Identification of key mutations responsible for the enhancement of receptor-binding affinity and immune escape of SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns worldwide due to its enhanced transmissibility and immune escapability. The first dominant Omicron BA.1 subvariant harbors more than 30 mutations in the spike protein from the prototype virus, of which 15 mutations are located at the receptor binding domain (RBD). These mutations in the RBD region attracted significant attention, which potentially enhance the binding of the receptor human angiotensin-converting enzyme 2 (hACE2) and decrease the potency of neutralizing antibodies/nanobodies. This study applied the molecular dynamics simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method, to investigate the molecular mechanism behind the impact of the mutations acquired by Omicron on the binding affinity between RBD and hACE2. Our results indicate that five key mutations, i.e., N440K, T478K, E484A, Q493R, and G496S, contributed significantly to the enhancement of the binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that the key mutations E484A and Y505H reduce the binding affinities to RBD for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs.

Longitudinal associations of serum survivin with the severity and prognosis of community-acquired pneumonia patients.

BACKGROUND: Survivin is a member of apoptosis inhibitor proteins that evokes cellular proliferation and inhibits apoptosis. However, the role of survivin in community-acquired pneumonia (CAP) patients remains to be firmly established. The aim of this cohort study was to evaluate the correlations of serum survivin with the severity and prognosis of CAP patients. METHODS: This research included 470 eligible CAP patients. Serum fasting samples were drawn from patients, and serum survivin was measured by enzyme-linked immunosorbent assay (ELISA). Meanwhile, demographic characteristics and clinical information were collected. The prognosis of CAP patients was tracked. RESULTS: Serum survivin gradually decreased with elevated CAP severity scores. Additionally, the correlative analysis suggested that serum survivin was associated with many clinical characteristics. Furthermore, mixed linear and logistic regression models indicated that serum survivin was negatively associated with severity. After adjusting for confounding factors, logistic regression analyses found that lower serum survivin on admission elevated the risks of mechanical ventilation, vasoactive agent usage, longer hospital stays, ICU admission, and even death during hospitalization. Serum survivin in combination with CAP severity scores elevated the predictive capacities for severity and death in CAP patients compared with a single indicator. CONCLUSION: On admission, there are inverse dose-response associations of serum survivin with severity and poor prognosis in CAP patients, demonstrating that serum survivin may be involved in the pathophysiology process of CAP. Serum survivin may serve as a potential biomarker for disease evaluation and prognosis in CAP patients.

A simplified viral RNA extraction method based on magnetic nanoparticles for fast and high-throughput detection of SARS-CoV-2.

The ongoing outbreak of the novel coronavirus disease 2019 (COVID-19) draws worldwide concerns due to its long incubation period and strong infectivity. Although RT-PCR-based methods are being widely applied for clinical diagnosis, timely and accurate diagnosis towards COVID-19 causing virus, the SARS-CoV-2, is still limited due to labor-intensive and time-consuming operations. Herein, we report a new viral RNA extraction method based on poly-(amino ester) with carboxyl group (PC)-coated magnetic nanoparticles (pcMNPs) for the sensitive detection of SARS-CoV-2. This method combines the lysis and binding steps into one step, and refines multiple washing steps into one step, giving a turnaround time of less than 9 min. Furthermore, the extracted pcMNP-RNA complexes can be directly introduced into subsequent RT-PCR reactions without elution. This simplified viral RNA method could be well adapted in fast manual and automated high-throughput nucleic acids extraction protocols suitable for different scenarios. A high sensitivity down to 100 copies/mL and a linear correlation between 100 and 106 copies/mL of SARS-CoV-2 pseudovirus particles are achieved in both protocols. Benefitting from the simplicity and excellent performances, this new method can dramatically improve the efficiency and reduce operational requirements for the early clinical diagnosis and large-scale SARS-CoV-2 nucleic acid screening.

Safety and Effectiveness of SA58 Nasal Spray Against COVID-19 Infection in Medical Personnel: An Open-Label, Blank-Controlled Study - Hohhot City, Inner Mongolia Autonomous Region, China, 2022.

What is already known about this topic?: The active ingredient of the SA58 Nasal Spray is a broad-spectrum neutralizing antibody with a high neutralizing capacity against different Omicron sub-variants in vitro studies. What is added by this report?: This study demonstrated the safety and effectiveness of SA58 Nasal Spray against coronavirus disease 2019 (COVID-19) infection in medical personnel for the first time. What are the implications for public health practice?: This study provides an effective approach for the public to reduce their risk of COVID-19 infection. The findings of this research have the potential to significantly reduce the risk of infection and limit human-to-human transmission in the event of a COVID-19 outbreak.

SARS-CoV-2 BA.2 (Omicron) variant infection in pediatric liver transplanted recipients and cohabitants during 2022 Shanghai outbreak: a prospective cohort.

BACKGROUND: The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients. METHODS: We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients' infection developments and liver functions. RESULTS: Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1-13) years. The infection duration was 29 (Range: 18-40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05). CONCLUSIONS: Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants.

Safety and immunogenicity of a mosaic vaccine booster against Omicron and other SARS-CoV-2 variants: a randomized phase 2 trial.

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.

Blue LED light promoting the growth, accumulation of high-value isoflavonoids and astragalosides, antioxidant response, and biosynthesis gene expression in Astragalus membranaceus (Fisch.) Bunge hairy root cultures (preprint)

The root of Astragalus membranaceus (Fisch.) Bunge is one of the most frequently used herbs in traditional Chinese medicine (TCM) formulae for fighting COVID-19 infections, due to the presence of isoflavonoids and astragalosides associated with antiviral and immune-enhancing activities. For the first time, the exposure of A. membranaceus hairy root cultures (AMHRCs) to different colors of LED lights i.e., red, green, blue, red/green/blue (1/1/1, RGB), and white, was conducted to promote the root growth and accumulation of isoflavonoids and astragalosides. LED light treatment regardless of colors was found beneficial for root growth, which might be a result of the formation of more root hairs upon light stimulation. Blue LED light was found most effective for enhancing phytochemical accumulation. Results showed that the productivity of root biomass in blue-light grown AMHRCs with an initial inoculum size of 0.6% for 55 days was 1.40-fold higher than that in dark (control), and yields of high-value isoflavonoids and astragalosides including calycosin, formononetin, astragaloside IV, and astragaloside I increased by 3.17-fold, 2.66-fold, 1.78-fold, and 1.52-fold relative to control, respectively. Moreover, the photooxidative stress together with transcriptional activation of biosynthesis genes might contribute to the enhanced accumulation of isoflavonoids and astragalosides in blue-light grown AMHRCs. Overall, this work offered a feasible approach for obtaining higher yields of root biomass and medicinally important compounds in AMHRCs via the simple supplementation of blue LED light, which made blue-light grown AMHRCs industrially attractive as plant factory in controlled growing systems.

Low COVID-19 vaccine coverage and guardian acceptance among pediatric transplant recipients.

To investigate COVID-19 vaccine coverage in immunosuppressed children, assess guardians' intention to vaccinate children, and determine reasons and associated factors. In addition, we attempted to capture the characteristics of them with Omicron. We obtained the vaccination coverage and guardian vaccine acceptance among pediatric transplant recipients through a web-based questionnaire conducted from April 12 to 28, 2022, and performed the statistical analysis. Seven organ transplant recipient children with Omicron were also clinically analyzed. The three-dose vaccine coverage for liver transplant (n = 563) and hematopoietic stem cell transplantation (n = 122) recipient children was 0.9% and 4.9%, and guardian vaccine acceptance was 63.8%. Independent risk factors for vaccine acceptance were the child's age, geographic location, type of transplant, guardian's vaccination status, guardian's level of distress about epidemic events, guardian's risk perception ability, anxiety, and knowledge of epidemic control. The main reasons for vaccine hesitancy were fear of vaccine-induced adverse events and doubts about efficacy. Ultimately, most children infected with Omicron have mild or no symptoms and are infected by intra-family. Since vaccine coverage and guardian acceptance are lowest among liver transplant children, and the infected are mainly intra-family, we should devise more targeted education and vaccination instructions for their guardians.

Establishment and application of multiplex RT-PCR procedure for detection of three virus from swine

Based on the M gene sequence of TGEV and PEDV and VP2 gene sequence of PoRV, the optimal reaction system and amplification procedure were established by optimizing primer, probe concentration and annealing temperature, and the Quantitative PCR method of TaqMan probes for three viruses is successfully established. On this basis, after further optimization of conditions, a triple real-time fluorescent quantitative PCR method for detecting TGEV, PEDV, and PoRV was established. The detection sensitivity of this method for TGEV, PEDV, and PoRV were 2.49 copies/ L, 4.36 copies/ L, and 4.96 copies/ L respectively. The maximum value of CV in repeated trials detected by TGEV, PEDV and PoRV were 2.5%, 3.8%, 4.3%, and the maximum value of CV in repeated trials between groups were 3.7%, 3.4%, 3.2%, which are no more than 5%.indicating that the established method has good reproducibility. Using this method to detect PRV, PCV1, and PRRSV virus samples, there is no cross-reaction, indicating that the method is specific. Using the established method to detect 40 clinical diseases, the samples were tested, and the positive rates of TGEV, PEDV, and PoRV were 5%, 30%, and 12.5%respectively. The mixed infection rate of TGEV and PEDV was 2.5%, the mixed infection rate of PEDV and PoRV was 5%. The results of the multiple fluorescence quantitative PCR method are consistent with those of the detection of a single fluorescent RT-PCR method, indicating that the established method has good clinical application value.

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants.

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein ­ the so-called spike protein ­ all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.

A nanomaterial targeting the spike protein captures SARS-CoV-2 variants and promotes viral elimination.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.

Safety and immunogenicity of a broad-spectrum mosaic vaccine as a booster dose against SARS-CoV-2 Omicron and other circulating variants (preprint)

BACKGROUNDThe rising breakthrough infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, especially Omicron and its sub-lineages, have raised an urgent need to develop broad-spectrum vaccines against coronavirus disease 2019 (COVID-19). We have developed a mosaic-type recombinant vaccine candidate, named NVSI-06-09, having immune potentials against a broad range of SARS-CoV-2 variants. METHODSAn ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of NVSI-06-09 as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had completed two or three doses of BBIBP-CorV vaccinations at least 6 months prior to the enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against SARS-CoV-2 Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. RESULTSA total of 516 participants received booster vaccination. Interim results showed a similar safety profile between NVSI-06-09 and BBIBP-CorV booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 after the booster vaccination, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline level elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those boosted by BBIBP-CorV. CONCLUSIONSA booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against SARS-CoV-2 prototype strain and immune-evasive variants, including Omicron and its sub-lineages. The immunogenicity of NVSI-06-09 as a booster vaccine was superior to that of BBIBP-CorV. (Funded by LIBP and BIBP of Sinopharm; ClinicalTrials.gov number, NCT05293548).

Immune thrombocytopenic purpura induced by the COVID-19 vaccine after the second dose in a 78-year-old patient: A case report.

Coronavirus disease 2019 (COVID-19) has become a global pandemic, but treatment options remain limited. Up to now, vaccination has been the main strategy to prevent transmission and reduce disease severity. However, with follow-up observations after massive vaccination, immune thrombocytopenic purpura (ITP) induced by COVID-19 vaccines has attracted the attention of investigators. The present study reported the case of a 78-year-old elderly female who presented with 'oral bleeding for 2 days and scattered bleeding spots on the extremities for 1 day' after vaccination with the COVID-19 vaccine (Vero Cells), and blood routine analysis indicated a white blood cell count of 6.27x109/l, hemoglobin levels of 144 g/l and a low platelet (PLT) count of 1x109/l. Bone marrow cytomorphology showed thrombocytopenia, while no platelet-producing megakaryocytes were observed. The patient was diagnosed with ITP and given symptomatic and supportive treatment, such as prednisone acetate 1 mg/kg, recombinant human thrombopoietin, intravenous injection of human immunoglobulin 0.4 g/kg and prevention of bleeding. At 1 week after the treatment started, the patient's PLT count began to increase, and 9 days later, it returned to normal levels. The aim of the present study was to raise the awareness of medical staff regarding this disease and to increase the vigilance of the general public. At the same time, the present study also provided an effective method to manage this type of adverse reaction to the COVID-19 vaccine.

Medical students' perceptions and performance in an online regional anatomy course during the Covid-19 pandemic.

The present study evaluated the students' psychological well-being, experiences, performance, and perception of learning regional anatomy remotely. A regional anatomy remote learning curriculum was designed and learning materials were delivered virtually to 120 undergraduate medical students at Jinan University, China. All the students consented and voluntarily participated in this study by completing self-administered online questionnaires including the Zung's Self-Rating Anxiety and Depression Scales at the beginning and end of the learning session. A subset participated in focus group discussions. Most of the students (90.0%) positively evaluated the current distance learning model. More than 80% were satisfied with the content arrangement and coverage. Many students preferred virtual lectures (68.2%) and videos showing dissections (70.6%) during the distance learning sessions. However, writing laboratory reports and case-based learning were the least preferred modes of learning as they were only preferred by 23.2% and 14.1% of the students, respectively. There was no significant lockdown-related anxiety or depression reported by students using depression and anxiety scales as well as feedback from focus group discussions. The surveyed students' confidence scores in distance learning were significantly higher after 5 weeks than at the beginning of the session (3.05 ± 0.83 vs. 3.70 ± 0.71, P < 0.05). Furthermore, the present results showed no significant differences between the current group's academic performance in the unit tests as well as the final overall evaluation for different parts of the course compared to that of the previous year's cohort. The findings above were congruent with focus group discussion data that the use of the online teaching platform for regional anatomy significantly improved the students' confidence in virtual and self-directed learning and did not negatively affect their academic performance.

Clustered Regularly Interspaced Short Palindromic Repeat/Cas12a Mediated Multiplexable and Portable Detection Platform for GII Genotype Porcine Epidemic Diarrhoea Virus Rapid Diagnosis

Porcine epidemic diarrhoea virus (PEDV) is a member of the genus Alphacoronavirus in the family Coronaviridae. It causes acute watery diarrhoea and vomiting in piglets with high a mortality rate. Currently, the GII genotype, PEDV, possesses a high separation rate in wild strains and is usually reported in immunity failure cases, which indicates a need for a portable and sensitive detection method. Here, reverse transcription–recombinase aided amplification (RT-RAA) was combined with the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas12a system to establish a multiplexable, rapid and portable detection platform for PEDV. The CRISPR RNA (crRNA) against Spike (S) gene of GII PEDV specifically were added into the protocol. This system is suitable for different experimental conditions, including ultra-sensitive fluorescence, visual, UV light, or flow strip detection. Moreover, it exhibits high sensitivity and specificity and can detect at least 100 copies of the target gene in each reaction. The CRISPR/Cas12a detection platform requires less time and represents a rapid, reliable and practical tool for the rapid diagnosis of GII genotype PEDV.

Comprehensive Clinical Characterisation of Brain Fog in Adults Reporting Long COVID Symptoms.

(1) Introduction: A subset of individuals experiencing long COVID symptoms are affected by 'brain fog', a lay term that often refers to general cognitive dysfunction but one that is still poorly characterised. In this study, a comprehensive clinical characterisation of self-reported brain fog was conducted vis-à-vis other long COVID symptoms and parameters of mental, cognitive, and physical health. (2) Methodology: Adult participants reporting long COVID symptoms were recruited from hospital clinics and as self-referrals. Participants completed a battery of questionnaires and clinical assessments, including COVID-19 history, symptomatology, self-reported scales (Chalder Fatigue Scale [CFQ], Center for Epidemiological Studies Depression Scale, and Impact of Events Scale-Revised), computer-based cognitive assessments (simple response time and choice reaction time tasks), physical performance tests (gait velocity and muscle strength assessments), and an orthostatic active stand test. A systematic comparison between participants with and without self-reported brain fog was conducted, and a backwards binary logistic regression model was computed to identify the strongest independent associations with brain fog. This was complemented by an automatic cluster analysis to rank the importance of associations. Finally, a structural equation model was postulated with a causal model of key symptomatic indicators and functional consequences of brain fog as a latent variable. (3) Results: Of 108 participants assessed, brain fog was a self-reported symptom in 71 (65.7%) participants. Those with brain fog were at a longer point in time since COVID-19 onset and reported longer duration of low activity during the acute illness. When assessed, those with brain fog had higher frequencies of subjective memory impairment, word-finding difficulties, dizziness, myalgia, arthralgia, hyperhidrosis, cough, voice weakness, throat pain, visual and hearing problems, dysosmia, paraesthesia, chest pain, skin rashes, and hair loss; mean scores in fatigue, depression, and post-traumatic stress scales were higher; performance in both computer-based cognitive tasks was poorer; and measured gait speed and grip strength were lower. The logistic regression suggested that the best independent associations with brain fog were memory impairment, CFQ, and myalgia. The cluster analysis suggested that the most important associations with brain fog were CFQ, dizziness, myalgia, reduced gait speed, word-finding difficulties, reduced grip strength, and memory impairment. The SEM was consistent with key indicators of brain fog being CFQ, dizziness, myalgia, word-finding difficulties, and memory impairment; and reduced grip strength, gait speed, and cognitive response times its functional consequences. (4) Conclusions: The findings indicate that self-reported brain fog in long COVID is a recognisable symptom cluster primarily characterised by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment and has adverse psychological and psychomotor correlates. In long COVID, brain fog should be regarded as a wide-ranging symptom and addressed holistically with medical, psychological, and rehabilitative supports as guided by individual needs.

Dose-response relationship between risk factors and incidence of COVID-19 in 325 hospitalized patients: A multicenter retrospective cohort study.

BACKGROUND: The epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19) patients have been widely reported, but the assessment of dose-response relationships and risk factors for mortality and severe cases and clinical outcomes remain unclear. AIM: To determine the dose-response relationship between risk factors and incidence of COVID-19. METHODS: In this retrospective, multicenter cohort study, we included patients with confirmed COVID-19 infection who had been discharged or had died by February 6, 2020. We used multivariable logistic regression and Cox proportional hazard models to determine the dose-response relationship between risk factors and incidence of COVID-19. RESULTS: It clarified that increasing risk of in-hospital death were associated with older age (HR: 1.04, 95%CI: 1.01-1.09), higher lactate dehydrogenase [HR: 1.04, 95% confidence interval (CI): 1.01-1.10], C-reactive protein (HR: 1.10, 95%CI: 1.01-1.23), and procalcitonin (natural log-transformed HR: 1.88, 95%CI: 1.22-2.88), and D-dimer greater than 1 µg/mL at admission (natural log transformed HR: 1.63, 95%CI: 1.03-2.58) by multivariable regression. D-dimer and procalcitonin were logarithmically correlated with COVID-19 mortality risk, while there was a linear dose-response correlation between age, lactate dehydrogenase, D-dimer and procalcitonin, independent of established risk factors. CONCLUSION: Higher lactate dehydrogenase, D-dimer, and procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality.

Predictors of Submaximal Exercise Test Attainment in Adults Reporting Long COVID Symptoms.

Adults with long COVID often report intolerance to exercise. Cardiopulmonary exercise testing (CPET) has been used in many settings to measure exercise ability but has been conducted in a few long COVID cohorts. We conducted CPET in a sample of adults reporting long COVID symptoms using a submaximal cycle ergometer protocol. We studied pre-exercise predictors of achieving 85% of the age-predicted maximum heart rate (85%HRmax) using logistic regression. Eighty participants were included (mean age 46 years, range 25-78, 71% women). Forty participants (50%) did not reach 85%HRmax. On average, non-achievers reached 84% of their predicted 85%HRmax. No adverse events occurred. Participants who did not achieve 85%HRmax were older (p < 0.001), had more recent COVID-19 illness (p = 0.012) with higher frequency of hospitalization (p = 0.025), and had been more affected by dizziness (p = 0.041) and joint pain (p = 0.028). In the logistic regression model including age, body mass index, time since COVID-19, COVID-19-related hospitalization, dizziness, joint pain, pre-existing cardiopulmonary disease, and use of beta blockers, independent predictors of achieving 85%HRmax were younger age (p = 0.001) and longer time since COVID-19 (p = 0.008). Our cross-sectional findings suggest that exercise tolerance in adults with long COVID has potential to improve over time. Longitudinal research should assess the extent to which this may occur and its mechanisms. ClinicalTrials.gov identifier: NCT05027724 (TROPIC Study).

Orthostatic Intolerance in Adults Reporting Long COVID Symptoms Was Not Associated With Postural Orthostatic Tachycardia Syndrome.

In this observational cross-sectional study, we investigated predictors of orthostatic intolerance (OI) in adults reporting long COVID symptoms. Participants underwent a 3-min active stand (AS) with Finapres® NOVA, followed by a 10-min unmedicated 70° head-up tilt test. Eighty-five participants were included (mean age 46 years, range 25-78; 74% women), of which 56 (66%) reported OI during AS (OIAS). OIAS seemed associated with female sex, more fatigue and depressive symptoms, and greater inability to perform activities of daily living (ADL), as well as a higher heart rate (HR) at the lowest systolic blood pressure (SBP) point before the first minute post-stand (mean HRnadir: 88 vs. 75 bpm, P = 0.004). In a regression model also including age, sex, fatigue, depression, ADL inability, and peak HR after the nadir SBP, HRnadir was the only OIAS predictor (OR = 1.09, 95% CI: 1.01-1.18, P = 0.027). Twenty-two (26%) participants had initial (iOH) and 5 (6%) classical (cOHAS) orthostatic hypotension, but neither correlated with OIAS. Seventy-one participants proceeded to tilt, of which 28 (39%) had OI during tilt (OItilt). Of the 53 who had a 10-min tilt, 7 (13%) had an HR increase >30 bpm without cOHtilt (2 to HR > 120 bpm), but six did not report OItilt. In conclusion, OIAS was associated with a higher initial HR on AS, which after 1 min equalised with the non-OIAS group. Despite these initial orthostatic HR differences, POTS was infrequent (2%). ClinicalTrials.gov Identifier: NCT05027724 (retrospectively registered on August 30, 2021).

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants (preprint)

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the inactivated vaccine BBIBP-CorV. Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.