A universal fluorescence polarization high throughput screening assay to target the SAM-binding sites of SARS-CoV-2 and other viral methyltransferases.

SARS-CoV-2 has caused a global pandemic with significant humanity and economic loss since 2020. Currently, only limited options are available to treat SARS-CoV-2 infections for vulnerable populations. In this study, we report a universal fluorescence polarization (FP)-based high throughput screening (HTS) assay for SAM-dependent viral methyltransferases (MTases), using a fluorescent SAM-analogue, FL-NAH. We performed the assay against a reference MTase, NSP14, an essential enzyme for SARS-CoV-2 to methylate the N7 position of viral 5'-RNA guanine cap. The assay is universal and suitable for any SAM-dependent viral MTases such as the SARS-CoV-2 NSP16/NSP10 MTase complex and the NS5 MTase of Zika virus (ZIKV). Pilot screening demonstrated that the HTS assay was very robust and identified two candidate inhibitors, NSC 111552 and 288387. The two compounds inhibited the FL-NAH binding to the NSP14 MTase with low micromolar IC50. We used three functional MTase assays to unambiguously verified the inhibitory potency of these molecules for the NSP14 N7-MTase function. Binding studies indicated that these molecules are bound directly to the NSP14 MTase with similar low micromolar affinity. Moreover, we further demonstrated that these molecules significantly inhibited the SARS-CoV-2 replication in cell-based assays at concentrations not causing cytotoxicity. Furthermore, NSC111552 significantly synergized with known SARS-CoV-2 drugs including nirmatrelvir and remdesivir. Finally, docking suggested that these molecules bind specifically to the SAM-binding site on the NSP14 MTase. Overall, these molecules represent novel and promising candidates to further develop broad-spectrum inhibitors for the management of viral infections.

Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial

Background Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. Methods This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. Findings Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively;p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7–837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0–672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0–71·4];p<0·0001). Interpretation A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. Funding National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.

Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial.

BACKGROUND: Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. METHODS: This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. FINDINGS: Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively; p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7-837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0-672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0-71·4]; p<0·0001). INTERPRETATION: A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. FUNDING: National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.

A high-throughput fully automatic biosensing platform for efficient COVID-19 detection.

We propose a label-free biosensor based on a porous silicon resonant microcavity and localized surface plasmon resonance. The biosensor detects SARS-CoV-2 antigen based on engineered trimeric angiotensin converting enzyme-2 binding protein, which is conserved across different variants. Robotic arms run the detection process including sample loading, incubation, sensor surface rinsing, and optical measurements using a portable spectrometer. Both the biosensor and the optical measurement system are readily scalable to accommodate testing a wide range of sample numbers. The limit of detection is 100 TCID50/ml. The detection time is 5 min, and the throughput of one single robotic site is up to 384 specimens in 30 min. The measurement interface requires little training, has standard operation, and therefore is suitable for widespread use in rapid and onsite COVID-19 screening or surveillance.

An Adapted Hybrid Model for Hands-On Practice on Disaster and Military Medicine Education in Undergraduate Medical Students During the COVID-19 Pandemic

Background The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial impacts on all aspects of medical education. Modern health systems must prepare for a wide variety of catastrophic scenarios, including emerging infectious disease outbreaks and human and natural disasters. During the COVID-19 pandemic, while the use of traditional teaching methods has decreased, the use of online-based teaching methods has increased. COVID-19 itself and the accompanying infection control measures have restricted full-scale practice. Therefore, we developed an adapted hybrid model that retained adequate hands-on practice and educational equality, and we applied it with a group of undergraduate medical students participating in a mandatory disaster education course in a military medical school. Methods The course covered the acquisition of skills used in emergency and trauma scenarios through designated interdisciplinary modules on disaster responses. Several asynchronous and synchronous online webinars were used in this one-credit mandatory disaster and military medicine education course. To allow opportunities for hands-on practice and ensure education equality, the students were divided into 15 groups, with 12 students in each group. The hands-on practice exercises were also recorded and disseminated to the students in the designated area for online learning. Results A total of 164 3rd-year medical students participated in this mandatory disaster and military medicine course during the COVID-19 pandemic. The satisfaction survey response rate was 96.5%. The students were satisfied with the whole curriculum (3.8/5). Most of the free-text comments regarding the course represented a high level of appreciation. The students felt more confident in the knowledge and skills they gained in hands-on exercises than they did in the knowledge and skills they gained in online exercises. The students showed significant improvements in knowledge after the course. Conclusions We demonstrated that this adapted hybrid arrangement provided an enhanced learning experience, but we also found that medical students were more confident in their knowledge and skills when they had real hands-on practice.

Irradiation accelerates SARS-CoV-2 infection by enhancing sphingolipid metabolism.

Cancer patients who receive radiotherapy have a high risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, but the concrete reason remains unclear. Herein, we investigated the influence of irradiation on the vulnerability of cancer cells to SARS-CoV-2 using S pseudovirions and probed the underlying mechanism via RNA-seq and other molecular biology techniques. Owing to the enhancement of sphingolipid metabolism, irradiation accelerated pseudovirion infection. Mechanistically, irradiation induced the expression of acid sphingomyelinase (ASM), which catalyses the hydrolysis of sphingomyelin to ceramide, contributing to lipid raft formation and promoting SARS-CoV-2 invasion. Inhibition of lipid raft formation with methyl-ß-cyclodextrin (MßCD) or the tyrosine kinase inhibitor genistein and ASM suppression through small interfering RNA or amitriptyline (AMT) treatment abolished the enhancing effect of irradiation on viral infection. Animal experiments supported the finding that irradiation promoted SARS-CoV-2 S pseudovirion infection in A549 cell tumour-bearing BALB/c nude mice, whereas AMT treatment dramatically decreased viral infection. This study discloses the role of sphingolipid metabolism in irradiation-induced SARS-CoV-2 infection, thus providing a potential target for clinical intervention to protect patients receiving radiotherapy from COVID-19.

Outbreak of acute respiratory disease caused by human adenovirus type 7 and human coronavirus-229E in Zhejiang Province, China.

In 2019, an outbreak of pharyngoconjunctival fever (PCF) occurred at a swimming center in Zhejiang Province, China. A total of 97 (13.55%) of the 716 amateur swimmers had illnesses, with 24 patients (24.74%) hospitalized in the pediatric ward. Human adenovirus serotype 7 (HAdV-7) was isolated from one concentrated water from the swimming pool, and 20 of 97 positive cases without liver damage. This outbreak led to a nosocomial outbreak in the pediatric ward, in which 1 nurse had a fever and was confirmed to be adenovirus positive. The hexon, fiber, and penton genes from 20 outbreak cases, 1 water sample, and 1 nurse had 100% homology. Furthermore, 2 cases admitted to the pediatric ward, 2 parents, and 1 doctor were confirmed to be human coronaviruses (HCoV-229E) positive. Finally, all outbreak cases had fully recovered, regardless of a single infection (adenovirus or HCoV-229E) or coinfection of these two viruses simultaneously. Thus, PCF and acute respiratory disease outbreaks in Zhejiang were caused by the completely homologous type 7 adenovirus and HCoV-229E, respectively. The swimming pool water contaminated with HAdV-7 was most likely the source of the PCF outbreak, whereas nosocomial transmission might be the source of HCoV-229E outbreak.

The clinical and virological features of two children's coinfections with human adenovirus type 7 and human coronavirus-229E virus.

Objective: Human adenovirus (HAdV) coinfection with other respiratory viruses is common, but adenovirus infection combined with human coronavirus-229E (HCoV-229E) is very rare. Study design and setting: Clinical manifestations, laboratory examinations, and disease severity were compared between three groups: one coinfected with HAdV-Ad7 and HCoV-229E, one infected only with adenovirus (mono-adenovirus), and one infected only with HCoV-229E (mono-HCoV-229E). Results: From July to August 2019, there were 24 hospitalized children: two were coinfected with HAdV-Ad7 and HCoV-229E, and 21 were infected with a single adenovirus infection. Finally, one 14-year-old boy presented with a high fever, but tested negative for HAdV-Ad7 and HCoV-229E. Additionally, three adult asymptotic cases with HCoV-229E were screened. No significant difference in age was found in the coinfection and mono-adenovirus groups (11 vs. 8 years, p = 0.332). Both groups had the same incubation period (2.5 vs. 3 days, p = 0.8302), fever duration (2.5 vs. 2.9 days, p = 0.5062), and length of hospital stay (7 vs. 6.76 days, p = 0.640). No obvious differences were found in viral loads between the coinfection and mono-adenovirus groups (25.4 vs. 23.7, p = 0.570), or in the coinfection and mono-HCoV-229E groups (32.9 vs. 30.06, p = 0.067). All cases recovered and were discharged from the hospital. Conclusion: HAdV-Ad7 and HCoV-229E coinfection in healthy children may not increase the clinical severity or prolong the clinical course. The specific interaction mechanism between the viruses requires further study.

γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5.

An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.

Establishment and evaluation of fluorescent RT-RAA assay for SARS-CoV-2 sgRNAs detection

Objective To establish a reverse-transcription recombinase-aided amplification assay（RT-RAA） to rapidly detect SARS-CoV-2 sub-genomic RNAs（sgRNAs）. Methods The primers and probe for isothermal nucleic acid amplification were designed based on the 5′-leader and 7a and N gene sequence of SARS-CoV-2, and the sgRNAs of SARS-COV-2 were rapidly detected within 30 min at 39 ℃.The sensitivity, specificity and consistency of the assay were evaluated. Results The detection limit of the method was 20 copies/μl and there were no cross-reactions with other respiratory pathogens, showing decent sensitivity and specificity.The results of the assay were concordant with that of real-time PCR, indicating a better consistency of two methods（κ=0.762,P<0.001）. Conclusions The fluorescence RT-RAA assay established in the study can be used for the rapid detection of SARS-CoV-2 sgRNAs, which is of great significance for the rapid diagnosis of COVID 19.

Antibody persistence and safety after heterologous boosting with orally aerosolised Ad5-nCoV in individuals primed with two-dose CoronaVac previously: 12-month analyses of a randomized controlled trial.

Antibody persistence and safety up to 12 months of heterologous orally administered adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in individuals who were primed with two-dose inactivated SARS-CoV-2 vaccine (CoronaVac) previously, has not been reported yet. This randomized, open-label, single-centre trial included Chinese adults who have received two-dose CoronaVac randomized to low-dose or high-dose aerosolised Ad5-nCoV group, or CoronaVac group. In this report, we mainly evaluated the geometric mean titres (GMTs) of neutralizing antibodies (NAbs) against live wild-type SARS-CoV-2 virus and omicron BA.4/5 pseudovirus at 12 months after the booster dose and the incidence of serious adverse events (SAEs) till month 12. Of 419 participants, all were included in the safety analysis and 120 (28.64%) were included in the immunogenicity analysis. Serum NAb GMT against live wild-type SARS-CoV-2 was 204.36 (95% CI 152.91, 273.14) in the low-dose group and 171.38 (95% CI 121.27, 242.19) in the high-dose group at month 12, significantly higher than the GMT in the CoronaVac group (8.00 [95% CI 4.22, 15.17], p < 0.0001). Serum NAb GMT against omicron BA.4/5 pseudovirus was 40.97 (95% CI 30.15, 55.67) in the low-dose group and 35.08 (95% CI 26.31, 46.77) in the high-dose group at month 12, whereas the GMT in the CoronaVac group was below the lower limit of detection. No vaccine-related SAEs were observed. Orally administered aerosolised Ad5-nCoV following two-dose CoronaVac priming has a good safety profile and is persistently more immunogenic than three-dose CoronaVac within 12 months after the booster dose.Trial registration: ClinicalTrials.gov identifier: NCT05043259..

The clinical and virological features of two children's coinfections with human adenovirus type 7 and human coronavirus-229E virus

Objective Human adenovirus (HAdV) coinfection with other respiratory viruses is common, but adenovirus infection combined with human coronavirus-229E (HCoV-229E) is very rare. Study design and setting Clinical manifestations, laboratory examinations, and disease severity were compared between three groups: one coinfected with HAdV-Ad7 and HCoV-229E, one infected only with adenovirus (mono-adenovirus), and one infected only with HCoV-229E (mono-HCoV-229E). Results From July to August 2019, there were 24 hospitalized children: two were coinfected with HAdV-Ad7 and HCoV-229E, and 21 were infected with a single adenovirus infection. Finally, one 14-year-old boy presented with a high fever, but tested negative for HAdV-Ad7 and HCoV-229E. Additionally, three adult asymptotic cases with HCoV-229E were screened. No significant difference in age was found in the coinfection and mono-adenovirus groups (11 vs. 8 years, p = 0.332). Both groups had the same incubation period (2.5 vs. 3 days, p = 0.8302), fever duration (2.5 vs. 2.9 days, p = 0.5062), and length of hospital stay (7 vs. 6.76 days, p = 0.640). No obvious differences were found in viral loads between the coinfection and mono-adenovirus groups (25.4 vs. 23.7, p = 0.570), or in the coinfection and mono-HCoV-229E groups (32.9 vs. 30.06, p = 0.067). All cases recovered and were discharged from the hospital. Conclusion HAdV-Ad7 and HCoV-229E coinfection in healthy children may not increase the clinical severity or prolong the clinical course. The specific interaction mechanism between the viruses requires further study.

Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial.

BACKGROUND: Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine. METHODS: We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine-Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0 × 1011 viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0 × 1011 viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259. FINDINGS: Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (p<0·0001). The low dose group had a serum NAb GMT of 744·4 (95% CI 520·1-1065·6) and the high dose group had a GMT of 714·1 (479·4-1063·7) 14 days after booster dose, significantly higher than the GMT in the CoronaVac group (78·5 [60·5-101·7]; p<0·0001). INTERPRETATION: We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination. FUNDING: National Natural Science Foundation of China and Jiangsu Provincial Key Research and Development Program.

COVID-19 Diagnostic Methods and Detection Techniques

Coronavirus disease 2019 (COVID-19) is an emerging human-to-human infectious disease that broke out in early December 2019 and threatens global public health, causing widespread concern. This respiratory disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The development of rapid and reliable techniques for COVID-19 diagnosis is a significant step to prevent further infections. Combinations of genome sequencing, nucleic acid molecular testing, clustered regularly interspaced short palindromic repeats editing technology, antigen/antibody detection, and computed tomography imaging have been implemented to identify and screen COVID-19 infections. Moreover, other new diagnosis methods such as dried blood spots and biosensors are being developed and are summarized here. This manuscript reviews currently available methods for SARS-CoV-2 detection with the aim of helping researchers develop timely and effective technologies to detect this emerging virus and its variants.

Do patients with and survivors of COVID-19 benefit from telerehabilitation? A meta-analysis of randomized controlled trials

Background Coronavirus disease 2019 (COVID-19) significantly impacts physical, psychological, and social functioning and reduces quality of life, which may persist for at least 6 months. Given the fact that COVID-19 is a highly infectious disease and therefore healthcare facilities may be sources of contagion, new methods avoiding face-to-face contact between healthcare workers and patients are urgently needed. Telerehabilitation is the provision of rehabilitation services to patients at a distance via information and communication technologies. However, high-quality evidence of the efficacy of telerehabilitation for COVID-19 is still lacking. This meta-analysis aimed to investigate the efficacy of telerehabilitation for patients with and survivors of COVID-19. Methods We searched the Cochrane Library, EMBASE, Medline (via PubMed), PEDro, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform from January 1st, 2020 to April 30th, 2022 for randomized controlled trials published in English, which aimed to evaluate the efficacy of telerehabilitation vs. face-to-face rehabilitation, usual care, or no treatment for COVID-19. Methodological quality and overall evidence quality of the included studies were assessed. The statistical reliability of the data was quantified using the trial sequential analysis. Results Seven randomized controlled trials with eight comparisons were included and all of them were used for meta-analysis. The meta-analyses of absolute values showed the superiority of telerehabilitation over no treatment or usual care for dyspnea (Borg scale: mean difference = −1.88, −2.37 to −1.39;Multidimensional dyspnea-12: mean difference = −3.70, −5.93 to −1.48), limb muscle strength (mean difference = 3.29;2.12 to 4.47), ambulation capacity (standardized mean difference = 0.88;0.62 to 1.14), and depression (mean difference = −5.68;−8.62 to −2.74). Significant improvement in these variables persisted in the meta-analyses of change scores. No significant difference was found in anxiety and quality of life. No severe adverse events were reported in any of the included studies. Conclusions Moderate- to very low-quality evidence demonstrates that telerehabilitation may be an effective and safe solution for patients with and survivors of COVID-19 in dyspnea, lower limb muscle strength, ambulation capacity, and depression. Further well-designed studies are required to evaluate the long-term effects, cost-effectiveness, and satisfaction in larger samples.

Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): A randomized, observer-blinded, placebo-controlled trial.

BACKGROUND: Heterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF). METHODS AND FINDINGS: We conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data. CONCLUSIONS: Heterologous boosting with ZF2001 following primary vaccination with Convidecia is more immunogenic than a single dose of Convidecia and is not associated with safety concerns. These results support flexibility in cooperating viral vectored and recombinant protein vaccines. TRIAL REGISTRATION: Study on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov NCT04833101.

Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19), with macrophages as one of the main cell types involved. It is urgent to understand the interactions among permissive cells, macrophages, and the SARS-CoV-2 virus, thereby offering important insights into effective therapeutic strategies. Here, we establish a lung and macrophage co-culture system derived from human pluripotent stem cells (hPSCs), modeling the host-pathogen interaction in SARS-CoV-2 infection. We find that both classically polarized macrophages (M1) and alternatively polarized macrophages (M2) have inhibitory effects on SARS-CoV-2 infection. However, M1 and non-activated (M0) macrophages, but not M2 macrophages, significantly up-regulate inflammatory factors upon viral infection. Moreover, M1 macrophages suppress the growth and enhance apoptosis of lung cells. Inhibition of viral entry using an ACE2 blocking antibody substantially enhances the activity of M2 macrophages. Our studies indicate differential immune response patterns in distinct macrophage phenotypes, which could lead to a range of COVID-19 disease severity.

Distribution of Yeast Species and Risk Factors of Oral Colonization after Oral-Care Education among the Residents of Nursing Homes.

Most yeasts causing infections in humans are part of commensal microflora and etiological agents of different infections when hosts become susceptible, usually due to becoming immunocompromised. The colonization of potentially pathogenic microbes in the oral cavity is increased by poor oral hygiene. This follow-up survey was conducted approximately two months after providing information on proper oral care at 10 nursing homes in Taiwan. Among the 117 of 165 residents colonized by yeasts, 67 were colonized by more than one yeast species. A total of 231 isolates comprising eight fungal genera and 25 species were identified. Candida albicans (44.6%) was the dominant species, followed by Candida glabrata (17.7%), Candida parapsilosis (8.7%), Candida tropicalis (7.8%), and Candida pararugosa (7.3%). Residents having a yeast colony-forming unit >10 (OR, 8.897; 95% CI 2.972-26.634; p < 0.001) or using a wheelchair (OR, 4.682; 95% CI 1.599-13.705; p = 0.005) were more likely to be colonized by multiple species. By comparing before and after oral-care education, dry mouth (OR, 3.199; 95% CI 1.448-7.068; p = 0.011) and having heart disease (OR, 2.681; 95% CI 1.068-6.732; p = 0.036) emerged as two independent risk factors for increased density of colonizing yeast.

Heterologous AD5-nCOV plus CoronaVac versus homologous CoronaVac vaccination: a randomized phase 4 trial.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and the waning of vaccine-elicited neutralizing antibodies suggests that additional coronavirus disease 2019 (COVID-19) vaccine doses may be needed for individuals who initially received CoronaVac. We evaluated the safety and immunogenicity of the recombinant adenovirus type 5 (AD5)-vectored COVID-19 vaccine Convidecia as a heterologous booster versus those of CoronaVac as homologous booster in adults previously vaccinated with CoronaVac in an ongoing, randomized, observer-blinded, parallel-controlled phase 4 trial ( NCT04892459 ). Adults who had received two doses of CoronaVac in the past 3-6 months were vaccinated with Convidecia (n = 96) or CoronaVac (n = 102). Adults who had received one dose of CoronaVac in the past 1-3 months were also vaccinated with Convidecia (n = 51) or CoronaVac (n = 50). The co-primary endpoints were the occurrence of adverse reactions within 28 d after vaccination and geometric mean titers (GMTs) of neutralizing antibodies against live wild-type SARS-CoV-2 virus at 14 d after booster vaccination. Adverse reactions after vaccination were significantly more frequent in Convidecia recipients but were generally mild to moderate in all treatment groups. Heterologous boosting with Convidecia elicited significantly increased GMTs of neutralizing antibody against SARS-CoV-2 than homologous boosting with CoronaVac in participants who had previously received one or two doses of CoronaVac. These data suggest that heterologous boosting with Convidecia following initial vaccination with CoronaVac is safe and more immunogenic than homologous boosting.