Immunization with lytic polysaccharide monooxygenase CbpD induces protective immunity against Pseudomonas aeruginosa pneumonia.

Pseudomonas aeruginosa (PA) CbpD belongs to the lytic polysaccharide monooxygenases (LPMOs), a family of enzymes that cleave chitin or related polysaccharides. Here, we demonstrate a virulence role of CbpD in PA pneumonia linked to impairment of host complement function and opsonophagocytic clearance. Following intratracheal challenge, a PA ΔCbpD mutant was more easily cleared and produced less mortality than the wild-type parent strain. The x-ray crystal structure of the CbpD LPMO domain was solved to subatomic resolution (0.75Å) and its two additional domains modeled by small-angle X-ray scattering and Alphafold2 machine-learning algorithms, allowing structure-based immune epitope mapping. Immunization of naive mice with recombinant CbpD generated high IgG antibody titers that promoted human neutrophil opsonophagocytic killing, neutralized enzymatic activity, and protected against lethal PA pneumonia and sepsis. IgG antibodies generated against full-length CbpD or its noncatalytic M2+CBM73 domains were opsonic and protective, even in previously PA-exposed mice, while antibodies targeting the AA10 domain were not. Preexisting antibodies in PA-colonized cystic fibrosis patients primarily target the CbpD AA10 catalytic domain. Further exploration of LPMO family proteins, present across many clinically important and antibiotic-resistant human pathogens, may yield novel and effective vaccine antigens.

Impact of the Agency for Healthcare Research and Quality's Safety Program for Perinatal Care.

BACKGROUND: The Safety Program for Perinatal Care (SPPC) seeks to improve safety on labor and delivery (L&D) units through three mutually reinforcing components: (1) fostering a culture of teamwork and communication, (2) applying safety science principles to care processes; and (3) in situ simulation. The objective of this study was to describe the SPPC implementation experience and evaluate the short-term impact on unit patient safety culture, processes, and adverse events. METHODS: We supported SPPC implementation by L&D units with a program toolkit, trainings, and technical assistance. We evaluated the program using a pre-post, mixed-methods design. Implementing units reported uptake of program components, submitted hospital discharge data on maternal and neonatal adverse events, and participated in semi-structured interviews. We measured changes in safety and quality using the Modified Adverse Outcome Index (MAOI) and other perinatal care indicators. RESULTS: Forty-three L&D units submitted data representing 97,740 deliveries over 10 months of follow-up. Twenty-six units implemented all three program components. L&D staff reported improvements in teamwork, communication, and unit safety culture that facilitated applying safety science principles to clinical care. The MAOI decreased from 5.03% to 4.65% (absolute change -0.38% [95% CI, -0.88% to 0.12%]). Statistically significant decreases in indicators for obstetric trauma without instruments and primary cesarean delivery were observed. A statistically significant increase in neonatal birth trauma was observed, but the overall rate of unexpected newborn complications was unchanged. CONCLUSIONS: The SPPC had a favorable impact on unit patient safety culture and processes, but short-term impact on maternal and neonatal adverse events was mixed.

Dynamics and thermodynamics of air-driven active spinners.

We report on the collective behavior of active particles in which energy is continuously supplied to rotational degrees of freedom. The active spinners are 3D-printed disks, 1 cm in diameter, that have an embedded fan-like structure, such that a sub-levitating up-flow of air forces them to spin. Single spinners exhibit Brownian motion with a narrow Gaussian velocity distribution function, P(v), for translational motion. We study the evolution of P(v) as the packing fraction and the average single particle spin speeds are varied. The interparticle hydrodynamic interaction is negligible, and the dynamics is dominated by hyperelastic collisions and dissipative forces. As expected for nonequilibrium systems, P(v) for a collection of many spinners deviates from Gaussian behavior. However, unlike translationally active systems, phase separation is not observed, and the system remains spatially homogeneous. We then search for a near-equilibrium counterpart for our active spinners by measuring the equation of state. Interestingly, it agrees well with a hard-sphere model, despite the dissipative nature of the single particle dynamics.

Integrated Approach to Reduce Perinatal Adverse Events: Standardized Processes, Interdisciplinary Teamwork Training, and Performance Feedback.

OBJECTIVE: To improve safety practices and reduce adverse events in perinatal units of acute care hospitals. DATA SOURCES: Primary data collected from perinatal units of 14 hospitals participating in the intervention between 2008 and 2012. Baseline secondary data collected from the same hospitals between 2006 and 2007. STUDY DESIGN: A prospective study involving 342,754 deliveries was conducted using a quality improvement collaborative that supported three primary interventions. Primary measures include adoption of three standardized care processes and four measures of outcomes. DATA COLLECTION METHODS: Chart audits were conducted to measure the implementation of standardized care processes. Outcome measures were collected and validated by the National Perinatal Information Center. PRINCIPAL FINDINGS: The hospital perinatal units increased use of all three care processes, raising consolidated overall use from 38 to 81 percent between 2008 and 2012. The harms measured by the Adverse Outcome Index decreased 14 percent, and a run chart analysis revealed two special causes associated with the interventions. CONCLUSIONS: This study demonstrates the ability of hospital perinatal staff to implement efforts to reduce perinatal harm using a quality improvement collaborative. Findings help inform the relationship between the use of standardized care processes, teamwork training, and improved perinatal outcomes, and suggest that a multiplicity of integrated strategies, rather than a single intervention, may be essential to achieve high reliability.

Decreasing Malpractice Claims by Reducing Preventable Perinatal Harm.

OBJECTIVE: To evaluate the association of improved patient safety practices with medical malpractice claims and costs in the perinatal units of acute care hospitals. DATA SOURCES: Malpractice and harm data from participating hospitals; litigation records and medical malpractice claims data from American Excess Insurance Exchange, RRG, whose data are managed by Premier Insurance Management Services, Inc. (owned by Premier Inc., a health care improvement company). STUDY DESIGN: A quasi-experimental prospective design to compare baseline and postintervention data. Statistical significance tests for differences were performed using chi-square, Wilcoxon signed-rank test, and t-test. DATA COLLECTION: Claims data were collected and evaluated by experienced senior claims managers through on-site claim audits to evaluate claim frequency, severity, and financial information. Data were provided to the analyzing institution through confidentiality contracts. PRINCIPAL FINDINGS: There is a significant reduction in the number of perinatal malpractice claims paid, losses paid, and indemnity payments (43.9 percent, 77.6 percent, and 84.6 percent, respectively) following interventions to improve perinatal patient safety and reduce perinatal harm. This compares with no significant reductions in the nonperinatal claims in the same hospitals during the same time period. CONCLUSIONS: The number of perinatal malpractice claims and dollar amount of claims payments decreased significantly in the participating hospitals, while there was no significant decrease in nonperinatal malpractice claims activity in the same hospitals.

A perinatal care quality and safety initiative: are there financial rewards for improved quality?

BACKGROUND: Although costs of providing care may decrease with hospital initiatives to improve obstetric and neonatal outcomes, the accompanying reduced adverse outcomes may negatively affect hospital revenues. METHODS: In 2008 a Minnesota-based hospital system (Fairview Health Services) launched the Zero Birth Injury (ZBI) initiative, which used evidence-based care bundles to guide management of obstetric services. A pre-post analysis of financial impacts of ZBI was conducted by using hospital administrative records to measure costs and revenues associated with changes in maternal and neonatal birth injuries before (2008) and after (2009-2011) the initiative. RESULTS: For the Fairview Health Services hospitals, after adjusting for relevant covariates, implementation of ZBI was associated with a mean 11% decrease in the rate of maternal and neonatal adverse outcomes between 2008 and 2011 (adjusted odds ratio [AOR] = 0.89, p = .076). As a result of the adverse events avoided, the hospital system saved $284,985 in costs but earned $324,333 less revenue, which produced a net financial decrease of $39,348 (or a $305 net financial loss per adverse event avoided) in 2011, compared with 2008. CONCLUSIONS: Adoption of a perinatal quality and safety initiative that reduced birth injuries had little net financial impact on the hospital. ZBI produced better clinical results at a lower cost, which represents potential savings for payers, but the hospital system offering improved quality reaped no clear financial rewards. These results highlight the important role for shared-savings collaborations (among patients, providers, government and third-party payers, and employers) to incentivize QI. Widespread adoption of perinatal safety initiatives combined with innovative payment models may contribute to better health at reduced cost.

Didactic and simulation nontechnical skills team training to improve perinatal patient outcomes in a community hospital.

BACKGROUND: Birth trauma is a low-frequency, high-severity event, making obstetrics a major challenge for patient safety. Yet, few strategies have been shown to eliminate preventable perinatal harm. Interdisciplinary team training was prospectively evaluated to assess the relative impact of two different learning modalities to improve nontechnical skills (NTS)--the cognitive and interpersonal skills, such as communication and teamwork, that supplement clinical and technical skills and are necessary to ensure safe patient care. METHODS: Between 2005 and 2008, perinatal morbidity and mortality data were prospectively collected using the Weighted Adverse Outcomes Score (WAOS) and a culture of safety survey (Safety Attitudes Questionnaire) at three small-sized community hospitals. In a small cluster randomized clinical trial conducted in the third quarter of 2007, one of the hospitals served as a control group and two served as the treatment intervention sites--one hospital received the TeamSTEPPS didactic training program and one hospital received both the TeamSTEPPS program along with a series of in-situ simulation training exercises. RESULTS: A statistically significant and persistent improvement of 37% in perinatal morbidity was observed between the pre- and postintervention for the hospital exposed to the simulation program. There were no statistically significant differences in the didactic-only or the control hospitals. Baseline perceptions of culture of safety were high at all three hospitals, and there were no significant changes. CONCLUSIONS: A comprehensive interdisciplinary team training program using in-situ simulation can improve perinatal safety in the hospital setting. This is the first evidence providing a clear association between simulation training and improved patient outcomes. Didactics alone were not effective in improving perinatal outcomes.

A model for developing high-reliability teams.

AIM: To develop a model for high reliability in health care quality and patient safety. BACKGROUND: A high-reliability health organization (HRO) has measurable near perfect performance in quality and safety. High reliability is necessary in health care where the consequences of error are high and the frequency is low. KEY ISSUES: Despite a decade of intense focus on quality and safety since a series of reports from the Institute of Medicine (IOM), health care is not a completely safe industry and quality is not what it should be to ensure high reliability for patients. CONCLUSIONS: A model for high reliability is presented that includes the individual skills necessary to assure high-reliability teams on a patient care unit. High-reliability teams (HRT) form an essential core of a HRO. These teams and their organizations value a culture of safety every day with every patient encounter. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers can lead in creating a HRO by first developing HRTs on their patient care unit.

Identifying key nursing and team behaviours to achieve high reliability.

AIM: The aim of the present study was to measure markers of key nursing behaviours in interdisciplinary teams during critical events to assess the extent of high reliability. BACKGROUND: Technical and team competence are necessary to achieve high reliability to ensure safe patient care. Technical competence is generally assured because of professional training, licensure and practice standards. During critical events, team competence is difficult to observe, measure and evaluate in interdisciplinary teams. METHOD: During critical events, in situ simulation was the method used to observe interdisciplinary interaction of nursing behaviours regarding communication. Seventeen trials were conducted and videotaped for evaluation at four hospital sites. RESULTS: Key nursing behavioural markers for interdisciplinary interaction were described: situational awareness, use of situation, background, assessment, recommendation-response (SBAR-R), closed-loop communication and shared mental model. CONCLUSION: Skills necessary for nurses to contribute to highly reliable, interdisciplinary teams are not consistently observed during critical events and constitute breaches in defensive barriers for ensuring patient safety. IMPLICATIONS FOR NURSING MANAGEMENT: Nurses have a key role in assuring effective team performance through the transfer of critical information. Nurses need to recognize and identify important clinical and environmental cues, and act in order to ensure that the team progresses along the optimal course for patient safety.

In situ simulation: a method of experiential learning to promote safety and team behavior.

The healthcare system has an inconsistent record of ensuring patient safety. One of the main factors contributing to this poor record is inadequate interdisciplinary team behavior. This article describes in situ simulation and its 4 components--briefing, simulation, debriefing, and follow-up-as an effective interdisciplinary team training strategy to improve perinatal safety. The purpose of this manuscript is to describe the experiential nature of in situ simulation for the participants. Involved in a pilot study of 35 simulations in 6 hospitals with over 700 participants called, "In Situ Simulation for Obstetric and Neonatal Emergencies," conducted by Fairview Health Services in collaboration with the University of Minnesota's Academic Health Center.

Evaluation of direct transport pathways of glycine receptor antagonists and an angiotensin antagonist from the nasal cavity to the central nervous system in the rat model.

PURPOSE: The aim of this study was to investigate and quantify drug movement to the brain via the neuro-olfactory system after intranasal dosing of four model drugs; three glycine receptor antagonists and one angiotensin antagonist. METHODS: The drugs were dosed to rats via intranasal or intravenous administration, after which a quantitative method for tissue distribution was utilised to determine drug distribution to the olfactory lobes, brain sections and the blood over 30 min. Autoradiography was used to visualise and quantify drug distribution throughout the brain and in the CSF. Micro-autoradiography was used to examine drug distribution throughout the olfactory nerve apparatus. RESULTS: The three glycine receptor antagonist compounds were transported to the CNS to differing degrees although they had similar molecular structures and similar physicochemical characteristics. All three compounds were shown to exploit a direct route of transport from nose to brain with Direct Transport Percentages (DTP) of 99.99%, 96.71% and 51.95%, respectively, although for the last molecule a major part of the brain content originated from systemic transport across the BBB. Intranasal administration of GR138950 resulted in over 3.5 times more drug in the olfactory lobes at 1 min post-dose compared to intravenous administration; and 5 times more drug was delivered to the olfactory lobes over 30 min. Micro-autoradiography showed that GR138950 could be found throughout the olfactory nerve apparatus. Autoradiography illustrated drug distribution throughout the brain and CSF, with drug concentrations in the CSF being equal or higher than in the brain tissue. It was determined that approximately 0.8% of the administered dose moved into the brain and CSF via the olfactory pathway over 30 min. CONCLUSIONS: Intranasal administration resulted in greater delivery of the model drugs to the olfactory lobes and brain as compared to intravenous dosing. It is proposed that the drug moved through the neuro-olfactory system, primarily via paracellular pathways.

Design and evaluation of an emulsion vehicle for paclitaxel. II. Suppression of the crystallization of paclitaxel by freeze-drying technique.

Although paclitaxel is soluble in vitamin E up to 40 mg per g, crystallization was detected at loadings higher than 15 mg per g. Water appeared to be an important factor causing the observed crystallization, and therefore, a freeze-drying technique was investigated to produce reconstitutible vitamin E emulsions, to increase drug loading without crystal formation after reconstitution. The emulsion was freeze-dried using a laboratory freeze-drier and the droplet size was measured using dynamic light scattering. The freeze-dried emulsions using sucrose as a cryoprotectant could be easily reconstituted. The loading of paclitaxel in the freeze-dried emulsions could be increased to 25 mg per g of vitamin E without crystal formation, and the mean emulsion droplet size remained smaller than 0.2 mum over 430 days (4 +/- 2 degrees C). The previously observed surfactant-enhanced crystallization could also be suppressed using the freeze-drying technique.

Evaluation of effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system.

It has been shown that vasoconstrictive drugs such as ephedrine derivatives are able to decrease systemic absorption of drugs administered by mucosal surfaces. The present paper set out to evaluate in the rat model the effect of co-administered nasal ephedrine on the absorption of GR138950 in a simple and in a pectin self-gelling formulation. It was hypothetised that a decrease in nasal systemic absorption would lead to an increase in direct nose-to-brain transport as demonstrated by the drug concentration in the olfactory lobes of the brain. It was found that ephedrine administered nasally with the drug in a simple aqueous solution resulted in a significant increase in nasal systemic absorption and also an increase in brain delivery; however, this trend was not observed with the pectin formulations. The pectin formulation with ephedrine resulted in lower systemic absorption of GR138950 and lower brain uptake compared to the simple solution formulation containing ephedrine.

The use of soluble polymers and polymer microparticles to provide improved vaccine responses after parenteral and mucosal delivery.

It is important when developing new vaccine systems to give proper attention to the question of delivery. In some cases the judicious choice of a delivery system can provide a greatly enhanced immune response and avoid the need to use a vaccine adjuvant. Delivery systems that have been developed originally for the administration of challenging drug can be used with success for vaccines. Polymer microspheres and lamellar particle based on the biodegradable materials polylactide and polylactide co-glycolide can be employed for the improved parenteral and mucosal administration of antigens. Likewise soluble biopolymers such as chitosan can be used for the improved nasal delivery of various antigens as well as DNA. Results from animal studies and recent clinical trials are provided.

Advances in the use of tocols as drug delivery vehicles.

There has been increasing interest in recent years in the drug delivery applications of tocols and their derivatives. Their biocompatibility and potential to deliver both poorly soluble and water-soluble drugs make tocols attractive as drug delivery vehicles. This review article will focus primarily on topical, oral, and parenteral drug administration using tocols, although other routes of delivery such as pulmonary and nasal will also be discussed. After an overview of the tocol structures, physicochemical properties with emphasis on their solvent properties, functions, and metabolism, specific case studies will be discussed where tocols have been successfully used in topical, oral, and parenteral drug formulations and marketed drug products. Case studies will be extended to those where tocol-based formulations were administered pulmonarily and nasally. As more clinical data and marketed drug products emerge, the utility and therapeutic value of tocols will certainly increase.

Formulation strategies for absorption windows.

Absorption windows in the proximal gut can limit the bioavailability of orally administered compounds and can be a major obstacle to the development of controlled release formulations for important drugs. Methods to increase the residence of drug formulations at or above the absorption window are discussed in this review. Two main approaches are presently being explored: (i) bioadhesive microspheres that have a slow intestinal transit; and (ii) the gastroretentive dosage system, which is based on multiparticulates or large single unit systems. A good understanding of gastrointestinal transit in humans and the effect of factors such as food can be helpful in the design of rational systems that will have clinical benefit.

Variations of bromide in potable ground water in the United States.

Concentrations of bromide in potable ground water that has <10 mg/L chloride range from 0.0032 to 0.058 mg/L with a median value of 0.016 mg/L. The chloride/bromide mass ratio for the same water ranges from 43 to 285 with a median value of 101. The ratios, which resulted from screening approximately 165 analyses of water from 32 locations in 24 states in the United States, show a distinct geographic variation with highest values near the coast and trending toward a value of approximately 50 in the continental interior.

Design and evaluation of an emulsion vehicle for paclitaxel. I. Physicochemical properties and plasma stability.

PURPOSE: The current formulation of paclitaxel contains ethanol and Cremophor EL and has been reported to cause serious adverse reactions. The purpose of the present work was to develop an improved emulsion vehicle for paclitaxel and to study the physicochemical properties of such a system. METHODS: Emulsions were prepared by either microfluidization or sonication method and the droplet size characterized by dynamic light scattering and light microscopy. RESULTS: Stable emulsions could be made using mixtures of lecithin/sodium deoxycholate as the emulsifiers. The formulation was further improved by using a combination of free acid and the sodium salt. Paclitaxel could be loaded into the emulsions at 2.5 mg/ml without the formation of drug crystals. While these emulsions were stable on storage, they flocculated when mixed with plasma. Steric stabilization of the emulsion droplets with poloxamer 188 increased the stability of the emulsions in plasma but promoted the crystallization of paclitaxel. The crystallization tendency could be reduced by using PEG5000PE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol) 5000]), a less water-soluble stabilizer. CONCLUSIONS: Emulsions with good stability characteristics containing 2.5 mg/ml paclitaxel could be made using bile salt/acid and lecithin, and the excellent stability of these emulsions in plasma was achieved by steric stabilization using PEG5000PE.

LEAPT: lectin-directed enzyme-activated prodrug therapy.

Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. & Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (II) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an alpha-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of alpha-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.