Adherence to a Healthy Lifestyle in Association With Microvascular Complications Among Adults With Type 2 Diabetes.

Importance: The association between an overall healthy lifestyle and the subsequent risk of microvascular complications among patients with diabetes remains unclear. Objective: To examine the association between adherence to a healthy lifestyle before and after diabetes diagnosis and the risk of subsequent microvascular complications among adults with diabetes. Design, Setting, and Participants: This prospective cohort study included incident patients with type 2 diabetes who were free of cardiovascular disease and cancer at the time of diabetes diagnosis and completed the diabetes supplementary questionnaires in the Nurses' Health Study (in 2000 and 2005) and the Health Professionals Follow-Up Study (in 2000, 2004, and 2008) in the US. Data were analyzed from April to August 2021. Exposures: Diet and lifestyle factors before and after diabetes diagnosis were assessed by validated questionnaires. A healthy lifestyle consisted of nonsmoking, having a healthy body weight (a body mass index of ≥18.5 or <25), engaging in moderate-to-vigorous physical activity (≥150 minutes per week), consuming a high-quality diet (top 40th percentile of the Alternative Healthy Eating Index), and moderate alcohol drinking (5-15 g/d for women and 5-30 g/d for men). Main Outcomes and Measures: Physician-diagnosed microvascular complications including diabetic neuropathy, retinopathy, nephropathy, and foot disorders were self-reported at questionnaire surveys. Results: A total of 7077 patients with type 2 diabetes were included in the cohort (4982 women in NHS and 2095 men in HPFS, mean [SD] age 61 [8.8], 94.2% White). During follow-up, 2878 patients developed microvascular complications. After multivariable adjustment, adherence to a healthy lifestyle before and after diabetes diagnosis were both associated with a lower risk of developing microvascular complications. The relative risk (RR) for participants with 4 or more low-risk lifestyle factors before diabetes diagnosis compared with zero was 0.73 (95% CI, 0.60-0.91) for any microvascular complications, 0.71 (95% CI, 0.54-0.93) for diabetic neuropathy, 0.76 (95% CI, 0.57-1.01) for diabetic retinopathy, 0.42 (95% CI, 0.23-0.79) for diabetic nephropathy, and 0.60 (95% CI, 0.35-1.00) for diabetic foot disorders. Similar results were observed for adherence to a healthy lifestyle after diabetes diagnosis, with an RR of 0.68 (95% CI, 0.55-0.83) for any microvascular complications, 0.67 (95% CI, 0.51-0.88) for diabetic neuropathy, 0.65 (95% CI, 0.48-0.86) for diabetic retinopathy, 0.57 (95% CI, 0.34-0.98) for diabetic nephropathy, and 0.62 (95% CI, 0.37-1.05) for diabetic foot disorders. In addition, greater improvement in lifestyle factors from before to after diabetes diagnosis was also significantly associated with a lower risk of neuropathy or total microvascular complications. Each increment in number of low-risk lifestyle factors was associated with a 6% (RR, 0.94; 95% CI, 0.90-0.98) lower risk for any microvascular complications and a 9% (RR, 0.91; 95% CI, 0.86-0.96) lower risk for diabetic neuropathy. Consistent results were observed when analyses were stratified by age at diabetes diagnosis, sex/cohort, or lifestyle factors before diabetes diagnosis. Conclusions and Relevance: In this cohort study, adhering to an overall healthy lifestyle was associated with a significantly lower risk of microvascular complications among individuals with diabetes. These findings suggest substantial reduction in the burden of microvascular complications associated with adopting a healthy lifestyle among patients with type 2 diabetes.

In Autologous Breast Reconstruction, Frailty Is a More Accurate Predictor of Postoperative Complications: A Retrospective Cohort Analysis.

BACKGROUND: Autologous breast reconstruction has a higher postoperative complication rate in vulnerable patients. Given the high prevalence of obesity and aging, operative risk prediction is critical. Age, body mass index, and American Society of Anesthesiologists class are inaccurate predictive factors of postoperative complications. Frailty-a measure of vulnerability-was reported to be a reliable predictor of postoperative complications in multiple surgical fields. Here, we hypothesized that it would be an accurate predictor also in autologous breast reconstruction. METHODS: Patients undergoing autologous breast reconstruction (CPT code 19364) were identified using the American College of Surgeons National Surgical Quality Improvement Program database (January of 2010 to December of 2018). Frailty was calculated using the validated modified Frailty Index. Rates of wound complications, bleeding episodes, readmissions, returns to the operating room, and deep venous thromboses were compared across modified Frailty Index score, body mass index, age, and American Society of Anesthesiologists class. RESULTS: A modified Frailty Index score of 2 or greater was associated with a 22.22 percent ( p < 0.001) rate of wound complications; a 15.79 percent ( p < 0.001) rate of bleeding episodes; an 8.20 percent ( p < 0.001) rate of readmissions; a 17.19 percent ( p < 0.001) rate of return to the operating room; and a 1.81 percent ( p < 0.05) rate of deep venous thromboses. Higher body mass index, age, and American Society of Anesthesiologists class did not significantly correlate with increased rates in one or more postoperative complications. Only a high modified Frailty Index was consistently associated with significantly higher odds in all complication types. CONCLUSION: As a reliable and accurate predictor of postoperative complications in autologous breast reconstruction, frailty could be used preoperatively to counsel patients and guide surgical care. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

NPWTi allows safe delayed free flap repair of Gustilo IIIb injuries: A prospective case series.

INTRODUCTION: Free flap lower extremity repair is associated with a high complication rate (>31%); higher rates are observed in more severe patients. In cases requiring prior systemic/local stabilization, delayed repair increases complication rate (+10% at 7 days): Negative-pressure Wound Therapy (NPWT) decreases complications but only when applied for less than 7 days. Recent limited evidence suggests that augmentation of NPWT with instillation for wound irrigation (NPWTi) might safely extend such window. This study hypothesizes that, through the combined cleansing effect of NPWT and instillation, NPWTi allows safe (low complication rate) delayed free flap repair in severe patients with Gustilo IIIb injuries (GIIIb). METHODS: A prospective case series was designed (inclusion criteria: GIIIb requiring microsurgical repair, severe patient/injury condition preventing immediate/early repair; exclusion criteria: allergy to NPWTi dressing). Patients received NPWTi (suction: 125 mmHg continuous; irrigation: NaCl 0.9%) until considered clinically ready for repair. Preoperative/postoperative complications (dehiscence, wound infection, bone non-union, osteomyelitis, flap failure) were monitored with clinical signs, imaging, and serum markers (CRP, WBC). RESULTS: Four patients (male: N = 4, female N = 1; Age: 59 [44-75] years-old) were treated. NPWTi was applied for 15.2 [9-28] days. No complication (0%) was observed preoperatively or postoperatively. Delayed repair occurred by latissimus dorsi musculocutaneous flap (N = 3), and anterolateral thigh flap (N = 2). All patients walked weight-bearing 12 [6-20] weeks after injury. CONCLUSIONS: NPWTi seems to allow safe delayed free flap repair in patients with severe lower extremity injuries unable to undergo immediate/early repair.

Applicant Familiarity Becomes Most Important Evaluation Factor in USMLE Step I Conversion to Pass/Fail: A Survey of Plastic Surgery Program Directors.

BACKGROUND: In 2020, Step 1 of the United States Medical Licensing Examination (USMLE) changed to a pass/fail reporting. Step 1 has been one of the main factors for both inviting applicants for interviews and for ranking in Plastic Surgery. Due to this change, we hypothesize that Step 2 CK - currently the only remaining, universal quantitative metric - will become the main factor in the residency selection process. METHODS: A survey-based cross-sectional study of United States (US) integrated plastic surgery program directors (PSPDs) investigated the factors that would assume importance following the change in the reporting pattern. RESULTS: Respondents reported that personal prior knowledge of the applicant, Letters of recommendation (LORs), Step 2 CK scores, and away rotation at the institution of interest would become the most important factors (median ratings of 5, 4.5, 4.5, 4.5, respectively on a 5-point Likert scale). Eighty-three percent of respondents were strongly dissatisfied with the conversion to pass/fail reporting. LOR's received the highest ranking (median,1; IQR,1-2) as the component used for offering away rotations after the implementation of the pass/fail reporting, followed by the applicant's medical school (median, 3; IQR, 3-4), and grades obtained during medical school (median,3; IQR,1.75-4). Standardized assessment during rotations are recommended by 67% of PSPDs. CONCLUSIONS: Future emphasis will be placed primarily on subjective metrics, including applicant familiarity. Step 2 CK, LORs, and away rotation at the institution of interest are other factors of importance. PSPDs welcome the adoption of objective assessments of patient care and medical knowledge to improve the current selection process.

Gender-specific Anatomical Distribution of Internal Pudendal Artery Perforator: A Radiographic Study for Perineal Reconstruction.

BACKGROUND: Cancer, trauma, infection, or radiation can cause perineal defects. Fasciocutaneous flaps based on perforator vessels (PV) from the internal pudendal artery (IPA) provide an ideal reconstructive option for moderate defects. We hypothesized that, due to gender differences in the pelvic-perineal region, the anatomical distribution of PV differs between genders. METHODS: Computed tomography angiographies from male and female patients without pelvic-perineal pathologies were retrospectively analyzed to study the vascular anatomy of the IPA. The number, size, type, and distribution of PV were recorded and compared between genders. Four anatomical regions were defined to describe the distribution of PV on each perineal side: anterior (A), anterior-central (AC), central-posterior (CP), and posterior (P). RESULTS: A total of 63 computed tomography angiographies were analyzed (men, 31; women, 32). Each IPA provides 2 ± 1 PV and 5 ± 2 terminal (cutaneous) branches: in both genders, 85% of PV are septocutaneous (15% musculocutaneous). In women, 70.5% of PV are located in AC, 28.2% in CP, 1.2% in A, and 0% in P: average diameter of the PV is 2.4 ± 0.3 mm. In men, 53.7% of PV are located in CP, 43.1% in AC, 3.3% in A, and 0% in P: average diameter of the PV is 2.8 ± 0.5 mm. Gender-specific differences in anatomical distribution of PV are significant (P < 0.001). CONCLUSIONS: Number, size, and type of terminal branches of PV of the IPA are consistent between genders, but their distribution is different, with women having an anterior predominance. Knowledge of gender-specific anatomy can guide preoperative planning and intraoperative dissection in flap-based perineal reconstruction.

Hydrosurgical Debridement Allows Effective Wound Bed Preparation of Pressure Injuries: A Prospective Case Series.

BACKGROUND: Pressure injuries (PIs) are common in hospitalized patients, with incidence exceeding 50% in high-risk patients. Immobilization causes a prolonged compression of vascular networks in tissues overlying bony prominences, leading to ischemia and ulceration. Traditionally, PIs are treated with a combination of surgical debridement and reconstruction. This approach can be invasive for debilitated patients who cannot tolerate prolonged surgeries and extensive tissue resection. Hydrosurgery uses high-pressure irrigation to low-invasively debride and cleanse wounds; its use has shown positive outcomes in burn and chronic wounds care. Here, we hypothesize that hydrosurgery allows low-invasive yet effective wound bed preparation in truncal PIs. METHODS: We conducted a single-center, prospective, uncontrolled case series. Inclusion criteria for this study were presence of a truncal PI (stage III or IV) and an American Society of Anesthesiologists physical status of ≥2 (no exclusion criteria). Measured outcomes included duration of hydrosurgery, postsurgical local (dehiscence, infection, seroma) or systemic complications in the first 30 days, and PI recurrence rate (6-month follow-up). RESULTS: Seven patients (3 sacral, 2 greater trochanteric, and 2 ischial tuberosity PIs) were enrolled for this study. Average duration of hydrosurgery was 12 minutes (±3.1). No local or systemic complications were observed at a 30-day follow-up (0/7, 0%). All flaps (6/7, 86%) and graft (1/7, 14%) reconstructions successfully survived, and no PI recurrence was reported within a 6-month follow-up (0/7, 0%). CONCLUSIONS: Hydrosurgery seems to allow safe, low-invasive, and effective wound bed preparation in truncal PIs. Larger controlled trials are needed to confirm this preliminary evidence, to guide its broader adoption for improved care of high-risk patients with PIs.

Embryonic stem cell extracts improve wound healing in diabetic mice.

AIMS/HYPOTHESIS: Impaired wound healing significantly impacts morbidity and mortality in diabetic patients, necessitating the development of novel treatments to improve the wound healing process. We here investigated the topical use of acellular embryonic stem cell extracts (EXTs) in wound healing in diabetic db/db mice. METHODS: Wounds were induced in diabetic db/db mice, which were subsequently treated with EXTs, with 3T3 fibroblast cell line protein extracts (3T3XTs) or with saline as a control. Pathology and mechanistic assays were then performed. RESULTS: The in vivo topical administration of EXTs facilitates wound closure, contraction and re-epithelialization. Moreover, EXTs reduced the number of wound-infiltrating CD45+ inflammatory cells and increased the rate of repair and of angiogenesis as compared to controls. Interestingly, the EXT effect was partly enhanced by the use of a collagen-based biocompatible scaffold. In vivo, topical administration of EXTs increased the percentage of regulatory T cells in the wounded tissue, while in vitro EXT treatment reduced T cell-mediated IFN-γ production. Proteomic screening revealed 82 proteins differentially segregating in EXTs as compared to 3T3 extracts, with APEX1 identified as a key player for the observed immunomodulatory effect of EXTs. CONCLUSIONS: EXTs are endowed with immunoregulatory and anti-inflammatory properties; their use improves wound healing in diabetic preclinical models.

Tissue-Engineered Soft-Tissue Reconstruction Using Noninvasive Mechanical Preconditioning and a Shelf-Ready Allograft Adipose Matrix.

BACKGROUND: Adipose tissue defects leading to severe functional (disability) and morphologic (disfigurement) morbidity are often treated in plastic surgery with fat grafting, which can be limited by resorption, necrosis, and cyst formation. This study aimed to assess whether adipose scaffolds could provide an environment for in situ autologous fat grafting, and to study whether adipose cell migration and proliferation (adipogenesis) within scaffolds could be enhanced by preliminarily increasing the vascularity (preconditioning) of the surrounding tissue receiving the scaffolds. METHODS: Using an established rodent model of subcutaneous tissue/scaffold grafting, the authors tested the potential of a human-derived, shelf-ready, injectable, decellularized allograft adipose matrix to reconstruct soft-tissue defects when used in combination with noninvasive mechanical (suction-induced) skin preconditioning. RESULTS: Combined use of the allograft adipose matrix and noninvasive skin preconditioning significantly improved long-term volume retention (50 to 80 percent higher at a 12-week follow-up) and histologic quality of reconstructed tissues compared with standard of care (autologous adipose grafts). The components of the allograft adipose matrix supported adipogenesis and angiogenesis. Combining the allograft adipose matrix with living adipose grafts mitigated negative outcomes (lower long-term volume retention, higher presence of cystic-like areas). CONCLUSIONS: This study suggests that the synergistic use of the allograft adipose matrix and noninvasive tissue preconditioning provides an effective solution for improving fat grafting. These strategies can easily be tested in clinical trials and could establish the basis for a novel therapeutic paradigm in reconstructive surgery.

Keratinocyte sheets prepared with temperature-responsive dishes show enhanced survival after in vivo grafting on acellular dermal matrices in a rat model of staged bi-layered skin reconstruction.

INTRODUCTION: Bi-layered skin reconstruction can be achieved by staged grafting of acellular dermal matrices (ADMs) and cultured epithelial keratinocyte sheets (KSs). Both KSs and ADMs have been used for long; yet, their combined use has shown poor effectiveness. This outcome has been related to the enzymatic treatment used in the preparation of KSs, which impairs their adhesion potential to ADMs and the formation of a basement membrane (BM). Temperature-responsive (TR) culture dishes allow for enzyme-free preparation of KSs with preservation of BMs and intercellular adhesion proteins; yet, their use has not been previously applied to staged bi-layered skin reconstruction. Using an in vivo rat model, we tested the hypothesis that TR cultures enhance KSs survival and BM preservation after sequential grafting on ADMs. METHODS: In nude rats (n = 9/group), a 9-cm [2] full-thickness dorsal skin defect was repaired with a commercial ADM. At 2 weeks after surgery, we grafted the ADM with KSs (circular, 25 mm diameter), prepared from human cells either by enzymatic Dispase treatment (DT control group) or a TR culture dish (TR experimental group). KSs survival and BMs preservation was assessed one week later by digital imaging, histology (hematoxylin & eosin), immunohistochemistry (collagen IV, pancytokeratins) and immunofluorescence (cytokeratin 1-5-6, laminin). RESULTS: The TR group showed a significantly higher KSs survival (120 ± 49 vs. 63 ± 42 mm2; p < 0.05) and epidermal thickness (165 ± 79 vs. 65 ± 54 µm; p < 0.01) compared with the control DT group, as well as higher epidermal maturation (cytokeratin) and a denser laminin and Collagen IV expression in the BMs in vitro and in vivo. CONCLUSION: These findings suggest that KSs prepared with TR culture dishes have significantly enhanced survival when grafted on ADMs; these outcomes could help improve current clinical strategies in wound care by skin reconstruction.

Mouse Mast Cell Protease-4 Recruits Leukocytes in the Inflammatory Phase of Surgically Wounded Skin.

Objective: Mouse mast cell protease-4 (mMCP-4, also known as chymase) has both pro- and anti-inflammatory roles depending on the disease model. However, its effects have not been studied in surgically wounded skin. Given the significant clinical applications of modulating the inflammatory response in wound healing, we examined the role of mMCP-4 and the effect of its inhibitor chymostatin on leukocyte and polymorphonuclear cell (PMN) recruitment in our skin model. Approach: Recruitment was assessed on day-1 postwounding of three groups of mice (n = 10 each): mMCP-4 null mice, wild-type (WT) mice treated with the mMCP-4 inhibitor chymostatin, and WT with no other intervention. Leukocytes were stained with CD-45 cell marker, and PMN cells were stained with chloroacetate esterase. Results: The WT mice had 27 ± 9 leukocytes per field compared with 11 ± 6 for the mMCP-4 nulls, a decrease of 60% (p = 0.03), whereas the chymostatin-injected group had a count comparable with the uninjected WT controls at 24 ± 9. The WT group had a PMN count of 96 ± 12 cells, compared with just 24 ± 8 in the mMCP-4 null group, a decrease of 75% (p = 0.001), whereas the chymostatin-treated group had 60 ± 18 cells, a decrease of 38% compared with the WT group (p = 0.03). Innovation: We showed that the inflammatory process can be influenced by impeding the arrival of PMNs into the surgically injured site using the mMCP-4 inhibitor chymostatin. Conclusion: Chymase contributes to the recruitment of white blood cells in surgically wounded skin.

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.