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Background: Hemodialysis patients exhibit a reduced response to vaccination and have different vaccine dose regimens. Vaccines induce antibodies and affect the inflammatory balance through antibody glycosylation and effector functions. Therefore, we aimed to analyze the antibody glycosylation profiles in hemodialysis patients who were vaccinated against severe acute respiratory syndrome coronavirus 2, infected with the virus, or both, and compare them with those of dialysis patients in a control group. Methods: Plasma samples from 112 hemodialysis patients were assigned to four groups: control, infected, vaccinated, and post-vaccine-infected. Paired plasma samples from 47 people with vaccination (vaccinees) were analyzed before and after the booster dose. The same analytical approach was applied to the four groups for a cross-sectional comparison. Results: Our study found that both vaccination and infection groups showed decreased fucosylation of IgG1, which is associated with a proinflammatory biosignature. However, vaccination also leads to increased galactosylation and bisection of IgG antibodies, which are associated with anti-inflammatory effects and the additional regulation of immune responses. In contrast, infection led to an additional decrease in the fucosylation of IgG2 and IgA, demonstrating a more intense proinflammatory biosignature than vaccination. Conclusions: Our findings emphasize the proinflammatory biosignature of afucosylation in both vaccination and infection groups. Additionally, we uncovered further regulated profiles related to galactosylation in vaccinees. These findings suggest that antibody investigation for vaccination or infection should not solely focus on neutralization but should also consider effector function-related glycosylation profiling. This comprehensive information can be valuable for fine-tuning vaccine development in the future.

Background: Little is known about the dermatologic manifestations of multisystem inflammatory syndrome in children (MIS-C) in children and adolescents. Objective: We sought to describe the demographic background, key clinical features, and the clinical consequences of developing rash manifestations in MIS-C patients at Texas Children’s Hospital. Methods: Descriptive retrospective cohort study of 290 hospitalized eligible patients between May 2020 and April 2022. Results: Among MIS-C patients, 51% exhibited a rash. We found that younger children (8.62 vs 9.49 years of age, P = .006) and White children (P = .002) had a higher likelihood of developing a rash in association with MIS-C. Additionally, patients without a rash had increased maximum troponin levels (0.11 ng/mL vs 0.07 ng/mL, P = .02) and a higher incidence of cardiac involvement (83.1% vs 72.3%, P = .03) compared to those with a rash but did not significantly affect the length of hospital stay or clinical course. The most commonly observed rash was an erythematous and maculopapular rash on the trunk and/or extremities. Limitations: Rash characteristics were initially described by a variety of physicians in the pediatric primary care services. Conclusion: Rash manifestations in MIS-C patients are associated with lower cardiac involvement and decreased troponin levels.

Background: The emergence of SARS-CoV-2 in late 2019 sparked the global COVID-19 pandemic, leading to varied vaccine policies worldwide. The evolving patterns of respiratory pathogens, aside from SARS-CoV-2, during the pandemic have had a significant impact on the development of vaccine strategies. Methods: This study explores the landscape of respiratory pathogens, encompassing SARS-CoV-2, respiratory syncytial virus (RSV), and influenza viruses, through a retrospective analysis of data obtained from the BioFire Respiratory Panel 2.1 (RP 2.1) at China Medical University Hospital (Taichung, Taiwan) spanning from January 2020 to November 2023. Results: Among the 7950 respiratory samples studied, pediatric cases exhibited higher positivity (64.9%, 2488/3835) and mixed detection rates (43.8%, 1090/2488) than adults. Annual mixed detection rates increased (27.9–48%). Prevalence analysis revealed diverse patterns across age groups, with higher rates in pediatrics. Notably, human rhinovirus/enterovirus predominated (48.1%). Mixed detection illustrated viral co-detections, notably with parainfluenza viruses and adenovirus. Government policies and pandemic dynamics influenced infection patterns, with RSV resurgence after May 2022. Age-specific RSV detection demonstrated a shift, influencing vaccine considerations. Amid global vaccine initiatives, RSV's increasing trend in adults warrants attention. Conclusions: This comprehensive analysis emphasizes the importance of multiplex PCR testing in shaping targeted vaccination strategies during evolving respiratory pathogen landscapes.

Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking. Materials and Methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code. Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58–0.85]; P = 4 ×10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 - 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

The severe respiratory effects of the coronavirus disease 2019 (COVID-19) pandemic have necessitated the immediate development of novel treatments. The majority of COVID-19-related fatalities are due to acute respiratory distress syndrome (ARDS). Consequently, this virus causes massive and aberrant inflammatory conditions, which must be promptly managed. Severe respiratory disorders, notably ARDS and acute lung injury (ALI), may be treated safely and effectively using cell-based treatments, mostly employing mesenchymal stem cells (MSCs). Since the high potential of these cells was identified, a great deal of research has been conducted on their use in regenerative medicine and complementary medicine. Multiple investigations have demonstrated that MSCs and their products, especially exosomes, inhibit inflammation. Exosomes serve a critical function in intercellular communication by transporting molecular cargo from donor cells to receiver cells. MSCs and their derived exosomes (MSCs/MSC-exosomes) may improve lung permeability, microbial and alveolar fluid clearance, and epithelial and endothelial repair, according to recent studies. This review focuses on COVID-19-related ARDS clinical studies involving MSCs/MSC-exosomes. We also investigated the utilization of Nano-delivery strategies for MSCs/MSC-exosomes and anti-inflammatory agents to enhance COVID-19 treatment.

Risk of cardiovascular events is increased after COVID-19. However, information on cardiovascular risk trends after COVID-19 infection is lacking and estimates by sex are inconsistent. Our aim was to examine cardiovascular outcomes and mortality in a large cohort (164,346 participants) of SARS-CoV-2 positive individuals compared to non-positive individuals, stratified by sex. Data were obtained from the Spanish Health System’s electronic medical records. Selected individuals were ≥ 45 years old with/without a positive SARS-CoV-2 test in the period March-May 2020. Follow-up was obtained until January 31, 2021, for cardiovascular events (angina/myocardial infarction, arrhythmias, bypass/revascularization, heart failure, peripheral artery disease, stroke/transient ischemic attack, and thrombosis), and until March 31, 2021, for mortality. Individuals were matched by propensity score. Incidence of cardiovascular events and mortality was compared with accelerated failure time models. The effect of matching and of COVID-19 severity was assessed with sensitivity analyses. In the first 3 months of follow-up, SARS-CoV-2 positive individuals had a higher risk of mortality and of all cardiovascular events. From 4–12 months, there was increased risk of mortality in SARS-CoV-2 positive individuals overall, of heart failure in SARS-CoV-2 positive females (HR= 1.26 [1.11–1.42]), and of arrhythmias and thrombosis in SARS-CoV-2 positive males (HR= 1.29 [1.14–1.47] and HR= 1.35 [1.03–1.77], respectively). When COVID-19 patients admitted to the ICU were excluded, incidence of thrombosis was similar in males regardless of positive/non-positive SARS-CoV-2 status. In the full year of follow-up, increased incidence of heart failure and of arrhythmias and thrombosis was observed in SARS-CoV-2 positive females and males, respectively.

Summary: Background and Aims: Passive transfer of antibodies through breastfeeding is a potential mode of protection for newborns and infants following maternal SARS-CoV-2 infection. The primary goal of this study was to evaluate and characterize SARS-CoV-2 Spike (S)-specific antibodies in human milk samples collected longitudinally from a cohort of convalescent mothers. Methods: SARS-CoV-2 infected participants enrolled in this study were lactating women aged 29–36 years with a confirmed COVID-19 diagnosis who donated milk samples at intervals over the six-month study period. Samples were evaluated for antibody subclass SARS-Cov-2 S glycoprotein binding activity by ELISA, and for the capacity of antibodies purified from these samples to mediate neutralizing antibody (nAb) activity in S pseudovirus inhibition assays and phagocytic activity in an antibody-dependent phagocytosis assay. Results: Robust S-reactive IgM, IgG and IgA ELISA titers were found at day 7 after enrollment, with IgG and IgA levels persisting through 6 months. The majority of S-reactive IgA in milk was secretory in nature. Strong IgG (mean IC50 value 29.19μg/ml) and IgA (mean IC50 value 10.17μg/ml) nAb activity was found in all convalescent samples at 14 days with a decline by 3 months after the onset of symptoms but was not seen in pre-pandemic controls. Both IgG and IgA antibodies mediated phagocytic activity in samples from all subjects by day 14 after the onset of symptoms. Conclusions: Our findings indicate that human milk from SARS-CoV-2 infected mothers have the capacity to transfer SARS-CoV-2-specific antibodies capable of mediating multiple functional activities to newborns via breastfeeding.

Coronavirus disease 2019 (COVID-19) is a viral pandemic and a matter of concern. It also mimics viral pneumonia with cough and fever but also causes severe sequels and various complications. Subdural empyema is a very rare brain infection presenting mostly with fever, weakness, and altered level of consciousness, and has been recently noted as a new complication of COVID-19. This report presents 3 cases of subdural empyema with a prior history of COVID-19. The first case is a 17-year-old female presented with a 1-week history of severe progressive headache, right-sided ptosis, and left-sided hemiplegia with a history of COVID-19 in about 40 days before admission. The second one is a 41-year-old female presented with a 2-week history of fatigue, severe progressive headache which deteriorated while sitting, left tarsal swelling, and left-sided hemiparesis accompanied by drowsiness since 1 day before admission and a history of COVID-19 in about 50 days before admission. The third one is a 47-year-old gentleman with a known case of epilepsy, who presented with a 2-day history of headache and fever and an event of Generalized Tonic Colonic (GTC) seizure on the day of admission. The patient had a history of multiple head traumas during past years, which led to craniectomy, and also a history of COVID-19 about 46 days before admission. Emergent surgery was performed to evacuate empyema, and patients underwent subsequent anti-bacterial treatment. All patients showed clinical improvement. This report highlights a potential link between SARS-COV-2 infection and the patient's development of subdural empyema.

Background: Data on SARSCoV-2 infection in children with hematological malignancies (HM) are limited. Here, we describe the clinical features of children with HM after SARS-CoV-2 infection and investigate the potential risk factors for disease severity. Methods: Children with HM and SARS-CoV-2 infection from five hospitals in five cities in Henan, China from October 2022 to January 2023 were retrospectively included. Clinical information and Coronavirus disease 2019 (COVID-19) vaccination status were collected for further analyses. Results: A total of 285 children with HM and SARS-CoV-2 infections were included. COVID-19 was asymptomatic in 3.2% of the patients (n = 9), mild in 89.1% (n = 254), moderate in 5.3% (n = 15), severe in 1.8% (n = 5), and critical in 0.7% (n = 2). Fever (92.4%) and cough (56.9%) were the most common symptoms. Most (249, 88.3%) children were managed at home during their COVID-19 illness. Of the 36 children admitted to the hospital, two required intensive care unit care, 11 required supplementary oxygen, and two non-invasive ventilation. A total of 283 (99.3%) children fully recovered and two (0.7%) died due to COVID-19. Significant risk factors for increased severity of infection in multivariable analyses were the presence of comorbidity (OR, 10.4; 95%CI, 2.8–38.7; p

Introduction and aims: Pandemic lockdown measures are a cause of concern, regarding their negative impact on the mental health of individuals. The results of numerous studies have associated the appearance of gastrointestinal symptoms with different psychologic disorders, such as stress, depression, and anxiety, due to gut-brain axis interaction. The aim of the present study was to determine the prevalence of, and factors associated with, gastrointestinal symptom onset related to the COVID-19 pandemic lockdown and various lifestyle modifications. Methods: An analytic, observational, and cross-sectional study was conducted on an open population that agreed to participate within the time frame of January to May 2021. Results: A total of 298 subjects, 165 of whom were women (55.4%), agreed to participate and the mean patient age was 36.1 ± 12.6 years. There was a significant increase in the frequency of several gastrointestinal symptoms: epigastric burning, early satiety, heartburn, regurgitation, constipation, and diarrhea. Changes in weight and modifications in lifestyle were found to be associated variables. Conclusions: The results of this study showed a significant increase in a wide variety of gastrointestinal symptoms related to lifestyle changes due to the pandemic lockdown. Weight change, supplement and multivitamin intake, and reduced physical activity were the main associated risk factors. Public healthcare systems should take a multidisciplinary approach into consideration for the care of affected individuals. Resumen: Antecedentes: Las medidas de confinamiento pandémico han generado preocupaciones sobre su impacto en la salud mental de las personas. La aparición de síntomas gastrointestinales ha sido asociada en múltiples estudios con diversos trastornos psicológicos como el estrés, la depresión y la ansiedad, debido a la interacción del eje intestino-cerebro. Este estudio tuvo como objetivo determinar la prevalencia y los factores asociados con el inicio de síntomas gastrointestinales relacionados con el confinamiento por la pandemia de COVID-19 y varias modificaciones en el estilo de vida. Métodos: Se realizó un estudio observacional, transversal y analítico en una población abierta que aceptó participar entre enero y mayo de 2021. Resultados: Doscientos noventa y ocho sujetos aceptaron participar, 165 mujeres (55,4%); la edad promedio fue de 36.1 ± 12.6 años, se observó un aumento significativo en la frecuencia de varios síntomas gastrointestinales: ardor epigástrico, saciedad temprana, acidez, regurgitación, estreñimiento y diarrea. Los cambios en el peso y las modificaciones en el estilo de vida se encontraron como variables asociadas. Conclusiones: En este estudio, se encontró un aumento significativo en una amplia variedad de síntomas gastrointestinales relacionados con modificaciones en el estilo de vida debido al confinamiento. Los cambios en el peso, la ingesta de suplementos y multivitaminas, y la disminución de la actividad física fueron los principales factores de riesgo asociados. Los sistemas de salud pública deben tener en cuenta un enfoque multidisciplinario para el cuidado de estas personas.

Detecting anti-PF4 antibodies remains the golden diagnostic method for heparin-induced thrombocytopenia (HIT) diagnosis with high sensitivity and specificity. Various lab tests detect anti-PF4 antibodies, including immunoassays and functional assays. Even with positive detection of the anti-PF4 antibody, several factors are involved in the result. The concept of anti-PF4 disorders was recently brought to light during the COVID pandemic since the development of vaccine-induced thrombotic thrombocytopenia (VITT) with the adenovirus-vectored-DNA vaccine during the pandemic. Circumstances that detect anti-PF4 antibodies are classified as anti-PF4 disorders, including VITT, autoimmune HIT and spontaneous HIT. Some studies showed a higher percentage of anti-PF4 antibody detection among the population infected by COVID-19 without heparin exposure and some supported the theory that the anti-PF4 antibodies were related to the disease severity. In this review article, we provide a brief review of anti-PF4 disorders and summarize the current studies of anti-PF4 antibodies and COVID-19 infection.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a global pandemic, and there remains an urgent demand for specific/targeted drugs for the disease. The 3C-like protease (3CLpro) is a promising target for developing anti-coronavirus drugs. Schisandra sphenanthera fruit is a well-known traditional Chinese medicine (TCM) with good antiviral activity. This study found that the ethanolic extract displayed a significant inhibitory effect against SARS-CoV-2 3CLpro. Forty-four compounds were identified in this extract using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Combining molecular docking and in vitro experiments, we found that two epimeric 7,8-secolignans, rel-(1S,2R)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (2) and rel-(1S,2S)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (4), potently inhibited 3CLpro with IC50 values of 4.88 ± 0.60 μM and 4.75 ± 0.34 μM, respectively. Moreover, in vivo and in vitro experiments indicated that compounds 2 and 4 were potent in regulating the inflammatory response and preventing lung injury. Our findings indicate that compounds 2 and 4 may emerge as promising SARS-CoV-2 inhibitors via 3CLpro inhibition and anti-inflammatory mechanisms.

Viruses often manipulate ubiquitination pathways to facilitate their replication and pathogenesis. CUL2ZYG11B known as the substrate receptor of cullin-2 RING E3 ligase, is bound by SARS-CoV-2 ORF10 to increase its E3 ligase activity, leading to degradation of IFT46, a protein component of the intraflagellar transport (IFT) complex B. This results in dysfunctional cilia, which explains certain symptoms that are specific to COVID-19. However, the precise molecular mechanism of how ORF10 recognizes CUL2ZYG11B remains unknown. Here, we determined the crystal structure of CUL2ZYG11B complexed with the N-terminal extension (NTE) of SARS-CoV-2 ORF10 (2.9 Å). The structure reveals that the ORF10 N-terminal heptapeptide (NTH) mimics the Gly/N-degron to bind CUL2ZYG11B. Mutagenesis studies identified key residues within ORF10 that are key players in its interaction with CUL2ZYG11B both in ITC assay and in vivo cells. In addition, we prove that enhancement of CUL2ZYG11B activity for IFT46 degradation by which ORF10-mediated correlates with the binding affinity between ORF10 and CUL2ZYG11B. Finally, we used a Global Protein Stability system to show that the NTH of ORF10 mimics the Gly/N-degron motif, thereby binding competitively to CUL2ZYG11B and inhibiting the degradation of target substrates bearing the Gly/N-degron motif. Overall, this study sheds light on how SARS-CoV-2 ORF10 exploits the ubiquitination machinery for proteasomal degradation, and offers valuable insights for optimizing PROTAC-based drug design based on NTH CUL2ZYG11B interaction, while pinpointing a promising target for the development of treatments for COVID-19.

There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172, demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro. In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

Background/Objective: Multiple cases of postvaccination immune-related adverse events have been reported. We, hereby, present a patient who presented with new-onset type 1 diabetes mellitus (DM) after COVID-19 messenger RNA (mRNA) vaccination. Case Report: A 38-year-old Caucasian man presented with sudden onset of polyuria, polydipsia, and blurry vision for 1 month. The patient received the second dose of the COVID-19 mRNA vaccine (Pfizer-BioNTech) 4 weeks prior to symptom onset. Initial workup revealed glucosuria and hemoglobin A1c of 9.4%. Antibodies against multiple pancreatic beta cell autoantigens were detected. The patient was then initiated on insulin. Discussion: Hypothesized mechanisms for development of type 1 DM after COVID-19 mRNA vaccination include molecular mimicry, autoimmune/inflammatory syndrome induced by adjuvants, and possible interaction between the angiotensin-I converting enzyme-2 receptor on beta cells and viral mRNA. An initial high index of suspicion should be accompanied by early autoantibody testing and initiation of insulin, if indicated. Finally, if diagnosed with type 1 diabetes, patients must have long-term follow-up as there may be brief periods where glycemic control is maintained off insulin. Conclusion: New-onset type 1 DM has been reported after COVID mRNA vaccination. Clinicians should maintain a high index of suspicion and pursue early testing for the same to reduce adverse outcomes and improve long-term prognosis.

Wastewater surveillance (WWS) can leverage its wide coverage, population-based sampling, and high monitoring frequency to capture citywide pandemic trends independent of clinical surveillance. Here we conducted a nine months daily WWS for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 12 wastewater treatment plants (WWTPs), covering approximately 80% of the population, to monitor infection dynamics in Hong Kong, China. We found that the SARS-CoV-2 virus concentration in wastewater was correlated with the daily number of reported cases and reached two pandemic peaks three days earlier during the study period. In addition, two different methods were established to estimate the prevalence/incidence rates from wastewater measurements. The estimated results from wastewater were consistent with findings from two independent citywide clinical surveillance programmes (rapid antigen test (RAT) surveillance and serology surveillance), but higher than the cases number reported by the Centre for Health Protection (CHP) of Hong Kong, China. Moreover, the effective reproductive number (Rt) was estimated from wastewater measurements to reflect both citywide and regional transmission dynamics. Our findings demonstrate that large-scale intensive WWS from WWTPs provides cost-effective and timely public health information, especially when the clinical surveillance is inadequate and costly. This approach also provides insights into pandemic dynamics at higher spatiotemporal resolutions, facilitating the formulation of effective control policies and targeted resource allocation.

Background: COVID-19 has further burdened the Brazilian healthcare system, especially emergencies. Patients may have delayed seeking care for surgical abdominal pain. Delays in the approach may have impacted clinical evolution and outcomes. This study evaluated appendectomies and their complications performed by the public system during one-year follow-up of COVID-19 in a hospital in southern Brazil. Materials and methods: In this hospital-based cross-sectional study, we included adult patients who underwent appendectomy from March 2019 to April 2021 (n = 162). Patients were divided into pre-pandemic (n = 78) and pandemic (n = 84) groups based on the surgery date. The analyzed variables included hospitalization duration, intensive care unit (ICU) admission, surgical approach, histopathological findings, COVID-19 testing, patient outcomes, and 30-day survival rate. Results: The cohorts exhibited similar epidemiology, with the sex ratio and average age being maintained. No statistical difference was found in the 30-day survival rate and clinical outcomes. Of the four patients admitted to the ICU, three belonged to the pandemic cohort and tested negative for COVID-19. Only 47.6 % of the patients in the pandemic cohort underwent COVID-19 polymerase chain reaction examination; one tested positive (2.5 %). Conclusion: This study demonstrated that there was no increased risk for appendectomies during the first wave of the pandemic. Surgeries were safe during this period. Patients continued to access the emergency service despite surgical abdominal pain and restrictive measures imposed by health authorities. The similar results observed across cohorts are attributed to the readiness of the teams and the availability of medical surgical equipment in safe quantities.

The global demand for single-use personal protective equipment (PPE) is rapidly increasing. Most PPE items are composed of plastics, which often end up in landfills or oceans, causing significant environmental harm. Additionally, the disposal of PPE is costly, as it is classified as biological waste. In this study, sanitary PPE components were sterilized using supercritical CO2 at 40°C and 10 MPa, with the addition of small amounts of additives (

Introduction: The current diagnostic methods for SARS-CoV-2 rely on quantitative RT-PCR. However, the presence of viral RNA in samples does not necessarily reflect the presence of an infectious virus. Therefore, the reliable detection of infectious SARS-CoV-2 in clinical samples is necessary to limit viral transmission. Methods: We developed a flow cytometry-based surrogate assay (FlowSA), wherein the presence of infectious SARS-CoV-2 was detected using virus nucleocapsid-specific antibodies. Results: We showed that FlowSA allows the detection of a wide range of viral titers of multiple SARS-CoV-2 variants. Furthermore, the assay was successfully used to detect infectious SARS-CoV-2 in nasopharyngeal swabs from SARS-CoV-2 positive individuals, including those with high Ct values. Notably, FlowSA identified the presence of infectious SARS-CoV-2 in biological specimens that scored negative for cytopathic effect (CPE) in cell culture and would otherwise be considered negative. Conclusion: We propose that FlowSA can be adopted as an alternative to conventional CPE methods for viral diagnostics.

Background: The lower humoral immunity response after the COVID-19 vaccine in kidney transplant recipients (KTR) has been reported in several studies. However, there are few studies on the efficacy of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine compared between various immunosuppressive regimens. Methods: We conducted a prospective cohort study at Siriraj Hospital, Bangkok, Thailand. Adult KTRs who received two doses of the ChAdOx1 nCoV-19 vaccine at intervals of 3 months were enrolled. Anti-SARS-COV-2 S-RBD-IgG antibody (anti-RBD) was assessed at the one month after the second dose and considered positive if the level ≥50 AU/mL or 7 BAU/mL. The primary outcome was the seropositivity of anti-RBD. The association between type, dose, and level of immunosuppressive regimen and anti-RBD seropositivity was analyzed. Results: Between October 2021 and January 2022, 139 KTRs with a median time of 55 months (IQR, 29–102 months), were enrolled. The mean age was 49.1 ± 11.3 years and 64.7 % were men. Seroconversion of anti-RBD was found in 72 patients (51.8 %). The seropositive rate was significantly higher in KTR who received tacrolimus (TAC)/everolimus (EVR)/prednisolone (CS) immunosuppression than EVR/mycophenolic acid (MPA)/CS and TAC/MPA/CS, respectively (95 % vs. 65 % vs. 34 %; p

Summary: Background: With limited access to mRNA COVID-19 vaccines in lower income countries, and people living with HIV (PLWH) largely excluded from clinical trials, Part A of the multicentre CoVPN 3008 (Ubuntu) study aimed to assess the safety of mRNA-1273, the relative effectiveness of hybrid versus vaccine immunity, and SARS-CoV-2 viral persistence among PLWH in East and Southern Africa during the omicron outbreak. Methods: Previously unvaccinated adults with HIV and/or other comorbidities associated with severe COVID-19 received either one (hybrid immunity) or two (vaccine immunity) 100-mcg doses of ancestral strain mRNA-1273 in the first month, depending on baseline evidence of prior SARS-CoV-2 infection. In a prospective cohort study design, we used covariate-adjusted Cox regression and counterfactual cumulative incidence methods to determine the hazard ratio and relative risk of COVID-19 and severe COVID-19 with hybrid versus vaccine immunity within six months. The ongoing Ubuntu study is registered on ClinicalTrials.gov (NCT05168813) and this work was conducted from December 2021 to March 2023. Findings: Between December 2021 and September 2022, 14,237 participants enrolled, and 14,002 (83% PLWH, 69% SARS-CoV-2 seropositive) were included in the analyses. Vaccinations were safe and well tolerated. Common adverse events were pain or tenderness at the injection site (26.7%), headache (20.4%), and malaise (20.3%). Severe adverse events were rare (0.8% of participants after the first and 1.1% after the second vaccination), and none were life-threatening or fatal. Among PLWH, the median CD4 count was 635 cells/μl and 18.5% had HIV viraemia. The six-month cumulative incidences in the hybrid immunity and vaccine immunity groups were 2.02% (95% confidence interval [CI] 1.61–2.44) and 3.40% (95% CI 2.30–4.49) for COVID-19, and 0.048% (95% CI 0.00–0.10) and 0.32% (95% CI 0.59–0.63) for severe COVID-19. Among all PLWH the hybrid immunity group had a 42% lower hazard rate of COVID-19 (hazard ratio [HR] 0.58; 95% CI 0.44–0.77; p

Summary: Background: Early host immunity to acute respiratory infections (ARIs) is heterogenous, dynamic, and critical to an individual's infection outcome. Due to limitations in sampling frequency/timepoints, kinetics of early immune dynamics in natural human infections remain poorly understood. In this nationwide prospective cohort study, we leveraged a Tasso-SST based self-blood collection and stabilization tool (homeRNA) to profile detailed kinetics of the presymptomatic to convalescence host immunity to contemporaneous respiratory pathogens. Methods: We enrolled non-symptomatic adults with recent exposure to ARIs who subsequently tested negative (exposed-uninfected) or positive for respiratory pathogens. Participants self-collected blood and nasal swabs daily for seven consecutive days followed by weekly blood collection for up to seven additional weeks. Symptom burden was assessed during each collection. Nasal swabs were tested for SARS-CoV-2 and common respiratory pathogens. 92 longitudinal blood samples spanning the presymptomatic to convalescence phase of eight participants with SARS-CoV-2 infection and 40 interval-matched samples from four exposed-uninfected participants were subjected to high-frequency longitudinal profiling of 785 immune genes. Generalized additive mixed models (GAMM) were used to identify temporally dynamic genes from the longitudinal samples and linear mixed models (LMM) were used to identify baseline differences between exposed-infected (n = 8), exposed-uninfected (n = 4), and uninfected (n = 13) participant groups. Findings: Between June 2021 and April 2022, 68 participants across 26 U.S. states completed the study and self-collected a total of 691 and 466 longitudinal blood and nasal swab samples along with 688 symptom surveys. SARS-CoV-2 was detected in 17 out of 22 individuals with study-confirmed respiratory infection, of which five were still presymptomatic or pre-shedding, enabling us to profile detailed expression kinetics of the earliest blood transcriptional response to contemporaneous variants of concern. 51% of the genes assessed were found to be temporally dynamic during COVID-19 infection. During the pre-shedding phase, a robust but transient response consisting of genes involved in cell migration, stress response, and T cell activation were observed. This is followed by a rapid induction of many interferon-stimulated genes (ISGs), concurrent to onset of viral shedding and increase in nasal viral load and symptom burden. Finally, elevated baseline expression of antimicrobial peptides was observed in exposed-uninfected individuals. Interpretation: We demonstrated that unsupervised self-collection and stabilization of capillary blood can be applied to natural infection studies to characterize detailed early host immune kinetics at a temporal resolution comparable to that of human challenge studies. The remote (decentralized) study framework enables conduct of large-scale population-wide longitudinal mechanistic studies. Funding: This study was funded by R35GM128648 to ABT for in-lab developments of homeRNA and data analysis, a Packard Fellowship for Science and Engineering from the David and Lucile Packard Foundation to ABT for the study execution, sample collection, and analysis, and R01AI153087 to AW for data analysis.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus which has resulted in the Coronavirus Disease 2019 (COVID-19) pandemic and has infected millions of people all over the world. SARS-CoV-2 has been mutating rapidly resulting in the emergence of multiple variants to escape the host immune system mainly by mutations in its receptor binding domain (RBD) of the spike protein. The RBD and full-length spike of SARS-CoV-2 are the main targets of the neutralizing antibodies (mainly IgGs). Many SARS-CoV-2 variants are considered to have potential to escape from the host immune system. This rapid evolution of the virus posed a great challenge regarding the efficacy and effectiveness of the current SARS-CoV-2 vaccines. Hence, in this study, RBD of Alpha, Beta, Gamma, Kappa and Omicron BA.1 and full-length spike of BA.1, BA.2, BA.3, BA.4/5, BQ.1.1 and XBB.1.5 Omicron variants were used as coating antigens in an indirect Enzyme Linked Immuno-Sorbent Assay (ELISA) to check the IgG binding capability to the COVID-19 convalescent sera from patients of first wave of infection occurring in Wuhan. Our results show that the currently circulating Omicron BQ.1.1, XBB.1.5 and previous Omicron BA.1, BA.2 and BA.4/5 do not show significant reduction in binding, while Omicron BA.3 and previous variants Alpha, Beta, Gamma, Kappa, and Omicron showed a significantly reduced binding when compared to the wild-type Wuhan strain. These results indicate that the patients recovering from natural infection of early original Wuhan strain may have the potential to resist infection of current circulating variants and the vaccines using the prototype antigen may still work for newly emerged variants.

Summary: Background: The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity in vitro, and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in therapeutic guidelines and their antiviral activity in vivo has not been characterised. Methods: PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. We recruited low-risk adult outpatients aged 18–50 with early symptomatic COVID-19 (symptoms 2 days follow-up).The viral clearance rate was estimated under a Bayesian hierarchical linear model fitted to the log10 viral densities measured in standardised duplicate oropharyngeal swab eluates taken daily over one week (18 measurements per patient). Secondary endpoints were all-cause hospital admission at 28 days, and time to resolution of fever and symptoms. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907). Findings: 271 patients were concurrently randomised to either fluoxetine (n = 120) or no study drug (n = 151). All patients had received at least one COVID-19 vaccine dose and 67% were female (182/271). In the primary analysis, viral clearance rates following fluoxetine were compatible with a small or no increase relative to the no study drug arm (15% increase; 95% credible interval (CrI): −2 to 34%). There were no deaths or hospitalisations in either arm. There were no significant differences in times to symptom resolution or fever clearance between the fluoxetine and the no study drug arms (although only a quarter of patients were febrile at baseline). Fluoxetine was well tolerated, there were no serious adverse events and only one grade 3 adverse event in the intervention arm. Interpretation: Overall, the evidence from this study is compatible with fluoxetine having a weak in vivo antiviral activity against SARS-CoV-2, although the primary endpoint is also compatible with no effect. This level of antiviral efficacy is substantially less than with other currently available antiviral drugs. Funding: Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

The problem of treating cancer patients with lung cancer has become more difficult due to the SARS-CoV-2 viral infection and concomitant bacterial lesions. The analysis shows that the photodynamic effect of long-wavelength polycationic photosensitizers suppresses the tumor process (including the destruction of cancer stem cells), SARS-CoV-2 coronavirus infection, Gram-positive and Gram-negative bacteria, including those that can cause pneumonia. Therefore, the photodynamic approach using such photosensitizers is promising for the development of an effective treatment method for patients with lung cancer, including those with SARS-CoV-2 infection and bacterial complications.

Background: Despite vaccination, patients receiving anti-CD20 monoclonal antibodies (mAbs) for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) have an increased risk of developing severe or protracted COVID-19. The aim of this study was to describe the effect of COVID-19 convalescent plasma (CCP) in patients with MS or NMOSD exposed to anti-CD20 and infected by SARS-CoV-2. Methods: This French national, retrospective cohort study was conducted between November 2020 and June 2023. Patients with MS or NMOSD, under anti-CD20 mAbs, with symptomatic COVID-19 and treated by CCP were screened. Protracted COVID-19 was defined by a duration of symptoms >21 days. The primary endpoint was the overall survival 30 days after CCP administration. Results: Ninety-two patients from 34 hospitals were included, 84 (91%) with MS and 8 (9%) with NMOSD. Overall, 30-day survival was 97% (IC95%: 91-99). SARS-CoV-2 viremia was positive in 47/75 (61%) patients before CCP versus 9/59 (15%) seven days post-CCP. In the 52 patients (57%) with protracted COVID-19, the duration of symptoms before CCP was 51 [28-69] days, including fever in 75% of cases, which disappeared in 100% of patients 7 days post-CCP. Conclusions: CCP could be a therapeutic option in patients exposed to anti-CD20 mAbs for inflammatory demyelinating disease, particularly in those with protracted COVID-19.

Objectives: To provide globally representative data on hospitalization and death in recently SARS-CoV-2-positive ambulatory populations. Methods: We enrolled SARS-CoV-2-positive ambulatory adults in the cohort studies, ICOS (47 sites, 5 continents), and PCOS (Liberia) and followed for 28-days. Kaplan-Meier estimates of percentage of those hospitalized or died were derived. Risk factors for hospitalization, death, and failure to recover were identified using Cox and logistic models respectively. Results: 9817(ICOS) and 125(PCOS) participants, 46.7% male; median age 43 years; 24.5% with comorbidity(s); 0.8% pregnant; 9.3% SARS-CoV-2 vaccinated, were enrolled June-2020 and January-2022. By 28 days, 424(4.3%) participants were hospitalized or had died; most within 7 days of enrolment(3.4%). Hospitalization or death declined over calendar time i.e. 7.5%(2020); 4.1(first-half 2021) and 2.1%(second-half 2021), P < 0.0001. Older age, male sex, comorbidities, pregnancy, symptomatic disease were each independently associated with hospitalization or death; SARS-CoV-2 vaccination reduced this risk. At 28 days, 26.1% and 29.9% reported ongoing symptoms and failure to return to pre-morbid health respectively. Conclusions: These global SARS-CoV-2 ambulatory cohort studies identified demographic/clinical risks for hospitalization or death. Vaccination does not fully explain hospitalization and death declines over time. Symptomatic recovery and return to premorbid health were incomplete at 28 days in ≈one third.

Summary: Background: After surviving Coronavirus Disease 2019 (COVID-19), some people develop symptoms known as post-acute sequelae of COVID-19 (PASC). PASC is an emerging phenomenon yet to be fully understood, and identifying risk factors has been challenging. This study investigated the association between the number of COVID-19 episodes and the incidence of PASC among essential workers. Methods: We analyzed data from 2511 essential workers, mainly first responders, with confirmed polymerase chain reaction, antibody, or antigen-positive test results for SARS-CoV-2 infection from March 2020 to February 2024. Data were collected through in-person questionnaires and surveys sent via text and email, internal medical records, follow-up calls, and external medical records. Participants who reported continuation or the development of new symptoms three months after the initial SARS-CoV-2 infection, with symptoms lasting for at least two months, were categorized as having PASC, while those without any COVID-19 or whose symptoms resolved were classified as non-PASC. PASC was common in this cohort so we used a Poisson regression model to compute multivariable-adjusted Relative Risk (RR) for the association between risk of PASC and SARS-CoV-2 re-infection, severity, and vaccination status at first infection. Findings: A total of 475 (prevalence = 18.9%, [95% confidence interval] = [17.4–20.5]) PASC patients were identified. The mean (standard deviation (SD)) age of participants who experienced PASC (54.8 (7.2) years) was similar to those who did not (54.2 (7.4) years). There were 403 (16.1% [14.6–17.5]) participants who experienced multiple instances of COVID-19. After adjusting for relevant demographic, lifestyle, and clinical variables, we found a significant association between the risk of experiencing PASC and multiple SARS-COV-2 infections (RR = 1.41 [1.14–1.74]), severe COVID-19 (RR = 3.17 [2.41–4.16]), and being unvaccinated at first infection (RR = 3.29 [2.46–4.41]). Interpretation: Although the pathogenetic mechanism for PASC remains unclear, identifying risk factors such as lack of vaccination or re-infection can assist in better understanding and managing the condition. Funding: National Institute on Aging (NIH/NIA R01 AG049953) and Centers for Disease Control and Prevention (CDC/NIOSH U01 OH011864) and (CDC/NIOSH U01 OH012275).

Objectives: Evidence indicates that people living with HIV (PLHIV) are more impacted by COVID-19. The burden of SARS-CoV-2 infection among PLHIV is unknown in Nigeria. Methods: We conducted repeated cross-sectional SARS-CoV-2 serosurveys in 14 states and the Federal Capital Territory in Nigeria among PLHIV who had an HIV viral load (VL) test during April 2022 to January 2023. Evidence of SARS-CoV-2 immunoglobulin G (IgG) antibodies was assessed using a multiplex bead assay to measure IgG to spike (S), receptor binding domain (RBD), and nucleocapsid (N) proteins to identify potential infection and/or vaccination status. Results: Between April 2022 and January 2023, 47,614 remnant VL samples were included and tested for SARS-CoV-2 antibodies. Seroprevalence of SARS-CoV-2 infection, defined as IgG antibodies to spike and RBD591 [S+] and nucleocapsid [N+], (S+N+), ranged between 21.1% (95% confidence intervals [CI]: 11.4-31.8) in Ekiti State in January 2023 to 71.4% (95% CI 71.9-81.9) in Gombe State in November 2022, with overall steady trends within and between states over time, across age and sex. Conclusion: High rates of SARS-CoV-2 antibody seroprevalence among PLHIV in Nigeria were observed. This underscores the need to understand the association between HIV and SARS-CoV-2 to inform strategies to reduce the threat posed by COVID-19.

Background: Leucas aspera (Willd.) Link, a member of the Lamiaceae family and commonly known as ''Thumbai,'' is found throughout India and has been utilized in traditional Indian medicine to treat various ailments. Purpose: This study entails methanolic extraction of Leucas aspera (Willd.) Link using a Soxhlet apparatus, followed by phytochemical screening and antioxidant activity assessment. Methods: The L. aspera methanolic leaf extract displayed a phenolic content of 100 µg/ml, consisting of 3.02 mg of gallic acid dry weight equivalents and a flavonoid content of 100 µg/ml with 3.35 mg quercetin equivalents per dry weight. The extract's free radical scavenging capabilities were at 150 µg/ml in DPPH, showing an 87 % effectiveness compared to the standard ascorbic acid 49 % inhibition capacity. The ABTS radical scavenging activity in 100 µg/ml extract measured 64.32 %, phosphomolybdate assay indicated 86.89%, and hydroxide radical scavenging capacity showed 126.72 %. Antibacterial activity was also assessed through agar well diffusion assays against Klebsiella pneumoniae, Salmonella typhi, Staphylococcus aureus, and Leucobacter sp., Where K. pneumoniae exhibits the highest zone of inhibition. The methanolic crude extract of L. aspera was further using TLC, FT-IR and HR-LC/MS to identify functional groups and phytocompound present in the extract. Results: HRLC-MS was used to conduct metabolite profiling of the methanolic crude extract of L. aspera leaves, discovering 37 positive and 43 negative compounds. To evaluate the ADMET properties and predict the drug-likeness of these 80 phytochemicals, an in silico analysis was performed. The results of this analysis revealed that only 19 of the compounds met the ADMET limitations and had suitable Log P values. Molecular docking of the 19 compounds against the SARS-CoV-2 main protease (3CLPro) protein (PDB ID: 6LU7) and spike protein receptor binding domain (SGp-RBD) protein (PDB ID: 2GHV) revealed Famprofazone and Loxtidine compounds having the highest binding affinity with LibDock scores of 105.53 and 116.70 respectively. Conclusion: Thus, our findings could serve as potential active molecules of L. aspera against this target protein. This study provides further proof of bioactive compounds produced by the L. aspera leaf extract.

Background: Accumulating evidence suggests that the receptor binding domain (RBD) of the SARS-CoV-2 Omicron variant has several times more binding affinity to the human angiotensin-converting enzyme 2 (ACE2) receptor compared to the RBD of the original Covid-19 strain. This increased binding affinity of the Omicron variant is responsible for its increased internalization and infectivity. Purpose: In the present study, the impact of Coronil, a tri-herbal formulation of extracts from Withania somnifera, Tinospora cordifolia and Ocimum sanctum on the binding properties of Omicron SARS-CoV-2 variant spike proteins (S proteins) was investigated. Methods: Chemical composition of Coronil was determined by the Prominence-XR UHPLC system. The ELISA-based ACE2 binding inhibition assay was performed to delineate the effect of Coronil on the interaction between human ACE2 receptor and different Omicron variant S-proteins such as BA.4/BA5, XBB, BA.2.75.2, BA4.6/BF.7, BA.2.75.2, BQ.1.1 and a recently found spike protein variant JN.1 which is thought to emerge from BA.2.86. Results: Coronil showed a dose-dependent inhibitory effect on the interactions between ACE2 and receptor binding domains (RBD) of all variants of S-proteins evaluated in this study including the recently emerged, highly transmissible variant spike protein JN.1. Although, Coronil significantly reduced the binding percentage in almost all the variant spike proteins, the maximum inhibition was achieved against BA.4/BA.5 where it inhibited the S protein – ACE2 interaction even at a low concentration of 3 µg/ml (16.6 %). This binding inhibition was further increased to 60.3 and 84.3 % at 100 and 300 µg/ml respectively. Conclusion: This capability of Coronil to inhibit the binding of S-protein variants with ACE2 receptor may interfere with viral binding and internalization resulting in reduced infectivity of these Omicron spike protein variants. Overall, our data underscores the potential of Coronil in combating the various newly emerged Omicron spike protein variants. These findings may provide a basis for further studies of Coronil for its clinical effectiveness against these Omicron variants.

Structured summary: Objective: Evaluation of the rate and symptoms of Post-COVID-19 condition in employees in childcare. Methods: A structured questionnaire collected data from two distinct collectives: Collective 1 (C1) consisted of a prospective cohort of 44 employees after COVID-19 disease, whereas Collective 2 (C2) included 222 employees who were retrospectively interviewed. The questionnaire mainly focused on symptoms and wellbeing during or after COVID-19. Results: The main symptoms of Post-COVID-19 condition were impairment of focus, fatigue/exhaustion, reduced stamina, headache and dyspnoea. 30 % of the employees in C1 and 7.6 % of C2 suffered from a clinically relevant Post-COVID-19 condition with impairment of the general wellbeing. According to the WHO definition, a Post-COVID-19 condition was found in 56.6 % (C1) and 25.5 % (C2). Conclusions: A Post-COVID-19 condition was a common finding in both our collectives but did not automatically cause an impairment of general wellbeing.

Given the global implementation of effective COVID-19 vaccines, which do not confer complete immunity, it is crucial to monitor the occurrence of breakthrough infections, particularly against newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Hence, we developed a label-free colorimetric assay using gold nanoparticles (GNPs) functionalized with a peptide dendrimer incorporating highly reactive epitopes of the nucleocapsid (N) protein. This assay relies on the tween-20 induced colorimetric changes caused by the aggregation of peptide dendrimer-coated GNPs in the absence of anti- SARS-CoV-2 N antibodies, and vice versa. Transmission electron microscopy, dynamic light scattering, and circular dichroism spectroscopy analyses all showed the formation of a uniform and highly stable coating of the peptide dendrimer over GNPs. Surface plasmon resonance experiments have demonstrated a strong binding affinity for the peptide dendrimer and anti- SARS-CoV-2 N antibodies, with a KD value of 525 nM. To validate the proof-of-concept, we have tested this assay on seventy human serum samples, and receiver operating characteristic curve analysis demonstrated high diagnostic sensitivity (88.89 %) and specificity (100 %). This approach opens up new avenues for the development of simple and rapid diagnostic assays for identifying antibodies against viral infections and other pathogens.

Background: Coronavirus disease (COVID-19) remains one of the most significant factors threatening public health security worldwide. The COVID-19 pandemic has been ongoing for more than 3 years; however, there are few studies on the clinical characteristics and mortality risk factors in patients with COVID-19 based on comprehensive data from multiple centers. Methods: A total of 53,030 patients with confirmed COVID-19 from 138 hospitals in Hubei Province were included in this study. We compared the clinical characteristics between survivors and non-survivors and analyzed the risk factors for in-hospital mortality. Results: Among the 53,030 patients with COVID-19, 49,320 (93.0 %) were discharged, and 3,710 (7.0 %) died during hospitalization. Cardiovascular disease was the most common comorbidity, followed by endocrine and digestive diseases. Male sex, >65-year-old, and high diastolic blood pressure, a series of abnormal laboratory test indicators and hyponatremia, hypokalemia, acute respiratory distress syndrome, shock, solid tumor, hematological tumor, and insulin use were independent risk factors for in-hospital mortality of patients with COVID-19. In addition, male sex, older age, and higher disease severity were associated with increased mortality in patients with COVID-19. Conclusion: Patients with early COVID-19 in Hubei Province had high mortality and a high proportion of severe cases and initial comorbidities. Cardiovascular disease was the most common comorbidity in patients with COVID-19. Male sex, older age, comorbidities, and abnormal laboratory data have been identified as independent risk factors for in-hospital mortality in patients with COVID-19. Therefore, there should be an increased focus on patients with COVID-19 with these risk factors.

In light of the transition of COVID-19 from a pandemic to an endemic phase, there is still a dire need to address challenges associated with drug resistance, particularly among immunocompromised and high-risk populations. This review explores the current state of research on SARS-CoV-2 drug resistance and underscores the ongoing need for effective therapeutic strategies. It critically evaluates existing knowledge on resistance mechanisms and therapeutic options, aiming to consolidate information and highlight areas for future research. By examining the complex interactions between the virus and its host, the review advocates for a multifaceted approach, including combination therapies, targeted drug development, and continuous surveillance of viral mutations. It also emphasizes the impact of evolving viral variants on antiviral efficacy and suggests adaptive treatment protocols. This review aims to enhance our understanding of SARS-CoV-2 drug resistance and contribute to more effective management of COVID-19 through a discussion of promising strategies such as drug repurposing and combination therapies.

Summary: Background: Liver involvement is a common complication of coronavirus disease 2019 (COVID-19), especially in hospitalized patients. However, the underlying mechanisms involved are not fully understood. Methods: Immunohistochemistry (IHC) staining of SARS-CoV-2 spike (S) and nucleocapsid (N) proteins was conducted on liver tissues from six patients with COVID-19. The 10x Genomics Visium CytAssist Spatial Gene Assay was designed to analyze liver transcriptomics. TCR CDR3 sequences were analyzed in DNA from liver tissues. Liver function indicators were retrospectively studied in 650 hospitalized patients with COVID-19. Findings: SARS-CoV-2 proteins were initially detected in the livers of naturally infected golden (Syrian) hamsters, prompting us to investigate the situation in clinical cases. Thus, we collected liver tissues from patients with abnormal liver biochemical values. Viral S and N proteins were detected in the livers of severe and deceased patients but not in those of moderate patients. We further demonstrated that hepatocytes and erythroid cells in hepatic sinusoids are major cells targeted by SARS-CoV-2. Immune cells, especially T cells, were enriched in surviving severe patients, characterized by enhanced CDR3α clonality and novel CDR3β recombination of the T-cell receptor. In contrast, hepatocyte apoptosis was triggered, and the transcription of albumin (ALB) was obviously impaired in the deceased patients. We then performed a retrospective study including patients with COVID-19. Serum aspartate aminotransferase (AST) and ALB levels at baseline significantly differed in the deceased cohort. However, AST regression did not decrease the risk of death. ALB recovery indicated clinical improvement, and declining or low serum ALB concentrations were associated with death. Interpretation: This study provides clinical evidence for liver infection with SARS-CoV-2, insight into the impact of SARS-CoV-2 on the liver, and a potential way to evaluate the risk of death via assessing serum ALB concentration fluctuations in patients with COVID-19. Funding: National Key R&D Program of China (2021YFC2300602), National Natural Science Foundation of China (92369110), National Natural Science Foundation of China (U23A20474), Shanghai Municipal Science and Technology Major Project (ZD2021CY001), Shanghai Jinshan District Medical and Health Technology Innovation Fund Project (2023-WS-31).

Background: SARS-CoV-2 infection during pregnancy poses health risks to both mother and fetus. This study investigates neutralizing antibodies (NAbs) against the SARS-CoV-2 JN.1 Omicron subvariant in pregnant women, focusing on responses to natural infection, vaccination, and passive immunity. Methods: A single-center, prospective study collected blood samples from 19 pregnant women at various pregnancy stages and postpartum. NAb titers were analyzed using a pseudovirus neutralization assay, with statistical analyses (p-value

The SARS-CoV-2 infection has spread to various areas of the world, and the number of infected people, seriously ill people, and deaths have increased in 2020∼2023. It is important to suppress the spread of virus from infected people to non-infected people in order to prevent the disease from becoming more severe. To protect widespread of virus, flavor/fragrances composition was selected as a convenient effective material to protect the inhibition. It was previously investigated whether flavor/fragrances composition inhibit the binding between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and host angiotensin converting enzyme 2 (ACE2) in the infection model assay. This binding lead to natural infection of SARS-CoV-2 to tissues. In a previous report, it was found that some Flavor/fragrances compositions strongly inhibited the binding between RBD and ACE2. To clarify whether these flavor/fragrances compositions actually inhibit the infection of SARS-CoV-2, the inhibition assay of infection to VeroE6/TMPRSS2 cells, the inhibition model in vitro, were performed by the treatment of these compositions. Some flavor/fragrances compositions excepting for cinnamyl alcohol, 0.25 %, strongly inhibited the infection of SARS-CoV-2 to VeroE6/TMPRSS2 cells because cinnamyl alcohol could not be completely melted by PBS (pH 7.4) containing 1.5 % Tween 20 and 0.5 % BSA. Among fragrance compounds, cinnamon flavor and cinnamon mint had stronger inhibition effects on the infection effects on SARS-C0V-2 than others. The strategy of using flavor/fragrances compositions such as cinnamon flavor and cinnamon mint may be useful to protect widespread of SARS-CoV-2 in their daily lives.

Objective: The aim of this prospective cohort study is to analyse the humoral and cellular vaccine responses in paediatric heart transplant recipients (HTR, n = 12), and compare it with the response in healthy controls (HC, n = 14). All participants were 5–18 years old and vaccinated with mRNA vaccine against SARS-CoV-2 between December 2021 and May 2022. Methods: The humoral response was measured by quantifying antibody titers against SARS-CoV-2 spike protein (anti-S). The T-lymphocyte phenotype and SARS-CoV2-specific CD4+ and CD8+ T-cell response was studied by multiparametric flow cytometry through peripheral blood mononuclear cells by the quantification of degranulation markers (CD107a) and intracellular cytokines (IFN-γ, TNF-α and IL-2) after in vitro stimulation with SARS-CoV-2 peptides from structural proteins (S, M, N, E) and non-structural viral proteins. Results: After vaccination, humoral response was found in all HTR, although they showed lower levels of anti-S IgG compared to HC (p = 0.003). However, in terms of cellular response, no significant differences were obtained in the prevalence of responders and magnitude of responses between groups. In addition, anti-S IgG levels directly correlated with a higher SARS-CoV-2 specific T-cell response (rho = 0.43; p = 0.027 and rho = 0.45; p = 0.02 for IFN-γ+ and TNF-α+ production of CD8+ T-cells, respectively). Activated T-cell phenotype in HTR was associated with a lower humoral response to SARS-CoV-2 vaccine. Conclusion: HTR had humoral response after vaccination, although they showed lower levels of specific anti-S antibodies compared to HC. There were no significant differences in the SARS-CoV2-specific cellular response between the two groups. Obtaining satisfactory data on this type of response could potentially challenge the current vaccine guideline recommendations.

Background: The SARS-CoV-2 pandemic caused millions of infections worldwide. Among the strategies for effective containment, frequent and massive testing was fundamental. Although sample pooling allows multiplying the installed analysis capacity, the definition of the number of samples to include in a pool is commonly guided more by economic parameters than analytical quality. Methods: We developed a mathematical model to determine the pooling conditions that maximize reagent efficiency and analytical sensitivity. We evaluated 30 samples individually and in 2-sample to 12-sample pools. Using Passing Bablok regressions, we estimated the shift of Ct values in the RT-qPCR reaction for each pool size. With this Ct shift, we estimated sensitivity in the context of the distribution of 1,030 individually evaluated positive samples. Findings: Our results showed that the most significant gain in efficiency occurred in the 4-sample pool, while at pools greater than 8-sample, there was no considerable reagent savings. Sensitivity significantly dropped to 87.18 %–92.52 % for a 4-sample pool and reached as low as 77.09 %–80.87 % in a 12-sample pooling. Conclusions: Our results suggest that a 4-sample pooling maximizes reagent efficiency and analytical sensitivity. These considerations are essential to increase testing capacity and efficiently detect and contain contagious.

Summary: Background: Vaccine co-administration can increase vaccination coverage. We assessed the safety, reactogenicity, and immunogenicity of concomitant administration of Ad26.COV2.S COVID-19 vaccine with seasonal influenza vaccines. Methods: This non-inferiority, Phase 3, randomised, double-blind study enrolled 859 healthy adults and was conducted between 02 November 2021 and 28 November 2022. Participants aged ≥18–64 years were randomised to receive a seasonal quadrivalent standard dose (SD) influenza vaccine (Afluria Quadrivalent, Seqirus) concomitantly with Ad26.COV2.S (Coad_SD) or placebo (0.9% NaCl; Control_SD) on Day 1 and placebo or Ad26.COV2.S on Day 29. Participants aged ≥65-years were randomised to the Coad_SD or Control_SD groups, or to Coad_HD or Control_HD groups that received a seasonal quadrivalent HD (high-dose) influenza vaccine (Fluzone High-Dose Quadrivalent, Sanofi Pasteur Inc) in the same schedules. The primary outcomes were haemagglutinin inhibition titres against the four influenza vaccine strains at Day 29, and SARS-CoV-2 Spike-specific antibodies at Day 29 in the Coad_SD group and Day 57 in the Control-SD group, with a non-inferiority margin (Control-SD group/Coad_SD group) of 1.5. Reactogenicity and safety were assessed in all participants (NCT05091307). Findings: Non-inferiority criteria for concomitant administration in the SD groups were met for SARS-CoV-2 Spike-specific antibodies (ratio 1.11, 95% CI 0.97–1.26) and haemagglutinin inhibition titres for all influenza strains (A/H3N2 1.23, 95% CI 1.05–1.45; B/Victoria 0.99, 95% CI 0.84–1.19; B/Yamagata, 1.03, 95% CI 0.88–1.21) except A/H1N1 (1.28, 95% CI 1.09–1.53) for which the upper limit of the 95% CI was >1.5. Concomitant administration of Ad26.COV2.S and SD influenza vaccine induced robust immune responses in terms of SARS-CoV-2 Spike-specific antibodies and haemagglutinin inhibition to all four influenza strains. Seroconversion and seroprotection rates against all influenza vaccine strains were comparable in the Coad and Control groups. Anti-Spike antibodies 28 days after receiving Ad26.COV2.S were similar whether administered with influenza vaccine or alone. Antibody responses persisted at least 6 months post-vaccination in all groups. The reactogenicity and safety profile following co-administration was consistent with the known safety profiles of the study vaccines. No safety concerns were identified. Coadministration was immunogenic and well tolerated in adults aged ≥65 years who received HD influenza vaccine. Interpretation: Co-administration of seasonal influenza vaccine with Ad26.COV2.S was immunogenic with an acceptable safety profile, supporting co-administration of these vaccines. Funding: Janssen Vaccines & Prevention BV and Biomedical Advanced Research and Development Authority.

Brazil's COVID-19 response has faced challenges due to the continuous emergence of variants of concern (VOCs), emphasizing the need for ongoing genomic surveillance and retrospective analyses of past epidemic waves to reassess and fine tune containment protocols. Rio Grande do Sul (RS), Brazil's southernmost state, has international borders and trades with Argentina and Uruguay, along with significant domestic connections within Brazil. The identification of source and sink transmission chains at national and international scales can identify main hubs and pathways to target future interventions. In this study we investigated the RS state role in the national and international SARS-CoV-2 transmission chains, which has not been fully explored. Nasopharyngeal samples from various municipalities in RS were collected between June 2020 and July 2022. SARS-CoV-2 whole genome amplification and sequencing were performed using high-throughput Illumina sequencing. Bioinformatics analysis encompassed the development of scripts and tools to perform subsampling taking into account epidemiological information to reduce sequencing disparities bias among the regions/countries, genome assembly, and large-scale alignment and phylogenetic reconstruction. We sequenced a total of 1,480 SARS-CoV-2 genomes from RS, covering all major regions. Sequences predominantly represented Gamma (April-June 2021) and Omicron (January-July 2022) lineages. Phylogenetic analysis revealed a regional pattern for transmission dynamics, particularly with Southeast Brazil for Gamma, and a range of inter-regional connections for Delta and Omicron within the country. On the other hand, international and cross-border transmission with Argentina and Uruguay was rather limited. We evaluated the three VOCs circulation over two years in RS using a new subsampling strategy based on the number of cases in each state during the circulation of each VOC. In summary, the retrospective analysis of genomic surveillance data demonstrated that virus transmission was less intense between country borders than within the country. These findings suggest that while non-pharmacological interventions were effective to mitigate transmission across international RS land borders, they were insufficient to contain transmission at the domestic level.

Introduction: Autoantibodies (AAbs) directed against interferon alpha (aIFNα), nuclear antigens (ANAs), anti-cardiolipin (aCL), and anti-beta 2 glycoprotein 1 (aβ2GP1), have been demonstrated to significantly correlate with the severity of acute Coronavirus Disease 2019 (COVID-19). However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces these AAbs and whether they are associated with long COVID remains unclear. Methods: The potential induction of aIFNα, ANAs, aCL, and aβ2GP1 by SARS-CoV-2 was assessed by measuring these AAbs in 224 pre- and post-infection paired serum samples from the Johns Hopkins Hospital Emergency Department (JHHED). The relationship between these AAbs and long COVID was assessed using 60 serum samples from participants in the Outpatient SARS-CoV-2 Mild and Asymptomatic Infection Response and Transmission study. Results: We found no evidence that these AAbs were induced in the JHHED cohort and no significant difference in their prevalence between patients with (n = 30) and without (n = 30) long COVID in the OutSMART cohort. Conclusion: These findings do not support the hypotheses that SARS-CoV-2 induces these AAbs or that they are related to long COVID.

Objectives: Children have been largely spared from serious disease through the COVID-19 pandemic despite a high exposure to SARS-CoV-2. Antibody responses to exposure and their role in protecting children from subsequent variant infection remain poorly understood. Methods: This is a prospective cohort study of children in a South African community through ancestral/Beta/Delta/Omicron BA.1/BA.2 and BA.4/BA.5 SARS-CoV-2 waves (March 2020-October 2022). Health seeking behavior/illness was recorded and postwave serum samples measured for immunoglobulin (Ig) G to spike (S) (CoV2-S-IgG) by electrochemiluminescent immunosorbent assay. To estimate the protective CoV2-S-IgG threshold levels, logistic functions were fit to describe the correlation of CoV2-S-IgG measured before a wave and the probability for seroconversion/boosting thereafter. Results: Despite little disease, 125 per 366 (34.2%) children (median age 6.7 years [interquartile range 5.99-7.4 years]) were seropositive after wave I, rising to 53.6%, 76.0%, and 96.2% and 99.2% after waves II (Beta), III (Delta), and IV and V (Omicron variants), respectively. CoV2-S-IgG induced by natural exposure protected against subsequent SARS-CoV-2 infection, with the greatest protection for Beta and least for Omicron. The levels of IgG specific for ancestral S antigen that provided a 50% protective threshold for the subsequent wave were lowest for the Beta and highest for the Omicron BA.1/BA.2 wave. In the multivariate analysis, maternal seropositivity (adjusted odds ratio = 2.57 [95% confidence interval: 1.72-3.82]) was strongly associated with child seropositivity. Conclusion: Children responded robustly to successive waves of SARS-CoV-2, mounting IgG responses to S antigen that were protective against subsequent waves. In the absence of vaccination, almost all children were seropositive after wave V but none were hospitalized, suggesting that natural immunity alone may be sufficient to protect children in a pandemic setting.

Summary: Background: Prior studies have reported lower effectiveness of XBB.1.5-adapted vaccines against hospitalization related to the Omicron JN.1 variant than the XBB variant. This study evaluated the effectiveness and durability of the BNT162b2 XBB.1.5-adapted vaccine against JN.1-related hospitalization during the 2023–2024 season in Europe. Methods: A test-negative case–control study was carried out in adults (≥18 y) hospitalized between 2 October 2023 and 2 April 2024 with severe acute respiratory infection (SARI) within the id.DRIVE partnership. This study included nine sites across Belgium, Germany, Italy, and Spain. Cases had a laboratory-confirmed JN.1 infection or a positive SARS-CoV-2 test with symptom onset during JN.1 predominance; controls had a negative SARS-CoV-2 test and symptom onset during JN.1 predominance. The primary objective was to estimate BNT162b2 XBB.1.5-adapted vaccine effectiveness (VE) against COVID-19 hospitalization. One case was matched with up to four controls, according to symptom onset date and site. Multivariable analyses were adjusted for symptom onset date, age, sex, and number of chronic conditions. Findings: Among 308 test-positive cases and 1117 test-negative controls, BNT162b2 XBB.1.5-adapted VE against hospitalization compared to no vaccination this season was 53.8% (95% CI 38.4–65.4) after a median of 63 days following vaccination. Protection was sustained through five months; VE was 52.2% (95% CI 41.3–61.1) 2 to

Objectives: We estimated vaccine effectiveness (VE) against SARS-CoV-2 infection among a statewide cohort of people with HIV (PWH) and compared the estimates with a matched cohort of people without HIV (PWoH) in South Carolina (SC), USA. Methods: A population-based cohort was retrieved from statewide electronic health records between January 2, 2021, and April 14, 2022, during which several variants were circulating in SC (i.e., Alpha, Delta, Omicron). We compared the odds of vaccination between test-positive cases and test-negative controls using logistic regression models for both SARS-CoV-2 infection and severe COVID-19 outcomes. The VE was derived as (1 − adjusted odds ratio) × 100%. Results: A total of 7279 test episodes in PWH and 72,790 matched test episodes in PWoH were included for analysis, representing 6561 unique PWH and 67,521 unique PWoH. The peak level of VE against SARS-CoV-2 infection occurred 7-59 days after receipt of the second dose of vaccine (PWH: 61.20%; PWoH: 67.09%), followed by a waning protective effect 90-119 days after the second dose in both PWH (35.80%) and PWoH (47.57%), where PWH had a proportionally lower and declined faster VE. Regarding the VE against severe outcomes of SARS-CoV-2 infection, a relatively higher level of protection was maintained in both populations (complete primary series: PWH: 69.06%; PWoH: 60.63%). Conclusions: A complete primary series of COVID-19 vaccines offered significant protection against SARS-CoV-2 infection and severe outcomes in both PWH and PWoH populations, although this wanes with time. However, the estimate of VE against SARS-CoV-2 infection appeared lower in PWH than in PWoH and the degree of waning over time was relatively quicker in PWH.

Objectives: Influenza-like-illness (ILI) is a commonly used symptom categorization in seasonal disease surveillance focusing on influenza in community and clinical settings. However, SARS-CoV-2 often causes presentation with a similar symptom profile. We explore how SARS-CoV-2-positive individuals can influence surveillance trends for the World Health Organization, the United States Centre for Disease Control, and the European Centre for Disease Control (ECDC) ILI criteria. Methods: Harnessing the Winter COVID-19 Infection Study in England, a cohort study, the prevalence of different ILI definitions is modeled using multilevel regression and poststratification using age and spatial stratifications with temporal smoothing. Trends over time across stratifications were compared for SARS-CoV-2 positive and negative individuals to understand differences in ILI trends. Symptom presentation across positive and negative SARS-CoV-2 cases were compared. Results: SARS-CoV-2 symptom profiles are shown to overlap with the ILI case definitions, particularly for “cough” and “fever”, causing SARS-CoV-2 positive individuals to be frequently detected as ILI cases. The trend of SARS-CoV-2 positives is a substantial component of the ILI-modeled trend, driving an earlier perceived peak in prevalence. The ECDC symptom definition was most influenced by SARS-CoV-2 positive individuals. Conclusions: Using a large community cohort we show how SARS-CoV-2 can impact ILI surveillance trends. SARS-CoV-2 makes up a substantial part of the community ILI burden and public health messaging should reflect this when discussing ILI. We show ILI is no longer a strong proxy for influenza activity alone.

Objectives: We evaluated all-cause healthcare utilization among those with vaccine-associated myocarditis, compared to vaccinees without postvaccination myocarditis. Methods: We conducted a retrospective cohort study in individuals aged 12 and older who received COVID-19 mRNA vaccination in British Columbia. Exposure was defined as an ED visit or hospitalization for myocarditis within 21 days postvaccination. The primary outcome was healthcare utilization. Ratios of rate ratios (RRRs) for exposure-associated healthcare utilization were calculated using a difference-in-differences (DiD) analysis. Results: In the postindex period, the exposed and unexposed groups showed substantial utilization rate difference (RD = 15.30 [95% CI, 14.47-16.13). A 51% overall increase in healthcare utilization was observed over 18 months among exposed individuals (RRR, 1.51 [95%CI, 1.08-2.11]). In the initial six months, healthcare utilization surpassed the 18-month estimate, exhibiting a 125% increase (RRR, 2.25 [95%CI, 1.43-3.52]), while the last 12 months showed no statistically significant change (RRR, 1.03 [95%CI, 0.72-1.47]). An additional 9.1 (95%CI, 8.53-9.71) visits per person were attributed to vaccine-associated myocarditis over 18 months (total excess = 938.26 healthcare visits). Conclusion: The initial surge in healthcare visits postexposure, mainly outpatient follow-ups, followed by a return to baseline rates, indicates a positive prognosis and supports the vaccine's safety profile.

Background: There have been over 670 million confirmed cases of SARS-CoV-2 infection globally, resulting in over 6.87 million deaths. With approximately 0.1 %−6.8 % experiencing reinfection. This retrospective cohort study aimed to compare the risk of short-term circulatory and respiratory sequelae between SARS-CoV-2 reinfection and initial infection, and assess the impact of vaccination. Method: Data from the TriNetX US Collaborative network (2020–2022) were used to create two cohorts based on reinfection status. The main outcome assessed were medical utilization, circulatory and respiratory symptoms, and circulatory and respiratory diseases. The Kaplan-Meier method was used to compare the risks between two cohorts. Four subgroup analyses (vaccination status, age, sex, race) and six sensitivity analyses (rigorous definition, modified exclusion criteria, treatment, different COVID-19 variants timeline, address survivorship bias, and E-value calculation) were also conducted. Results: The reinfection cohort showed a significant reduction in medical utilization [ Hazard ratio, HR: 0.867, (95 % confidence interval, CI:0.839–0.896) for hospitalization, 0.488 (0.418–0.570) for critical care services, and 0.476 (0.360–0.629) for mechanical ventilation], lower risk of circulatory diseases [ HR: 0.701 (95 % CI:0.637–0.772), 0.695 (0.583–0.829), 0.660 (0.605–0.719), 0.741 (0.644–0.854), 0.614 (0.535–0.705), and 0.758 (0.656–0.876) for ischemic heart disease, inflammatory heart disease, dysrhythmias, venous thromboembolism, other cardiac disorders, and cerebrovascular diseases, respectively], and lower risk of respiratory diseases such as pneumonia, other acute lower respiratory infections, asthma, and hypoxemia [HR: 0.302 (95 % CI: 0.273–0.333), 0.811 (0.686–0.958), 0.791 (0.735–0.850), and 0.392 (0.338–0.455), respectively]. The vaccinated reinfection cohort showed no significant differences in medical utilization, circulatory diseases, or respiratory conditions but had a higher risk of breathing abnormalities. breathing abnormalities [HR: 1.195 (95 % CI:1.087–1.313)]. Conclusions: The individuals who experienced reinfection exhibited milder short-term sequelae in the circulatory and respiratory systems. Vaccine administration protects against cardiovascular or respiratory systems.