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Purpose of Review In this review, we summarize current evidence on the association between antibiotics and the subsequent development of obesity through modulation of the gut microbiome. Particular emphasis is given on (i) animal and human studies and their limitations; (ii) the reservoir of antibiotics in animal feed, emerging antibiotic resistance, gut dysbiosis, and obesity; (iii) the role of infections, specifically viral infections, as a cause of obesity; and (iv) the potential therapeutic approaches other than antibiotics to modulate gut microbiome. Recent Findings Overall, the majority of animal studies and meta-analyses of human studies on the association between antibiotics and subsequent development of obesity are suggestive of a link between exposure to antibiotics, particularly early exposure in life, and the development of subsequent obesity as a result of alterations in the diversity of gut microbiota. The evidence is strong in animal models whereas evidence in humans is inconclusive requiring well-designed, long-term longitudinal studies to examine this association. Based on recent meta-analyses and epidemiologic studies in healthy children, factors, such as the administration of antibiotics during the first 6 months of life, repeated exposure to antibiotics for ≥ 3 courses, treatment with broad-spectrum antibiotics, and male gender have been associated with increased odds of overweight/obesity. Early antibiotic exposure in animal models has shown that reductions in the population size of specific microbiota, such as Lactobacillus, Allobaculum, Rikenellaceae, and Candidatus Arthromitus, are related to subsequent adiposity. These data suggest that the loss of diversity of the gut microbiome, especially early in life, may have potential long-term detrimental effects on the adult host gut microbiome and metabolic health. Genetic, environmental, and age-related factors influence the gut microbiome throughout the lifetime. More large-scale, longer-term, longitudinal studies are needed to determine whether changes that occur in the microbiome after exposure to antibiotics, particularly early exposure, are causal of subsequent weight gain or consequent of weight gain in humans. Summary Further well-designed, large-scale RCTs in humans are required to evaluate the effects of administration of antibiotics, particularly early administration, and the subsequent development of overweight/obesity. Therapeutic interventions, such as bacteriophage treatment or the use of probiotics, especially genetically engineered ones, need to be evaluated in terms of prevention and management of obesity.

Purpose of Review A growing body of evidence suggests that obesity and increased visceral adiposity are strongly and independently linked to adverse outcomes and death due to COVID-19. This review summarizes current epidemiologic data, highlights pathogenetic mechanisms on the association between excess body weight and COVID-19, compares data from previous pandemics, discusses why COVID-19 challenges the “obesity paradox,” and presents implications in prevention and treatment as well as future perspectives. Recent Findings Data from meta-analyses based on recent observational studies have indicated that obesity increases the risks of infection from SARS-CoV-2, severe infection and hospitalization, admission to the ICU and need of invasive mechanical ventilation (IMV), and the risk of mortality, particularly in severe obesity. The risks of IMV and mortality associated with obesity are accentuated in younger individuals (age ≤ 50 years old). The meta-inflammation in obesity intersects with and exacerbates underlying pathogenetic mechanisms in COVID-19 through the following mechanisms and factors: (i) impaired innate and adaptive immune responses; (ii) chronic inflammation and oxidative stress; (iii) endothelial dysfunction, hypercoagulability, and aberrant activation of the complement; (iv) overactivation of the renin–angiotensin–aldosterone system; (v) overexpression of the angiotensin-converting enzyme 2 receptor in the adipose tissue; (vi) associated cardiometabolic comorbidities; (vii) vitamin D deficiency; (viii) gut dysbiosis; and (ix) mechanical and psychological issues. Summary Mechanistic and large epidemiologic studies using big data sources with omics data exploring genetic determinants of risk and disease severity as well as large randomized controlled trials (RCTs) are necessary to shed light on the pathways connecting chronic subclinical inflammation/meta-inflammation with adverse COVID-19 outcomes and establish the ideal preventive and therapeutic approaches for patients with obesity.

We explored the association between circulating 25OHD and adherence to the Mediterranean Diet (MedDiet) in 402 Greek (21–65 years, 188 men and 214 women), normal weight, non-smoker, healthy volunteers in the Athens metropolitan area during summer and autumn, taking into account skin phototype, anthropometric, and lifestyle variables. Circulating 25OHD, parathormone, creatinine, calcium, and phosphate were determined. A vitamin D status of ≤25, ≤50, and ≤75 nmol/L was observed in 4.5, 37.3, and 74.1% of the subjects, respectively. The independent predictors of 25OHD deficiency were autumn, darker skin phototype, BMI, or waist circumference (WC), sunscreen use, less physical outdoor activity, and less adherence to the MedDiet. Higher intake of fish and olive oil was a positive independent predictor of elevated circulating 25OHD levels. In conclusion, higher adherence to the MedDiet, fish and olive oil consumption, were positively associated with circulating 25OHD independently from BMI or WC, skin phototype, season, and physical activity.

As the coronavirus 2019 disease (COVID-19) pandemic is going through its second year, the world is counting more than 4.9 million lives lost. Many repurposed immunomodulatory drugs have been tried and failed to treat COVID-19. The only successful treatments that improve survival are systemic corticosteroids and tocilizumab, by targeting the systemic inflammatory cascade. An intriguing observation that patients with chronic respiratory disease seem to be less prone to COVID-19 gave ground to the hypothesis that inhaled corticosteroids (ICS) may protect them from SARS-CoV-2 infection. In this review, we summarize current evidence regarding the therapeutic role of inhaled and systemic corticosteroids in COVID-19, and we present experimental data on the potential actions of ICS against SARS-CoV-2 infection. We also discuss safety issues as well as therapeutic considerations and clinical implications of the use of ICS in COVID-19. Four randomized controlled trials (RCT) with more than 3,000 participants suggest that ICS may lead to earlier clinical improvement and lower rate of hospitalization in patients with mild COVID-19, while 9 ongoing RCTs are anticipated to provide more evidence for the use of ICS in COVID-19. Recent evidence has shown promise that ICS could provide tangible benefits to patients suffering from COVID-19.

Aberrant circulating omentin-1, which is an anti-inflammatory and pro-apoptotic adipokine, has been reported in various solid tumors. Therefore, we investigated whether or not circulating omentin-1 could be associated with postmenopausal BC (PBC) and could be used as a potential diagnostic and clinical tool taking into consideration clinicopathologic features, tumor markers, as well as anthropometric, metabolic, and inflammatory parameters. Serum omentin-1, tumor markers (CA15-3 and CEA), metabolic (insulin, glucose, HOMA index, and serum lipids), anthropometric (BMI, waist circumference, and fat mass), and inflammatory (TNF-α, IL-6, hsCRP) parameters, classic adipokines (leptin and adiponectin), the Mediterranean diet (MedDiet) score, and cardiovascular (CVD) risk were determined in 103 postmenopausal women with pathologically confirmed incident invasive BC, 103 controls matched on age, 51 patients with benign breast lesions (BBL), and 50 obese postmenopausal women of similar age. The mean serum omentin-1 was significantly lower in cases than in controls and patients with BBL (p &lt, 0.001). In the patients, omentin-1 was inversely associated with tumor, metabolic and inflammatory biomarkers, cancer stage, and the number of infiltrated lymph nodes (p &lt, 0.05). In all study participants, omentin-1 was negatively correlated with CVD risk and positively correlated with MedDiet score. Lower circulating omentin-1 was independently associated with PBC occurrence above and beyond known risk factors. According to the ROC curve analysis, the overall diagnostic performance of omentin-1 (0.84, 95% CI 0.79–0.89) is similar to CA15-3. Circulating omentin-1 may be a biomarker at the intersection of PBC and cardiometabolic risk in postmenopausal women, and could be modulated by the adoption of a MedDiet. Further mechanistic and large multicentric prospective and longitudinal studies are required to elucidate the ontological role of omentin-1 in BC and CVD risks, as well as its diagnostic and prognostic ability and its therapeutic potential.

The recognition of the rare but serious and potentially lethal complication of vaccine induced thrombotic thrombocytopenia (VITT) raised concerns regarding the safety of COVID-19 vaccines and led to the reconsideration of vaccination strategies in many countries. Following the description of VITT among recipients of adenoviral vector ChAdOx1 vaccine, a review of similar cases after Ad26.COV2·S vaccination gave rise to the question whether this entity may constitute a potential class effect of all adenoviral vector vaccines. Most cases are females, typically younger than 60 years who present shortly (range: 5-30 days) following vaccination with thrombocytopenia and thrombotic manifestations, occasionally in multiple sites. Following initial incertitude, concrete recommendations to guide the diagnosis (clinical suspicion, initial laboratory screening, PF4-polyanion-antibody ELISA) and management of VITT (non-heparin anticoagulants, corticosteroids, intravenous immunoglobulin) have been issued. The mechanisms behind this rare syndrome are currently a subject of active research and include the following: 1) production of PF4-polyanion autoantibodies; 2) adenoviral vector entry in megacaryocytes and subsequent expression of spike protein on platelet surface; 3) direct platelet and endothelial cell binding and activation by the adenoviral vector; 4) activation of endothelial and inflammatory cells by the PF4-polyanion autoantibodies; 5) the presence of an inflammatory co-signal; and 6) the abundance of circulating soluble spike protein variants following vaccination. Apart from the analysis of potential underlying mechanisms, this review aims to synopsize the clinical and epidemiologic features of VITT, to present the current evidence-based recommendations on diagnostic and therapeutic work-up of VITT and to discuss new dilemmas and perspectives that emerged after the description of this entity.

BACKGROUND Leptin, the prototype adipokine, exerts immunomodulatory actions being implicated in inflammatory responses during sepsis. Clinical evidence regarding its role in sepsis has been contradictory, while free leptin has not been studied. The aim of this study was to jointly investigate circulating total leptin, its soluble receptor (sOB-R), and free leptin, as well as their kinetics in critically ill patients with sepsis regarding their diagnostic and prognostic value. METHODS In a prospective study, serum total leptin, sOB-R and free leptin index (FLI) were determined in 102 critically ill patients with sepsis within 48 hours from sepsis onset and one week after enrollment, and in 102 age and gender-matched healthy controls. RESULTS Upon enrolment, total leptin, sOB-R and FLI were significantly higher in septic patients compared to controls and they were positively correlated with sepsis severity scores, while they presented a significant decrease during the first week (P

The adipocytokines eNampt and resistin are involved in the regulation of inflammation exerting pro-inflammatory actions. Our aim was to jointly investigate whether circulating eNampt and resistin, and their kinetics predict 28-day mortality of sepsis.In a prospective study, serum eNampt and resistin were determined in 102 critically ill patients fulfilling the diagnostic criteria of SEPSIS-3, at enrollment and one week after, and in 102 healthy controls matched on age, gender and month of diagnosis.Serum eNampt and resistin were significantly higher in septic patients than controls (p 0.001), and higher in septic shock compared to sepsis (p 0.001). Both eNampt and resistin decreased significantly during the first week of sepsis (p 0.001). However, patients with septic shock presented a sustained elevation of eNampt and resistin compared to patients with sepsis. Both adipocytokines were positively correlated with sepsis severity scores and lactate. Baseline eNampt was a better discriminator of sepsis and septic shock compared to C-reactive protein and procalcitonin. Serum eNampt and resistin were higher in nonsurvivors than in survivors during the first week of sepsis. Prolonged and sustained elevation of both eNampt and resistin, as reflected by a lower percentage change from their baseline values, was independently associated with 28-day mortality (HR: 0.05, 95% C.I. 0.01-0.28, p = 0.001; HR: 0.19, 95% C.I. 0.07-0.50, p = 0.001, respectively), after adjustment for significant clinical and laboratory biomarkers.Circulating eNampt and resistin, and their kinetics may represent useful diagnostic and prognostic biomarkers in critically ill septic patients. More prospective studies are needed to elucidate their ontological and pathophysiological role in sepsis.

Liver dysfunction during sepsis is associated with increased bilirubin and decreased fetuin-A, a major hepatokine. We aimed to explore the association of bilirubin to fetuin-A (B/F) ratio early in sepsis with severity and outcome in critically ill patients. Based on a previous prospective study, we analyzed data of 90 critically ill patients (52 males, age: 65 ± 15 years, APACHE II: 24 ± 7 and SOFA: 10 ± 3) with sepsis. Bilirubin and fetuin-A increased during the first week of sepsis, (median (IQR) 0.45 (0.32-1) vs 0.55 (0.29-0.78) mg/dL, p = 0.03 and 302 (248-336) vs 358 (307-399) μg/mL, p < 0.001, respectively) while the B/F ratio did not change significantly. However, the B/F ratio at baseline and one week later was significantly higher in patients with septic shock (N = 38) and nonsurvivors (N = 28) compared to patients with sepsis (N = 52) and survivors (N = 62), respectively. The B/F ratio was positively associated with severity scores and outperformed bilirubin as a predictor of mortality in ROC curve analysis (AUC 0.78 (0.69-0.88), p < 0.001 and 0.69 (0.57-0.8), p = 0.003 respectively). The B/F ratio may be a promising sepsis biomarker with possible predictive value in critically ill patients.

Evidence from observational studies suggests that obesity is associated with low vitamin D. As both obesity and hypovitaminosis D present an alarmingly increased prevalence worldwide, there is an intense research interest to clarify all aspects of this association. This review summarizes current evidence from meta-analyses investigating vitamin D status in obesity, including the effects of weight loss and bariatric surgery on vitamin D status and the outcomes of vitamin D supplementation on body weight. We also discuss potential pathophysiologic mechanisms and important controversies. Data from meta-analyses consistently support an inverse association of vitamin D levels with body weight. However, the impact of weight loss on improving vitamin D status is small, while studies on the supplementation with vitamin D after bariatric surgery have shown conflicting results regarding vitamin D status. Moreover, interventional studies do not support a beneficial effect of vitamin D supplementation on body weight. These findings warrant a cautious interpretation due to important methodological limitations and confounding factors, such as high heterogeneity of studies, variable methods of determination of vitamin D and definition of deficiency/insufficiency, use of various adiposity measures and definitions of obesity, and inadequate adjustment for confounding variables influencing vitamin D levels. The underlying pathogenetic mechanisms associating low vitamin D in obesity include volumetric dilution, sequestration into adipose tissue, limited sunlight exposure, and decreased vitamin D synthesis in the adipose tissue and liver. Experimental studies have demonstrated that low vitamin D may be implicated in adipose tissue differentiation and growth leading to obesity either by regulation of gene expression or through modulation of parathyroid hormone, calcium, and leptin. Obesity is associated with low vitamin D status but weight loss has little effect on improving this; vitamin D supplementation is also not associated with weight loss. Evidence regarding vitamin D status after bariatric surgery is contradicting. The link between vitamin D and obesity remains controversial due to important limitations and confounding of studies. More research is needed to clarify the complex interplay between vitamin D and adiposity.

Aims and Objectives: Sepsis is an acute life-threatening systemic inflammatory response to infection. C-reactive protein (CRP) and albumin are positive and negative acute phase proteins respectively, following opposing patterns in sepsis. We aim to investigate whether CRP/albumin ratio is a better prognostic marker of 28-day mortality in critically ill patients with sepsis than CRP alone. Methods: In a prospective study, CRP and albumin were determined in serum of 102 critically ill patients (57 males, age 65±15 years, APACHE II 23±7, SOFA 10±3) at sepsis onset and one week after. Results: Thirty patients (29.4%) died within 28 days from enrolment. CRP and CRP/albumin ratio decreased significantly one week after sepsis onset (145±94 vs 91±71mg/L, p Conclusions: CRP/albumin ratio is a good predictor of 28-day mortality in critically ill patients with sepsis, similar to CRP but better than SOFA and APACHE II scores.

Aims and Objectives: Sepsis constitutes an acute inflammatory response to infection affecting liver function. Increased serum bilirubin as well as decreased fetuin-A, a major hepatokine, have been shown in critically ill patients with sepsis. We aim to explore the association of serum bilirubin/fetuin-A (B/F) ratio early in sepsis with severity and outcome. Methods: In a prospective study, serum total bilirubin and fetuin-A were determined in 90 critically ill patients (52 males, age 65±15 years, APACHE II 24 ±7, SOFA 10±3) at sepsis onset and one week after. B/F ratio was calculated using the formula 10.000 x Bilirubin (mg/dL) / Fetuin-A (μg/mL). Mortality rate at 28 days after enrollment was the primary outcome. Results: Twenty eight patients (31%) died within 28 days. Bilirubin and fetuin-A increased one week after sepsis onset compared to baseline (1.16±2.3 vs 1.38±2.84mg/dL, p=0.03 and 306±107 vs 372±147μg/mL, p Conclusions: B/F ratio at sepsis onset is associated with severity and outcome and may be a useful prognostic biomarker in critically ill septic patients.

Aims and Objectives: Sepsis results in severe lipid metabolic alterations. Lipids exert important immunomodulatory actions during infection. We aim to investigate whether serum lipid changes early in sepsis are associated with severity and outcome. Methods: In a prospective study, serum total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TG) were determined in 82 critically ill patients (49 males, age 65±14 years, APACHE II 23±7, SOFA 10±3) at sepsis onset and one week after, and in 82 age and gender-matched healthy controls. Results: Upon enrollment, TC, HDL and LDL were significantly lower and TG were higher in patients compared to controls (p Conclusions: Critically ill septic patients exhibit significant alterations of serum lipids associated with sepsis severity and outcome.

Endothelial cell involvement with COVID-19 has been shown in the lung, heart, kidney, intestine and brain with histopathological evidence of endotheliitis and vasculitis. Viral RNA of COVID-19 has been detected in the retina of affected patients and recent publications highlight the possibility of retinal microangiopathy in patients with confirmed COVID-19 infection. Given the magnitude of the current pandemic, emphasis should be given to better reporting of clinically significant ocular symptoms, e.g. new scotoma, which could indicate the need for a retinal examination as well as follow-up testing after recovery from COVID-19.

Patient: Male, 73-year-old Final Diagnosis: Severe COVID-19 pneumonia complicated by right atrium thrombus Symptoms: Fever • dyspnea • cough Medication:— Clinical Procedure: — Specialty: Critical Care Medicine Objective: Educational purpose Background: Recent studies demonstrated evidence of coagulation dysfunction in hospitalized patients with severe coronavirus disease 2019 (COVID-19) due to excessive inflammation, hypoxia, platelet activation, endothelial dysfunction, and stasis. Effective anticoagulation therapy may play a dominant role in the management of severe COVID-19 cases. Case Report: A 73-year-old man with a 6-day history of fever up to 38.5°C, dyspnea, cough, and fatigue was diagnosed with COVID-19. He had a past medical history significant for hypertension and coronary artery bypass grafting. Two days after hospital admission, the patient developed acute respiratory failure, requiring intubation, mechanical ventilation, and transfer to the intensive care unit (ICU). He received treatment including antibiotics, hydroxychloroquine, tocilizumab, vasopressors, prone positioning, and anticoagulation with enoxaparin at a prophylactic dose. After a 15-day ICU stay, the patient was hemodynamically stable but still hypoxemic; a transthoracic echocardiogram at that time, followed by a transesophageal echocardiogram for better evaluation, revealed the presence of a right atrium thrombus without signs of acute right ventricular dilatation and impaired systolic function. Since the patient was hemodynamically stable, we decided to treat him with conventional anticoagulation under close monitoring for signs of hemodynamic deterioration; thus, the prophylactic dose of enoxaparin was replaced by therapeutic dosing, which was a key component of the patient’s successful outcome. Over the next few days he showed significant clinical improvement. The follow-up transesophageal echo-cardiogram 3 weeks after effective therapeutic anticoagulation revealed no signs of right heart thrombus. Conclusions: The presented COVID-19 case, one of the first reported cases with evidence of right heart thrombus by transesophageal echocardiography, highlights the central role of diagnostic imaging strategies and the importance of adequate anticoagulation therapy in the management of severe COVID-19 cases in the ICU.

The most severe presentation of COVID-19 is characterized by a hyperinflammatory state attributed to the massive pro-inflammatory cytokine release, called "cytokine storm". Several specific anti-inflammatory/immunosuppressive agents are being evaluated by ongoing clinical trials; however, there is currently insufficient evidence for their efficacy and safety in COVID-19 treatment. Given the role of phosphodiesterase 4 (PDE) 4 and cyclic adenosine monophosphate in the inflammatory response, we hypothesize that selective PDE4 inhibition may attenuate the cytokine storm in COVID-19, through the upstream inhibition of pro-inflammatory molecules, particularly TNF-α, and the regulation of the pro-inflammatory/anti-inflammatory balance. Conversely, other anti-cytokine agents lead to the downstream inhibition of specific targets, such as IL-1, IL-6 or TNF-α, and may not be efficient in blocking the cytokine storm, once it has been triggered. Due to their mechanism of action targeting an early stage of the inflammatory response and ameliorating lung inflammation, we believe that selective PDE4 inhibitors may represent a promising treatment option for the early phase of COVID-19 pneumonia before the cytokine storm and severe multiorgan dysfunction take place. Furthermore, PDE4 inhibitors present several advantages including an excellent safety profile; the oral route of administration; the convenient dosing; and beneficial metabolic properties. Interestingly, obesity and diabetes mellitus type 2 have been reported to be risk factors for the severity of COVID-19. Therefore, randomized clinical trials of PDE4 inhibitors are necessary to explore their potential therapeutic effect as an adjunct to supportive measures and other therapeutic regiments.

Chemerin is an emerging adipocytokine at the intersection of inflammation, chemotaxis, thrombosis, fibrinolysis and metabolism. Our aims were 1) to explore circulating chemerin in resectable non-small cell lung cancer (NSCLC) taking into account its several interfaces; 2) to study its diagnostic potential; and 3) to assess its associations with clinicopathological features of NSCLC.In a large case-control study, serum chemerin, insulin resistance and lipid parameters, classic adipocytokines, inflammatory, coagulation, fibrinolysis and tumor biomarkers were determined in 110 consecutive patients with resectable NSCLC and 110 healthy controls matched on age (± 5 years), gender and date of blood draw (± 1 month).NSCLC cases exhibited significantly elevated circulating chemerin compared to controls (p 0.001). In NSCLC cases, chemerin was positively associated with Homeostasis model assessment score of insulin resistance (HOMA-IR), fibrinogen, plasminogen activity, tumor and inflammatory biomarkers, adiponectin, number of infiltrated lymph nodes and NSCLC stage. In control participants, circulating chemerin was positively correlated with somatometric, metabolic, lipid, hemostatic and inflammatory biomarkers, and leptin. Serum chemerin was independently associated with NSCLC, above and beyond NSCLC risk factors (OR: 2.20, 95% CI: 1.09-4.40, p = 0.03). In cases, hemostatic parameters (platelet count and plasminogen activity), HOMA-IR, CYFRA 21-1, creatinine and plant food consumption emerged as independent predictors of circulating chemerin (p 0.05). Serum chemerin greater than 220 μg/L (cut-off point) yielded a sensitivity and a specificity of 63% and 91.8% respectively with a modest discriminative ability (AUC = 0.72, 95% C.I. 0.64-0.79) for the diagnosis of NSCLC.Chemerin may represent a potentially useful biomarker in NSCLC integrating tumor-promoting networks, inflammatory and hemostatic mechanisms, and cancer-related metabolic pathways. More preclinical, prospective and longitudinal studies highlighting the pathogenetic role of chemerin in NSCLC are needed to corroborate and extend these data.

Fetuin-A and adiponectin, major hepatokine and adipokine respectively, have been implicated in systematic inflammation. Our aim was to jointly investigate whether kinetics of circulating fetuin-A, adiponectin and its isoform HMWA predict 28-day mortality in sepsis.In a prospective study, serum fetuin-A, adiponectin and HMWA were determined in 102 ICU patients fulfilling the diagnostic criteria of SEPSIS-3, at enrollment and one week after, and in 102 healthy controls matched on age and gender.Serum fetuin-A was significantly lower in septic patients than controls (p0.001). Among septic patients, those with septic shock and nonsurvivors presented lower fetuin-A, but higher adiponectin and HMWA compared to patients with sepsis and survivors respectively, both at baseline and day 7 (p0.001). Fetuin-A exhibited negative correlations with APACHE II, CRP, procalcitonin, adiponectin and IL-6 but a positive one with albumin. Reduced fetuin-A as well as lower serum kinetics of fetuin-A (HR: 0.55, 95% C.I. 0.34-0.91, p=0.02), adiponectin but not HMWA were independently associated with 28-day mortality adjusting for age, gender, BMI, APACHE II, septic shock and laboratory biomarkers.Circulating fetuin-A kinetics may be a prognostic biomarker in septic patients. More research is essential to elucidate fetuin-A's ontological role in sepsis pathophysiology.

Controversies in outcomes with the parenteral administration of antioxidants as adjuvant therapies led to the measurement of malondialdehyde (MDA), a product of lipid peroxidation, in serum collected from 120 patients with primary Gram-negative bacteremia during the first 24 h from sepsis onset. MDA was measured by the thiobarbiturate assay, followed by high-performance liquid chromatography (HPLC) analysis. After receiver operator characteristic (ROC) curve analysis, patients were divided into those with high levels of MDA and low levels of MDA. The primary endpoint was the association of the level of MDA with septic shock. The level of MDA as an index of neutrophil function and associations with outcome and with infections by carbapenem-resistant Klebsiella pneumoniae were the secondary endpoints. In total, 63 patients had high and 57 had low MDA levels; 27% and 49.1%, respectively, had septic shock (p = 0.015). The rate of the concentration of MDA to the total neutrophil count was used as an expression of neutrophil function; this was lower among patients with septic shock. The odds ratio (OR) for death among patients without septic shock and low level of MDA was 4.00; this was 0.48 for patients with septic shock (p = 0.020 between the two ORs). The OR for resistance to carbapenems among patients with bacteremia by K. pneumoniae and low level of MDA was 7.50 (p = 0.011 compared to patients with bacteremia by other pathogens). Low level of circulating MDA is associated with susceptibility to septic shock and infections by carbapenem-resistant K. pneumoniae.

Since the beginning of the COVID-19 pandemic, researchers have focused on repurposing of existing antibiotics, antivirals and anti-inflammatory drugs to find an effective therapy. Fluoroquinolones are broad spectrum synthetic antimicrobial agents, being chemical derivatives of quinoline, the prodrome of chloroquine. Interestingly, fluoroquinolones may exert antiviral actions against vaccinia virus, papovavirus, CMV, VZV, HSV-1, HSV-2, HCV and HIV. A recent in silico study has shown that the fluoroquinolones, ciprofloxacin and moxifloxacin, may inhibit SARS-CoV-2 replication by exhibiting stronger capacity for binding to its main protease than chloroquine and nelfinavir, a protease inhibitor antiretroviral drug. Remarkably, fluoroquinolones have shown multiple immunomodulatory actions leading to an attenuation of the inflammatory response through the inhibition of pro-inflammatory cytokines. Noteworthy, respiratory fluoroquinolones, levofloxacin and moxifloxacin, constitute fist line therapeutic agents for the management of severe community-acquired pneumonia. They are characterized by advantageous pharmacokinetic properties; higher concentrations in the lungs; and an excellent safety profile comparable to other antibiotics used to treat respiratory infections, such as macrolides and b-lactams. Based on their potential antiviral activity and immunomodulatory properties, the favorable pharmacokinetics and safety profile, we propose the use of respiratory fluoroquinolones as adjuncts in the treatment of SARS-CoV-2 associated pneumonia.

Sepsis has become a global health problem with rising incidence and high mortality, creating a substantial social and economic burden. Early diagnosis and treatment can improve outcome, but reliable sepsis biomarkers are lacking. This review summarizes current evidence of the pathophysiological mechanisms linking adipose tissue to sepsis and presents experimental and clinical data on adipokines and sepsis along with important insights into the obesity paradox in sepsis survival. Sepsis is characterized by significant alterations in circulating cytokines and adipokines, biologically active molecules produced by the adipose tissue, being implicated in metabolic and inflammatory processes. Although data are inconclusive regarding classic adipokines such as leptin and adiponectin, recent evidence have highlighted the striking elevation of resistin and visfatin in critical illness and sepsis as well as their association with sepsis severity and outcomes. Given that inflammatory and metabolic pathways are involved in sepsis, studying adipokines presents an attractive, innovative, and promising research field that may provide more powerful diagnostic and prognostic biomarkers as well as novel therapeutic targets, empowering the therapeutic armamentarium for sepsis management in order to improve survival.

Introduction: Non small cell lung cancer (NSCLC) is the leading cause of cancer-related death globally. There is a tremendous interest in identifying novel biomarkers. The pathophysiological role of classic and novel adipokines in NSCLC is not yet fully understood and their value as diagnostic biomarkers is currently under research. Aim: To explore the diagnostic potential of classic (leptin, adiponectin) and novel adipokines (chemerin, plasminogen activator inhibitor-1 activity/PAI-1) in resectable NSCLC. Methods: In a large case-control study, circulating chemerin, adiponectin, leptin and PAI-1 were determined in 110 consecutive patients with resectable NSCLC and 110 healthy controls matched on age (± 5 years), gender and date of blood draw (± 1 month). Serum leptin, chemerin and adiponectin were determined by ELISA (BioVendor and ALPCO). Plasma PAI-1 activity was determined using Berichrom® PAI (Siemens). Results: Patients with NSCLC had significantly higher chemerin and PAI-1 activity (p Conclusion: Novel adipokines showed higher discriminative ability than classic adipokines in the NSCLC diagnosis. More prospective studies are required to assess the potential diagnostic significance of novel adipokines in NSCLC.

Introduction: Non-traumatic coma (NTC) is a common cause of critical illness with diverse etiology and prognosis Aim: To investigate the etiology and outcome of NTC in ICU patients and to explore prognostic factors Methods: In a retrospective study we reviewed the medical records of all patients admitted to the ICU of a teaching hospital due to NTC, from January 2018 to January 2019. Demographic data, medical history, APACHE II score, etiology of coma and ICU mortality were recorded. Results: Among 250 medical records, we identified 30 cases (16 males, mean age 68±14, APACHE II 21±7) of NTC. The etiology of NTC was: intracerebral hemorrhage (8), respiratory failure (6), sepsis (5), post-anoxic (4), CNS infection (3), ischemic stroke (2), metabolic coma (2). Thirteen patients died in the ICU (43%) and 17 were discharged. Sepsis presented the highest ICU mortality (80%), followed by post-anoxic (75%), intracerebral hemorrhage (62%) and ischemic stroke (50%). All patients with respiratory failure, CNS infection and metabolic coma survived to discharge. Sex, age, APACHE II score and history of chronic kidney, respiratory, cardiovascular disease or malignancy were not correlated with ICU mortality (p>0.05). Elevated serum lactate (p:0.018), acute kidney injury (p:0.005) and hypotension (p:0.033) at admission were associated with ICU mortality. Acute kidney injury on the day of admission tripled the risk of death (HR:2.8, 95%CI: 1.2-6.6, p Conclusion: Intracerebral hemorrhage was the leading cause of NTC, followed by respiratory failure and sepsis. Acute kidney injury was the best predictor of ICU mortality.

Background Subclinical hypothyroidism (SH) is more frequent in females than males, with a female to male ratio ranging from 1.5 to 5 in the general population. The aim of this study was to evaluate for the first time the association of reproductive factors, particularly age at menarche, with SH risk. Materials and methods In a cross-sectional study, reproductive factors such as age at menarche, at menopause and at first birth, lactation, parity, full-term pregnancies, reproductive years, use of oral contraceptives and hormonal replacement therapy, somatometric data and insulin resistance parameters were recorded in 72 consecutive female patients with SH and 72 healthy female controls matched on age (±5 years) and date of diagnosis (±1 month). Results SH cases exhibited significantly younger age at menarche than controls (12.6 ± 1.2 vs. 13.3 ± 0.8 years, respectively, p < 0.001). Cases presented later age at first pregnancy with a lower number of full-term pregnancies (p = 0.04). Early age at menarche was independently associated with SH risk, above and beyond thyroid autoimmunity, body mass index (BMI), hip circumference (HC), homeostatic model assessment of insulin resistance and alcohol consumption [odds ratio (OR): 0.22, 95% confidence interval (CI): 0.11–0.44; p < 0.001]. Conclusions It is possible that an interplay of early exposure to estrogens, as expressed by early menarche, and induction of thyroid autoimmunity may be associated with SH risk. More prospective studies shedding light on the role of estrogens in SH are required to confirm these findings.

Αbstract: Remdesivir (GS-5734), a drug initially developed to treat hepatitis C and Ebola virus disease, was the first approved treatment for severe coronavirus disease 2019 (COVID-19). However, apart from remdesivir, there is a paucity of other specific anti-viral agents against SARS-CoV-2 infection. In 2017, researchers had documented the anti-coronavirus potential of remdesivir in animal models. At the same time, trials performed during two Ebola outbreaks in Africa showed that the drug was safe. Although vaccines against SARS-CoV-2 infection have emerged at an enormously high speed, equivalent results from efforts towards the development of anti-viral drugs, which could have played a truly life-saving role in the current stage of the pandemic, have been stagnating. In this review, we will focus on the current treatment options for COVID-19 which mainly consist of repurposed agents or treatments conferring passive immunity (convalescent plasma or monoclonal antibodies). Additionally, potential specific anti-viral therapies under development will be reviewed, such as the decoy miniprotein CTC-445.2d, protease inhibitors, mainly against the Main protein Mpro, nucleoside analogs, such as molnupiravir and compounds blocking the replication transcription complex proteins, such as zotatifin and plitidepsin. These anti-viral agents seem to be very promising but still require meticulous clinical trial testing in order to establish their efficacy and safety. The continuous emergence of viral variants may pose a real challenge to the scientific community towards that end. In this context, the advent of nanobodies together with the potential administration of a combination of anti-viral drugs could serve as useful tools in the armamentarium against COVID-19.

The pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant threat to global health. Currently, no specific prophylactic and therapeutic treatment is available. No evidence from randomized clinical trials (RCTs) that a treatment may ameliorate the clinical outcome of patients with COVID-19 exists with the only exception of preliminary evidence from remdesivir trials. Here, we present evidence from the literature and a compelling hypothesis on the potential immunomodulatory, iron chelating and anti-oxidant effects of iron chelators in the treatment of COVID-19 and its complications. Interestingly, iron chelation has been shown in vitro to suppress endothelial inflammation in viral infection, which is the main pathophysiologic mechanism behind systemic organ involvement induced by SARS-CoV-2, by inhibiting IL-6 synthesis through decreasing NF-kB. Iron chelators exhibit iron chelating, antiviral and immunomodulatory effects in vitro and in vivo, particularly against RNA viruses. These agents could attenuate ARDS and help control SARS-CoV-2 via multiple mechanisms including: 1) inhibition of viral replication; 2) decrease of iron availability; 3) upregulation of B cells; 4) improvement of the neutralizing anti-viral antibody titer; 5) inhibition of endothelial inflammation and 6) prevention of pulmonary fibrosis and lung decline via reduction of pulmonary iron accumulation. Both retrospective analyses of data in electronic health records, as well as proof of concept studies in humans and large RCTs are needed to fully elucidate the efficacy and safety of iron chelating agents in the therapeutic armamentarium of COVID-19, probably as an adjunctive treatment.

Background: Experimental and clinical data have shown that the adipocytokines eNAMPT and resistin interact with cytokines and other inflammatory molecules in the pathogenesis of sepsis. Objective: To investigate eNAMPT and resistin’s role as biomarkers of sepsis compared to well-established inflammatory markers and cytokines. Methods: We prospectively studied 102 critically ill patients (57 males, mean age 65±15years) fulfilling the diagnostic criteria of SEPSIS-3, during the first week of sepsis. Serum eNAMPT and resistin were determined by ELISA (Phoenix Pharmaceuticals, CA, USA) at sepsis onset and one week after. We also determined C-reactive protein (CRP), procalcitonin, interleukins IL-6, IL-10, tumor necrosis factor alpha (TNF-α) and soluble urokinase-type plasminogen activator receptor (suPAR). The discriminating power of measured parameters as predictors of sepsis and septic shock was obtained by Receiver Operating Characteristic (ROC) curves. Results: Sixty patients presented with sepsis and 42 with septic shock. Mortality within 28 days was 29.4%. eNAMPT exhibited significantly positive correlations with CRP, procalcitonin and IL-10 at admission, and with procalcitonin one week after enrollment. Resistin was positively correlated with IL-6, IL-10 and TNF-α at admission and with procalcitonin one week after enrollment. Area under ROC curves showed that eNAMPT (AUROC>0.83) and CRP (AUROC>0.78) outperformed procalcitonin (AUROC>0.71), resistin (AUROC>0.69), IL-6 (AUROC>0.69), IL-10 (AUROC>0.68) and suPAR (AUROC>0.64) in discriminating sepsis from septic shock. Conclusion: eNAMPT is a better discriminator biomarker for sepsis and septic shock, while resistin’s performance is comparable to procalcitonin.

Background: eNAMPT, an adipokine with pro-inflammatory properties, has been implicated in acute and chronic inflammation. However, its kinetics has not been studied in sepsis. Objective: To investigate whether eNAMPT and its kinetics early in sepsis predict severity and outcome. Methods: In a prospective case-control study, serum eNAMPT concentrations were determined by ELISA in 102 critically ill patients (57 males, mean age 65±15 years) fulfilling the diagnostic criteria of SEPSIS-3, at sepsis onset and one week after, and in 102 age and gender-matched healthy controls. Results: Sixty patients presented with sepsis and 42 with septic shock. Mean APACHE II was 23±7. Thirty patients died within 28 days (mortality 29.4%). At admission, serum eNAMPT was significantly higher in patients compared to controls (79.1±19.5 vs 44.9±27.5ng/mL, p Conclusion: eNAMPT in early sepsis may be a novel diagnostic and prognostic biomarker in critically ill septic patients.

[No Abstract Available].

Irisin, a newly discovered adipo-myokine, is implicated in the modulation of the adipose phenotype, increasing energy expenditure and ameliorating systemic metabolism. Our aim was to investigate circulating irisin in subclinical hypothyroidism (SH) and study its associations with cardiometabolic risk factors. In a large case–control study, serum irisin, insulin resistance and lipid parameters, classic adipokines, inflammatory and hepatic biomarkers, and cardiovascular risk factors were determined in 120 consecutive patients with SH and 120 healthy controls matched on age, gender, and date of blood draw. Sixteen patients with SH received L-T4 treatment and, after 6 months, serum irisin and other biomarkers were assessed. SH cases exhibited significantly higher circulating irisin than controls (p

Background: Adiponectin, the most abundant active adipokine, exhibits anti-inflammatory properties affecting survival in critical illness. Objective: To explore whether kinetics of serum adiponectin and its main isoform HMWA is associated with 28-day mortality in sepsis. Methods: In a prospective study, serum adiponectin and HMWA concentrations were determined by ELISA (ALPCO) in 102 ICU patients fulfilling the diagnostic criteria of SEPSIS-3, at enrollment and one week after, and in 102 healthy controls matched on age and gender. Results: At admission, serum adiponectin (and HMWA) was significantly elevated in septic patients than in healthy controls (10.33 ± 2.96 vs 6.25 ± 1.53 μg/mL, p Conclusion: Kinetics of serum adiponectin may be independently associated with mortality in septic patients.

Contains fulltext : 138898.pdf (Publisher’s version ) (Closed access) BACKGROUND: Infections are a leading cause of death in patients with advanced cirrhosis, but there are relatively few data on the epidemiology of infection in intensive care unit (ICU) patients with cirrhosis. AIMS: We used data from the Extended Prevalence of Infection in Intensive Care (EPIC) II 1-day point-prevalence study to better define the characteristics of infection in these patients. METHODS: We compared characteristics, including occurrence and types of infections in non-cirrhotic and cirrhotic patients who had not undergone liver transplantation. RESULTS: The EPIC II database includes 13,796 adult patients from 1265 ICUs: 410 of the patients had cirrhosis. The prevalence of infection was higher in cirrhotic than in non-cirrhotic patients (59 vs. 51%, P < 0.01). The lungs were the most common site of infection in all patients, but abdominal infections were more common in cirrhotic than in non-cirrhotic patients (30 vs. 19%, P < 0.01). Infected cirrhotic patients more often had Gram-positive (56 vs. 47%, P < 0.05) isolates than did infected non-cirrhotic patients. Methicillin-resistant Staphylococcus aureus (MRSA) was more frequent in cirrhotic patients. The hospital mortality rate of cirrhotic patients was 42%, compared to 24% in the non-cirrhotic population (P < 0.001). Severe sepsis and septic shock were associated with higher in-hospital mortality rates in cirrhotic than in non-cirrhotic patients (41% and 71% vs. 30% and 49%, respectively, P < 0.05). CONCLUSIONS: Infection is more common in cirrhotic than in non-cirrhotic ICU patients and more commonly caused by Gram-positive organisms, including MRSA. Infection in patients with cirrhosis was associated with higher mortality rates than in non-cirrhotic patients.

Neural tube defects are the second most common congenital anomaly. Among the known risk factors, low levels of folic acid rank first as responsible for the majority of cases recorded worldwide. In 1986, the mandatory folic acid food fortification in the U.S.A. led to dramatic reduction of disease incidence, while for many people it was considered as one of the most successful interventions in the history of public health promotion. Despite the satisfactory results from all countries that adopted similar policies, a significant number of countries, including the EU, preferred alternative ways to address it, considering the very limited safety data for such an intervention. Today, after 20 years of mandatory fortification from a sufficiently representative sample (1/3 of the planet), the necessity to apply this at global level should probably be reviewed, since until now no correlation with unfavourable impacts has been demonstrated. Objective of the present review was to assess the necessity of mandatory folic acid food fortification in the context of congenital neural tube defects (NTDs) prevention. Material – Method : an extensive search in the electronic database PubMed was performed. Animal or in vivo studies and articles were excluded, due to the inability to draw conclusions that is frequently observed, as well as the strong suspicion of failure to respond to clinical data. Furthermore, part of the studies was derived from searches to the References of the articles of the aforementioned database. Conclusions : the decision of mandatory folic acid food fortification should be determined by specific factors as: disease prevalence, rates of planned pregnancies, efficiency of existing measures to decrease significantly the overall disease’s incidence and the folate level in the general population.

Aspergillus, a ubiquitous fungus, may cause a variety of clinical syndromes in the lung, depending on immune status of the host as well as the presence of underlying lung disease. The clinical spectrum of pulmonary aspergillosis ranges from aspergilloma in patients with cavitary lung diseas

Background: Abdominal infections are frequent causes of sepsis and septic shock in the intensive care unit (ICU) and are associated with adverse outcomes. We analyzed the characteristics, treatments and outcome of ICU patients with abdominal infections using data extracted from a one-day point prevalence study, the Extended Prevalence of Infection in the ICU (EPIC) II.Methods: EPIC II included 13,796 adult patients from 1,265 ICUs in 75 countries. Infection was defined using the International Sepsis Forum criteria. Microbiological analyses were performed locally. Participating ICUs provided patient follow-up until hospital discharge or for 60 days.Results: Of the 7,087 infected patients, 1,392 (19.6%) had an abdominal infection on the study day (60% male, mean age 62 ± 16 years, SAPS II score 39 ± 16, SOFA score 7.6 ± 4.6). Microbiological cultures were positive in 931 (67%) patients, most commonly Gram-negative bacteria (48.0%). Antibiotics were administered to 1366 (98.1%) patients. Patients who had been in the ICU for ≤2 days prior to the study day had more Escherichia coli, methicillin-sensitive Staphylococcus aureus and anaerobic isolates, and fewer enterococci than patients who had been in the ICU longer. ICU and hospital mortality rates were 29.4% and 36.3%, respectively. ICU mortality was higher in patients with abdominal infections than in those with other infections (29.4% vs. 24.4%, p < 0.001). In multivariable analysis, hematological malignancy, mechanical ventilation, cirrhosis, need for renal replacement therapy and SAPS II score were independently associated with increased mortality.Conclusions: The characteristics, microbiology and antibiotic treatment of abdominal infections in critically ill patients are diverse. Mortality in patients with isolated abdominal infections was higher than in those who had other infections. © 2014 De Waele et al. licensee BioMed Central Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published

Metastases distal to the elbow and the knee (acrometastases) are rare, accounting for approximately 0.1 % of all cases. Acrometastases can appear in patients of every age, with men being twice as likely as women to be affected. The most common primary cancer site is the lung (>50 %), followed by the colon, breast and genito-urinary tract. They mainly appear in cancer patients with wide-spread disseminated disease. Rarely, they may be the first presentation of occult silent cancer, mimicking a benign condition. Current evidence supports that the tumor cells reach the bones of the hands through the circulation and not the lymphatic system; the malignant cells from the lungs have an easy access through the arterial circulation of the arms. The rare incidence of foot acrometastases is believed to be due to the lack of red marrow in these bones, a further distance from the primary cancer site, and the valveless paravertebral venous plexuses (Batson’s plexuses), which allow retrograde tumor cell embolization through the iliofemoral venous system. Treatment depends on staging and tumor extent. Amputative surgery is the more common approach, especially for cancers with poor response to radiation therapy and chemotherapy. In the majority of cases, disarticulation of the ray is required to achieve wide margin resection. In the foot, amputation can be that of a ray, midfoot or transtibial, depending on the location and spread of the tumor. If unresectable, palliative treatment with radiation therapy, bisphosphonates and chemotherapy is recommended. The prognosis of the patients with acrometastatic cancer is poor; the mean survival time after diagnosis is

The role of the D allele of the angiotensin-converting enzyme (ACE) gene I/D polymorphism in the clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains controversial. We assessed simultaneously the effect of the ACE I/D polymorphisms as well as the serum and BALF ACE levels on prognosis of ARDS patients.

Objectives: To provide a global, up-to-date picture of the prevalence, treatment, and outcomes of Candida bloodstream infections in intensive care unit patients and compare Candida with bacterial bloodstream infection. Design: A retrospective analysis of the Extended Prevalence of Infection in the ICU Study (EPIC II). Demographic, physiological, infection-related and therapeutic data were collected. Patients were grouped as having Candida, Gram-positive, Gram-negative, and combined Candida/bacterial bloodstream infection. Outcome data were assessed at intensive care unit and hospital discharge. Setting: EPIC II included 1265 intensive care units in 76 countries. Patients: Patients in participating intensive care units on study day. Interventions: None. MEASUREMENT AND MAIN RESULTS:: Of the 14,414 patients in EPIC II, 99 patients had Candida bloodstream infections for a prevalence of 6.9 per 1000 patients. Sixty-one patients had candidemia alone and 38 patients had combined bloodstream infections. Candida albicans (n = 70) was the predominant species. Primary therapy included monotherapy with fluconazole (n = 39), caspofungin (n = 16), and a polyene-based product (n = 12). Combination therapy was infrequently used (n = 10). Compared with patients with Gram-positive (n = 420) and Gram-negative (n = 264) bloodstream infections, patients with candidemia were more likely to have solid tumors (p < .05) and appeared to have been in an intensive care unit longer (14 days [range, 5-25 days], 8 days [range, 3-20 days], and 10 days [range, 2-23 days], respectively), but this difference was not statistically significant. Severity of illness and organ dysfunction scores were similar between groups. Patients with Candida bloodstream infections, compared with patients with Gram-positive and Gram-negative bloodstream infections, had the greatest crude intensive care unit mortality rates (42.6%, 25.3%, and 29.1%, respectively) and longer intensive care unit lengths of stay (median [interquartile range]) (33 days [18-44], 20 days [9-43], and 21 days [8-46], respectively); however, these differences were not statistically significant. Conclusion: Candidemia remains a significant problem in intensive care units patients. In the EPIC II population, Candida albicans was the most common organism and fluconazole remained the predominant antifungal agent used. Candida bloodstream infections are associated with high intensive care unit and hospital mortality rates and resource use. Copyright 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Nosocomial infections are responsible for significant morbidity and mortality in ICU patients. This is particularly important considering the emergence of multidrug-resistant bacteria. Our aim was to retrospectively study the bacterial population responsible for colonization and infection of patients hospitalized in a multidisciplinary seven-bed ICU in a general hospital, as well as antibiotic resistance, during a 4-year period.

The aim of our study was to compare the characteristics of older patients (Group A, age ≥ 65 years) and younger ones (Group B, age