Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Pathogenicity, tissue tropism and potential vertical transmission of SARSr-CoV-2 in Malayan pangolins.

Malayan pangolin SARS-CoV-2-related coronavirus (SARSr-CoV-2) is closely related to SARS-CoV-2. However, little is known about its pathogenicity in pangolins. Using CT scans we show that SARSr-CoV-2 positive Malayan pangolins are characterized by bilateral ground-glass opacities in lungs in a similar manner to COVID-19 patients. Histological examination and blood gas tests are indicative of dyspnea. SARSr-CoV-2 infected multiple organs in pangolins, with the lungs the major target, and histological expression data revealed that ACE2 and TMPRSS2 were co-expressed with viral RNA. Transcriptome analysis indicated that virus-positive pangolins were likely to have inadequate interferon responses, with relative greater cytokine and chemokine activity in the lung and spleen. Notably, both viral RNA and viral proteins were detected in three pangolin fetuses, providing initial evidence for vertical virus transmission. In sum, our study outlines the biological framework of SARSr-CoV-2 in pangolins, revealing striking similarities to COVID-19 in humans.

Virus diversity, wildlife-domestic animal circulation and potential zoonotic viruses of small mammals, pangolins and zoo animals.

Wildlife is reservoir of emerging viruses. Here we identified 27 families of mammalian viruses from 1981 wild animals and 194 zoo animals collected from south China between 2015 and 2022, isolated and characterized the pathogenicity of eight viruses. Bats harbor high diversity of coronaviruses, picornaviruses and astroviruses, and a potentially novel genus of Bornaviridae. In addition to the reported SARSr-CoV-2 and HKU4-CoV-like viruses, picornavirus and respiroviruses also likely circulate between bats and pangolins. Pikas harbor a new clade of Embecovirus and a new genus of arenaviruses. Further, the potential cross-species transmission of RNA viruses (paramyxovirus and astrovirus) and DNA viruses (pseudorabies virus, porcine circovirus 2, porcine circovirus 3 and parvovirus) between wildlife and domestic animals was identified, complicating wildlife protection and the prevention and control of these diseases in domestic animals. This study provides a nuanced view of the frequency of host-jumping events, as well as assessments of zoonotic risk.

Trends and Characteristics of New Drug Approvals in China, 2011-2021.

BACKGROUND: In the past decade, the Chinese drug regulatory system has undergone many changes. A major reform starting in 2015 has significantly reshaped the regulatory processes. It was important to assess the impact of the reform on new drug approvals in China. METHOD: We analyzed the temporal trends of regulatory characteristics of the new drugs approved by the Chinese regulatory agency from 2011 to 2021, using data collected in the Pharmcube database. RESULTS: A total of 353 new drugs were approved, including 220 small molecule drugs, 86 biological products and 47 vaccines. The annual number of new drug approvals increased dramatically since 2017, reaching a record high of 70 in 2021. The median NDA approval time was 15.4 months in 2017-2021, the shortest in the decade, and was significantly shorter than that in the pre-reform period. The newly instituted expedited pathways such as priority review (PR) and accelerated approval for urgently needed overseas drugs (UNOD) significantly reduced new drug application (NDA) approval times compared with standard review. For imported drugs, in 2017-2021, the median time difference between the first approval in the world and the approval in China was 5 years, representing significant "drug lag". However, the proportion of the imported drugs approved in China within 3 years of its first foreign approval has increased to 24.4% in 2017-2021. CONCLUSION: The regulatory reform has produced significant, positive immediate outcomes in several metrics of drug regulatory approval. China's regulatory system will continue to evolve as there still are many areas requiring further reform and improvement.

Combined cooling, heating, power and oxygen for hospital buildings employing photovoltaic power and liquefied methane

To enhance the energy and gas supply security and reduce the greenhouse gas emission simultaneously, this paper presents a new cryogen-based co-production concept of combined cooling, heating, power and oxygen (CCHPO) for hospital buildings. By integrating with local photovoltaic power generation, two cryogenic liquids of liquefied methane and liquefied oxygen are used to store and produce multiple energies and medical gas. Detailed system modeling and performance analysis are carried out regarding the actual energy and gas consumption data from hospital buildings. The results obtained show the proposed CCHPO solution can be expected to fulfill the simultaneous requirements of energy conservation during normal operation and sustainable energy and gas supply during emergency operations.

Serologic response and safety of COVID-19 vaccination in HSCT or CAR T-cell recipients: a systematic review and meta-analysis.

BACKGROUND: Patients receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR T-cell) therapy are immunocompromised and at high risk of viral infection, including SAR2-CoV-2 infection. However, the effectiveness and safety of COVID-19 vaccines in these recipients is not well characterized. The present meta-analysis evaluated the serologic response and safety of COVID-19 vaccines in these population. METHODS: Literature databases (MEDLINE, EMBASE, Web of Science, MedRvix and BioRvix) were searched for original studies with serologic response post COVID-19 vaccination in HSCT or CAR T-cell recipients published until July 14, 2022. The analysis included 27 observational studies with a total of 2899 patients receiving allogeneic HSCT (2506), autologous HSCT (286) or CAR T-cell therapy (107), and 683 healthy participants with serologic response data. Random effects models were used to pool the rate of serologic response to COVID-19 vaccination in HSCT or CAR T-cell recipients and odds ratio comparing with healthy controls. RESULTS: The pooled seropositivity rates in HSCT and CAR T-cell recipients were 0.624 [0.506-0.729] for one dose, 0.745 [0.712-0.776] for two doses. The rates were significantly lower than those in healthy controls (nearly 100%). In subgroup analysis, CAR T-cell recipients exhibited an even lower seroconversion rate (one dose: 0.204 [0.094-0.386]; two doses: 0.277 [0.190-0.386]) than HSCT counterparts (one dose: 0.779 [0.666-0.862]; two doses: 0.793 [0.762-0.821]). The rates were comparable between autologous and allogeneic HSCT recipients. Other possible impact factors related to seropositivity were time interval between therapy and vaccination, use of immunosuppressive drugs and immune cell counts. Most vaccine-related adverse effects were mild and resolvable, comparable to general population. CONCLUSIONS: This analysis revealed a diminished response to COVID-19 vaccines in HSCT or CAR T-cell recipients. Our findings may inform regular COVID-19 vaccination at appropriate intervals after HSCT or CAR T-cell therapy.

Smart Mushroom-Inspired Imprintable and Lightly Detachable (MILD) Microneedle Patterns for Effective COVID-19 Vaccination and Decentralized Information Storage.

The key to controlling the spread of the coronavirus disease 2019 (COVID-19) and reducing mortality is highly dependent on the safe and effective use of vaccines for the general population. Current COVID-19 vaccination practices (intramuscular injection of solution-based vaccines) are limited by heavy reliance on medical professionals, poor compliance, and laborious vaccination recording procedures, resulting in a waste of health resources and low vaccination coverage, etc. In this study, we developed a smart mushroom-inspired imprintable and lightly detachable (MILD) microneedle platform for the effective and convenient delivery of multidose COVID-19 vaccines and decentralized vaccine information storage. The mushroom-like structure allows the MILD system to be easily pressed into the skin and detached from the patch base, acting as a "tattoo" to record the vaccine counts in situ without any storage equipment, offering quick accessibility and effortless readout, saving a great deal of valuable time and energy for both patients and health professionals. After loading inactivated SARS-CoV-2 virus-based vaccines, MILD system induced a high level of antibodies against the SARS-CoV-2 receptor-binding domain (RBD) in vivo without eliciting systemic toxicity and local damage. Collectively, this smart delivery platform serves as a promising carrier to improve COVID-19 vaccination efficacy through its dual capabilities of vaccine delivery and in situ data storage, thus exhibiting great potential for helping to contain the COVID-19 pandemic or a resurgence.

Hospital-oriented quad-generation (HOQG)-A combined cooling, heating, power and gas (CCHPG) system.

Along with the global spread of the COVID-19 pandemic, a number of hospitals are operating in the over-loaded state, which results in the ever-increasing requirements of cooling, heating, power, and medical gas supplies. This paper investigates a novel concept of hospital-oriented quad-generation (HOQG) to produce a combined cooling, heating, power and gas (CCHPG) system. Local renewable energy source (RES), high temperature superconducting (HTS) power cable and superconducting magnetic energy storage (SMES) device are used as the low-carbon electricity producer, carrier and regulator, respectively. Compared to the conventional copper cable and electrochemical battery, HTS terminal power units have superior advantages of high-efficiency power delivery and high-quality power compensation. To accommodate the surplus electricity from local RESs and guarantee emergency supply for the targeted hospital buildings, three cryogenic fluids of liquefied methane gas, liquefied oxygen and liquefied nitrogen are used as back-ups for both energy fuel and medical gas. By adopting a series of cascade energy utilization and thermally-activated energy conversion facilities, multiple clean energies of cooling, heating and power are produced to supply medical devices, and multiple medical gases of oxygen, nitrogen and carbon dioxide are delivered to hospitals for patient treatments. Compared to conventional diesel oil and compressed gas back-ups, these three cryogenic liquids have advantages of high-capacity, high-security storage and low-pollution utilization. Another possible benefit can be the low-temperature environment of these medical gases offers vaccines an appropriate delivering pathway against the COVID-19 pandemic. Therefore, the proposed HOQG can be expected to fulfill the demand of energy conservation and emission reduction simultaneously during the normal operation, as well as the demand of sustainable energy and medical gas supply under severe conditions such as natural and man-made disasters.

Base Composition and Host Adaptation of the SARS-CoV-2: Insight From the Codon Usage Perspective.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading rapidly all over the world and has raised grave concern globally. The present research aims to conduct a robust base compositional analysis of SARS-CoV-2 to reveal adaptive intricacies to the human host. Multivariate statistical analysis revealed a complex interplay of various factors including compositional constraint, natural selection, length of viral coding sequences, hydropathicity, and aromaticity of the viral gene products that are operational to codon usage patterns, with compositional bias being the most crucial determinant. UpG and CpA dinucleotides were found to be highly preferred whereas, CpG dinucleotide was mostly avoided in SARS-CoV-2, a pattern consistent with the human host. Strict avoidance of the CpG dinucleotide might be attributed to a strategy for evading a human immune response. A lower degree of adaptation of SARS-CoV-2 to the human host, compared to Middle East respiratory syndrome (MERS) coronavirus and SARS-CoV, might be indicative of its milder clinical severity and progression contrasted to SARS and MERS. Similar patterns of enhanced adaptation between viral isolates from intermediate and human hosts, contrasted with those isolated from the natural bat reservoir, signifies an indispensable role of the intermediate host in transmission dynamics and spillover events of the virus to human populations. The information regarding avoided codon pairs in SARS-CoV-2, as conferred by the present analysis, promises to be useful for the design of vaccines employing codon pair deoptimization based synthetic attenuated virus engineering.

Pathogenicity and transmissibility of a novel respirovirus isolated from a Malayan pangolin.

The identification of SARS-CoV-2-like viruses in Malayan pangolins (Manis javanica) has focused attention on these endangered animals and the viruses they carry. We successfully isolated a novel respirovirus from the lungs of a dead Malayan pangolin. Similar to murine respirovirus, the full-length genome of this novel virus was 15 384 nucleotides comprising six genes in the order 3'-(leader)-NP-P-M-F-HN-l-(trailer)-5'. Phylogenetic analysis revealed that this virus belongs to the genus Respirovirus and is most closely related to murine respirovirus. Notably, animal infection experiments indicated that the pangolin virus is highly pathogenic and transmissible in mice, with inoculated mice having variable clinical symptoms and a fatality rate of 70.37 %. The virus was found to replicate in most tissues with the exception of muscle and heart. Contact transmission of the virus was 100 % efficient, although the mice in the contact group displayed milder symptoms, with the virus mainly being detected in the trachea and lungs. The isolation of a novel respirovirus from the Malayan pangolin provides new insight into the evolution and distribution of this important group of viruses and again demonstrates the potential infectious disease threats faced by endangered pangolins.

Capturing Cytokines with Advanced Materials: A Potential Strategy to Tackle COVID-19 Cytokine Storm.

The COVID-19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great impact on the global economy and people's daily life. In the clinic, most patients with COVID-19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection-induced cytokine release syndrome (the so-called "cytokine storm"). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID-19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose-limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID-19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody-based and broad-spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID-19 cytokine storm and other inflammatory diseases.

Decoy nanoparticles protect against COVID-19 by concurrently adsorbing viruses and inflammatory cytokines.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.

Reducing False Negatives in COVID-19 Testing by Using Microneedle-Based Oropharyngeal Swabs.

Coronavirus disease 2019 (COVID-19) has become a severe threat to human health worldwide. Early etiological diagnosis plays a critical role in controlling COVID-19 pandemic. However, etiological diagnosis has been largely compromised by high "false-negative" rates of viral nucleic acid testing, resulting from limited sampling efficiency using conventional oropharyngeal swabs. Here, we engineer regular swabs by using a microneedle (MN) patch to significantly improve the quality and quantity of virus collection. The combination of MNs with different crosslinking levels endows the patches with dual capability of mucus penetration and virus extraction. Moreover, the antibody (Ab) against viral spike protein was integrated into the patch, conferring MNs with an active virus capture potential. By taking advantage of the biological and engineered species, we believe that the designed MN/Ab swabs could serve as a promising tool to improve current sampling efficiency with fewer false negatives, contributing to the containment of the COVID-19 pandemic.

Calming the Cytokine Storm in Pneumonia by Biomimetic Nanoparticles.

Recently, the Wang group at Soochow University and the Gu group at the University of California, Los Angeles demonstrated the targeting ability of platelet-derived extracellular vesicles to deliver anti-inflammatory drug [5-(p-fluorophenyl)-2-ureido] thiophene-3-carboxamide (TPCA-1) to pneumonia for calming the local cytokine storm in acute lung injury.