miR-709 exerts an angiogenic effect through a FGF2 upregulation induced by a GSK3B downregulation.

The aim of this study was to identify angiogenic microRNAs (miRNAs) that could be used in the treatment of hindlimb ischemic tissues. miRNAs contained in extracellular vesicles (EVs) deriving from the plasma were analyzed in C57BL/6 mice, which have ischemia tolerance, and in BALB/c mice without ischemia tolerance as part of a hindlimb ischemia model; as a result 43 angiogenic miRNA candidates were identified. An aortic ring assay was employed by using femoral arteries isolated from BALC/c mice and EVs containing miRNA; as a result, the angiogenic miRNA candidates were limited to 14. The blood flow recovery was assessed after injecting EVs containing miRNA into BALB/c mice with hindlimb ischemia, and miR-709 was identified as a promising angiogenic miRNA. miR-709-encapsulating EVs were found to increase the expression levels of the fibroblast growth factor 2 (FGF2) mRNA in the thigh tissues of hindlimb ischemia model BALB/c mice. miR-709 was also found to bind to the 3'UTR of glycogen synthase kinase 3 beta (GSK3B) in three places. GSK3B-knockdown human artery-derived endothelial cells were found to express high levels of FGF2, and were characterized by increased cell proliferation. These findings indicate that miR-709 induces an upregulation of FGF2 through the downregulation of GSK3B.

LGBTQ Young Adults' Identity Disclosure in the Workplace: A Longitudinal Qualitative Analysis of Disclosure Intentions and Outcomes.

Research shows that LGBTQ workers make strategic decisions about whether to disclose their sexual and gender identities to their colleagues as they assess potential costs and benefits. The present study sought to extend this literature by examining how they plan their identity disclosure in future workplace interactions and why they may diverge from their initial intentions. The analysis used longitudinal data from in-depth interviews, in which young LGBTQ workers reported disclosure intentions and their outcomes two years later. Participants often expressed intentions to disclose their LGBTQ identities while emphasizing the importance of identity disclosure for self-authenticity and the LGBTQ community's visibility. Sometime over the course of the study, however, a substantial number of participants did not carry out their intentions because of unanticipated workplace constraints such as a lack of opportunities for personal conversations, an expectation for professionalism, and an absence of LGBTQ colleagues. However, participants who diverged from their initial disclosure intentions maintained an identity as an open LGBTQ person by emphasizing their willingness for disclosure.

Prognostic Implications and Efficacy of Catheter Ablation by Atrial Fibrillation Type.

Background Catheter ablation (CA) for atrial fibrillation (AF) is preferred for paroxysmal AF (PAF) but selectively performed in patients with persistent AF (PersAF). This study aimed to investigate the prognostic differences and consequences of CA based on the AF type. Methods and Results Data from a multicenter AF cohort study were analyzed, categorizing patients as PAF or PersAF according to AF duration (≤7 or >7 days, respectively). A composite of all-cause death, heart failure hospitalization, stroke, and bleeding events during 2-year follow-up and changes in the Atrial Fibrillation Effect on Quality-of-life score were compared. Additionally, propensity score matching was performed to compare clinical outcomes of patients with and without CA in both AF types. Among 2788 patients, 51.6% and 48.4% had PAF and PersAF, respectively. Patients with PersAF had a higher incidence of the composite outcome (12.8% versus 7.2%; P<0.001) and smaller improvements in Atrial Fibrillation Effect on Quality-of-life scores than those with PAF. After adjusting for baseline characteristics, PersAF was an independent predictor of adverse outcomes (adjusted hazard ratio, 1.35 [95% CI, 1.30-1.78], P=0.031) and was associated with poor improvements in Atrial Fibrillation Effect on Quality-of-life scores. Propensity score matching analysis showed that the CA group had significantly fewer adverse events than the medication group among patients with PAF (odds ratio, 0.31 [95% CI, 0.18-0.68]; P=0.002). Patients with PersAF showed a similar but nonsignificant trend. Conclusions PersAF is a risk factor for worse clinical outcomes, including patients' health status. CA is associated with fewer adverse events, although careful consideration is required based on the AF type.

Fibroblasts are the most suitable cell source for regenerative medicine due to their high intracellular fibroblast growth factor 2 content.

In our previous study, we found that dry-preserved multilayered fibroblast cell sheets promoted angiogenesis and wound healing in a mouse ulcer model by releasing high levels of intracellular fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF), from dried cells. In the present study, to identify which cell types are suitable for human dry-preserved cell sheets (dry sheets), we compared the intracellular FGF2 levels in seven types of cells reported as cell sheets for clinical use or preclinical studies. FGF2 levels were high in mesenchymal cells, including human oral fibroblasts (HOFs) and human dermal fibroblasts (HDFs), human dental pulp stem cells (DPSCs), and human mesenchymal stem cells (MSCs); in contrast, FGF2 levels in human umbilical vascular endothelial cells (HUVECs), human skeletal muscle myoblasts (SkMMs), and human epidermal keratinocytes (HEKs) were remarkably low, approximately 25% those in fibroblasts. In addition, we prepared dry sheets from HOFs, DPSCs, and MSCs, and analyzed the growth factors released from each dry sheet upon rehydration. High levels of FGF2, HGF, and VEGF were detected in the eluate prepared by immersing each dry sheet. In particular, FGF2 and HGF were the most abundant in HOFs. An in vitro cell proliferation assay showed that these eluates significantly enhanced HUVEC proliferation compared to control cells. Furthermore, cells incubated with HOF eluate showed significantly higher cell proliferation than cells incubated with DPSC and MSC eluates. However, this proliferative response was significantly blocked by FGF2-neutralizing antibodies. These results demonstrate that growth factors released from human dry sheets have physiological activity and that this activity is mainly mediated by the effect of FGF2. Fibroblasts are ideal for the clinical application of dry-preserved cell sheets in humans owing to their high intracellular FGF2 content, fast cell proliferation, ease of handling, availability, and low culture costs, making them the most suitable cell source for regenerative medicine, with FGF2 release as the mechanism of action.

Allogenic multilayered fibroblast sheets promote anastomotic site healing in a rat model of esophageal reconstruction.

OBJECTIVE: Anastomotic leakage is a common and severe complication of esophageal reconstruction. Accordingly, there is a clinical need for novel methods to prevent it. We developed multilayered, growth factor-secreting fibroblast sheets that promote wound healing and angiogenesis. The present study aimed to assess the utility of allogenic multilayered fibroblast sheets in preventing esophageal anastomotic leakage in a rat model of esophageal reconstruction. METHODS: Allogenic multilayered fibroblast sheets prepared from oral mucosal tissues were implanted at esophageal anastomotic sites. RESULTS: The allogenic multilayered fibroblast sheet group had significantly higher burst pressure and collagen deposition compared to a control group five days postoperatively. The expression levels of collagen type I and III mRNAs around esophageal suture sites were higher in the allogenic multilayered fibroblast sheet group compared to the control group on postoperative days 0, 3, and 5. There was a trend toward lower anastomotic leakage and lower abscess scores in the allogenic multilayered fibroblast sheet group compared to the control group; however, these differences did not reach statistical significance. Allogenic multilayered fibroblast sheets completely disappeared at ten days after implantation. Further, no inflammation was observed at suture sites with implanted allogenic multilayered fibroblast sheets at five days after surgery. CONCLUSION: Allogenic multilayered fibroblast sheets may represent a promising method of preventing esophageal anastomotic leakage.

Postoperative changes in a bronchial stump following covering with free fat tissue in a rat model.

OBJECTIVES: Covering the bronchial stump with free fat tissue has been used as minimally invasive prophylaxis against bronchial stump fistulas; however, postoperative changes in the bronchial stump have not been well validated. Our goal was to examine changes in the bronchial stump in response to covering with free fat tissue in a rat model. METHODS: A left pneumonectomy was performed on 16 Wistar/ST rats, 12 of which had a bronchial stump covered with free subcutaneous fat tissue. Four rats that underwent a left pneumonectomy alone were sacrificed on postoperative day 7, and the 12 rats whose bronchial stumps were additionally covered with fat tissue were sacrificed on postoperative days 7, 14 and 56. Macroscopic and histological changes and pressure resistance of the bronchial stumps due to coverage with free fat tissue were examined. RESULTS: None of the rats showed macroscopic infection or necrosis in the thoracic cavity at the time of the rethoracotomy. The normal bronchial stumps remained mostly exposed, whereas the bronchial stumps covered with fat tissue were well-coated with tissue mass. Histologically, fibrous connective tissue containing microvessels gradually formed around the bronchial stump covered with fat tissue, and some of the tissue masses still had normal fat structures 56 days postoperatively. Covering with fat tissue significantly increased the pressure resistance of the bronchial stump 7 days postoperatively and further increased with time. CONCLUSIONS: Covering the bronchial stump with free fat tissue formed fibrous connective tissue around the bronchial stump and reinforced its closure.

Sexuality Discourses and LGBQ Students' Interpretations of Campus Climate in the Contemporary US.

Recent US studies showed that perceptions of campus climate vary considerably across individual LGBQ students, with some students reporting friendly climates and others reporting persistent hostility. Although researchers have identified several factors that contribute to the perceptual variations, they have paid limited attention to the role of sexuality discourses. The present study sought to fill this gap in the literature by analyzing in-depth interviews. The analysis showed that LGBQ students drew on two major discourses to guide their interpretations of campus climate. A majority of students drew on post-closet discourse to celebrate their visibility on campus, LGBQ-friendly courses, and straight classmates' positive reactions. A smaller number of students drew on queer discourse to question the meaning of LGBQ students' visibility and criticize heterosexist biases in classrooms. Overall, these results highlighted the importance of the competing discourses, which set LGBQ students' expectations and guided their interpretations of campus experiences.

Rate versus rhythm control in patients with newly diagnosed atrial fibrillation: Effects of the treatment timing on health status outcomes.

BACKGROUND: Recent randomized clinical trials have demonstrated that applying rhythm control during the early stage of atrial fibrillation (AF) may lead to improved clinical outcomes. However, the effects of this modality on health-related quality of life (HRQoL) have not been fully investigated. We aimed to assess the association between the AF stage, determined by the time between AF diagnosis and referral to the cardiology clinic, and HRQoL outcomes. METHODS: Using an outpatients-based multicenter AF registry (n = 3,313), we analyzed 2,070 patients with AF diagnosed within 5 years. The patients were divided into 2 groups according to AF stage: early and late AF (AF duration ≤1 and >1 year, respectively). All patients had HRQoL information collected at baseline and 1 year after their initial treatment (assessed via the Atrial Fibrillation Effect on Quality-of-Life-overall summary [AFEQT-OS] score, with higher scores reflecting better HRQoL). The change in AFEQT-OS was adjusted for patient characteristics using a generalized linear mixed model. RESULTS: The early AF group (n = 1,644) was older (early, 68.5 ± 11.1, late, 64.4 ± 10.6 years, P < .001) and had more heart failure (early, 19.9%, late, 12.7%, P < .001) than the late AF group (n = 426). At 1 year after treatment, the adjusted changes in AFEQT-OS were similar in patients with rhythm (adjusted difference [SE], early, 8.4 [1.2], late, 7.2 [1.4], P = .15) or rate (early, 4.0 [0.7], late, 2.3 [1.4], P = .16) control, regardless of AF stage. Furthermore, the improvement in HRQoL was similar between early and late AF in patients undergoing catheter ablation (early, 10.2 [2.1], late, 9.8 [2.4], P = .78), whereas a significant difference was observed in those receiving antiarrhythmic drug therapy alone (early, 10.2 [1.4], late, 3.5 [2.2], P < .001). CONCLUSIONS: Rhythm control therapy provided clinically meaningful improvements in HRQoL, regardless of AF stage. For patients with impaired HRQoL, AF duration should not be a deterrent to treatment, especially catheter ablation.

Cryopreserved allogenic fibroblast sheets: development of a promising treatment for refractory skin ulcers.

The purpose of this study was to investigate the therapeutic effect of cryopreserved allogenic fibroblast cell sheets in a mouse model of skin ulcers. It is necessary to reduce the cost of regenerative medicine for it to be widely used. We consider that cell sheets could be applied to various diseases if cryopreservation of allogenic cell sheets was possible. In this study, fibroblasts were frozen using a three-dimensional freezer. Freeze-thawed fibroblasts had ~80% cell viability, secreted ≥ 50% vascular endothelial growth factor, hepatocyte growth factor, and stromal derived factor-1α compared with non-frozen fibroblast sheets, and secreted approximately the same amount of transforming growth factor-ß1. There was no difference in wound-healing rates in the skin ulcer model between non-frozen and freeze-thawed fibroblast sheets regardless of autologous and allogenic cells. The degree of angiogenesis was comparable between autologous and allogenic cells. The number of CD3-positive cells in healed tissues was larger for allogenic fibroblast sheets compared with autologous fibroblast sheets. However, histopathological images showed that the fibrosis, microvascular density, and healing phase of the wound in allogenic freeze-thawed fibroblast sheets were more similar to autologous freeze-thawed fibroblast sheets than to allogenic non-frozen fibroblast sheets. These results suggest that allogenic freeze-thawed fibroblast sheets may be a promising therapeutic option for refractory skin ulcers.

D-dimer for screening of aortic dissection in patients with ST-elevation myocardial infarction.

BACKGROUND: Acute aortic dissection (AAD) with concurrent ST-segment elevation myocardial infarction (STEMI) is relatively rare and sometimes overlooked. As D-dimer testing has been reported to have high sensitivity to diagnose AAD in a clinical scale, Aortic Dissection Detection Risk Score (ADD-RS), a point-of-care D-dimer analyzer capable of measuring in 10 min would be useful to deny AAD with concurrent STEMI. However, an optimal cut-off value of D-dimer in such population remains unclear. Therefore, the aim of this study was to elucidate the optimal D-dimer threshold in patients clinically diagnosed with STEMI. METHODS: This retrospective cohort study was conducted at two tertiary care centers between 2014 and 2019. Patients clinically diagnosed with STEMI who underwent serum D-dimer measurement on hospital arrival were included. The primary outcome was the diagnosis of AAD. The area under the receiver operating characteristic curve (AUROC) for D-dimer values to diagnose AAD was evaluated, particularly in patients with low to moderate risks of AAD (1 of ADD-RS). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with several cut-off values. RESULTS: A total of 322 patients were included, and 28 were diagnosed with AAD. The AUROC for D-dimer to diagnose AAD was 0.970 (95% confidence interval: 0.948-0.993) in 262 patients with 1 of ADD-RS. If D-dimer ≥750 ng/mL was used as a cut-off value, sensitivity, specificity, PPV and NPV were 100%, 86.4%, 37.7%, and 100%, respectively. AAD could be denied in 209 (79.8%) patients using the cut-off value (D-dimer <750 ng/mL). CONCLUSIONS: Serum D-dimer ≥750 ng/mL exhibited high sensitivity and NPV to diagnose AAD with concurrent STEMI, while the ADD-RS originally utilized ≥500 ng/mL as a cut-off for any suspected AAD. A point-of-care D-dimer measurement with the new cut-off would be useful to rule-out AAD among patients with STEMI.

Dry preserved multilayered fibroblast cell sheets are a new manageable tool for regenerative medicine to promote wound healing.

This study investigated the therapeutic effects of dry-preserved multi-layered fibroblast cell sheets (dry sheets) on cutaneous ulcers. Dry sheets were prepared by air-drying multi-layered fibroblast cell sheets (living sheets) to cease their life activities. Before in vivo application, we tested the release of growth factors into the medium to examine the mechanisms of dry sheets in wound healing. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were released from both dry and living sheets, while high levels of fibroblast growth factor-2 (FGF-2) and high mobility group box 1 (HMGB1) protein were only from dry sheets. An in vitro fibroblast proliferation assay revealed that the dry sheet eluate significantly enhanced cell proliferation and VEGF and HGF production compared with living sheet eluate. FGF-2-neutralizing antibodies significantly blocked this proliferative response. In wounds created on diabetic mice, the dry sheet-treatment groups using autologous or allogeneic cells showed significantly accelerated wound closure compared with that in the no-treatment group. The storage stability of the dry sheet was better at refrigeration temperature than at room temperature and remained stable for at least 4 weeks. Our data indicated that allogeneic dry sheets represent a promising new tool for regenerative medicine that promotes wound healing.

Autologous Multilayered Fibroblast Sheets Can Reinforce Bronchial Stump in a Rat Model.

Bronchopleural fistula is one of the most serious postoperative complications caused by the incomplete healing of a bronchial stump. Fibroblasts play an important role in wound healing by facilitating connective tissue formation and inducing angiogenesis. We developed a method for production of multilayered fibroblast sheets that secreted some growth factors and promoted wound healing. The present study aimed to assess the treatment effect of multilayered fibroblast sheets on bronchial stump healing. In this rat model, left pneumonectomy was performed, and multilayered fibroblast sheets derived from autologous oral mucosal tissues were transplanted to the bronchial stump. The changes in the bronchial stump were examined macroscopically, histologically, and mechanically. The fibroblast sheets promoted the formation of thick connective tissues around the bronchial stump. The formed connective tissues were accompanied by new blood vessels, and fibrosis was observed over time. Then, 7 days after the transplantation of the fibroblast sheets, the bronchial wall became significantly thicker, and the area of the blood vessels for the bronchial wall tissues was significantly larger in the experimental group than in the control group. In addition, the burst pressure in the bronchial stump was significantly higher in the experimental group than in the control group. Bronchial stumps were reinforced by the transplantation of multilayered fibroblast sheets derived from autologous oral mucosal tissues.

Freezing of cell sheets using a 3D freezer produces high cell viability after thawing.

In cell therapy, transplanting an appropriate number of cells to the target site is crucial. One way to achieve this is to transplant cell sheets. Transplantation of cell sheets has already been utilized for various diseases in clinical practice. However, reducing the cost of cell sheet utilization is essential so as to facilitate the spread of regenerative medicine. Several ways to reduce costs are available, one of which is the use of allogenic cells. Another alternative is the use of cell sheets, which necessitates the development of methods for freezing cell sheets. This is the first study to report the use of a 3D Freezer for freezing cells. 3D Freezers have been used in the field of food processing and technology for a long time. The 3D Freezer freezes objects using cold air at a uniform temperature from all directions. In this study, we analyzed the cooling speed of human fibroblast sheets in 11 cell preservation solutions using a 3D Freezer and a Program Freezer. The cooling speed was -2 °C per min in the 3D Freezer. Supercooling in 10 cell preservation solutions was lower in the 3D Freezer than in the Program Freezer. Cell viability after freeze-thaw of the cell sheets using 3D Freezer was more than 70% in five cell preservation solutions. The levels of hepatocyte growth factor and transforming growth factor-ß1 were the same not only in the fibroblast sheets frozen using the five cell preservation solutions but also in the non-frozen fibroblast sheets. These results suggest that the 3D Freezer can freeze implantable cell sheets immediately after thawing.

A pilot study using cell-mixed sheets of autologous fibroblast cells and peripheral blood mononuclear cells to treat refractory cutaneous ulcers.

BACKGROUND/AIMS: We invented a cell-mixed sheet consisting of autologous fibroblast cells and peripheral blood mononuclear cells (PBMNCs) to treat refractory cutaneous ulcers. These sheets secrete the growth factors needed throughout the wound healing process in animal models. METHODS: We performed this study as a pilot phase I clinical trial (UMIN-CTR: UMIN000031645). Fibroblast cells were isolated and cultured from the oral tissue, and PBMNCs were collected by apheresis. A cell-mixed sheet was prepared by co-culturing these collected cells for 3 days. The primary observation index was safety, including all adverse events. Additional observation indices were wound healing over 1, 3, and 6 months; wound healing rate at 7 days and 1, 3, and 6 months. RESULTS: Six patients with venous leg ulcers (VLUs) were enrolled in the study, including three patients who were treated with the cell-mixed sheet transplantation. One patient was excluded because no fibroblast cells grew from the oral tissue culture, and other two were excluded because the growth factor secreted from mixed-cell sheets did not reach the reference value. The VLUs of two patients who received the cell-mixed sheet transplantation healed, and the VLU in one patient decreased in size. CONCLUSIONS: This pilot study demonstrated that cell-mixed sheets might be a new topical intervention to treat VLUs. However, it was also suggested that this treatment might be limited when using autologous cells collected from patients with VLUs. Therefore, it may be necessary to use high-quality allogeneic cells instead of autologous cells to improve the feasibility of this treatment.

In-hospital Bleeding Outcomes of Oral Anticoagulant and Dual Antiplatelet Therapy During Percutaneous Coronary Intervention: An Analysis From the Japanese Nationwide Registry.

ABSTRACT: The type of periprocedural antithrombotic regimen that is the safest and most effective in percutaneous coronary intervention (PCI) patients on oral anticoagulant (OAC) therapy has not been fully investigated. We aimed to retrospectively investigate the in-hospital bleeding outcomes of patients receiving OAC and antiplatelet therapies during PCI using Japanese nationwide multicenter registry data. A total of 26,938 patients who underwent PCI with OAC and antiplatelet therapies between 2016 and 2017 were included. We investigated in-hospital bleeding requiring blood transfusion, mortality, and stent thrombosis according to the antithrombotic regimens used at the time of PCI: OAC + single antiplatelet therapy (double therapy) and OAC + dual antiplatelet therapy (triple therapy). The antiplatelet agents included aspirin, clopidogrel, and prasugrel. The OAC agents included warfarin and direct OACs. Adjusting the dose of OAC or intermitting OAC before PCI was at each operator's discretion. In the study population [mean age (SD), 73.5 (9.5) years; women, 21.5%], the double therapy and triple therapy groups comprised 5546 (20.6%) and 21,392 (79.4%) patients, respectively. Bleeding requiring transfusion was not significantly different between the groups [adjusted odds ratio (aOR), 0.700; 95% confidence interval (CI), 0.420-1.160; P = 0.165] (triple therapy as a reference). Mortality was not significantly different (aOR, 1.370; 95% CI, 0.790-2.360; P = 0.258). Stent thrombosis was significantly different between the groups (aOR, 3.310; 95% CI, 1.040-10.500; P = 0.042) (triple therapy as a reference). In conclusion, for patients on OAC therapy who underwent PCI, periprocedural triple therapy may be safe with respect to in-hospital bleeding risks. However, further investigations are warranted to establish the safety and efficacy of periprocedural triple therapy.

Novel bone microenvironment model of castration-resistant prostate cancer with chitosan fiber matrix and osteoblasts.

The interaction between prostate cancer cells and osteoblasts is essential for the development of bone metastasis. Previously, novel androgen receptor axis-targeted agents (ARATs) were approved for metastatic castration-naïve and non-metastatic castration-resistant prostate cancer (CRPC); both of which are pivotal for investigating the association between the bone microenvironment and tumors. The present study established a novel in vitro 3D microenvironment model that simulated the bone microenvironment of CRPC, and evaluated the drug susceptibility of ARATs and the efficacy of the combination of abiraterone and dutasteride. Green fluorescent protein-transferred C4-2 cells (a CRPC cell line) and red fluorescent protein-transferred human osteoblasts differentiated from human mesenchymal stem cells were co-cultured in chitosan nanofiber matrix-coated culture plates to simulate the 3D scaffold of the bone microenvironment. The growth of C4-2 was quantified using live-cell imaging and the Cell3 iMager duos analysis system. The growth of C4-2 colonies were quantified for a maximum of 30 days. The expression of TGF-ß increased and promoted EMT in C4-2 cells co-cultured with osteoblasts, indicating resistance to ARATs. The IC50 of each drug and the combination effect of abiraterone and dutasteride were evaluated using this model. Combination treatment with abiraterone and dutasteride synergistically inhibited the growth of C2-4 colonies compared with individual investigational agents. This could be attributed to the reduction of 3-keto-5α-abiraterone, an androgen receptor agonist. The bone microenvironment model of the present study is unique and useful for evaluating new drug susceptibility testing in prostate cancer cells. This model may help to reveal the unknown mechanisms underlying micro- to clinical bone metastasis in prostate cancer.

Autologous transplantation of multilayered fibroblast sheets prevents postoperative pancreatic fistula by regulating fibrosis and angiogenesis.

INTRODUCTION: Postoperative pancreatic fistula (POPF) is a serious complication after gastrointestinal or pancreatic surgery. Despite intensive investigations, the occurrence has not significantly decreased in the past decades. The aims of this study were to clarify the pathophysiology of POPF and establish the preventive measures using multilayered fibroblast sheets. METHODS: We developed a pancreatic fistula (PF) model of rat with transection of the splenic duct and surrounding pancreatic parenchyma. Multilayered fibroblast sheets prepared from tails were autologously transplanted to this model. The preventive effect was biochemically and histologically evaluated by measuring the ascitic levels of pancreatic enzymes and conducting immunohistochemistry and real-time polymerase chain reaction analyses of pancreatic tissue. Findings were compared to those obtained with acellular materials simply sealing the wound. RESULTS: In the PF model, the ascitic levels of pancreatic enzymes were transiently up-regulated. Inflammation and necrosis were histologically observed in a wide range. Islets were damaged even in remote areas. Transplantation of multilayered fibroblast sheets dramatically reduced the ascitic leakage of enzymes, suppressed inflammation, and broadly preserved the islets. Compared with acellular materials, these sheets offered superior prevention of cellular activity through the spaciotemporal regulation of fibrosis and angiogenesis. Notably, the leakage hole appeared to have been plugged with the fibrotic matrix, which might have been the most crucial mechanism minimizing pancreatic damage. CONCLUSIONS: The autologous transplantation of multilayered fibroblast sheets significantly prevented PF and protected the pancreas, underscoring the potential utility of this approach for POPF prevention.

Association of decreasing hemoglobin levels with the incidence of acute kidney injury after percutaneous coronary intervention: a prospective multi-center study.

Acute kidney injury (AKI) is common in patients undergoing percutaneous coronary intervention (PCI). One risk factor for AKI is periprocedural hemoglobin drop level (> 3 g/dL); however, whether the relationship between hemoglobin drop and AKI is linear or nonlinear remains unknown. We aimed to investigate the relationship between periprocedural hemoglobin drop and AKI after PCI. We evaluated 14,273 consecutive patients undergoing PCI between September 2008 and March 2019. AKI was defined as an absolute or a relative increase in serum creatinine level of 0.3 mg/dL or 50%, respectively. Restricted cubic spline was constructed to assess the association between hemoglobin drop and AKI by logistic regression and machine learning (ML) models, which were used to predict the risk of AKI. The patients' mean age was 68.4 ± 11.6 years; the AKI incidence was 10.5% (N = 1499). An absolute > 3 g/dL or 20% relative decrease in hemoglobin level was an independent predictor of AKI incidence (odds ratio, OR [95% confidence interval, CI]: 2.24 [1.92-2.61], P < 0.001; 2.35 [2.04-2.71], P < 0.001, respectively). An adjusted restricted cubic spline demonstrated that absolute/relative decrease in hemoglobin was linearly associated with AKI. Logistic and ML models with absolute/relative hemoglobin changes were comparable while estimating the risk of AKI (absolute area under the curve [AUC] (logistic):0.826, AUC (ML): 0.820; relative AUC (logistic): 0.818, AUC (ML): 0.816). An absolute/relative decrease in periprocedural hemoglobin after PCI was linearly associated with AKI. Detection of a relative/absolute decrease in hemoglobin may help clinicians identify individuals as high risk for AKI after PCI.

Independent and cumulative association of clinical and morphological heart failure with long-term outcome after percutaneous coronary intervention.

BACKGROUND: Heart failure (HF) is a risk factor for adverse post-procedural outcome after revascularization; however, it is unclear how left ventricular systolic dysfunction (LVSD) and clinical HF symptoms affect percutaneous coronary intervention (PCI) outcomes. We investigated the characteristics and long-term outcomes of patients with clinical HF or LVSD after PCI. METHODS: This was a Japanese multicenter registry study of adult patients receiving PCI. Among 4689 consecutive patients who underwent PCI at 15 hospitals from January 2009 to December 2012, we analyzed 2634 (56.2%) with documented left ventricular ejection fraction (LVEF). They were divided into four groups based on clinical HF (symptoms or HF hospitalization) and LVEF [≥35% and <35% (HF due to LVSD)]. The primary outcome was major adverse cardiovascular events (MACE), comprising all-cause death, acute coronary syndrome, HF hospitalization, performance of coronary artery bypass grafting, and stroke within 2 years after the initial PCI. RESULTS: Our findings revealed 354 patients (13.4%) with HF (clinical HF, n = 173, 48.9%; LVSD, n = 132, 37.3%; both, n = 49; 13.8%). The incidence of MACE was higher in patients with clinical HF or LVSD, and was largely due to higher non-cardiac death and HF hospitalization. After adjustment, clinical HF (hazard ratio 2.16, 95% confidence interval; 1.49-3.14) and lower LVEF (per 10%, hazard ratio 0.89, 95% confidence interval; 0.81-0.99) were independently associated with higher MACE risk. CONCLUSIONS: Clinical HF and LVSD were independently associated with adverse long-term clinical outcomes, particularly with non-cardiac death and HF readmission, in patients treated with PCI.