Investigation of Serum Endocan Levels in SARS-CoV-2 Patients.

Endocan is an endothelial-cell-specific proteoglycan (ESM-1) and has emerged as an endothelial dysfunction and inflammatory marker in recent years. Endocan can be used as a marker of inflammatory endothelial dysfunction in endothelium-dependent disease: cardiovascular disease, sepsis, lung and kidney disease and malignancies. Recent data suggest that endothelial dysfunction is a key mechanism in COVID-19 pathogenesis. Endotheliitis and thrombo-inflammation are associated with severe forms of SARS-CoV-2 infection, and endocan is currently under investigation as a potential diagnostic and prognostic marker. The aim of this study was to determine serum endocan levels in patients with COVID-19 to evaluate the correlation between endocan levels and clinical disease diagnosis and prognosis. This study enrolled 56 patients, divided into three groups depending on disease severity: mild (15), moderate (25) and severe (16). The biochemical, demographic, clinical and imagistic data were collected and evaluated in correlation with the endocan levels. Serum endocan levels were significantly higher in the COVID-19 patients compared to the control group; also, endocan concentration correlated with vaccination status. The results revealed significantly elevated serum endocan levels in COVID-19 patients compared to the control group, with a correlation observed between endocan concentration and vaccination status. These findings suggest that endocan may serve as a novel biomarker for detecting inflammation and endothelial dysfunction risk in COVID-19 patients. There was no significant relationship between serum endocan levels and disease severity or the presence of cardiovascular diseases. Endocan can be considered a novel biomarker for the detection of inflammation and endothelial dysfunction risk in COVID-19 patients.

Systematic Review: Strategies for Improving HIV Testing and Detection Rates in European Hospitals.

Undiagnosed HIV infection is a prominent clinical issue throughout Europe that requires the continuous attention of all healthcare professionals and policymakers to prevent missed testing opportunities and late diagnosis. This systematic review aimed to evaluate interventions to increase HIV testing rates and case detection in European hospitals. Out of 4598 articles identified, 29 studies fulfilled the selection criteria. Most of the studies were conducted in single Western European capital cities, and only one study was from Eastern Europe. The main interventions investigated were test-all and indicator-condition-based testing strategies. Overall, the prevalence of undiagnosed HIV was well above 0.1%. The studied interventions increased the HIV testing rate and the case detection rate. The highest prevalence of undiagnosed HIV was found with the indicator-condition-driven testing strategy, whereas the test-all strategy had the most profound impact on the proportion of late diagnoses. Nevertheless, the HIV testing rates and case-finding varied considerably across studies. In conclusion, effective strategies to promote HIV testing in European hospitals are available, but relevant knowledge gaps regarding generalizability and sustainability remain. These gaps require the promotion of adherence to HIV testing guidelines, as well as additional larger studies representing all European regions.

Antibiotic Prescribing in Dental Medicine-Best Practices for Successful Implementation.

With rising rates of antimicrobial resistance throughout the world, it is time to revisit antibiotic prescribing policies and practices, and dentistry is an important area for focused intervention, as it accounts for up to 15% of all antimicrobial prescriptions. In this narrative review, we have analyzed the current state of the knowledge, attitudes, and practice regarding antimicrobial use among dental professionals, and we have identified a set of seven recurring themes that drive inappropriate antibiotic prescribing in dental medicine. These include: 1. Prescribing antibiotics to delay or avoid dental treatment. 2. Overlooking the 5Ds-dental treatment (source control), dental condition (indication), drug (antibiotic choice), dose, and duration. 3. Relying on education from the distant past and on previous experience. 4. The heterogeneity of (too many) guideline recommendations leads to confusion and over-prescribing. 5. Decreased access to guideline information in private practice. 6. Psychological factors such as pressure to prescribe, comfort prescribing and the weekend effect, and 7. Feeling removed from antimicrobial resistance and externalizing responsibility. Based on the existing knowledge, we propose a framework based on four key pillars for focused intervention: 1. Education. 2. Internalizing responsibility. 3. Recognizing recurring counter-productive practices, and 4. Addressing recurring counter-productive practices. This framework can be applied in different dental settings to ensure best practices for the successful implementation of rational antimicrobial prescribing.

The Impact of Obesity on the Host-Pathogen Interaction with Influenza Viruses - Novel Insights: Narrative Review.

After exposure to a viral pathogen, the host-pathogen interaction is essential to determine whether or not infection will ensue, and what the clinical outline of the infection will be. Recent research has shown that the patient with obesity presents a set of particular pathophysiological changes that lead to higher severity of viral infections, and this is particularly true for infection with influenza viruses. Herein, we describe the main metabolic, endocrine, and immune dysregulations that occur in the presence of obesity and their impact on driving intra-host viral diversity, leading to heightened severity and virulence of influenza. We show that obesity is linked to modified responses of both the innate and adaptive immune systems during viral infections, including influenza. Due to chronic inflammation and metabolic, endocrine, and signaling pathway disruptions, individuals with obesity have a suboptimal immune response. This results in longer illness duration, increased virus shedding, higher risk of hospitalization and complications, and greater mortality rates. Additionally, they may have a blunted response to vaccination and a higher likelihood of genetic mutation selection. Understanding the intricate interplay between obesity and viral pathogenesis is crucial for developing efficacious therapeutic approaches and public health policies, particularly in light of the escalating worldwide incidence of obesity.

Implementation of Recommendations on the Use of Corticosteroids in Severe COVID-19.

Importance: Research diversity and representativeness are paramount in building trust, generating valid biomedical knowledge, and possibly in implementing clinical guidelines. Objectives: To compare variations over time and across World Health Organization (WHO) geographic regions of corticosteroid use for treatment of severe COVID-19; secondary objectives were to evaluate the association between the timing of publication of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial (June 2020) and the WHO guidelines for corticosteroids (September 2020) and the temporal trends observed in corticosteroid use by region and to describe the geographic distribution of the recruitment in clinical trials that informed the WHO recommendation. Design, Setting, and Participants: This prospective cohort study of 434 851 patients was conducted between January 31, 2020, and September 2, 2022, in 63 countries worldwide. The data were collected under the auspices of the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC)-WHO Clinical Characterisation Protocol for Severe Emerging Infections. Analyses were restricted to patients hospitalized for severe COVID-19 (a subset of the ISARIC data set). Exposure: Corticosteroid use as reported to the ISARIC-WHO Clinical Characterisation Protocol for Severe Emerging Infections. Main Outcomes and Measures: Number and percentage of patients hospitalized with severe COVID-19 who received corticosteroids by time period and by WHO geographic region. Results: Among 434 851 patients with confirmed severe or critical COVID-19 for whom receipt of corticosteroids could be ascertained (median [IQR] age, 61.0 [48.0-74.0] years; 53.0% male), 174 307 (40.1%) received corticosteroids during the study period. Of the participants in clinical trials that informed the guideline, 91.6% were recruited from the United Kingdom. In all regions, corticosteroid use for severe COVID-19 increased, but this increase corresponded to the timing of the RECOVERY trial (time-interruption coefficient 1.0 [95% CI, 0.9-1.2]) and WHO guideline (time-interruption coefficient 1.9 [95% CI, 1.7-2.0]) publications only in Europe. At the end of the study period, corticosteroid use for treatment of severe COVID-19 was highest in the Americas (5421 of 6095 [88.9%]; 95% CI, 87.7-90.2) and lowest in Africa (31 588 of 185 191 [17.1%]; 95% CI, 16.8-17.3). Conclusions and Relevance: The results of this cohort study showed that implementation of the guidelines for use of corticosteroids in the treatment of severe COVID-19 varied geographically. Uptake of corticosteroid treatment was lower in regions with limited clinical trial involvement. Improving research diversity and representativeness may facilitate timely knowledge uptake and guideline implementation.

Efficacy and safety of zapnometinib in hospitalised adult patients with COVID-19 (RESPIRE): a randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial.

Background: Zapnometinib is an oral, non-ATP-competitive, small-molecule inhibitor of MEK1/MEK2 with immunomodulatory and antiviral properties. We aimed to investigate the safety and efficacy of zapnometinib in patients with COVID-19. Methods: In this randomised, double-blind, placebo-controlled, multicentre, proof-of-concept, phase 2 trial, we recruited hospitalised adults with moderate or severe COVID-19 from 18 hospitals in Germany, India, Romania, South Africa, and Spain. Those requiring ICU admission or ventilator support at screening or randomisation were excluded. Patients were randomly assigned (1:1) to receive oral zapnometinib (900 mg on Day 1; 600 mg on Days 2-6) or matching placebo, on top of standard of care. Randomisation, stratified by baseline clinical severity status (CSS 3 or 4, measured on a 7-point ordinal scale), was done using Interactive Response Technology. Patients, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was CSS at Day 15 and was conducted on the full analysis set (FAS: all patients who were randomised to the study, received at least one dose of study medication and had at least one post-dose assessment of CSS, as randomised). Safety analyses were conducted on the safety analysis set (all study participants who received at least one dose of study medication, as treated). This study is registered at ClinicalTrials.gov (NCT04776044) and EudraCT (2020-004206-59). Findings: The trial was terminated early as the emergence of the Omicron variant impacted recruitment. Between 12th April 2021 and 9th August 2022, 104 of the planned 220 patients were enrolled and randomly assigned, 103 were treated, and 101 were included in the FAS (zapnometinib: n = 50; placebo: n = 51). The primary outcome was not significantly different between the two groups, but patients on zapnometinib had higher odds of improved CSS versus placebo (odds ratio [OR] 1.54 [95% CI 0.72-3.33]; p = 0.26). Predefined subgroup analyses identified trends for improved CSS in patients with severe disease at baseline (OR 2.57 [0.76-8.88]; p = 0.13) and non-Omicron variants (OR 2.36 [0.85-6.71]; p = 0.10); the p value of the CSS subgroup by Treatment interaction term in the model was p = 0.28. The frequency and intensity of adverse events was low and similar between arms. Twenty (39.2%) patients treated with zapnometinib experienced adverse events compared with eighteen (34.6%) patients treated with placebo. One patient receiving zapnometinib and two patients receiving placebo died during the study. None of the deaths were considered related to study medication. Interpretation: These results provide proof-of-concept for the innovative approach of targeting the Raf/MEK/ERK pathway in patients with hospitalised moderate/severe COVID-19. Further clinical studies will be required to evaluate the clinical benefit of zapnometinib in this and other indications. Funding: Atriva Therapeutics GmbH and the Federal Ministry of Education and Research, Germany.

Exposure to Biological Fluids in Dental Practice-Narrative Review on Appropriate Risk Assessment to Guide Post-Exposure Management.

Accidental exposure to blood or other biological fluids is a common occurrence in dentistry, and its post-exposure management is a key component of infection prevention and control programs designed to prevent the transmission of blood-borne pathogens such as hepatitis B and C viruses (HBV, HCV) and human immunodeficiency virus (HIV). This narrative review aims to comprehensively review the risk assessment process for each of these pathogens at all steps of the epidemiological process, i.e., source-exposure route-receptive person, in order to provide a better understanding of the delicate differences that influence the transmission risk and that drive the individualized post-exposure management.

Therapeutic developments for SARS-CoV-2 infection-Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice.

This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.

EPI-Net One Health reporting guideline for antimicrobial consumption and resistance surveillance data: a Delphi approach.

Strategic and standardised approaches to analysis and reporting of surveillance data are essential to inform antimicrobial resistance (AMR) mitigation measures, including antibiotic policies. Targeted guidance on linking full-scale AMR and antimicrobial consumption (AMC)/antimicrobial residues (AR) surveillance data from the human, animal, and environmental sectors is currently needed. This paper describes the initiative whereby a multidisciplinary panel of experts (56 from 20 countries-52 high income, 4 upper middle or lower income), representing all three sectors, elaborated proposals for structuring and reporting full-scale AMR and AMC/AR surveillance data across the three sectors. An evidence-supported, modified Delphi approach was adopted to reach consensus among the experts for dissemination frequency, language, and overall structure of reporting; core elements and metrics for AMC/AR data; core elements and metrics for AMR data. The recommendations can support multisectoral national and regional plans on antimicrobials policy to reduce resistance rates applying a One Health approach.

Liver Transaminases in Pediatric Adenovirus Infection-A Five-Year Study in Two Major Reference Centers from Romania.

Human adenovirus causes infections with a very heterogeneous clinical picture, and children are often the most frequently affected group. Interest in adenovirus has increased with the 2022 outbreak of severe acute hepatitis of unknown etiology as human adenovirus was considered as one of the possible etiological agents. We conducted a retrospective study over a 5-year period in two major tertiary hospitals in the Romanian capital with the aim to characterize the clinical picture and the dynamics of liver function tests in children with confirmed adenovirus infection. The study included 1416 children with a median age of 1.1 years (IQR: 0.3, 2.3 years). Digestive symptoms were predominant in 95.2% of children, mainly diarrhea (90.5%) and vomiting (50.5%), and 38.0% had respiratory symptoms. Increased transaminases were identified in 21.5% of patients. Age over 1 year, lethargy, vomiting and dehydration significantly increased the odds of liver cytolysis independent of other risk factors such as chronic conditions or co-infections. Aspartate aminotransferase (AST) was more commonly increased compared to alanine aminotransferase (ALT). Only six children had transaminase increases above 500 U/L, three of which had co-infections with rotavirus, Epstein-Barr virus (EBV), or respiratory syncytial virus (RSV). Liver function tests should be part of routine monitoring for pediatric patients with adenovirus infection. The current study fills a gap in current knowledge related to the frequency and the extent of liver involvement in human adenovirus infection among pediatric patients.

Omicron in Infants-Respiratory or Digestive Disease?

The Omicron variant of SARS-CoV-2 has caused a large number of cases and hospitalizations in the pediatric population. Infants due to their age are susceptible to viral infections that may have a worse prognosis. Therefore, the aim of the current study has been to characterize the clinical features and the outcome of infants hospitalized with confirmed SARS-CoV-2 infection during the Omicron wave. We conducted a retrospective study of all consecutive infants hospitalized with symptomatic COVID-19 and no other co-infections, from January to September 2022 in one of the largest infectious diseases hospitals from Bucharest, Romania. A total of 613 infants were included in the analysis. The median age was 5 months (IQR: 3, 8 months). The clinical features were dominated by fever (96.4%), cough (64.8%) and loss of appetite (63.3%), and overall, respiratory symptoms were the most numerous (76.0%). Infants between 1-3 months old had a 1.5-fold increased risk of elevated alanine aminotransferase (ALT) values, and a longer length of hospitalization as compared to older infants. Infants between 7-9 months of age had 1.5-fold higher odds of loss of appetite, 1.7-fold more frequent cough and 1.6-fold more frequent digestive symptoms compared to infants in other age groups. The presence of digestive symptoms increased the probability of hepatic cytolysis (increased ALT) by 1.9-fold. Continued monitoring of COVID-19 among infants is very necessary, given the progressive character of SARS-CoV-2, in order to take correct and rapid therapeutic measures and to adapt to clinical changes driven by viral variant change.

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19.

BACKGROUND: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world's largest international, standardized data sets concerning hospitalized patients. METHODS: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). RESULTS: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. CONCLUSIONS: Age was the strongest determinant of risk of death, with a ∼30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death.

Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain?

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.

Prevalence of undiagnosed hepatitis B virus infection in patients with COVID-19A single center retrospective study.

At its onset, the coronavirus disease 2019 (COVID-19) pandemic brought significant challenges to healthcare systems, changing the focus of medical care on acute illness. Disruptions in medical service provision have impacted the field of viral hepatitis, with screening programs paused throughout much of 2020 and 2021. We performed a retrospective study on consecutive outpatients with COVID-19 during the second and third wave of COVID-19 in Romania, from November 2020 to April 2021, aiming to characterize the prevalence of undiagnosed hepatitis B virus (HBV) infection among patients presenting with acute illness. Overall, 522 patients had available records during the study timespan. Their mean ±â€…standard deviation age was 51 ±â€…13 years; 274 (52.5%) were male. We identified 16 (3.1%) cases of active HBV infection; only six of these patients were aware of their HBV status, and 3 of the newly diagnosed cases were identified as candidates for HBV treatment. A total of 96 patients (18.4%) had serological markers suggestive for prior HBV vaccination. A large proportion of patients (n = 120, 23.0%) had positive HBV core antibodies; among these, 90 (17.2%) had cleared a previous HBV infection (being positive for HBV surface antibodies and HBV core antibodies). We identified the following parameters that were significantly more frequent in patients with a history of HBV infection: older age (P < .001), hypoalbuminemia (P = .015), thrombocytopenia (P < .001), thrombocytopenia followed by thrombocytosis (P = .041), increased blood urea nitrogen (P < .001) and increased creatinine (P = .011). In conclusion, the COVID-19 pandemic has taught us essential lessons about the importance of maintaining access to screening programs and of ensuring active monitoring of patients with chronic infections such as hepatitis B, even during a medical crisis.

Real-World Use of Molnupiravir in the Treatment of Outpatients with SARS-CoV-2 Infection-A Patient Profile Based on the Experience of a Tertiary Infectious Disease Center.

During the current pandemic, the gap between fundamental research and clinical practice has been narrowing at a faster pace than ever before. While clinical trials play the main role of confirming the safety and efficacy of new drugs, a drug's introduction into clinical practice creates the need for further research in order to best position the use of the novel drug in terms of when, to whom, and how it would be best administered to achieve the best possible outcome under feasible clinical circumstances. We briefly present the results of a retrospective analysis of the characteristics of outpatients treated with molnupiravir in a tertiary care infectious disease hospital in Bucharest, Romania, between February and March 2022, when Romania was experiencing its fifth wave of COVID-19. A total of 46 outpatients received molnupiravir treatment and had complete clinical data available; of them, 56.5% (n = 20) were males and the median age was 48.5 years (IQR: 37.8, 67.0 years). A total of 54.2% (n = 26) of patients had at least one chronic condition. Of the 45 patients who underwent lung CT imaging evaluation, 13 (28.9%) showed changes suggestive of COVID-19 pneumonia. COVID-19 vaccination status was strongly protective for pneumonia (p = 0.002). All patients were symptomatic, and molnupiravir was initiated at a mean time from onset of symptoms of 3.5 (±1.5) days. At phone follow-up 5 days after the initial evaluation and initiation of molnupiravir treatment, all patients, except for one, confirmed a favorable course under treatment, with no worsening of COVID-19 severity and improvement in symptoms; none of them progressed to respiratory failure or required hospitalization. In conclusion, treatment was well tolerated and associated a favorable outcome of COVID-19 in routine practice in a clinical population that was slightly older and had a smaller burden of comorbidities and a higher rate of COVID-19 vaccination compared to that from the pivotal trial.