Creutzfeldt-Jakob Disease with Initial Typical Parkinsonism Precipitated by COVID-19? A Case Report (preprint)

Background Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disease caused by the accumulation of PrPSc. While COVID-19-induced sporadic CJD (sCJD) with parkinsonism as the initial symptom is extremely uncommon, this report aims to raise awareness of sCJD cases that present with parkinsonism that are not associated with genetic mutations or pathological α-synuclein (α-Syn) accumulation. Case presentation This report presents the case of a 72-year-old man with probable sporadic Creutzfeldt-Jakob disease (sCJD) who initially showed symptoms of parkinsonism, which worsened rapidly after contracting COVID-19. Despite a history of responsive tremor and bradykinesia, his condition deteriorated following the viral infection, leading to rapid consciousness decline and diffuse myoclonus. Diagnostic tests, including brain MRI, cerebrospinal fluid analysis, and EEG, pointed towards prion disease. PrPSc, a marker for CJD, was detected in both the cerebrospinal fluid and skin samples using RT-QuIC, further confirming the diagnosis. Notably, skin analysis revealed PrPSc but no pathological α-synuclein deposits, ruling out typical Parkinson's disease.  Conclussion This case underscores the importance of considering sCJD in patients with parkinsonism, especially if they experience sudden neuropsychiatric symptoms, especially if they do not exhibit pathological α-Syn accumulation or have genetic mutations.

LSR is a cell-intrinsic defence factor against SARS-CoV-2 infection in small intestine (preprint)

The identification of host factors with antiviral potential is important for developing effective prevention as well as therapeutic strategies against SARS-CoV-2. Here, we have identified the lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host-defense factor against SARS-CoV-2 infection in small intestine using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues, and humanized ACE2 mouse model as proof-of-principle systems. Loss of endogenous LSR enhances ACE2-dependent infection by pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protect against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to Spike protein, and thus blocking viral entry and restricting Spike-mediated cell-cell fusion. These results identify both a previously unknown function for LSR and an associated antiviral host defense mechanism against SARS-CoV-2. The capacity of a small LSR-derived peptide to block Spike binding to the ACE2 receptor holds promise for pan-variant therapeutic interventions.

Study on prescription medication mode and mechanism of traditional Chinese medicine in the treatment of noncritical COVID-19 based on data mining

Background: As of 2023, coronavirus disease 2019 (COVID-19) is still spreading globally. Therefore, we aim to integrate non-critical COVID-19 high-frequency and high-targeting Chinese medicines to provide a reference for clinical prescriptions to improve COVID-19-related symptoms. Materials and methods: The information on non-critical COVID-19 high-frequency Chinese medicines in the diagnosis and treatment of COVID-19 was obtained by the TCM inheritance support platform. Using network pharmacology and molecular docking technology, high-targeting Chinese medicines with good docking activity with COVID-19 receptors angiotensin-converting enzyme-II (ACE2), 3CLpro and tyrosine-protein kinase receptor UFO (AXL) were obtained. A new prescription for non-critical COVID-19 was established by integrating high-frequency and high-targeting Chinese medicines. Rats with acute lung injury induced by lipopolysaccharide were used as the experimental model. The histopathological changes in the lungs of rats in each group were observed by hematoxylin-eosin staining. The lung coefficient of rats was measured. The levels of IL-6, TNF-a, and IL-1ß in serum were detected by enzyme-linked immunosorbent assay. The mRNA and protein levels of ACE2 and AXL in lung tissue were detected by real-time quantitative polymerase chain reaction and western blot. Results: Through data mining, it was found that there were 39 high-frequency traditional Chinese medicines for non-critical COVID-19 in the diagnosis and treatment guidelines. According to network pharmacology and molecular docking, 30 highly targeted traditional Chinese drugs for COVID-19 were found. The new prescriptions for non-critical COVID-19 were comprehensively obtained, including Glycyrrhizae Radix, Ephedra Herba, Amygdalus Communis Vas, Gypsum Fibrosum, Descurainiae Semen, Atractylodes Lancea, Scutellariae Radix, Amomum Tsao-Ko Crevostet, Forsythiae Fructus, Pogostemon cablin, Magnolia Officinalis. Compared with the LPS-induced lung injury model group, the medium dose of the new prescription group had significantly alleviated pathological changes in lung tissue, decreased lung coefficient, decreased contents of IL-6, TNF-a and IL-1ß, and increased mRNA and protein expression of ACE2 and AXL (P < 0.05). Conclusion: Based on data mining, network pharmacology and molecular docking technology, the new prescription for non-critical COVID-19 established by this method has an anti-inflammatory effect on rats with acute lung injury induced by lipopolysaccharide and can provide a reference for clinicians to alleviate the symptoms related to non-critical COVID-19. [ FROM AUTHOR] Copyright of Traditional Medicine Research is the property of TMR Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

How Risky if China Moves Away from Its Zero-COVID Policy? (preprint)

There are two contrary opinions regarding the risk if mainland China (MC) moves away from its zero-COVID policy. Some experts think the risk shall be much lower than influenza as per MC’s own COVID-19 case fatality rate (CFR), while some other experts think the risk shall be much higher than influenza as per the COVID-19 CFRs of other regions. We elucidate here that this and multiple other striking differences in the CFR between various scenarios all support and substantially resulted from the view that good IDM is highly powerful to mitigate COVID-19, where IDM (isolation-disinfection-maintenance) means isolation of COVID-19 cases from other people, disinfection of their living environments, and health maintenance (e.g., rest, nutrition, breathing). The high effect of good IDM is also supported by the theoretic functions of IDM in minimizing co-infections and maintaining body functions, and the fact that all the 505 COVID-19 deaths reported in MC in 2022 before May 5 died directly of severe underlying diseases with COVID-19. Although it is tough for people in poverty to obtain good IDM, good IDM can be feasible at home for the most mild cases and in hospitals for the most severe cases. Therefore, good IDM can be crucial to mitigating COVID-19 worldwide. It also suggests that the risk for China to end its zero-COVID policy depends on China’s control policies or measures. Based on the effect of IDM, the cautious co-existence policy was proposed for COVID-19 control. This policy could reduce the whole death toll in MC because good IDM is non-specific and can reduce deaths of various other diseases. The cautious co-existence policy (non-specific) and the vaccination policy (specific) aid each other to mitigate COVID-19, and they cannot replace each other. Those who are qualified in health for vaccination should be vaccinated against COVID-19 timely.

Neutralizing breadth of antibodies targeting diverse conserved epitopes between SARS-CoV and SARS-CoV-2 (preprint)

Antibody therapeutics for the treatment of COVID-19 has been highly successful while faces a challenge of the recent emergence of the Omicron variant which escapes the majority of existing SARS-CoV-2 neutralizing antibodies (nAbs). Here, we successfully generated a panel of SARS-CoV-2/SARS-CoV cross-neutralizing antibodies by sequential immunization of the two pseudoviruses. Of which, nAbs X01, X10 and X17 showed broadly neutralizing breadths against most variants of concern (VOCs) and X17 was further identified as a Class 5 nAb with undiminished neutralization against the Omicron variant. Cryo-EM structures of three-antibody in complex with the spike proteins of prototyped SARS-CoV-2, Delta, Omicron and SARS-CoV defined three non-overlapping conserved epitopes on the receptor-binding domain (RBD). The triple antibody cocktail exhibited enhanced resistance to viral escape and effective protection against the infection of Beta variant in hamsters. Our finding will aid the development of both antibody therapeutics and broad vaccines against SARS-CoV-2 and emerging variants.

Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine (preprint)

The widespread SARS-CoV-2 in humans results in the continuous emergence of new variants. Recently emerged Omicron variant with multiple spike mutations sharply increases the risk of breakthrough infection or reinfection, highlighting the urgent need for new vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x), which showed high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine comprised of STFK and STFK1628x elicited high titers of broad-spectrum antibodies to neutralize all 14 circulating SARS-CoV-2 variants, including Omicron; and fully protected vaccinees from intranasal SARS-CoV-2 challenges of either the ancestral strain or immune-evasive Beta variant. Strikingly, the vaccination of hamsters with the bivalent vaccine completely blocked the within-cage virus transmission to unvaccinated sentinels, for either the ancestral SARS-CoV-2 or Beta variant. Thus, our study provides new insights and antigen candidates for developing next-generation COVID-19 vaccines.

Molecular basis of broad neutralization against SARS-CoV-2 variants including Omicron by a human antibody (preprint)

Omicron, a newly emerging SARS-CoV-2 variant, carried a large number of mutations in the spike protein leading to an unprecedented evasion from many neutralizing antibodies (nAbs). Here, we performed a head-to-head comparison of Omicron with other existing highly evasive variants in terms of their reduced sensitivities to antibodies, and found that Omicron variant is significantly more evasive than Beta and Mu variants. Of note, some key mutations occur in the conserved epitopes identified previously, especially in the binding sites of Class 4 nAbs, contributing to the increased Ab evasion. We also reported a broadly nAb (bnAb), VacW-209, which effectively neutralized all tested SARS-CoV-2 variants and even SARS-CoV. Finally, we determined six cryo-electron microscopy structures of VacW-209 complexed with the spike ectodomains of wild-type, Delta, Mu, C.1.2, Omicron, and SARS-CoV, and revealed the molecular basis of the broadly neutralizing activities of VacW-209 against SARS-CoV-2 variants. Overall, Omicron has once again raised the alarm over virus variation with significantly compromised neutralization. BnAbs targeting more conserved epitopes among variants will continue to play a key role in pandemic control and prevention. One sentence summaryStructural and functional analyses reveal that a human antibody named VacW-209 confers broad neutralization against SARS-CoV-2 variants including Omicron by recognizing a highly conserved epitope.

Cross-neutralizing antibodies bind a SARS-CoV-2 cryptic site and resist to circulating variants (preprint)

The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the still ravaging COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses’ receptor binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Significantly, both antibodies confer good mutation resistance to the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics, and can also inform the design of pan-sarbecovirus vaccines.

Association Between Cystatin C, Cystatin C Rangeability and Mortality of COVID-19 Patients With or Without Type 2 Diabetes Mellitus: An Opportunistic Retrospective Analysis (preprint)

Background: Since December of 2019, novel coronavirus (SARS-CoV-2)-induced pneumonia (COVID-19) exploded in Wuhan, and rapidly spread throughout China. Patients with COVID-19 demonstrated quite different appearances and outcomes in clinical manifestations. We aimed to figure out whether risk factors of the cystatin C (CysC) and the CysC rangeability are influencing the prognosis of COVID-19 patients with or without type 2 diabetes mellitus (T2DM).Methods: 675 T2DM patients and 602 non-T2DM patients were divided into low CysC group, high CysC group and low CysC rangeability group, high CysC rangeability group according to the serum CysC level and the change range of CysC. Demographic characteristics, clinical data and laboratory results of the four groups were collected and analyzed.Results: Our data showed that COVID-19 patients with high CysC level and CysC rangeability had more organic damage and higher mortality rate compared to those with low level or low rangeability of CysC. Furthermore, patients with higher CysC level and CysC rangeability also demonstrated higher blood lymphocytes (lymph), C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) which may greatly influence disease progression and poor prognosis of COVID-19. After adjusting for possible confounders, multivariate analysis revealed that CysC≤0.93mg/dl as a reference, CysC＞0.93mg/dl were significantly associated with the risk of heart failure (OR=2.401, 95% CI: 1.118–5.156) and all-cause death (OR=2.734, 95% CI: 1.098-6.811); referring to CysC rangeability≤0, CysC rangeability＞0 significantly associated with all-cause death (OR=4.029, 95% CI: 1.864-8.706). Further grouped by T2DM, these associations were stronger in T2DM than in non-T2DM.Conclusions: It suggests that CysC level and CysC rangeability contribute to clinical manifestations and may influence the prognosis of COVID-19. The CysC is considered as a potential risk factor of the prognosis of COVID-19. Special medical care and appropriate intervention should be performed in COVID-19 patients with elevated CysC during hospitalization and later clinical follow-up, especially for those with T2DM.

Analysis and reflection on the transmission routes of SARS-COV-2

The novel coronavirus disease 2019 (COVID-19) outbreak occurred in December last year and spread quickly in the world, causing great harm to people. The rapid progression of this epidemic makes scholars in various fields conduct research on the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, the wildly accepted routes are droplets and close contact. Controversially, some researchers believe that other routes include aerosol diffusion, fecal-oral transmission, contacting urine, conjunctival infection, and mother-to-infant transmission may also infect people. In this article, combining the newest research and reports, the authors systematically analyzed the theoretical possibility and real-life probability of the transmission routes of the virus in order to help with the research and clinical judgment of the spread of infectious diseases in the future.

Clinical Characteristics and Risk factors for developed COVID-19 patients transferring to designated hospital from Jianghan Fangcang shelter Hospital: a retrospective, observational study (preprint)

Background The outbreak of coronavirus disease 2019 (COVID-19) has become a world-wide emergency. Fangcang shelter hospitals have been applied in COVID-19 to ease ongoing shortage of medical resources in Wuhan since February 2020. Methods This study enrolled all cases (no=1848) with mild or moderate type of COVID-19 in Fangcang shelter hospital of Jianghan in Wuhan from Feb 5th to Mar 9th, 2020. Diagnosis of COVID-19 was based on the National health commission of China. Epidemiological history, comorbidity, vital signs, symptoms and signs were recorded in detail. Laboratory tests included biochemical indicators and nucleic acid tests by throat swabs have been performed as well. Findings A total of 1327 patients reached the criteria of isolation release. Meanwhile, 521 patients have been transferred to the designated hospitals for further treatment, including severe type, fever more than 3 days, and severe comorbidity. The case-severity rate (rate of mild or moderate type transforming to severe type) was 3.0% in the shelter hospital. The patients from mild or moderate type to severe type showed the following clinical characteristics: the median incubation (onset to shelter) period was 10 days; they were all symptomatic at admission; fever, cough, and fatigue were the most common symptoms; hypertension, diabetes and coronary heart diseases were common co-morbidities; most of the patients had elevated levels of CRP at ill onset with 33.3% over 10 mg per L; bilateral distribution and ground-glass opacity were the most common manifestations in chest CT. Interpretation The potential risk factors of fever, fatigue, high level of C-reactive protein were the risk factors to identify the progression of COVID-19 patients with mild or moderate type. Fangcang shelter hospitals have substantially reduced the time from the onset of severe symptoms transfer to a designated hospital. Early application of the Fangcang shelter hospital may contribute to decrease the ratio of mild transforming to severe patients. Funding No specific grant from any funding was applied to this research.

Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation (preprint)

Pandemic coronavirus disease 2019 (COVID-19) is caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there are no efficacious vaccines or therapeutics that are urgently needed. We expressed three versions of spike (S) proteins--receptor binding domain (RBD), S1 subunit and S ectodomain--in insect cells. RBD appears monomer in solutions, whereas S1 and S associate into homotrimer with substantial glycosylation. The three proteins confer excellent antigenicity with six convalescent COVID-19 patient sera. Cryo-electron microscopy (cryo-EM) analyses indicate that the SARS-CoV-2 S trimer dominate in a unique conformation distinguished from the classic prefusion conformation of coronaviruses by the upper S1 region at lower position ~15 [A] proximal to viral membrane. Such conformation is proposed as an early prefusion state for the SARS-CoV-2 spike that may broaden the knowledge of coronavirus and facilitate vaccine development.

Exploration and analysis of the management mode of a cabin hospital during the outbreak of COVID-19 / 中华医院管理杂志

Since the outbreak of COVID-19 in Wuhan, cabin hospitals have played an important role in preventing the spread of the epidemic and admitting all the patients and suspected ones. As one of the first three cabin hospitals in Wuhan, Jianghan cabin hospital under care of Wuhan Union Hospital has efficiently fulfilled its purpose of admitting patients of mild symptoms. Measures taken by the cabin hospital include clearing its positioning, optimizing its layout, establishing organization structure, setting up the rules and regulations, and strengthening the prevention and control of hospital infection. This article briefly summed up the operation and management practices of the cabin hospital, and analyzed its management difficulties, hence putting forwards suggestions on medical emergency management system of China, for references of hospitals and authorities in charge.