Cardio-Oncoimmunology: Cardiac Toxicity, Cardiovascular Hypersensitivity, and Kounis Syndrome.

Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT prolongation, torsades de pointes, pericardial effusion, and hypotension, as well as chronic conditions, such as hypertension, and systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovascular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovascular side effect continues even after the causative medication is stopped, it is referred to as a cardiotoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even at very low medication dosages, and can present as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome, and myocarditis caused by cancer therapy.

The role of gut barrier dysfunction in postoperative complications in liver transplantation: pathophysiological and therapeutic considerations.

PURPOSE: Gut barrier dysfunction is a pivotal pathophysiological alteration in cirrhosis and end-stage liver disease, which is further aggravated during and after the operational procedures for liver transplantation (LT). In this review, we analyze the multifactorial disruption of all major levels of defense of the gut barrier (biological, mechanical, and immunological) and correlate with clinical implications. METHODS: A narrative review of the literature was performed using PubMed, PubMed Central and Google from inception until November 29th, 2023. RESULTS: Systemic translocation of indigenous bacteria through this dysfunctional barrier contributes to the early post-LT infectious complications, while endotoxin translocation, through activation of the systemic inflammatory response, is implicated in non-infectious complications including renal dysfunction and graft rejection. Bacterial infections are the main cause of early in-hospital mortality of LT patients and unraveling the pathophysiology of gut barrier failure is of outmost importance. CONCLUSION: A pathophysiology-based approach to prophylactic or therapeutic interventions may lead to enhancement of gut barrier function eliminating its detrimental consequences and leading to better outcomes for LT patients.

Altered Expression of Intestinal Tight Junctions in Patients with Chronic Kidney Disease: A Pathogenetic Mechanism of Intestinal Hyperpermeability.

BACKGROUND: Systemic inflammation in chronic kidney disease (CKD) is associated (as a cause or effect) with intestinal barrier dysfunction and increased gut permeability, with mechanisms not yet fully understood. This study investigated different parameters of the intestinal barrier in CKD patients, especially tight junction (TJ) proteins and their possible association with systemic endotoxemia and inflammation. METHODS: Thirty-three patients with stage I-IV CKD (n = 17) or end-stage kidney disease (ESKD) (n = 16) and 11 healthy controls underwent duodenal biopsy. Samples were examined histologically, the presence of CD3+ T-lymphocytes and the expression of occludin and claudin-1 in the intestinal epithelium was evaluated by means of immunohistochemistry, circulating endotoxin concentrations were determined by means of ELISA and the concentrations of the cytokines IL-1ß, IL-6, IL-8, IL-10 and TNF-α in serum were measured using flow cytometry. RESULTS: Patients with stage I-IV CKD or ESKD had significantly higher serum endotoxin, IL-6, IL-8 and IL-10 levels compared to controls. Intestinal occludin and claudin-1 were significantly decreased, and their expression was inversely correlated with systemic endotoxemia. Regarding occludin, a specific expression pattern was observed, with a gradually increasing loss of its expression from the crypt to the tip of the villi. CONCLUSION: The expression of occludin and claudin-1 in enterocytes is significantly reduced in patients with CKD, contributing to systemic endotoxemia and inflammatory responses in these patients.

"When," "Where," and "How" of SARS-CoV-2 Infection Affects the Human Cardiovascular System: A Narrative Review.

Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of cardiovascular complications during and after acute COVID-19 infection have been hypothesized. The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as one of the deadliest pandemics in modern history. The myocardial injury in COVID-19 patients has been associated with coronary spasm, microthrombi formation, plaque rupture, hypoxic injury, or cytokine storm, which have the same pathophysiology as the three clinical variants of Kounis syndrome. The angiotensin-converting enzyme 2 (ACE2), reninaldosterone system (RAAS), and kinin-kallikrein system are the main proposed mechanisms contributing to cardiovascular complications with the COVID-19 infection. ACE receptors can be found in the heart, blood vessels, endothelium, lungs, intestines, testes, neurons, and other human body parts. SARS-CoV-2 directly invades the endothelial cells with ACE2 receptors and constitutes the main pathway through which the virus enters the endothelial cells. This causes angiotensin II accumulation downregulation of the ACE2 receptors, resulting in prothrombotic effects, such as hemostatic imbalance via activation of the coagulation cascade, impaired fibrinolysis, thrombin generation, vasoconstriction, endothelial and platelet activation, and pro-inflammatory cytokine release. The KKS system typically causes vasodilation and regulates tissue repair, inflammation, cell proliferation, and platelet aggregation, but SARS-CoV-2 infection impairs such counterbalancing effects. This cascade results in cardiac arrhythmias, cardiac arrest, cardiomyopathy, cytokine storm, heart failure, ischemic myocardial injuries, microvascular disease, Kounis syndrome, prolonged COVID, myocardial fibrosis, myocarditis, new-onset hypertension, pericarditis, postural orthostatic tachycardia syndrome, pulmonary hypertension, stroke, Takotsubo syndrome, venous thromboembolism, and thrombocytopenia. In this narrative review, we describe and elucidate when, where, and how COVID-19 affects the human cardiovascular system in various parts of the human body that are vulnerable in every patient category, including children and athletes.

Altered Expression of Intestinal Tight Junction Proteins in Heart Failure Patients with Reduced or Preserved Ejection Fraction: A Pathogenetic Mechanism of Intestinal Hyperpermeability.

Although intestinal microbiota alterations (dysbiosis) have been described in heart failure (HF) patients, the possible mechanisms of intestinal barrier dysfunction leading to endotoxemia and systemic inflammation are not fully understood. In this study, we investigated the expression of the intestinal tight junction (TJ) proteins occludin and claudin-1 in patients with HF with reduced (HFrEF) or preserved ejection fraction (HFpEF) and their possible association with systemic endotoxemia and inflammation. Ten healthy controls and twenty-eight patients with HF (HFrEF (n = 14), HFpEF (n = 14)) underwent duodenal biopsy. Histological parameters were recorded, intraepithelial CD3+ T-cells and the expression of occludin and claudin-1 in enterocytes were examined using immunohistochemistry, circulating endotoxin concentrations were determined using ELISA, and concentrations of cytokines were determined using flow cytometry. Patients with HFrEF or HFpEF had significantly higher serum endotoxin concentrations (p < 0.001), a significantly decreased intestinal occludin and claudin-1 expression (in HfrEF p < 0.01 for occludin, p < 0.05 for claudin-1, in HfpEF p < 0.01 occludin and claudin-1), and significantly increased serum concentrations of IL-6, IL-8, and IL-10 (for IL-6 and IL-10, p < 0.05 for HFrEF and p < 0.001 for HFpEF; and for IL-8, p < 0.05 for both groups) compared to controls. Occludin and claudin-1 expression inversely correlated with systemic endotoxemia (p < 0.05 and p < 0.01, respectively). Heart failure, regardless of the type of ejection fraction, results in a significant decrease in enterocytic occludin and claudin-1 expression, which may represent an important cellular mechanism for the intestinal barrier dysfunction causing systemic endotoxemia and inflammatory response.

Oral Antibiotics for Bacteremia and Infective Endocarditis: Current Evidence and Future Perspectives.

Bacteremia and endocarditis are two clinical syndromes that, for decades, were managed exclusively with parenteral antimicrobials, irrespective of a given patient's clinical condition, causative pathogen, or its antibiotic susceptibility profile. This clinical approach, however, was based on low-quality data and outdated expert opinions. When a patient's condition has improved, gastrointestinal absorption is not compromised, and an oral antibiotic regimen reaching adequate serum concentrations is available, a switch to oral antibacterials can be applied. Although available evidence has reduced the timing of the oral switch in bacteremia to three days/until clinical improvement, there are only scarce data regarding less than 10-day intravenous antibiotic therapy in endocarditis. Many standard or studied oral antimicrobial dosages are smaller than the approved doses for parenteral administration, which is a risk factor for treatment failure; in addition, the gastrointestinal barrier may affect drug bioavailability, especially when the causative pathogen has a minimum inhibitory concentration that is close to the susceptibility breakpoint. A considerable number of patients infected by such near-breakpoint strains may not be potential candidates for oral step-down therapy to non-highly bioavailable antibiotics like beta-lactams; different breakpoints should be determined for this setting. This review will focus on summarizing findings about pathogen-specific tailoring of oral step-down therapy for bacteremia and endocarditis, but will also present laboratory and clinical data about antibiotics such as beta-lactams, linezolid, and fosfomycin that should be studied more in order to elucidate their role and optimal dosage in this context.

Laboratory Surveillance of Acinetobacter spp. Bloodstream Infections in a Tertiary University Hospital during a 9-Year Period.

Multidrug-resistant Acinetobacter baumannii infections have become a threat for public health worldwide. The aim of the present study was to follow-up resistance patterns of Acinetobacter spp. bloodstream isolates in a Tertiary University Hospital over the last nine years, from 2014 to 2022. Susceptibility patterns were followed for the following antimicrobial agents: amikacin, gentamicin, tobramycin, ciprofloxacin, levofloxacin, imipenem, meropenem, tigecycline, trimethoprim/sulfamethoxazole, and colistin. Minimal inhibitory concentration (MIC) values to ampicillin/sulbactam, cefepime, ceftazidime, minocycline, piperacillin/tazobactam were evaluated from 2020 to 2023. During the study period, 853 Acinetobacter spp. bloodstream infections (BSIs) were recorded, accounting for 5.36% of all BSIs. A. baumannii was isolated in 795 cases (93.2%), during the study period. Most BSIs were recorded in adult intensive care units (ICU) (46.2%) and medical wards (42%). Among A. baumannii isolates, 4.5% were multidrug-resistant, 84.7% were extensively drug-resistant, and 8.5% were pandrug-resistant. Resistance to carbapenems was over 95%. Resistance to tigecycline increased significantly during the last years of the study (2020-2022); A. baumannii isolates with MIC ≤ 2 µg/mL accounted for 28.5% of all isolates. Resistance to colistin exhibited an increasing pattern up to 42.2% in 2022. Increasing resistance rates and the evolution of pandrug-resistant isolates call for the urgent application of preventive and response actions.

Thyroid Eye Disease as Initial Manifestation of Graves' Disease Following Viral Vector SARS-CoV-2 Vaccine: Report of a Case and Review of the Literature.

COVID-19, a contagious disease caused by the novel coronavirus SARS-CoV-2, emerged in 2019 and quickly became a pandemic, infecting more than 700 million people worldwide. The disease incidence, morbidity and mortality rates have started to decline since the development of effective vaccines against the virus and the widespread immunization of the population. SARS-CoV-2 vaccines are associated with minor local or systemic adverse reactions, while serious adverse effects are rare. Thyroid-related disorders have been reported after vaccination for COVID-19, and Graves' disease (GD) is the second most common amongst them. Thyroid eye disease (TED), an extrathyroidal manifestation of GD, is rarely observed post-COVID-19 vaccination. All TED cases followed mRNA-based vaccinations, but two new onset mild TED cases post-viral vector vaccine (ChAdox1nCoV-19) have also been reported. We report the case of a 63-year-old woman who presented with new onset hyperthyroidism and moderate-to-severe and active TED 10 days after she received the first dose of a viral vector vaccine against SARS-CoV-2. This is the first case of moderate-to-severe TED after such a vaccine. Our patient was initially treated with intravenous glucocorticoids, and subsequently with intravenous rituximab, due to no response. The disease was rendered inactive after rituximab, but constant diplopia persisted, and the patient was referred for rehabilitative surgery.

Septic Tibial Nonunions on Proximal and Distal Metaphysis-A Systematic Narrative Review.

BACKGROUND: Infected nonunion of the tibia represents a challenging complication for orthopedic surgeons and poses a major financial burden to healthcare systems. The situation is even more compounded when the nonunion involves the metaphyseal region of long bones, a rare yet demanding complication due to the poor healing potential of infected cancellous bone; this is in addition to the increased likelihood of contamination of adjacent joints. The purpose of this study was to determine the extent and level of evidence in relation to (1) available treatment options for the management of septic tibial metaphyseal nonunions; (2) success rates and bone healing following treatment application; and (3) functional results after intervention. METHODS: We searched the MEDLINE, Embase, and CENTRAL databases for prospective and retrospective studies through to 25 January 2021. Human-only studies exploring the efficacy of various treatment options and their results in the setting of septic, quiescent, and metaphyseal (distal or proximal) tibia nonunions in the adult population were included. For infection diagnosis, we accepted definitions provided by the authors of source studies. Of note, clinical heterogeneity rendered data pooling inappropriate. RESULTS: In terms of the species implicated in septic tibial nonunions, staphylococcus aureus was found to be the most commonly isolated microorganism. Many authors implemented the Ilizarov external fixation device with a mean duration of treatment greater than one year. Exceptional or good bone and functional results were recorded in over 80% of patients, although the literature is scarce and possible losses of the follow-up were not recorded. CONCLUSION: A demanding orthopedic condition that is scarcely studied is infected metaphyseal tibial nonunion. External fixation seems promising, but further research is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO No. CRD42020205781.

Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential.

Although coronavirus disease 2019 (COVID-19) is primarily associated with mild respiratory symptoms, a subset of patients may develop more complicated disease with systemic complications and multiple organ injury. The gastrointestinal tract may be directly infected by SARS-CoV-2 or secondarily affected by viremia and the release of inflammatory mediators that cause viral entry from the respiratory epithelium. Impaired intestinal barrier function in SARS-CoV-2 infection is a key factor leading to excessive microbial and endotoxin translocation, which triggers a strong systemic immune response and leads to the development of viral sepsis syndrome with severe sequelae. Multiple components of the gut immune system are affected, resulting in a diminished or dysfunctional gut immunological barrier. Antiviral peptides, inflammatory mediators, immune cell chemotaxis, and secretory immunoglobulins are important parameters that are negatively affected in SARS-CoV-2 infection. Mucosal CD4+ and CD8+ T cells, Th17 cells, neutrophils, dendritic cells, and macrophages are activated, and the number of regulatory T cells decreases, promoting an overactivated immune response with increased expression of type I and III interferons and other proinflammatory cytokines. The changes in the immunologic barrier could be promoted in part by a dysbiotic gut microbiota, through commensal-derived signals and metabolites. On the other hand, the proinflammatory intestinal environment could further compromise the integrity of the intestinal epithelium by promoting enterocyte apoptosis and disruption of tight junctions. This review summarizes the changes in the gut immunological barrier during SARS-CoV-2 infection and their prognostic potential.

Intestinal barrier dysfunction as a key driver of severe COVID-19.

The intestinal lumen harbors a diverse consortium of microorganisms that participate in reciprocal crosstalk with intestinal immune cells and with epithelial and endothelial cells, forming a multi-layered barrier that enables the efficient absorption of nutrients without an excessive influx of pathogens. Despite being a lung-centered disease, severe coronavirus disease 2019 (COVID-19) affects multiple systems, including the gastrointestinal tract and the pertinent gut barrier function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can inflict either direct cytopathic injury to intestinal epithelial and endothelial cells or indirect immune-mediated damage. Alternatively, SARS-CoV-2 undermines the structural integrity of the barrier by modifying the expression of tight junction proteins. In addition, SARS-CoV-2 induces profound alterations to the intestinal microflora at phylogenetic and metabolomic levels (dysbiosis) that are accompanied by disruption of local immune responses. The ensuing dysregulation of the gut-lung axis impairs the ability of the respiratory immune system to elicit robust and timely responses to restrict viral infection. The intestinal vasculature is vulnerable to SARS-CoV-2-induced endothelial injury, which simultaneously triggers the activation of the innate immune and coagulation systems, a condition referred to as "immunothrombosis" that drives severe thrombotic complications. Finally, increased intestinal permeability allows an aberrant dissemination of bacteria, fungi, and endotoxin into the systemic circulation and contributes, to a certain degree, to the over-exuberant immune responses and hyper-inflammation that dictate the severe form of COVID-19. In this review, we aim to elucidate SARS-CoV-2-mediated effects on gut barrier homeostasis and their implications on the progression of the disease.

Vitamin D and Microbiome: Molecular Interaction in Inflammatory Bowel Disease Pathogenesis.

Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. This review examines the role of the gut microbiome in IBD and discusses how vitamin D-vitamin D receptor (VDR)-associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D-VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.

Efficacy of Fosfomycin-Containing Regimens for Treatment of Bacteremia Due to Pan-Drug Resistant Acinetobacter baumannii in Critically Ill Patients: A Case Series Study.

Acinetobacter baumannii (AB) has evolved over the last decades as a major problem in carbapenem-resistant gram-negative nosocomial infections, associated with high mortality rates especially in the intensive care unit (ICU). Recent reports highlight the increasing prevalence of resistance to colistin, a last resort therapeutic option for carbapenem-resistant AB. We retrospectively evaluated the characteristics, treatment regimens and outcomes of twenty patients with pan-drug resistant (PDR) AB primary bacteremia hospitalized in the ICU of the University General Hospital of Patras, during a two-year period (October 2020-September 2022). The 28-day mortality reached 50%. Between survivors and non-survivors, no differences were found regarding age, gender, and Charlson comorbidity index (CCI). However, non-survivors had higher APACHE II scores and higher prevalence of septic shock and COVID-19 infection. A significantly higher percentage in the survivor group received Fosfomycin as part of the combination regimen. Inclusion of fosfomycin in the combination therapeutic regimen was associated with significantly better survival as compared to non-fosfomycin-containing regimens. In view of the increasing prevalence of PDR-AB infections in ICUs, its associated high rates of mortality and the lack of effective treatment options, the observed survival benefit with fosfomycin inclusion in the therapeutic regimen merits further validation in larger prospective studies.

Treatment of Infected Tibial Metaphyseal Nonunions Using the Ilizarov Method: Protocol for a Prospective Nonrandomized Study.

BACKGROUND: The management of infected metaphyseal nonunion of the tibia is devastating, especially when associated with significant bone loss, poor soft tissues, draining sinuses, axial deformity, knee or ankle joint stiffness, limb discrepancy, and multiresisted pathogens. A systematic review, performed recently by the primary investigators but not yet published, yielded the lack of studies in the field and the huge heterogeneity of the presented results. We found several bias and controversies such as no clear definition of the exact part of the tibia where the nonunion was located, the pathogen causing the fracture-related infection, the number of previous interventions and time to presentation, and the exact type of treatment methods including the use of muscle flaps or bone grafting. Time to final union as a functional score is another important but missing data. OBJECTIVE: The proposed study is designed to evaluate a sufficient number of patients with infected metaphyseal tibial nonunions using various general health, functional, and bone scores. METHODS: This prospective clinical trial study, with a minimum follow-up period of 36 months, focuses on the effectiveness of the Ilizarov method after radical nonunion debridement and targeted antibiotic therapy in patients with infected metaphyseal tibial nonunions. The primary outcomes would be the definite healing of nonunion and infection-free results. Secondary outcomes would be limb alignment and discrepancy, alteration in the patient's quality of life, and functional results. A power analysis calculated a minimum of 11 patients to obtain statistical power, but we aim to include at least 25 patients. Limb discrepancy, clinical validation of infection eradication and fracture healing, radiographic validation, and patient-reported outcome measures will be highlighted and correlated. Statistical analysis of the results will offer data missing from the literature so far. Measurements are scheduled at specific times for each patient: preoperatively, 3 and 6 months postoperatively, 1 month after Ilizarov frame removal, and once per semester afterward until the end of the follow-up period (minimum 36 months). Laboratory evaluation will be assessed once per month. Any complication will be reported and treated when it occurs. RESULTS: The trial has already started. It was funded in June 2020. As of May 2022, 19 participants have been recruited and no major complications have been noticed yet. Data analysis will be performed after data collection ends, and results will be published afterward. CONCLUSIONS: An infected metaphyseal tibial nonunion is a rare condition with limited treatment options and many controversies. There is no consensus in the literature about the best treatment strategy, and this lack of evidence should be fulfilled. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 30905788; https://www.isrctn.com/ISRCTN30905788. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39319.

NAFLD and HBV interplay - related mechanisms underlying liver disease progression.

Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.

Surgical management in hepatocellular carcinoma with portal vein tumour thrombosis: is this the end of the road or a chance to expand the criteria for resectability?

Portal vein thrombosis is a common complication associated with malignancies such as hepatocellular carcinoma, with a dismal and negative impact on prognosis. A thorough literature search in Pubmed and Google Scholar, under the terms 'hepatocellular carcinoma AND portal vein thrombosis', regarding the surgical management of portal vein thrombosis was conducted by the authors, and the associated results are presented in this narrative review. Precise classification of portal vein thrombosis and identification of subgroups of patients that will benefit from surgery is of paramount importance. Evolution of novel surgical techniques in liver resection and associated low morbidity and mortality rates in specialized hepatobiliary centres worldwide have been linked with promising results from the adoption of surgical management in these patients, when compared to systemic chemotherapy or arterial chemoembolization management that has traditionally been followed in such cases.

A Seven-Year Microbiological and Molecular Study of Bacteremias Due to Carbapenemase-Producing Klebsiella Pneumoniae: An Interrupted Time-Series Analysis of Changes in the Carbapenemase Gene's Distribution after Introduction of Ceftazidime/Avibactam.

Background: Ceftazidime/avibactam (CZA) is a new option for the treatment of KPC-producing Klebsiella pneumoniae. The aim of this study was to determine resistance patterns and carbapenemase genes among K. pneumoniae (CP-Kp) bacteremic isolates before and after CZA introduction. Methods: K. pneumoniae from blood cultures of patients being treated in a Greek university hospital during 2015−21 were included. PCR for blaKPC, blaVIM, blaNDM and blaOXA-48 genes was performed. Results: Among 912 K. pneumoniae bacteremias: 725 (79.5%) were due to carbapenemase-producing isolates; 488 (67.3%) carried blaKPC; 108 (14.9%) blaVIM; 100 (13.8%) blaNDM; and 29 (4%) carried a combination of blaKPC, blaVIM or blaNDM. The incidence of CP-Kp bacteremias was 59 per 100,000 patient-days. The incidence of CP-Kp changed from a downward pre-CZA trend to an upward trend in the CZA period (p = 0.007). BSIs due to KPC-producing isolates showed a continuous downward trend in the pre-CZA and CZA periods (p = 0.067), while BSIs due to isolates carrying blaVIM or blaNDM changed from a downward trend in the pre-CZA to an upward trend in the CZA period (p < 0.001). Conclusions: An abrupt change in the epidemiology of CP-Kp was observed in 2018, due to the re-emergence of VIM-producing isolates after the suppression of KPC-producing ones via the use of CZA.

The Chemokines CXC, CC and C in the Pathogenesis of COVID-19 Disease and as Surrogates of Vaccine-Induced Innate and Adaptive Protective Responses.

COVID-19 is one of the progressive viral pandemics that originated from East Asia. COVID-19 or SARS-CoV-2 has been shown to be associated with a chain of physio-pathological mechanisms that are basically immunological in nature. In addition, chemokines have been proposed as a subgroup of chemotactic cytokines with different activities ranging from leukocyte recruitment to injury sites, irritation, and inflammation to angiostasis and angiogenesis. Therefore, researchers have categorized the chemotactic elements into four classes, including CX3C, CXC, CC, and C, based on the location of the cysteine motifs in their structures. Considering the severe cases of COVID-19, the hyperproduction of particular chemokines occurring in lung tissue as well as pro-inflammatory cytokines significantly worsen the disease prognosis. According to the studies conducted in the field documenting the changing expression of CXC and CC chemokines in COVID-19 cases, the CC and CXC chemokines contribute to this pandemic, and their impact could reflect the development of reasonable strategies for COVID-19 management. The CC and the CXC families of chemokines are important in host immunity to viral infections and along with other biomarkers can serve as the surrogates of vaccine-induced innate and adaptive protective responses, facilitating the improvement of vaccine efficacy. Furthermore, the immunogenicity elicited by the chemokine response to adenovirus vector vaccines may constitute the basis of vaccine-induced immune thrombotic thrombocytopaenia.

SARS CoV-2-Induced Viral Sepsis: The Role of Gut Barrier Dysfunction.

A considerable proportion of patients with severe COVID-19 meet Sepsis-3 criteria and share common pathophysiological mechanisms of multiorgan injury with bacterial sepsis, in absence of secondary bacterial infections, a process characterized as "viral sepsis". The intestinal barrier exerts a central role in the pathophysiological sequence of events that lead from SARS-CoV-2 infection to severe systemic complications. Accumulating evidence suggests that SARS-CoV-2 disrupts the integrity of the biological, mechanical and immunological gut barrier. Specifically, microbiota diversity and beneficial bacteria population are reduced, concurrently with overgrowth of pathogenic bacteria (dysbiosis). Enterocytes' tight junctions (TJs) are disrupted, and the apoptotic death of intestinal epithelial cells is increased leading to increased gut permeability. In addition, mucosal CD4(+) and CD8(+) T cells, Th17 cells, neutrophils, dendritic cells and macrophages are activated, and T-regulatory cells are decreased, thus promoting an overactivated immune response, which further injures the intestinal epithelium. This dysfunctional gut barrier in SARS-CoV-2 infection permits the escape of luminal bacteria, fungi and endotoxin to normally sterile extraintestinal sites and the systemic circulation. Pre-existing gut barrier dysfunction and endotoxemia in patients with comorbidities including cardiovascular disease, obesity, diabetes and immunosuppression predisposes to aggravated endotoxemia. Bacterial and endotoxin translocation promote the systemic inflammation and immune activation, which characterize the SARS-CoV-2 induced "viral sepsis" syndrome associated with multisystemic complications of severe COVID-19.