Impact of Nicotine Replacement Therapy on Breast Surgery Outcomes.

BACKGROUND: Smoking cessation therapy, including nicotine replacement therapy (NRT), is used perioperatively to assist patients to reduce their tobacco smoke intake and consequently decrease their risk of smoking-associated complications. There are, however, theoretical concerns that nicotine-induced peripheral vasoconstriction could impair wound healing. This study investigated the effect of NRT on postoperative outcomes in patients undergoing breast surgery. METHODS: A retrospective chart review of patients undergoing breast surgery within the Yale New Haven Health System from the years 2014 to 2020 was performed. Documented smoking status within 6 months before surgery, use or prescription of NRT, type of surgery, and surgical complications of infection, wound dehiscence, tissue necrosis, hematoma, seroma, fat necrosis, and return to operating room within 30 days were recorded. Demographic and complication data were compared between patients with NRT usage and those without using t-tests and chi-square analyses. Multivariable logistic regression models were created to predict the effect of NRT usage on the occurrence of any complication. RESULTS: A total of 613 breast procedures met inclusion criteria, of which 105 (17.2%) had documented NRT use. The NRT cohort and the non-NRT cohort were well balanced with respect to demographics and procedural variables. Upon multivariable modeling for risk of any surgical complication, NRT was not a significant predictor (odds ratio [OR]: 1.199, p = 0.607 and OR: 0.974, p = 0.912, respectively), whereas procedure type, increased body mass index, and increased age were. CONCLUSION: NRT use was not associated with an increased risk of postoperative complications compared with not using NRT as part of smoking cessation therapy prior to operation.

TNF-α Preconditioning Promotes a Proangiogenic Phenotype in hiPSC-Derived Vascular Smooth Muscle Cells.

Introduction: hiPSC-VSMCs have been suggested as therapeutic agents for wound healing and revascularization through the secretion of proangiogenic factors. However, methods of increasing cell paracrine secretion and survivability have thus far yielded inconsistent results. This study investigates the effect of pre-conditioning of hiPSC-VSMCs with TNF-α and their integration into 3D collagen scaffolds on cellular viability and secretome. Methods: hiPSC-VSMCs were dual-plated in a 2D environment. TNF-α was introduced to one plate. Following incubation, cells from each plate were divided and added to type-I collagen scaffolds. TNF-α was introduced to two sets of scaffolds, one from each 2D plate. Following incubation, scaffolds were harvested for their media, tested for cell survivability, cytotoxicity, and imaged. Intra-media VEGF and bFGF levels were evaluated using ELISA testing. Results: hiPSC-VSMCs exposed to TNF-α during collagen scaffold proliferation and preconditioning showed an increase in cell viability and less cytotoxicity compared to non-exposed cells and solely-preconditioned cells. Significant increases in bFGF expression were found in pre-conditioned cell groups with further increases found in cells subsequently exposed during intra-scaffold conditioning. A significant increase in VEGF expression was found in cell groups exposed during both pre-conditioning and intra-scaffold conditioning. Fibroblasts treated with any conditioned media demonstrated increased migration potential. Conclusions: Conditioning hiPSC-VSMCs embedded in scaffolds with TNF-α improves cellular viability and increases the secretion of paracrine factors necessary for wound healing mechanisms such as migration. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-023-00764-0.

Transcriptional heterogeneity in human diabetic foot wounds.

Wound repair requires the coordination of multiple cell types including immune cells and tissue resident cells to coordinate healing and return of tissue function. Diabetic foot ulceration is a type of chronic wound that impacts over 4 million patients in the US and over 7 million worldwide (Edmonds et al., 2021). Yet, the cellular and molecular mechanisms that go awry in these wounds are not fully understood. Here, by profiling chronic foot ulcers from non-diabetic (NDFUs) and diabetic (DFUs) patients using single-cell RNA sequencing, we find that DFUs display transcription changes that implicate reduced keratinocyte differentiation, altered fibroblast function and lineages, and defects in macrophage metabolism, inflammation, and ECM production compared to NDFUs. Furthermore, analysis of cellular interactions reveals major alterations in several signaling pathways that are altered in DFUs. These data provide a view of the mechanisms by which diabetes alters healing of foot ulcers and may provide therapeutic avenues for DFU treatments.

The Impact of Social Determinants of Health on Pressure Injury Progression: A Retrospective Chart and Scoping Review.

OBJECTIVE: To understand the effects of nutrition security and social determinants of health (SDOHs) on pressure injury (PI) progression through a scoping review and retrospective review of patients reporting to New England's largest healthcare system. METHODS: Authors performed a scoping review for full-text, original articles reporting outcomes data specific to PIs in patients with socially informed nutrition insecurity. Investigators also performed a retrospective review of all patients from 2012 to 2021 to search for patients with PI documentation and International Classification of Diseases, Tenth Revision Z codes related to the SDOHs. RESULTS: A full-text review of 2,323 articles from 1965 to 2020 failed to locate any eligible studies. Investigators identified 1,044 patients who met the inclusion criteria; 50.7% were men, 74.3% were White, and 13.3% had evidence of detrimental SDOHs. The average PI duration was 12.13 days (interquartile range, 6 days). Multivariate regression analysis revealed that PI duration was longer in men, Black patients, and patients with evidence of detrimental SDOHs compared with their converse counterparts (P < .0001). The presence of detrimental SDOHs independently predicted an increased duration of disease by 13.07 days (95% CI, 8.99-17.15; t = 6.29, P < .0001). CONCLUSIONS: A patient's SDOH history has a significant and considerably stronger correlation with disease progression than predictors that are traditionally studied such as sex, race, or body mass index. These findings are novel, as highlighted by the absence of data uncovered in the literature. These data carry relevance for plastic surgeons wishing to prevent early recurrence following operative closure of PI-related wounds.

The effect of COVID-19 on the pressure injury reporting gap.

Responsibilities placed on nurses increased during the COVID-19 pandemic. Hospital-acquired PI monitoring was deferred in favor of more critical patient needs. It was hypothesized that a counterintuitive dip in HAPI reporting would be observed despite maximum hospital capacity across much of the United States. The electronic medical records of patients treated in the YNHH System between December 2017 and February 2021 were retrospectively reviewed to identify patients with HAPIs, defined as PIs not documented upon admission but subsequently present during the patient's hospital stay. Paired t test revealed a significantly lower number of reported incidents mid-pandemic than during the prepandemic baseline months (P <.0001). The data in this report show interdisciplinary clinician-led teams must continue to monitor for HAPIs and congruous conditions to minimize reporting gaps and progression in PI severity despite COVID-19 pandemic-related conditions and additional related responsibilities.

Surgical Outcomes and Prognostic Factors of G3 Pancreatic Neuroendocrine Carcinomas: A Consecutive Analysis Based on Previous Study Results.

In 2017, the World Health Organization (WHO) officially defined pancreatic neuroendocrine neoplasms into well-differentiated tumors, namely G1/G2/G3 pancreatic neuroendocrine tumors, and poorly differentiated carcinomas referring to G3 pancreatic neuroendocrine carcinomas (p-NECs). However, the surgical outcomes and prognostic factors of G3 p-NECs are still unclear. Methods: We retrospectively collected and analyzed the data of eligible patients with G3 p-NECs defined by the WHO 2017 grading classification. Results: We eventually identified 120 patients with G3 p-NECs, including 72 females and 48 males, with a median age of 53 y. The 3-year overall survival (OS) of G3 p-NECs by Kaplan−Meier method was 37.3%. The 3-year OS for functional G3 p-NECs was 57.4%, which was statistically longer than 23.0% of non-functional ones (p = 0.002). Patients with surgical resection presented a significantly better 3-year OS than those with palliative operation (43.3% vs. 13.1%; p < 0.001). The 3-year OS for Stage Ⅰ, Stage Ⅱ, Stage Ⅲ, and Stage Ⅳ was 87.1%, 56.5%, 12.9%, and not applicable, respectively (p < 0.001). We demonstrated in a Cox regression model that palliative operation (p = 0.013), vascular infiltration (p = 0.039), lymph node involvement (p = 0.024), and distant metastasis (p = 0.016) were independent predictors of poor outcome for patients with surgically treated G3 p-NECs. Conclusion: Our data in the present analysis indicated that patients with G3 p-NECs could significantly benefit from surgical resection. Meanwhile, vascular infiltration, lymph node involvement, and distant metastasis were independent predictors of poor outcome for these patients.

Perceived Age and Attractiveness Using Facial Recognition Software in Rhinoplasty Patients: A Proof-of-Concept Study.

ABSTRACT: Artificial intelligence (Al)-based analyses may serve as a more objective tool for measuring cosmetic improvements following aesthetic plastic surgery. This preliminary proof-of-concept study utilized a novel commercial facial recognition software to assess perceived changes in age and attractiveness among patients receiving rhinoplasty.This study was a retrospective evaluation of three-dimensional photographs of patients who underwent rhinoplasty by the senior author (DS). Both pre- and post-operative (> 12-month follow-up) Vectra three-dimensional images (Canfield Scientific, Parsippany, NJ) were assessed using Haystack AI Software (Haystack AI, New York, NY). Facial attractiveness (score 1-10) and apparent age were predicted. A retrospective chart review of demographic variables was additionally performed. Paired t tests were used to compare age and attractiveness scores before and after surgery. Multivariate linear regression was performed to identify factors associated with age and attractiveness scores.One hundred twenty-four patients receiving rhinoplasty met the study criteria (average age: 35.58). Overall, rhinoplasty was associated with increases in Al-rated attractiveness (+0.28, P = 0.03) and decreases in perceived age relative to the patient's true age (-1.03 years, P = 0.03). Greater decreases in postoperative perceived age were achieved in patients who appeared older than their actual age preoperatively ( P < 0.001).Facial recognition software was successfully used to evaluate improvements in perceived age and attractiveness in patients undergoing aesthetic rhinoplasty. Patients were perceived by the software as younger and more attractive following rhinoplasty. Age reversal was greatest among patients who appeared much older than their actual age at the time of surgery.Level of Evidence: IV.

Human iPSC-Derived Vascular Smooth Muscle Cells in a Fibronectin Functionalized Collagen Hydrogel Augment Endothelial Cell Morphogenesis.

Tissue-engineered constructs have immense potential as autologous grafts for wound healing. Despite the rapid advancement in fabrication technology, the major limitation is controlling angiogenesis within these constructs to form a vascular network. Here, we aimed to develop a 3D hydrogel that can regulate angiogenesis. We tested the effect of fibronectin and vascular smooth muscle cells derived from human induced pluripotent stem cells (hiPSC-VSMC) on the morphogenesis of endothelial cells. The results demonstrate that fibronectin increases the number of EC networks. However, hiPSC-VSMC in the hydrogel further substantiated the number and size of EC networks by vascular endothelial growth factor and basic fibroblast growth factor secretion. A mechanistic study shows that blocking αvß3 integrin signaling between hiPSC-VSMC and fibronectin impacts the EC network formation via reduced cell viability and proangiogenic growth factor secretion. Collectively, this study set forth initial design criteria in developing an improved pre-vascularized construct.

Integrin ß3 targeting biomaterial preferentially promotes secretion of bFGF and viability of iPSC-derived vascular smooth muscle cells.

Human-induced pluripotent stem cell-derived-vascular smooth muscle cells (hiPSC-VSMC) and their secretome have been shown to promote angiogenesis and wound healing. However, there is a paucity of research on how the extracellular matrix (ECM) microenvironment may impact the hiPSC-VSMC's functions. In this study, we investigated the effect of specific ECM ligand-integrin interaction on hiPSC-VSMC's paracrine secretion, cell viability, and morphology. Here, we show precise modulation of hiPSC-VSMC in a fibronectin functionalized fibrillar collagen scaffold by targeting their integrin ß3. The secretion of proangiogenic growth factor, basic fibroblast growth factor (bFGF) was found to be fibronectin-dependent via αvß3 integrin interactions. In addition, our data show the possible role of a positive feedback loop between integrin ß3, bFGF, and matrix metalloproteinase-2 in regulating hiPSC-VSMC's morphology and cell viability. Finally, the secretome with enhanced bFGF shows potential for future wound healing applications.

Essential roles of insulin and IGF-1 receptors during embryonic lineage development.

The insulin and insulin-like growth factor-1 (IGF-1) receptors are important for the growth and development of embryonic tissues. To directly define their roles in the maintenance of pluripotency and differentiation of stem cells, we knocked out both receptors in induced pluripotent stem cells (iPSCs). iPSCs lacking both insulin and IGF-1 receptors (double knockout, DKO) exhibited preserved pluripotency potential despite decreased expression of transcription factors Lin28a and Tbx3 compared to control iPSCs. While embryoid body and teratoma assays revealed an intact ability of DKO iPSCs to form all three germ layers, the latter were composed of primitive neuroectodermal tumor-like cells in the DKO group. RNA-seq analyses of control vs DKO iPSCs revealed differential regulation of pluripotency, developmental, E2F1, and apoptosis pathways. Signaling analyses pointed to downregulation of the AKT/mTOR pathway and upregulation of the STAT3 pathway in DKO iPSCs in the basal state and following stimulation with insulin/IGF-1. Directed differentiation toward the three lineages was dysregulated in DKO iPSCs, with significant downregulation of key markers (Cebpα, Fas, Pparγ, and Fsp27) in adipocytes and transcription factors (Ngn3, Isl1, Pax6, and Neurod1) in pancreatic endocrine progenitors. Furthermore, differentiated pancreatic endocrine progenitor cells from DKO iPSCs showed increased apoptosis. We conclude that insulin and insulin-like growth factor-1 receptors are indispensable for normal lineage development and perturbations in the function and signaling of these receptors leads to upregulation of alternative compensatory pathways to maintain pluripotency.

An in situ collagen-HA hydrogel system promotes survival and preserves the proangiogenic secretion of hiPSC-derived vascular smooth muscle cells.

Human-induced pluripotent stem cell-derived vascular smooth muscle cells (hiPSC-VSMCs) with proangiogenic properties have huge therapeutic potential. While hiPSC-VSMCs have already been utilized for wound healing using a biomimetic collagen scaffold, an in situ forming hydrogel mimicking the native environment of skin offers the promise of hiPSC-VSMC mediated repair and regeneration. Herein, the impact of a collagen type-I-hyaluronic acid (HA) in situ hydrogel cross-linked using a polyethylene glycol-based cross-linker on hiPSC-VSMCs viability and proangiogenic paracrine secretion was investigated. Our study demonstrated increases in cell viability, maintenance of phenotype and proangiogenic growth factor secretion, and proangiogenic activity in response to the conditioned medium. The optimally cross-linked and functionalized collagen type-I/HA hydrogel system developed in this study shows promise as an in situ hiPSC-VSMC carrier system for wound regeneration.

A Dense Fibrillar Collagen Scaffold Differentially Modulates Secretory Function of iPSC-Derived Vascular Smooth Muscle Cells to Promote Wound Healing.

The application of human-induced pluripotent stem cells (hiPSCs) to generate vascular smooth muscle cells (hiPSC-VSMCs) in abundance is a promising strategy for vascular regeneration. While hiPSC-VSMCs have already been utilized for tissue-engineered vascular grafts and disease modeling, there is a lack of investigations exploring their therapeutic secretory factors. The objective of this manuscript was to understand how the biophysical property of a collagen-based scaffold dictates changes in the secretory function of hiPSC-VSMCs while developing hiPSC-VSMC-based therapy for durable regenerative wound healing. We investigated the effect of collagen fibrillar density (CFD) on hiPSC-VSMC's paracrine secretion and cytokines via the construction of varying density of collagen scaffolds. Our study demonstrated that CFD is a key scaffold property that modulates the secretory function of hiPSC-VSMCs. This study lays the foundation for developing collagen-based scaffold materials for the delivery of hiPSC-VSMCs to promote regenerative healing through guiding paracrine signaling pathways.