Skin Inflammation with a Focus on Wound Healing.

Significance: The skin is the crucial first-line barrier against foreign pathogens. Compromise of this barrier presents in the context of inflammatory skin conditions and in chronic wounds. Skin conditions arising from dysfunctional inflammatory pathways severely compromise the quality of life of patients and have a high economic impact on the U.S. health care system. The development of a thorough understanding of the mechanisms that can disrupt skin inflammation is imperative to successfully modulate this inflammation with therapies. Recent Advances: Many advances in the understanding of skin inflammation have occurred during the past decade, including the development of multiple new pharmaceuticals. Mechanical force application has been greatly advanced clinically. Bioscaffolds also promote healing, while reducing scarring. Critical Issues: Various skin inflammatory conditions provide a framework for analysis of our understanding of the phases of successful wound healing. The large burden of chronic wounds on our society continues to focus attention on the chronic inflammatory state induced in many of these skin conditions. Future Directions: Better preclinical models of disease states such as chronic wounds, coupled with enhanced diagnostic abilities of human skin, will allow a better understanding of the mechanism of action. This will lead to improved treatments with biologics and other modalities such as the strategic application of mechanical forces and scaffolds, which ultimately results in better outcomes for our patients.

Modulation of Lymphangiogenesis in Incisional Murine Diabetic Wound Healing Using Negative Pressure Wound Therapy.

Objective: Despite the significant function of lymphatics in wound healing, and frequent clinical use of Negative Pressure Wound Therapy (NPWT), the effect of mechanical force application on lymphangiogenesis remains to be elucidated. We utilize a murine incisional wound healing model to assess the mechanisms of lymphangiogenesis following NPWT. Approach: Dorsal incisional skin wounds were created on diabetic mice (genetically obese leptin receptor-deficient mice [db/db]; n = 30) and covered with an occlusive dressing (Control, n = 15) or NPWT (-125 mmHg, continuous, 24 h for 7 days; NPWT, n = 15). The wounds were macroscopically assessed for 28 days. Tissue was harvested on day 10 for analysis. Qualitative functional analysis of lymphatic drainage was performed on day 28 using Evans Blue staining (n = 2). Results: NPWT increased lymphatic vessel density (40 ± 20 vs. 12 ± 6 podoplanin [PDPN]+ and 25 ± 9 vs. 14 ± 8 lymphatic vessel endothelial receptor 1 [LYVE-1]+) and vessel diameter (28 ± 9 vs. 12 ± 2 µm). Western blotting verified the upregulation of LYVE-1 with NPWT. Leukocyte presence was higher with NPWT (22% ± 3.7% vs. 9.1% ± 4.1% lymphocyte common antigen [CD45]+) and the leukocytes were predominately B cells clustered within vessels (8.8% ± 2.5% vs. 18% ± 3.6% B-lymphocyte antigen CD20 [CD20]+). Macrophage presence was lower in the NPWT group. Lymphatic drainage was increased in the NPWT group, which exhibited greater Evans Blue positivity. Innovation: The lymphangiogenic effects take place independent of macrophage infiltration, appearing to correlate with B cell presence. Conclusion: NPWT promotes lymphangiogenesis in incisional wounds, significantly increasing the lymph vessel density and diameter. This study highlights the potential of NPWT to stimulate lymphatic drainage and wound healing of surgical incisions.

Continuous NPWT Regulates Fibrosis in Murine Diabetic Wound Healing.

Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, −125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP (p = 0.04) but decreased En1 (p = 0.0001) and CD26 (p < 0.0001). The pro-fibrotic factors Vimentin (p = 0.04), α-SMA (p = 0.04) and HSP47 (p = 0.0008) were decreased with NPWT. Fibronectin was higher (p = 0.01) and collagen deposition lower in the NPWT group (p = 0.02). NPWT increased cellular proliferation (p = 0.002) and decreased apoptosis (p = 0.03). Western blotting demonstrated increased YAP (p = 0.02) and RhoA (p = 0.03) and decreased Caspase-3 (p = 0.03) with NPWT. NPWT uncouples YAP from EPF activation, through downregulation of Caspace-3, a pro-apoptotic factor linked to keloid formation. Mechanotransduction decreases multiple pro-fibrotic factors. Through this multifactorial process, NPWT significantly decreases fibrosis and offers promising potential as a mode to improve scar appearance.

Xenogenic induction of adipose tissue and maintenance through pre- and post-conditioning using external volume expansion.

External volume expansion (EVE) has been shown to improve fat graft survival. In this study, we investigated the xenogenic implantation of human allograft adipose matrix (AAM) in non-immunocompromised mice in combination with pre- and post-conditioning with EVE to assess long-term adipose tissue survival. Sixty-eight recipient sites in thirty-four eight-week-old wild type (C57BL/6J) mice were separated into four groups. Thirty-four sites received no conditioning and either a subcutaneous injection of 300 µl saline (n= 17; PBS group) or AAM (n= 17; AAM group). Thirty-four sites received pre-conditioning with EVE (Day -7-3 pre-grafting) and 300 µl of AAM. Seventeen of these sites received immediate post-conditioning (Day 1-5 post-grafting) and 17 delayed post-conditioning (Day 28-32 post-grafting). Tissue was harvested at week 12 for analysis. At 12 weeks, immediate and delayed post-conditioning enabled higher volume retention (p= 0.02 andp< 0.0001, respectively). Adipose Stem Cells were greater in the AAM+Del-EVE group compared to the AAM (p= 0.01). Microvessel density was lower in the AAM group compared to the AAM+Imm-EVE (p= 0.04) and AAM+Del-EVE group (p= 0.02). Macrophage infiltration was lower in the AAM+Imm-EVE (p= 0.002) and AAM+Del-EVE (p= 0.003) groups compared to the AAM group. PCR analysis and Western blotting identified a significantly higher expression of PPAR-γ, LPL and VEGF with delayed-conditioning. Pre- and post-conditioning, particularly delayed-post-conditioning, of the recipient site optimized the microenvironment allowing significant adipogenesis and survival of neo-adipose tissue through robust angiogenesis. This study supports that xenogenic transplantation of adipose matrix allows adipose tissue formation and survival with EVE as an adjuvant.

Impact of diabetes on outcomes in breast reconstruction: A systematic review and meta-analysis.

BACKGROUND: As rates of breast cancer and type II diabetes increase, so does the number of women with diabetes undergoing breast reconstruction (BR). Patients with diabetes are at increased risk of postoperative complications. This meta-analysis seeks to evaluate the post-operative outcomes of women with diabetes who underwent BR following mastectomy. METHOD: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The EMBASE, PUBMED, and MEDLINE electronic databases were searched from inception to November 1, 2020 for studies published in English. Outcomes evaluated were overall complications, surgical complications, and longer hospital stay. Subgroup analysis investigated outcomes, such as implant/flap failure, infection, and necrosis. RESULTS: Sixty-five studies met our inclusion criteria and 38 provided data to be included in the meta-analysis. A total of 151,585 patients were included, of which 9299 had diabetes. Women with diabetes were more likely to experience overall complications (11.6% vs 5.6%; p<0.0001) and surgical complications (7.7% vs 3.3%; p<0.0001), and were more likely to have a prolonged hospital stay (p = 0.04) than women without diabetes. Subgroup analysis showed that implant loss (2.5% vs 1.6%; p = 0.0003), infection (6.8% vs 2.5%; p<0.0001) and necrosis (23.8% vs 6.5; p = 0.001) were significantly higher in women with diabetes. CONCLUSIONS: This study provides evidence that diabetes mellitus increases the risk of complications in patients with breast cancer undergoing BR after mastectomy. Prospective studies are required to establish whether diabetes that is well-controlled prior to reconstruction, including diabetes that is paired with adjuvant radiation therapy, reduces the perioperative risks.

Adherence to Personal Protective Equipment Guidelines During the COVID-19 Pandemic Among Health Care Personnel in the United States.

OBJECTIVES: Protecting frontline health care workers with personal protective equipment (PPE) is critical during the coronavirus disease (COVID-19) pandemic. Through an online survey, we demonstrated variable adherence to the Centers for Disease Control and Prevention (CDC) PPE guidelines among health care personnel (HCP). METHODS: CDC guidelines for optimal and acceptable PPE usage in common situations faced by frontline health care workers were referenced to create a short online survey. The survey was distributed to national, statewide, and local professional organizations across the United States and to HCP, using a snowball sampling technique. Responses were collected between June 15 and July 17, 2020. RESULTS: Responses totaling 2245 were received from doctors, nurses, midwives, paramedics, and medical technicians in 44 states. Eight states with n > 20 (Arizona, California, Colorado, Louisiana, Oregon, South Carolina, Texas, and Washington) and a total of 436 responses are included in the quantitative analysis. Adherence to CDC guidelines was observed to be highest in the scenario of patient contact when COVID-19 was not suspected (86.47%) and lowest when carrying out aerosol generating procedures (AGPs) (42.47%). CONCLUSIONS: Further research is urgently needed to identify the reasons underlying variability between professions and regions to pinpoint strategies for maximizing adherence and improving the safety of HCPs.

Letter to the Editor: Insights into migraine surgery - An ACS-NSQIP data analysis over a 13- year period.

We demonstrate the safety of MS based on big data database research and outline the clinical relevance of white female migraineurs affected by menstrual migraines.

Adherence to Personal Protective Equipment Guidelines During the COVID-19 Pandemic Among Health-Care Personnel: A Louisiana Case Study.

OBJECTIVE: The aim of this study was to determine the extent that appropriate personal protective equipment (PPE), per Centers for Disease Control and Prevention (CDC) guidance, was used during the coronavirus diseases 2019 (COVID-19) pandemic by health-care personnel (HCP) in Louisiana in 5 clinical settings. METHODS: An online questionnaire was distributed to the LA Nursery registry. Appropriate use of PPE in each of the 5 clinical scenarios was defined by the authors based on CDC guidelines. The scenarios ranged from communal hospital space to carrying out aerosol generating procedures (AGPs). A total of 1760 HCP participated between June and July 2020. RESULTS: The average adherence in LA was lowest for the scenario of carrying out AGPs at 39.5% compliance and highest for the scenario of patient contact when COVID-19 not suspected at 82.8% compliance. Adherence among parishes varied widely. Commentary to suggest a shortage of PPE supply and the practice of re-using PPE was strong. CONCLUSIONS: Use of appropriate PPE varied by setting. It was higher in scenarios where only face masks (or respirators) were the standard (ie, community hospital or when COVID-19 not suspected) and lower in scenarios where additional PPE (eg, gloves, eye protection, and isolation gown) was required.

Measuring visual attention to faces with cleft deformity.

BACKGROUND: Limited data are available regarding observers' visual attention to faces with congenital difference. We implemented eye tracking technology to examine this issue, as it pertains particularly to faces with cleft deformity. METHOD: Four hundred three observers assessed 273 clinical images, while their eye movements were unobtrusively tracked using an infrared sensor. Forty-one facial images of the repaired cleft lip, 137 images of other facial conditions, and 95 images of matched controls were assessed. Twenty facial regions of interest ("lookzones") were considered for all images observed. A separate cohort of 720 raters evaluated the images for attractiveness. Observer and image demographic information was collected. Visual fixation counts and durations were computed across all 20 lookzones for all images. The effect of a variety of variables on lookzone fixation was analyzed using factorial ANOVA testing. RESULTS: Cleft-repaired faces were rated as less attractive and drew observers' attention preferentially to the affected upper lip lookzone (p<.001). Images rated as less attractive garnered greater visual attention in the cleft-affected lookzones (p<.001). The eye tracking methodology demonstrated exquisite sensitivity to laterality of cleft deformity (p<.001). Individuals reporting a personal or a family history of facial deformity fixated more on the perioral region of cleft-repaired faces than did naïve observers (p<.001). CONCLUSION: These findings highlight the utility of eye tracking measures for understanding critical variables that influence the visual processing of faces with cleft deformity. The data may provide analytical tools for assessing surgical outcome and direct priority setting during surgeons' conversations with patients.