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Background: The organism-wide effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection are well studied, but little is known about the dynamics of how the infection spreads in time among or within cells due to the scarcity of suitable high-resolution experimental systems. It has been reported that SARS-CoV-2 infection pathways converge at calcium influx and subcellular calcium distribution changes. Imaging combined with a proper staining technique is an effective tool for studying subcellular calcium-related infection and replication mechanisms at such resolutions., Methods: Using two-photon (2P) fluorescence imaging with our novel Ca-selective dye, automated image analysis and clustering analysis were applied to reveal titer and variant effects on SARS-CoV-2-infected Vero E6 cells., Results: The application of a new calcium sensor molecule is shown, combined with a high-end 2P technique for imaging and identifying the patterns associated with cellular infection damage within cells. Vero E6 cells infected with SARS-CoV-2 variants, D614G or B.1.1.7, exhibit elevated cytosolic calcium levels, allowing infection monitoring by tracking the cellular changes in calcium level by the internalized calcium sensor. The imaging provides valuable information on how the level and intracellular distribution of calcium are perturbed during the infection. Moreover, two-photon calcium sensing allowed the distinction of infections by two studied viral variants via cluster analysis of the image parameters. This approach will facilitate the study of cellular correlates of infection and their quantification depending on viral variants and viral load., Conclusions: We propose a new two-photon microscopy-based method combined with a cell-internalized sensor to quantify the level of SARS-CoV-2 infection. We optimized the applied dye concentrations to not interfere with viral fusion and viral replication events. The presented method ensured the proper monitoring of viral infection, replication, and cell fate. It also enabled distinguishing intracellular details of cell damage, such as vacuole and apoptotic body formation. Using clustering analysis, 2P microscopy calcium fluorescence images were suitable to distinguish two different viral variants in cell cultures. Cellular harm levels read out by calcium imaging were quantitatively related to the initial viral multiplicity of infection numbers. Thus, 2P quantitative calcium imaging might be used as a correlate of infection or a correlate of activity in cellular antiviral studies., (© 2024. The Author(s).)

Background: In Hungary, although six types of vaccines were widely available, the percentage of people receiving the primary series of COVID-19 vaccination remained below the EU average. This paper investigates the reasons for Hungary's lower vaccination coverage by exploring changing attitudes towards vaccination, socio-demographic determinants, and individual reasons for non-acceptance during the 3 rd - 5 th pandemic waves of COVID-19., Methods: The study's empirical analysis is based on representative surveys conducted in Hungary between February 19, 2021, and June 30, 2022. The study used a total of 17 surveys, each with a sample size of at least 1000 respondents. Binomial logistic regression models were used to investigate which socio-demographic characteristics are most likely to influence vaccine hesitancy in Hungary. The study analysed 2506 open-ended responses to identify reasons for vaccine non-acceptance. The responses were categorised into four main categories and 13 sub-categories., Results: Between the third and fifth wave of the pandemic, attitudes towards COVID-19 vaccination have significantly changed. Although the proportion of vaccinated individuals has increased steadily, the percentage of individuals who reported not accepting the vaccine has remained almost unchanged. Socio-demographic characteristics were an important determinant of the observed vaccine hesitancy, although they remained relatively stable over time. Individuals in younger age groups and those with lower socioeconomic status were more likely to decline vaccination, while those living in the capital city were the least likely. A significant reason behind vaccine refusal can undoubtedly be identified as lack of trust (specifically distrust in science), facing an information barrier and the perception of low personal risk., Conclusion: Although compulsory childhood vaccination coverage is particularly high in Hungary, voluntary adult vaccines, such as the influenza and COVID-19 vaccines, are less well accepted. Vaccine acceptance is heavily affected by the social-demographic characteristics of people. Mistrust and hesitancy about COVID-19 vaccines, if not well managed, can easily affect people's opinion and acceptance of other vaccines as well. Identifying and understanding the complexity of how vaccine hesitancy evolved during the pandemic can help to understand and halt the decline in both COVID-19 and general vaccine confidence by developing targeted public health programs to address these issues., (© 2024. The Author(s).)

Background: Although COVID-19 is primarily an acute respiratory infection, 5%-40% of patients develop late and prolonged symptoms with frequent neurological complaints, known as long COVID syndrome. The presentation of the disease suggests that COVID infection may cause functional and/or morphological central nervous system alterations, but studies published in the literature report contradictory findings., Purpose: To investigate the chronic effects of COVID-19 on cerebral grey matter in a group of young patients without comorbidities, with mild course of COVID infection and no medical complaints at the time of examination., Study Type: Prospective., Population: Thirty-eight young (age = 26.6 ± 5.0 years; male/female = 14/24), adult participants who recovered from mild COVID infection without a history of clinical long COVID and 37 healthy control subjects (age = 25.9 ± 2.8 years; male/female = 14/23)., Field Strength/sequence: Three Tesla, 3D T1-weighted magnetization-prepared rapid gradient-echo, 2D T2-weighted turbo spin-echo., Assessment: MRI-based morphometry and volumetry along with neuropsychological testing and self-assessed questionnaire., Statistical Tests: Fisher's exact test, Mann-Whitney U-test, and multiple linear regression analyses were used to assess differences between COVID and healthy control groups. P < 0.05 was used as cutoff for significance., Results: In the COVID group, significantly lower bilateral mean cortical thickness (left/right-hemisphere: 2.51 ± 0.06 mm vs. 2.56 ± 0.07 mm, η 2 p  = 0.102/2.50 ± 0.06 mm vs. 2.54 ± 0.07 mm, η 2 p  = 0.101), lower subcortical gray matter (57881 ± 3998 mm 3 vs. 60470 ± 5211 mm 3 , η 2 p  = 0.100) and lower right olfactory bulb volume (52.28 ± 13.55 mm 3 vs. 60.98 ± 15.8 mm 3 , η 2 p  = 0.078) were found. In patients with moderate to severe anosmia, cortical thickness was significantly lower bilaterally, as compared to patients without olfactory function loss (left/right-hemisphere: 2.50 ± 0.06 mm vs. 2.56 ± 0.05 mm, η 2  = 0.173/2.49 ± 0.06 mm vs. 2.55 ± 0.05 mm, η 2  = 0.189). Using further exploratory analysis, significantly reduced cortical thickness was detected locally in the right lateral orbitofrontal cortex in the COVID group (2.53 ± 0.10 mm vs. 2.60 ± 0.09 mm, η 2 p  = 0.112)., Data Conclusion: Even without any subjective or objective neurological complaints at the time of the MR scan, subjects in the COVID group showed gray matter alterations in cortical thickness and subcortical gray matter volume., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 3., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: We retrospectively analyzed serum level of human epididymis protein 4 (HE4) as a pulmonary inflammatory biomarker in patients with COVID-19 pneumonia in association with disease severity and outcome., Methods: Ninety-nine (40 critically ill, 40 severe and 19 mild) COVID-19 patients and as controls 25 age- and sex-matched non-COVID-19 bacterial sepsis subjects were included. Serum HE4 was measured by an immunoassay (Architect ® i1000SR, Abbott) in the baseline samples of all study participants obtained at intensive care unit (ICU) admission or during outpatient clinic visit and follow-up sera were available in case of 30 COVID-19 subjects with life-threating conditions. Associations were studied between serum HE4, routinely available laboratory parameters, clinical characteristics, and disease progression., Results: Baseline HE4 level was significantly higher (P < 0.0001) in critically ill (524.7 [300.1-1153.0] pmol/L) than severe COVID-19 subjects (157.4 [85.2-336.9] pmol/L) and in mild SARS-CoV-2 infection (46.7 [39.1-57.2] pmol/L). Similarly increased HE4 concentrations were found in bacterial sepsis (1118.0 [418.3-1953.0] pmol/L, P = 0.056) compared to critically ill COVID-19 individuals. Serum HE4 levels significantly correlated with age, SOFA-score, inflammation-dependent biomarkers, and the degree of lung manifestation evaluated by chest CT examination in ICU COVID-19 individuals. Based on ROC-AUC curve analysis, baseline HE4 independently indicated the severity of COVID-19 with an AUC value of 0.816 (95% CI [0.723-0.908]; P < 0.0001), while binary logistic regression test found HE4 as an independent prognostic parameter for death (OR: 10.618 [2.331-48.354]; P = 0.002). Furthermore, COVID-19 non-survivors showed much higher baseline HE4 levels without a substantial change under treatment vs. survivors (P < 0.0001). Finally, pre-treatment HE4 level of ≥ 331.7 pmol/L effectively predicted a larger risk for mortality (Log-Rank P < 0.0001) due to severe COVID-19 pneumonia., Conclusion: Elevated serum HE4 level at ICU admission highly correlates with COVID-19 severity and predicts disease outcome., (© 2023. The Author(s).)

Monitoring the effective reproduction number [Formula: see text] of a rapidly unfolding pandemic in real-time is key to successful mitigation and prevention strategies. However, existing methods based on case numbers, hospital admissions or fatalities suffer from multiple measurement biases and temporal lags due to high test positivity rates or delays in symptom development or administrative reporting. Alternative methods such as web search and social media tracking are less directly indicating epidemic prevalence over time. We instead record age-stratified anonymous contact matrices at a daily resolution using a longitudinal online-offline survey in Hungary during the first two waves of the COVID-19 pandemic. This approach is innovative, cheap, and provides information in near real-time for estimating [Formula: see text] at a daily resolution. Moreover, it allows to complement traditional surveillance systems by signaling periods when official monitoring infrastructures are unreliable due to observational biases., (© 2023. The Author(s).)

COVID-19 associated coagulopathy (CAC), characterized by endothelial dysfunction and hypercoagulability, evokes pulmonary immunothrombosis in advanced COVID-19 cases. Elevated von Willebrand factor (vWF) levels and reduced activities of the ADAMTS13 protease are common in CAC. Here, we aimed to determine whether common genetic variants of these proteins might be associated with COVID-19 severity and hemostatic parameters. A set of single nucleotide polymorphisms (SNPs) in the vWF (rs216311, rs216321, rs1063856, rs1800378, rs1800383) and ADAMTS13 genes (rs2301612, rs28729234, rs34024143) were genotyped in 72 COVID-19 patients. Cross-sectional cohort analysis revealed no association of any polymorphism with disease severity. On the other hand, analysis of variance (ANOVA) uncovered associations with the following clinical parameters: (1) the rs216311 T allele with enhanced INR (international normalized ratio); (2) the rs1800383 C allele with elevated fibrinogen levels; and (3) the rs1063856 C allele with increased red blood cell count, hemoglobin, and creatinine levels. No association could be observed between the phenotypic data and the polymorphisms in the ADAMTS13 gene. Importantly, in silico protein conformational analysis predicted that these missense variants would display global conformational alterations, which might affect the stability and plasma levels of vWF. Our results imply that missense vWF variants might modulate the thrombotic risk in COVID-19.

Background: Occupational accidents are rising, but there is little evidence on the outcomes of patients who received case management during Return to work (RTW) programs. This study examined the case management-based on RTW program features that improve the work ability index (WAI) and quality of life (QoL)., Methods: This cross-sectional research involved 230 disabled workers due to an occupational injury in Indonesia, 154 participated in RTW, and 75 did not participate in RTW (non-RTW) during the COVID-19 pandemic. Sociodemographic and occupational factors were used to examine the RTW results. We used the Finnish Institute of Occupational Health's WAI questionnaires to measure the work ability index and World Health Organization Quality of Life Brief Version (WHOQOL-BREF) for quality of life., Results: The study found a statistically significant difference in working duration and preferred treatment for RTW between the groups ( p -value = 0.039). Furthermore, the quality of life in the domain of environmental health and work ability index score also demonstrated a significant difference between the groups ( p -value = 0.023 and 0.000, respectively)., Conclusions: During the COVID-19 pandemic, this study found that the RTW program improved the quality of life and work abilities of disabled workers.

Background and Objectives: Medical imaging is a key element in the clinical workup of patients with suspected oncological disease. In Hungary, due to the high number of patients, waiting lists for Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) were created some years ago. The Municipality of Budapest and Semmelweis University signed a cooperation agreement with an extra budget in 2020 (HBP: Healthy Budapest Program) to reduce the waiting lists for these patients. The aim of our study was to analyze the impact of the first experiences with the HBP. Material and Methods : The study database included all the CT/MRI examinations conducted at Semmelweis University with a referral diagnosis of suspected oncological disease within the first 13 months of the HBP (6804 cases). In our retrospective, two-armed, comparative clinical study, different components of the waiting times in the oncology diagnostics pathway were analyzed. Using propensity score matching, we compared the data of the HBP-funded patients ( n = 450) to those of the patients with regular care provided by the National Health Insurance Fund (NHIF) ( n = 450). Results : In the HBP-funded vs. the NHIF-funded patients, the time interval from the first suspicion of oncological disease to the request for imaging examinations was on average 15.2 days shorter (16.1 vs. 31.3 days), and the mean waiting time for the CT/MRI examination was reduced by 13.0 days (4.2 vs. 17.2 days, respectively). In addition, the imaging medical records were prepared on average 1.7 days faster for the HBP-funded patients than for the NHIF-funded patients (3.4 vs. 5.1 days, respectively). No further shortening of the different time intervals during the subsequent oncology diagnostic pathway (histological investigation and multidisciplinary team decision) or in the starting of specific oncological therapy (surgery, irradiation, and chemotherapy) was observed in the HBP-funded vs. the NHIF-funded patients. We identified a moderately strong negative correlation (r = -0.5736, p = 0.0350) between the CT/MR scans requested and the active COVID-19 case rates during the pandemic waves. Conclusion : The waiting lists for diagnostic CT/MR imaging can be effectively shortened with a targeted project, but a more comprehensive intervention is needed to shorten the time from the radiological diagnosis, through the decisions of the oncoteam, to the start of the oncological treatment.

Voluntary isolation is one of the most effective methods for individuals to help prevent the transmission of diseases such as COVID-19. Understanding why people leave their homes when advised not to do so and identifying what contextual factors predict this non-compliant behavior is essential for policymakers and public health officials. To provide insight on these factors, we collected data from 42,169 individuals across 16 countries. Participants responded to items inquiring about their socio-cultural environment, such as the adherence of fellow citizens, as well as their mental states, such as their level of loneliness and boredom. We trained random forest models to predict whether someone had left their home during a one week period during which they were asked to voluntarily isolate themselves. The analyses indicated that overall, an increase in the feeling of being caged leads to an increased probability of leaving home. In addition, an increased feeling of responsibility and an increased fear of getting infected decreased the probability of leaving home. The models predicted compliance behavior with between 54% and 91% accuracy within each country's sample. In addition, we modeled factors leading to risky behavior in the pandemic context. We observed an increased probability of visiting risky places as both the anticipated number of people and the importance of the activity increased. Conversely, the probability of visiting risky places increased as the perceived putative effectiveness of social distancing decreased. The variance explained in our models predicting risk ranged from < .01 to .54 by country. Together, our findings can inform behavioral interventions to increase adherence to lockdown recommendations in pandemic conditions., Competing Interests: Author Martin Voracek is a PLOS ONE Editorial Board Member. This does not alter the author’s adherence to PLOS ONE Editorial policies and criteria., (Copyright: © 2022 Hajdu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Patients with hematological malignancies (HMs) are at a higher risk of developing severe form and protracted course of COVID-19 disease. We investigated whether the combination of viral replication inhibition with remdesivir and administration of anti-SARS-CoV-2 immunoglobulins with convalescent plasma (CP) therapy might be sufficient to treat B-cell-depleted patients with COVID-19. We enrolled 20 consecutive patients with various HMs with profound B-cell lymphopenia and COVID-19 pneumonia between December 2020 and May 2021. All patients demonstrated undetectable baseline anti-SARS-CoV-2 immunoglobulin levels before CP. Each patient received at least a complete course of remdesivir and at least one unit of CP. Previous anti-CD20 therapy resulted in a more prolonged SARS-CoV-2 PCR positivity compared to other causes of B-cell lymphopenia (p = 0.004). Timing of CP therapy showed a significant impact on the clinical outcome. Simultaneous use of remdesivir and CP reduced time period for oxygen weaning after diagnosis (p = 0.017), length of hospital stay (p = 0.007), and PCR positivity (p = 0.012) compared to patients who received remdesivir and CP consecutively. In addition, time from the diagnosis to CP therapy affected the length of oxygen dependency (p < 0.001) and hospital stay (p < 0.0001). In those cases where there were at least 10 days from the diagnosis to plasma administration, oxygen dependency was prolonged vs. patients with shorter interval (p = 0.006). In conclusion, the combination of inhibition of viral replication with passive immunization was proved to be efficient and safe. Our results suggest the clear benefit of early, combined administration of remdesivir and CP to avoid protracted COVID-19 disease among patients with HMs and B-cell lymphopenia., (© 2022. The Author(s).)

Vaccination against SARS-CoV-2 to prevent COVID-19 is highly recommended for immunocompromised patients with autoimmune rheumatic and musculoskeletal diseases (aiRMDs). Little is known about the effect of booster vaccination or infection followed by previously completed two-dose vaccination in aiRMDs. We determined neutralizing anti-SARS-CoV-2 antibody levels and applied flow cytometric immunophenotyping to quantify the SARS-CoV-2 reactive B- and T-cell mediated immunity in aiRMDs receiving homologous or heterologous boosters or acquired infection following vaccination. Patients receiving a heterologous booster had a higher proportion of IgM+ SARS-CoV-2 S+ CD19+CD27+ peripheral memory B-cells in comparison to those who acquired infection. Biologic therapy decreased the number of S+CD19+; S+CD19+CD27+IgG+; and S+CD19+CD27+IgM+ B-cells. The response rate to a booster event in cellular immunity was the highest in the S-, M-, and N-reactive CD4+CD40L+ T-cell subset. Patients with a disease duration of more than 10 years had higher proportions of CD8+TNF-α+ and CD8+IFN-γ+ T-cells in comparison to patients who were diagnosed less than 10 years ago. We detected neutralizing antibodies, S+ reactive peripheral memory B-cells, and five S-, M-, and N-reactive T-cells subsets in our patient cohort showing the importance of booster events. Biologic therapy and <10 years disease duration may confound anti-SARS-CoV-2 specific immunity in aiRMDs.

Many countries have secured larger quantities of COVID-19 vaccines than their population is willing to take. The abundance and the large variety of vaccines created not only an unprecedented intensity of vaccine related public discourse, but also a historical moment to understand vaccine hesitancy better. Yet, the heterogeneity of hesitancy by vaccine types has been neglected in the existing literature so far. We address this problem by analysing the acceptance and the assessment of five vaccine types. We use information collected with a nationally representative survey at the end of the third wave of the COVID-19 pandemic in Hungary. During the vaccination campaign, individuals could reject the assigned vaccine to wait for a more preferred alternative that enables us to quantify revealed preferences across vaccine types. We find that hesitancy is heterogenous by vaccine types and is driven by individuals' trusted source of information. Believers of conspiracy theories are more likely to evaluate the mRNA vaccines (Pfizer and Moderna) unacceptable. Those who follow the advice of politicians are more likely to evaluate vector-based (AstraZeneca and Sputnik) or whole-virus vaccines (Sinopharm) acceptable. We argue that the greater selection of available vaccine types and the free choice of the individual are desirable conditions to increase the vaccination rate in societies., (© 2022. The Author(s).)

Various measures have been implemented around the world to prevent the spread of SARS-CoV-2. A potential tool to reduce disease transmission is regular mass testing of a high percentage of the population, possibly with pooling (testing a compound of several samples with one single test). We develop a compartmental model to study the applicability of this method and compare different pooling strategies: regular and Dorfman pooling. The model includes isolated compartments as well, from where individuals rejoin the active population after some time delay. We develop a method to optimize Dorfman pooling depending on disease prevalence and establish an adaptive strategy to select variable pool sizes during the course of the epidemic. It is shown that optimizing the pool size can avert a significant number of infections. The adaptive strategy is much more efficient, and may prevent an epidemic outbreak even in situations when a fixed pool size strategy can not.

Common variable immunodeficiency (CVID) patients have markedly decreased immune response to vaccinations. In this study we evaluated humoral and T cell-mediated responses against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) with additional flow cytometric changes in CVID patients receiving booster vaccination with BNT162b2 after two ChAdOx1 nCoV-19. The BNT162b2 vaccine raised the anti-spike protein S immunoglobulin G over the cut-off value from 70% to 83% in CVID, anti-neutralizing antibody had been raised over a cut-off value from 70% to 80% but levels after boosting were significantly less in both tests than in healthy controls (*p=0.02; **p=0.009 respectively). Anti-SARS-CoV-2 immunoglobulin A became less positive in CVID after boosting, but the difference was not significant. The cumulative interferon-γ positive T cell response by ELISpot was over the cut-off value in 53% of the tested individuals and raised to 83% after boosting. This and flow cytometric control of cumulative CD4+ and CD8+ virus-specific T cell absolute counts in CVID were also statistically not different from healthy individuals after boosting. Additional flow cytometric measures for CD45+ lymphocytes, CD3+, and CD19+ cells have not shown significant differences from controls except for lower CD4+T cell counts at both time points (**p=0.003; **p=0.002), in parallel CD4+ virus-specific T-cell ratio was significantly lower in CVID patients at the first time point (*p: 0.03). After boosting, in more than 33% of both CVID patients and also in their healthy controls we detected a decrease in absolute CD45+, CD3+, CD3+CD4+, and CD3+CD8+, CD19+, and CD16+56+ cell counts. CD16+CD56+ cell counts were significantly lower compared to controls before and after boosting (*p=0.02, *p=0.02). CVID patients receiving immunosuppressive therapy throughout the previous year or autologous stem cell transplantation two years before vaccination had worse responses in anti-spike, anti-neutralizing antibody, CD3+CD4+T, CD19+ B, and natural killer cell counts than the whole CVID group. Vaccinations had few side effects. Based on these data, CVID patients receiving booster vaccination with BNT162b2 after two ChadOx1 can effectively elevate the levels of protection against COVID-19 infection, but the duration of the immune response together with COVID-19 morbidity data needs further investigation among these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goda, Kriván, Kulcsár, Gönczi, Tasnády, Matula, Nagy, Bekő, Horváth, Uher, Szekanecz and Vályi-Nagy.)

SARS-CoV-2, the causative agent of COVID-19, has caused devastating health and economic impacts around the globe since its appearance in late 2019. The advent of effective vaccines leads to open questions on how best to vaccinate the population. To address such questions, we developed a model of COVID-19 infection by age that includes the waning and boosting of immunity against SARS-CoV-2 in the context of infection and vaccination. The model also accounts for changes to infectivity of the virus, such as public health mitigation protocols over time, increases in the transmissibility of variants of concern, changes in compliance to mask wearing and social distancing, and changes in testing rates. The model is employed to study public health mitigation and vaccination of the COVID-19 epidemic in Canada, including different vaccination programs (rollout by age), and delays between doses in a two-dose vaccine. We find that the decision to delay the second dose of vaccine is appropriate in the Canadian context. We also find that the benefits of a COVID-19 vaccination program in terms of reductions in infections is increased if vaccination of 15-19 year olds are included in the vaccine rollout., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Due to various factors, the chances of infectious disease emergence or re-emergence have increased in the 21st century, thus, the likelihood of new emerging pandemics has also increased. The COVID-19 pandemic, which appeared in 2019, has highlighted that certain new and re-emerging infectious diseases - in the case of lack or delay in effective measures - can spread very rapidly. The main tool for the fight against infectious diseases is immunization through vaccination. While focusing on the personal health, public health, economic and societal benefits of a lifelong immunization strategy, especially in light of the aging society, the goal of this paper is to present the benefits of vaccines. In order to increase the added value of vaccinations it is recommended to create a lifelong immunization strategy.

Background: Vaccine-induced immunity is essential for controlling the COVID-19 pandemic. Data on humoral and cellular immunogenicity and safety of different SARS-CoV-2 vaccines in patients with autoimmune rheumatic and musculoskeletal diseases (RMDs) are limited., Methods: A single center observational study evaluated the immunogenicity and safety of the two-dose regimen of the BBIBP-CorV inactivated, Gam-COVID-Vac and AZD1222 adenovirus-based, and BNT162b2 and mRNA-1273 mRNA-based vaccines in patients with RMDs (n = 89) compared with healthy controls (n = 74). Neutralizing anti-RBD (receptor binding domain) specific antibodies and SARS-CoV-2 specific T-cell response were measured one and four months after the second vaccine dose in parallel with vaccination efficacy and safety., Results: Disease-specific comparison showed that antibody response at four months was higher in spondylarthropathies compared to rheumatoid arthritis and autoimmune RMDs. Risk factors for reduced immunogenicity included longer disease duration, positive immunoserological profile and anti-CD20 therapy of patients. The rate of positive anti-RBD antibody response for healthy controls versus patients after 4 months post vaccination was 69% vs. 55% for the inactivated viral vaccine BBIBP-CorV, 97% vs. 53% for the pooled data of adenovirus vector-based vaccines Gam-COVID-Vac and AZD1222, or 100% vs. 81% for the pooled data of mRNA vaccines BNT162b2 and mRNA-1273, respectively. Patients who received the Gam-COVID-Vac or mRNA-1273 vaccines had a higher proportion of TNF-α producing CD4+ T-cells upon SARS-CoV-2 antigen stimulation compared to the inactivated viral vaccine., Conclusion: All five investigated vaccines were immunogenic in the majority of patients and healthy controls with variable antibody and T-cell response and an acceptable safety profile., Competing Interests: Author GS was employed by the company Cs-Smartlab Devices Ltd. Authors LN and LP were employed by the company Avidin Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Szebeni, Gémes, Honfi, Szabó, Neuperger, Balog, Nagy, Szekanecz, Puskás, Toldi and Balog.)

We report on children with cancer in Hungary suffering from COVID-19, surveying a 13-months-long period of time. We performed a retrospective clinical trial studying the medical documentation of children treated in seven centers of the Hungarian Pediatric Oncology-Hematology Group. About 10% of children admitted to tertiary hemato-oncological centers for anti-neoplastic treatment or diagnosis for de novo malignancies were positive for SARS-CoV-2 infection. Nearly two-thirds of the infected patients were asymptomatic or had only mild symptoms but showed seropositivity by 1-4.5 months after positive PCR. One third of the SARS-CoV-2-positive children were hospitalized due to symptomatic COVID-19. Five children required antiviral treatment with remdesivir. One child was referred to the intensive care unit, requiring intubation and mechanical ventilation. Delay in the scheduled anti-cancer treatment did not exceed 2 weeks in the majority (89%) of cases. There was only one patient requiring treatment deferral longer than a month. There was no COVID-19-related death in patients under 18 years of age, and nor was multisystem inflammatory syndrome diagnosed. In conclusion, SARS-CoV-2 infection did not represent an untoward risk factor among children with cancer in Hungary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Müller, Szűcs-Farkas, Szegedi, Csóka, Garami, Tiszlavicz, Hauser, Kriván, Csanádi, Ottóffy, Nagy, Kiss and Kovács.)

The unprecedented behavioural responses of societies have been evidently shaping the COVID-19 pandemic, yet it is a significant challenge to accurately monitor the continuously changing social mixing patterns in real-time. Contact matrices, usually stratified by age, summarise interaction motifs efficiently, but their collection relies on conventional representative survey techniques, which are expensive and slow to obtain. Here we report a data collection effort involving over [Formula: see text] of the Hungarian population to simultaneously record contact matrices through a longitudinal online and sequence of representative phone surveys. To correct non-representative biases characterising the online data, by using census data and the representative samples we develop a reconstruction method to provide a scalable, cheap, and flexible way to dynamically obtain closer-to-representative contact matrices. Our results demonstrate that although some conventional socio-demographic characters correlate significantly with the change of contact numbers, the strongest predictors can be collected only via surveys techniques and combined with census data for the best reconstruction performance. We demonstrate the potential of combined online-offline data collections to understand the changing behavioural responses determining the future evolution of the outbreak, and to inform epidemic models with crucial data., (© 2022. The Author(s).)

In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, host-pathogen, and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy. Here, we describe a workflow we designed for a semiautomated integration of rapidly emerging data sets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 63 278 host-host protein, and 1221 drug-target interactions. The resultant Neo4j graph database named "Neo4COVID19" is made publicly accessible via a web interface and via API calls based on the Bolt protocol. Details for accessing the database are provided on a landing page (https://neo4covid19.ncats.io/). We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19.

Objectives: Angiotensin-converting enzyme 2 (ACE2) represents the primary receptor for SARS-CoV-2 to enter endothelial cells. Here we investigated circulating ACE2 activity to predict the severity and mortality of COVID-19., Methods: Serum ACE2 activity was measured in COVID-19 (110 critically ill and 66 severely ill subjects at hospital admission and 106 follow-up samples) and in 32 non-COVID-19 severe sepsis patients. Associations between ACE2, inflammation-dependent biomarkers, pre-existing comorbidities, and clinical outcomes were studied., Results: Initial ACE2 activity was significantly higher in critically ill COVID-19 patients (54.4 [36.7-90.8] mU/L) than in severe COVID-19 (34.5 [25.2-48.7] mU/L; P<0.0001) and non-COVID-19 sepsis patients (40.9 [21.4-65.7] mU/L; P=0.0260) regardless of comorbidities. Circulating ACE2 activity correlated with inflammatory biomarkers and was further elevated during the hospital stay in critically ill patients. Based on ROC-curve analysis and logistic regression test, baseline ACE2 independently indicated the severity of COVID-19 with an AUC value of 0.701 (95% CI [0.621-0.781], P<0.0001). Furthermore, non-survivors showed higher serum ACE2 activity vs. survivors at hospital admission (P<0.0001). Finally, high ACE2 activity (≥45.4 mU/L) predicted a higher risk (65 vs. 37%) for 30-day mortality (Log-Rank P<0.0001)., Conclusions: Serum ACE2 activity correlates with COVID-19 severity and predicts mortality., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pandemic management requires reliable and efficient dynamical simulation to predict and control disease spreading. The COVID-19 (SARS-CoV-2) pandemic is mitigated by several non-pharmaceutical interventions, but it is hard to predict which of these are the most effective for a given population. We developed the computationally effective and scalable, agent-based microsimulation framework PanSim, allowing us to test control measures in multiple infection waves caused by the spread of a new virus variant in a city-sized societal environment using a unified framework fitted to realistic data. We show that vaccination strategies prioritising occupational risk groups minimise the number of infections but allow higher mortality while prioritising vulnerable groups minimises mortality but implies an increased infection rate. We also found that intensive vaccination along with non-pharmaceutical interventions can substantially suppress the spread of the virus, while low levels of vaccination, premature reopening may easily revert the epidemic to an uncontrolled state. Our analysis highlights that while vaccination protects the elderly from COVID-19, a large percentage of children will contract the virus, and we also show the benefits and limitations of various quarantine and testing scenarios. The uniquely detailed spatio-temporal resolution of PanSim allows the design and testing of complex, specifically targeted interventions with a large number of agents under dynamically changing conditions., Competing Interests: The authors have declared that no competing interests exist.

Background: Studies examining epilepsy as a COVID-related death risk have come to conflicting conclusions. Our aim was to assess the prevalence of epilepsy among COVID-related deaths in Hungary., Methods: Each COVID-19 infection case is required to be reported on a daily basis to the National Public Health Center of Hungary. This online report includes the beginning and end of the infection, as well as information on comorbidities. Death during infection is regarded as COVID-related. The anonymized data of each deceased patient are published on an information website (www.koronavirus.gov.hu) and provides up-to-date information on each patient with the date of death, the patient's sex, age, and chronic illness., Results: There were 11,968 patients who died of COVID-19 in Hungary between 13 March 2020 and 23 January 2021. Among 11,686 patients with no missing values for comorbidities, 255 patients had epilepsy (2.2%). Epilepsy was much more common among those who died at a young age: 9.3% of those who died under the age of 50 had epilepsy, compared with only 1.3% in those over the age of 80. The younger an age group was, the higher was the prevalence of epilepsy., Conclusion: Patients who died of COVID-19 under the age of 50 were 10 to 20 times more likely to have epilepsy than what would have been expected from epidemiological data. Our results highlight the need for increased protection of young people with epilepsy from COVID-19 infection and the development of a vaccination strategy accordingly., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: The willingness to get COVID-19 or seasonal influenza vaccines has not yet been thoroughly investigated together, thus, this study aims to explore this notion within the general adult population., Methods: The responses of 840 Hungarian participants were analysed who took part in a nationwide computer-assisted telephone interviewing. During the survey questions concerning various demographic characteristics, perceived financial status, and willingness to get the two types of vaccines were asked. Descriptive statistics, comparative statistics and word co-occurrence network analysis were conducted., Results: 48.2% of participants were willing to get a COVID-19 vaccine, while this ratio for the seasonal influenza was only 25.7%. The difference was significant. Regardless of how the participants were grouped, based on demographic data or perceived financial status, the significant difference always persisted. Being older than 59 years significantly increased the willingness to get both vaccines when compared to the middle-aged groups, but not when compared to the younger ones. Having higher education significantly elevated the acceptance of COVID-19 vaccination in comparison to secondary education. The willingness of getting any type of COVID-19 vaccine correlated with the willingness to get both influenza and COVID-19. Finally, those who were willing to get either vaccine coupled similar words together to describe their thoughts about a COVID-19 vaccination., Conclusion: The overall results show a clear preference for a COVID-19 vaccine and there are several similarities between the nature of willingness to get either type of vaccine., (© 2021. The Author(s).)

Experimental work on highly pathogenic viruses such as Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus-2 requires high-level biosafety facilities. Here, we provide a detailed step-by-step protocol which details the production and application of replication-incompetent murine leukemia virus-based pseudotyped particles to monitor and quantify the viral entry efficiency in human cell lines under biosafety level-2 conditions. We describe the use of viral particles encoding luciferase gene and the quantification of transduction efficiency by measuring luciferase activity. For complete details on the use and execution of this protocol, please refer to Imre et al. (2021)., Competing Interests: The authors declare no competing interest., (© 2021 The Author(s).)

Background: The National COVID-19 Chest Imaging Database (NCCID) is a centralized database containing mainly chest X-rays and computed tomography scans from patients across the UK. The objective of the initiative is to support a better understanding of the coronavirus SARS-CoV-2 disease (COVID-19) and the development of machine learning technologies that will improve care for patients hospitalized with a severe COVID-19 infection. This article introduces the training dataset, including a snapshot analysis covering the completeness of clinical data, and availability of image data for the various use-cases (diagnosis, prognosis, longitudinal risk). An additional cohort analysis measures how well the NCCID represents the wider COVID-19-affected UK population in terms of geographic, demographic, and temporal coverage., Findings: The NCCID offers high-quality DICOM images acquired across a variety of imaging machinery; multiple time points including historical images are available for a subset of patients. This volume and variety make the database well suited to development of diagnostic/prognostic models for COVID-associated respiratory conditions. Historical images and clinical data may aid long-term risk stratification, particularly as availability of comorbidity data increases through linkage to other resources. The cohort analysis revealed good alignment to general UK COVID-19 statistics for some categories, e.g., sex, whilst identifying areas for improvements to data collection methods, particularly geographic coverage., Conclusion: The NCCID is a growing resource that provides researchers with a large, high-quality database that can be leveraged both to support the response to the COVID-19 pandemic and as a test bed for building clinically viable medical imaging models., (© The Author(s) 2021. Published by Oxford University Press GigaScience.)

Összefoglaló. A COVID-19 világméretű járvány kapcsán már jól ismertek az általános akut tünetek, mint a láz, a száraz köhögés, a nehézlégzés, a tüdőgyulladás, a hasi panaszok, a hasmenés, az ízérzés- és szaglásvesztés. Talán kevésbé ismertek a betegség neurológiai szövődményei: az encephalitis, a fejfájás és szédülés, az ischaemiás stroke, az akut haemorrhagiás nekrotizáló encephalopathia, de agitáltság és exekutív funkciózavar is kialakulhat. Hosszabb távon az úgynevezett poszt-COVID-szindróma jelenhet meg, perzisztáló testi panaszokkal, krónikusfáradtság-érzéssel, depresszióval, mentális problémákkal. A perifériás idegrendszeri betegségek közül a Guillain-Barré-szindróma fordul elő gyakrabban. Jelen közleményünkben egy diplegia nervi facialis, dysarthria és négy végtagot érintő szubjektív paraesthesiák miatt hospitalizált 41 éves férfi betegünk esetét ismertetjük, akinek felső légúti tünetekkel és lázzal járó SARS-CoV-2-infekciót 10-14 nappal követően jelentek meg neurológiai tünetei. Elektrofiziológiai és liquor laboratóriumi vizsgálat során alátámasztott módon, ritka Guillain-Barré-szindróma-variáns - bifacialis paresis paraesthesiával - igazolódott. Fontos, hogy a vírus idegrendszeri szövődményeit is ismerjük, mert az esetszámok a jövőben várhatóan növekedni fognak. Orv Hetil. 2021; 162(45): 1803-1807. Summary. After the worldwide spread of COVID-19, common symptoms are already well known as fever, coughing, shortness of breath, pneumonia, abdominal pain and diarrhea, either loss of olfaction or sense of taste. Neurological complications are perhaps less known as headache, dizziness, agitation, executive dysfunction or, in particular cases, viral encephalitis and acute hemorrhagic necrotizing encephalitis may also occur. In COVID-19 patients, ischemic stroke or cerebral vein thrombosis are also more commonly related to the increased risk of thrombosis. In the long term, so called post-COVID syndrome can emerge in the form of fatigue, depression or many other mental disorders. The most common disease of the peripheral nervous system is Guillain-Barré syndrome. This chapter reviews a case of a 41-year-old man presented to the Department of Neurology with facial diplegia, dysarthria and intermittent paresthesia of the upper and lower extremities. 10-14 days before the onset of neurological symptoms, he has gone through COVID-19 infection that involved fever and upper respiratory tract symptoms. Electrophysiology and liquor samples showed typical signs of a rare Guillain-Barré syndrome subtype - bifacial weakness with paresthesias. We are reviewing the neurological complications of the virus due to the expected increase of case numbers. Orv Hetil. 2021; 162(45): 1803-1807.

It is a fundamental question in disease modeling how the initial seeding of an epidemic, spreading over a network, determines its final outcome. One important goal has been to find the seed configuration, which infects the most individuals. Although the identified optimal configurations give insight into how the initial state affects the outcome of an epidemic, they are unlikely to occur in real life. In this paper we identify two important seeding scenarios, both motivated by historical data, that reveal a complex phenomenon. In one scenario, the seeds are concentrated on the central nodes of a network, while in the second one, they are spread uniformly in the population. Comparing the final size of the epidemic started from these two initial conditions through data-driven and synthetic simulations on real and modeled geometric metapopulation networks, we find evidence for a switchover phenomenon: When the basic reproduction number [Formula: see text] is close to its critical value, more individuals become infected in the first seeding scenario, but for larger values of [Formula: see text], the second scenario is more dangerous. We find that the switchover phenomenon is amplified by the geometric nature of the underlying network and confirm our results via mathematically rigorous proofs, by mapping the network epidemic processes to bond percolation. Our results expand on the previous finding that, in the case of a single seed, the first scenario is always more dangerous and further our understanding of why the sizes of consecutive waves of a pandemic can differ even if their epidemic characters are similar., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Regular exercise can upgrade the efficiency of the immune system and beneficially alter the composition of the gastro-intestinal microbiome. We tested the hypothesis that active athletes have a more diverse microbiome than sedentary subjects, which could provide better protection against COVID-19 during infection. Twenty active competing athletes (CA) (16 male and 4 females of the national first and second leagues), aged 24.15 ± 4.7 years, and 20 sedentary subjects (SED) (15 male and 5 females), aged 27.75 ± 7.5 years, who had been diagnosed as positive for COVID-19 by a PCR test, served as subjects for the study. Fecal samples collected five to eight days after diagnosis and three weeks after a negative COVID-19 PCR test were used for microbiome analysis. Except for two individuals, all subjects reported very mild and/or mild symptoms of COVID-19 and stayed at home under quarantine. Significant differences were not found in the bacterial flora of trained and untrained subjects. On the other hand, during COVID-19 infection, at the phylum level, the relative abundance of Bacteroidetes was elevated during COVID-19 compared to the level measured three weeks after a negative PCR test ( p < 0.05) when all subjects were included in the statistical analysis. Since it is known that Bacteroidetes can suppress toll-like receptor 4 and ACE2-dependent signaling, thus enhancing resistance against pro-inflammatory cytokines, it is suggested that Bacteroidetes provide protection against severe COVID-19 infection. There is no difference in the microbiome bacterial flora of trained and untrained subjects during and after a mild level of COVID-19 infection.

Our goal was to assess agility, explosive power, and speed-endurance capacity by implementing noninvasive procedures and sport-specific tests. We hypothesized that agility, speed, explosive power, and speed-endurance capacity might be maintained or increased by an individualized home-based training program. Eleven adolescent athletes participated in our study; they executed three tests before the coronavirus outbreak and 13 weeks later, after the pandemic curfew. We used the SpeedCourt System to assess the sport-specific speed and agility parameters and monitor speed-endurance capacity. We conducted the first measurement at the end of the preparatory period, on 28 February 2020. The second session consisted of 4 weeks of regular training and 9 weeks of individual, home-based activities. Compared to the first (pre-pandemic) testing session, our participants demonstrated a significantly improved capacity of the lower limbs' explosive strength after completing the home-based exercise routine, compared to the first (pre-pandemic) testing session. We found that agility, speed, and explosive power might be maintained at the same level under home-based conditions. We found that it was challenging for the participants to increase their "pre-pandemic" endurance capacities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, and the number of worldwide cases continues to rise. The zoonotic origins of SARS-CoV-2 and its intermediate and potential spillback host reservoirs, besides humans, remain largely unknown. Because of ethical and experimental constraints and more important, to reduce and refine animal experimentation, we used our repository of well-differentiated airway epithelial cell (AEC) cultures from various domesticated and wildlife animal species to assess their susceptibility to SARS-CoV-2. We observed that SARS-CoV-2 replicated efficiently only in monkey and cat AEC culture models. Whole-genome sequencing of progeny viruses revealed no obvious signs of nucleotide transitions required for SARS-CoV-2 to productively infect monkey and cat AEC cultures. Our findings, together with previous reports of human-to-animal spillover events, warrant close surveillance to determine the potential role of cats, monkeys, and closely related species as spillback reservoirs for SARS-CoV-2.

Background: During the COVID-19 pandemic, most of the health care systems suspended their non-urgent activities. This included the cancellation of consultations for patients with rare diseases, such as severe pulmonary hypertension (PH), resulting in potential medication shortage and loss of follow-up. Thus, the aim of the study was to evaluate PH patient health status evolution, access to health care and mental health experience during the early phase of the pandemic., Methods: We conducted an online patient survey, available in 16 languages, between 22/05/2020 and 28/06/2020. The survey included questions corresponding to demographic, COVID-19 and PH related information., Results: 1073 patients (or relatives, 27%) from 52 countries all over the world participated in the survey. Seventy-seven percent (77%) of responders reported a diagnosis of pulmonary arterial hypertension and 15% of chronic thromboembolic PH. The COVID-19 related events were few: only 1% of all responders reported a diagnosis of COVID-19. However, 8% of patients reported health deterioration possibly related to PH, and 4% hospitalization for PH. Besides, 11% of the patients reported difficulties to access their PH expert centre, and 3% interruption of treatment due to shortage of medication. Anxiety or depression was reported by 67% of the participants., Conclusion: Although COVID-19 incidence in PH patients was low, PH related problems occurred frequently as the pandemic progressed, including difficulties to have access to specialized care. The importance of primary health care was emphasized. Further studies are needed to evaluate the long-term consequences of COVID-related PH care disruption.

The COVID-19 pandemic forced authorities worldwide to implement moderate to severe restrictions in order to slow down or suppress the spread of the disease. It has been observed in several countries that a significant number of people fled a city or a region just before strict lockdown measures were implemented. This behavior carries the risk of seeding a large number of infections all at once in regions with otherwise small number of cases. In this work, we investigate the effect of fleeing on the size of an epidemic outbreak in the region under lockdown, and also in the region of destination. We propose a mathematical model that is suitable to describe the spread of an infectious disease over multiple geographic regions. Our approach is flexible to characterize the transmission of different viruses. As an example, we consider the COVID-19 outbreak in Italy. Projection of different scenarios shows that (i) timely and stricter intervention could have significantly lowered the number of cumulative cases in Italy, and (ii) fleeing at the time of lockdown possibly played a minor role in the spread of the disease in the country.

In order to understand the transmission and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to understand the functions of each of the gene products encoded in the viral genome. One feature of the SARS-CoV-2 genome that is not present in related, common coronaviruses is ORF10, a putative 38-amino acid protein-coding gene. Proteomic studies found that ORF10 binds to an E3 ubiquitin ligase containing Cullin-2, Rbx1, Elongin B, Elongin C, and ZYG11B (CRL2 ZYG11B ). Since CRL2 ZYG11B mediates protein degradation, one possible role for ORF10 is to "hijack" CRL2 ZYG11B in order to target cellular, antiviral proteins for ubiquitylation and subsequent proteasomal degradation. Here, we investigated whether ORF10 hijacks CRL2 ZYG11B or functions in other ways, for example, as an inhibitor or substrate of CRL2 ZYG11B While we confirm the ORF10-ZYG11B interaction and show that the N terminus of ORF10 is critical for it, we find no evidence that ORF10 is functioning to inhibit or hijack CRL2 ZYG11B Furthermore, ZYG11B and its paralog ZER1 are dispensable for SARS-CoV-2 infection in cultured cells. We conclude that the interaction between ORF10 and CRL2 ZYG11B is not relevant for SARS-CoV-2 infection in vitro., Competing Interests: Competing interest statement: S.J.E. is a cofounder of TSCAN Therapeutics, MAZE Therapeutics, ImmuneID, and Mirimus. S.J.E. is an advisor for MPM Capital and serves on the scientific advisory boards of Homology Medicines, Inc. and TSCAN Therapeutics. M.P. is a cofounder of Coho Therapeutics and serves on the scientific advisory board of Coho Therapeutics, CullGen Inc., Kymera Therapeutics, Santi Therapeutics, and SEED Therapeutics. A reviewer (E.O.) and the authors E.L.M., C.O., and S.J.E. share an affiliation at Harvard Medical School. Their primary appointments are at different institutions and they have no shared collaborative work., (Copyright © 2021 the Author(s). Published by PNAS.)