US FDA Patient Decision Checklist for Breast Implants: Results of a Survey to Members of The Aesthetic Society, April 2022.

The US Food and Drug Administration (FDA), in response to concerns that patients undergoing breast implant surgery were not adequately informed about the risks of receiving an implanted medical device, mandated a Patient Decision Checklist (PDC) in October 2021. Breast implant manufactures communicated with plastic surgeons in 2022 regarding the use of the PDC as a condition for the sale of breast implants. Plastic surgeons voiced concerns over the accuracy of the content in the PDC and its confusing statements about the risk of adverse events associated with breast surgery. In April 2022, The Aesthetic Society developed a survey that was sent to its members regarding their experiences with the PDC. This was a 5-question survey, with 1 additional place for comments. The purpose of this survey was to develop data based on the 6-month experience of plastic surgeons with the PDC. A total of 206 Aesthetic Society members (9%) participated in the survey (1849 total active members in the United States). Patients deserve appropriate information prior to breast implant surgery to make an informed decision after reviewing the potential risks and benefits. The authors believe that there is still more work to be done to create an ideal PDC that is fair and balanced, scientifically describes risk incidence in a way that patients understand, and can be updated.

Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogen Citrobacter rodentium.

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.

Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma.

Fibrolamellar carcinoma (FLC) is characterized by in-frame fusion of DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) with protein kinase cAMP-activated catalytic subunit α (PRKACA) and by dense desmoplasia. Surgery is the only effective treatment because mechanisms supporting tumor survival are unknown. We used single-cell RNA sequencing to characterize a patient-derived FLC xenograft model and identify therapeutic targets. Human FLC cells segregated into four discrete clusters that all expressed the oncogene Yes-associated protein 1 (YAP1). The two communities most enriched with cells coexpressing FLC markers [CD68, A-kinase anchoring protein 12 (AKAP12), cytokeratin 7, epithelial cell adhesion molecule (EPCAM), and carbamoyl palmitate synthase-1] also had the most cells expressing YAP1 and its proproliferative target genes (AREG and CCND1), suggesting these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, indicating these were fibrogenic FLC cells. All clusters expressed the YAP1 target gene and mesothelial progenitor marker mesothelin, and many mesothelin-positive cells coexpressed albumin. Trajectory analysis predicted that the four FLC communities were derived from a single cell type transitioning among phenotypic states. After establishing a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, YAP1 was inhibited, which significantly reduced expression of known YAP1 target genes as well as cell growth and migration. Thus, both FLC epithelial and stromal cells appear to arise from DNAJB1-PRKACA fusion in a YAP1-dependent liver mesothelial progenitor, identifying YAP1 as a target for FLC therapy.

In Vitro Evaluation of Common Antimicrobial Solutions Used for Breast Implant Soaking and Breast Pocket Irrigation-Part 2: Efficacy Against Biofilm-Associated Bacteria.

BACKGROUND: Biofilm-associated bacteria have been observed in both breast implant revision and tissue expander-implant exchange surgeries. The utilization of antimicrobial solutions in breast surgery, especially those containing triple antibiotics (TAB) and/or 10% povidone-iodine (PI), may help reduce existing biofilm-associated bacteria, which is particularly important in a mature breast pocket that may contain residual bacteria from a previously colonized implant surface or, theoretically, bacteria that may arrive postoperatively through hematogenous spread. OBJECTIVES: A series of in vitro assessments was performed to evaluate the antimicrobial utility of TAB and PI, either alone or in combination, against preformed biofilm-associated bacteria. METHODS: Preformed biofilm-associated gram-positive and gram-negative bacterial strains were exposed to TAB and PI ± TAB for up to 30 minutes in a bacterial time-kill assay. Efficacy of various dilutions of PI and the effects of serum protein on PI efficacy were also investigated. RESULTS: TAB was ineffective at the timeframes tested when utilized alone; when utilized in conjunction with PI, significant log reduction of all biofilm-associated bacterial species tested was achieved when treated for at least 5 minutes. PI alone at a concentration of 25% or higher was also effective, although its efficacy was negatively affected by increasing serum protein concentration only for Staphylococcus epidermidis. CONCLUSIONS: Our data indicate that PI-containing solutions significantly reduce biofilm-associated bacteria, suggesting potential utility for breast pocket irrigation during revision or exchange surgeries. Care should be taken to minimize excessive dilution of PI to maintain efficacy.

In Vitro Evaluation of Common Antimicrobial Solutions Used for Breast Implant Soaking and Breast Pocket Irrigation-Part 1: Efficacy Against Planktonic Bacteria.

BACKGROUND: Planktonic bacteria can be inadvertently introduced during breast surgery procedures, which are hypothesized to lead to complications such as infection, capsular contracture, breast implant-associated anaplastic large cell lymphoma, and a prolonged local inflammatory response. The utilization of antimicrobial solutions such as triple antibiotic solution (TAB) and/or 10% povidone-iodine (PI) in breast pocket irrigation or implant soaking has been proposed to reduce planktonic bacterial attachment and potential complications. OBJECTIVES: A series of in vitro assessments were performed to evaluate the antimicrobial utility of TAB and PI, either alone or in combination, against planktonic bacteria. METHODS: Planktonic gram-positive and gram-negative bacterial strains were exposed to TAB and PI ± TAB for up to 10 minutes in a bacterial time-kill assay. The efficacy of various dilutions of PI as well as the effects of serum protein on PI efficacy were also investigated. RESULTS: TAB was ineffective at the timeframes tested (≤10 minutes) when utilized alone; however, when utilized with PI, significant log reduction of all tested planktonic species was achieved. PI alone was also effective, even including dilute concentrations (eg, 0.5% PI), although the presence of serum proteins required higher concentrations of PI (eg, 2.5%) to eradicate the bacterial load. CONCLUSIONS: Our data suggest PI-containing solutions may be preferred over either saline or TAB without PI for primary breast pocket irrigation and implant soaking in primary breast surgeries as a means to significantly reduce planktonic bacteria. These data provide an impetus for surgeons to re-evaluate the efficacy of TAB solution in these clinical settings.

Lactation Outcomes in More Than 3500 Women Following Primary Augmentation: 5-Year Data From the Breast Implant Follow-Up Study.

BACKGROUND: Women with breast implants may have concerns about their ability to successfully breast-feed. The Breast Implant Follow-up Study (BIFS-001) is a large, 10-year observational study evaluating the performance and safety of Natrelle round silicone gel-filled breast implants. OBJECTIVES: This analysis compared lactation outcomes in women enrolled in BIFS-001 who gave birth after they underwent primary augmentation with Natrelle round silicone implants or saline implants. METHODS: At baseline and annually after surgery (>5-year visit window), patients completed questionnaires regarding pregnancy and lactation. Comparisons were made using summary statistics and odds ratios with 90% confidence intervals (OR [90% CI]). RESULTS: A total of 4679 subjects gave birth at least once after primary augmentation for a total of 5736 live births during the study (silicone, 3695 births; saline, 2041 births). Of these, 3715 (79.4%) women breast-fed at least 1 child, resulting in 80.0% (silicone) and 75.9% (saline) of babies being breast-fed. The most common complication was insufficient milk production, which was reported for 19.6% (silicone) and 19.8% (saline) of single births (OR, 0.94 [0.83, 1.06]). Complications occurred at similar rates in each group when evaluated by incision type, implant size, pocket location, and age. CONCLUSIONS: In this large group of women who gave birth after primary breast augmentation with Natrelle round silicone implants or saline implants, most were able to breast-feed their infants without complications. Lactation complications were comparable between the silicone and saline cohorts, and the incidence was comparable to reports in the general population of women who breast-feed.

Physical Properties of Silicone Gel Breast Implants.

BACKGROUND: Surgical applications using breast implants are individualized operations to fill and shape the breast. Physical properties beyond shape, size, and surface texture are important considerations during implant selection. OBJECTIVES: Compare form stability, gel material properties, and shell thickness of textured shaped, textured round, and smooth round breast implants from 4 manufacturers: Allergan, Mentor, Sientra, and Establishment Labs, through bench testing. METHODS: Using a mandrel height gauge, form stability was measured by retention of dimensions on device movement from a horizontal to vertical supported orientation. Dynamic response of the gel material (gel cohesivity, resistance to gel deformation, energy absorption) was measured using a synchronized target laser following application of graded negative pressure. Shell thickness was measured using digital thickness gauge calipers. RESULTS: Form stability, gel material properties, and shell thickness differed across breast implants. Of textured shaped devices, Allergan Natrelle 410 exhibited greater form stability than Mentor MemoryShape and Sientra Shaped implants. Allergan Inspira round implants containing TruForm 3 gel had greater form stability, higher gel cohesivity, greater resistance to gel deformation, and lower energy absorption than those containing TruForm 2 gel and in turn, implants containing TruForm 1 gel. Shell thickness was greater for textured vs smooth devices, and differed across styles. CONCLUSIONS: Gel cohesivity, resistance to gel deformation, and energy absorption are directly related to form stability, which in turn determines shape retention. These characteristics provide information to aid surgeons choosing an implant based on surgical application, patient tissue characteristics, and desired outcome.

Liver regeneration requires Yap1-TGFß-dependent epithelial-mesenchymal transition in hepatocytes.

BACKGROUND & AIMS: Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFß, since TGFß signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. METHODS: Wild-type mice underwent 70% partial hepatectomy (PH); TGFß expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72 h after PH. To determine the role of Yap1 in regulating TGFß signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice. RESULTS: TGFß expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1α1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation. CONCLUSION: Interactions between the TGFß and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFß-enriched microenvironment and regenerate injured livers. LAY SUMMARY: The adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.

Betadine and Breast Implants.

In the fourth quarter of 2017, the US FDA reviewed and approved a request by one of the breast implant manufacturers for a change in the Directions for Use (DFU) that removed warnings regarding the use of Betadine (povidone-iodine [PI] 10% solution, 1% available iodine [Purdue Frederick Company, Stamford, CT], also available in generic formulations [Aplicare, Inc., Meriden, CT]). Previously, in 2000, there were concerns by the FDA that PI would degrade the silicone elastomer shell. This change in the DFU represents an important advance that will benefit patients through the permitted use of PI to reduce the risk of bacterial contamination of implant surfaces. What was formerly an off-label practice can be openly practiced by plastic surgeons as an anti-infective and biofilm-mitigation strategy. PI has an ideal spectrum effect for gram-positive and gram-negative organisms. Gram-positive organisms have been linked to capsular contracture and gram-negative Ralstonia picketti to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). R picketti is resistant to aminoglycoside antibiotics, but it is susceptible to at least a 50% solution of PI. We believe that the strategy of antisepsis and biofilm mitigation is an integral part of a contemporary approach for breast augmentation. This is beneficial regarding reduction of the risk of surgical infection, capsular contracture, and BIA-ALCL. Outcome data so far indicate that antibiotics/anti-infectives seem to reduce the incidence of these adverse events that lead to reoperation and increased costs. It behooves plastic surgeons to take all actionable steps that enhance the quality of breast implant outcomes and reduce the rate of reoperation.

Loss of pericyte smoothened activity in mice with genetic deficiency of leptin.

BACKGROUND: Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation. RESULTS: We found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage. CONCLUSIONS: Leptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage.

Hedgehog regulates yes-associated protein 1 in regenerating mouse liver.

UNLABELLED: Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1- and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up-regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. CONCLUSIONS: Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post-PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. (Hepatology 2016;64:232-244).

Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. OBJECTIVES: We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. METHODS: CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. RESULTS: Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were increased in mice with NASH. Decreased hepatic free CoA content was associated with increased caspase-2 activity and correlated with worse liver cell apoptosis, inflammation, and fibrosis. Treatment with pantothenate and N-acetylcysteine did not inhibit caspase-2 activation, improve NASH, normalize PANK expression, or restore free CoA levels in MCD diet-fed mice. CONCLUSION: In mice with NASH, hepatic CoA metabolism is impaired, leading to decreased free CoA content, activation of caspase-2, and increased liver cell apoptosis. Dietary supplementation with CoA precursors did not restore CoA levels or improve NASH, suggesting that alternative approaches are necessary to normalize free CoA during NASH.