Determination of Fibrin Fiber Diameter Using Scanning Electron Microscopy and Image Processing Software

Injectable, biodegradable scaffolds that mimic local tissue properties have great potential for aiding and accelerating the natural wound healing process. Ideally, scaffolds will have physical properties e.g., stiffness and microstructures, that are comparable to the tissue in which they will be applied. Fibrin is an insoluble protein that is formed in vivo during hemostasis via action of the enzyme thrombin on the soluble protein fibrinogen. It acts as a glue that holds together a loose platelet plug - a blood clot - that is degraded as wound healing progresses. The stiffness of this material can be easily tuned by adjusting its composition, as has been previously shown. These combined factors make fibrin a suitable scaffolding candidate for promoting cell delivery to wound sites, cell growth, and proliferation which are important parameters influencing the healing process. Scanning electron microscopy as well as other techniques are currently being leveraged in order to better understand fibrin's microstructure. Fibrin hydrogels are prepared in vitro by mixing fibrinogen, thrombin, and CaCl2 at various compositions. After additional processing, samples are then dried using either critical point drying or freeze-drying techniques to retain structure, and are subsequently sputter coated with gold/palladium, and imaged using a Hitachi SU7000. A MATLAB script was created that allows for the random selection and analysis of fibers. The resulting image is transferred into ImageJ where fiber sizes are measured. Average fiber diameter for fibrin gels prepared using fibrinogen at 6mg/ml and thrombin at 1U/ml is estimated to be 77nm

Improving Chronic Pain Management Processes in Primary Care Using Practice Facilitation and Quality Improvement: The Central Appalachia Inter-Professional Pain Education Collaborative

Purpose: With the increasing burden of chronic pain and opioid use, provider shortages in Eastern Kentucky and West Virginia have experienced many challenges related to chronic pain management. This study tested a practice facilitator model in both academic and community clinics that selected and implemented best practice processes to better assist patients with chronic pain and increase the use of interdisciplinary health care services. Methods: Using a quasi-experimental design, a practice facilitator was assigned to each state’s clinics and trained clinic teams in quality improvement methods to implement chronic pain tool(s) and workflow processes. Charts for 695 patients with chronic pain using opioids, from 8 randomly selected clinics in eastern Appalachia, were reviewed to assess for changes in clinic processes. Results: Statistically significant improvements were found in 10 out of 16 chronic pain best practice process measures. These included improved workflow implementation (P < 0.001), increased urine drug screen test orders (P = 0.001) and increased utilization of controlled medication agreements (P = 0.004). In total, 7 of 8 clinics significantly improved in at least one, if not all, selected and implemented process measures. Conclusions: Our findings indicate that practice facilitation, standardization of workflows and formation of structured clinical teams can improve processes of care in chronic pain management and facilitate the use of interdisciplinary services. Future studies are needed to assess long-term patient-centered outcomes that may result from improved processes of chronic pain care

Coastal natural and nature-based features: international guidelines for flood risk management

Natural and nature-based features (NNBF) have been used for more than 100 years as coastal protection infrastructure (e.g., beach nourishment projects). The application of NNBF has grown steadily in recent years with the goal of realizing both coastal engineering and environment and social co-benefits through projects that have the potential to adapt to the changing climate. Technical advancements in support of NNBF are increasingly the subject of peer-reviewed literature, and guidance has been published by numerous organizations to inform technical practice for specific types of nature-based solutions. The International Guidelines on Natural and Nature-Based Features for Flood Risk Management was recently published to provide a comprehensive guide that draws directly on the growing body of knowledge and practitioner experience from around the world to inform the process of conceptualizing, planning, designing, engineering, and operating NNBF. These Guidelines focus on the role of nature-based solutions and natural infrastructure (beaches, dunes, wetlands and plant systems, islands, reefs) as a part of coastal and riverine flood risk management. In addition to describing each of the NNBF types, their use, design, implementation, and maintenance, the guidelines describe general principles for employing NNBF, stakeholder engagement, monitoring, costs and benefits, and adaptive management. An overall systems approach is taken to planning and implementation of NNBF. The guidelines were developed to support decision-makers, project managers, and practitioners in conceptualizing, planning, designing, engineering, implementing, and maintaining sustainable systems for nature-based flood risk management. This paper summarizes key concepts and highlights challenges and areas of future research

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

*WINNER* Rheological and Turbidimetric Characterization of Early-phase Wound Gels

Treatment of dermal wounds and development of new techniques by which dermal wound healing can be accelerated with minimal scarring are of global interest. During the early stages of the wound healing process, a loose platelet plug is stabilized by the formation of a fibrin gel matrix. A fibrin gel is formed when the protein fibrinogen is enzymatically cleaved by thrombin and crosslinked by Factor XIII. These fibrin matrices help to halt blood flow from the wounded site and serve as a scaffold by which cell transport and adhesion may occur. Various medical disorders, deficiencies, and diseases can result in abnormal wound healing, i.e. scarring or inability to form stable, lasting clots. The study of these bio-gels is expected to result in advancements in wound healing techniques and a better understanding of the behavior of dermal wounds, transport of cellular and other items through such wounds, and resultant scarring control. Towards this end, rheological techniques were explored to characterize structural properties of such early-phase wound media during gel formation. Fibrin gels were prepared using 1, 3, 6, and 12 mg/ml fibrinogen, 1 U/ml thrombin, and 5mM CaCl2, final concentrations. Rheology and turbidity data indicate that gels formed in the presence of higher fibrinogen concentrations develop more rigid structures sooner than those formed at lower fibrinogen concentrations. Such results provide a foundation for future studies to explore the effects of mixing and the influence of modified versions of fibrinogen on gel properties and species transport through such gels

Optimal Passive Dynamics for Physical Interaction: Catching a Mass

For manipulation tasks in uncertain environments, intentionally designed series impedance in mechanical systems can provide significant benefits that cannot be achieved in software. Traditionally, the design of actuated systems revolves around sizing torques, speeds, and control strategies without considering the system’s passive dynamics. However, the passive dynamics of the mechanical system, including inertia, stiffness, and damping along with other parameters such as torque and stroke limits often impose performance limitations that cannot be overcome with software control. In this paper, we develop relationships between an actuator’s passive dynamics and the resulting performance for the purpose of better understanding how to tune the passive dynamics for catching an unexpected object. We use a mathematically optimal controller subject to force limitations to stop the incoming object without breaking contact and bouncing. The use of an optimal controller is important so that our results directly reflect the physical system’s performance. We analytically calculate the maximum velocity that can be caught by a realistic actuator with limitations such as force and stroke limits. The results show that in order to maximize the velocity of an object that can be caught without exceeding the actuator’s torque and stroke limits, a soft spring along with a strong damper will be desired

Orthotic shorts for improving gait and walking in multiple sclerosis: a feasibility study

Purpose: To explore the acceptability and potential efficacy of orthotic shorts in people with multiple sclerosis. Materials and methods: This mixed-methods, cross-over study utilised qualitative data to investigate acceptability, including perceived effectiveness. Quantitative data included wear times, self-selected walking speed, spatiotemporal gait parameters, and participant-perceived walking ability. Fifteen participants were assessed with and without two pairs of custom-made shorts: one designed as an orthotic and a second looser pair. Each were worn at home for two weeks. Semi-structured interviews were conducted at the first and final appointments. Quantitative data were analysed using Cohen’s d; qualitative analysis used a thematic framework. A triangulation protocol integrated qualitative and quantitative data. Results: Orthotic shorts were acceptable to most users who described improved control, stability, and function. Where shorts were less acceptable, this was due to restriction of hip flexion or appearance. Effect sizes were in the moderate category for participant-perceived walking ability and for those spatiotemporal gait parameters that reflect mediolateral stability. Small effect sizes were seen for walking speed and related spatiotemporal parameters, such as step length. Conclusion: Orthotic shorts are acceptable and potentially efficacious for improving walking, stability, and function in people with multiple sclerosis. Further research and design development are warranted. Implications for rehabilitation: • Orthotic shorts are a type of fabric orthosis that have not been previously researched but might assist pelvic stability. • Orthotic shorts appear to be acceptable to those people with multiple sclerosis who perceive themselves to be unstable around the trunk and hips. • Orthotic shorts might improve gait stability and self-perceived walking ability