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.

National medical specialty guidelines of HIV indicator conditions in Europe lack adequate HIV testing recommendations: a systematic guideline review.

BackgroundAdequate identification and testing of people at risk for HIV is fundamental for the HIV care continuum. A key strategy to improve timely testing is HIV indicator condition (IC) guided testing.AimTo evaluate the uptake of HIV testing recommendations in HIV IC-specific guidelines in European countries.MethodsBetween 2019 and 2021, European HIV experts reviewed guideline databases to identify all national guidelines of 62 HIV ICs. The proportion of HIV IC guidelines recommending HIV testing was reported, stratified by subgroup (HIV IC, country, eastern/western Europe, achievement of 90-90-90 goals and medical specialty).ResultsOf 30 invited European countries, 15 participated. A total of 791 HIV IC guidelines were identified: median 47 (IQR: 38-68) per country. Association with HIV was reported in 69% (545/791) of the guidelines, and 46% (366/791) recommended HIV testing, while 42% (101/242) of the AIDS-defining conditions recommended HIV testing. HIV testing recommendations were observed more frequently in guidelines in eastern (53%) than western (42%) European countries and in countries yet to achieve the 90-90-90 goals (52%) compared to those that had (38%). The medical specialties internal medicine, neurology/neurosurgery, ophthalmology, pulmonology and gynaecology/obstetrics had an HIV testing recommendation uptake below the 46% average. None of the 62 HIV ICs, countries or medical specialties had 100% accurate testing recommendation coverage in all their available HIV IC guidelines.ConclusionFewer than half the HIV IC guidelines recommended HIV testing. This signals an insufficient adoption of this recommendation in non-HIV specialty guidelines across Europe.

The 2017-2018 influenza season in Bucharest, Romania: epidemiology and characteristics of hospital admissions for influenza-like illness.

BACKGROUND: Seasonal influenza causes a considerable burden to healthcare services every year. To better measure the impact of severe influenza cases in Romania, we analyzed active surveillance data collected during the 2017-2018 season from patients admitted for influenza-like illness (ILI) at a tertiary care hospital in Bucharest. METHODS: Patients admitted for acute ILI were included if they were resident in the Bucharest-Ilfov region, had been hospitalized for at least 24 h, and had onset of symptoms within 7 days before admission. Patient demographics, healthcare use, vaccination status, and outcome data were collected by questionnaire or by searching clinical records. Respiratory swabs were also obtained from each patient to confirm influenza A (A/H1 and A/H3 subtypes) or influenza B (Yamagata and Victoria lineages) infection by real-time reverse-transcription polymerase chain reaction assay. RESULTS: The study included 502 patients, many (45.2%) of whom were aged < 5 years. Overall, 108 patients (21.5%) had one or more comorbidities. Seventeen adults aged 18-64 years (3.4%) had been vaccinated against influenza. Patients were hospitalized for a median of 5 days and most (90.4%) were prescribed antiviral treatment. More than one-half of the patients (n = 259, 51.6%) were positive for influenza. Most influenza cases were caused by B viruses (172/259, 66.4%), which were mostly of the B/Yamagata lineage (85 of 94 characterized, 90.4%). Most of the subtyped A viruses were A/H1 (59/74, 79.7%). A/H1 viruses were frequently detected in influenza-positive admissions throughout the 2017-2018 season, whereas the predominant B/Yamagata viruses were detected around the middle of the season, with a peak in cases at week 7 of 2018. Eleven patients were admitted to an intensive care unit; of these, one patient with confirmed B/Yamagata infection died. CONCLUSIONS: These results show that seasonal influenza results in considerable hospitalization in Bucharest-Ilfov, Romania and suggest vaccine coverage should be extended, especially to the youngest age groups. The data from this study should help inform and optimize national influenza healthcare policies.

Comparative evaluation of aggressiveness traits in staphylococcal strains from severe infections versus nasopharyngeal carriage.

Despite their commensal status, staphylococci can become problematic pathogens expressing multiple and redundant virulence factors. This study aimed to evaluate aggressiveness markers comparatively in staphylococcal strains isolated from severe infections versus asymptomatic carriage in order to identify clinically relevant bacterial traits that could easily be detected in clinical practice and could be suggestive for particular host-pathogen interactions such as cyto-adhesion or biofilm formation, ultimately orienting the clinical decision-making process. We have used in vitro phenotypic methods to assess adhesion to and invasion of eukaryotic cells, biofilm development, and expression of soluble virulence factors in 92 Staphylococcus spp. strains. The adhesion index, invasion capacity, biofilm formation and expression of soluble factors did not differ significantly between clinical and commensal strains. The major bacterial traits we found to be significantly more prevalent in clinical staphylococci were the aggregative adhesion pattern (P = 0.012), cluster adhesion (P = 0.001) and tetrad morphology (P = 0.018). The aggregative adhesion pattern was correlated with higher cyto-adhesion (P < 0.001), higher invasion capacity (P = 0.003) and lower Carmeli scores (P = 0.002). Three major bacterial traits, namely tetrad morphology, aggregative adhesion pattern, and resistance to methicillin (acronym: TAM), can be used to compute an aggressiveness score (SAS) predictive of the staphylococcal strain's virulence and capacity to initiate and develop a biofilm-driven chronic infectious process versus a fulminant acute infection, in a susceptible host.

Prevalence of osteo-renal impairment in the Romanian HIV cohort.

BACKGROUND: The Romanian HIV cohort has certain particularities that render it unique in Europe. We have performed a study to evaluate the prevalence of bone and kidney impairment in this particular group of HIV-infected patients. METHODS: We performed dual-energy X-ray absorptiometry (DXA) evaluation of the lumbar vertebrae and the femur, as well as laboratory tests including standard serum panels, bone-related markers and urinalysis in patients from the Romanian HIV cohort. RESULTS: The study included 72 patients, of which 46 (58.3 %) were males. The median (IQR) age was 38 (18) years and the median (IQR) time from HIV infection diagnosis was 9 (13) years. Most patients (55.6 %) were non-smokers, but a relatively high proportion (37.5 %) was currently smoking. Only a small percentage of patients (20.8 %) did not present any comorbidities, while 40.3 % had one comorbidity, the most frequent being dyslipidemia (present in 25 patients, 38.5 %). Only 6 patients had a medical history suggestive for renal disease and 3 for bone-related abnormalities. The median (IQR) glomerular filtration rate was 97.5 (33.0) mL/min/1.73sqm. We diagnosed 21 patients (29.6 %) with stage 2 chronic kidney disease and one patient (1.4 %) with stage 3 chronic kidney disease. Proteinuria was present in 9 (12.7 %) patients. The estimated glomerular filtration rate was significantly lower in patients with cardiac comorbidities (p = 0.013). Vitamin D was significantly lower in smokers compared with non-smokers, with a mean value of 15 vs. 21 ng/mL and a moderate effect size (Cohen's d = -0.5) (p = 0.046). Lumbar osteopenia and osteoporosis were diagnosed in 33.3 and 13.7 % of patients, while femoral osteopenia and osteoporosis were diagnosed in 37.3 and 7.8 %, respectively. Lower nadir CD4 cell counts were found in patients with bone-related comorbidities (p = 0.000). CONCLUSIONS: We identified a relatively high prevalence of chronic kidney disease in the Romanian HIV cohort, and a fairly low prevalence of osteopenia and osteoporosis, compared with other European countries. In this category of patients smoking should be avoided altogether, as it may be an indirect risk factor for kidney disease (associating cardiac comorbidities) and it may impair bone metabolism by altering serum levels of hydroxy-vitamin D.

Microbiologic Safety of the Transareolar Approach in Breast Augmentation.

BACKGROUND: In aesthetic breast augmentation, especially by the transareolar approach, there is increasing concern regarding the occurrence of capsular contracture and its potential correlation with intraoperative implant contamination from putative endogenous breast flora of the nipple and lactiferous ducts. However, detectable bacteria cannot be considered synonymous with established resident microflora. OBJECTIVES: The authors sought to elucidate the existence of endogenous breast flora and assess the microbiologic safety of transareolar breast augmentation. METHODS: In this prospective study (BREAST-MF), the authors collected microbiologic samples from the breast skin, ductal tissue, and parenchyma of 39 consecutive female patients who underwent breast procedures in a plastic surgery clinic. Swabs collected pre-, intra-, and postoperatively were processed for bacterial and fungal growth. Positive cultures underwent identification through VITEK and MALDI-TOF, as well as antimicrobial susceptibility testing. RESULTS: Staphylococcus species accounted for 95 of 106 (89.6%) positive results from native breast skin, 15 of 18 (83.3%) positive results from decontaminated breast skin, and 4 of 4 (100%) positive results from the breast parenchyma. Methicillin resistance was present in 26.4% of S. epidermidis, 25.3% of S. hominis, and 71.4% of S. haemolyticus strains. CONCLUSIONS: During transareolar breast augmentation, in the nipple-areola region it is more likely to find bacteria populating the skin, rather than endogenous breast flora, as previously considered. Appropriate preoperative decontamination is essential for minimizing the risk of postoperative infections. LEVEL OF EVIDENCE 3: Risk.

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.

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.

Knowledge, Attitudes, and Practices of Dental Students from Romania Regarding Self-Perceived Risk and Prevention of Infectious Diseases.

University education is a leading source of information for dental practitioners. Particular emphasis should be given to determining the extent to which students acquire positive knowledge, attitudes, and practices (KAP) and positive metacompetences beyond the scope of each studied dental discipline. We performed a cross-sectional questionnaire-based study among dentistry students from Romania to assess self-perceived risk of infectious diseases and their KAP on topics related to infectious disease prevention. The surveyed students presented good knowledge regarding personal protective equipment (PPE), and their PPE practices significantly correlated with the perceived usefulness of PPE. Only 45.1% correctly recognized all vaccine-preventable diseases (VPDs), but knowledge regarding VPDs significantly improved with increasing year of study (τb = 0.298, p = 0.001), confirming a positive education effect. Awareness regarding the need for screening for bloodborne viruses is poor; the majority of students had never performed a test for hepatitis C virus infection (HCV) (59.4%) or for human immunodeficiency virus (HIV) infection (60.4%). Furthermore, most respondents incorrectly considered themselves at high or very high risk of acquiring BBV, and perceived risk was inversely correlated with willingness to treat patients with hepatitis B virus (HBV) infection (τb = -0.214, p = 0.018), HCV infection (τb = -0.234, p = 0.013), or HIV infection (τb = -0.242, p = 0.006). This led to 3.0% of respondents stating that they would hypothetically deny dental treatment to a patient with HBV infection, 5.0% for HCV infection, and 10.9% for HIV infection, the proportion being significantly higher for HIV (z = -2.2, p = 0.026). In conclusion, better knowledge is needed among dental students regarding their own vaccination history, screening for bloodborne viruses, accurate estimates for their risk of acquiring bloodborne viruses during routine dental practice, and the existence of post-exposure measures following occupational exposure. Improving student knowledge and awareness could translate into a higher willingness to treat patients with chronic viral infections and into a safer and more inclusive dental practice. We propose an adaptation to the university curriculum to cover these key areas for targeted focus to empower future dental practitioners and to facilitate the improvement of across-discipline metacompetences for infection prevention and control.

Influenza Vaccination of Romanian Medical Students during COVID-19 Times: From Knowledge to Behavior.

In Romania, influenza vaccination uptake among healthcare workers decreased over time despite access to the vaccine being constantly improved. The aim of this paper is to provide a comparative analysis of the knowledge and attitudes of Dental Medicine and Medicine students towards recommended vaccinations for healthcare workers, focusing on influenza vaccination. A cross-sectional study was conducted during the entire 2021-2022 academic year. Data were collected using 2 electronic questionnaires which were applied to the students from the Faculty of Medicine (n = 883) and, respectively, the Faculty of Dental Medicine of the Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. The questionnaires were offered to 1187 students and completed by 911 students (response rate = 77%). Out of these, 85% (n = 778) identified the influenza vaccine as recommended; 35% (n = 321) reported getting an annual influenza vaccination; and 37% (333) reported getting an influenza vaccination in the previous season. Overall, 45% (n = 222) of the respondents who completed the questionnaires from October 2021 to February 2022 reported that they intend to get vaccinated against influenza in the 2021-2022 season and approximately 8% (n = 39) reported that they had already been vaccinated. The multivariable analysis showed that the habit of getting annually vaccinated against influenza as well as the knowledge that influenza vaccine is recommended for all healthcare workers were associated with a higher probability of intending to get vaccinated. The current study emphasizes the need to raise awareness among medical students regarding influenza vaccination and to involve medical education institutions, public health authorities, and healthcare facilities in promoting this vaccination among students since the influenza vaccine uptake rate among medical students included in this study was suboptimal.

Hospitalizations for Acute Otitis and Sinusitis in Patients Living with HIV: A Retrospective Analysis of a Tertiary Center in Romania.

Background/Objectives: Acute or chronic ear, nose and throat (ENT) conditions in people living with HIV can lead to hospitalization and affect their quality of life. The aim of our study was to determine the frequency and characteristics of hospitalizations for acute sinusitis (AS) and acute otitis (AO) in people living with HIV. Methods: We performed a retrospective analysis over the course of six years (from January 2018 to December 2023), assessing all hospitalizations for AS and/or AO occurring in patients living with HIV, at the largest infectious diseases hospital in Romania. Results: We identified a total of 179 cases, among which 149 cases (83.2%) were attributed to AS and 41 cases (22.9%) were due to AO. Among cases of AS, maxillary sinuses were most frequently involved (n = 140/149, 94.0%), and among cases of AO, acute congestive otitis media (n = 14, 34.1%) and acute purulent otitis media (n = 13, 31.7%) were the most common forms. The underlying HIV infection was classified as stage C3 in 57.5% of cases. In 19.6% of cases, it was possible to identify either the trigger or the etiological agent, and the most frequent bacterial pathogens were Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. Conclusions: In conclusion, this study highlights that hospitalizations due to acute sinus and ear involvement are not isolated events in people living with HIV. A prospective follow-up is needed to gain a deeper and more dynamic understanding of how ENT health is affected in people with HIV infection. Furthermore, promoting prevention through vaccination may reduce to a certain extent the burden of ENT infections in this population.

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.

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.

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.

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.

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.

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.

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.

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.

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.