Design of medical tympanostomy conduits with selective fluid transport properties.

Implantable tubes, shunts, and other medical conduits are crucial for treating a wide range of conditions from ears and eyes to brain and liver but often impose serious risks of device infection, obstruction, migration, unreliable function, and tissue damage. Efforts to alleviate these complications remain at an impasse because of fundamentally conflicting design requirements: Millimeter-scale size is required to minimize invasiveness but exacerbates occlusion and malfunction. Here, we present a rational design strategy that reconciles these trade-offs in an implantable tube that is even smaller than the current standard of care. Using tympanostomy tubes (ear tubes) as an exemplary case, we developed an iterative screening algorithm and show how unique curved lumen geometries of the liquid-infused conduit can be designed to co-optimize drug delivery, effusion drainage, water resistance, and biocontamination/ingrowth prevention in a single subcapillary-length-scale device. Through extensive in vitro studies, we demonstrate that the engineered tubes enabled selective uni- and bidirectional fluid transport; nearly eliminated adhesion and growth of common pathogenic bacteria, blood, and cells; and prevented tissue ingrowth. The engineered tubes also enabled complete eardrum healing and hearing preservation and exhibited more efficient and rapid antibiotic delivery to the middle ear in healthy chinchillas compared with current tympanostomy tubes, without resulting in ototoxicity at up to 24 weeks. The design principle and optimization algorithm presented here may enable tubes to be customized for a wide range of patient needs.

Viscoelastic Notch Signaling Hydrogel Induces Liver Bile Duct Organoid Growth and Morphogenesis.

Cholangiocyte organoids can be used to model liver biliary disease; however, both a defined matrix to emulate cholangiocyte self-assembly and the mechano-transduction pathways involved therein remain elusive. A series of defined viscoelastic hyaluronan hydrogels to culture primary cholangiocytes are designed and it is found that by mimicking the stress relaxation rate of liver tissue, cholangiocyte organoid growth can be induced and expression of Yes-associated protein (YAP) target genes could be significantly increased. Strikingly, inhibition of matrix metalloproteinases (MMPs) does not significantly affect organoid growth in 3D culture, suggesting that mechanical remodeling of the viscoelastic microenvironment-and not MMP-mediated degradation-is the key to cholangiocyte organoid growth. By immobilizing Jagged1 to the hyaluronan, stress relaxing hydrogel, self-assembled bile duct structures form in organoid culture, indicating the synergistic effects of Notch signaling and viscoelasticity. By uncovering critical roles of hydrogel viscoelasticity, YAP signaling, and Notch activation, cholangiocyte organogenesis is controlled, thereby paving the way for their use in disease modeling and/or transplantation.

Outcomes of a 2-Portal Endoscopic Technique for Osseous Lesions Resulting in Posterior Ankle Impingement Syndrome.

Posterior ankle impingement syndrome is common in sporting populations and encompasses a range of disorders that cause posterior ankle pain during maximal forced plantarflexion. The aim of this study was to evaluate the short- and medium- to long-term outcomes of 2-portal endoscopic surgery for osseous lesions causing posterior ankle impingement syndrome. This was a retrospective case series analysis of all patients who underwent 2-portal endoscopic surgery at a single institution between 2005 and 2016. Visual analogue scales and selected components of the Short Form of the Revised Foot Function Index were used to assess ankle function, with the median follow-up time being 4.8 years. Of the 52 patients, 49 (94%) were able to return to their previous sport/physical activity, with the mean time taken being 5.8 months. At the completion of follow-up, the mean pain score during exercise had improved from 7.5 to 0.9 points. The mean work and sporting function scores also improved, from 5.9 to 9.6 points and 2.9 to 8.8 points, respectively. The mean score of the Short Form of the Revised Foot Function Index also improved by 77.7 points, from 84.4 to 6.7 at the completion of follow-up. There were no postoperative infections or any other major complications. This study provides strong supporting evidence for the use of hindfoot endoscopy in the treatment of posterior ankle impingement syndrome in athletes.

Laser-Directed Assembly of Nanorods of 2D Materials.

Herein, the previously unrealized ability to grow nanorods and nanotubes of 2D materials using femtosecond laser irradiation is demonstrated. In as short as 20 min, nanorods of tungsten disulfide, molybdenum disulfide, graphene, and boron nitride are grown in solutions. The technique fragments nanoparticles of the 2D materials from bulk flakes and leverages molecular scale alignment by nonresonant intense laser pulses to direct their assembly into nanorods up to several micrometers in length. The laser treatment process is found to induce phase transformations in some of the materials, and also results in the modification of the nanorods with functional groups from the solvent atoms. Notably, the WS2 nanoparticles, which are ablated from semiconducting 2H WS2 crystallographic phase flakes, reassemble into nanorods consisting of the 1T metallic phase. Due to this transition, and the 1D nature of the fabricated nanorods, the WS2 nanorods display substantial improvements in electrical conductivity and optical transparency when employed as transparent conductors.

Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design.

A HTS campaign identified compound 1, an excellent hit-like molecule to initiate medicinal chemistry efforts to optimize a dual ROCK1 and ROCK2 inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Cocrystal structures of an early lead compound were obtained in PKA, ROCK1, and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. The structural data indicated the preferred configuration at the central benzylic carbon would be ( R), and application of this information to compound design resulted in compound 16. This compound was shown to be a potent and selective dual ROCK inhibitor in both enzyme and cell assays and efficacious in the retinal nerve fiber layer model after oral dosing. This tool compound has been made available through the AbbVie Compound Toolbox. Finally, the cocrystal structures also identified that aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, could be targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor with excellent predicted drug-like properties.

Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.

IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive α,ß-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.

A cross-disciplinary assessment of student loans debt, financial support for study and career preferences upon graduation.

AIM: To explore relationships between student loans debt, financial support and career preferences upon graduation for all healthcare disciplines offered at the Faculty of Medical and Health Sciences, University of Auckland. METHODS: The Faculty Tracking Project is a longitudinal study which invites students to complete a questionnaire at the beginning and end of their educational programmes, including questions on debt, financial support and career preference. Our analysis comprised three phases: (1) a descriptive analysis of data related to debt and financial support; (2) a principal component analysis in order to find related categories of career choice; and (3) logistic regression models to determine how career preference categories could be explained by either levels of student loans debt or financial support. RESULTS: Data from 2,405 participating students were included. Students in health sciences, nursing and pharmacy typically accrue levels of student loans debt of around $15,000 to $29,999, while optometry students accrue debt around $15,000 higher. Medical students show debt distributed around modes of $0 and $90,000 or more. All students typically access three sources of financial support during study. Career preferences at graduation reduced to four categories for all health disciplines. We found five significant effects, involving students in health sciences, medicine and pharmacy, relating the number of sources of financial support to the four categories of career preference. No significant effects were found related to level of student loans debt. CONCLUSIONS: Our results suggest that financial support is a more strongly determining factor in career choices than the level of student loans debt. The four-category framework for student career preferences appears to be a useful model for further research.

Electrospun Poly(l-lactide)/Poly(ethylene glycol) Scaffolds Seeded with Human Amniotic Mesenchymal Stem Cells for Urethral Epithelium Repair.

Tissue engineering-based urethral replacement holds potential for repairing large segmental urethral defects, which remains a great challenge at present. This study aims to explore the potential of combining biodegradable poly(l-lactide) (PLLA)/poly(ethylene glycol) (PEG) scaffolds and human amniotic mesenchymal cells (hAMSCs) for repairing urethral defects. PLLA/PEG fibrous scaffolds with various PEG fractions were fabricated via electrospinning. The scaffolds were then seeded with hAMSCs prior to implantation in New Zealand male rabbits that had 2.0 cm-long defects in the urethras. The rabbits were randomly divided into three groups. In group A, hAMSCs were grown on PLLA/PEG scaffolds for two days and then implanted to the urethral defects. In group B, only the PLLA/PEG scaffolds were used to rebuild the rabbit urethral defect. In group C, the urethral defect was reconstructed using a regular urethral reparation technique. The repair efficacy was compared among the three groups by examining the urethral morphology, tissue reconstruction, luminal patency, and complication incidence (including calculus formation, urinary fistula, and urethral stricture) using histological evaluation and urethral radiography methods. Findings from this study indicate that hAMSCs-loaded PLLA/PEG scaffolds resulted in the best urethral defect repair in rabbits, which predicts the promising application of a tissue engineering approach for urethral repair.

Polymeric Biodegradable Stent Insertion in the Esophagus.

Esophageal stent insertion has been used as a well-accepted and effective alternative to manage and improve the quality of life for patients diagnosed with esophageal diseases and disorders. Current stents are either permanent or temporary and are fabricated from either metal or plastic. The partially covered self-expanding metal stent (SEMS) has a firm anchoring effect and prevent stent migration, however, the hyperplastic tissue reaction cause stent restenosis and make it difficult to remove. A fully covered SEMS and self-expanding plastic stent (SEPS) reduced reactive hyperplasia but has a high migration rate. The main advantage that polymeric biodegradable stents (BDSs) have over metal or plastic stents is that removal is not require and reduce the need for repeated stent insertion. But the slightly lower radial force of BDS may be its main shortcoming and a post-implant problem. Thus, strengthening support of BDS is a content of the research in the future. BDSs are often temporarily effective in esophageal stricture to relieve dysphagia. In the future, it can be expect that biodegradable drug-eluting stents (DES) will be available to treat benign esophageal stricture, perforations or leaks with additional use as palliative modalities for treating malignant esophageal stricture, as the bridge to surgery or to maintain luminal patency during neoadjuvant chemoradiation.

Quickly promoting angiogenesis by using a DFO-loaded photo-crosslinked gelatin hydrogel for diabetic skin regeneration.

Changes in blood vessel formation, especially microvasculature formation, are one of the most important factors contributing to the poor wound healing capabilities of diabetic patients. Furthermore, recovery of the vascular network in the early stages after injury is a key factor in the prevention of wound expansion and ulcer formation. A hydrogel is a popular scaffold type and has many biological advantages, however, it is incapable of rapidly recruiting angiogenesis-related cells and cytokines to the wound area under the disturbed microcirculatory conditions of diabetics. For the above reasons, we devised a desferrioxamine (DFO)-loaded photo-crosslinked hydrogel (gelatin methacrylamide (Gelma)) for quickly developing the vascular network and accelerating skin reconstruction. The controlled release of DFO peaking at 16 h followed by a steady release after 48 h through the swelling of the Gelma hydrogel led to a significant increase of neovascularization. The in vitro results showed that DFO-Gelma provided an excellent microenvironment for cell viability, adhesion and proliferation, and up-regulated the expression of HIF-1α, which was critical for blood vessel formation. The in vivo studies showed new blood vessels, high quality granulation tissues, and early epithelialization in wound beds by treating them with DFO-loaded hydrogels. Through this investigation, the mechanism associated with wound healing was further investigated. This study demonstrated that DFO-Gelma was safe, reliable, and highly effective for the diabetic wound healing process.

Synthesis and characterization of the crystal structure, the magnetic and the electrochemical properties of the new fluorophosphate LiNaFe[PO4]F.

The new compound LiNaFe[PO(4)]F was synthesized by a solid state reaction route, and its crystal structure was determined using neutron powder diffraction data. LiNaFe[PO(4)]F was characterized by (57)Fe Mössbauer spectroscopy, magnetic susceptibility, specific heat capacity, and electrochemical measurements. LiNaFe[PO(4)]F crystallizes with orthorhombic symmetry, space group Pnma, with a = 10.9568(6) Å, b = 6.3959(3) Å, c = 11.4400(7) Å, V = 801.7(1) Å(3) and Z = 8. The structure consists of edge-sharing FeO(4)F(2) octahedra forming FeFO(3) chains running along the b axis. These chains are interlinked by PO(4) tetrahedra forming a three-dimensional framework with the tunnels and the cavities filled by the well-ordered sodium and lithium atoms, respectively. The specific heat and magnetization measurements show that LiNaFe[PO(4)]F undergoes a three-dimensional antiferromagnetic ordering at T(N) = 20 K. The neutron powder diffraction measurements at 3 K show that each FeFO(3) chain along the b-direction is ferromagnetic (FM), while these FM chains are antiferromagnetically coupled along the a and c-directions with a non-collinear spin arrangement. The galvanometric cycling showed that without any optimization, one mole of alkali metal is extractable between 1.0 V and 5.0 V vs. Li(+)/Li with a discharge capacity between 135 and 145 mAh g(-1).

A template for integrated community sustainability planning.

This article describes a template for implementing an integrated community sustainability plan. The template emphasizes community engagement and outlines the components of a basic framework for integrating ecological, social and economic dynamics into a community plan. The framework is a series of steps that support a sustainable community development process. While it reflects the Canadian experience, the tools and techniques have applied value for a range of environmental planning contexts around the world. The research is case study based and draws from a diverse range of communities representing many types of infrastructure, demographics and ecological and geographical contexts. A critical path for moving local governments to sustainable community development is the creation and implementation of integrated planning approaches. To be effective and to be implemented, a requisite shift to sustainability requires active community engagement processes, political will, and a commitment to political and administrative accountability, and measurement.

Antifluorite-type lithium chromium oxide nitrides: synthesis, structure, order, and electrochemical properties.

Antifluorite-type lithium chromium oxide nitrides were prepared by solid-state reaction of Li(3)N, Li(2)O, and Cr(2)N. Depending on the reaction time and starting Li/Cr and O/Cr ratios, either an ordered or a disordered phase (or mixtures of both) is obtained. The formation of the former is favored by short reaction times and low Cr/O ratios whereas the formation of the latter is favored by higher Cr/O ratios and longer reaction times. The two phases were characterized, and the first one was confirmed to be the already reported Li(14)Cr(2)N(8)O phase, whereas the stoichiometry of the second is Li(10)CrN(4)O(2). Interestingly, even if both contain cationic vacancies in the structure, electrochemical lithium intercalation could only be achieved for Li(10)CrN(4)O(2). This phase exhibits a reversible capacity of 160 mAh/g very stable upon cycling. Bond valence and first-principles DFT calculations were carried out to understand the absence of lithium insertion in Li(14)Cr(2)N(8)O. Li-Li repulsion and destabilization of the tetrahedral CrN(4) units induced by occupation of the potential sites, as well as the absence of energetically favorable pathways for transport of the ions to these sites, are suggested to be the reasons.