Innate immune mechanisms of mRNA vaccines.

The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.

Analysis and interpretation of Coronavirus infection children's incidence, contributing factors, risks of complications and their relationship.

OBJECTIVE: Aim: To study and investigate the incidence of Coronavirus infection in children, the course of the disease, the risks of complications and their interrelationships. PATIENTS AND METHODS: Materials and Methods: Study included the analysis and observation of children (n=55, aged 14.36±3.62 years) with confirmed Coronerovirus infection, who were observed in the CNE ≪CMCH≫ in Uzhgorod in outpatient conditions. A study of clinical presentations, a clinical and laboratory examination followed by a mathematical analysis of the symptoms data in children with an identified Coronavirus infection and in the dynamics up to week 30 (with survey intervals in 3 weeks) from the diagnosis verification was carried out. RESULTS: Results: A dynamic analysis of the clinical manifestation of symptoms in children with an identified Corona virus infection and within 30 weeks (with survey intervals of 3 weeks) from the beginning of the diagnosis verification was carried out. Complaints from the respiratory system were prevailed. The most long-lasting complaint was observed ≪changes in the sense of taste and smell≫ (from 35(63.6%) to 6(10.9%) up to 18 weeks inclusive. Other complaints ≪Cough, Rhinitis, Shortness of breath, Pain in the chest≫ was observed for 6 weeks. Sore throat, muscular and joint pain were persisted for 3 weeks. Fever was not identified at week 3. Illness with other viral respiratory diseases started at week 9 and was observed until week 30 (from 10(18.2%) to 19(34.5%)) with varying levels. A decrease in cases of IgM identification was observed within 6 weeks (from 55, 100% to 20, 36, 4%). On the 9th week, the presence of IgM was not established. There is also an increase in the number of cases of detection of IgG in patients with a level maximum of 6 weeks. CONCLUSION: Conclusions: There is a positive effect of the CRP level on the occurrence of symptoms of cough, rhinitis, shortness of breath, chest pain, change in taste and smell, muscle and joint pain (r=0.33-0.55), with the most significant data for the symptom of pain in chest (p=0.00001). Ferritin level interactions mostly had a negative direction (r=-0.35-0.48, p=0.02-0.00001) on the development of symptoms, with the exception of rhinorrhea (r=0.48, p=0.00002) and chest pains (r=0.39, 0.003). According to multiple logistic regression analysis the chance of the symptom of a change in taste and smell increases due to an increasing in the level of Procalcitonin in 1.48 times. The chance of the symptom of shortness of breath increased due to an increasing in the Ferritin level in 1.025 times.

Evidence of greater severity of diabetic foot ulcers during COVID-19 pandemic: A real-life single-centre cohort study.

AIMS: In the Sars-Cov-2 pandemic era, patients with diabetes mellitus (DM) manifested more severe forms of Sars-Cov-2 with greater mortality than non-diabetic patients. Several studies documented more aggressive forms of diabetic foot ulcers (DFU) during the pandemic period even though the results were not unanimously confirmed. The aim of this study was to evaluate the clinical-demographic differences between a cohort of Sicilian diabetic patients hospitalised for DFU in the pre-pandemic 3 years and a cohort of patients hospitalised in the pandemic 2 years. MATERIALS AND METHODS: One hundred and eleven patients from the pre-pandemic period 2017-2019 (Group A) and 86 patients from the pandemic period 2020-2021 (Group B) with DFU, admitted to the division of Endocrinology and Metabolism of the University Hospital of Palermo, were retrospectively evaluated. The clinical assessment of the type, staging and grading of the lesion, and the infective complication from DFU was performed. RESULTS: No differences in HbA1c values were observed between the two groups. Group B showed a significantly higher prevalence of male subjects (p = 0.010), neuro-ischaemic ulcers (p < 0.001), deep ulcers with involvement of bones (p < 0.001), white blood count levels (p < 0.001), and reactive C protein (p = 0.001) compared to group A. CONCLUSIONS: Our data show that in the COVID-19 pandemic, a greater severity of ulcers requiring a significantly greater number of revascularisations and more expensive therapy, but without an increase in the amputation rate, was observed. These data provide novel information on the impact of the pandemic on diabetic foot ulcer risk and progression.

Risk of severe disease and mortality of COVID-19 in patients with Budd-Chiari syndrome: A population-based matched cohort study.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare and potentially life-threatening disorder characterized by obstruction of the hepatic outflow tract. It is unknown whether patients with BCS represent a high risk for severe disease and mortality from coronavirus disease 2019 (COVID-19). Thus, we aimed to assess hospitalization rates, severe disease, all-cause mortality, intensive care unit (ICU) requirement and acute kidney injury (AKI) from COVID-19 diagnoses. METHODS & RESULTS: We identified 467 patients with BCS with COVID-19, 96 427 non-chronic liver disease (CLD) and 9652 non-BCS CLD. The BCS and non-CLD cohorts (n = 467 each) and BCS and non-BCS CLD (n = 440 each) were well balanced after propensity matching. When compared to the non-CLD cohort, the BCS group had a higher risk of all-cause mortality (5.1% vs. 2.4%, HR 2.18; 95% CI, 1.08-4.40), severe disease (6.0% vs. 2.4%, HR 2.20; 95% CI, 1.09-4.43), hospitalization (24.6% vs. 13.1%, HR 1.77; 95% CI, 1.30-2.42) and AKI (7.9% vs. 2.8%, HR 2.57; 95% CI, 1.37-4.85), but no significant differences in ICU requirements (2.4% vs. 2.1%, HR 0.75; 95% CI, 0.27-2.08) at 60-days time points. When compared to the non-BCS CLD cohort, the BCS group had a higher risk of all-cause mortality (3.6% vs. 2.5%, HR 3.94; 95% CI, 1.31-11.79), hospitalization (29.8% vs. 21.6%, HR 1.43; 95% CI, 1.09-1.86), but differences in ICU requirements (HR 0.90 (0.38-2.12)), AKI (HR 1.41 (0.86-2.30)) or severe disease (HR 1.92 (0.99-3.71)) did not reach statistical significance at 60-day follow up. CONCLUSION: In conclusion, COVID-19 infection in patients with BCS is associated with poor outcomes. Patients with BCS infected with COVID-19 carry a significantly higher risk of hospitalization and all-cause mortality and a possible effect on severe disease and AKI compared with COVID-19 patients without CLD or with non-BCS-CLD.

Elevated interleukin (IL)-6 as a predictor of disease severity among Covid-19 patients: a prospective cohort study.

BACKGROUND: accompanied to the spreading of coronavirus disease 2019 (Covid-19) in the world, identifying factors related to the severity of the disease is one of the interests of physician and medical researchers. We hypothesized that interleukin 6 serum level is associated with severe outcome. METHODS: In this longitudinal prospective cohort study we enrolled 208 confirmed COVID-19 patients who were admitted to the Tohid Hospital (Sanandaj, Iran). Patients were classified into two groups based on IL-6 value in the first day of admission, elevated (n = 107) or not elevated/normal (n = 101), and followed until the occurrence of final outcome (death or discharge from the hospital). Data were analyzed using univariate methods, Chi-squared and independent two sample T test. The relationship between the independent variables and our interesting outcomes were investigated by multiple linear and penalized logistic regression modeling. RESULTS: A total of 208 patients, 51% female and mean age 53.6 ± 16.3 years, including 107 elevated and 101 non-elevated IL-6 patients, were followed. No significant difference was observed between the two groups in demographic and clinical characteristics. Although not significant, logistic regression results showed that the chance of death occurrence among patients with elevated IL-6 are 3.91 times higher. According to the multiple linear regression modeling, elevated IL-6 significantly increased the duration of hospital stay (P = 0.02). Frequency of ICU admission (P = 0.04) and mean of ICU stay (P = 0.8) are also higher in elevated IL-6 group. CONCLUSION: This study revealed that elevated IL-6 is significantly related to prolongation of hospital stay in Covid-19 patients. Although not significant, the occurrence of death among patients who had increased IL-6 in the time of admission was higher than patients with normal or lower serum levels of IL-6.

Health-related quality of life of Australians during the 2020 COVID-19 pandemic: a comparison with pre-pandemic data and factors associated with poor outcomes.

PURPOSE: Compare the health-related quality of life (HRQL) of the Australian general population during the COVID-19 pandemic (2020) with pre-pandemic data (2015-2016) and identify pandemic-related and demographic factors associated with poorer HRQL. METHODS: Participants were quota sampled from an online panel by four regions (defined by active COVID-19 case numbers); then by age and sex. Participants completed an online survey about their HRQL [EORTC QLQ-C30 questionnaire and General Health Question (GHQ)], demographic characteristics, and the impact of the pandemic on daily life. HRQL scores were compared to a 2015-2016 reference sample using independent t-tests, adjusted for multiple testing. Associations between 22 pre-specified factors (pandemic-related and demographic) and 15 QLQ-C30 domains and GHQ, were assessed with multiple regressions. RESULTS: Most domains were statistically significantly worse for the 2020 sample (n = 1898) compared to the reference sample (n = 1979), except fatigue and pain. Differences were largest for the youngest group (18-29 years) for cognitive functioning, nausea, diarrhoea, and financial difficulties. Emotional functioning was worse for 2020 participants aged 18-59, but not for those 60 +. All models were statistically significant at p < .001; the most variance was explained for emotional functioning, QLQ-C30 global health/QOL, nausea/vomiting, GHQ, and financial difficulties. Generally, increased workload, negative COVID-19 impacts, COVID-19-related worries, and negative attitudes towards public health order compliance were associated with poorer HRQL outcomes. CONCLUSION: During the COVID-19 pandemic, Australians reported poorer HRQL relative to a pre-pandemic sample. Risk factors for poor HRQL outcomes included greater negative pandemic-related impacts, poorer compliance attitudes, and younger age. TRIAL REGISTRATION: ANZCTR number is: ACTRN12621001240831. Web address of your trial: https://www.anzctr.org.au/ACTRN12621001240831.aspx . Date submitted: 26/08/2021 2:56:53 PM. Date registered: 14/09/2021 9:40:31 AM. Registered by: Margaret-Ann Tait. Principal Investigator: Madeleine King.

Respiratory syncytial virus: can we still believe that after pandemic bronchiolitis is not a critical issue for public health?

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children, resulting in annual epidemics worldwide. Since the beginning of the COVID-19 pandemic, non-pharmacological interventions were applied, interfering with the circulation of most respiratory viruses, including RSV. The aim of this study is to analyze the RSV infection trend among hospitalized infants during the actual epidemic season (2022-2023) in comparison with the last pre-pandemic season (2018-2019), in order to outline whether significant differences emerge due to COVID-19 pandemia. We retrospectively reviewed medical data on infants hospitalized at the Bambino Gesù Children's Hospital with diagnosis of bronchiolitis in the current epidemic season and in the last pre-pandemic season, 2018-2019. RSV remains the main etiological agent of bronchiolitis in terms of frequency and severity of infections in the ongoing epidemic season. The first RSV case of the 2022-2023 season was detected at week 42 vs week 47 in the 2018-2019 season. The length of epidemic season was of 17 weeks in 2022-2023 vs 18 weeks in 2018-2019. Comparing the two seasons, age at admission was significantly higher in the current season (median age 2022-2023 65 days vs median age 2018-2019 58 days), but the disease severity was similar.       Conclusions: The 2022-2023 bronchiolitis season in Italy started earlier than the usual pre-pandemic seasons but seasonality pattern may be going back to the pre-pandemic one. This season was not more severe than the previous ones. The impact of RSV disease on health care systems and costs remains a critical issue. What is Known: • RSV is one of the major leading causes of hospitalization among children aged less than 3 months. SarsCOV2 pandemic interfered with the seasonal circulation of most respiratory viruses, Including RSV. What is New: • The 2022-2023 bronchiolitis season in Italy started and peaked earlier than the usual pre-pandemic seasons but seasonality pattern may be realigning to the pre-pandemic one. The impact of RSV disease on health care systems and costs is concerning.

The impact of a two-year long COVID-19 public health restriction program on mechanical thrombectomy outcomes in a stroke network.

OBJECTIVE: The purpose of this study was to evaluate the impact of COVID-19 pandemic public health restrictions on our drip and ship mechanical thrombectomy program in Santiago Chile. MATERIALS AND METHODS: This was a retrospective analysis of a prospectively collected database comparing two cohorts, one during a two-year period before COVID-19 and the second during the two years of the pandemic at our metropolitan stroke program. RESULTS: A total of 100 patients were included in the pre COVID-19 cohort (cohort 1) and 121 in the COVID-19 cohort (cohort 2). There was a significant difference between cohorts, with older patients, different occlusion sites and higher door to arterial puncture time during the COVID-19 period. A non-significant trend for worse 90-day outcomes and higher mortality was present in cohort 2. There were no statistical differences in safety treatment parameters. CONCLUSIONS: COVID-19 pandemic has had a measurable impact on our mechanical thrombectomy program. Results showed similarities to other reported Latin American series, where less robust health systems could adapt less efficiently compared to developed countries. After two years of public health restrictions, there were changes in the treatment population characteristics, delay in some internal management metrics and a non-significant trend to worse 90-day outcomes and higher mortality.

COVID-19 spatialization by empirical Bayesian model in São Paulo, Brazil.

The new Acute Respiratory Syndrome, COVID-19, has affected the health and the economy worldwide. Therefore, scientists have been looking for ways to understand this disease. In this context, the main objective of this study was the spatialization of COVID-19, thinking in distinguishing areas with high transmissibility yet, verifying if these areas were associated with the elderly population occurrence. The work was delineated, supposing that spatialization could support the decision-making to combat the outbreak and that the same method could be used for spatialization and prevent other diseases. The study area was a municipality near Sao Paulo Metropolis, one of Brazil's main disease epicenters. Using official data and an empirical Bayesian model, we spatialized people infected by region, including older people, obtaining reasonable adjustment. The results showed a weak correlation between regions infected and older adults. Thus, we define a robust model that can support the definition of actions aiming to control the COVID-19 spread.

Severe Multi-inflammatory Syndrome in Children Temporally Related to COVID 19-Clinical Course, Laboratory Profile and Outcomes from a North Indian PICU.

Objective: We describe the trajectory of clinical course, laboratory markers and outcomes in children with severe multi-inflammatory syndrome temporally related to COVID-19 (MIS-C) admitted to our pediatric intensive care unit (PICU). Methods: This was a prospective case series of children admitted to PICU between May 1, 2020 and January 31, 2021, fulfilling the case definition of MIS-C published by World Health Organization (WHO) or Centers for Disease Control and Prevention (CDC). We analyzed demographic, clinical, laboratory data and echocardiographic findings. We also plotted the variation in trends between survivors and nonsurvivors. Results: Of the 34 critically ill children referred to PICU with diagnosis of MIS-C only 17 fulfilled the WHO/CDC classification of MIS-C, rest were MISC mimickers albeit other tropical infections. Median age at admission was 4 years (range 1y 6 mo-8 years). Fever, rash and conjunctival redness were most prominent symptoms. Myocardial involvement was seen in 70.5% while 76.4% developed shock; Invasive mechanical ventilation was required in 64.7% cases. Inflammatory markers showed a downward trend such as-median C- reactive protein (mg/L) had a serial reduction in levels-from (median/IQR) 210 (132.60, 246.90) at admission to 52.3 (42, 120) on Day 3. Median Ferritin (ng/ml) (n = 12) was 690 (203, 1324), serum LDH (IU/L) (n = 12) was 505 (229.5, 1032) and Mean D-dimer (ng/ml) (n = 7) was 5093.85 (1991.65), suggestive of hyperinflammatory syndrome. Twelve patients received intravenous immune globulin, with adjunctive steroid therapy used in two third of the cases. Six children died, 4 of them were under-5 years of age. Tocilizumab was prescribed in two children with high vasotrope inotrope score (VIS), cardiogenic shock and oxygenation index more than 15, both survived. Conclusions: Severe MIS-C has a heterogenous presentation, local or regional outbreaks of prevalent infectious diseases often lead to confusion and overdiagnosis. Higher proportion of mortality was seen in Under -5 children with MISC. Shock-like presentation, presence of myocardial dysfunction or nonsurvivor status is associated with higher trend of inflammatory markers and more profound multi-organ dysfunction. If disease progresses rapidly despite first line therapy (IvIg and steroids), use of Tocilizumab should be considered-as a rescue therapy under resource limitations in the absence of extracorporeal support.