Resource stewardship and Choosing Wisely in a children's hospital.

Objectives: Evidence suggests that approximately 30% of the tests and treatments currently prescribed in healthcare are potentially unnecessary, may not add value, and in some cases cause harm. We describe the evolution of our hospital's Choosing Wisely (CW) program over the first 5 years of existence, highlighting the enablers, challenges, and overall lessons learned with the goal of informing other healthcare providers about implementing resource stewardship initiatives in paediatric healthcare settings. Methods: We describe the development of de novo "top 5" CW lists of recommendations using anonymous surveys and Likert scale scoring. Composition and role of the steering committee, measurement of data and outcomes, and implementation strategies are outlined. Results: Many projects have resulted in a successful decrease in inappropriate utilization while simultaneously monitoring for unintended consequences. Examples include respiratory viral testing in the emergency department (ED) decreased by greater than 80%; ankle radiographs for children with ankle injuries decreased from 88% to 54%; and use of IVIG for treatment of typical ITP cases decreased from 88% to 55%. Early involvement focused within General Paediatrics and the ED, but later expanded to include perioperative services and paediatric subspecialties. Conclusions: An internally developed CW program in a children's hospital can reduce targeted areas of potentially unnecessary tests and treatments. Enablers include credible clinician champions, organizational leadership support, reliable measurement strategies, and dedicated resource stewardship education. The lessons learned may be generalizable to other paediatric healthcare settings and providers looking to introduce a similar approach to target unnecessary care in their own organizations.

Electrospun electroconductive constructs of aligned fibers for cardiac tissue engineering.

Myocardial infarction remains the leading cause of death in the western world. Since the heart has limited regenerative capabilities, several cardiac tissue engineering (CTE) strategies have been proposed to repair the damaged myocardium. A novel electrospun construct with aligned and electroconductive fibers combining gelatin, poly(lactic-co-glycolic) acid and polypyrrole that may serve as a cardiac patch is presented. Constructs were characterized for fiber alignment, surface wettability, shrinkage and swelling behavior, porosity, degradation rate, mechanical properties, and electrical properties. Cell-biomaterial interactions were studied using three different types of cells, Neonatal Rat Ventricular Myocytes (NRVM), human lung fibroblasts (MRC-5) and induced pluripotent stem cells (iPSCs). All cell types showed good viability and unique organization on construct surfaces depending on their phenotype. Finally, we assessed the maturation status of NRVMs after 14 days by confocal images and qRT-PCR. Overall evidence supports a proof-of-concept that this novel biomaterial construct could be a good candidate patch for CTE applications.

Mimicking cardiac tissue complexity through physical cues: A review on cardiac tissue engineering approaches.

Cardiovascular diseases are the number one killer in the world.1,2 Currently, there are no clinical treatments to regenerate damaged cardiac tissue, leaving patients to develop further life-threatening cardiac complications. Cardiac tissue has multiple functional demands including vascularization, contraction, and conduction that require many synergic components to properly work. Most of these functions are a direct result of the cardiac tissue structure and composition, and, for this reason, tissue engineering strongly proposed to develop substitute engineered heart tissues (EHTs). EHTs usually have combined pluripotent stem cells and supporting scaffolds with the final aim to repair or replace the damaged native tissue. However, as simple as this idea is, indeed, it resulted, after many attempts in the field, to be very challenging. Without design complexity, EHTs remain unable to mature fully and integrate into surrounding heart tissue resulting in minimal in vivo effects.3 Lately, there has been a growing body of evidence that a complex, multifunctional approach through implementing scaffold designs, cellularization, and molecular release appears to be essential in the development of a functional cardiac EHTs.4-6 This review covers the advancements in EHTs developments focusing on how to integrate contraction, conduction, and vascularization mimics and how combinations have resulted in improved designs thus warranting further investigation to develop a clinically applicable treatment.

Double Network Hydrogels that Mimic the Modulus, Strength, and Lubricity of Cartilage.

The development of a hydrogel-based synthetic cartilage has the potential to overcome many limitations of current chondral defect treatments. Many attempts have been made to replicate the unique characteristics of cartilage in hydrogels, but none have simultaneously achieved high modulus, strength, and toughness while maintaining the necessary hydration required for lubricity. Herein, double network (DN) hydrogels, composed of a poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) first network and a poly( N-isopropylacrylamide- co-acrylamide) [P(NIPAAm- co-AAm)] second network, are evaluated as a potential off-the-shelf material for cartilage replacement. While predominantly used for its thermosensitivity, PNIPAAm is employed to achieve superior mechanical properties with its thermal transition temperature tuned above the physiological range. These PNIPAAm-based DNs demonstrate a 50-fold increase in compressive strength (∼25 MPa, similar to cartilage) compared to traditional single network hydrogels while also achieving cartilage-like modulus (∼1 MPa) and hydration (∼80%). In direct comparison to healthy cartilage (porcine), these hydrogels were confirmed to not only parallel the strength, modulus, and hydration of native articular cartilage but also exhibit a 50% lower coefficient of friction (COF). The exceptional cartilage-like properties of the PAMPS/P(NIPAAm- co-AAm) DN hydrogels makes them candidates for synthetic cartilage grafts for chondral defect repair, even in load-bearing regions of the body.

Thermoresponsive Double Network Hydrogels with Exceptional Compressive Mechanical Properties.

The utility of thermoresponsive hydrogels, such as those based on poly(N-isopropylacrylamide) (PNIPAAm), is severely limited by their deficient mechanical properties. In particular, the simultaneous achievement of high strength and stiffness remains unreported. In this work, a thermoresponsive hydrogel is prepared having the unique combination of ultrahigh compressive strength (≈23 MPa) and excellent compressive modulus (≈1.5 MPa). This is accomplished by employing a double network (DN) design comprised of a tightly crosslinked, highly negatively charged 1st network based on poly(2-acrylamido-2-methylpropane sulfonic acid (PAMPS) and a loosely crosslinked, zwitterionic 2nd network based on a copolymer of thermoresponsive NIPAAm and zwitterionic 2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (MEDSAH). Comparison to other DN designs reveals that this PAMPS/P(NIPAAm-co-MEDSAH) DN hydrogel's remarkable properties stem from the intra- and internetwork ionic interactions of the two networks. Finally, this mechanically robust hydrogel retains the desirable thermosensitivity of PNIPAAm hydrogels, exhibiting a volume phase transition temperature of ≈35 °C.

Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity.

CONTEXT: Mitotic kinase enzymes regulate critical stages of mitosis and are amenable to pharmacological inhibition. Since natural products have been a rich source of antimitotic inhibitors, we postulated that natural products would also provide effective inhibitors of mitotic kinases. OBJECTIVE: To explore unique marine and terrestrial natural product sources for new anticancer drug leads, we screened our natural product extract library for polo-like kinase-1 (Plk1) kinase inhibitors. MATERIALS AND METHODS: Extracts of the lichen Parmotrema sp. (Parmeliaceae) exhibited in vitro inhibitory activity. Bioassay-guided fractionation of the Parmotrema sp. extract led to the isolation of depside inhibitors. RESULTS: A new depside 1 has been isolated from the Sri Lankan lichen Parmotrema sp. along with the known metabolites 2 (ß-collatolic acid) and 3 (ß-alectoronic acid). The structure of depside 1 was elucidated by spectroscopic analysis. The three depsides 1-3 exhibited moderate inhibition of purified recombinant Plk1 kinase with IC50 of 2.8, 0.7, and 1.7 µM, respectively, at 1 µM ATP. Inhibitory activity was also observed at high concentrations of ATP, suggesting the potential for activity in a cellular environment. The depsides were also tested against a panel of 23 other recombinant kinases and were found to possess up to 30-fold selectivity toward Plk1. DISCUSSION AND CONCLUSION: These data suggest that the depsides 1-3 may serve as core structures that can be further explored as potential inhibitors of Plk1 and other kinases.