Thyroid hormone treatment counteracts cellular phenotypical remodeling in diabetic organs.

Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract the cellular remodeling that occurs in diabetic cardiomyocytes, podocytes, and pancreatic beta cells. Treating diabetic rats with T3 prevents dedifferentiation, pathological growth, and ultrastructural alterations in podocytes and cardiomyocytes. In vitro, T3 reverses glucose-induced growth in human podocytes and cardiomyocytes, restores cardiomyocyte cytoarchitecture, and reverses pathological alterations in kidney and cardiac organoids. Finally, T3 treatment counteracts glucose-induced transdifferentiation, cell growth, and loss in pancreatic beta cells through TH receptor alpha1 activation. Our studies indicate that TH signaling activation substantially counteracts diabetes-induced pathological remodeling, and provide a potential therapeutic approach for the treatment of diabetes and its complications.

Early versus late tracheostomy for traumatic brain injury: a systematic review and meta-analysis.

INTRODUCTION: Tracheostomy is the most frequent bedside surgical procedure performed on patients with traumatic brain injury who require mechanical ventilation. To compare the effects of early tracheostomy vs. late tracheostomy on the duration of mechanical ventilation in patients with traumatic brain injury, we carried out a systematic review and meta-analysis. EVIDENCE ACQUISITION: MEDLINE, Scopus, Web of Science, and Cochrane were searched from inception to 17th October 2022. Eligible clinical trials and observational studies reporting early versus late tracheostomy in TBI were searched. Two reviewers extracted data and independently assessed the risk of bias. The duration of mechanical ventilation was the primary outcome. EVIDENCE SYNTHESIS: We pooled standardized mean differences and risk differences for random effects model. A total of 368 studies were retrieved and screened. Nineteen studies were selected, including 6253 patients. Mean time for early tracheostomy and late tracheostomy procedures was 6±2.9 days and 17±10.7 days, respectively. Early tracheostomy was associated with shorter mechanical ventilation duration (SMD=-1.79, 95% CI -2.71; -0.88) and fewer ventilator associated pneumonia (RD=-0.11, 95% CI -0.16; -0.06) when compared with late tracheostomy. Moreover, intensive care unit (ICU) (SMD=-1.64, 95% CI -2.44; -0.84) and hospital (SMD=-1.26, 95% CI -1.97; -0.56) length of stay were shorter when compared with late tracheostomy. CONCLUSIONS: The findings from this meta-analysis suggest that early tracheostomy in severe TBI patients contributes to a lower exposure to secondary insults and nosocomial adverse events, increasing the opportunity of patient's early rehabilitation and discharge.

Regional Cerebral Oxygen Saturation to Predict Favorable Outcome in Extracorporeal Cardiopulmonary Resuscitation: A Systematic Review and Meta-Analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to investigate the role of regional cerebral oxygen saturation (rSO2) in predicting survival and neurologic outcomes after extracorporeal cardiopulmonary resuscitation (ECPR). DESIGN: The study authors performed a systematic review and meta-analysis of all available literature. SETTING: The authors searched relevant databases (Pubmed, Medline, Embase) for studies measuring precannulation rSO2 in patients undergoing ECPR and reporting mortality and/or neurologic outcomes. PARTICIPANTS: The authors included both in-hospital and out-of-hospital cardiac arrest patients receiving ECPR. They identified 3 observational studies, including 245 adult patients. INTERVENTIONS: The authors compared patients with a low precannulation rSO2 (≤15% or 16%) versus patients with a high (>15% or 16%) precannulation rSO2. In addition, the authors carried out subgroup analyses on out-of-hospital cardiac arrest (OHCA) patients. MEASUREMENTS AND MAIN RESULTS: A high precannulation rSO2 was associated with an overall reduced risk of mortality in ECPR recipients (98 out of 151 patients [64.9%] in the high rSO2 group, v 87 out of 94 patients [92.5%] in the low rSO2 group, risk differences [RD] -0.30; 95% CI -0.47 to -0.14), and in OHCA (78 out of 121 patients [64.5%] v 82 out of 89 patients [92.1%], RD 0.30; 95% CI -0.48 to -0.12). A high precannulation rSO2 also was associated with a significantly better neurologic outcome in the overall population (42 out of 151 patients [27.8%] v 2 out of 94 patients [2.12%], RD 0.22; 95% CI 0.13-0.31), and in OHCA patients (33 out of 121 patients [27.3%] v 2 out of 89 patients [2.25%] RD 0.21; 95% CI 0.11-0.30). CONCLUSIONS: A low rSO2 before starting ECPR could be a predictor of mortality and survival with poor neurologic outcomes.

Hybrid fibroin/polyurethane small-diameter vascular grafts: from fabrication toin vivopreliminary assessment.

To address the need of alternatives to autologous vessels for small-calibre vascular applications (e.g. cardiac surgery), a bio-hybrid semi-degradable material composed of silk fibroin (SF) and polyurethane (Silkothane®) was herein used to fabricate very small-calibre grafts (Øin= 1.5 mm) via electrospinning. Bio-hybrid grafts werein vitrocharacterized in terms of morphology and mechanical behaviour, and compared to similar grafts of pure SF. Similarly, two native vessels from a rodent model (abdominal aorta and vena cava) were harvested and characterized. Preliminary implants were performed on Lewis rats to confirm the suitability of Silkothane® grafts for small-calibre applications, specifically as aortic insertion and femoral shunt. The manufacturing process generated pliable grafts consisting of a randomized fibrous mesh and exhibiting similar geometrical features to rat aortas. Both Silkothane® and pure SF grafts showed radial compliances in the range from 1.37 ± 0.86 to 1.88 ± 1.01% 10-2mmHg-1, lower than that of native vessels. The Silkothane® small-calibre devices were also implanted in rats demonstrating to be adequate for vascular applications; all the treated rats survived the surgery for three months after implantation, and 16 rats out of 17 (94%) still showed blood flow inside the graft at sacrifice. The obtained results lay the basis for a deeper investigation of the interaction between the Silkothane® graft and the implant site, which may deal with further analysis on the potentialities in terms of degradability and tissue formation, on longer time-points.

Automatic cyst and kidney segmentation in autosomal dominant polycystic kidney disease: Comparison of U-Net based methods.

Autosomal Dominant Polycystic Kidney Disease is a genetic disease that causes uncontrolled growth of fluid-filled cysts in the kidney. Kidney enlargement resulting from the expansion of cysts is continuous and often associated with decreased renal function and kidney failure. Mouse and rat models are necessary to discover new drugs able to halt the progression of the disease. The analysis of the effects of pharmacological interventions in these models is based on renal morphology and quantification of changes in total renal volume and cyst volume. This requires a proper, reproducible and fast segmentation of the kidney images. We propose a set of fully convolutional networks for kidney and cyst segmentation in micro-CT images, based on the U-Net architecture, to compare them and analyze which ones perform better on contrast-enhanced micro-CT images from normal rats and rats with Autosomal Dominant Polycystic Kidney Disease. Networks have been tested on a series images, and the performance has been evaluated in terms of Intersection over Union and Dice coefficients. Results showed that the best performing networks are the U-Net in which a batch normalization layer is applied after each pair of 3 × 3 convolutions, and the U-Net in which convolutional layers are replaced by inception blocks. Results also showed accurate cyst-to-kidney volume ratios obtained from the segmented images, which is one of main metrics of interest. Finally, segmentation performance has been found to be stable as the images in the training set vary. Therefore, the proposed automatic methodology is suitable and immediately applicable to segment cysts and kidney from micro-CT images, and directly provides the cyst-to-kidney volume ratio.

Vancomycin-nanofunctionalized peptide-enriched silk fibroin to prevent methicillin-resistant Staphylococcus epidermidis-induced femoral nonunions in rats.

Introduction: Implant-related infections and infected fractures are significant burdens in orthopedics. Staphylococcus epidermidis is one of the main causes of bone infections related to biofilm formation upon implants. Current antibiotic prophylaxis/therapy is often inadequate to prevent biofilm formation and results in antibiotic resistance. The development of bioactive materials combining antimicrobial and osteoconductive properties offers great potential for the eradication of microorganisms and for the enhancement of bone deposition in the presence of infections. The purpose of this study is to prevent the development of methicillin-resistant S. epidermidis (MRSE)-infected nonunion in a rat model. Methods: To this end, a recently developed in our laboratories bioactive material consisting of antibiotic-loaded nanoparticles based on carboxylic acid functionalized hyperbranched aliphatic polyester (CHAP) that are integrated into peptide-enriched silk fibroin sponges with osteoconductive properties (AFN-PSF) was employed, whose biocompatibility and microbiological tests provided proof of its potential for the treatment of both orthopedic and dental infections. In particular, non-critical femoral fractures fixed with plates and screws were performed in Wistar rats, which were then randomly divided into three groups: 1) the sham control (no infection, no treatment); 2) the control group, infected with MRSE and treated with peptide-enriched silk fibroin sponges incorporating non-drug-loaded functionalized nanoparticles (PSF); 3) the treated group, infected with MRSE and treated with peptide-enriched silk fibroin sponges incorporating vancomycin-loaded functionalized nanoparticles (AFN-PSF). After 8 weeks, bone healing and osteomyelitis were clinically assessed and evaluated by micro-CT, microbiological and histological analyses. Results: The sham group showed no signs of infection and complete bone healing. The PSF group failed to repair the infected fracture, displaying 75% of altered bone healing and severe signs of osteomyelitis. The AFN-PSF treated group reached 70% of fracture healing in the absence of signs of osteomyelitis, such as abscesses in the cortical and intraosseous compartments and bone necrosis with sequestra. Discussion: AFN-PSF sponges have proven effective in preventing the development of infected nonunion in vivo. The proposed nanotechnology for local administration of antibiotics can have a significant impact on patient health in the case of orthopedic infections.

Post-translational modifications by SIRT3 de-2-hydroxyisobutyrylase activity regulate glycolysis and enable nephrogenesis.

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have emerged as possible regulators that link epigenetic processes to the metabolism. Here, we discovered a novel role for the NAD+-dependent deacylase SIRT3 in kidney development. In the embryonic kidney, SIRT3 was highly expressed only as a short isoform, with nuclear and extra-nuclear localisation. The nuclear SIRT3 did not act as deacetylase but exerted de-2-hydroxyisobutyrylase activity on lysine residues of histone proteins. Extra-nuclear SIRT3 regulated lysine 2-hydroxyisobutyrylation (Khib) levels of phosphofructokinase (PFK) and Sirt3 deficiency increased PFK Khib levels, inducing a glycolysis boost. This altered Khib landscape in Sirt3-/- metanephroi was associated with decreased nephron progenitors, impaired nephrogenesis and a reduced number of nephrons. These data describe an unprecedented role of SIRT3 in controlling early renal development through the regulation of epigenetics and metabolic processes.

Tumor vascular remodeling by thrombospondin-1 enhances drug delivery and antineoplastic activity.

The disorganized and inefficient tumor vasculature is a major obstacle to the delivery and efficacy of antineoplastic treatments. Antiangiogenic agents can normalize the tumor vessels, improving vessel function and boosting the distribution and activity of chemotherapy. The type III repeats (T3R) domain of thrombospondin-1 contains different potential antiangiogenic sequences. We therefore hypothesized that it might affect the tumor vasculature. Ectopic expression of the T3R domain by the tumor cells or by the host, or administration of recombinant T3R, delayed the in vivo growth of experimental tumors. Tumors presented marked reorganization of the vasculature, with abundant but smaller vessels, associated with substantially less necrosis. Mechanistically, the use of truncated forms of the domain, containing different active sequences, pointed to the FGF2/FGFR/ERK axis as a target for T3R activity. Along with reduced necrosis, the expression of T3R promoted tumor distribution of chemotherapy (paclitaxel), with a higher drug concentration and more homogeneous distribution, as assessed by HPLC and MALDI imaging mass spectrometry. T3R-expressing tumors were more responsive to paclitaxel and cisplatin. This study shows that together with its known role as a canonical inhibitor of angiogenesis, thrombospondin-1 can also remodel tumor blood vessels, affecting the morphological and functional properties of the tumor vasculature. The ability of T3R to reduce tumor growth and improve the response to chemotherapy opens new perspectives for therapeutic strategies based on T3R to be used in combination therapies.

Rapid reorganization of the Milan metropolitan public safety answering point operations during the initial phase of the COVID-19 outbreak in Italy.

Objective: To quantify how the first public announcement of confirmed coronavirus disease 2019 (COVID-19) in Italy affected a metropolitan region's emergency medical services (EMS) call volume and how rapid introduction of alternative procedures at the public safety answering point (PSAP) managed system resources. Methods: PSAP processes were modified over several days including (1) referral of non-ill callers to public health information call centers; (2) algorithms for detection, isolation, or hospitalization of suspected COVID-19 patients; and (3) specialized medical teams sent to the PSAP for triage and case management, including ambulance dispatches or alternative dispositions. Call volumes, ambulance dispatches, and response intervals for the 2 weeks after announcement were compared to 2017-2019 data and the week before. Results: For 2 weeks following outbreak announcement, the primary-level PSAP (police/fire/EMS) averaged 56% more daily calls compared to prior years and recorded 9281 (106% increase) on Day 4, averaging ∼400/hour. The secondary-level (EMS) PSAP recorded an analogous 63% increase with 3863 calls (∼161/hour; 264% increase) on Day 3. The COVID-19 response team processed the more complex cases (n = 5361), averaging 432 ± 110 daily (∼one-fifth of EMS calls). Although community COVID-19 cases increased exponentially, ambulance response intervals and dispatches (averaging 1120 ± 46 daily) were successfully contained, particularly compared with the week before (1174 ± 40; P = 0.02). Conclusion: With sudden escalating EMS call volumes, rapid reorganization of dispatch operations using tailored algorithms and specially assigned personnel can protect EMS system resources by optimizing patient dispositions, controlling ambulance allocations and mitigating hospital impact. Prudent population-based disaster planning should strongly consider pre-establishing similar highly coordinated medical taskforce contingencies.

Copper-dependent biological effects of particulate matter produced by brake systems on lung alveolar cells.

Road traffic is one of the main sources of particulate emissions into the environment and has an increasing, negative impact on the release of potentially dangerous materials. Vehicle brakes release a significant amount of wear particles, and knowledge regarding their possible adverse effects is limited. One of the most dangerous elements contained in brake pads is copper (Cu), known to be toxic for human health. Therefore, our aim was to study the cell toxicity of particulate matter (PM) produced by different combinations of braking discs and pads containing different amounts of Cu. We investigated whether brake-derived microparticles have toxic effects on lung cells proportionally to their Cu content. Analyte content was measured in friction materials by XRFS and in PM2.5 captured during braking tests using SEM/EDX. The biological impact of brake-derived PM2.5 was investigated on a human epithelial alveolar cell line (A549). Cell viability, oxidative stress, mitochondrial membrane potential, apoptosis, and the pro-inflammatory response of the cells, as well as gene expression, were assessed following exposure to increasing PM2.5 concentrations (1, 10, 100, 200, and 500 µg/ml). The brake debris with the lowest Cu content did not induce significant changes in biological effects on A549 cells compared to normal controls, except for ROS production and IL6 gene expression. PM2.5 containing higher Cu quantities induced cell toxicity that correlated with Cu concentration. Our data suggest that the toxicity of PM2.5 from the brake system is mainly related to Cu content, thus confirming that eliminating Cu from brake pads will be beneficial for human health in urbanized environments.

Levosimendan to facilitate weaning from cardiorespiratory support in critically ill patients: current evidence and future directions.

Appropriate weaning is of crucial importance for critically ill patients requiring respiratory support. However, a remarkable proportion of them are difficult to wean. Levosimendan is a positive inotropic agent characterized by vasodilatory properties, which is used for the treatment of acute decompensated heart failure or in patients needing inotropic treatment, including cardiogenic shock, septic shock, pulmonary hypertension and right ventricular dysfunction, needed for hemodynamic support in patients with diuretic resistance, and weaning either from ventilator or from extracorporeal membrane oxygenation. This position paper will discuss the use of levosimendan in facilitating weaning from cardiorespiratory support in critically ill patients, according to available evidence and the personal experience of a group of Italian Experts.

Does additional coronary artery bypass grafting to aortic valve replacement in elderly patients affect the early and long-term outcome?

Early and long-term outcomes in elderly patients who underwent isolated aortic valve replacement (iAVR) are well defined. Conflicting data exist in elderly patients who underwent AVR plus coronary artery bypass grafting (CABG). We sought to evaluate the early and long-term outcomes of combined AVR + CABG in patients older than 75 years of age. From June 1999 to June 2018, 402 patients ≥ 75 years who underwent iAVR (n = 200; 49.7%) or combined AVR plus CABG (n = 202; 50.3%) were retrospectively analysed. AVR + CABG patients were older than iAVR patients (78.5 ± 2.5 vs 77.6 ± 2.8 years; p < 0.0001), with greater co-morbidities and more urgent/emergency surgery. 30-day mortality was 6.5% in the AVR + CABG and 4.5% in the iAVR group (p = 0.38). Multivariate analysis identified EuroSCORE II [odd ratio (OR) 1.13] postoperative stroke (OR 12.53), postoperative low cardiac output syndrome (OR 8.72) and postoperative mechanical ventilation > 48 h (OR 8.92) as independent predictors of 30-day mortality; preoperative cerebrovascular events (OR 3.43), creatinine (OR 7.27) and extracorporeal circulation time (OR 1.01) were independent predictors of in-hospital major adverse cardiovascular and cerebral events (MACCE). Treatment was not an independent predictor of 30-day mortality and in-hospital MACCE. Survival at 1, 5 and 10 years was 94.7 ± 1.6%, 72.6 ± 3.6% and 31.7 ± 4.8% for iAVR patients and 89.1 ± 2.3%, 73.9 ± 3.5% and 37.2 ± 4.8% for AVR + CABG subjects (p = 0.99). Using adjusted Cox regression model, creatinine [hazard ration (HR) 1.50; p = 0.018], COPD (HR 1.97; p = 0.003) and NYHA class (HR 1.39; p < 0.0001) were independent predictors of late mortality; the combined AVR + CABG was not associated with increased risk of late mortality (HR 0.83; p = 0.30). In patients aged ≥ 75 years, combined AVR + CABG was not associated with increased 30-day mortality, in-hospital MACCE and long-term mortality. Surgical revascularization can be safely undertaken at the time of AVR in elderly patients.

Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.