KANET evaluation in patients with SARS-CoV-2.

OBJECTIVES: To determine a possible correlation between SARS-CoV-2 infection during pregnancy and altered fetal behavior. METHODS: Kurjak's antenatal neurodevelopmental test (KANET) was applied from 28 to 40 weeks in 38 gestations (group A) diagnosed with COVID-19 infection during the first week and 43 non-COVID pregnant women (group B). RESULTS: No statistically significant differences considering maternal age (33±3.9 years for group A vs. 31±4.1 years for group B) and gestational age (33±1.6 weeks for group A compared to 33±2.1 weeks for group B) were observed. KANET scores were not different between the two groups. CONCLUSIONS: Fetal behavior differences are not altered in women diagnosed with SARS-CoV-2 infection during the third trimester of pregnancy.

Reversible effects of the SARS-CoV-2 on semen parameters.

Despite that the SARS-CoV-2 pandemic has been controlled, it has affected a large proportion of the population, raising some concerns about potential sequelae in men at reproductive age. To contribute to the clarification of this issue, we performed a retrospective study comparing semen parameters values before and after confirmed SARS-CoV-2 infection in a large cohort of infertile men, compared to a control group that did not undergo SARS-CoV-2 infection. Wilcoxon test on paired samples and general linear regression model showed that SARS-CoV-2 infection has a detrimental effect on semen volume values (p < 0.005). However, semen volume seems to be significantly lower only during the first spermatogenic cycle after SARS-COV-2 infection (p < 0.005) and mainly in unvaccinated patients (p < 0.05). In addition, we detected alterations in progressive motility in patients infected with the alpha SARS-COV-2 strain (p < 0.05). In conclusion, our results show that although SARS-CoV-2 has a small effect on semen volume and sperm motility in infertile men, depending on the infectious strain or vaccination status, pre-infection values of semen parameters appear to be restored over one spermatogenic cycle after infection.

Differential associations between SARS-CoV-2 infection, perceived burden of the pandemic and mental health in the German population-based cohort for digital health research.

Understanding the potential adverse effects of the COVID-19-pandemic on mental health remains a challenge for public health. Differentiation between potential consequences of actual infection with SARS-CoV-2 and the subjective burden of the pandemic due to measures and restrictions to daily life still remains elusive. Therefore, we investigated the differential association between infection with SARS-Cov-2 and subjective burden of the pandemic in a study cohort of 7601 participants from the German population-based cohort for digital health research (DigiHero), who were recruited between March 4th and April 25th 2022. Data was collected using the online survey tool LimeSurvey® between March and October 2022 in consecutive surveys, which included questionnaires on infection status and symptoms following COVID-19 as well as retrospective assessment of the subjective burden of the pandemic. We observed an association of a past SARS-CoV-2 infection on deteriorated mental health related symptoms, whereas no association or interaction with burden of the pandemic occurred. The association was driven by participants with persistent symptoms 12 weeks after infection. On a symptom specific level, neuropsychiatric symptoms such as exhaustion and fatigue, concentration deficits and problems with memory function were the primary drivers of the association with small effect sizes between 0.048 and 0.062 ηp2.

Understanding antibody magnitude and durability following vaccination against SARS-CoV-2.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in transient antibody response against the spike protein. The individual immune status at the time of vaccination influences the response. Using mathematical models of antibody decay, we determined the dynamics of serum immunoglobulin G (IgG) and serum immunoglobulin A (IgA) over time. Data fitting to longitudinal IgG and IgA titers was used to quantify differences in antibody magnitude and antibody duration among infection-naïve and infection-positive vaccinees. We found that prior infections result in more durable serum IgG and serum IgA responses, with prior symptomatic infections resulting in the most durable serum IgG response and prior asymptomatic infections resulting in the most durable serum IgA response. These findings can guide vaccine boosting schedules.

Latent Class Analysis Reveals, in patient profiles, COVID-19-related better prognosis by calcifediol treatment than glucocorticoids.

Calcifediol and glucocorticoids have been repositioned for the treatment of COVID-19 and may reduce severity, the need for intensive care unit admission and death. OBJECTIVE: to identify class or profiles of patients hospitalized and treated with COVID-19 pneumonia using latent class clustering methods to assess the clinical and prognostic relevance of the resulting patients' profiles. Poor prognosis was defined as death or need for ICU admission, good prognosis, the opposite. With special interest in differential responses to calcifediol. SETTING: Reina Sofia University Hospital, Córdoba Spain. Patients Retrospective observational cohort study of patients admitted for COVID-19. CLINICALTRIALS: gov public database (NCT05819918). INCLUSION CRITERIA: (i) Age ≥ 18 and ≤ 90 years, (ii) Pneumonia characterized by the presence of infiltrates on chest X-ray or CT scan, (iii) SARS-CoV-2 infection, confirmed, and (iv) CURB Scale 65 >1. DESIGN: Latent class analysis, for obtaining homogeneous clusters, without specifying a priori the belonging group, and selecting the optimal number of clusters by minimizing information criteria. Evaluating the differences between groups for each variable by means of chi-square, Fisher's exact test and Kruskal-Wallis test. RESULTS: 707 patients hospitalized from 10 March 2020 until 4 March 2022 were included. For the treatment variable, differences were found between class 3 (60% treated with calcifediol only) and classes 1 (less than 1% calcifediol only vs. 82% treated with both), 2 (less than 1% calcifediol only vs. 82% treated with both) and 4 (1% calcifediol only vs. 84% treated with both). Class 3, (60% with calcifediol), had a significantly better prognosis compared to patients treated with glucocorticoids alone (OR: 15.2, 95% CI: [3.73 - 142], p<0.001) or no treatment (OR: 7.38, 95% CI: [2.63 - 30.2], p<0.001). CONCLUSIONS: our real-life study shows that calcifediol treatment significantly reduces the need for ICU admission and improved prognosis in patients hospitalized for COVID-19 pneumonia, especially in the profile of patients receiving it without glucocorticoids.

Indirect effectiveness of a novel SAR-COV-2 vaccine (SCB-2019) in unvaccinated household contacts in the Philippines: a cluster randomised analysis.

BACKGROUND: Though observational evidence supports indirect effects of SARS-CoV-2 vaccines, randomised experiments are lacking. To address this gap, the double-blinded, prospective follow-up of the household contacts (HHCs) of Philippine participants of the individually-randomised, placebo-controlled trial of the adjuvanted-subunit protein COVID-19 vaccine, SCB-2019, (EudraCT, 2020-004272-17; ClinicalTrials.gov, NCT04672395) was analyzed in a cluster-randomised fashion. METHODS: Over an eight-week period, HHCs were followed by rRT-PCR and paired rapid antibody tests (RATs) to detect symptomatic (SCI, primary) and all (ACI, secondary) SARS-CoV-2 infection. A standard analysis estimated the indirect effectiveness of SCB-2019 for each endpoint, excluding HHC RAT-positive at enrollment. A secondary analysis employed enzyme-linked immunosorbent assay (ELISA) results to correct for suspected bias. FINDINGS: SCB-2019 (N=3470) and placebo (N = 3225) exposed HHCs contributed to at least one analysis. The standard analysis estimated that SCB-2019 reduced the risk of SCI by 83% (95% confidence/credible interval [CI: 32% to 96%), with no effect against ACI. The bias-corrected relative risk reduction was 97% (95% CI: 74% to 100%) for SCI and 79% (95% CI: 14% to 96%) for ACI, with an estimated one SARS-CoV-2 infection prevented per 4.8 households where one member received SCB-2019. INTERPRETATION: SCB-2019 demonstrated bias-corrected indirect effectiveness against SARS-CoV-2 infection among HHC, even at a modest coverage level in the household (approximately 25%). Further research into the indirect effects of SARS-CoV-2 vaccines is needed to optimize the impact of limited doses in low and middle-income settings. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease.

COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CLpro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CLpro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CLpro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43(EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 µM) in Huh7 cells. Taken together, this study devised two series of 3CLpro inhibitors and provided the potent SARS-CoV-2 3CLpro inhibitor (12b) which may be used for treating coronavirus infections.

Reduced Risk of SARS-CoV-2 Infection Among Household Contacts with Recent Vaccination and Past COVID-19 Infection: Results from Two Multi-Site Case-Ascertained Household Transmission Studies.

Households are a primary setting for transmission of SARS-CoV-2. We examined the role of prior SARS-CoV-2 immunity on the risk of infection in household close contacts. Households in the United States with an individual who tested positive for SARS-CoV-2 during September 2021-May 2023 were enrolled if the index case's illness began ≤6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. The effects of prior SARS-CoV-2 immunity (vaccination, prior infection, or hybrid immunity) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Of 1,532 contacts (905 households), 8% had immunity from prior infection alone, 51% from vaccination alone, 29% hybrid immunity, and 11% had no prior immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The adjusted risk of SARS-CoV-2 infection was lowest among contacts with vaccination and prior infection (aRR: 0.81, 95% CI: 0.70, 0.93, compared with contacts with no prior immunity) and was lowest when the last immunizing event occurred ≤6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). In high-transmission settings like households, immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection.

Trends in the Implementation of Workplace COVID-19 Measures in Japanese Companies: A One-Year Prospective Cohort Study.

This study evaluated trends in the implementation of workplace measures against COVID-19 by Japanese companies. We conducted a prospective cohort study, using data from December 2020 and December 2021, with 13,419 respondents participating in the follow-up survey. We evaluated nine workplace measures against COVID-19 (e.g., encouraging mask-wearing at work) and used the McNemar test and the Chi-square test for trend in the analysis. Small-sized companies (1-9 employees) exhibited a significant increase in the implementation of all the measures, with a rate of increase ranging from 8.4% to 16.1% (P-value: <0.001). Medium-sized companies (10-49 employees) also showed significant improvements in nearly all the measures (rate of increase: 3.5% to 10.5%, P-values: <0.001 to 0.004), except for one specific measure. Larger companies (more than 50 employees) displayed a mixed pattern, with some measures increasing and others decreasing. A persistent gap was observed between smaller (fewer than 50 employees) and larger companies in the implementation rates of these measures. The findings revealed a positive shift in workplace measures against COVID-19 among smaller companies in Japan over 1 year, although gaps between them and larger companies persisted.

Trends in covalent drug discovery: a 2020-23 patent landscape analysis focused on select covalent reacting groups (CRGs) found in fda-approved drugs.

INTRODUCTION: Covalent drugs contain electrophilic groups that can react with nucleophilic amino acids located in the active sites of proteins, particularly enzymes. Recently, there has been considerable interest in using covalent drugs to target non-catalytic amino acids in proteins to modulate difficult targets (i.e. targeted covalent inhibitors). Covalent compounds contain a wide variety of covalent reacting groups (CRGs), but only a few of these CRGs are present in FDA-approved covalent drugs. AREAS COVERED: This review summarizes a 2020-23 patent landscape analysis that examined trends in the field of covalent drug discovery around targets and organizations. The analysis focused on patent applications that were submitted to the World International Patent Organization and selected using a combination of keywords and structural searches based on CRGs present in FDA-approved drugs. EXPERT OPINION: A total of 707 patent applications from > 300 organizations were identified, disclosing compounds that acted at 71 targets. Patent application counts for five targets accounted for ~ 63% of total counts (i.e. BTK, EGFR, FGFR, KRAS, and SARS-CoV-2 Mpro). The organization with the largest number of patent counts was an academic institution (Dana-Farber Cancer Institute). For one target, KRAS G12C, the discovery of new drugs was highly competitive (>100 organizations, 186 patent applications).

N121T and N121S substitutions on the SARS-CoV-2 spike protein impact on serum neutralization.

The N121 site on the spike protein of SARS-CoV-2 is associated with heme and its metabolite, biliverdin, which can affect antibody binding. Both N121T and N121S substitutions have been observed in natural conditions and in a hamster model of dual infection with SARS-CoV-2 and Influenza A virus. Serum pseudotype neutralization assays against HIV-1 particles carrying wild-type, N121T, and N121S spikes with immune mouse and human sera revealed that N121T and N121S mutations had a greater impact on serum neutralization than biliverdin treatment. Although N121T and N121S substitutions are not currently major SARS-CoV-2 variants of concern, this study could provide fundamental information to prepare for potential future mutations at the N121 site of SARS-CoV-2.

Humoral immune response as an indicator for protection against Covid-19 after anti-SARS-COV2-booster vaccination in hematological and oncological patients.

Cancer patients are at a higher risk to develop severe COVID-19 symptoms after SARS-CoV-2 infection compared to the general population and regularly show an impaired immune response to SARS-CoV-2 vaccination. In our oncological center, 357 patients with hematological and oncological diseases were monitored for neutralizing antibodies from October 2021 over 12 months. All patients had received three anti-SARS-CoV-2 vaccinations with an mRNA-(Comirnaty/BionTech or Spikevax/Moderna) or a vector vaccine (Vakzevria/AstraZeneca or JCOVDEN/Johnson&Johnson). Neutralizing anti-SARS-CoV-2 IgG antibodies in the patients' sera were detected within 3 months before, 3-10 weeks and 5-7 months after the booster vaccination (third vaccination). 112 patients developed a breakthrough SARS-CoV-2 infection during the observation period. High anti-SARS-Cov-2 antibody levels before infection significantly protected against symptomatic Covid-19 disease (p = .003). The median antibody titer in patients with asymptomatic Covid-19 disease was 2080 BAU/ml (binding antibody units per Milliliter) and 765 BAU/ml in symptomatic patients. 98% of the solid tumor patients reached seroconversion after the booster vaccination in comparison to 79% of the hematological patients. High antibody titers of >2080 BAU/ml after the booster vaccination were detected in 61% of the oncological and 34.8% of the hematological patients. 7-10 months after the booster vaccination, the anti-SARS-CoV-2 antibody titer declined to an average of 849 BAU/ml. Considering the heterogenous humoral immune response of cancer patients observed in this study, an individual vaccination strategy based on regular measurement of anti-SARS-CoV-2 antibody levels should be considered in contrast to fixed vaccination intervals.

Detection of SARS-CoV-2 binding receptors and miscellaneous targets as well as mucosal surface area of the human lacrimal drainage system.

PURPOSE: Our aim was to evaluate a potential role for the lacrimal drainage system (LDS) as a portal of entry and conduit for SARS-CoV-2 in human infection. We also investigate the mucosal surface area. The relatively long tear contact time in a closed system raises the possibility that this pathway may contribute to the initiation of systemic infection. We looked for expression of ACE2, the main receptor for SARS-CoV-2, as well as cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin which also play a role in SARS-CoV-2 infection, in this system. METHODS: Human tissue samples of the draining tear ducts from body donors were analyzed by RT-PCR, Western blot and immunohistochemistry. It is not known whether the respective body donors were Sars-Cov-2 positive at any time; they were negative when they entered the institute. Besides, the draining LDS of body donors were measured to determine the mucosal surface in the lacrimal system. RESULTS: The expression of the main receptor studied, ACE2, cofactors such as TMPRSS2 and other enzymes such as cathepsinB, CD147, elastase1, furin, neuropilin1, neuropilin2, TMPRSS11D and trypsin were all detected at the gene and protein level. The average mucosal surface area of the lacrimal sac and nasolacrimal duct was calculated to be 110 mm2. CONCLUSION: The results show the presence of all analyzed receptors in the efferent LDS. With an average tear passage time of 3 min and a relatively large mucosal surface area, the LDS could therefore be considered as a portal of entry and conduit for SARS-CoV-2. In addition, it represents a surface that should be taken into consideration in the administration of topically applied medication to the ocular surface.

A case report of prolonged viral shedding of SARS-CoV-2 in a patient who receive ibrutinib for CLL therapy.

Patients on B cell immunosuppressive treatments have been shown to have persistent infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this report, a woman treated with ibrutinib for chronic lymphocytic leukemia experienced more than 40 days of coronavirus disease 2019 (COVID-19) infection. Unexpectedly, her peripheral blood experiments showed a normal SARS-CoV-2-specific antibody level and a relatively elevated percentage of CD19 + B cells, while an obvious decrease in the percentages of NK cells, CD4 + T cells and CD8 + T cells. Further SARS-CoV-2-specific T cell analysis in this patient indicated a significant decrease in the percentage of SARS-CoV-2-specific IFN-γ, TNF-α or IL-2 producing CD4 + T or CD8 + T cells. Most notably, ten days after the cease of ibrutinib, the PCR for SARS-CoV-2 turned negative and the reduced proportions of peripheral CD4 + T cells and CD8 + T cells recovered. Our research predicted that the depleted B-cell function therapies may play considerable role in the development of long COVID-19 and the abnormal T-cell subset distribution might be the underlying mechanism.

Integrated viral and immune monitoring in a prospective COVID-19 cohort from India.

In this study, we report on longitudinal kinetics of cellular immune subsets following SARS-CoV-2 infection in a cohort of hospitalized individuals and evaluate the interplay of these profiles with infecting viral variants, humoral immunity including neutralizing responses, vaccination history and clinical outcomes. A cohort of 121 SARS-CoV-2 infected individuals exhibiting varying disease states were prospectively evaluated for lymphopenic profiles, anti-viral humoral responses and infecting viral variants for a period of up to 90 days spanning the period, February 2021-January 2022 (2nd and 3rd waves of infection). A total of 51 participants received at least one vaccine dose of indigenous vaccines (Covishield or Covaxin) prior to recruitment. When stratified in terms of mortality, B and NK cells, in contrast to the T cell compartment, did not recover from nadir levels in non-survivors who were largely unvaccinated. No discriminatory signature was identified for non-survivors in terms of anti-NC or anti-S1-RBD IgG CLIA profiles including GenScript S1-RBD assays. Evaluation of sVCAM and sMAdCAM revealed opposing dynamics that correlated with disease severity and convalescence respectively. Viral variant analysis revealed delta and omicron variants to comprise majority of the infections which reflected national transmission kinetics during the period of recruitment. Our results demonstrate the importance of monitoring circulating biomarkers for convalescence as well as mortality in COVID-19 progression. Delta variants of SARS-CoV-2 clearly demonstrated increased pathogenicity and warrants sustained viral surveillance for re-emergence of these strains. Our findings with respect to vaccination advocate for continued vaccine development and administration of COVID-19 vaccines.

Visceral Adiposity and Neutralizing Antibody Expression: An Adult-Based Cross-Sectional Study.

Purpose: Visceral adiposity is a significant risk factor for severe COVID-19. However, the impact of the Chinese visceral adiposity index (CVAI) on the efficacy of SARS-CoV-2 vaccines remains poorly understood. This study aims to explore the impact of CVAI on the production of neutralizing antibodies (NAb) in inactivated SARS-CoV-2 vaccines and the potential mechanism, thereby optimizing vaccination guidance. Methods: In this cross-sectional study, 206 health workers (completed two SARS-CoV-2 vaccination on February 8th and March 10th, 2021, respectively) were recruited. All baseline anthropometric parameters of the participants were collected, and venous blood samples were obtained 6 weeks later to measure peripheral innate immune cells, inflammatory cytokines, and NAb titers against SARS-CoV-2. CVAI were calculated according to the formula and divided participants into two groups depending on CVAI median. Results: The median NAb titer among healthcare workers was 12.94 AU/mL, with an efficacy of 87.86% for the SARS-CoV-2 vaccine. NAb titers were lower in the CVAI dysfunction group than in the CVAI reference group (median: 11.40 AU/mL vs 15.57 AU/mL), the hsCRP levels (median: 0.50 mg/L vs 0.30 mg/L) and peripheral monocyte count (mean: 0.47 × 109/L vs 0.42 × 109/L) in the CVAI dysfunction group were higher than in the CVAI reference group. Additionally, CVAI showed positive correlations with hsCRP, monocytes, lymphocytes, and B-lymphocytes, and a negative correlation with NAb titers. Conclusion: CVAI may inhibit SARS-CoV-2 neutralizing antibody expression through inducing immune dysfunction and chronic inflammation. Thus, more attention should be paid to the vaccination for high CVAI population to improve the effectiveness of vaccination, which could provide more robust support for COVID-19 epidemic prevention and control.

Vascular Consequences: A Case Report on Posterior Circulation Infarction as a Sequela of COVID-19.

This case report presents a posterior circulation infarction in a previously healthy 39-year-old male, three months post-severe COVID-19. He presented with right-sided homonymous hemianopia and elevated inflammatory markers and D-dimer levels. Imaging revealed an acute left occipital infarct. Such post-COVID-19 posterior circulation strokes are rare. This report discusses the pathophysiology, optimal anticoagulation therapy for COVID-19-related thrombotic complications, and early predictor models. This case underscores the need to recognize thromboembolic events as potential late sequelae in severe COVID-19 cases.

Clinical characteristics, treatment and prognosis of children with SARS-CoV-2 infection complicated with severe neurological dysfunctions in Foshan, China.

Objective: To analyze the clinical characteristics, treatment, and prognosis of children infected with SARS-CoV-2 following the adjustment of COVID-19 prevention and control policies in China in December 2022. Methods: A retrospective study was conducted on 9 cases of severe neurological dysfunction caused by SARS-CoV-2 infection in children admitted to Foshan First People's Hospital from December 17 to 31, 2022. Results: Among the 9 cases, 7 (71.43%) were under 3 years old, and 2 (22.2%) were over 3 years old with underlying diseases. All patients presented with fever and neurological symptoms such as consciousness disturbance and/or convulsions, and their conditions deteriorated rapidly within 24 h after the onset of fever, without respiratory symptoms. Levels of IL-6, LDH, and d-dimer were significantly elevated. Five cases died within 48 h of admission, one case died after 7 days of treatment due to secondary bacterial infection, and three cases survived for more than 48 h after the initial rescue. All patients developed rapid shock, and five cases experienced multi-organ failure within a short period. In terms of treatment, glucocorticoids were used in 5 cases, intravenous immunoglobulin (IVIG) in 3 cases, and blood purification and tocilizumab in 2 cases. Conclusion: SARS-CoV-2 infection in children can lead to severe neurological damage. High fever, convulsions, and inflammatory factors serve as early warning indicators. Glucocorticoids, immunoglobulins, blood purification, and tocilizumab may have some therapeutic effects, but further research is needed to confirm the efficacy.