Strong humoral response after Covid-19 vaccination correlates with the common HLA allele A*03:01 and protection from breakthrough infection.

Few data exist on the role of genetic factors involving the HLA system on response to Covid-19 vaccines. Moving from suggestions of a previous study investigating the association of some HLA alleles with humoral response to BNT162b2, we here compared the HLA allele frequencies among weak (n = 111) and strong (n = 123) responders, defined as those healthcare workers with the lowest and the highest anti-Spike antibody levels after vaccination. Individuals with clinical history of Covid-19 or positive anti-nucleocapside antibodies were excluded. We found the common HLA-A*03:01 allele as an independent predictor of strong humoral response (OR = 12.46, 95% CI: 4.41-35.21, p < 0.0001), together with younger age of vaccines (p = 0.004). Correlation between antibody levels and protection from breakthrough infection has been observed, with a 2-year cumulative incidence of 42% and 63% among strong and weak responders, respectively (p = 0.03). Due to the high frequency of HLA-A*03:01 and the need for seasonal vaccinations against SARS-CoV-2 mutants, our findings provide useful information about the inter-individual differences observed in humoral response after Covid-19 vaccine and might support further studies on the next seasonal vaccines.

Role of airway epithelium in viral respiratory infections: Can carbocysteine prevent or mitigate them?

Alterations in airway epithelial homeostasis increase viral respiratory infections risk. Viral infections frequently are associated with chronic obstructive pulmonary disease (COPD) exacerbations, events that dramatically promote disease progression. Mechanism promoting the main respiratory viruses entry and virus-evocated innate and adaptive immune responses have now been elucidated, and an oxidative stress central role in these pathogenic processes has been recognized. Presence of reactive oxygen species in macrophages and other cells allows them to eliminate virus, but its excess alters the balance between innate and adaptive immune responses and proteases/anti-proteases and leads to uncontrolled inflammation, tissue damage, and hypercoagulability. Different upper and lower airway cell types also play a role in viral entry and infection. Carbocysteine is a muco-active drug with anti-oxidant and anti-inflammatory properties used for the management of several chronic respiratory diseases. Although the use of anti-oxidants has been proposed as an effective strategy in COPD exacerbations management, the molecular mechanisms that explain carbocysteine efficacy have not yet been fully clarified. The present review describes the most relevant features of the common respiratory virus pathophysiology with a focus on epithelial cells and oxidative stress role and reports data supporting a putative role of carbocysteine in viral respiratory infections.

Exploring the risk of infection events in patients with asthma receiving anti-IL-5 monoclonal antibodies: A rapid systematic review and a meta-analysis.

Introduction: Benralizumab, mepolizumab, and reslizumab are novel monoclonal antibodies approved for asthma, targeting eosinophilic inflammation. Benralizumab is directed against IL-5 receptor (IL-5R), while mepolizumab and reslizumab are directed against IL-5. The three drugs cause a reduction in eosinophils, but benralizumab also causes a cytotoxic effect on eosinophils and basophils. Recently, it has been reported that suboptimal responders to benralizumab presented exacerbations associated with concomitant infections and sputum neutrophilia and the incidence of infections was greater in patients receiving benralizumab compared to mepolizumab and reslizumab. For this reason, we wanted to explore potential differences in terms of infectious adverse events between the three different anti-IL-5 antibodies. Methods: We performed a rapid systematic review on PubMed up to April 28, 2022. We included randomized controlled trials (RCTs) evaluating benralizumab, mepolizumab, or reslizumab in patients with asthma. Included outcomes were the reporting of any respiratory tract infection and any emergency department (ED) or hospital admission for infection or asthma exacerbation. A Mantel-Haenszel meta-analysis was performed with Cochrane RevMan 5.4 to estimate pooled odds ratios (OR) with 95 % confidence intervals (CI). A subgroup analysis for the different active treatments was performed. Results: From 163 references we included 21 studies reporting the results of 23 different RCTs for a total population of 9156 patients. All studies compared anti-IL-5 antibodies against placebo. Anti-IL-5 treatment resulted in non-significant differences compared to placebo in the odds for nasopharyngitis (OR = 0.90; 95 % CI from 0.76 to 1.07), pharyngitis (OR = 1.45; 95 % CI from 0.92 to 2.28), upper respiratory tract infection (URTI) (OR = 0.97; 95 % CI from 0.82 to 1.15), rhinitis (OR = 1.01; 95 % CI from 0.71 to 1.44), pneumonia (OR = 0.56; 95 % CI from 0.10 to 2.01), and influenza (OR = 0.84; 95 % CI from 0.65 to 1.09). We observed significant reductions in the reporting of sinusitis (OR = 0.75; 95 % CI from 0.53 to 1.06), bronchitis (OR = 0.71; 95 % CI from 0.59 to 0.86), and ED or hospital admission due to asthma exacerbation for overall anti-IL-5 antibodies compared to placebo (OR = 0.59; 95 % CI from 0.40 to 0.88). We were not able to discriminate whether exacerbations were associated with infections or to increased sputum eosinophilia. From the subgroup analysis, we observed differences in directions and magnitudes of the effect size in the reporting of some events. Benralizumab was associated with increased odds of pharyngitis (OR = 1.56; 95 % CI from 0.97 to 2.52) and a similar trend was observed for mepolizumab in the reporting of rhinitis (OR = 1.85; 95 % CI from 0.72 to 4.78), both non-statistically significant. In terms of effect size, benralizumab also showed higher odds for bronchitis and pneumonia in comparison to mepolizumab and reslizumab (OR = 0.76, OR = 0.69, and OR = 0.60 for bronchitis and OR = 0.80, OR = 0.20, and OR = 0.45, respectively, all non-significant). Conclusion: Anti-IL-5 treatments might have different effects on the reporting of some infection events in patients with asthma. However, the evidence is limited by sample size and far than conclusive and suggest the need of future studies to evaluate the risk of infections in patients with asthma receiving anti-IL-5 treatments.

Why are adults exposed to liquid laundry detergent capsules?

INTRODUCTION: Exposures to liquid laundry detergent capsules in adults are less well characterized than in children. METHODS: All enquiries to the Centro Antiveleni di Milano regarding adults (>18 years) who were exposed to these capsules between July 2010 and July 2023 were analyzed. Enquiries were followed up with one or more recalls depending on the severity of the patient. RESULTS: Over the study period, 127 adults were exposed. The age distribution was as follows: 34 patients were aged 18-39 years, 29 were 40-59 years, 24 were 60-79 years, 26 were 80-96 years, and the age was unknown in 14. Exposure occurred mainly as a result of ingestion alone (n = 54), skin contact alone (n = 23), and eye contact alone (n = 31). Oral exposure without swallowing occurred in nine cases, and inhalation of the odour from a disintegrated capsule in four. Multiple routes of exposure were involved in six patients. Thirty-four (63 per cent) of the 54 ingestions occurred in those with dementia or intellectual disability, and three patients in this group died. Dermal or eye exposures did not involve those with dementia. CONCLUSIONS: These data show that the majority of adults in Italy who ingest liquid laundry detergent capsules are suffering from dementia or other cognitive impairment.

Secondary Prevention and Extreme Cardiovascular Risk Evaluation (SEVERE-1), Focus on Prevalence and Associated Risk Factors: The Study Protocol.

INTRODUCTION: Despite significant improvement in secondary CardioVascular (CV) preventive strategies, some acute and chronic coronary syndrome (ACS and CCS) patients will suffer recurrent events (also called "extreme CV risk"). Recently new biochemical markers, such as uric acid (UA), lipoprotein A [Lp(a)] and several markers of inflammation, have been described to be associated with CV events recurrence. The SEcondary preVention and Extreme cardiovascular Risk Evaluation (SEVERE-1) study will accurately characterize extreme CV risk patients enrolled in cardiac rehabilitation (CR) programs. AIM:  Our aims will be to describe the prevalence of extreme CV risk and its association with newly described biochemical CV risk factors. AIM: Our aims will be to describe the prevalence of extreme CV risk and its association with newly described biochemical CV risk factors. METHODS: We will prospectively enrol 730 ACS/CCS patients at the beginning of a CR program. Extreme CV risk will be retrospectively defined as the presence of a previous (within 2 years) CV events in the patients' clinical history. UA, Lp(a) and inflammatory markers (interleukin-6 and -18, tumor necrosis factor alpha, C-reactive protein, calprotectin and osteoprotegerin) will be assessed in ACS/CCS patients with extreme CV risk and compared with those without extreme CV risk but also with two control groups: 1180 hypertensives and 765 healthy subjects. The association between these biomarkers and extreme CV risk will be assessed with a multivariable model and two scoring systems will be created for an accurate identification of extreme CV risk patients. The first one will use only clinical variables while the second one will introduce the biochemical markers. Finally, by exome sequencing we will both evaluate polygenic risk score ability to predict recurrent events and perform mendellian randomization analysis on CV biomarkers. CONCLUSIONS: Our study proposal was granted by the European Union PNRR M6/C2 call. With this study we will give definitive data on extreme CV risk prevalence rising attention on this condition and leading cardiologist to do a better diagnosis and to carry out a more intensive treatment optimization that will finally leads to a reduction of future ACS recurrence. This will be even more important for cardiologists working in CR that is a very important place for CV risk definition and therapies refinement.

Quantitative SARS-CoV-2 subgenomic RNA as a surrogate marker for viral infectivity: Comparison between culture isolation and direct sgRNA quantification.

Detection of subgenomic (sg) SARS-CoV-2 RNAs are frequently used as a correlate of viral infectiousness, but few data about correlation between sg load and viable virus are available. Here, we defined concordance between culture isolation and E and N sgRNA quantification by ddPCR assays in 51 nasopharyngeal swabs collected from SARS-CoV-2 positive hospitalized patients. Among the 51 samples, 14 were SARS-CoV-2 culture-positive and 37 were negative. According to culture results, the sensitivity and specificity of E and N sgRNA assays were 100% and 100%, and 84% and 86%, respectively. ROC analysis showed that the best E and N cut-offs to predict positive culture isolation were 32 and 161 copies/mL respectively, with an AUC (95% CI) of 0.96 (0.91-1.00) and 0.96 (0.92-1.00), and a diagnostic accuracy of 88% and 92%, respectively. Even if no significant correlations were observed between sgRNA amount and clinical presentation, a higher number of moderate/severe cases and lower number of days from symptoms onset characterized patients with sgRNA equal to or higher than sgRNA cut-offs. Overall, this study suggests that SARS-CoV-2 sgRNA quantification could be helpful to estimate the replicative activity of SARS-CoV-2 and can represent a valid surrogate marker to efficiently recognize patients with active infection. The inclusion of this assay in available SARS-CoV-2 diagnostics procedure might help in optimizing fragile patients monitoring and management.

An overview of SARS-CoV-2 variants circulating in the 2020-2022 period in Lombardy.

Since the beginning of the pandemic, SARS-CoV-2 has shown genetic variability. All the variants that have sustained pandemic waves have shown several mutations, especially in the Spike protein that could affect viral pathogenesis. A total of 15,729 respiratory samples, collected between December 2020 and August 2022, have been included in this study. We report the circulation of SARS-CoV-2 variants in the Lombardy region, Italy, in a 2-year study period. Alpha, Delta, and Omicron variants became predominant causing the majority of cases whereas Beta or Gamma variants mostly caused local outbreaks. Next-generation sequencing revealed several mutations and few deletions in all of the main variants. For example, 147 mutations were observed in the Spike protein of Omicron sublineages; 20% of these mutations occurred in the receptor-binding domain region.

Effectiveness and Safety of Remdesivir in Treating Hospitalised Patients with COVID-19: A Propensity Score Analysis of Real-Life Data from a Monocentric Observational Study in Times of Health Emergency.

BACKGROUND AND OBJECTIVES: Remdesivir is an antiviral agent, which was shown to be safe and effective in treating early COVID-19, but its favourable impact in hospitalised patients with non-critical disease is still under investigation. The present study aimed to assess the effectiveness and safety of remdesivir as a treatment for hospitalised patients with COVID-19 by a propensity score analysis of observational data. METHODS: In this monocentric retrospective cohort study, the effectiveness and safety of a 5-day course of remdesivir (200 mg intravenously at Day 1, then 100 mg from Days 2-5) in association with the standard of care were assessed in comparison with the standard of care only. The primary endpoint was the proportion of recovery on Day 14. RESULTS: Of 3662 eligible inpatients who tested positive for the severe acute respiratory syndrome coronavirus 2 genome by nasopharyngeal swab at admission, 861 (24%) non-critical patients were included in a propensity score analysis and 281 (33%) were exposed to remdesivir. In total, 242/281 (86.1%) and 435/580 (75.0%) patients recovered in exposed and non-exposed, respectively, with a relative improvement of 11.1% (95% CI + 5.8 to 16.5%; unadjusted odds ratio: 2.07, 95% CI 1.40-3.05, p = 0.0001; after adjustment by propensity score weighting, odds ratio: 1.92, 95% CI 1.30-2.83, p = 0.001). In treated patients, 1 (0.03%) anaphylactic reaction and 1 (0.03%) acute reaction during drug injection were reported, and 24 (8.5%) patients stopped the treatment due to adverse reactions. No significant differences were found with respect to the secondary efficacy endpoints (in-hospital all-cause death, need for intensive care treatments, clinical improvement score at Day 28) and safety endpoints (any and serious adverse reactions). CONCLUSION: A 5-day course of remdesivir in association with the standard of care effectively promoted recovery from COVID-19 among non-critical in-hospital patients and had an acceptable safety profile.

Nature of the Interaction of Alpha-D-Mannose and Escherichia coli Bacteria, and Implications for its Regulatory Classification. A Delphi Panel European Consensus Based on Chemistry and Legal Evidence.

The nature of alpha-D-mannose-natural aldohexose sugar, C-2 glucose epimer, whose intended use is for preventing urinary tract infections-in the interaction with E. coli is addressed in order to drive the issue of its regulatory classification as a medicinal product or medical device. PRISMA systematic review approach was applied; Delphi Panel method was used to target consensus on statements retrieved from evidence. Based on regulatory definitions and research evidence, the mechanism of D-mannose does not involve a metabolic or immunological action while there is uncertainty regarding the pharmacological action. Specific interaction between the product and the bacteria within the body occurs, but its nature is inert: it does not induce a direct response activating or inhibiting body processes. Moreover, the action of D-mannose takes place, even if inside the bladder, outside the epithelium on bacteria that have not yet invaded the urothelial tissue. Therefore, its mechanism of action is not directed to host structures but to structures (bacteria) external to the host's tissues. On the basis of current regulation, the uncertainty as regard a pharmacological action of alpha-D-mannose makes possible its medical device classification: new regulations and legal judgments can add further considerations. From a pharmacological perspective, research is driven versus synthetic mannosides: no further considerations are expected on alpha-D-mannose.

Efficacy and safety of direct oral anticoagulants in the pediatric population: a systematic review and a meta-analysis.

BACKGROUND: Direct oral anticoagulants (DOACs) represent a cornerstone of adult venous thromboembolism (VTE) treatment. Recently, randomized controlled trials (RCTs) investigating DOACs in pediatrics have been performed. OBJECTIVES: To evaluate the efficacy and safety of DOACs in the pediatric population. METHODS: We systematically searched MEDLINE (PubMed), EMBASE, and ClinicalTrials.gov from initiation up to August 20, 2022, for RCTs comparing DOACs to standard of care (SOC) in patients aged <18 years according to PRISMA guidelines (PROSPERO registration CRD42022353870). The primary analysis was performed according to the anticoagulation intensity and clinical setting (ie, prophylaxis in cardiac disease or treatment in VTE). Efficacy outcomes were all-cause mortality and VTE. Safety outcomes were major bleeding (MB), clinically relevant non-MB, any bleeding, serious adverse events, and discontinuation due to adverse events (AEs). RESULTS: Seven RCTs were included in the systematic review and 6 in the meta-analysis (3 prophylaxis in cardiac disease and 3 treatment in VTE). DOACs showed a significant reduction of VTE recurrence for treatment (odds ratio [OR] = 0.42; 95% CI, 0.19-0.94) and a nonsignificant reduction in VTE occurrence in prophylaxis (OR = 0.22; 95% CI, 0.03-1.55). No differences were observed for any bleeding, serious AEs, and MB in prophylaxis. Nonsignificant trends were observed for clinically relevant non-MB, MB in treatment, and discontinuation due to AE in prophylaxis. We found a significant increase in discontinuation due to AE in treatment. CONCLUSIONS: DOAC treatment seems to reduce VTE compared with SOC without major safety issues in the pediatric population, whereas DOAC prophylaxis seems at least comparable to SOC.

The Association between Dysnatraemia during Hospitalisation and Post-COVID-19 Mental Fatigue.

COVID-19 may induce short- and long-term cognitive failures after recovery, but the underlying risk factors are still controversial. Here, we investigated whether (i) the odds of experiencing persistent cognitive failures differ based on the patients' disease course severity and sex at birth; and (ii) the patients' electrolytic profile in the acute stage represents a risk factor for persistent cognitive failures. We analysed data from 204 patients suffering from COVID-19 and hospitalised during the first pandemic wave. According to the 7-point WHO-OS scale, their disease course was classified as severe or mild. We investigated the presence of persistent cognitive failures collected after hospital discharge, while electrolyte profiles were collected during hospitalisation. The results showed that females who suffered from a mild course compared to a severe course of COVID-19 had a higher risk of presenting with persistent mental fatigue after recovery. Furthermore, in females who suffered from a mild course of COVID-19, persistent mental fatigue was related to electrolyte imbalance, in terms of both hypo- and hypernatremia, during hospitalisation in the acute phase. These findings have important implications for the clinical management of hospitalised COVID-19 patients. Attention should be paid to potential electrolyte imbalances, mainly in females suffering from mild COVID-19.

Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: an umbrella review of systematic reviews and 12 meta-analyses.

PURPOSE: To perform a systematic umbrella review with meta-analysis to evaluate the certainty of evidence on mortality risk associated with digoxin use in patients with atrial fibrillation (AF) with or without heart failure (HF). METHODS: We systematically searched MEDLINE, Embase, and Web of Science databases from inception to 19 October 2021. We included systematic reviews and meta-analyses of observational studies investigating digoxin effects on mortality of adult patients with AF and/or HF. The primary outcome was all-cause mortality; secondary outcome was cardiovascular mortality. Certainty of evidence was evaluated by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool and the quality of systematic reviews/meta-analyses by the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR2) tool. RESULTS: Eleven studies accounting for 12 meta-analyses were included with a total of 4,586,515 patients. AMSTAR2 analysis showed a high quality in 1, moderate in 5, low in 2, and critically low in 3 studies. Digoxin was associated with an increased all-cause mortality (hazard ratio [HR] 1.19, 95% confidence interval [95%CI] 1.14-1.25) with moderate certainty of evidence and with an increased cardiovascular mortality (HR 1.19, 95%CI 1.06-1.33) with moderate certainty of evidence. Subgroup analysis showed that digoxin was associated with all-cause mortality both in patients with AF alone (HR 1.23, 95%CI 1.19-1.28) and in those with AF and HF (HR 1.14, 95%CI 1.12-1.16). CONCLUSION: Data from this umbrella review suggests that digoxin use is associated with a moderate increased risk of all-cause and cardiovascular mortality in AF patients regardless of the presence of HF. TRIAL REGISTRATION: This review was registered in PROSPERO (CRD42022325321).

Role of epigenetics in the clinical evolution of COVID-19 disease. Epigenome-wide association study identifies markers of severe outcome.

BACKGROUND: COVID-19 has a wide spectrum of clinical manifestations and given its impact on morbidity and mortality, there is an unmet medical need to discover endogenous cellular and molecular biomarkers that predict the expected clinical course of the disease. Recently, epigenetics and especially DNA methylation have been pointed out as a promising tool for outcome prediction in several diseases. METHODS AND RESULTS: Using the Illumina Infinium Methylation EPIC BeadChip850K, we investigated genome-wide differences in DNA methylation in an Italian Cohort of patients with comorbidities and compared severe (n = 64) and mild (123) prognosis. Results showed that the epigenetic signature, already present at the time of Hospital admission, can significantly predict risk of severe outcomes. Further analyses provided evidence of an association between age acceleration and a severe prognosis after COVID-19 infection. The burden of Stochastic Epigenetic Mutation (SEMs) has been significantly increased in patients with poor prognosis. Results have been replicated in silico considering COVID-19 negative subjects and available previously published datasets. CONCLUSIONS: Using original methylation data and taking advantage of already published datasets, we confirmed in the blood that epigenetics is actively involved in immune response after COVID-19 infection, allowing the identification of a specific signature able to discriminate the disease evolution. Furthermore, the study showed that epigenetic drift and age acceleration are associated with severe prognosis. All these findings prove that host epigenetics undergoes notable and specific rearrangements to respond to COVID-19 infection which can be used for a personalized, timely, and targeted management of COVID-19 patients during the first stages of hospitalization.

Artificial intelligence for differentiating COVID-19 from other viral pneumonias on CT: comparative analysis of different models based on quantitative and radiomic approaches.

BACKGROUND: To develop a pipeline for automatic extraction of quantitative metrics and radiomic features from lung computed tomography (CT) and develop artificial intelligence (AI) models supporting differential diagnosis between coronavirus disease 2019 (COVID-19) and other viral pneumonia (non-COVID-19). METHODS: Chest CT of 1,031 patients (811 for model building; 220 as independent validation set (IVS) with positive swab for severe acute respiratory syndrome coronavirus-2 (647 COVID-19) or other respiratory viruses (384 non-COVID-19) were segmented automatically. A Gaussian model, based on the HU histogram distribution describing well-aerated and ill portions, was optimised to calculate quantitative metrics (QM, n = 20) in both lungs (2L) and four geometrical subdivisions (GS) (upper front, lower front, upper dorsal, lower dorsal; n = 80). Radiomic features (RF) of first (RF1, n = 18) and second (RF2, n = 120) order were extracted from 2L using PyRadiomics tool. Extracted metrics were used to develop four multilayer-perceptron classifiers, built with different combinations of QM and RF: Model1 (RF1-2L); Model2 (QM-2L, QM-GS); Model3 (RF1-2L, RF2-2L); Model4 (RF1-2L, QM-2L, GS-2L, RF2-2L). RESULTS: The classifiers showed accuracy from 0.71 to 0.80 and area under the receiving operating characteristic curve (AUC) from 0.77 to 0.87 in differentiating COVID-19 versus non-COVID-19 pneumonia. Best results were associated with Model3 (AUC 0.867 ± 0.008) and Model4 (AUC 0.870 ± 0.011. For the IVS, the AUC values were 0.834 ± 0.008 for Model3 and 0.828 ± 0.011 for Model4. CONCLUSIONS: Four AI-based models for classifying patients as COVID-19 or non-COVID-19 viral pneumonia showed good diagnostic performances that could support clinical decisions.

CMV seroprevalence and coronary CMV-DNA detection in immunocompetent patients with heart diseases.

BACKGROUND: Acute coronary syndromes (ACS) are a major cause of morbidity and mortality. As cytomegalovirus (CMV) may contribute to cardio-vascular (CV) manifestations, we sought to provide a proof-of-concept for the involvement of coronary and/or systemic CMV-reactivation as a possible ACS trigger. METHODS: We prospectively enrolled consecutive patients undergoing a coronary angiography for ACS (acute-cases, N.=136), or non-ACS reasons (chronic-cases, N.=57). Matched coronary and peripheral blood-samples were processed for quantification of CMV-DNAemia (RT-PCR), CMV-IgG/IgM, and CMV-IgG avidity (ELISA). Peripheral-blood samples from 17 healthy subjects were included as controls. RESULTS: Out of the 193 cases included, 18.1% were aged ≤55 years, 92.5% were Central-European, and 100% immunocompetent. CMV-IgG seroprevalence was 91.7% (95%CI: 87.8-95.6), significantly higher than in healthy-controls (52.9% [95%CI: 29.2-76.5]; P<0.001), yet consistent across age-groups (P=0.602), male/females (P=0.765), and acute/chronic-cases (P=0.157). Median (IQR) IgG titers were 110 (84-163) AU/mL, with 0.62 (0.52-0.72) avidity, supporting a long history of infection. No acute CMV infections were found. In 22.6% (n/N.=40/177) of the IgG-positive cases low-level coronary and/or systemic CMV-DNAemia (always <40 copies/mL) was detected. While no differences in peripheral CMV-DNAemia prevalence were observed nor among cases nor controls, coronary CMV-DNAemia was more frequent in acute-cases without modifiable CV risk-factors (n/N.=4/10; 40.0%), than in chronic-cases (n/N.=6/55, 10.9%; P=0.029), or acute-cases with risk-factors (n/N.=16/112, 14.3%; P=0.058). CONCLUSIONS: CMV-IgG seroprevalence was high in patients with heart diseases. CMV-DNAemia can be found, although uncommonly, in coronary circulation during an ACS, with increased prevalence in older subjects and in absence of CV risk-factors, identifying possible areas for novel interventions.

Diagnostic Performance in Differentiating COVID-19 from Other Viral Pneumonias on CT Imaging: Multi-Reader Analysis Compared with an Artificial Intelligence-Based Model.

Growing evidence suggests that artificial intelligence tools could help radiologists in differentiating COVID-19 pneumonia from other types of viral (non-COVID-19) pneumonia. To test this hypothesis, an R-AI classifier capable of discriminating between COVID-19 and non-COVID-19 pneumonia was developed using CT chest scans of 1031 patients with positive swab for SARS-CoV-2 (n = 647) and other respiratory viruses (n = 384). The model was trained with 811 CT scans, while 220 CT scans (n = 151 COVID-19; n = 69 non-COVID-19) were used for independent validation. Four readers were enrolled to blindly evaluate the validation dataset using the CO-RADS score. A pandemic-like high suspicion scenario (CO-RADS 3 considered as COVID-19) and a low suspicion scenario (CO-RADS 3 considered as non-COVID-19) were simulated. Inter-reader agreement and performance metrics were calculated for human readers and R-AI classifier. The readers showed good agreement in assigning CO-RADS score (Gwet's AC2 = 0.71, p < 0.001). Considering human performance, accuracy = 78% and accuracy = 74% were obtained in the high and low suspicion scenarios, respectively, while the AI classifier achieved accuracy = 79% in distinguishing COVID-19 from non-COVID-19 pneumonia on the independent validation dataset. The R-AI classifier performance was equivalent or superior to human readers in all comparisons. Therefore, a R-AI classifier may support human readers in the difficult task of distinguishing COVID-19 from other types of viral pneumonia on CT imaging.

2-Arylmelatonin analogues: Probing the 2-phenyl binding pocket of melatonin MT1 and MT2 receptors.

In crystal structures of melatonin MT1 and MT2 receptors, a lipophilic subpocket has been characterized which accommodates the phenyl ring of the potent agonist 2-phenylmelatonin. This subpocket appears a key structural element to achieve high binding affinity and selectivity for the MT2 receptor. A series of 2-arylindole ligands was synthesized to probe the requirements for the optimal occupation and interaction with the 2-phenyl binding pocket. Thermodynamic integration simulations applied to MT1 and MT2 receptors in complex with the α-naphthyl derivative provided a rationale for the MT2-selectivity and investigation on the binding mode of a couple of atropisomers allowed to define the available space and arrangement of substituents inside the subpocket. Interestingly, more hydrophilic 2-aza-substituted compounds displayed high binding affinity and molecular dynamics simulations highlighted polar interaction with residues from the subpocket that could be responsible for their potency.

Systematic Review and Meta-analysis Seem to Indicate that Cannabinoids for Chronic Primary Pain Treatment Have Limited Benefit.

INTRODUCTION: The IASP ICD-11 chronic primary pain (CPP) definition includes 19 different painful conditions. In recent years, interest in the potential role of cannabinoids in the management of CPP has increased, since they demonstrated a possible efficacy in treating pain, especially in secondary pain conditions. However, limited evidence is available for patients with CPP. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of cannabinoid administration in CPP. METHODS: PubMed, EMBASE, and Cochrane Library were searched form the beginning up to 31 October 2021 to retrieve published articles of randomized controlled trials (RCTs) or observational, retrospective or prospective, studies, investigating cannabinoids in CPP. The study screening process was completed during November 2021. The primary outcome was pain reduction by means of the visual analogue scale (VAS). Secondary outcomes were quality of life by means of the fibromyalgia impact questionnaire (FIQ) or other available scales, appetite, anxiety, depression, and sleep by means of any available scales. Safety was assessed with the reporting of serious adverse events (SAE) and discontinuation due to adverse events. Risk of bias was assessed. The weighted generic inverse variance method and Mantel-Haenszel method were used to estimate the mean difference (MD) and odds ratios (OR) with 95% confidence intervals (CI) for continuous and dichotomous outcomes, respectively. For outcome measures reported with different scales (pain, anxiety, depression), we used the standardized MD (SMD) as the effect measure and then converted it into units of the VAS scale for pain, the Beck Anxiety Inventory (BAI) for anxiety, and the Beck Depression Inventory (BDI) for depression. Summary of findings was produced using GRADEproGDT. RESULTS: From 3007 identified records, we included eight articles reporting the results of eight different RCTs (four parallel and four crossover studies; seven compared to placebo and one to amitriptyline), with a total population of 240 patients. VAS pain reduction was non-significant for cannabinoids against placebo (MD = - 0.64; 95% CI - 1.30 to 0.02) or amitriptyline (MD = - 0.19; 95% CI - 0.58 to 0.19). More than 4 weeks cannabinoid treatment significantly reduced pain compared to placebo in parallel studies with more than 4 weeks of treatment duration (MD = - 1.28; 95% CI - 2.33 to - 0.22). Differences for the FIQ (MD = - 21.69; 95% CI - 46.20 to 2.82), BAI (MD = - 2.32; 95% CI - 7.99 to 3.08), and BDI (MD = 2.32; 95% CI - 1.71 to 6.35) were non-significant, likewise for discontinuation due to adverse events (OR = 2.15; 95% CI 0.44-10.65), when comparing cannabinoids to placebo. The quality of the evidence was generally low mainly as a result of imprecision and risk of bias. CONCLUSION: Cannabinoid treatment in patients with CPP had limited benefit on pain relief; however, it might improve pain with long-term administration.

Effects of Levofloxacin, Aztreonam, and Colistin on Enzyme Synthesis by P. aeruginosa Isolated from Cystic Fibrosis Patients.

(1) Background: Cystic fibrosis (CF) is characterized by chronic pulmonary inflammation and persistent bacterial infections. P. aeruginosa is among the main opportunistic pathogens causing infections in CF. P. aeruginosa is able to form a biofilm, decreasing antibiotic permeability. LOX, a lipoxygenase enzyme, is a virulence factor produced by P. aeruginosa and promotes its persistence in lung tissues. The aim of this study is to evaluate if antibiotics currently used for aerosol therapy in CF are able to interfere with the production of lipoxygenase from open isolates of P. Aeruginosa from patients with CF. (2) Methods: Clinical isolates of P. aeruginosa from patients with CF were grown in Luria broth (LB). Minimum inhibitory concentration (MIC) was performed and interpreted for all isolated strains according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. We selected four antibiotics with different mechanisms of action: aztreonam, colistin, amikacin, and levofloxacin. We used human pulmonary epithelial NCI-H929 cells to evaluate LOX activity and its metabolites according to antibiotic action at increasing concentrations. (3) Results: there is a correlation between LOX secretion by clinical isolates of P. aeruginosa and biofilm production. Levofloxacin exhibits highly significant inhibitory activity compared to the control. Amikacin also exhibits significant inhibitory activity against LOX production. Aztreonam and colistin do not show inhibitory activity. These results are also confirmed for LOX metabolites. (4) Conclusions: among the evaluated antibiotics, levofloxacin and amikacin have an activity on LOX secretion.

High prevalence of anal papillomavirus infection in men who have sex with men PrEP users.

OBJECTIVES: Human papillomavirus (HPV) is the most common STI and is associated with a wide range of diseases from anogenital warts to malignancies. Anal HPV infection is considerably more common in men who have sex with men (MSM) living with HIV. Aims of the present study are to (i) describe the prevalence of anal HPV infection in MSM who started pre-exposure prophylaxis (PrEP) and (ii) analyse factors associated with anal infection from genotypes that would be covered by nonavalent vaccination. METHODS: This monocentric, cross-sectional study included all subjects who started PrEP from May 2018 to November 2021. PrEP candidates underwent full behavioural and clinical evaluation, including digital anal rectal examination and swabbing for HPV determination. Descriptive statistics, Mann-Whitney U test for continuous and χ2 tests for categorical variables were adopted. Unadjusted and adjusted regression analyses were performed to assess factors associated with positive anal swabs and to the presence of genotypes covered by the nonavalent vaccination. RESULTS: The analysis included 288 subjects: anal swabs tested positive in 87.2% of cases, 79.2% of the subjects had a high-risk genotype (mainly 16), whereas 67.4% had a genotype covered by nonavalent vaccine. Sexual role was the only factor associated with anal HPV infection. Use of recreational drugs and a diagnosis of ≥2 STIs correlated with the presence of genotypes that would have been covered by vaccine, while previous vaccination had a protective role. CONCLUSIONS: PrEP candidates showed a high prevalence of anal HPV infection, especially due to high-risk genotypes, comparable to what has been reported in MSM living with HIV.