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IL-6 remains a key molecule of the cytokine storms characterizing COVID-19, exerting both proinflammatory and anti-inflammatory effects. Emerging research underscores the significance of IL-6 trans-signaling over classical signaling pathways, which has shifted the focus of therapeutic strategies. Additionally, the synergistic action of TNF-α and IFN-γ has been found to induce inflammatory cell death through PANoptosis, further amplifying the severity of cytokine storms. Long COVID-19 patients, as well as those with cytokine storms triggered by other conditions, exhibit distinct laboratory profiles, indicating the need for targeted approaches to diagnosis and management. Growing evidence also highlights the gut microbiota's crucial role in modulating the immune response during COVID-19 by affecting cytokine production, adding further complexity to the disease's immunological landscape. Targeted intervention strategies should focus on specific cytokine cutoffs, though accurate cytokine quantification remains a clinical challenge. Current treatment strategies are increasingly focused on inhibiting IL-6 trans-signaling, which offers promise for more precise therapeutic approaches to manage hyperinflammatory responses in COVID-19. In light of recent discoveries, this review summarizes key research findings on cytokine storms, particularly their role in COVID-19 and other inflammatory conditions. It explores emerging therapeutic strategies targeting cytokines like IL-6, TNF-α, and IFN-γ, while also addressing open questions, such as the need for better biomarkers to detect and manage cytokine storms. Additionally, the review highlights ongoing challenges in developing targeted treatments that mitigate hyperinflammation without compromising immune function, emphasizing the importance of continued research in this field.

Introduction: Over the past four years, the COVID-19 pandemic has posed serious global health challenges. The severe form of disease and death resulted from the failure of immune regulatory mechanisms, closely highlighted by the dual proinflammatory cytokine and soluble immune checkpoint (sICP) storm. Identifying the individual factors impacting on disease severity, evolution and outcome, as well as any additional interconnections, have become of high scientific interest., Methods: In this study, we evaluated a novel panel composed of ten sICPs for the predictive values of COVID-19 disease severity, mortality and Delta vs. Omicron variant infections in relation to hyperinflammatory biomarkers. The serum levels of sICPs from confirmed SARS-CoV-2 infected patients at hospital admission were determined by Luminex, and artificial neural network analysis was applied for defining the distinct patterns of molecular associations with each form of disease: mild, moderate, and severe., Results: Notably, distinct sICP profiles characterized various stages of disease and Delta infections: while sCD40 played a central role in all defined diagrams, the differences emerged from the distribution levels of four molecules recently found and relatively less investigated (sCD30, s4-1BB, sTIM-1, sB7-H3), and their associations with various hematological and biochemical inflammatory biomarkers. The artificial neural network analysis revealed the prominent role of serum sTIM-1 and Galectin-9 levels at hospital admission in discriminating between survivors and non-survivors, as well as the role of specific anti-interleukin therapy (Tocilizumab, Anakinra) in improving survival for patients with initially high sTIM-1 levels. Furthermore, strong associations between sCD40 and Galectin-9 with suPAR defined the Omicron variant infections, while the positive match of sCD40 with sTREM-1 serum levels characterized the Delta-infected patients., Conclusions: Of importance, this study provides a comprehensive analysis of circulatory immune factors governing the COVID-19 pathology, and identifies key roles of sCD40, sTIM-1, and Galectin-9 in predicting mortality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paranga, Pavel-Tanasa, Constantinescu, Iftimi, Plesca, Miftode, Cianga and Miftode.)

This article aims to analyze the relationship between non-obstructive coronary artery disease (NOCAD) and atrial fibrillation (AF), exploring the underlying pathophysiological mechanisms and implications for clinical management. NOCAD and AF are prevalent cardiovascular conditions that often coexist, yet their interrelation is not well understood. NOCAD can lead to ischemic necrosis of cardiomyocytes and their replacement with fibrous tissue, sustaining focal ectopic activity in atrial myocardium. Atrial fibrillation, on the other hand, the most common sustained cardiac arrhythmia, is able to accelerate atherosclerosis and increase oxygen consumption in the myocardium, creating a mismatch between supply and demand, and thus promoting the development or worsening of coronary ischemia. Therefore, NOCAD and AF seem to be a complex interplay with one begets another.

Background: The aim of our study was to analyze the factors associated with the increased risk of urinary tract infection (UTI) with carbapenem-resistant (CR) Klebsiella pneumoniae ( Kpn ) and the antibiotic resistance spectrum of the strains in patients. As secondary objectives, we elaborated the profile of these patients and the incidence of different types of carbapenemases., Methods: We conducted a retrospective case-control study in which we compared a group of 62 patients with urinary tract infections with CR Kpn with a control group consisting of 136 patients with urinary tract infections with multidrug-resistant (MDR), but carbapenem-sensitive (CS), Kpn , who were hospitalized between 1 January 2022 and 31 March 2024., Results: Compared to patients with urinary tract infections with CS Kpn , patients with urinary tract infections with CR Kpn were preponderant in rural areas (62.9% vs. 47.1%, p = 0.038) and more frequently had an upper urinary tract infection (69.4% vs. 36.8%, p < 0.01). Among the risk factors examined, patients in the study group had a higher presence of urinary catheters inserted for up to one month (50% vs. 34.6%, p = 0.03), rate of hospitalization in the last 180 days (96.8% vs. 69.9%, p < 0.01) and incidence of antibiotic therapy in the last 180 days (100% vs. 64.7%, p < 0.01). They also had a higher rate of carbapenem treatment in the last 180 days (8.1% vs. 0%, p < 0.01). Patients in the study group had a broader spectrum of resistance to all antibiotics tested ( p < 0.01), with the exception of sulfamethoxazole-trimethoprim, where the resistance rate was similar in both groups (80.6% vs. 67.6%, p = 0.059). In the multivariate analysis, transfer from other hospitals (OR = 3.51, 95% and CI: 1.430-8.629) and treatment with carbapenems in the last 180 days (OR = 11.779 and 95% CI: 1.274-108.952) were factors associated with an increased risk of disease compared to the control group. The presence of carbapenemases was observed in all patients with CR Kpn , in the order of frequency New Delhi metallo-ß-lactamase (NDM) (52.2%), Klebsiella pneumoniae carbapenemase (KPC) (32.6%), and carbapenem-hydrolyzing oxacillinase (Oxa-48) (15.2%)., Conclusions: The environment of origin and previous treatment with carbapenems appear to be the factors associated with an increased risk of urinary tract infection with CR Kpn compared to patients with urinary tract infections with CS Kpn . CR Kpn exhibits a broad spectrum of antibiotic resistance, among which is resistance to carbapenem antibiotics.

Clostridioides difficile infection (CDI), though identified nearly five decades ago, still remains a major challenge, being associated with significant mortality rates. The strains classified as hypervirulent, notably 027/NAP1/BI, have garnered substantial attention from researchers and clinicians due to their direct correlation with the severity of the disease. Our study aims to elucidate the significance of toxigenic Clostridioides difficile (CD) strains in the clinical and therapeutic aspects of managing patients diagnosed with CDI. We conducted a single-center prospective study, including patients with CDI from north-eastern Romania. We subsequently conducted molecular biology testing to ascertain the prevalence of the presumptive 027/NAP1/BI strain within aforementioned geographic region. The patients were systematically compared and assessed both clinically and biologically, employing standardized and comparative methodologies. The study enrolled fifty patients with CDI admitted between January 2020 and June 2020. Among the investigated patients, 43 (86%) exhibited infection with toxigenic CD strains positive for toxin B genes ( tcdB ), binary toxin genes ( cdtA and cdtB ), and deletion 117 in regulatory genes ( tcdC ), while the remaining 7 (14%) tested negative for binary toxin genes ( cdtA and cdtB ) and deletion 117 in tcdC . The presence of the presumptive 027/NAP1/BI strains was linked to a higher recurrence rate (35.56%, p = 0.025), cardiovascular comorbidities (65.1% vs. 14.2%, p = 0.016), and vancomycin treatment (55.8% vs. 14.3%, p = 0.049). The findings of our investigation revealed an elevated incidence of colitis attributed to presumptive 027/NAP1/BI. Despite the prevalence of the presumptive 027 strain and its associated heightened inflammation among the patients studied, no significant differences were observed regarding the clinical course or mortality outcomes.

Introduction: Antimicrobial resistance (AMR) is currently a growing concern among healthcare providers, underscoring the importance of describing the regional susceptibility profile for common microorganisms that are associated with urinary tract infections (UTIs). This knowledge serves as the foundation for proper empirical therapeutic recommendations tailored to local susceptibility patterns., Results: We found a high prevalence of ESBL-producing strains (36.9%), with Escherichia coli and Klebsiella spp. being the most prevalent isolated bacteria. Among the catheterized patients, Klebsiella spp. emerged as the primary etiology, with a significant correlation between catheterization and Proteus spp. ( p = 0.02) and Providencia stuartii ( p < 0.0001). We observed significant correlations between urinary catheterization and older age (68.9 ± 13.7 years vs. 64.2 ± 18.1 years in non-catheterized patients, p = 0.026) and with the presence of an isolate with extensive drug resistance ( p < 0.0001) or even pandrug resistance ( p < 0.0001). Susceptibility rates significantly decreased for almost all the tested antibiotics during the study period. Notably, susceptibility was markedly lower among catheterized patients, with the most pronounced differences observed for carbapenems (59.6% versus 83.4%, p < 0.0001) and aminoglycosides (37.1% versus 46.9%, p = 0.0001)., Materials and Methods: We conducted a retrospective study analyzing the susceptibility profiles of 724 extended-spectrum beta-lactamases (ESBL)-producing Enterobacterales isolated from urine cultures. Our focus was on highlighting susceptibility profiles among isolates associated with urinary catheterization and assessing the shifts in the susceptibility rates over time., Conclusions: The constant rise in AMR rates among Enterobacterales presents significant challenges in treating severe infections, particularly among urinary catheterized patients. This trend leaves clinicians with limited or no effective treatment options. Consequently, the development and implementation of personalized treatment protocols are imperative to ensure efficient empirical therapies.

Among the factors incriminated in the appearance of eating disorders, intestinal microbiota has recently been implicated. Now there is evidence that the composition of gut microbiota is different in anorexia nervosa. We gathered many surveys on the changes in the profile of gut microbiota in patients with anorexia nervosa. This review comprehensively examines the contemporary experimental evidence concerning the bidirectional communication between gut microbiota and the brain. Drawing from recent breakthroughs in this area of research, we propose that the gut microbiota significantly contributes to the intricate interplay between the body and the brain, thereby contributing to overall healthy homeostasis while concurrently impacting disease risk, including anxiety and mood disorders. Particular attention is devoted to elucidating the structure and functional relevance of the gut microbiota in the context of Anorexia Nervosa., Competing Interests: The authors declare no conflict of interest.

Background and Objectives: Urosepsis is a significant cause of maternal and fetal mortality. While certain risk factors for urinary tract infections (UTIs) in pregnant women are well established, those associated with an elevated risk of urosepsis in pregnant women with upper UTIs remain less defined. This study aims to identify factors linked to an increased risk of urosepsis and examine urologic treatment outcomes in such cases. Materials and Methods: We conducted a retrospective analysis on 66 pregnant women diagnosed with urosepsis over a nine-year period. A control group included 164 pregnant women with upper UTIs, excluding urosepsis, admitted during the same timeframe. This study highlights factors potentially contributing to urosepsis risk, including comorbidities like anemia, pregnancy-related hydronephrosis or secondary to reno-ureteral lithiasis, prior UTIs, coexisting urological conditions, and urologic procedures. Outcomes of urologic treatments, hospitalization duration, obstetric transfers due to fetal distress, and complications associated with double-J catheters were analyzed. Results: Pregnant women with urosepsis exhibited a higher prevalence of anemia (69.7% vs. 50.0%, p = 0.006), 2nd-3rd grade hydronephrosis (81.8% vs. 52.8%, p = 0.001), and fever over 38 °C (89.4% vs. 42.1%, p = 0.001). They also had a more intense inflammatory syndrome (leukocyte count 18,191 ± 6414 vs. 14,350 ± 3860/mmc, p = 0.001, and C-reactive protein (CRP) 142.70 ± 83.50 vs. 72.76 ± 66.37 mg/dL, p = 0.001) and higher creatinine levels (0.77 ± 0.81 vs. 0.59 ± 0.22, p = 0.017). On multivariate analysis, factors associated with increased risk for urosepsis were anemia (Odds Ratio (OR) 2.622, 95% CI 1.220-5.634), 2nd-3rd grade hydronephrosis (OR 6.581, 95% CI 2.802-15.460), and fever over 38 °C (OR 11.612, 95% CI 4.804-28.07). Regarding outcomes, the urosepsis group had a higher rate of urological maneuvers (87.9% vs. 36%, p = 0.001), a higher rate of obstetric transfers due to fetal distress (22.7% vs. 1.2%, p = 0.001), and migration of double-J catheters (6.1% vs. 0.6%, p = 0.016), but no maternal fatality was encountered. However, they experienced the same rate of total complications related to double-J catheters (19.69% vs. 12.80%, p > 0.05). The pregnant women in both groups had the infection more frequently on the right kidney, were in the second trimester and were nulliparous. Conclusions: Pregnant women at increased risk for urosepsis include those with anemia, hydronephrosis due to gestational, or reno-ureteral lithiasis, and fever over 38 °C. While the prognosis for pregnant women with urosepsis is generally favorable, urological intervention may not prevent a higher incidence of fetal distress and the need for obstetric transfers compared to pregnant women with uncomplicated upper UTIs.

The Coronavirus disease 2019 (COVID-19) pandemic has brought new challenges across medical disciplines, particularly in infectious disease medicine. In Romania, the incidence of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection increased dramatically since March 2020 until March 2022. Antibiotic administration for pulmonary superinfections in COVID-19 intensified and, consequently, increased rates of Clostridioides difficile infection (CDI) were hypothesized. We conducted a single-center, retrospective, observational study on patients from North-Eastern Romania to assess clinical characteristics and outcomes of COVID-19 and Clostridioides difficile (CD) coinfection, and to identify risk factors for CDI in COVID-19 patients. The study enrolled eighty-six CDI and COVID-19 coinfected patients admitted during March 2020-February 2021 (mean age 59.14 years, 53.49% men, 67.44% urban residents) and a group of eighty-six COVID-19 patients. On admission, symptoms were more severe in mono-infected patients, while coinfected patients associated a more intense acute inflammatory syndrome. The main risk factors for severe COVID-19 were smoking, diabetes mellitus, and antibiotic administration. Third generation cephalosporins (55%) and carbapenems (24%) were the main antibiotics used, and carbapenems were significantly associated with severe COVID-19 in patients coinfected with CD during hospitalization. Coinfection resulted in longer hospitalization and poorer outcomes. The extensive use of antibiotics in COVID-19, particularly carbapenems, contributed substantially to CD coinfection., Competing Interests: The authors declare no conflicts of interest.

C-reactive protein (CRP) has been one of the most investigated inflammatory-biomarkers during the ongoing COVID-19 pandemics caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The severe outcome among patients with SARS-CoV-2 infection is closely related to the cytokine storm and the hyperinflammation responsible for the acute respiratory distress syndrome and multiple organ failure. It still remains a challenge to determine which of the hyperinflammatory biomarkers and cytokines are the best predictors for disease severity and mortality in COVID-19 patients. Therefore, we evaluated and compared the outcome prediction efficiencies between CRP, the recently reported inflammatory modulators (suPAR, sTREM-1, HGF), and the classical biomarkers (MCP-1, IL-1β, IL-6, NLR, PLR, ESR, ferritin, fibrinogen, and LDH) in patients confirmed with SARS-CoV-2 infection at hospital admission. Notably, patients with severe disease had higher serum levels of CRP, suPAR, sTREM-1, HGF and classical biomarkers compared to the mild and moderate cases. Our data also identified CRP, among all investigated analytes, to best discriminate between severe and non-severe forms of disease, while LDH, sTREM-1 and HGF proved to be excellent mortality predictors in COVID-19 patients. Importantly, suPAR emerged as a key molecule in characterizing the Delta variant infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Paranga, Pavel-Tanasa, Constantinescu, Plesca, Petrovici, Miftode, Moscalu, Cianga and Miftode.)

Fever of unknown origin (FUO) is a serious challenge for physicians. The aim of the present study was to consider epidemiology and dynamics of FUO in countries with different economic development. The data of FUO patients hospitalized/followed between 1st July 2016 and 1st July 2021 were collected retrospectively and submitted from referral centers in 21 countries through ID-IRI clinical research platform. The countries were categorized into developing (low-income (LI) and lower middle-income (LMI) economies) and developed countries (upper middle-income (UMI) and high-income (HI) economies). This research included 788 patients. FUO diagnoses were as follows: infections (51.6%; n = 407), neoplasms (11.4%, n = 90), collagen vascular disorders (9.3%, n = 73), undiagnosed (20.1%, n = 158), miscellaneous diseases (7.7%, n = 60). The most common infections were tuberculosis (n = 45, 5.7%), brucellosis (n = 39, 4.9%), rickettsiosis (n = 23, 2.9%), HIV infection (n = 20, 2.5%), and typhoid fever (n = 13, 1.6%). Cardiovascular infections (n = 56, 7.1%) were the most common infectious syndromes. Only collagen vascular disorders were reported significantly more from developed countries (RR = 2.00, 95% CI: 1.19-3.38). FUO had similar characteristics in LI/LMI and UMI/HI countries including the portion of undiagnosed cases (OR, 95% CI; 0.87 (0.65-1.15)), death attributed to FUO (RR = 0.87, 95% CI: 0.65-1.15, p-value = 0.3355), and the mean duration until diagnosis (p = 0.9663). Various aspects of FUO cannot be determined by the economic development solely. Other development indices can be considered in future analyses. Physicians in different countries should be equally prepared for FUO patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

(1) Background: Acute heart failure (HF) represents a complex clinical syndrome burdened by increased mortality and a high rate of systemic complications. Although natriuretic peptides (e.g., NT-proBNP) currently represent the diagnostic and prognostic gold standard in acute HF, those molecules do not accurately reflect all the pathophysiological mechanisms involved in the progression of this pathology when determined independently. Therefore, the current paradigm tends to focus on a multi-marker approach for the risk stratification of patients with acute HF. Syndecan-1 is a less studied biomarker in cardiovascular diseases; its assessment in patients with acute HF being potentially able to reflect the myocardial pathological changes, such as fibrosis, inflammation, endothelial dysfunction or global wall stress. (2) Methods: We conducted a single center prospective study that enrolled 173 patients (120 patients admitted for acute HF, compared to 53 controls with stable chronic HF). A complete standardized clinical, echocardiography and laboratory evaluation was performed at admission, including serum samples for the determination of syndecan-1 by the enzyme-linked immunosorbent assay (ELISA) method. (3) Results: The serum concentration of syndecan-1 was significantly higher in patients with acute HF, compared to controls [121.4 (69.3-257.9) vs. 72.1 (41.4-135.8) ng/mL, p = 0.015]. Syndecan-1 was a significant predictor for the diagnosis of acute HF, expressed by an area under the curve (AUC) of 0.898, similar to NT-proBNP (AUC: 0.976) or cardiac troponin (AUC: 0.839). Moreover, syndecan-1 was independently associated with impaired kidney and liver function at admission, being also a predictor for early, subclinical organ dysfunction in patients with normal biological parameters at admission. When included in the multi-marker model, syndecan-1 levels influenced mortality more significantly than NT-proBNP or troponin. A multivariable regression including syndecan-1, NT-proBNP and troponin provided additional prognostic value compared to each independent biomarker. (4) Conclusions: Syndecan-1 can be considered a promising novel biomarker in acute HF, exhibiting adequate diagnostic and prognostic value. Additionally, syndecan-1 can be used as a surrogate biomarker for non-cardiac organ dysfunction, as its highs levels can accurately reflect early acute kidney and liver injury.

(1) Background: Antibiotic resistance and coronavirus disease-19 (COVID-19) represent a dual challenge in daily clinical practice, inducing a high burden on public health systems. Hence, we aimed to dynamically evaluate the impact of COVID-19 on patients with carbapenem-resistant Enterobacterales (CRE) urinary tract infections (UTIs), as well as the antibiotic resistance trends after the onset of the pandemic. (2) Methods: We conducted a prospective study including patients with CRE UTIs who were enrolled both pre- and during the pandemic from 2019 to 2022. We further performed a standardized and comparative clinical, paraclinical, and microbiological assessment between patients with and without COVID-19. (3) Results: A total of 87 patients with CRE UTIs were included in this study (46 pre-pandemic and 41 during the pandemic, of which 21 had associated Severe Acute Respiratory Syndrome Coronavirus-2 infection). Klebsiella pneumoniae was the main etiological agent of the UTIs, with the majority of strains (82.7%) being carbapenemase producers (mainly OXA-48 producers), while five of the 34 colistin-resistant isolates were harboring the mobile colistin resistance-1 ( mcr-1 ) gene. COVID-19 patients presented a significantly worse outcome with higher rates of intensive care unit (ICU) admissions (66.7% for COVID patients vs. 18.2% for non-COVID patients, p < 0.001), while the fatality rates were also considerably higher among patients with concomitant viral infection (33.3% vs. 12.1%, p < 0.001). Besides COVID-19, additional risk factors associated with increased mortality were urinary catheterization, sepsis with K. pneumoniae , impaired liver and kidney function, and an inappropriate initial empiric antibiotic therapy. (4) Conclusions: COVID-19 showed a pronounced negative impact on patients with CRE UTIs, with significantly longer hospitalizations and higher ICU admissions and mortality rates., Competing Interests: The authors declare no conflict of interest.

1., Background: Literature data on bacterial infections and their impact on the mortality rates of COVID-19 patients from Romania are scarce, while worldwide reports are contrasting. 2., Materials and Methods: We conducted a unicentric retrospective observational study that included 280 patients with SARS-CoV-2 infection, on whom we performed various microbiological determinations. Based on the administration or not of the antibiotic treatment, we divided the patients into two groups. First, we sought to investigate the rates and predictors of bacterial infections, the causative microbial strains, and the prescribed antibiotic treatment. Secondly, the study aimed to identify the risk factors associated with in-hospital death and evaluate the biomarkers' performance for predicting short-term mortality. 3., Results: Bacterial co-infections or secondary infections were confirmed in 23 (8.2%) patients. Acinetobacter baumannii was the pathogen responsible for most of the confirmed bacterial infections. Almost three quarters of the patients (72.8%) received empiric antibiotic therapy. Multivariate logistic regression has shown leukocytosis and intensive care unit admission as risk factors for bacterial infections and C-reactive protein, together with the length of hospital stay, as mortality predictors. The ROC curves revealed an acceptable performance for the erythrocyte sedimentation rate (AUC: 0.781), and C-reactive protein (AUC: 0.797), but a poor performance for fibrinogen (AUC: 0.664) in predicting fatal events. 4., Conclusions: This study highlighted the somewhat paradoxical association of a low rate of confirmed infections with a high rate of empiric antibiotic therapy. A thorough assessment of the risk factors for bacterial infections, in addition to the acknowledgment of various mortality predictors, is crucial for identifying high-risk patients, thus allowing a timely therapeutic intervention, with a direct impact on improving patients' prognosis.

(1) Background: Acute heart failure (HF) represents one of the most common yet extremely severe presentations in emergency services worldwide, requiring prompt diagnosis, followed by an adequate therapeutic approach, and a thorough risk stratification. Natriuretic peptides (NPs) are currently the most widely implemented biomarkers in acute HF, but due to their lack of specificity, they are mainly used as ruling-out criteria. Growth differentiation factor-15 (GDF-15) is a novel molecule expressing different pathophysiological pathways in HF, such as fibrosis, remodeling, and oxidative stress. It is also considered a very promising predictor of mortality and poor outcome. In this study, we aimed to investigate the GDF-15’s expression and particularities in patients with acute HF, focusing mainly on its role as a prognosis biomarker, either per se or as part of a multimarker panel. (2) Methods: This unicentric prospective study included a total of 173 subjects, divided into 2 subgroups: 120 patients presented in emergency with acute HF, while 53 were ambulatory-evaluated controls with chronic HF. At admission, all patients were evaluated according to standard clinical echocardiography and laboratory panel, including the assessment of GDF-15. (3) Results: The levels of GDF-15 were significantly higher in patients with acute HF, compared to controls [596 (305−904) vs. 216 (139−305) ng/L, p < 0.01]. GDF-15 also exhibited an adequate diagnostic performance in acute HF, expressed as an area under the curve (AUC) of 0.883 [confidence interval (CI) 95%: 0.828−0.938], similar to that of NT-proBNP (AUC: 0.976, CI 95%: 0.952−1.000), or troponin (AUC: 0.839, CI 95%: 0.733−0.944). High concentrations of GDF-15 were significantly correlated with mortality risk. In a multivariate regression model, GDF-15 was the most important predictor of a poor outcome, superior to NT-proBNP or troponin. (4) Conclusions: GDF-15 proved to be a reliable tool in the multimarker assessment of patients with acute HF. Compared to the gold standard NT-proBNP, GDF-15 presented a similar diagnostic performance, doubled by a significantly superior prognostic value, making it worth being included in a standardized multimarker panel.

We explored the self-reported antibiotic stewardship (AS), and infection prevention and control (IPC) activities in intensive care units (ICUs) of different income settings. A cross-sectional study was conducted using an online questionnaire to collect data about IPC and AS measures in participating ICUs. The study participants were Infectious Diseases-International Research Initiative (IDI-IR) members, committed as per their institutional agreement form. We analyzed responses from 57 ICUs in 24 countries (Lower-middle income (LMI), n = 13; Upper-middle income (UMI), n = 33; High-income (HI), n = 11). This represented (~5%) of centers represented in the ID-IRI. Surveillance programs were implemented in (76.9%-90.9%) of ICUs with fewer contact precaution measures in LMI ones (p = 0.02); (LMI:69.2%, UMI:97%, HI:100%). Participation in regional antimicrobial resistance programs was more significantly applied in HI (p = 0.02) (LMI:38.4%,UMI:81.8%,HI:72.2%). AS programs are implemented in 77.2% of institutions with AS champions in 66.7%. Infectious diseases physicians and microbiologists are members of many AS teams (59%&50%) respectively. Unqualified healthcare professionals(42.1%), and deficient incentives(28.1%) are the main barriers to implementing AS. We underscore the existing differences in IPC and AS programs' implementation, team composition, and faced barriers. Continuous collaboration and sharing best practices on APM is needed. The role of regional and international organizations should be encouraged. Global support for capacity building of healthcare practitioners is warranted., (Copyright © 2022. Published by Elsevier Ltd.)

The intricate relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the cardiovascular system is an extensively studied pandemic topic, as there is an ever-increasing amount of evidence that reports a high prevalence of acute cardiac injury in the context of viral infection. In patients with Coronavirus disease 2019, COVID-19, a significant increase in serum levels of cardiac troponin or other various biomarkers was observed, suggesting acute cardiac injury, thus predicting both a severe course of the disease and a poor outcome. Pathogenesis of acute cardiac injury is not yet completely elucidated, though several mechanisms are allegedly involved, such as a direct cardiomyocyte injury, oxygen supply-demand inequity caused by hypoxia, several active myocardial depressant factors during sepsis, and endothelial dysfunction due to the hyperinflammatory status. Moreover, the increased levels of plasma cytokines and catecholamines and a significantly enhanced prothrombotic environment may lead to the destabilization and rupture of atheroma plaques, subsequently triggering an acute coronary syndrome. In the present review, we focus on describing the epidemiology, pathogenesis, and role of biomarkers in the diagnosis and prognosis of patients with acute cardiac injury in the setting of the COVID-19 pandemic. We also explore some novel therapeutic strategies involving immunomodulatory therapy, as well as their role in preventing a severe form of the disease, with both the short-term outcome and the long-term cardiovascular sequelae being equally important in patients with SARS-CoV-2 induced acute cardiac injury.

(1) Background: The evolution of bacterial resistance to antibiotics is one of the factors that make infectious pathology an extremely dynamic field, also inducing a significant burden on public health systems; therefore, continuous updates on the bacterial resistance to antibiotics and their particular regional patterns is crucial for the adequate approach of various infectious diseases. (2) Methods: We retrospectively analyzed 354 patients with Enterobacterales urinary tract infections (UTIs), determined their antibiotic resistance pattern, thus aiming to correlate them with the outcome and other specific markers of poor prognosis. (3) Results: The most frequent causative agent was Escherichia coli , representing 64.6% of all UTIs. We identified 154 patients resistant to multiple antibiotic classes, of which 126 were multidrug-resistant (MDR), 17 were extensive drug-resistant (XDR) and 11 were pandrug-resistant (PDR). Moreover, 25 isolates were resistant to carbapenems (CRE), 25 were difficult-to-treat (DTR), and 84 were extended-spectrum cephalosporin-resistant (ESC), with only 95 isolates susceptible to all tested antibiotics. Mortality ranged from 1% for UTIs caused by isolates susceptible to all tested antibiotics, to 24% for the ones caused by DTR or CRE isolates. Other significant risk factors associated with mortality were: prolonged hospital stay ( p = 0.0001), Charlson comorbidity index ≥ 3 ( p = 0.02), urinary catheterization ( p = 0.001), associated respiratory pathologies ( p = 0.004), obesity ( p = 0.047), a history of previous hospitalizations ( p = 0.007), inappropriate empiric antibiotic regimen ( p = 0.001), or hyper inflammatory status ( p = 0.006). Basically, we observed that a multiple regression model comprising urinary catheterization, inappropriate empiric anti-biotherapy, obesity, and respiratory comorbidities exhibits the best correlation with mortality rate in patients with UTI (R = 0.347, R 2 = 0.12). (4) Conclusions: By focusing on the novel resistance patterns, our study provides complementary evidence concerning the resistance profiles found in an Eastern European region, as well as their prognostic implications in patients with UTI.

(1) Background: There are limited clinical data in patients from the Eastern European regions hospitalized for a severe form of Coronavirus disease 2019 (COVID-19). This study aims to identify risk factors associated with intra-hospital mortality in patients with COVID-19 severe pneumonia admitted to a tertiary center in Iasi, Romania. (2) Methods: The study is of a unicentric retrospective observational type and includes 150 patients with severe COVID-19 pneumonia divided into two subgroups, survivors and non-survivors. Demographic and clinical parameters, as well as comorbidities, laboratory and imaging investigations upon admission, treatments, and evolution during hospitalization were recorded. First, we sought to identify the risk factors associated with intra-hospital mortality using logistic regression. Secondly, we assessed the correlations between D-Dimer and C-reactive protein and predictors of poor prognosis. (3) Results: The predictors of in-hospital mortality identified in the study are D-dimers >0.5 mg/L ( p = 0.002), C-reactive protein >5 mg/L ( p = 0.001), and heart rate above 100 beats per minute ( p = 0.001). The biomarkers were also significantly correlated the need for mechanical ventilation, admission to intensive care unit, or multiple organ dysfunction syndrome. By area under the curve (AUC) analysis, we noticed that both D-Dimer (AUC 0.741) and C-reactive protein (AUC 0.707) exhibit adequate performance in predicting a poor prognosis in patients with severe viral infection. (4) Conclusions: COVID-19's outcome is significantly influenced by several laboratory and clinical factors. As mortality induced by severe COVID-19 pneumonia is considerable, the identification of risk factors associated with negative outcome coupled with an early therapeutic approach are of paramount importance, as they may significantly improve the outcome and survival rates.

Background : Heart failure (HF) is a complex clinical syndrome that represents a great burden on public health systems due to its increased prevalence, disability and mortality rates. There are multiple triggers that can induce or aggravate a preexisting HF, socioeconomic status (SES) emerging as one of the most common modifiable risk factors. Our study aimed to analyze the influence of certain SES indicators on the outcome, clinical aspects and laboratory parameters of patients with HF in North-Eastern Romania, as well as their relationship with other traditional cardiovascular risk factors. Methods : We conducted a prospective, single-center study comprising 120 consecutively enrolled patients admitted for acute HF. The evaluation of individual SES was based upon a standard questionnaire and evidence from official documents. Results : the patients' age ranged between 18 and 94 years; Out of 120 patients, 49 (40.8%) were women and 71 (59.2%) were men, residing in rural 59 (49.2%) or urban 61 (50.8%) areas. 14.2% were university graduates, while 15.8% had only attended primary school. The majority of the patients are or were employed in the service sector (54.5%), followed by industry (29.2%) and agriculture (20%). The mean monthly income was 306.1 ± 177.4 euro, while the mean hospitalization cost was 2471.8 ± 2073.8 euro per patient. The individual income level was positively correlated with urban area of residence, adequate household sanitation facilities and healthcare access, and negatively associated with advanced age and previous hospitalizations due to HF. However, the individual financial situation was also positively correlated with the increased prevalence of certain cardiovascular risk factors, such as arterial hypertension, anemia or obesity, but not with total cholesterol or male gender. Concerning the direct impact of a poor economic status upon prognosis in the setting of acute HF, our results showed no statistically significant differences concerning the in-hospital or at 1-month follow-up mortality rates. Rather than inducing a direct impact on the short-term outcome, these findings concerning SES indicators are meant to enhance the implementation of policies aimed to provide adequate healthcare for people from all social layers, with a primary focus on modifiable cardiovascular risk factors.

Evaluating trends in antibiotic resistance is a requisite. The study aimed to analyze the profile of multidrug-resistant organisms (MDROs) among hospitalized patients with bacteremia in intensive care units (ICUs) in a large geographical area. This is a 1-month cross-sectional survey for blood-borne pathogens in 57 ICUs from 24 countries with different income levels: lower-middle-income (LMI), upper-middle-income (UMI), and high-income (HI) countries. Multidrug-resistant (MDR), extensively drug-resistant (XDR), or pan-drug-resistant isolates were searched. Logistic regression analysis determined resistance predictors among MDROs. Community-acquired infections were comparable to hospital-acquired infections particularly in LMI (94/202; 46.5% vs 108/202; 53.5%). Although MDR (65.1%; 502/771) and XDR (4.9%; 38/771) were common, no pan-drug-resistant isolate was recovered. In total, 32.1% of MDR were Klebsiella pneumoniae, and 55.3% of XDR were Acinetobacter baumannii. The highest MDR and XDR rates were in UMI and LMI, respectively, with no XDR revealed from HI. Predictors of MDR acquisition were male gender (OR, 12.11; 95% CI, 3.025-15.585) and the hospital-acquired origin of bacteremia (OR, 2.643; 95%CI, 1.462-3.894), and XDR acquisition was due to bacteremia in UMI (OR, 3.344; 95%CI, 1.189-5.626) and admission to medical-surgical ICUs (OR, 1.481; 95% CI, 1.076-2.037). We confirm the urgent need to expand stewardship activities to community settings especially in LMI, with more paid attention to the drugs with a higher potential for resistance. Empowering microbiology laboratories and reports to direct prescribing decisions should be prioritized. Supporting stewardship in ICUs, the mixed medical-surgical ones in particular, is warranted., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Acute heart failure (HF) represents an increasingly common and challenging presentation in the emergency room, also inducing a great socio-economic burden. Extensive research was conducted toward finding an ideal biomarker of acute HF, both in terms of sensitivity and specificity, but today practicians' interest has shifted towards a more realistic multimarker approach. Natriuretic peptides (NPs) currently represent the gold standard for diagnosing HF in routine clinical practice, but novel molecules, such as sST2, emerge as potentially useful biomarkers, providing additional diagnostic and prognostic value., Methods: We conducted a prospective, single-center study that included 120 patients with acute HF and 53 controls with chronic HF. Of these, 13 patients (eight with acute HF, five from the control group) associated the coronavirus-19 disease (COVID-19). The diagnosis of HF was confirmed by a complete clinical, biological and echocardiographic approach., Results: The serum levels of all studied biomarkers (sST2, NT-proBNP, cardiac troponin) were significantly higher in the group with acute HF. By area under the curve (AUC) analysis, we noticed that NT-proBNP (AUC: 0.976) still had the best diagnostic performance, closely followed by sST2 (AUC: 0.889). However, sST2 was a significantly better predictor of fatal events, showing positive correlations for both in-hospital and at 1-month mortality rates. Moreover, sST2 was also associated with other markers of poor prognosis, such as the use of inotropes or high lactate levels, but not with left ventricle ejection fraction, age, body mass index or mean arterial pressure. sST2 levels were higher in patients with a positive history of COVID-19 as compared with non-COVID-19 patients, but the differences were statistically significant only within the control group. Bivariate regression showed a positive and linear relationship between NT-proBNP and sST2 ( r (120) = 0.20, p < 0.002)., Conclusions: we consider that sST2 has certain qualities worth integrating in a future multimarker test kit alongside traditional biomarkers, as it provides similar diagnostic value as NT-proBNP, but is emerging as a more valuable prognostic factor, with a better predictive value of fatal events in patients with acute HF.

The incidence of urinary tract infections (UTIs) caused by Klebsiella pneumoniae has exhibited an increasing trend and has become a high burden for many public health systems, especially in hospital settings. Multidrug resistance associated with the production of extended-spectrum β-lactamases (ESBL) among K. pneumoniae isolates is endemic in Southeastern Europe. We retrospectively analyzed 75 cases admitted to 'St. Parascheva' Clinical Hospital of Infectious Diseases in Iasi, Romania, during the first 6 months of 2019 (January 1 to June 30), who had a confirmed diagnosis of K. pneumoniae UTI at discharge. From a total of 75 patients, 34 (45.3%) presented ESBL + K. pneumoniae. The mean age was 66 years (70.1 for the ESBL + patients vs. 62.6 for the ESBL - patients, P=0.0365). There was a symmetrical sex distribution (37 men vs . 38 women). Of these, 22 men had ESBL + K. pneumoniae UTIs, compared to only 15 with an ESBL - strain, P=0.0087. Another risk factor for ESBL + K. pneumoniae UTIs was the presence of hospitalization in the past 6 months; 20 (58.82%) patients with ESBL + infections were previously hospitalized, compared to only 5 (12.19%) patients with ESBL - strains, P<0.0001. The urinary catheter carriers presented an increased prevalence of ESBL + infections (15/34 vs. 5/41, P=0.0012). Regarding mortality, ESBL + infections caused 6 fatalities, compared to only 1 death in the ESBL - group, P=0.0166. ESBL + K. pneumoniae strains represent an important cause of healthcare-related UTIs, with a significantly higher mortality rate compared to ESBL - strains. Early identification and adequate management of the risk factors incriminated in ESBL + UTIs should be a priority for physicians in order to limit the dissemination of the ESBL-producing strains and thus to improve the outcome of these patients., Competing Interests: There are no competing interests regarding the authors of this research., (Copyright: © Miftode et al.)

Atrial cardiomyopathy (ACM) represents a constantly evolving concept, with increasing importance in contemporary research and clinical practice. A better understanding of the mechanisms involved in atrial remodeling and its clinical correlations especially with atrial fibrillation (AF) and other cardiometabolic comorbidities may induce a significant impact on the diagnosis, prognosis, and therapeutic approach of ACM-related comorbidities. Although initially described several decades ago, investigators have only recently highlighted that several renal, metabolic, and cardiovascular diseases are determining factors for atrial remodeling and subsequent ACM. Based on data from multiple recent studies, our research emphasizes the correlations between ACM and other coexisting pathologies including cardiovascular, respiratory, or metabolic diseases, with fibrosis being the most incriminated pathophysiological mechanism. In addition to the usual tests, the paraclinical assessment of ACM is increasingly based on the use of various cardiac biomarkers, while the cardiac magnetic resonance (CMR) has become an increasingly tempting diagnostic too for describing morphofunctional aspects of the heart chambers, with the gadolinium contrast enhanced CMR (LGE-CMR) emerging as a commonly used technique aiming to identify and quantify the precise extent of atrial fibrosis. Further research should be conducted in order to clarify our knowledge regarding atrial remodeling and, therefore, to develop new and improved therapeutic approaches in these patients.

The increasing incidence of coronavirus disease 19 (COVID-19) and its polymorphic clinical manifestations due to local and systemic inflammation represent a high burden for many public health systems. Multiple evidence revealed the interdependence between the presence of cardiovascular comorbidities and a severe course of COVID-19, with heart failure (HF) being incriminated as an independent predictor of mortality. Suppression of tumorigenicity-2 ST2 has emerged as one of the most promising biomarkers in assessing the evolution and prognosis of patients with HF. The uniqueness of ST2 is determined by its structural particularities. Its transmembrane isoform exerts cardioprotective effects, while the soluble isoform (sST2), which is detectable in serum, is associated with myocardial fibrosis and poor outcome in patients with HF. Some recent data also suggested the potential role of sST2 as a marker of inflammation, while other studies highlighted it as a valuable prognostic factor in patients with COVID-19. In this review, we summarized the pathways by which sST2 is related to myocardial injury and its connection to the severity of inflammation in patients with COVID-19. Also, we reviewed possible perspectives of using it as a dual cardio-inflammatory biomarker, for both early diagnosis, risk stratification and prognosis assessment of patients with concomitant HF and COVID-19.

The close connection and interaction between the cardiac and the liver functions are well-known, as cirrhotic cardiomyopathy is an important clinical entity which best describes the mutual pathogenical influence between these two organs. Due to the fact that cardiac dysfunction in patients with chronic hepatic disorders is oligosymptomatic or even asymptomatic, an early diagnosis represents a challenge for every physician. Syndecan-1-a transmembrane proteoglycan that exerts its functions mainly via its heparane sulfate chains-is a very promising biomarker, correlated not only with the degree of cardiac fibrosis but also with the severity of liver fibrosis. Many studies highlighted its role in the development of cardiac fibrosis or atherogenesis, being significantly correlated with the activity of angiotensin II. Multiple evidence revealed that syndecan-1 is also associated with tissue injury and may regulate inflammatory and regenerative responses, being considered a protective molecule that limits the inflammation and reduces cardiac remodelling and dysfunction after a myocardial infarction. Syndecan-1 may also be used as a reliable biomarker for the noninvasive assessment of liver fibrosis. Under various fibrogenetic conditions, shedding of syndecan's extracellular domain took place, becoming a soluble form that binds different growth factors and inhibits further fibrosis. This complex molecule is also involved in the lipid metabolism, by altering the clearance of cholesterol particles, and in chronic hepatitis, by enhancing the viral invasion of hepatocytes. Due to the growing interest in this biomarker, multiple studies aimed at revealing syndecan-1's potential benefits in the diagnosis and prognosis assessment in patients with heart failure or chronic liver disorders. In this review, we review the mechanisms by which syndecan-1 exerts its effects and the possible perspectives opened by its use as a dual cardio-hepatic biomarker., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2019 Radu-Stefan Miftode et al.)