Moral injury and suicidal ideation among health professionals: The role of mental health.

BACKGROUND: The prolonged COVID-19 pandemic has burdened health professionals mentally and physically. This study aims to explore the relationship between moral injury (MI) and suicidal ideation (SI), and the role of mental health conditions in this relationship. METHODS: Three-wave repeated online cross-sectional study with a total of 10,388 health professionals were conducted in different stages (2020-2022) of the COVID-19 pandemic in mainland China. Participants completed the Chinese version of the Moral Injury Symptoms Scale-Health Professional, Post-Traumatic Stress Disorder (PTSD) Checklist for DSM-5 coupled with a blanket of scales. RESULTS: The prevalence of SI and MI among health professionals was 9.8 % and 40.2 %, respectively. The prevalence risk of SI was lower in wave 2 (OR = 0.64, 95 % CI: 0.54-0.77) and wave 3 (OR = 0.71, 95 % CI: 0.60-0.84) when compared with wave 1. MI (OR = 4.66, 95 % CI: 3.99-5.43), medical error (OR = 1.15, 95 % CI: 1.00-1.32), workplace violence (OR = 1.13, 95 % CI: 0.97-1.32), depression (OR = 94.08, 95 % CI: 63.37-139.69), anxiety (OR = 25.54, 95 % CI: 21.22-30.74), PTSD (OR = 24.51, 95 % CI: 19.01-31.60) were associated with a higher risk of SI. The mediation model revealed that depressive, anxiety, and PTSD symptoms explained 90.6 % of the total variance in the relationship between MI and SI. CONCLUSIONS: The risk of SI has reduced among health professionals since the first peak of the COVID-19 pandemic in China. MI may contribute to prevalent SI, and mental health conditions, especially depressive symptoms, play a significant role as mediators. LIMITATIONS: Cross-sectional design precludes the investigation of casual relationships. The nonrandom sampling method limits the generalization.

Evolution of Immune Evasion and Host Range Expansion by the SARS-CoV-2 B.1.1.529 (Omicron) Variant.

Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 (Omicron) has rapidly become the dominant strain, with an unprecedented number of mutations within its spike gene. However, it remains unknown whether these variants have alterations in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies and entry inhibitors. In this study, we found that Omicron spike has evolved to escape neutralization by three-dose inactivated-vaccine-elicited immunity but remains sensitive to an angiotensin-converting enzyme 2 (ACE2) decoy receptor. Moreover, Omicron spike could use human ACE2 with a slightly increased efficiency while gaining a significantly increased binding affinity for a mouse ACE2 ortholog, which exhibits limited binding with wild-type (WT) spike. Furthermore, Omicron could infect wild-type C57BL/6 mice and cause histopathological changes in the lungs. Collectively, our results reveal that evasion of neutralization by vaccine-elicited antibodies and enhanced human and mouse ACE2 receptor engagement may contribute to the expanded host range and rapid spread of the Omicron variant. IMPORTANCE The recently emerged SARS-CoV-2 Omicron variant with numerous mutations in the spike protein has rapidly become the dominant strain, thereby raising concerns about the effectiveness of vaccines. Here, we found that the Omicron variant exhibits a reduced sensitivity to serum neutralizing activity induced by a three-dose inactivated vaccine but remains sensitive to entry inhibitors or an ACE2-Ig decoy receptor. Compared with the ancestor strain isolated in early 2020, the spike protein of Omicron utilizes the human ACE2 receptor with enhanced efficiency while gaining the ability to utilize mouse ACE2 for cell entry. Moreover, Omicron could infect wild-type mice and cause pathological changes in the lungs. These results reveal that antibody evasion, enhanced human ACE2 utilization, and an expanded host range may contribute to its rapid spread.

The impact of the COVID-19 pandemic on the prevalence and risk factors of workplace violence among healthcare workers in China.

Background: The pandemic of COVID-19 has significantly increased the burden on healthcare workers and potentially affect their risk of workplace violence (WPV). This study aimed to explore the prevalence and risk factors of WPV among healthcare workers during the peaking and the remission of the COVID-19 pandemic in China. Methods: Using the snowball method, a repeated online questionnaire survey was conducted among Chinese healthcare workers from March 27th to April 26th in 2020 and 2021, respectively. Data included healthcare workers' socio-demographic and occupational characteristics, psychological status, and workplace violence. Results: A total of 3006 samples in 2020 and 3465 samples in 2021 were analyzed. In 2020, the prevalence of WPV and witnessing colleagues suffering from WPV among healthcare workers were 64.2% and 79.7% respectively. Compared with 2020, the prevalence decreased by 11.0% and 14.4% in 2021, respectively. Logistic regression showed that WPV in 2020 was influenced by males, long working experience, working in the psychiatric department, direct contact with COVID-19 patients, self-discovery of medical errors, moral injury, depression, and anxiety (minimum OR = 1.22, maximum OR = 2.82). While risk factors of WPV in 2021 included males, working in psychiatric departments, self-discovery of medical errors, moral injury, depression, and anxiety (minimum OR = 1.33, maximum OR = 3.32); and protective factors were holding a master's degree (OR = 0.78) and working in other departments (OR = 0.54). Conclusion: This study retains the common effects of WPV among healthcare workers, though after the baptism of the COVID-19 pandemic, the prevalence of WPV among healthcare workers decreased; however, part of the influencing factors changed. In addition, COVID-19 has seriously affected the mental health of healthcare workers, and the effect of mental health problems on WPV should also attract more attention.

Comparison of viral propagation and drug response among SARS-CoV-2 VOCs using replicons capable of recapitulating virion assembly and release.

Several variants of concern (VOCs) have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first isolated in January 2020. Due to mutations in the spike (S) protein, these VOCs have evolved to enhance viral infectivity and immune evasion. However, whether mutations of the other viral proteins lead to altered viral propagation and drug resistance remains obscure. The replicon is a noninfectious viral surrogate capable of recapitulating certain steps of the viral life cycle. Although several SARS-CoV-2 replicons have been developed, none of them were derived from emerging VOCs and could only recapitulate viral genome replication and subgenomic RNA (sgRNA) transcription. In this study, SARS-CoV-2 replicons derived from the WIV04 strain and two VOCs (the Beta and Delta variants) were prepared by removing the S gene from their genomes, while other structural genes remained untouched. These replicons not only recapitulate viral genome replication and sgRNA transcription but also support the assembly and release of viral-like particles, as manifested by electron microscopic assays. Thus, the S-deletion replicon could recapitulate virtually all the post-entry steps of the viral life cycle and provides a versatile tool for measuring viral intracellular propagation and screening novel antiviral drugs, including inhibitors of virion assembly and release. Through the quantification of replicon RNA released into the supernatant, we demonstrate that viral intracellular propagation and drug response to remdesivir have not yet substantially changed during the evolution of SARS-CoV-2 from the WIV04 strain to the Beta and Delta VOCs.

Recombinant chimpanzee adenovirus vector vaccine expressing the spike protein provides effective and lasting protection against SARS-CoV-2 infection in mice.

SARS-CoV-2 infection is a global public health threat. Vaccines are considered amongst the most important tools to control the SARS-CoV-2 pandemic. As expected, deaths from SARS-CoV-2 infection have dropped dramatically with widespread vaccination. However, there are concerns over the duration of vaccine-induced protection, as well as their effectiveness against emerging variants of concern. Here, we constructed a recombinant chimpanzee adenovirus vectored vaccine expressing the full-length spike of SARS-CoV-2 (AdC68-S). Rapid and high levels of humoral and cellular immune responses were observed after immunization of C57BL/6J mice with one or two doses of AdC68-S. Notably, neutralizing antibodies were observed up to at least six months after vaccination, without substantial decline. Single or double doses AdC68-S immunization resulted in lower viral loads in lungs of mice against SARS-CoV-2 challenge both in the short term (21 days) and long-term (6 months). Histopathological examination of AdC68-S immunized mice lungs showed mild histological abnormalities after SARS-CoV-2 infection. Taken together, this study demonstrates the efficacy and durability of the AdC68-S vaccine and constitutes a promising candidate for clinical evaluation.

Protein sensors combining both on-and-off model for antibody homogeneous assay.

Protein sensors based on allosteric enzymes responding to target binding with rapid changes in enzymatic activity are potential tools for homogeneous assays. However, a high signal-to-noise ratio (S/N) is difficult to achieve in their construction. A high S/N is critical to discriminate signals from the background, a phenomenon that might largely vary among serum samples from different individuals. Herein, based on the modularized luciferase NanoLuc, we designed a novel biosensor called NanoSwitch. This sensor allows direct detection of antibodies in 1 µl serum in 45 min without washing steps. In the detection of Flag and HA antibodies, NanoSwitches respond to antibodies with S/N ratios of 33-fold and 42-fold, respectively. Further, we constructed a NanoSwitch for detecting SARS-CoV-2-specific antibodies, which showed over 200-fold S/N in serum samples. High S/N was achieved by a new working model, combining the turn-off of the sensor with human serum albumin and turn-on with a specific antibody. Also, we constructed NanoSwitches for detecting antibodies against the core protein of hepatitis C virus (HCV) and gp41 of the human immunodeficiency virus (HIV). Interestingly, these sensors demonstrated a high S/N and good performance in the assays of clinical samples; this was partly attributed to the combination of off-and-on models. In summary, we provide a novel type of protein sensor and a working model that potentially guides new sensor design with better performance.

RBD-homodimer, a COVID-19 subunit vaccine candidate, elicits immunogenicity and protection in rodents and nonhuman primates.

The pandemic of COVID-19 caused by SARS-CoV-2 has raised a new challenges to the scientific and industrious fields after over 1-year spread across different countries. The ultimate approach to end the pandemic is the timely application of vaccines to achieve herd immunity. Here, a novel SARS-CoV-2 receptor-binding domain (RBD) homodimer was developed as a SARS-CoV-2 vaccine candidate. Formulated with aluminum adjuvant, RBD dimer elicited strong immune response in both rodents and non-human primates, and protected mice from SARS-CoV-2 challenge with significantly reducing viral load and alleviating pathological injury in the lung. In the non-human primates, the vaccine could prevent majority of the animals from SARS-CoV-2 infection in the respiratory tract and reduce lung damage. In addition, antibodies elicited by this vaccine candidate showed cross-neutralization activities to SARS-CoV-2 variants. Furthermore, with our expression system, we provided a high-yield RBD homodimer vaccine without additional biosafety or special transport device supports. Thus, it may serve as a safe, effective, and low-cost SARS-CoV-2 vaccine candidate.

A human antibody of potent efficacy against SARS-CoV-2 in rhesus macaques showed strong blocking activity to B.1.351.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.

A SARS-CoV-2 neutralizing antibody with extensive Spike binding coverage and modified for optimal therapeutic outcomes.

COVID-19 pandemic caused by SARS-CoV-2 constitutes a global public health crisis with enormous economic consequences. Monoclonal antibodies against SARS-CoV-2 can provide an important treatment option to fight COVID-19, especially for the most vulnerable populations. In this work, potent antibodies binding to SARS-CoV-2 Spike protein were identified from COVID-19 convalescent patients. Among them, P4A1 interacts directly with and covers majority of the Receptor Binding Motif of the Spike Receptor-Binding Domain, shown by high-resolution complex structure analysis. We further demonstrate the binding and neutralizing activities of P4A1 against wild type and mutant Spike proteins or pseudoviruses. P4A1 was subsequently engineered to reduce the potential risk for Antibody-Dependent Enhancement of infection and to extend its half-life. The engineered antibody exhibits an optimized pharmacokinetic and safety profile, and it results in complete viral clearance in a rhesus monkey model of COVID-19 following a single injection. These data suggest its potential against SARS-CoV-2 related diseases.

A high-resolution typical pollution source emission inventory and pollution source changes during the COVID-19 lockdown in a megacity, China.

To control the spread of COVID-19, China has imposed national lockdown policies to restrict the movement of its population since the Chinese New Year of January 2020. In this study, we quantitatively analyzed the changes of pollution sources in Shanghai during the COVID-19 lockdown; a high-resolution emission inventory of typical pollution sources including stationary source, mobile source, and oil and gas storage and transportation source was established based on pollution source data from January to February 2020. The results show that the total emissions of sulfur dioxide (SO2), nitrogen oxides (NOx), particulate matter (PM), and volatile organic compounds (VOCs) were 9520.2, 37,978.6, 2796.7, and 7236.9 tons, respectively, during the study period. Affected by the COVID-19 lockdown, the mobile source experienced the largest decline. The car mileage and oil sales decreased by about 80% during the COVID-19 lockdown (P3) when compared with those during the pre-Spring Festival (P1). The number of aircraft activity decreased by approximately 50%. The impact of the COVID-19 epidemic on industries such as iron and steel and petrochemicals was less significant, while the greater impact was on coatings, chemicals, rubber, and plastic. The emissions of SO2, NOx, PM2.5, and VOCs decreased by 11%, 39%, 37%, and 47%, respectively, during P3 when compared with those during P1. The results show that the measures to control the spread of the COVID-19 epidemic made a significant contribution to emission reductions. This study may provide a reference for other countries to assess the impact of the COVID-19 epidemic on emissions and help establish regulatory actions to improve air quality.

Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.

Spatiotemporal variations of ambient air pollutants and meteorological influences over typical urban agglomerations in China during the COVID-19 lockdown.

To investigate the air quality change during the COVID-19 pandemic, we analyzed spatiotemporal variations of six criteria pollutants in nine typical urban agglomerations in China using ground-based data and examined meteorological influences through correlation analysis and backward trajectory analysis under different responses. Concentrations of PM2.5, PM10, NO2, SO2 and CO in urban agglomerations respectively decreased by 18%-45% (30%-62%), 17%-53% (22%-39%), 47%-64% (14%-41%), 9%-34% (0%-53%) and 16%-52% (23%-56%) during Lockdown (Post-lockdown) period relative to Pre-lockdown period. PM2.5 pollution events occurred during Lockdown in Beijing-Tianjin-Hebe (BTH) and Middle and South Liaoning (MSL), and daily O3 concentration rose to grade Ⅱ standard in Post-lockdown period. Distinct from the nationwide slump of NO2 during Lockdown period, a rebound (∼40%) in Post-lockdown period was observed in Cheng-Yu (CY), Yangtze River Middle-Reach (YRMR), Yangtze River Delta (YRD) and Pearl River Delta (PRD). With slightly higher wind speed compared with 2019, the reduction of PM2.5 (51%-62%) in Post-lockdown period is more than 2019 (15%-46%) in HC (Harbin-Changchun), MSL, BTH, CP (Central Plain) and SP (Shandong-Peninsula), suggesting lockdown measures are effective to PM2.5 alleviation. Although O3 concentrations generally increased during the lockdown, its increment rate declined compared with 2019 under similar sunlight duration and temperature. Additionally, unlike HC, MSL and BTH, which suffered from additional (> 30%) air masses from surrounding areas after the lockdown, the polluted air masses reaching YRD and PRD mostly originated from the long-distance transport, highlighting the importance of joint regional governance.

Characterization of neutralizing antibody with prophylactic and therapeutic efficacy against SARS-CoV-2 in rhesus monkeys.

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.

Insights into chemical composition, abatement mechanisms and regional transport of atmospheric pollutants in the Yangtze River Delta region, China during the COVID-19 outbreak control period.

To investigate chemical characteristics, abatement mechanisms and regional transport of atmospheric pollutants during the COVID-19 outbreak control period in the Yangtze River Delta (YRD) region, China, the measurements of air pollutants including fine particulate matter (PM2.5) and volatile organic compounds (VOCs) on non-control period (NCP, 24 December 2019-23 January 2020) and control period (CP, 24 January-23 February 2020) were analyzed at the urban Pudong Supersite (PD) and the regional Dianshan Lake Supersite (DSL). Due to the stricter outbreak control, the levels of PM2.5 and VOCs, and the occurrence frequencies of haze-fog episodes decreased substantially from NCP to CP, with average reduction rates of 31.6%, 38.9% and 35.1% at PD, and 34.5%, 50.7% and 37.9% at DSL, respectively. The major source for PM2.5 was secondary sulfate & nitrate in both periods, and the emission control of primary sources such as coal burning and vehicle exhaust decreased the levels of precursors gas sulfur dioxide and nitrogen oxide, which highly contributed to the abatement of PM2.5 from NCP to CP. The higher levels of ozone at both PD and DSL on CP might be due to the weak nitrogen monoxide titration, low relative humidity and high visibility compared with NCP. Vehicle exhaust and fugitive emission from petrochemical industry were the major contributors of ambient VOCs and their decreasing activities mainly accounted for VOCs abatement. Moreover, the high frequency of haze-fog events was closely impacted by medium-scale regional transport within Anhui and Jiangsu provinces. Therefore, the decreasing regional transported air pollutants coincided with the emission control of local sources to cause the abatement of haze-fog events in YRD region on CP. This study could improve the understanding of the change of atmospheric pollutants during the outbreak control period, and provide scientific base for haze-fog pollution control in YRD region, China.

Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques.

The 2019 novel coronavirus (SARS-CoV-2) outbreak is a major challenge for public health. SARS-CoV-2 infection in human has a broad clinical spectrum ranging from mild to severe cases, with a mortality rate of ~6.4% worldwide (based on World Health Organization daily situation report). However, the dynamics of viral infection, replication and shedding are poorly understood. Here, we show that Rhesus macaques are susceptible to the infection by SARS-CoV-2. After intratracheal inoculation, the first peak of viral RNA was observed in oropharyngeal swabs one day post infection (1 d.p.i.), mainly from the input of the inoculation, while the second peak occurred at 5 d.p.i., which reflected on-site replication in the respiratory tract. Histopathological observation shows that SARS-CoV-2 infection can cause interstitial pneumonia in animals, characterized by hyperemia and edema, and infiltration of monocytes and lymphocytes in alveoli. We also identified SARS-CoV-2 RNA in respiratory tract tissues, including trachea, bronchus and lung; and viruses were also re-isolated from oropharyngeal swabs, bronchus and lung, respectively. Furthermore, we demonstrated that neutralizing antibodies generated from the primary infection could protect the Rhesus macaques from a second-round challenge by SARS-CoV-2. The non-human primate model that we established here provides a valuable platform to study SARS-CoV-2 pathogenesis and to evaluate candidate vaccines and therapeutics.

A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2.

An outbreak of coronavirus disease 2019 (COVID-19)1-3, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)4, has spread globally. Countermeasures are needed to treat and prevent further dissemination of the virus. Here we report the isolation of two specific human monoclonal antibodies (termed CA1 and CB6) from a patient convalescing from COVID-19. CA1 and CB6 demonstrated potent SARS-CoV-2-specific neutralization activity in vitro. In addition, CB6 inhibited infection with SARS-CoV-2 in rhesus monkeys in both prophylactic and treatment settings. We also performed structural studies, which revealed that CB6 recognizes an epitope that overlaps with angiotensin-converting enzyme 2 (ACE2)-binding sites in the SARS-CoV-2 receptor-binding domain, and thereby interferes with virus-receptor interactions by both steric hindrance and direct competition for interface residues. Our results suggest that CB6 deserves further study as a candidate for translation to the clinic.