Topical pravibismane as adjunctive therapy for moderate or severe diabetic foot infections: A phase 1b randomized, multicenter, double-blind, placebo-controlled trial.

This Phase 1b study was designed to evaluate the safety and efficacy of pravibismane, a novel broad-spectrum topical anti-infective, in managing moderate or severe chronic diabetic foot ulcer (DFU) infections. This randomized, double-blind, placebo-controlled, multicenter study consisted of 39 individuals undergoing pravibismane treatment and 13 individuals in the placebo group. Assessment of safety parameters included clinical observations of tolerability and pharmacokinetics from whole blood samples. Pravibismane was well-tolerated and exhibited minimal systemic absorption, as confirmed by blood concentrations that were below the lower limit of quantitation (0.5 ng/mL) or in the low nanomolar range, which is orders of magnitude below the threshold of pharmacological relevance for pravibismane. Pravibismane treated subjects showed approximately 3-fold decrease in ulcer size compared to the placebo group (85% vs. 30%, p = 0.27). Furthermore, the incidence of ulcer-related lower limb amputations was approximately 6-fold lower (2.6%) in the pooled pravibismane group versus 15.4% in the placebo group (p = 0.15). There were no treatment emergent or serious adverse events related to study drug. The initial findings indicate that topical pravibismane was safe and potentially effective treatment for improving recovery from infected chronic ulcers by reducing ulcer size and facilitating wound healing in infected DFUs (ClinicalTrials.gov Identifier NCT02723539).

From theory to pamphlet: the 3Ws and an H process for the development of meaningful patient education resources.

There is growing recognition of the importance of patient education given the prevalence and consequences of low health literacy in Canada and the USA. Research has shown that in addition to plain language, the use of theories of learning can contribute to the effectiveness of patient education resources, and as such, various guidelines and toolkits have been put together to help healthcare providers utilize these theories. Despite these efforts, this knowledge is not consistently applied in practice. To address this gap, we describe a new theory-based protocol, the "3Ws and an H," that is designed to guide healthcare providers in the production of effective patient education resources. Adult learning theory underpins each step of the process, and by using the "3Ws and an H," relevant theories are applied as the steps of the protocol are followed. To facilitate the adoption of this process, we describe it using a resource development project for survivors of endometrial cancer as an example.

The effect of an organizational network for patient safety on safety event reporting.

Health care organizations continue to implement organization-wide educational approaches to enhance patient safety with less attention on evaluating the impact of these approaches. In this context, a study was conducted to measure the impact of an organization-wide patient safety network approach on patient safety event reporting. A time-series analysis with reported rates of adverse events (major and moderate), near misses, sentinel events, and incidents from 2 years prior through 13 months following implementation was conducted. Study findings include a significant increase in reporting of patient safety events (an approximately 50% increase in overall reporting of safety events was observed; p < .001), especially near misses (an approximately 100% increase following implementation; p = .002). Study findings suggest that a multifaceted networked approach does contribute to improving patient safety event reporting.

Use of audit and feedback with fluorescent targeting to achieve rapid improvements in room cleaning in the intensive care unit and ward settings.

Environmental contamination of high-touch surfaces in patient rooms can lead to the transmission of clinically significant pathogens; thus, such surfaces should be cleaned routinely and thoroughly. Fluorescent targeting can be used to provide feedback to frontline cleaning staff on the thoroughness of room cleaning, which can result in substantial improvements in performance. We demonstrate that auditing with fluorescent targeting can be implemented in both the ward and intensive care unit settings using only modest resources, resulting in rapid improvements in cleaning thoroughness.

Engineering of stable bispecific antibodies targeting IL-17A and IL-23.

Bispecific antibodies (bsAbs) present an attractive opportunity to combine the additive and potentially synergistic effects exhibited by combinations of monoclonal antibodies (mAbs). Current challenges for engineering bsAbs include retention of the binding affinity of the parent mAb or antibody fragment, the ability to bind both targets simultaneously, and matching valency with biology. Other factors to consider include structural stability and expression of the recombinant molecule, both of which may have significant impact on its development as a therapeutic. Here, we incorporate selection of stable, potent single-chain variable fragments (scFvs) early in the engineering process to assemble bsAbs for therapeutic applications targeting the cytokines IL-17A/A and IL-23. Stable scFvs directed against human cytokines IL-23p19 and IL-17A/A were isolated from a human Fab phage display library via batch conversion of panning output from Fabs to scFvs. This strategy integrated a step for shuffling V regions during the conversion and permitted the rescue of scFv molecules in both the V(H)V(L) and the V(L)V(H) orientations. Stable scFvs were identified and assembled into several bispecific formats as fusions to the Fc domain of human IgG1. The engineered bsAbs are potent neutralizers of the biological activity of both cytokines (IC(50) < 1 nM), demonstrate the ability to bind both target ligands simultaneously and display stability and productivity advantageous for successful manufacture of a therapeutic molecule. Pharmacokinetic analysis of the bsAbs in mice revealed serum half-lives similar to human mAbs. Assembly of bispecific molecules using stable antibody fragments offers an alternative to reformatting mAbs and minimizes subsequent structure-related and manufacturing concerns.

Rapid control of a methicillin resistant Staphylococcus aureus (MRSA) outbreak in a medical surgical intensive care unit (ICU).

BACKGROUND: Outbreaks of methicillin resistant Staphylococcus aureus in the intensive care unit setting can be prolonged and difficult to control. This report describes the rapid control of an outbreak of methicillin resistant Staphylococcus aureus in a 24-bed open-concept medical surgical intensive care unit with a baseline methicillin resistant Staphylococcus aureus acquisition rate of 1.5 cases per 1000 patient days. INTERVENTIONS/RESULTS: This institution's infection control policy mandates an outbreak investigation if two cases of hospital-acquired methicillin resistant Staphylococcus aureus colonization or infection are identified in an intensive care unit within a four-week period. In July 2007, methicillin resistant Staphylococcus aureus was identified in the sputum of two patients within a one-week period. Screening of all patients in the intensive care unit identified one additional case and a fourth case was identified from a clinical specimen before control measures were implemented. Initial control measures included healthcare worker education, enhanced surveillance, patient cohorting, and enhanced environmental cleaning. Despite these measures, three more cases occurred. All patients were then placed in contact isolation, healthcare workers were screened, and the nursing staff was cohorted. After two weeks without a case, two additional cases were identified. Decolonization of all positive patients was initiated. No further cases occurred over a five-week period and the outbreak was declared over. The outbreak resulted in nine cases of methicillin resistant Staphylococcus aureus colonization (n = 8) or infection (n = 1) over an 11-week period. Only one of 175 healthcare workers was colonized and it was not the outbreak strain. CONCLUSIONS: Early detection and the stepwise addition of infection control measures resulted in the rapid control of an outbreak of methicillin resistant Staphylococcus aureus in a medical surgical intensive care unit without unit closure. A low threshold of suspicion and the rapid initiation of unit wide surveillance were the key steps in limiting the size of the outbreak. Complete cessation of transmission occurred after the initiation of decolonization for all positive patients.

Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions.

Cytokines that signal through Class II receptors form a distinct family that includes the interferons and interleukin 10 (IL-10). Recent identification of several IL-10 homologs has defined a cytokine subfamily that includes AK155, IL-19, IL-20, IL-22, and IL-24. Within this subfamily, IL-19, IL-20, and IL-24 exhibit substantial sharing of receptor complexes; all three are capable of signaling through IL-20RA/IL-20RB, and IL-20 and IL-24 both can also use IL-22R/IL-20RB. However, the biological effects of these three cytokines appear quite distinct: immune activity with IL-19, skin biology with IL-20, and tumor apoptosis with IL-24. To more fully elucidate their interactions with the receptor complexes, we have performed a series of in vitro assays. Reporter, proliferation, and direct STAT activation assays using cell lines expressing transfected receptors revealed differences between the receptor complexes. IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation. These results demonstrate that, although this subclass exhibits receptor complex redundancy, there are differences in ligand/receptor interactions and in signal transduction that may lead to specificity and a distinct biology for each cytokine.