Non-Invasive Ventilation Reduces Postoperative Respiratory Failure in Patients Undergoing Bariatric Surgery: A Retrospective Analysis.

Background and Objectives: Postoperative non-invasive ventilation (NIV) has been proposed as an attractive strategy to reduce morbidity in obese subjects undergoing general anaesthesia. The increased body mass index (BMI) correlates with loss of perioperative functional residual capacity, expiratory reserve volume, and total lung capacity. The aim of the current study is to evaluate the efficacy of NIV in a post-anaesthesia care unit (PACU) in reducing post-extubation acute respiratory failure (ARF) after biliointestinal bypass (BIBP) in obese patients. Materials and Methods: A retrospective analysis was conducted from January 2019 to December 2020 to compare acute respiratory failure within the first 72 postoperative hours and oximetry values of obese patients who underwent BIBP after postoperative NIV adoption or conventional Venturi mask. Results: In total, 50 patients who received NIV postoperative protocol and 57 patients who received conventional Venturi mask ventilation were included in the study. After 120 min in PACU pH, pCO2, pO2, and SpO2 were better in the NIV group vs. control group (p < 0.001). Seventy-two hours postoperatively, one patient (2%) in the NIV group vs. seven patients (12.2%) in the control group developed acute respiratory failure. Therefore, conventional Venturi mask ventilation resulted in being significantly associated (p < 0.05) with postoperative ARF with an RR of 0.51 (IC 0.27-0.96). Conclusions: After bariatric surgery, short-term NIV during PACU observation promotes a more rapid recovery of postoperative lung function and oxygenation in obese patients, reducing the necessity for critical care in the days following surgery. Therefore, as day-case surgery becomes more advocated even for morbid obesity, it might be considered a necessary procedure.

A delayed complication of a port-a-cath insertion via subclavian venous access: Case report of a "pinch-off syndrome".

INTRODUCTION: Port-a-caths are long-stay central catheters often used for chemotherapy or parenteral nutrition. The implantation of a port-a cath, despite being involved in routine procedures, is also associated with immediate and delayed complications. Complications are rare but must be known and managed by operators. CASE REPORT: A delayed complication related to the presence of a port-a-cath, consisting in the fragmentation of the catheter, has been reported, in a 63-years-old female patient. The port was placed via subclavian venous access and affected by pinch-off syndrome, which resulted in catheter malfunction and then in fragmentation from compression by the subclavius-costoclavicular complex. The onset symptom was device malfunction. DISCUSSION AND CONCLUSION: The focus in the management of this rare but possible complication was the quick removal of the device and of the catheter fragment in the endovascular lumen with collaboration between different medical specialists.

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways.Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor.

Advances in the Pharmacological Management of Pediatric Acute Respiratory Distress Syndrome.

INTRODUCTION: Noninvasive mechanical ventilation is the main supportive measure used in patients with pediatric ARDS (PARDS), but adjunctive pharmacological therapies (corticosteroids, inhaled nitric oxide [iNO], surfactant replacement therapy and neuromuscular blocking drugs) are also used, although limited data exists to inform of this practice. AREAS COVERED: The authors review the current challenges in the pharmacological management of PARDS and highlight the few certainties currently available. EXPERT OPINION: Children with PARDS must not be treated as young adults with ARDS, essentially because children's lungs differ substantially from those of adults and PARDS occurs in children differently than ARDS in adults. Pharmacological treatments available for PARDS are relatively few and, since there is great uncertainty about their effectiveness also because of the extreme heterogeneity of this syndrome, it is necessary to conduct large clinical trials using currently available definitions and considering recent pathobiological knowledge. The aim is to identify homogeneous subgroups or phenotypes of children with PARDS that may benefit from the specific pharmaceutical approach examined. It will be then necessary to link endotypes and outcomes to appropriately target therapies in future trials, but this will be possible only after it will be possible to identify the different PARDS endotypes.

The FHP01 DDX3X Helicase Inhibitor Exerts Potent Anti-Tumor Activity In Vivo in Breast Cancer Pre-Clinical Models.

Inhibition of DDX3X expression or activity reduces proliferation in cells from various tumor tissues, in particular in breast cancer, and its expression often correlates to tumor aggressiveness. This makes DDX3X a prominent candidate for the design of drugs for novel personalized therapeutic strategies. Starting from an in silico drug discovery approach, a group of molecules has been selected by molecular docking at the RNA binding site of DDX3X. Here, the most promising among them, FHP01, was evaluated in breast cancer preclinical models. Specifically, FHP01 exhibited very effective antiproliferative and killing activity against different breast cancer cell types, among which those from triple-negative breast cancer (TNBC). Interestingly, FHP01 also inhibited WNT signaling, a key tumorigenic pathway already correlated to DDX3X functions in breast cancer model cell lines. Ultimately, FHP01 also caused a significant reduction, in vivo, in the growth of MDA MB 231-derived TNBC xenograft models. Importantly, FHP01 showed good bioavailability and no toxicity on normal peripheral blood mononuclear cells in vitro and on several mouse tissues in vivo. Overall, our data suggest that the use of FHP01 and its related compounds may represent a novel therapeutic approach with high potential against breast cancer, including the triple-negative subtype usually correlated to the most unfavorable outcomes because of the lack of available targeted therapies.

MAPK15 Controls Hedgehog Signaling in Medulloblastoma Cells by Regulating Primary Ciliogenesis.

In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative "smart" therapies in medulloblastomas.

Decapneization as supportive therapy for the treatment of status asthmaticus: a case report.

BACKGROUND: Acute severe asthma is a life-threatening medical emergency. Characteristics of asthma include increased airway resistance and dynamic pulmonary hyperinflation that can manifest in dangerous levels of hypercapnia and acidosis, with significant mortality and morbidity. Severe respiratory distress can lead to endotracheal intubation followed by mechanical ventilation, which can cause increased air trapping with dynamic hyperinflation, predisposing the lungs to barotraumas. CASE PRESENTATION: The present case report describes the use of the minimally invasive ECCO2R ProLUNG® (Estor) with protective low-tidal-volume ventilation, in a Caucasian patient with near-fatal asthma and with no response to conventional therapy. CONCLUSIONS: Since hypercarbia rather than hypoxemia is the primary abnormality in status asthmaticus, a rescue therapeutic strategy combining the ECCO2R membrane ProLUNG® (Estor) with ultra-protective low-tidal-volume ventilation can be successfully applied to limit the risk of severe barotrauma during invasive mechanical ventilation. ECCO2R ProLUNG® is a partial respiratory support technique that, based on the use of an extracorporeal circuit with a gas-exchange membrane, achieves relevant CO2 clearance directly from the blood using double-lumen venous-venous vascular access, at blood flow in the range of 0.4-1.0 L/minute.

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

Ultrasound guided percutaneous dilatation tracheotomy (US-PDT) to prevent potentially life-threatening complications: A case report.

INTRODUCTION: Percutaneous dilatation tracheotomy (PDT) is a relatively recent technique that enables non surgeons to perform tracheotomies at bedside reducing operation rooms schedules. It is burdened by a moderate risk of postoperative bleeding. PRESENTATION OF CASE: The patient was a 57 years old with a temporal intraparenchymal hematoma, submitted to percutaneous dilatation tracheotomy. Despite the favorable anatomical features, a pre-procedural US was performed, identifying a pulsating vessel with an arterial pattern, 2 cm above the hollow. The procedure was then considered at high risk, an operation room was required for the technique and an on-call surgeon was alerted. The procedure was ended safely and any bleeding was avoided because the technique was practiced with the best precautions. DISCUSSION: PDT strength is the possibility for non surgeons to perform tracheotomies in selected patients at bedside, reducing operation rooms congestion. Such technique though is a "blind" technique, and postoperative bleedings can occur and represent a feared complication. Conversely, the surgical tracheotomy permits a better control of hemorrhages, but needs the involvement of a surgeon and availability of an operation room. Performing a PDT guided by a neck ultrasound is useful to identify eventual aberrant vessel whose course could complicate the tracheotomy, it is part of PDT guidelines of some States. CONCLUSION: US-PDT could help reducing procedure related complications selecting those high risk patients still in need of operating room and surgical assistance. US-PDT feasibility combined to its easy availability and low costs encourage its introduction into everyday practice.

Large-Scale Human Dendritic Cell Differentiation Revealing Notch-Dependent Lineage Bifurcation and Heterogeneity.

The ability to generate large numbers of distinct types of human dendritic cells (DCs) in vitro is critical for accelerating our understanding of DC biology and harnessing them clinically. We developed a DC differentiation method from human CD34+ precursors leading to high yields of plasmacytoid DCs (pDCs) and both types of conventional DCs (cDC1s and cDC2s). The identity of the cells generated in vitro and their strong homology to their blood counterparts were demonstrated by phenotypic, functional, and single-cell RNA-sequencing analyses. This culture system revealed a critical role of Notch signaling and GM-CSF for promoting cDC1 generation. Moreover, we discovered a pre-terminal differentiation state for each DC type, characterized by high expression of cell-cycle genes and lack of XCR1 in the case of cDC1. Our culture system will greatly facilitate the simultaneous and comprehensive study of primary, otherwise rare human DC types, including their mutual interactions.

Constitutive resistance to viral infection in human CD141+ dendritic cells.

Dendritic cells (DCs) are critical for the launching of protective T cell immunity in response to viral infection. Viruses can directly infect DCs, thereby compromising their viability and suppressing their ability to activate immune responses. How DC function is maintained in light of this paradox is not understood. By analyzing the susceptibility of primary human DC subsets to viral infections, we report that CD141+ DCs have an innate resistance to infection by a broad range of enveloped viruses, including HIV and influenza virus. In contrast, CD1c+ DCs are susceptible to infection, which enables viral antigen production but impairs their immune functions and survival. The ability of CD141+ DCs to resist infection is conferred by RAB15, a vesicle-trafficking protein constitutively expressed in this DC subset. We show that CD141+ DCs rely on viral antigens produced in bystander cells to launch cross-presentation-driven T cell responses. By dissociating viral infection from antigen presentation, this mechanism protects the functional capacity of DCs to launch adaptive immunity against viral infection.

SIRT1 regulates macrophage self-renewal.

Mature differentiated macrophages can self-maintain by local proliferation in tissues and can be extensively expanded in culture under specific conditions, but the mechanisms of this phenomenon remain only partially defined. Here, we show that SIRT1, an evolutionary conserved regulator of life span, positively affects macrophage self-renewal ability in vitro and in vivo Overexpression of SIRT1 during bone marrow-derived macrophage differentiation increased their proliferative capacity. Conversely, decrease of SIRT1 expression by shRNA inactivation, CRISPR/Cas9 mediated deletion and pharmacological inhibition restricted macrophage self-renewal in culture. Furthermore, pharmacological SIRT1 inhibition in vivo reduced steady state and cytokine-induced proliferation of alveolar and peritoneal macrophages. Mechanistically, SIRT1 inhibition negatively regulated G1/S transition, cell cycle progression and a network of self-renewal genes. This included inhibition of E2F1 and Myc and concomitant activation of FoxO1, SIRT1 targets mediating cell cycle progression and stress response, respectively. Our findings indicate that SIRT1 is a key regulator of macrophage self-renewal that integrates cell cycle and longevity pathways. This suggests that macrophage self-renewal might be a relevant parameter of ageing.

Hyperbaric oxygen therapy reduces the toll-like receptor signaling pathway in multiple organ failures.

PURPOSE: Zymosan-induced generalized inflammation is the only experimental model that reproduces characteristics of human multiple organ dysfunction syndrome (MODS). Toll-like receptors (TLRs) are key components in innate immune responses and their signaling pathway is known to activate target genes such as nuclear factor-κB (NF-κB) and cytokines that are involved in inflammation and immune responses. We previously reported that hyperbaric oxygen (HBO) therapy is effective in the treatment of severe zymosan-induced inflammation in MODS. The aim of this study was to investigate the effect of HBO exposure on TLR2 and TLR4 signal transduction and organ dysfunction during MODS induced by zymosan in the rat. METHODS: Male Wistar rats were randomized into four groups and treated as follows: (1) saline solution (control); (2) zymosan; (3) HBO 4 and 11 h after zymosan injection; (4) HBO 4 and 11 h after saline solution injection. Zymosan-induced damage of the lungs, liver, and small intestine was evaluated using histology and biochemistry. The activation of the TLR signaling pathway was measured with Western blot, reverse transcriptase polymerase chain reaction analysis (RT-PCR), and immunohistochemistry. RESULTS: Zymosan induced a severe inflammatory response characterized by the activation of the TLR signaling pathway and by an organ dysfunction. HBO exposure significantly reduced the development of lung, liver, and intestine injury in our experimental model. It also significantly reduced the zymosan-induced expression of TLR2 and TLR4, NF-κB activation, and cytokine production. CONCLUSIONS: Taken together, these results suggest that, by interfering with the TLR pathway, HBO treatment may exert a protective effect against tissue injury caused by zymosan-induced generalized inflammation.

B-cell differentiation in EBV-positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA-altered expression.

Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.

Hyperbaric oxygen therapy prevents coagulation disorders in an experimental model of multiple organ failure syndrome.

OBJECTIVE: To evaluate the effects of hyperbaric oxygen (HBO) therapy on the coagulation cascade using an experimental model of multiple organ failure syndrome (MOFS). DESIGN: MOFS was induced by zymosan (500mg/kg i.p.) in rats. HBO therapy (2ATA) was administered in a cylindrical steel chamber 4 and 11h after zymosan administration. In a separate set of experiments animals were monitored for 72h, and systemic toxicity was scored. INTERVENTION: Eighteen hours after zymosan administration, rats were killed and blood samples were used for analysis of hemocoagulative parameters, hemodynamics, and arterial blood gas. MAIN RESULTS: Zymosan administration caused MOFS by affecting the coagulation cascade, as shown by a significant increase in plasma levels of fibrinogen, tissue plasminogen activator, inhibitor of tissue plasminogen activator of type 1, and plasma levels of fibrin degradation products vs. control rats. Zymosan-induced MOFS was also characterized by a significant increase in von Willebrand antigen plasma levels vs. controls. Moreover, zymosan administration induced a significant fall in mean arterial blood pressure and alteration in blood gas values. HBO therapy significantly reduced the derangements of coagulation cascade, the fall in mean blood pressure and alteration in blood gas induced by zymosan administration. CONCLUSIONS: The hypercoagulability induced by zymosan could be responsible for organ failure and death. Our data demonstrate that HBO therapy significantly prevents the alteration in the coagulation cascade and arterial blood gas in an experimental model of MOFS.

Hyperbaric oxygen therapy prevents vascular derangement during zymosan-induced multiple-organ-failure syndrome.

OBJECTIVE: This study investigated the effects of hyperbaric oxygen (HBO) therapy on the cardiovascular alteration (e.g. mean arterial pressure, vascular reactivity of thoracic aorta rings changes) caused by zymosan in rats. DESIGN: Rats. SETTING: University research laboratory. INTERVENTION AND MEASUREMENTS: We investigated the effects of HBO therapy (2 ATA at the fourth and eleventh hours after study onset) on the cardiovascular alteration caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in rats. Cardiovascular alterations were assessed 18 h after administration of zymosan and/or HBO therapy. RESULTS: Treatment of rats with HBO therapy attenuated the vasoplegic response to zymosan. In fact, the analysis of arterial pressure curves revealed no signs of vasoplegic shock. The aorta rings of animals treated with zymosan and HBO had a significantly increased contraction to norepinephrine (NE) and endothelin-1 (ET-1) and dilation to acetylcholine (ACh) compared with the zymosan group. The HBO therapy also attenuated the increase of malondialdehyde (MDA) levels caused by zymosan in the aorta. Immunohistochemical analysis for nitrotyrosine and for iNOS revealed positive staining in the aorta from zymosan-treated rats. The degree of staining for nitrotyrosine and iNOS was markedly reduced in tissue sections obtained from zymosan-rats treated with HBO therapy. CONCLUSION: This study provides the first evidence that HBO therapy attenuates the degree of zymosan-induced cardiovascular derangement in the rat.

Bronchoscopic transillumination guidance for open standard surgical tracheostomy.

The standard tracheostomy technique, described in 1909 by Jackson, has been increasingly used in intensive care units. Since 1957, several different types of percutaneous tracheostomy techniques have been described and performed with the support of bronchoscopic transillumination. The authors present the case of a respiratory failure due to obstruction of the upper airway by an exceptionally large goiter, which was successfully resolved by a standard open surgical tracheostomy. In this case, surgical tracheostomy was preceded by bronchoscopic transillumination, which facilitated identification of the appropriate tracheostomy site.

Case report: requirement of supplemental morphine during sedation with propofol in a critically ill patient undergoing hemodiafiltration.

OBJECTIVE: Propofol has been shown to produce a predictable and easily attainable level of sedation in postcardiac, head-injured, general trauma patients. The commencement of hemodiafiltration itself has not been shown to significantly influence the requirement for propofol. We report on a patient who underwent binephrectomy complicated by sepsis-induced adult respiratory distress syndrome (ARDS). DESIGN: Case report. SETTING: Largest nonteaching hospital in Southern Italy. PATIENTS/SUBJECTS: An 18-year-old male underwent a surgical procedure for splenectomy and right nephrectomy for severe abdominal trauma. On the 10th postoperative day, the patient was admitted into our intensive care unit (ICU) for acute respiratory and renal failure due to ARDS and left renal infarction. INTERVENTIONS: Continuous venovenous hemodiafiltration was carried out through a double-lumen cannula. Sedation was initially achieved with propofol up to standard doses into a nonfemoral venous site. Because the optimal level of sedation was not achieved, the initial propofol infusion rate was increase to 3.5 mg/kg, and then an intravenous bolus of morphine (.01 mg/kg) was administered twice daily. RESULTS: The administration of morphine was fundamental to achieving an optimal level of sedation. ARDS resolved and, 10 days later, the patient was transferred to the surgical unit, then discharged home after 14 days. CONCLUSION: Hemodiafiltration was found to influence the clinical requirement for propofol. The optimal level of sedation is achieved with the addition of morphine.