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The binding of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein to the host cell receptor angiotensin-converting enzyme 2 (ACE2) is the first step in human viral infection. Therefore, understanding the mechanism of interaction between RBD and ACE2 at the molecular level is critical for the prevention of COVID-19, as more variants of concern, such as Omicron, appear. Recently, atomic force microscopy has been applied to characterize the free energy landscape of the RBD–ACE2 complex, including estimation of the distance between the transition state and the bound state, xu. Here, using a coarse-grained model and replica-exchange umbrella sampling, we studied the free energy landscape of both the wild type and Omicron subvariants BA.1 and XBB.1.5 interacting with ACE2. In agreement with experiment, we find that the wild type and Omicron subvariants have similar xu values, but Omicron binds ACE2 more strongly than the wild type, having a lower dissociation constant KD. [ABSTRACT FROM AUTHOR]

Parkinson's disease is accompanied by the presence of amyloids in the brain that are formed of α-synuclein chains. The correlation between COVID-19 and the onset of Parkinson's disease led to the idea that amyloidogenic segments in SARS-COV-2 proteins can induce aggregation of α-synuclein. Using molecular dynamic simulations, we show that the fragment FKNIDGYFKI of the spike protein, which is unique for SARS-COV-2, preferentially shifts the ensemble of α-synuclein monomer toward rod-like fibril seeding conformations and, at the same time, differentially stabilizes this polymorph over the competing twister-like structure. Our results are compared with earlier work relying on a different protein fragment that is not specific for SARS-COV-2. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the virus causing COVID-19, initiates cell invasion by deploying a receptor binding domain (RBD) to recognize the host transmembrane peptidase angiotensin-converting enzyme 2 (ACE2). Numerous experimental and theoretical studies have adopted high-throughput and structure-guided approaches to (i) understand how the RBD recognizes ACE2, (ii) rationalize, and (iii) predict the effect of viral mutations on the binding affinity. Here, we investigate the allosteric signal triggered by the dissociation of the ACE2-RBD complex. To this end, we construct an Elastic Network Model (ENM), and we use the Structural Perturbation Method (SPM). Our key result is that complex dissociation opens the ACE2 substrate-binding cleft located away from the interface and that fluctuations of the ACE2 binding cleft are facilitated by RBD binding. These and other observations provide a structural and dynamical basis for the influence of SARS-CoV-2 on ACE2 enzymatic activity. In addition, we identify a conserved glycine (G502 in SARS-CoV-2) as a key participant in complex disassembly. [ABSTRACT FROM AUTHOR]

We present a hybrid, multi-method, computational scheme for protein/ligand systems well suited to be used on modern and forthcoming massively parallel computing systems. The scheme relies on a multi-scale polarizable molecular modeling, approach to perform molecular dynamics simulations, and on an efficient Density Functional Theory (DFT) linear scaling method to post-process simulation snapshots. We use this scheme to investigate recent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2 virus. We assessed the reliability and the coherence of the hybrid scheme, in particular, by checking the ability of MM and DFT to reproduce results from high-end ab initio computations regarding such inhibitors. The DFT approach enables an a posteriori fragmentation of the system and an investigation into the strength of interaction among identified fragment pairs. We show the necessity of accounting for a large set of plausible protease/inhibitor conformations to generate reliable interaction data. Finally, we point out ways to further improve α-ketoamide inhibitors to more strongly interact with particular protease domains neighboring the active site. [ABSTRACT FROM AUTHOR]

• First study of ancestral recombinant vaccine, S-268019-b for prevention in Vietnam. • The vaccine efficacy for prevention not verified in Omicron-dominant period. • S-268019-b immunogenicity and tolerability confirmed. • Similar efficacy and safety of S-268019-b with other ancestral strain vaccines. Clinical trials of new vaccines based on existing variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are often impacted by the emergence of new virus variants. We evaluated the efficacy, immunogenicity, and safety of S-268019-b, a recombinant spike protein subunit vaccine based on the ancestral strain, for preventing symptomatic coronavirus disease 2019 (COVID-19) during the Omicron (BA.2)-dominant period in Vietnam. In this multicentre, phase 3, randomised (2:1), observer-blind, placebo-controlled crossover study, participants received 2 intramuscular doses (28 days apart) of either 10 µg of S-268019-b (Recombinant S-protein vaccine) or placebo. The primary endpoint was incidence of laboratory-confirmed symptomatic COVID-19 before crossover, with onset within 14 days following the second dose, in participants who were seronegative and reverse transcription polymerase chain reaction (RT-PCR)-negative at baseline. The secondary endpoints included immunogenicity and safety. In total, 8,594 participants were randomised (S-268019-b [n = 5,727]; placebo [n = 2,867]). Vaccine efficacy versus placebo was 39·1 % (95 % confidence interval [CI]:26·6–49·5; one-sided P = 0·0723). The incidence rate (95 % CI) of symptomatic COVID-19 was 776·41/1,000 person-years (682·04–880·19) in the S-268019-b group and 1272·87/1,000 person-years (1101·32–1463·57) in the placebo group. The geometric mean titres (95 % CI) of the SARS-CoV-2 neutralising antibody increased on Day 57 versus baseline with S-268019-b (34·66 [27·04–44·41] versus 2·50 (non-estimable) but not with placebo. There were no safety concerns regarding S-268019-b. S-268019-b did not demonstrate the targeted efficacy threshold against symptomatic COVID-19; however, findings were comparable with other prophylactic vaccines based on ancestor strain during the Omicron-dominant period. S-268019-b demonstrated immunogenicity and was well-tolerated. ClinicalTrials.gov identifier: NCT05212948. [ABSTRACT FROM AUTHOR]

With the continuous emergence of coronavirus disease 2019 (COVID-19) waves, the scientific community has developed a vaccine that offers broad-spectrum protection at virus-targeted organs for inhibiting the transmission and protection of disease development. In the present study, a bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine containing receptor-binding domain (RBD) protein of spike from Wuhan-1 and omicron BA.1 loaded in nanoparticles, bivalent RBD NPs, was developed. The immunogenicity and protective efficacy of this vaccine candidate were evaluated using an in vivo model. Results showed that mice that received intranasal cGAMP-adjuvanted bivalent RBD-NPs vaccine elicited robust and durable antibody responses. The stimulated antibody broadly neutralized the ancestral strain and variants of concerns (delta and omicron BA.1) in the upper and lower respiratory tracts. Furthermore, the immunized mice developed T-cell response in their lung tissue. Importantly, intranasal immunization with this vaccine candidate efficiently protected mice from nasal infection caused by both Wuhan-1 and BA.1 viruses. Immunized mice that remained susceptible to nasal infection did not develop any symptoms. This is because activated responses in the nasal cavity significantly suppressed virus production. Another word is this nasal vaccine completely protected the mice from disease development and mortality. Therefore, the bivalent RBD vaccine platform has potential to be developed into an anti-SARS-CoV-2 universal vaccine. [ABSTRACT FROM AUTHOR]

• Higher doses of Ad26.COV2.S tended to be more immunogenic and more reactogenic than lower doses. • VNAs and S-bAbs persisted for at least 6 months after just 1 dose of Ad26.COV2.S 5 × 1010 vp. • Immune responses increased when the time interval between dose 1 and dose 2 increased. • Rapid, marked responses in all groups after vaccine antigen exposure indicate immune memory. • Durable immune responses were observed in all groups up to at least 6 months post vaccine antigen exposure. A single dose of Ad26.COV2.S is well-tolerated and effective in preventing moderate-to-severe disease outcomes due to COVID-19. We evaluated the impact of dose level, number of doses, and dose interval on immunogenicity, reactogenicity, and safety of Ad26.COV2.S in adults. Anamnestic responses were also explored. This randomised, double-blind, placebo-controlled, Phase 2a study was conducted in adults aged 18–55 years and ≥ 65 years (NCT04535453). Four dose levels (1.25 × 1010, 2.5 × 1010, 5 × 1010, and 1 × 1011 viral particles [vp], single and 2-dose schedules, and dose intervals of 56 and 84 days, were assessed. Four or 6 months post-primary vaccination, Ad26.COV2.S 1.25 × 1010 vp was given to evaluate anamnestic responses. Humoral and cell-mediated immune responses were measured. Reactogenicity and safety were assessed in all participants. All Ad26.COV2.S schedules induced humoral responses with evidence of a dose response relationship. A single dose of Ad26.COV2.S (5 × 1010 vp) induced antibody and cellular immune responses that persisted for up to at least 6 months. In the 2-dose regimens, antibody responses were higher than 1-dose regimens at comparable dose levels, and the magnitude of the immune response increased when the interval between doses was increased (84 days vs 56 days). Rapid, marked immune responses were observed in all groups after vaccine antigen exposure indicating immune memory. Durable immune responses were observed in all groups for up to at least 6 months post-antigen exposure. Strong and consistent correlations between neutralising and binding antibodies were observed CD4 + and CD8 + T cell responses were similar after all regimens. Reactogenicity within 7 days post-vaccination tended to be dose-related. The study supports the primary, single dose schedule with Ad26.COV2.S at 5 × 1010 vp and homologous booster vaccination after a 6 month interval. Rapid and marked responses to vaccine antigen exposure indicate induction of immune memory by 1- and 2-dose primary vaccination. [ABSTRACT FROM AUTHOR]

As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. Despite the recent advances regarding vaccines against COVID-19, nontoxic novel adjuvants with the potential to enhance vaccine efficacy are urgently desired. In this connection, it has been well-documented that STING agonists are applied to combat COVID-19. This approach is of major significance for boosting immune responses most likely through an autophagy-dependent manner in susceptible individuals against infection induced by severe acute respiratory syndrome Coronavirus (SARS‑CoV‑2). Given that STING agonists exert substantial immunomodulatory impacts under a wide array of pathologic conditions, these agents could be considered novel adjuvants for enhancing immunogenicity against the SARS-related coronavirus. Here, we intend to discuss the recent advances in STING agonists' recruitment to boost innate immune responses upon vaccination against SARS-related coronavirus infections. In light of the primordial role of autophagy modulation, the potential of being an antiviral vaccine adjuvant was also explored. [ABSTRACT FROM AUTHOR]

Background: Estimation of the SARS-CoV-2 incubation time distribution is hampered by incomplete data about infection. We discuss two biases that may result from incorrect handling of such data. Notified cases may recall recent exposures more precisely (differential recall). This creates bias if the analysis is restricted to observations with well-defined exposures, as longer incubation times are more likely to be excluded. Another bias occurred in the initial estimates based on data concerning travellers from Wuhan. Only individuals who developed symptoms after their departure were included, leading to under-representation of cases with shorter incubation times (left truncation). This issue was not addressed in the analyses performed in the literature. Methods: We performed simulations and provide a literature review to investigate the amount of bias in estimated percentiles of the SARS-CoV-2 incubation time distribution. Results: Depending on the rate of differential recall, restricting the analysis to a subset of narrow exposure windows resulted in underestimation in the median and even more in the 95th percentile. Failing to account for left truncation led to an overestimation of multiple days in both the median and the 95th percentile. Conclusion: We examined two overlooked sources of bias concerning exposure information that the researcher engaged in incubation time estimation needs to be aware of. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has had an enormous impact on the healthcare systems. Along with its common complications, novel complications such as Rectus Sheath Hematoma (RSH) have been reported. We present 2 cases of RSH. (A) A 63-year-old woman with a known case of COVID-19 with severe cough presented sudden tachycardia and hypogastric pain; on physical examination, a huge lower abdominal tender mass was noticed. All the differential diagnoses were ruled out. (B) A 57-year-old woman with COVID-19 started complaining of tachycardia, pain, and a mass in the lower abdomen. On the physical examination, a lower abdominal tender mass was noticed. Both of the patients underwent an abdomen CT scan which confirmed a huge RSH. Conservative treatment and cessation of anticoagulant medications were continued. Both of them recovered and no evidence of further expansion was seen after 4 weeks of follow-up. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: The messenger RNA (mRNA)-based coronavirus disease 2019 vaccines approved for use in children <5 years of age have different antigen doses and administration schedules that could affect vaccine immunogenicity and effectiveness. We sought to compare the strength and breadth of serum binding and neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicited by monovalent mRNA-based coronavirus disease 2019 vaccines in young children. METHODS: We conducted a prospective cohort study of children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines. Serum was collected 1 month after primary vaccine series completion for the measurement of SARS-CoV-2-specific humoral immune responses, including antibody binding responses to Spike proteins from an ancestral strain (D614G) and major variants of SARS-CoV-2 and antibody neutralizing activity against D614G and Omicron subvariants (BA.1, BA.4/5). RESULTS: Of 75 participants, 40 (53%) received mRNA-1273 and 35 (47%) received BNT162b2. Children receiving either primary vaccine series developed robust and broad SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron subvariants. Children with a previous history of SARS-CoV-2 infection developed significantly higher antibody binding responses and neutralization titers to Omicron subvariants, which is consistent with the occurrence of identified infections during the circulation of Omicron subvariants in the region. CONCLUSIONS: Monovalent mRNA-1273 and BNT162b2 elicited similar antibody responses 1 month after vaccination in young children. In addition, previous infection significantly enhanced the strength of antibody responses to Omicron subvariants. The authors of future studies should evaluate incorporation of these vaccines into the standard childhood immunization schedule. [ABSTRACT FROM AUTHOR]

Background Coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome requiring veno-venous extracorporeal membrane oxygenation (vv-ECMO) is related with poor outcome, especially in Germany. We aimed to analyze whether changes in vv-ECMO therapy during the pandemic were observed and lead to changes in the outcome of vv-ECMO patients. Methods All patients undergoing vv-ECMO support for COVID-19 between 2020 and 2021 in a single center (n = 75) were retrospectively analyzed. Weaning from vv-ECMO and in-hospital mortality were defined as primary and peri-interventional adverse events as secondary endpoints of the study. Results During the study period, four infective waves were observed in Germany. Patients were assigned correspondingly to four study groups: ECMO implantation between March 2020 and September 2020: first wave (n = 11); October 2020 to February 2021: second wave (n = 23); March 2021 to July 2021: third wave (n = 25); and August 2021 to December 2021: fourth wave (n = 20). Preferred cannulation technique changed within the second wave from femoro-femoral to femoro-jugular access (p < 0.01) and awake ECMO was implemented. Mean ECMO run time increased by more than 300% from 10.9 ± 9.6 (first wave) to 44.9 ± 47.0 days (fourth wave). Weaning of patients was achieved in less than 20% in the first wave but increased to approximately 40% since the second one. Furthermore, we observed a continuous numerically decrease of in-hospital mortality from 81.8 to 57.9% (p = 0.61). Conclusion Preference for femoro-jugular cannulation and awake ECMO combined with preexisting expertise and patient selection are considered to be associated with increased duration of ECMO support and numerically improved ECMO weaning and in-hospital mortality. [ABSTRACT FROM AUTHOR]

Background Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. Objectives This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir. Methods A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825 mg for up to 3.5 days. Results AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 mg twice daily. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4–5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. Conclusions The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the frozen–thawed embryo transfer (FET) cycle affect embryo implantation and pregnancy rates? SUMMARY ANSWER There is no evidence that SARS-CoV-2 infection of women during the FET cycle negatively affects embryo implantation and pregnancy rates. WHAT IS KNOWN ALREADY Coronavirus disease 2019 (COVID-19), as a multi-systemic disease, poses a threat to reproductive health. However, the effects of SARS-CoV-2 infection on embryo implantation and pregnancy following fertility treatments, particularly FET, remain largely unknown. STUDY DESIGN, SIZE, DURATION This retrospective cohort study, included women who underwent FET cycles between 1 November 2022 and 31 December 2022 at an academic fertility centre. PARTICIPANTS/MATERIALS, SETTING, METHODS Women who tested positive for SARS-CoV-2 during their FET cycles were included in the COVID-19 group, while those who tested negative during the same study period were included in the non-COVID-19 group. The primary outcome was ongoing pregnancy rate. Secondary outcomes included rates of implantation, biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy. Multivariate logistic regression models were applied to adjust for potential confounders including age, body mass index, gravidity, vaccination status, and endometrial preparation regimen. Subgroup analyses were conducted by time of infection with respect to transfer (prior to transfer, 1–7 days after transfer, or 8–14 days after transfer) and by level of fever (no fever, fever <39°C, or fever ≥39°C). MAIN RESULTS AND THE ROLE OF CHANCE A total of 243 and 305 women were included in the COVID-19 and non-COVID-19 group, respectively. The rates of biochemical pregnancy (58.8% vs 62.0%, P  = 0.46), clinical pregnancy (53.1% vs 54.4%, P  = 0.76), implantation (46.4% vs 46.2%, P  = 0.95), early pregnancy loss (24.5% vs 26.5%, P  = 0.68), and ongoing pregnancy (44.4% vs 45.6%, P  = 0.79) were all comparable between groups with or without infection. Results of logistic regression models, both before and after adjustment, revealed no associations between SARS-CoV-2 infection and rates of biochemical pregnancy, clinical pregnancy, early pregnancy loss, or ongoing pregnancy. Moreover, neither the time of infection with respect to transfer (prior to transfer, 1–7 days after transfer, or 8–14 days after transfer) nor the level of fever (no fever, fever <39°C, or fever ≥39°C) was found to be related to pregnancy rates. LIMITATIONS, REASONS FOR CAUTION The retrospective nature of the study is subject to possible selection bias. Additionally, although the sample size was relatively large for the COVID-19 group, the sample sizes for certain subgroups were relatively small and lacked adequate power, so these results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS The study findings suggest that SARS-CoV-2 infection during the FET cycle in females does not affect embryo implantation and pregnancy rates including biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy, indicating that cycle cancellation due to SARS-CoV-2 infection may not be necessary. Further studies are warranted to verify these findings. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key Research and Development Program of China (2023YFC2705500, 2019YFA0802604), National Natural Science Foundation of China (82130046, 82101747), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210201, SHSMU-ZLCX20210200, SSMU-ZLCX20180401), Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003), Science and Technology Commission of Shanghai Municipality (23Y11901400), Shanghai Sailing Program (21YF1425000), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161413). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

We sought to investigate possible impaired hyperaemia during dynamic handgrip exercise (HGE) in young healthy individuals who had recovered from COVID‐19. We tested the vascular function in individuals recovered from COVID‐19 using a nitric oxide donor (i.e., sodium nitroprusside; SNP), which could revert a possible impaired endothelial function during HGE. Further, we tested whether individuals who recovered from COVID‐19 would present exaggerated brachial vascular resistance under an adrenergic agonist (i.e., phenylephrine; PHE) stimuli during HGE. Participants were distributed into two groups: healthy controls (Control; men: n = 6, 30 ± 3 years, 26 ± 1 kg/m2; and women: n = 5, 25 ± 1 years, 25 ± 1 kg/m2) and subjects recovered from COVID‐19 (post‐COVID; men: n = 6, 29 ± 3 years, 25 ± 1 kg/m2; and women: n = 10, 32 ± 4 years, 22 ± 1 kg/m2). Participants in the post‐COVID group tested positive (RT‐PCR) 12–14 weeks before the protocol. Heart rate (HR), brachial blood pressure (BP), brachial blood flow (BBF) and vascular conductance (BVC) at rest were not different between groups. The HGE increased HR (Control: Δ9 ± 0.4 bpm; and post‐COVID: Δ11 ± 0.4 bpm) and BP (Control: Δ6 ± 1 mmHg; and post‐COVID: Δ12 ± 0.6 mmHg) in both groups. Likewise, BBF (Control: Δ632 ± 38 ml/min; and post‐COVID: Δ620 ± 27 ml/min) and BVC (Control: Δ6.6 ± 0.4 ml/min/mmHg; and post‐COVID: Δ6.1 ± 0.3 ml/min/mmHg) increased during HGE. SNP did not change HGE‐induced hyperaemia but did decrease BP, which induced a reflex‐related increase in HR. PHE infusion also did not change the HGE‐induced hyperaemia but raised BP and reduced HR. In conclusion, exercise‐induced hyperaemia is preserved in healthy young subjects 12–14 weeks after recovery from COVID‐19 infection. What is the central question of this study?How does vascular function compare during dynamic handgrip exercise in young healthy adult males and females who recovered from COVID‐19?What is the main finding and its importance?No differences were observed in exercise hyperaemia in healthy young adults, males and females, who recovered from COVID‐19 compared to the healthy control group. Vascular function seems to be preserved in individuals 12–14 weeks after COVID‐19 during dynamic handgrip exercise in young healthy adults, males and females. [ABSTRACT FROM AUTHOR]

Objective: Mathematical models are vital tools to understand transmission dynamics and assess the impact of interventions to mitigate COVID‐19. However, historically, their use in Africa has been limited. In this scoping review, we assess how mathematical models were used to study COVID‐19 vaccination to potentially inform pandemic planning and response in Africa. Methods: We searched six electronic databases: MEDLINE, Embase, Web of Science, Global Health, MathSciNet and Africa‐Wide NiPAD, using keywords to identify articles focused on the use of mathematical modelling studies of COVID‐19 vaccination in Africa that were published as of October 2022. We extracted the details on the country, author affiliation, characteristics of models, policy intent and heterogeneity factors. We assessed quality using 21‐point scale criteria on model characteristics and content of the studies. Results: The literature search yielded 462 articles, of which 32 were included based on the eligibility criteria. Nineteen (59%) studies had a first author affiliated with an African country. Of the 32 included studies, 30 (94%) were compartmental models. By country, most studies were about or included South Africa (n = 12, 37%), followed by Morocco (n = 6, 19%) and Ethiopia (n = 5, 16%). Most studies (n = 19, 59%) assessed the impact of increasing vaccination coverage on COVID‐19 burden. Half (n = 16, 50%) had policy intent: prioritising or selecting interventions, pandemic planning and response, vaccine distribution and optimisation strategies and understanding transmission dynamics of COVID‐19. Fourteen studies (44%) were of medium quality and eight (25%) were of high quality. Conclusions: While decision‐makers could draw vital insights from the evidence generated from mathematical modelling to inform policy, we found that there was limited use of such models exploring vaccination impacts for COVID‐19 in Africa. The disparity can be addressed by scaling up mathematical modelling training, increasing collaborative opportunities between modellers and policymakers, and increasing access to funding. [ABSTRACT FROM AUTHOR]

[Display omitted] • Stachytarpheta cayennensis is used in traditional medicine for COVID-19 treatment. • Butanolic fraction inhibits SARS-CoV-2 gamma and delta variants entry in vitro. • Compounds in the butanol fraction inhibit the spike-ACE2 interaction. • 6-β-hydroxy-ipolamiide exhibited the highest inhibitory activity. The COVID-19 pandemic has emphasized the urgent need for new treatments for SARS-CoV-2, especially with the emergence of variants of concern. These variants can partially evade monoclonal therapeutic or neutralizing antibodies from natural infection or vaccination. Thus, identifying effective treatments against SARS-CoV-2 variants is crucial. Stachytarpheta cayennensis is known for its anti-inflammatory properties and has recently been used to treat COVID-19. In this study, we performed a chemical fractionation of the S. cayennensis extract and evaluated its viral entry inhibition activity using the pseudovirus method. UPLC-ESI-MS analysis was conducted to identify the active components in the fractions. Additionally, molecular docking simulations were performed to assess the effect of the compounds on the interaction between the SARS-CoV-2 spike protein and its human receptor, angiotensin-converting enzyme-2 (ACE2). Our findings revealed that the methanol extract and butanol fraction of S. cayennensis exhibited significant entry inhibitory activity against SARS-CoV-2 gamma and delta VOCs. 6-β-hydroxy-ipolamiide, ipolamiide, and verbascoside/isoverbascoside were identified as the prominent compounds in the butanol fraction. Molecular docking analysis revealed that 6-β-hydroxy-ipolamiide was the most potent inhibitor, while the other compounds also bound to the spike-ACE2 complex, contributing to an additive inhibitory effect. This study revealed the therapeutic potential of S. cayennensis in treating COVID-19 and provided valuable insights into the molecular mechanisms underlying its antiviral activity. [ABSTRACT FROM AUTHOR]

acknowledges that it may be considered on a case-by-case basis. Overall, the article presents a range of perspectives and recommendations from different medical organizations regarding the use of convalescent plasma in immunocompromised patients with COVID-19, highlighting the need for further research and individualized decision-making. [Extracted from the article]

Hypercoagulability is a prominent feature of coronavirus disease 2019 (COVID-19) and can lead to fatal consequences. Although the impact of COVID-19 on several disorders is well-established, its effect on congenital bleeding disorders (CBDs) is not well-documented. To address this ambiguity, a systematic review was conducted on the available studies to determine the impact of COVID-19 and vaccination aimed to prevent COVID-19 on patients with CBDs. We performed a systematic literature review using relevant keywords and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol. We conducted our search on the PubMed, Scopus, and Web of Science databases until July 2023. Out of 31 included studies, 12 case series covering 770 patients with CBD and COVID-19 were further analyzed. The majority of the patients had hemophilia A (n = 352, ∼46%) or hemophilia B (n = 74, ∼10%), while the remaining patients had von Willebrand disease (n = 43, 5.6%) or rare bleeding disorders (n = 27, 3.5%). A total of 25 deaths (3.2%) and 22 intensive care unit admissions (2.8%) were recorded. Bleeding complications were reported in the majority of the 12 case series (n = 7, 58.3%) and in most of the case reports (n = 8, ∼57%), while thrombotic complications were only reported in two studies (16.6%). The mortality rate ranged from 0% in five studies (41.6%) to 5.7% and the rate of hospitalization ranged from 0 to 40%. Bleeding complications were reported in a range of 0 to 81%, while the thrombotic complication rate in one study was 6.9%. The mortality rate varied from 0 to 5.7%, and the hospitalization rate ranged from 0 to 40%. Bleeding complications were reported in a range of 0 to 81%, while the rate of thrombotic complications in one study was 6.9%. Vaccination was reported in five case series, which included 821 patients with CBDs with the majority having hemophilia A (n = 479; 67.2%) and hemophilia B (n = 85; ∼12%). The most frequently reported side effects were myalgia (6.5%), flu-like symptoms (4.8%), fever (4.7%), and headache (4%). COVID-19 in patients with CBDs appears to provoke thrombotic complications and bleeding events more frequently, as well as a higher rate of hospitalization, which may be partially due to the increased risk of bleeding events. Although it seems that patients with CBD have lower mortality rates, further studies are necessary to fully understand this, especially considering comorbidities and low number of available studies. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a previously healthy young male who developed large vessel vasculopathy and recurrent thrombosis after recovering from COVID-19. The patient presented with acute limb pain and was found to have hypercoagulability and evidence of chronic endothelial dysfunction. Radiological and histopathological evidence showed damage to the arterial walls and thrombosis. The study suggests that persistent endothelial dysfunction and hypercoagulability may contribute to post-COVID-19 thrombosis, and further research is needed to understand the mechanisms and identify effective treatments. [Extracted from the article]

Microscopy imaging has enabled us to establish the presence of fibrin(ogen) amyloid (fibrinaloid) microclots in a range of chronic, inflammatory diseases. Microclots may also be induced by a variety of purified substances, often at very low concentrations. These molecules include bacterial inflammagens, serum amyloid A, and the S1 spike protein of severe acute respiratory syndrome coronavirus 2. Here, we explore which of the properties of these microclots might be used to contribute to differential clinical diagnoses and prognoses of the various diseases with which they may be associated. Such properties include distributions in their size and number before and after the addition of exogenous thrombin, their spectral properties, the diameter of the fibers of which they are made, their resistance to proteolysis by various proteases, their cross-seeding ability, and the concentration dependence of their ability to bind small molecules including fluorogenic amyloid stains. Measuring these microclot parameters, together with microscopy imaging itself, along with methodologies like proteomics and imaging flow cytometry, as well as more conventional assays such as those for cytokines, might open up the possibility of a much finer use of these microclot properties in generative methods for a future where personalized medicine will be standard procedures in all clotting pathology disease diagnoses. [ABSTRACT FROM AUTHOR]

There is tremendous interindividual and interracial variability in the outcome of SARS-CoV-2 infection, suggesting the involvement of host genetic factors. Here, we investigated whether IgG allotypes GM (γ marker) 3 and GM 17, genetic markers of IgG1, contributed to the severity of COVID-19. IgG1 plays a pivotal role in response against SARS-CoV-2 infection. We also investigated whether these GM alleles synergistically/epistatically with IGHG3 and FCGR2A alleles—which have been previously implicated in COVID-19—modulated the extent of COVID-19 severity. The study population consisted of 316 COVID-19 patients who needed treatment in the intensive care unit of Hospital Universitario Central de Asturias. All individuals were genotyped for GM 3/17, IGHG3 hinge length, and FCGR2A rs1801274 A/G polymorphisms. Among the 316 critical patients, there were 86 deaths. The risk of death among critical patients was significantly higher in subjects with GM 17 (IgG1) and short hinge length (IgG3). GM 17-carriers were at almost three-fold higher risk of death than non-carriers (p < 0.001; OR = 2.86, CI 1.58–5.16). Subjects with short hinge length of IgG3 had a two-fold higher risk of death than those with medium hinge length (p = 0.01; OR = 2.16, CI 1.19–3.90). GM 3/3 and IGHG3 (MM) genotypes were less frequent among death vs. survivors (9% vs 36%, p < 0.001) and associated with protective effect (OR = 0.18, 95% CI = 0.08–0.39). This is the first report implicating IgG1 allotypes in COVID-19-spurred death. It needs to be replicated in an independent study population. [ABSTRACT FROM AUTHOR]

This retrospective cohort study examined the incidence of post-COVID psychiatric disorders in older adults according to hospitalization status and SARS-CoV-2 variant period in Japan. Claims data, COVID-19 case-related information, and vaccination records were obtained from three Japanese municipalities. We identified individuals aged ≥65 years who had COVID-19 or other respiratory tract infection (RTI) between March 2021 and December 2022. Participants were categorized into non-hospitalized and hospitalized patients, and the study period was divided into the Alpha (March to May 2021), Delta (June to December 2021), Omicron BA.1/BA.2 (January to June 2022), and Omicron BA.5 (July to December 2022) periods. Modified Poisson regression analyses were performed to estimate the incidence rate ratios (IRRs) for the occurrence of psychiatric disorders (organic mental disorders, psychotic disorders, mood disorders, anxiety disorders, and insomnia) three months after COVID-19 (reference: other RTI). For overall psychiatric disorders, we analyzed 19,489 non-hospitalized patients (COVID-19: 6,728, Other RTI: 12,761) and 2925 hospitalized patients (COVID-19: 1,036, Other RTI: 1889). When compared with other RTI cases, COVID-19 cases had significantly lower IRRs for overall psychiatric disorders in both non-hospitalized (IRR: 0.59, P < 0.001) and hospitalized cases (IRR: 0. 83, P = 0.045) during the Omicron BA.1/BA.2 period, but only in non-hospitalized cases (IRR: 0.45, P < 0.001) during the Omicron BA.5 period. The incidences of the individual post-COVID psychiatric disorders varied according to disorder type, hospitalization status, and SARS-CoV-2 variant period. These findings provide a foundation for further research to explore these variations and improve the provision of psychiatric care in future epidemics. [ABSTRACT FROM AUTHOR]

Fingolimod is approved in Italy as a second-line therapy for relapsing–remitting multiple sclerosis (RRMS). Discontinuation of fingolimod may elevate the risk of relapses, typically manifesting after a relatively prolonged drug-free interval and often necessitating high doses of intravenous steroids for management. Similar to other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can act as a trigger for MS relapses. In this context, we present a case of rebound following fingolimod discontinuation during a SARS-CoV-2 infection. Notably, the rebound occurred shortly after stopping the medication and responded effectively to low doses of oral steroids. Our case is discussed in light of existing literature, with speculation on potential mechanisms governing this unconventional disease course rebound. We also consider the possibility that SARS-CoV-2 infection might have contributed to or even triggered the MS relapse. [ABSTRACT FROM AUTHOR]

A preserved sense of smell and taste allows us to understand many environmental "messages" and results in meaningfully improvements to quality of life. With the COVID-19 pandemic, it became clear how important these senses are for social and nutritional status and catapulted this niche chemosensory research area towards widespread interest. In the current exploratory work, we assessed two groups of post-COVID-19 patients who reported having had (Group 1) or not (Group 2) a smell/taste impairment at the disease onset. The aim was to compare them using validated smell and taste tests as well as with brain magnetic resonance imaging volumetric analysis. Normative data were used for smell scores comparison and a pool of healthy subjects, recruited before the pandemic, served as controls for taste scores. The majority of patients in both groups showed an olfactory impairment, which was more severe in Group 1 (median UPSIT scores: 24.5 Group 1 vs 31.0 Group 2, p = 0.008), particularly among women (p = 0.014). No significant differences emerged comparing taste scores between Group 1 and Group 2, but dysgeusia was only present in Group 1 patients. However, for taste scores, a significant difference was found between Group 1 and controls (p = 0.005). No MRI anatomical abnormalities emerged in any patients while brain volumetric analysis suggested a significant difference among groups for the right caudate nucleus (p = 0.028), although this was not retained following Benjamini–Hochberg correction. This exploratory study could add new information in COVID-19 chemosensory long-lasting impairment and address future investigations on the post-COVID-19 patients' research. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO), a gaseous free radical produced from L-arginine catalyzed by NO synthase, functions as an important signaling molecule in the human body. Its antiviral activity was confirmed in the 1990s, and has been studied more extensively since the outbreak of the SARS pandemic in 2003. In the fight against the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, some recent studies have revealed the potential of NO in the treatment of coronavirus disease 2019 (COVID-19). The progress in this field, including several noteworthy clinical trials of inhaled NO for the treatment of COVID-19 and the emergency approval of NO nasal spray by the regulatory agencies of Israel, Bahrain, Thailand and Indonesia for the treatment of COVID-19 pneumonia, offers a new perspective for addressing the raging coronavirus infection and greatly broadens the clinical application of NO therapy. This review aims to explore the underlying molecular mechanisms of NO-based therapy against SARS-CoV-2, including direct viral inhibition, immune regulation, and protection against pulmonary and cardiovascular symptoms. Furthermore, the potential therapeutic applications of inhaled NO, NO donors and drugs involved in the NO pathway are discussed. In the context of a global vaccination campaign and newly proposed strategy of "coexistence with COVID-19," the advantages of NO therapies as symptomatic and adjuvant treatments are expected to deliver breakthroughs in the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

• A comprehensive demonstration of how to characterize and understand the self-assembly behavior of amphiphilic molecules in solution-based parenteral drug products, including CMC determination by DOSY NMR. • An innovative use of computational tools and multiple orthogonal experimental techniques to inform robust drug product design, contribute to impurity control strategies and help enable rapid progression of an anti-infective parenteral drug product to the clinic. • A case study of lipophilic impurity solubilization by prodrug self-assembly that informs when impurities might precipitate, leading to undesired particulate matter formation, for example during dose administration or on stability. PF-07304814 is a water-soluble phosphate ester prodrug of a small molecule inhibitor for the SARS CoV-2 3CL protease designed for the treatment of COVID-19. The amphiphilicity and self-assembly behavior of the prodrug was investigated computationally and experimentally via multiple orthogonal techniques to better design formulations for intravenous infusion. The self-assembly of PF-07304814 into micellar structures enabled an increase in the solubility of lipophilic impurities by up to 1900x in clinically relevant formulations. The observed solubilization could help extend the drug product shelf-life and in use stability through inhibition of precipitation, without the need for solubilizing excipients. The work presented in this manuscript provides a roadmap for the characterization of prodrug self-assembly and highlights the potential for prodrug modifications to enhance solubility of both active ingredients and impurities and to extend drug product shelf-life. [ABSTRACT FROM AUTHOR]

Purpose: Identify variables, including moderating variables, associated with adolescents, young adults, and parents' intention to receive a COVID-19 vaccine in January 2021. Design: Cross-sectional survey. Setting: United States Midwestern academic medical center. Sample: Adolescents (n = 242); young adults (n = 333); parents (n = 563). Measures: Associations between predictors—participant characteristics, general vaccine hesitancy, COVID-19 and vaccine knowledge, perceptions, and normative beliefs—and intention to receive a COVID-19 vaccine (outcome) were assessed. To determine variables impacting the strength of the relationship between predictors and outcome, moderators included 2020/2021 influenza vaccine receipt, having experienced discrimination, and primary sources of information for COVID-19. Analysis: Multivariable logistic regression examined associations, including moderating effects, for adolescents, young adults, parents, and parents for child. Results: With 20,231 email addresses receiving the survey, 1138 participants were included in the analysis. Intention to receive a COVID-19 vaccine was reported by 60.7% adolescents (n = 147), 65.2% young adults (n = 217), and 38.5% parents (n = 217) and 38.2% parents (n = 215) intended to vaccinate their child. Intention was associated with lower general vaccine hesitancy for adolescents (AOR = 1.50), young adults (AOR = 1.39), parents (AOR = 1.18), and parents' intention for their child (AOR = 1.17). Parents citing reputable medical experts as primary source of COVID-19 information positively moderated vaccine perceptions and intention for self (AOR = 8.25) and child (AOR = 6.37). Conclusion: Clinician training to address vaccine hesitancy may be effective at promoting positive COVID-19 vaccine perceptions. [ABSTRACT FROM AUTHOR]

Abstract: The legal neuropsychological assessment of individuals following infection with the Coronavirus disease 2019 (COVID-19) who exhibit potential symptoms of the Post-COVID-Syndrome (PCS) not only requires adherence to local regulations but also consideration of general professional guidelines. The assessment of PCS proves challenging both for the individual and the evaluator in the presence of ambiguous functional deficits or causal relationships. This article offers an overview of pathogenetic findings relevant to legal assessment and reflects on current German regulations and frameworks. In Germany, the legal neuropsychological assessment of PCS should align with guidelines of the Gesellschaft für Neuropsychologie (GNP) and integrate published neurological criteria. As PCS research rapidly advances, an interdisciplinary professional exchange is vital for further refining the legal neuropsychological assessment of PCS. [ABSTRACT FROM AUTHOR]

Abstract: This practice-oriented paper extends the utility of the perspectives of psychiatry model originally developed at Johns Hopkins University to clinical neuropsychology, focusing particularly on its relevance for post-COVID condition (PCC). By integrating the model's four key perspectives – disease, dimension, behavior, and life story – it offers a nuanced and comprehensive understanding of the neuropsychological and somatic symptoms associated with PCC. Our arguments are substantiated by empirical evidence and clinical case studies that demonstrate the model's applicability in crafting targeted therapeutic strategies based on a multidimensional case conceptualization. Overall, the perspectives of psychiatry model emerges as a valuable framework for clinical neuropsychologists, enriching both diagnostic and treatment approaches for complex conditions such as PCC. [ABSTRACT FROM AUTHOR]

Multisystem inflammatory syndrome in children (MIS-C), is a rare but severe, hyperinflammatory complication of COVID-19, in which cardiovascular abnormalities are frequently detected. In this prospective study, we describe the echocardiographic findings in patients with MIS-C, with the use of conventional Echocardiography and Speckle-Tracking Echocardiography (STE) with Left Ventricular (LV) Global Longitudinal Strain (GLS) analysis, in the acute and follow-up phase. In total, 25 MIS-C patients [64% females, mean (± SD) age: 8.3 (± 3.72) years] were included. In the acute phase, median (IQR) Troponin and NT-proBNP and mean heart rate, were 8.07 (14.52) pg/mL, 2875.00 (7713.00) pg/mL, and 102.87 (± 22.96) bpm, respectively. Median (IQR) LV Ejection Fraction (LVEF) was 66 (8)% and LVEF impairment was detected in 2/25 (8%) patients. On follow-up (mean time interval:9.50 ± 4.59 months), heart rate was significantly lower, with a mean value of 90.00 (± 14.56) bpm (p-value = 0.017). Median (IQR) LVEF was 66.00 (6.70)% (p-value = 0.345) and all 25 participants had normal LVEF. In 14/25 patients, additional LV-GLS analysis was performed. During the acute phase, mean LV-GLS was − 18.02 (± 4.40)%. LV-GLS was abnormal in 6/14 patients (42.9%) and among them, only one patient had reduced LVEF. On follow-up (median (IQR) time interval:6.93 (3.66) months), mean LV-GLS was -20.31 (± 1.91)% (p-value = 0.07) and in 1/14 patient (7.1%), the LV-GLS impairment persisted. In conclusion, in the acute and follow-up phase, we detected abnormal LV-GLS values in some patients, in the presence of normal LVEF, indicating that STE-GLS is a valuable tool for identifying subclinical myocardial injury in MIS-C. [ABSTRACT FROM AUTHOR]

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to intranasal inoculation with SARS-CoV-2, they did not show gross phenotypic abnormalities. Next, we generated a Rosa26hACE2;CMV-Cre mouse line that ubiquitously expresses the human ACE2 receptor. By day 3 post infection with SARS-CoV-2, Rosa26hACE2;CMV-Cre mice showed significant weight loss, a variable degree of alveolar wall thickening and reduced survival rates. Viral load measurements confirmed inoculation in lung and brain tissues of infected Rosa26hACE2;CMV-Cre mice. The phenotypic spectrum displayed by our different mouse models translates to the broad range of clinical symptoms seen in the human patients and can serve as a resource for the community to model and explore both treatment strategies and long-term consequences of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background: It was evidenced that cetylpyridinium‐chloride (CPC) mouthwash could inhibit SARS‐COV‐2 activity and reduce salivary viral load, thus reducing SARS‐CoV‐2 transmission. However, due to insufficient residence time in the oral cavity, CPC‐containing mouthwashes have no prolonged antiviral effect. The duration of action of the CPC buccal tablet is expected to be longer than that of the mouthwash. However, there are currently no reports on the salivary drug concentration of CPC buccal tablets. Objective: The study aimed to investigate the salivary drug concentration of CPC buccal tablets and the antiviral effect of CPC on SARS‐CoV‐2 in vitro. Trial design: This is a single‐dose, single‐arm clinical trial, involving 10 Chinese healthy subjects who received 2‐mg CPC buccal tablet to collect saliva samples and to detect saliva concentration at different timepoints within 2 h (Clinical Trial Registration Number: NCT05802628, Registration Date: April 6, 2023). Materials and methods: CPC concentration in saliva was detected by liquid chromatography tandem mass spectrometry (LC–MS/MS), and pharmacokinetic parameters were calculated based on the non‐compartmental model. With an in vitro antiviral experiment, the activity of CPC buccal tablets against SARS‐CoV‐2 and its cellular toxicity was tested. Results: Drug concentrations in saliva at 15 min, 30 min, 1 h, 1.5 h, and 2 h after administration were 8008.33 (1042.25, 41081.11), 2093.34 (373.15, 5759.83), 1016.58 (378.66, 3480.68), 891.77 (375.66, 6322.07), and 717.43 (197.87, 2152.71) ng/mL. PK parameters of saliva concentration: Cmax = 8008.33 (1042.25, 41081.11) ng/mL, AUC0‐t = 4172.37 (904.42, 13912.61) ng/mL * h, AUC0‐∞ = 6712.85 (1856.77, 19971.12) ng/mL * h, T1/2 = 1.22 (0.59, 2.83) h, Tmax = 0.25 (0.25, 0.25) h. As determined in in vitro experiment, CPC was active on SARS‐CoV‐2 with cytotoxic and inhibitory activity of CC50 = 35.75 μM (≈12155 ng/mL) and EC50 = 7.39 μM (≈2512.6 ng/mL). Conclusions: The comparison between the salivary CPC concentration and EC50/CC50 values from in vitro antiviral experiments suggests that CPC buccal tablets may inhibit SARS‐CoV‐2 activity, and the inhibition may last for approximately 30 min without cytotoxicity. [ABSTRACT FROM AUTHOR]

Background: "Herd immunity" became a contested term during the COVID‐19 pandemic. Although the term "herd immunity" is often used to refer to thresholds at which some diseases can be eliminated (e.g., due to mass vaccination), the term has multiple referents. Different concepts of herd immunity have been relevant throughout the history of immunology and infectious disease epidemiology. For some diseases, herd immunity plays a role in the development of an endemic equilibrium, rather than elimination via threshold effects. Methods: We reviewed academic literature from 1920 to 2022, using historical and philosophical analysis to identify and develop relevant concepts of herd immunity. Results: This paper analyses the ambiguity surrounding the concept of herd immunity during the pandemic. We argue for the need to recapture a long‐standing interpretation of this concept as one of the factors that leads to a dynamic endemic equilibrium between a host population and a mutating respiratory pathogen. Conclusions: Informed by the history of infectious disease epidemiology, we argue that understanding the concept in this way will help us manage both SARS‐CoV‐2 and hundreds of other seasonal respiratory pathogens with which we live but which have been disrupted due to sustained public health measures/non‐pharmaceutical interventions targeting SARS‐CoV‐2. [ABSTRACT FROM AUTHOR]

Background: Classical pulmonary thromboembolism (TE) and local pulmonary thrombosis (PT) have been suggested as mechanisms of thrombosis in COVID‐19. However, robust evidence is still lacking because this was mainly based on retrospective studies, in which patients were included when TE was suspected. Methods: All patients with COVID‐19 pneumonia underwent computed tomography and pulmonary angiography in a prospective study. The main objective was to determine the number and percentage of thrombi surrounded by lung opacification (TSO) in each patient, as well as their relationship with percentage of lung involvement (TLI), to distinguish classical TE (with a random location of thrombi that should correspond to a percentage of TSO equivalent to the TLI) from PT. We determined TLI by artificial intelligence. Analyses at patient level (TLI and percentage of TSO) and at thrombi level (TLI and TSO) were performed. Results: We diagnosed TE in 70 out of 184 patients. Three (2–8) thrombi/patient were detected. The percentage of TSO was 100% (75–100) per patient, and TLI was 19.9% (4.6–35.2). Sixty‐five patients (92.9%) were above the random scenario with higher percentage of TSO than TLI. Most thrombi were TSO (n = 299, 75.1%). When evaluating by TLI (<10%, 10%–20%, 20%–30% and >30%), percentage of TSO was higher in most groups. Thrombi were mainly in subsegmental/segmental arteries, and percentage of TSO was higher in all locations. Conclusions: Thrombi in COVID‐19 were found within lung opacities in a higher percentage than lung involvement, regardless of TLI and clot location, supporting the hypothesis of local PT rather than "classic TE". [ABSTRACT FROM AUTHOR]

The aim of this study was to provide a scoping and comprehensive review for the clinical outcomes from the cross-link of Type 2 diabetes mellitus (T2DM), COVID-19, and sarcopenia. By using PRISMA guidelines and searching through different databases that could provide findings of evidence on the association of T2DM, COVID-19, and sarcopenia. Thirty-three studies reported a relationship between sarcopenia with T2DM, twenty-one studies reported the prognosis COVID-19 in patients with T2DM, ten studies reported the prognosis of COVID-19 in patients with sarcopenia, five studies discussed the outcomes of sarcopenia in patients with COVID-19, and one study reported sarcopenia outcomes in the presence of T2DM and COVID-19. There is an obvious multidimensional relationship between T2DM, COVID-19 and sarcopenia which can cause prejudicial effects, poor prognosis, prolonged hospitalisation, lowered quality of life and a higher mortality rate during the current COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Context: Patients with inflammatory bowel disease (IBD) were found to have the higher intestinal expression of Angiotensin-Converting Enzyme2 (ACE2) that could consequently increase susceptibility to COVID-19 infection. Objective: This study reports the outcomes of COVID-19 infection in a large cohort of IBD patients. We compare levels of serum ACE and IFN-α between COVID19 patients with and without IBD. We performed a cross-sectional retrospective multicenter study. Methods: We enrolled patients with IBD screened for SARS-COV-2 in six medical centres in Iran from June to November 2020. The blood samples were drawn to measure COVID-19 IgM and IgG, and serum levels of sACE2, sACE1, and interferon-α, regardless of suspicious symptoms have done the molecular test. Results: A total of 534 IBD patients were included in the study. Of these, 109 (20.0%) cases had detectable IgG and IgM against SARS-CoV-2. sACE2 levels were higher in IBD patients than controls, whereas ACE1and IFN-α levels were similar among groups. [ABSTRACT FROM AUTHOR]

This study explored the coronavirus disease 2019 (COVID-19) vaccination coverage among children with epilepsy (CwE), factors affecting vaccination coverage, and the effect of COVID-19 vaccines on epilepsy after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A questionnaire was administered to CwE and their parents at the Pediatric Neurology Clinic of the Second Affiliated Hospital of Xi'an Jiaotong University between December 12, 2022, and February 28, 2023. Data were analyzed using the t-tests, chi-square tests, and logistic regression. The analysis included 250 CwE who responded to the survey; of these, 152 (60.8%) had been vaccinated against COVID-19. COVID-19 vaccine hesitancy in parents whose CwE were not vaccinated was mostly due to concerns of vaccine-related exacerbation of seizures and of vaccine-related adverse reactions (44.30% and 41.90% of the respondents, respectively). Univariate analysis showed that vaccination and number of doses of vaccine did not affect seizure incidence within 1 month of SARS-CoV-2 infection. Logistic regression analysis showed that CwE below primary school age, and those taking two or more antiseizure medication (ASMs) were less likely to be vaccinated (p = 0.007). Conclusion: The primary reasons for vaccine hesitancy among parents of unvaccinated CwE were concerns regarding seizure exacerbation and adverse reactions following COVID-19 vaccination. CwE who were below primary school age and those who took two or more ASMs were less likely to be vaccinated. Addressing parents' concerns is necessary to build their confidence in COVID-19 vaccines and ensure that CwE are vaccinated. What is Known: • People with epilepsy have a higher risk of severe and fatal COVID-19 than those without epilepsy but, despite this, COVID-19 vaccination coverage is considerably lower in people with epilepsy than in people without epilepsy. What is New: • In unvaccinated children with epilepsy, the foremost reasons for COVID-19 vaccine hesitancy among parents were concerns about seizure exacerbation and vaccine-related adverse reactions. • Vaccination and number of doses of vaccine did not exacerbate seizures in children with epilepsy, those below primary school level and those taking two or more antiseizure medications were less likely to be vaccinated. [ABSTRACT FROM AUTHOR]

The purpose of the study was to assess and compare short- and long-term cardiac complications of the multisystem inflammatory syndrome in children (MIS-C) by predominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants throughout the pandemic. The analysis of prospectively collected data comparing cardiac complications of MIS-C during and after hospitalization across the original/alpha, delta, and omicron waves. Cardiac complications were defined as cardiac failure with systolic function impairment or hypotension or abnormalities in echocardiographic findings (decrease in LVEF, FS, valvular insufficiency, pericardial effusion, or coronary artery abnormalities). A total of 120 patients with MIS-C admitted to the Children's Hospital of Krakow between November 1, 2020, and May 5, 2023, were included in the study (74 during original/alpha dominance, 31 delta, and 15 omicron). Patients in the omicron group were found to be younger than those in the alpha and delta groups (37 vs. 75 vs. 80 months, p = 0.03). The frequency of cardiac failure with systolic function impairment or hypotension was diagnosed more frequently in the original/alpha and delta groups than in the omicron group (44.59% vs. 41.94% vs. 13.33%, p = 0.08) also echocardiographic abnormalities changed, with rates of 60.8%, 35.5%, and 13.3% (p < 0.001) accordingly. The multivariable regression revealed an older age (OR = 1.19, 95% CI = 1.07–1.33, p = 0.002) as the only independent factors of cardiac failure with systolic function impairment or hypotension. In all patients, signs of cardiac failure resolved during the hospitalization. Moreover, in 98.3% of patients, all echocardiagraphic abnormalities resolved completely during the observation period. Conclusion: The cardiac complications of MIS-C appeared to advance less severely in younger children during the Omicron outbreak. In long-term observation, symptoms of cardiac failure resolve completely. Similarly, also echocardiographic abnormalities normalize in the vast majority of patients. What is Known: • Knowledge about the long-term cardiac complications of MIS-C is still evolving and uncertain. • The greatest concern of MIS-C is cardiac complications, including cardiac failure and coronary artery dilatation. What is New: • Long-term observations revealed complete resolution of cardiac complications in the vast majority of patients with MIS-C, irrespective of the dominant variant. • Cardiac complications of MIS-C were less common in younger children during subsequent pandemic waves in our patient population. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to provide insights to the characteristics of headache in the context of COVID‐19 on behalf of the Headache Scientific Panel and the Neuro‐COVID‐19 Task Force of the European Academy of Neurology (EAN) and the European Headache Federation (EHF). Methods: Following the Delphi method the Task Force identified six relevant questions and then conducted a systematic literature review to provide evidence‐based answers and suggest specific diagnostic criteria. Results: No data for facial pain were identified in the literature search. (1) Headache incidence during acute COVID‐19 varies considerably, with higher prevalence rates in prospective compared to retrospective studies (28.9%–74.6% vs. 6.5%–34.0%). (2) Acute COVID‐19 headache is usually bilateral or holocranial and often moderate to severe with throbbing pain quality lasting 2–14 days after first signs of COVID‐19; photo‐phonophobia, nausea, anosmia and ageusia are common associated features; persistent headache shares similar clinical characteristics. (3) Acute COVID‐19 headache is presumably caused by immune‐mediated mechanisms that activate the trigeminovascular system. (4) Headache occurs in 13.3%–76.9% following SARS‐CoV‐2 vaccination and occurs more often amongst women with a pre‐existing primary headache; the risk of developing headache is higher with the adenoviral‐vector‐type vaccines than with other preparations. (5) Headache related to SARS‐CoV‐2 vaccination is mostly bilateral, and throbbing, pressing, jolting or stabbing. (6) No studies have been conducted investigating the underlying mechanism of headache attributed to SARS‐CoV‐2 vaccines. Conclusion: The results of this joint EAN/EHF initiative provide a framework for a better understanding of headache in the context of SARS‐CoV‐2 infection and vaccination. [ABSTRACT FROM AUTHOR]

Saccharomyces cerevisiae has been demonstrated to be an excellent platform for the multi-fragment assembly of large DNA constructs through its powerful homologous recombination ability. These assemblies have invariably used the stable centromeric single copy vectors. However, many applications of these assembled genomes would benefit from assembly in a higher copy number vector for improved downstream extraction of intact genomes from the yeast. A review of the literature revealed that large multi-fragment assemblies did not appear to have been attempted in multicopy vectors. Therefore, we devised a toolkit that would enable one to seamlessly transition with the same assembling fragments between a single copy and a multicopy vector. We evaluated the assembly of a 28 kb attenuated SARS-CoV-2 genome (lacking the N gene) from 10 fragments in both single copy and multicopy vector systems. Our results reveal that assembly was comparably efficient in the two vector systems. The findings should add to the synthetic biology toolkit of S. cerevisiae and should enable researchers to utilize any of these vector systems depending on their downstream applications. [ABSTRACT FROM AUTHOR]

As we know the recent pandemic, coronavirus disease (COVID-19) due to SARS CoV-2 virus has led to an increase in the consumption of various drugs as medicines by the patients. Paracetamol (acetaminophen, APAP) act as an emerging contaminant classified among the class pharmaceutical and personal care pollutant (PPCP) and is detected in wastewater and sewage systems. The enrichment culture approach was used for the isolation APAP-degrading bacterium wastewater sample. Microscopic examination, biochemical and 16S rRNA sequence analysis showed that the isolate PYP-2 belongs to the Bacillus pumilus strain. Shake flask and batch culture degradation studies have shown that the strain can degrade APAP. Further, the response surface methodology (RSM) plot was used to know the best physical condition for biodegradation by optimization study. The optimum pH of 5.0, temperature of 30 °C, agitation speed of 146 rpm, and APAP 267 mg/L concentration were reported for PYP-2-based degradation. Bacterial biomass kinetic analysis was performed at the best physical condition, and the results showed that the specific growth rate (µ) was 713 mg/L. Oxalic acid, 2-isopropyl-5-methyl cyclohexanone, and phenothiazine were the intermediates of the APAP degradation pathway detected by the GC-MS chromatogram peaks. Therefore, this research has shown that Bacillus pumilus strain PYP-2 has the metabolic capacity to biodegrade APAP, providing new tools for bioremediation. [ABSTRACT FROM AUTHOR]

Background: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID‐19 have substantial morbidity and mortality related to SARS‐CoV‐2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID‐19 vaccination series in pediatric KTRs. Methods: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID‐19 were enrolled and data were collected pertaining to SARS‐CoV‐2 infection incidence and severity, graft outcomes and post‐vaccination safety profile, as well as overall patient survival. Results: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5–15). SARS‐CoV‐2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post‐transplant, within the defined follow‐up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor‐specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA‐tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed. Conclusions: Observationally, infectious outcomes of SARS‐CoV‐2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort. [ABSTRACT FROM AUTHOR]

Introduction: AZD7442 is a combination of two neutralizing antibodies (tixagevimab/cilgavimab) with demonstrated efficacy in reducing the risk of symptomatic coronavirus disease 2019 (COVID-19) among individuals at high risk of severe COVID-19 ≤ 6 months after administration. On February 15, 2022, the Israeli Ministry of Health (IMoH) authorized the administration of 300 mg AZD7442 as pre-exposure prophylaxis (PrEP) against severe acute respiratory syndrome coronavirus 2 infection among immunocompromised individuals aged ≥ 12 years. This study describes the real-world uptake of AZD7442 in Israel. Methods: This descriptive, observational study analyzed data from Israel's largest health maintenance organization, Clalit Health Services (CHS). Individuals were assessed for AZD7442 eligibility between February 13 and December 11, 2022, and were included if they were aged ≥ 12 years, had ≥ 1 year of continuous CHS membership, had ≥ 1 moderate or severe immunocompromising condition, and were eligible for AZD7442 per IMoH recommendations during this time frame. Results: Overall, 19,161 AZD7442-eligible individuals with immunocompromising conditions were identified during the study period; 2829 (14.8%) received AZD7442. A higher proportion of individuals receiving AZD7442 were older (aged ≥ 65 years), male, not current smokers and residents in large cities; required more physician visits (> 50 visits); and had ≥ 1 COVID-19 hospitalization over 12 months, while uptake was lowest among ultra-orthodox Jewish individuals. AZD7442 uptake was also higher among individuals with multiple comorbidities (Charlson Comorbidity Index ≥ 5), including hypertension, diabetes and chronic kidney disease. In specific immunocompromised types, AZD7442 uptake was highest among individuals with lung transplantation (41%), primary immunodeficiency (32%), bone marrow transplantation (29%) and multiple myeloma (25%) or those receiving anti-CD20 therapy (26%) and was lowest in individuals with lymphoma (8%). Conclusion: These results show AZD7442 uptake among the eligible population of Israel in 2022 was relatively low, at 14.8%. Uptake was generally higher among immunocompromised individuals who may be perceived to be frail or at highest risk of COVID-19 infection and complications, although at 25–41%, further improvements in uptake would be more impactful. These results also indicate there is opportunity to expand AZD7442 uptake across immunocompromised groups and ensure more equitable uptake among some other sociodemographic groups. Overall, this study will help inform and reassess future implementation strategies for vulnerable populations. [ABSTRACT FROM AUTHOR]

Introduction: The phase 3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies. Methods: In PROVENT, participants were randomized 2:1 to receive 300 mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8 days of exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300 mg AZD7442 (n = 749) or placebo (n = 372). Results: In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day 183 (95% CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day 366 (95% CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day 366 (95% CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95% CI − 25.9, 64.7; p = 0.212), 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day 366 (95% CI − 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day 366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration–time profiles over 457 days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90 days). Conclusion: This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article. Clinicaltrials.gov Identifiers: PROVENT (NCT04625725) and STORM CHASER (NCT04625972). Plain Language Summary: Antibodies are proteins produced by the body's immune system to specifically target foreign substances, such as viruses. AZD7442 is made up of an antibody pair (tixagevimab and cilgavimab) that specifically bind and neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). AZD7442 was designed to give several months of protection against the virus. These antibodies were tested in two clinical trials to see if they could either protect people from getting COVID-19 (PROVENT trial) or prevent people already exposed to SARS-CoV-2 from getting COVID-19 (STORM CHASER trial). In the two trials, approximately 6000 adults received AZD7442 or placebo (injections that look exactly like AZD7442 but contain no medicine). Protection against COVID-19 was monitored for up to 1 year, and safety for up to 15 months. The percentage of trial participants who reported side effects was similar in the AZD7442 and placebo groups, in both trials. The PROVENT trial showed that AZD7442 reduced the risk of getting COVID-19 up to 6 months and protected against severe COVID-19 for up to 1 year. In STORM CHASER, participants were treated after SARS-CoV-2 exposure but before a positive COVID-19 test. Some participants were already infected with SARS-CoV-2 at the start of the trial, others were not. STORM CHASER showed that AZD7442 protected people against COVID-19 for up to 6 months if they were not already infected at the start. The results of these trials provide proof of concept to support the long-term safety of AZD7442 for the prevention of COVID-19. [ABSTRACT FROM AUTHOR]

Background and Objectives: Clinical manifestations of coronavirus disease 2019 (COVID-19) often persist after acute disease resolution. Underlying molecular mechanisms are unclear. The objective of this original article was to longitudinally measure plasma levels of markers of the innate immune response to investigate whether they associate with and predict post-COVID symptomatology. Methods: Adult patients with previous severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during the first pandemic wave who underwent the 6-month multidisciplinary follow-up were included. Plasma levels of pentraxin 3 (PTX3), the complement components C3a and C5a, and chitinase-3 like-protein-1 (CHI3L1) were measured at hospital admission during acute disease (baseline) and at 1 and 6 months after hospital discharge. Associations with post-COVID-19 sequelae at 6 months were investigated using descriptive statistic and multiple regression models. Results: Ninety-four COVID-19 patients were included. Baseline PTX3, C5a, C3a, and CHI3L1 did not predict post-COVID-19 sequelae. The extent of the reduction of PTX3 over time (delta PTX3) was associated with lower depressive and anxiety symptoms at 6 months (both p < 0.05). When entering sex, age, need for intensive care unit or non-invasive ventilation during hospital stay, psychiatric history, and baseline PTX3 as nuisance covariates into a generalized linear model (GLM), the difference between baseline and 6-month PTX3 levels (delta PTX3) significantly predicted depression (χ2 = 4.66, p = 0.031) and anxiety (χ2 = 4.68, p = 0.031) at 6 months. No differences in PTX3 levels or PTX3 delta were found in patients with or without persistent or new-onset other COVID-19 symptoms or signs at 6 months. Plasma levels of C3a, C5a, and CHI3L1 did not correlate with PTX3 levels at either time point and failed to associate with residual or de novo respiratory or systemic clinical manifestations of the disease at 6 months. Conclusions: A lower reduction of plasma PTX3 after acute COVID-19 associates with the presence of depression and anxiety, suggesting an involvement of inflammation in post-COVID-19 psychopathology and a potential role of PTX3 as a biomarker. [ABSTRACT FROM AUTHOR]