Topical Application of an Irreversible Small Molecule Inhibitor of Lysyl Oxidases Ameliorates Skin Scarring and Fibrosis

Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases

INSPEX: Make environment perception available as a portable system

International audienceObstacle avoidance systems for autonomous vehicles combine multiple sensing technologies (i.e. LiDAR, Radar, Ultrasound and Visual) to detect different types of obstacles across the full range of lighting and weather conditions. Sensor data are fused with vehicle orientation (obtained for instance from an Inertial Measurement Unit and/or compass) and navigation subsystems. Power hungry, they require powerful computational capability, which limits their use to high-end vehicles and robots. 2 INSPEX ambition The H2020 INSPEX project plans to make obstacle detection capabilities available as a personal portable multi-sensors, miniaturised, low power device. This device will detect, locate and warn of obstacles under different environmental conditions, in indoor/outdoor environments, with static and mobile obstacles. Potential applications range from safer human navigation in reduced visibility conditions (e.g. for first responders and fire brigades), small robot/drone obstacle avoidance systems to navigation for the visually and mobility impaired people. As primary demonstrator (Fig.1), we will plug the INSPEX device on a white cane (see Fig. 1) for Visually Impaired and Blind (VIB) people to detect obstacle over the whole person height, provide audio feedback about harmful obstacles, improve their mobility confidence and reduce injuries, especially at waist and head levels [1]. The device will offer a "safety cocoon" to its user

INSPEX: design and integration of a portable/wearable smart spatial exploration system

The INSPEX H2020 project main objective is to integrate automotive-equivalent spatial exploration and obstacle detection functionalities into a portable/wearable multi-sensor, miniaturised, low power device. The INSPEX system will detect and localise in real-time static and mobile obstacles under various environmental conditions in 3D. Potential applications range from safer human navigation in reduced visibility, small robot/drone obstacle avoidance systems to navigation for the visually/mobility impaired, this latter being the primary use-case considered in the project

Burn injury leads to increased long-term susceptibility to respiratory infection in both mouse models and population studies

Background: Burn injury initiates an acute inflammatory response that subsequently drives wound repair. However, acute disruption to the immune response is also common, leading to susceptibility to sepsis and increased morbidity and mortality. Despite increased understanding of the impact of burn injury on the immune system in the acute phase, little is known about longterm consequences of burn injury on immune function. This study was established to determine whether burn injury has long-term clinical impacts on patients' immune responses. Methods: Using a population-based retrospective longitudinal study and linked hospital morbidity and death data from Western Australia, comparative rates of hospitalisation for respiratory infections in burn patients and a non-injured comparator cohort were assessed. In addition, a mouse model of non-severe burn injury was also used in which viral respiratory infection was induced at 4 weeks post-injury using a mouse modified version of the Influenza A virus (H3NN; A/mem/71-a). Results and conclusions: The burn injured cohort contained 14893 adult patients from 1980-2012 after removal of those patients with evidence of smoke inhalation or injury to the respiratory tract. During the study follow-up study a total of 2,884 and 2,625 respiratory infection hospital admissions for the burn and uninjured cohorts, respectively, were identified. After adjusting for covariates, the burn cohort experienced significantly elevated admission rates for influenza and viral pneumonia (IRR, 95%CI: 1.73, 1.27-2.36), bacterial pneumonia (IRR, 95%CI: 2.05, 1.85-2.27) and for other types of upper and lower respiratory infections (IRR, 95% CI: 2.38, 2.09-2.71). In the mouse study an increased viral titre was observed after burn injury, accompanied by a reduced CD8 response and increased NK and NKT cells in the draining lymph nodes. This data suggests burn patients are at long-term increased risk of infection due to sustained modulation of the immune response

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Characterisation of the cell suspension harvested from the dermal epidermal junction using a ReCell® kit

Background: The use of non-cultured autologous cells to promote wound healing and in reconstructive procedures is increasing. One common method for preparing these cells is the use of the ReCell® device. However, despite its current clinical use, no characterisation of the cell suspension produced using a ReCell® device has been published. Objective: To characterise the ReCell suspension that is applied to wounds for cell type, viability, yield, stability and proliferative potential. Methods: The ReCell® device was used to harvest cells from a 2 cm2 piece of split-thickness skin isolated using a dermatome. The resulting cell suspension was analysed for cell yield, cell type, viability over time, proliferative potential and reproducibility. Results: Average viable cell yield was 1.7 × 106/cm2 of tissue, with 75.5% of the total cell isolate viable. Total viable cell number was not significantly reduced after 4 h storage at 22 °C or 4 °C, and was stable for 24 h at 4 °C. Proliferative potential was assessed using a colony forming assay, with 0.3% of viable cells isolated forming keratinocyte colonies. Predominantly the suspension contained keratinocytes (64.3 ± 28.8%) and fibroblasts (30.3 ± 14.0%), with a small population of melanocytes also identified (3.5 ± 0.5%). Finally, the supernatant contained low total protein (0.92 mg/ml) and the supernatant had no significant effects on cell viability or growth when applied ex vivo. Conclusions: These results suggest the ReCell® device provides a method for the preparation of a cell suspension with high viability and proliferative potential, containing viable melanocytes and no apparent toxic cell debris. Further work on the sustained viability of these cells in vivo, and in particular after application to the wound, will be important to better understand the potential of the ReCell® device in the clinic

Long-term mortality among older adults with burn injury: a population-based study in Australia

AbstractObjective To assess if burn injury in older adults is associated with changes in long-term all-cause mortality and to estimate the increased risk of death attributable to burn injury.Methods We conducted a population-based matched longitudinal study - based on administrative data from Western Australia's hospital morbidity data system and death register. A cohort of 6014 individuals who were aged at least 45 years when hospitalized for a first burn injury in 1980-2012 was identified. A non-injury comparison cohort, randomly selected from Western Australia's electoral roll (n= 25 759), was matched to the patients. We used Kaplan-Meier plots and Cox proportional hazards regression to analyse the data and generated mortality rate ratios and attributable risk percentages.Findings For those hospitalized with burns, 180 (3%) died in hospital and 2498 (42%) died after discharge. Individuals with burn injury had a 1.4-fold greater mortality rate than those with no injury (95% confidence interval, CI: 1.3-1.5). In this cohort, the long-term mortality attributable to burn injury was 29%. Mortality risk was increased by both severe and minor burns, with adjusted mortality rate ratios of 1.3 (95% CI: 1.1-1.9) and 2.1 (95% CI: 1.9-2.3), respectively.Conclusion Burn injury is associated with increased long-term mortality. In our study population, sole reliance on data on in-hospital deaths would lead to an underestimate of the true mortality burden associated with burn injury

Retrospective cohort study of health service use for cardiovascular disease among adults with and without a record of injury hospital admission

Objective To quantify postinjury cardiovascular-related health service use experienced by mid to older aged adults hospitalised for injury, compared with uninjured adults. Additionally, to explore the effect of beta-blocker medications on postinjury cardiovascular hospitalisations among injury patients, given the potential cardioprotective effects of beta blockers.Design A retrospective cohort study using linked administrative and survey data.Participants Records of 35 026 injured and 60 823 uninjured matched adults aged over 45 from New South Wales, Australia, who completed the 45 and up survey.Primary and secondary outcome measures Admission rates and cumulative lengths of stay for cardiovascular hospitalisations, and prescription rates for cardiovascular medications. Negative binomial and Cox proportional hazards regression modelling were used to generate incident rate ratios (IRRs) and HR.Results Compared with the uninjured, those with injury had a 19% higher adjusted rate of postinjury cardiovascular admissions (IRR 1.19, 95% CI 1.14 to 1.25), spent 40% longer in hospital for ardiovascular disease (IRR 1.40, 95% CI 1.26 to 1.57) and had slightly higher cardiovascular prescription rates (IRR 1.04, 95% CI 1.02 to 1.06), during study follow-up. Those in the injury cohort that used beta blockers both prior to and after injury (continuous) appeared to have reduced need for post-injury cardiovascular hospitalisation (IRR 1.09, 95% CI 1.17 to 1.42) compared with those commencing on beta blockers after injury (after 30 days: IRR 1.69, 95% CI 1.37 to 2.08).Conclusions Apparent increased postinjury hospitalisation rates and prolonged length of stay related to cardiovascular disease suggest that injury patients may require clinical support for an extended period after injury. Additionally, injury patients who were on continuous beta blocker treatment appeared to have lower need for post-injury cardiovascular hospitalisations. However, the data do not allow us to draw clear conclusions and further clinical research is required

Burn Injury Leads to Increased Long-Term Susceptibility to Respiratory Infection in both Mouse Models and Population Studies.

Burn injury initiates an acute inflammatory response that subsequently drives wound repair. However, acute disruption to the immune response is also common, leading to susceptibility to sepsis and increased morbidity and mortality. Despite increased understanding of the impact of burn injury on the immune system in the acute phase, little is known about long-term consequences of burn injury on immune function. This study was established to determine whether burn injury has long-term clinical impacts on patients' immune responses.Using a population-based retrospective longitudinal study and linked hospital morbidity and death data from Western Australia, comparative rates of hospitalisation for respiratory infections in burn patients and a non-injured comparator cohort were assessed. In addition, a mouse model of non-severe burn injury was also used in which viral respiratory infection was induced at 4 weeks post-injury using a mouse modified version of the Influenza A virus (H3NN; A/mem/71-a).The burn injured cohort contained 14893 adult patients from 1980-2012 after removal of those patients with evidence of smoke inhalation or injury to the respiratory tract. During the study follow-up study a total of 2,884 and 2,625 respiratory infection hospital admissions for the burn and uninjured cohorts, respectively, were identified. After adjusting for covariates, the burn cohort experienced significantly elevated admission rates for influenza and viral pneumonia (IRR, 95%CI: 1.73, 1.27-2.36), bacterial pneumonia (IRR, 95%CI: 2.05, 1.85-2.27) and for other types of upper and lower respiratory infections (IRR, 95% CI: 2.38, 2.09-2.71). In the mouse study an increased viral titre was observed after burn injury, accompanied by a reduced CD8 response and increased NK and NKT cells in the draining lymph nodes. This data suggests burn patients are at long-term increased risk of infection due to sustained modulation of the immune response