Reinforcement of Shear Thinning Protein Hydrogels by Responsive Block Copolymer Self-Assembly

Shear thinning hydrogels are promising materials that exhibit rapid self-healing following the cessation of shear, making them attractive for applications including injectable biomaterials. Here, self-assembly is demonstrated as a strategy to introduce a reinforcing network within shear thinning artificially engineered protein gels, enabling a responsive transition from an injectable state at low temperatures with a low yield stress to a stiffened state at physiological temperatures with resistance to shear thinning, higher toughness, and reduced erosion rates and creep compliance. Protein-polymer triblock copolymers capable of the responsive self-assembly of two orthogonal networks are synthesized. Midblock association forms a shear-thinning network, while endblock aggregation at elevated temperatures introduces a second, independent physical network into the protein hydrogel. These reversible crosslinks introduce extremely long relaxation times and lead to a five-fold increase in the elastic modulus, significantly larger than is expected from transient network theory. Thermoresponsive reinforcement reduces the high temperature creep compliance by over four orders of magnitude, decreases the erosion rate by at least a factor of five, and increases the yield stress by up to a factor of seven. Combined with the demonstrated potential of shear thinning artificial protein hydrogels for various uses, this reinforcement mechanism broadens the range of applications that can be addressed with shear-thinning physical gels

Oxidatively Responsive Chain Extension to Entangle Engineered Protein Hydrogels

Engineering artificial protein hydrogels for medical applications requires precise control over their mechanical properties, including stiffness, toughness, extensibility, and stability in the physiological environment. Here we demonstrate topological entanglement as an effective strategy to robustly increase the mechanical tunability of a transient hydrogel network based on coiled-coil interactions. Chain extension and entanglement are achieved by coupling the cysteine residues near the N- and C-termini, and the resulting chain distribution is found to agree with the Jacobson–Stockmayer theory. By exploiting the reversible nature of the disulfide bonds, the entanglement effect can be switched on and off by redox stimuli. With the presence of entanglements, hydrogels exhibit a 7.2-fold enhanced creep resistance and a suppressed erosion rate by a factor of 5.8, making the gels more mechanically stable in a physiologically relevant open system. While hardly affecting material stiffness (only resulting in a 1.5-fold increase in the plateau modulus), the entanglements remarkably lead to hydrogels with a toughness of 65 000 J m^(–3) and extensibility to approximately 3000% engineering strain, which enables the preparation of tough yet soft tissue simulants. This improvement in mechanical properties resembles that from double-network hydrogels but is achieved with the use of a single associating network and topological entanglement. Therefore, redox-triggered chain entanglement offers an effective approach for constructing mechanically enhanced and responsive injectable hydrogels

111th Congress

This report examines Member use of one specific new electronic communication medium: Twitter. After providing an overview and background of Twitter, the report analyzes patterns of Member use of Twitter during two one-week periods in July and August 2009. This report is inherently a snapshot in time of a dynamic process. As with any new technology, the number of Members using Twitter and the patterns of use may change rapidly in short periods of time

112th Congress

This report examines Member adoption and use of two social networking services: Twitter and Facebook. The report analyzes data on Member use of Twitter and Facebook collected by an academic institution in collaboration with the Congressional Research Service during a two-month period between August and October 2011 and the adoption of both platforms as of January 2012

111th Congress

This report examines Twitter usage by Members of Congress during August and September 2009. It includes background about Twitter and data analysis of Member registration, usage, tweets, and followers

Decreases in Antimicrobial Use Associated With Multihospital Implementation of Electronic Antimicrobial Stewardship Tools.

BackgroundAntimicrobial stewards may benefit from comparative data to inform interventions that promote optimal inpatient antimicrobial use.MethodsAntimicrobial stewards from 8 geographically dispersed Veterans Affairs (VA) inpatient facilities participated in the development of antimicrobial use visualization tools that allowed for comparison to facilities of similar complexity. The visualization tools consisted of an interactive web-based antimicrobial dashboard and, later, a standardized antimicrobial usage report updated at user-selected intervals. Stewards participated in monthly learning collaboratives. The percent change in average monthly antimicrobial use (all antimicrobial agents, anti-methicillin-resistant Staphylococcus aureus [anti-MRSA] agents, and antipseudomonal agents) was analyzed using a pre-post (January 2014-January 2016 vs July 2016-January 2018) design with segmented regression and external comparison with uninvolved control facilities (n = 118).ResultsIntervention sites demonstrated a 2.1% decrease (95% confidence interval [CI], -5.7% to 1.6%) in total antimicrobial use pre-post intervention vs a 2.5% increase (95% CI, 0.8% to 4.1%) in nonintervention sites (absolute difference, 4.6%; P = .025). Anti-MRSA antimicrobial use decreased 11.3% (95% CI, -16.0% to -6.3%) at intervention sites vs a 6.6% decrease (95% CI, -9.1% to -3.9%) at nonintervention sites (absolute difference, 4.7%; P = .092). Antipseudomonal antimicrobial use decreased 3.4% (95% CI, -8.2% to 1.7%) at intervention sites vs a 3.6% increase (95% CI, 0.8% to 6.5%) at nonintervention sites (absolute difference, 7.0%; P = .018).ConclusionsComparative data visualization tool use by stewards at 8 VA facilities was associated with significant reductions in overall antimicrobial and antipseudomonal use relative to uninvolved facilities

Rationale for the Diabetic Retinopathy Clinical Research Network Treatment Protocol for Center-Involved Diabetic Macular Edema

Objective: Describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network (DRCR.net) randomized clinical trial. Design: Discussion of treatment protocol for DME. Participants: Subjects with vision loss from DME involving the center of the macula. Methods: The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser in eyes with vision loss from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes, compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. In order to share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. Main Outcome Measures: Clinical guidelines based on a DRCR.net protocol. Results: The treatment protocol required real time feedback from a web-based data entry system for intravitreal injections, focal/grid laser, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month, or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. Conclusions: Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Comparison of Time-Domain OCT and Fundus Photographic Assessments of Retinal Thickening in Eyes with Diabetic Macular Edema

To explore the correlation between optical coherence tomography (OCT) and stereoscopic fundus photographs (FP) for the assessment of retinal thickening (RT) in diabetic macular edema (DME) within a clinical trial

Depression and anxiety symptoms post-stroke/TIA:prevalence and associations in cross-sectional data from a regional stroke registry

BACKGROUND: Mood disorders are commonly seen in those with cerebrovascular disease. Literature to-date has tended to focus on depression and on patients with stroke, with relatively little known about post-stroke anxiety or mood disorder in those with transient ischaemic attack (TIA). We aimed to describe prevalence of depression and anxiety symptoms in stroke and TIA cohorts and to explore association with clinical and socio-demographic factors. METHODS: We used a city wide primary care stroke registry (Glasgow Local Enhanced Service for Stroke - LES). All community dwelling stroke-survivors were included. We described cross-sectional prevalence of depression and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS). Data on clinical and demographic details was collected and univariable and multivariable analyses performed to describe associations with HADS scores. We examined those with a diagnosis of 'stroke' and 'TIA' as separate cohorts. RESULTS: From 13,283 potentially eligible stroke patients in the registry, we had full HADS data on 4,079. Of the 3,584 potentially eligible TIA patients, we had full HADS data on 1,247 patients. Across the stroke cohort, 1181 (29%) had HADS anxiety scores suggestive of probable or possible anxiety; 993 (24%) for depression. For TIA patients, 361 (29%) had anxiety and 254 (21%) had depression. Independent predictors of both depression and anxiety symptoms were female sex, younger age and higher socioeconomic deprivation score (all p < 0.001). CONCLUSION: Using HADS, we found a high prevalence of anxiety and depression symptoms in a community-based cohort of patients with cerebrovascular disease