Burden of Pressure Injuries: Findings From the Global Burden of Disease Study.

Background: Pressure injuries remain among the most common problems faced by plastic surgeons and comprise a large portion of wound clinic practice. However, little is known about the overall morbidity related to the disease. This research sought to identify the burden related to the diagnosis of pressure injuries. Methods: We used the Global Burden of Disease Study 2017 to extract information about incidence and disability-adjusted life years (DALYs) related to pressure injuries from 1990 to 2017. Descriptive statistics were used to identify changes in the outcomes of interest. Results: A relative though not statistically significantly decrease in the incidence and burden of pressure injuries was observed between 1990 and 2017. Rates of incidence in the US appear higher than other higher socio-demographic index countries. No clinically and statistically significant changes were observed based on age or sex. Conclusions: Pressure injury incidence and burden have remained relatively stable between 1990 and 2017 with no significant improvement noted. There is room for improvement on a national performance level, and further research is needed regarding inconsistencies in regional outcomes.

Trends in Skin Melanoma Burden: Findings From the Global Burden of Disease Study.

Background: Melanoma is the third most common skin cancer and the leading cause of skin cancer mortality. This study sought to investigate trends in melanoma incidence, mortality, and burden of disease. Methods: The authors assessed the records of the Global Burden of Disease Study 2017 to extract information about the incidence, mortality, and disability adjusted life years (DALY) related to melanoma during 1990-2017 in the US and other countries based on their socio-demographic index (SDI). Results: Melanoma incidence in the US increased 1.6 times, although the difference was not statistically significant. For patients over the age of 60, the incidence was significantly increased by 1.72 to 164.6 times. Mortality was relatively stable during the study period; however, it was increased for patients over 65 years of age (range: 1.03 to 70 times), although not statistically significant. Mortality-to-incidence ratio was decreased, but the difference was not statistically significant. For patients over 75 years of age, DALYs were statistically significantly increased by 1.34 to 1.71 times. Conclusions: This study highlights differences in melanoma incidence and mortality from 1990-2017. Physicians involved in melanoma care should be aware of these changes in order to anticipate care needs.

Trends of Medicare Reimbursement Rates for Common Plastic Surgery Procedures.

BACKGROUND: Knowledge of Medicare reimbursement is essential for plastic surgeons providing care to Medicare beneficiaries. The authors sought to evaluate changes in Medicare reimbursement for common plastic surgery procedures from 2010 to 2020. METHODS: The authors assessed the Physician Fee Schedule of the Centers for Medicare and Medicaid Services website. Rates of work-, facility-, or malpractice-related relative value units and total monetary units for 26 common plastic surgery procedures between 2010 and 2020 were evaluated. Descriptive statistics were used to calculate relative differences and to compare observed changes over time with the rate of inflation. RESULTS: For the selected procedures, the authors found an average relative difference in terms of monetary units of an increase by 2.02 percent. However, after adjusting for inflation, the average relative difference was a decrease by 14.31 percent. The authors' analysis indicates that, on average, there was a 1.55 percent decrease in physician relative value units between 2010 and 2020. CONCLUSIONS: Medicare reimbursement rates have changed significantly over the past decade. However, these changes did not keep pace with the rate of inflation. Plastic surgeons should be aware of these trends and advocate for more fair reimbursement rates.

P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils.

G-protein-coupled receptors (GPCRs) regulate the organisation of the actin cytoskeleton by activating the Rac subfamily of small GTPases. The guanine-nucleotide-exchange factor (GEF) P-Rex1 is engaged downstream of GPCRs and phosphoinositide 3-kinase (PI3K) in many cell types, and promotes tumorigenic signalling and metastasis in breast cancer and melanoma, respectively. Although P-Rex1-dependent functions have been attributed to its GEF activity towards Rac1, we show that P-Rex1 also acts as a GEF for the Rac-related GTPase RhoG, both in vitro and in GPCR-stimulated primary mouse neutrophils. Furthermore, loss of either P-Rex1 or RhoG caused equivalent reductions in GPCR-driven Rac activation and Rac-dependent NADPH oxidase activity, suggesting they both function upstream of Rac in this system. Loss of RhoG also impaired GPCR-driven recruitment of the Rac GEF DOCK2, and F-actin, to the leading edge of migrating neutrophils. Taken together, our results reveal a new signalling hierarchy in which P-Rex1, acting as a GEF for RhoG, regulates Rac-dependent functions indirectly through RhoG-dependent recruitment of DOCK2. These findings thus have broad implications for our understanding of GPCR signalling to Rho GTPases and the actin cytoskeleton.

GPCR activation of Ras and PI3Kc in neutrophils depends on PLCb2/b3 and the RasGEF RasGRP4.

The molecular mechanisms by which receptors regulate the Ras Binding Domains of the PIP3-generating, class I PI3Ks remain poorly understood, despite their importance in a range of biological settings, including tumorigenesis, activation of neutrophils by pro-inflammatory mediators, chemotaxis of Dictyostelium and cell growth in Drosophila. We provide evidence that G protein-coupled receptors (GPCRs) can stimulate PLCb2/b3 and diacylglycerol- dependent activation of the RasGEF, RasGRP4 in neutrophils. The genetic loss of RasGRP4 phenocopies knock-in of a Ras-insensitive version of PI3Kc in its effects on PI3Kc-dependent PIP3 accumulation, PKB activation, chemokinesis and reactive oxygen species (ROS) formation. These results establish a new mechanism by which GPCRs can stimulate Ras, and the broadly important principle that PLCs can control activation of class I PI3Ks.

SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor.

Short chain fatty acids (SCFAs) have recently attracted attention as potential mediators of the effects of gut microbiota on intestinal inflammation. Some of these effects have been suggested to occur through the direct actions of SCFAs on the GPR43 receptor in neutrophils, though the precise role of this receptor in neutrophil activation is still unclear. We show that mouse bone marrow derived neutrophils (BMNs) can chemotax effectively through polycarbonate filters towards a source of acetate, propionate or butyrate. Moreover, we show that BMNs move with good speed and directionality towards a source of propionate in an EZ-Taxiscan chamber coated with fibrinogen. These effects of SCFAs were mimicked by low concentrations of the synthetic GPR43 agonist phenylacetamide-1 and were abolished in GPR43(-/-) BMNs. SCFAs and phenylacetamide-1 also elicited GPR43-dependent activation of PKB, p38 and ERK and these responses were sensitive to pertussis toxin, indicating a role for Gi proteins. Phenylacetamide-1 also elicited rapid and transient activation of Rac1/2 GTPases and phosphorylation of ribosomal protein S6. Genetic and pharmacological intervention identified important roles for PI3Kγ, Rac2, p38 and ERK, but not mTOR, in GPR43-dependent chemotaxis. These results identify GPR43 as a bona fide chemotactic receptor for neutrophils in vitro and start to define important elements in its signal transduction pathways.

PI3Kß plays a critical role in neutrophil activation by immune complexes.

Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (FcγRs). Here, we used genetic and pharmacological approaches to define a selective role for the ß isoform of phosphoinositide 3-kinase (PI3Kß) in FcγR-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3Kß alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3Kß and PI3Kδ, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kß by immune complexes involved cooperation between FcγRs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B4. Coincident activation by a tyrosine kinase-coupled receptor (FcγR) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the ß isoform of PI3K. PI3Kß-deficient mice were highly protected in an FcγR-dependent model of autoantibody-induced skin blistering and were partially protected in an FcγR-dependent model of inflammatory arthritis, whereas combined deficiency of PI3Kß and PI3Kδ resulted in near-complete protection in the latter case. These results define PI3Kß as a potential therapeutic target in inflammatory disease.