Polymer-Functionalized Mitochondrial Transplantation to Fibroblasts Counteracts a Pro-Fibrotic Phenotype.

Fibroblast-to-myofibroblast transition (FMT) leads to excessive extracellular matrix (ECM) deposition-a well-known hallmark of fibrotic disease. Transforming growth factor-ß (TGF-ß) is the primary cytokine driving FMT, and this phenotypic conversion is associated with mitochondrial dysfunction, notably a metabolic reprogramming towards enhanced glycolysis. The objective of this study was to examine whether the establishment of favorable metabolic phenotypes in TGF-ß-stimulated fibroblasts could attenuate FMT. The hypothesis was that mitochondrial replenishment of TGF-ß-stimulated fibroblasts would counteract a shift towards glycolytic metabolism, consequently offsetting pro-fibrotic processes. Isolated mitochondria, functionalized with a dextran and triphenylphosphonium (TPP) (Dex-TPP) polymer conjugate, were administered to fibroblasts (MRC-5 cells) stimulated with TGF-ß, and effects on bioenergetics and fibrotic programming were subsequently examined. Results demonstrate that TGF-ß stimulation of fibroblasts led to FMT, which was associated with enhanced glycolysis. Dex-TPP-coated mitochondria (Dex-TPP/Mt) delivery to TGF-ß-stimulated fibroblasts abrogated a metabolic shift towards glycolysis and led to a reduction in reactive oxygen species (ROS) generation. Importantly, TGF-ß-stimulated fibroblasts treated with Dex-TPP/Mt had lessened expression of FMT markers and ECM proteins, as well as reduced migration and proliferation. Findings highlight the potential of mitochondrial transfer, as well as other strategies involving functional reinforcement of mitochondria, as viable therapeutic modalities in fibrosis.

Prophylactic mesh augmentation after laparotomy for elective and emergency surgery: meta-analysis.

BACKGROUND: Incisional hernia is a common short- and long-term complication of laparotomy and can lead to significant morbidity. The aim of this systematic review and meta-analysis is to provide an up-to-date overview of the laparotomy closure method in elective and emergency settings with the prophylactic mesh augmentation technique. METHODS: The Scopus, PubMed, and Web of Science databases were screened without time restrictions up to 21 June 2022 using the keywords 'laparotomy closure', 'mesh', 'mesh positioning', and 'prophylactic mesh', and including medical subject headings terms. Only RCTs reporting the incidence of incisional hernia and other wound complications after elective or emergency midline laparotomy, where patients were treated with prophylactic mesh augmentation or without mesh positioning, were included. The primary endpoint was to explore the risk of incisional hernia at different follow-up time points. The secondary endpoint was the risk of wound complications. The risk of bias for individual studies was assessed according to the Revised Cochrane risk-of-bias tools for randomized trials. RESULTS: Eighteen RCTs, including 2659 patients, were retrieved. A reduction in the risk of incisional hernia at every time point was highlighted in the prophylactic mesh augmentation group (1 year, risk ratio 0.31, P = 0.0011; 2 years, risk ratio 0.44, P < 0.0001; 3 years, risk ratio 0.38, P = 0.0026; 4 years, risk ratio 0.38, P = 0.0257). An increased risk of wound complications was highlighted for patients undergoing mesh augmentation, although this was not significant. CONCLUSIONS: Midline laparotomy closure with prophylactic mesh augmentation can be considered safe and effective in reducing the incidence of incisional hernia. Further trials are needed to identify the ideal type of mesh and technique for mesh positioning, but surgeons should consider prophylactic mesh augmentation to decrease incisional hernia rate, especially in high-risk patients for fascial dehiscence and even in emergency settings. PROSPERO REGISTRATION ID: CRD42022336242 (https://www.crd.york.ac.uk/prospero/record_email.php).

Lipid nanoparticle-mediated mRNA delivery in lung fibrosis.

mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics. eGFP mRNA LNP transfection in human primary cells proved dose- and time-dependent in vitro. In a bleomycin mouse model of lung fibrosis, luciferase mRNA LNPs administered intratracheally led to site-specific lung accumulation. Importantly, bioluminescence signal was detected in lungs as early as 2 h after delivery, with signal still evident at 48 h. Of note, LNPs were found associated with AEC2 and fibroblasts in vivo. Findings highlight the potential for pulmonary delivery of mRNA in IPF, opening therapeutic avenues aimed at halting and potentially reversing disease progression.

Hiatal Surface Area's CT scan measurement is useful in hiatal hernia's treatment of bariatric patients.

INTRODUCTION: Hiatal surface area (HSA) measurement has been recently proposed as useful tool for tailored treatment of hiatal defects. Multidetector CT scan (MDCT) of the hiatal area was shown to be useful in hiatal hernia (HH) management. PURPOSE: MDCT preoperative HSA measurements validation as a useful method in the surgical repair decision making process of hiatal defects in candidates to antireflux ± bariatric surgery. MATERIAL AND METHODS: Twenty-five obese patients (group A), candidates to laparoscopic cruroplasty ± bariatric surgery, were prospectively evaluated preoperatively and after one year, using an original MDCT algorithm, compared with intraoperative HSA measurement. Twelve non-obese (group B) and 12 obese patients (group C), without GERD or HH, were used as control groups. RESULTS: Median preoperative HSA was 7.9 cm2, (interquartile IQR 5.97-9.80) while intraoperative median HSA was 6 cm2 (6-9.5), p = .84. Postoperative median HSA was 3.8 cm2 (3.21-4.8), showing the efficacy of cruroplasty, comparable with HSA calculated in the control groups (3.98 for B and 3.69 cm2 for C, p = .8547). No statistically significant difference between MDCT preoperative measurement and intraoperative findings was observed. CONCLUSIONS: Preliminary results demonstrate MDCT scan HSA measurements as a valid, non-invasive method to predict intraoperative findings. It allows the HSA monitoring in order to correlate the symptoms onset and failure of cruroplasty.

Active safety systems for powered two-wheelers: A systematic review.

Objective: Active safety systems, of which antilock braking is a prominent example, are going to play an important role to improve powered two-wheeler (PTW) safety. This paper presents a systematic review of the scientific literature on active safety for PTWs. The aim was to list all systems under development, identify knowledge gaps and recognize promising research areas that require further efforts.Methods: A broad search using "safety" as the main keyword was performed on Scopus, Web of Science and Google Scholar, followed by manual screening to identify eligible papers that underwent a full-text review. Finally, the selected papers were grouped by general technology type and analyzed via structured form to identify the following: specific active safety system, study type, outcome type, population/sample where applicable, and overall findings.Results: Of the 8,000 papers identified with the initial search, 85 were selected for full-text review and 62 were finally included in the study, of which 34 were journal papers. The general technology types identified included antilock braking system, autonomous emergency braking, collision avoidance, intersection support, intelligent transportation systems, curve warning, human machine interface systems, stability control, traction control, and vision assistance. Approximately one third of the studies considered the design and early stage testing of safety systems (n. 22); almost one fourth (n.15) included evaluations of system effectiveness.Conclusions: Our systematic review shows that a multiplicity of active safety systems for PTWs were examined in the scientific literature, but the levels of development are diverse. A few systems are currently available in the series production, whereas other systems are still at the level of early-stage prototypes. Safety benefit assessments were conducted for single systems, however, organized comparisons between systems that may inform the prioritization of future research are lacking. Another area of future analysis is on the combined effects of different safety systems, that may be capitalized for better performance and to maximize the safety impact of new technologies.

Reproducible and Characterized Method for Ponatinib Encapsulation into Biomimetic Lipid Nanoparticles as a Platform for Multi-Tyrosine Kinase-Targeted Therapy.

Ponatinib (Pon) is a multi-tyrosine kinase inhibitor that demonstrated high efficiency for treating cancer. However, severe side effects caused by Pon off-targeting effects prevent its extensive use. Using our understanding into the mechanisms by which Pon is transported by bovine serum albumin in the blood, we have successfully encapsulated Pon into a biomimetic nanoparticle (NP). This lipid NP (i.e., "leukosomes") incorporates membrane proteins purified from activated leukocytes that enable immune evasion, and enhanced targeting of inflamed endothelium NPs have been characterized for their size, charge, and encapsulation efficiency. Membrane proteins enriched on the NP surface enabled modulation of Pon release. These NP formulations showed promising dose-response results on two different murine osteosarcoma cell lines, F420 and RF379. Our results indicate that our fabrication method is reproducible, nonuser-dependent, efficient in loading Pon, and applicable toward repurposing numerous therapeutic agents previously shelved due to toxicity profiles.

A prospective evaluation on external jugular vein cut-down approach for TIVAD implantation.

BACKGROUND: Totally implantable venous access devices can be implanted both by percutaneous approaches and by surgical approaches with cephalic vein or external jugular vein cut-down techniques that are related to low intraoperative complication rates. The authors report a prospective evaluation of 83 consecutive external jugular vein cut-down approaches for totally implantable venous access devices implantation. METHODS: Eighty three consecutive patients (28 M, 55 F, mean age 54.2) suffering from solid tumors (58) or hematologic diseases (25) were consecutively submitted to totally implantable venous access devices insertion through external jugular vein cut-down approach (75 on right side, 8 on left side). RESULTS: All devices were surgically implanted; no instances of intraoperative complications were detected. After a minimum follow-up of 150 days, only one case of wound hematoma and one case of device malfunction due to incorrect catheter angulation were noted. Postoperative patient satisfaction was evaluated by the use of specific questionnaire that demonstrated a good satisfaction and compliance (92.8%) of patients with implanted devices. CONCLUSIONS: Despite the lack of controlled studies comparing external jugular vein cut-down approach vs other approaches, this approach should be considered as a tool for long-term central vein catheters positioning, both as an alternative and for primary approach.