (BPF) uptake was two- and four-fold higher than APF in MT-2 T-cells and Caco-2 intestinal epithelial cells, respectively. There was no detectable punctate fluorescence in either cell line suggesting that BPF directly enters the cytosol thus avoiding endosomal entrapment. After colorectal administration in mice, BPF mucosal concentrations were 21-fold higher than APF concentrations. BPF concentrations also remained constant for the 5 days of the study suggesting that (1) the NC’s structural characteristics (i.e., the size of the PEG carrier and the presence of a CPP) significantly influenced tissue persistence and (2) the NCs were probably lodged in the lamina propria since the average rodent colon mucosal cell turnover time is 2–3 days. These encouraging results suggest that Bac7 functionalized NCs delivered locally to the colorectal mucosa may form drug delivery depots that are capable of sustaining colorectal drug concentrations. Although the exact mechanisms for tissue persistence are unclear and will require further study, these results provide proof-of-concept feasibility for mPrEP.