Evaluating the Stress Factors of Dermatology Nurses during the COVID-19 pandemic in Vietnam

Objectives: Nursing is among the top three most stressful jobs, yet stress in nurses has diminishing impacts on their personal health and productivity. The COVID-19 pandemic might elevate stress in nurses, in particular dermatology nurses. This study aims to examine the prevalence of stress among dermatology nurses and its related factors. Methodology: A cross-section study was conducted among 154 nurses at the National Hospital of Dermatology and Venereology in Vietnam. Data were collected during the third cluster of COVID-19 pandemic spread in Hanoi. Nurse stress was measured by stress items of the DASS-21. Factors related to stress included personal, family, work-related and social factors. Results: 51.9% of nurses met the criteria for stress according to DASS-21. All nurses reported at least 1 symptom of stress in the past week. Factors significantly related to stress among nurses included personal, family, work-related and social factors. While many factors in these four groups created stress in nurses, only work-related and social factors elevated the severity of stress in nurses. Conclusion: Hospital management should develop strategies to support nurses deal with stress, since most of the factors that elevate stress can be addressed by system-level interventions, such as management of professional relationships, organizational justice, and the welfare system.

A hyperinflammation clinical risk tool, HI5-NEWS2, stratifies hospitalised COVID-19 patients to associate risk of death and effect of early dexamethasone in an observational cohort.

BACKGROUND: The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. METHODS: Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FINDINGS: Of 1265 patients, high risk of HI (high HI5-NEWS2) (n = 367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n = 455, 36.0%). An intermediate risk group (n = 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p = 0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p = 0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p = 0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p = 0.31). INTERPRETATION: Higher HI5-NEWS2 scores measured at COVID-19 diagnosis, strongly associate with increased mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention in all cases.

Safety and immunogenicity of Nanocovax, a SARS-CoV-2 recombinant spike protein vaccine: Interim results of a double-blind, randomised controlled phase 1 and 2 trial.

Background: Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminium hydroxide adjuvant. Methods: We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 mcg, 50 mcg, and 75 mcg doses, aluminium hydroxide adjuvanted (0·5 mg/dose) in 2-dose regime, 28 days apart (ClinicalTrials.gov number, NCT04683484). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2, 560 healthy adults received either vaccine doses similar in phase 1 (25 or 50 or 75 mcg S antigen in 0·5 mg aluminium per dose) or adjuvant (0·5 mg aluminium) in a ratio of 2:2:2:1. One primary outcome was the vaccine safety, including solicited adverse events for 7 day and unsolicited adverse events for 28 days after each injection as well as serious adverse event or adverse events of special interest throughout the study period. Another primary outcome was anti-S IgG antibody response (Index unit/ml). Secondary outcomes were surrogate virus neutralisation (inhibition percentage), wild-type SARS-CoV-2 neutralisation (dilution fold), and T-cell responses by intracellular staining for interferon gamma (IFNg). Anti-S IgG and neutralising antibody levels were compared with convalescent serum samples from symptomatic Covid-19 patients. Findings: For phase 1 study, no serious adverse events were observed for all 60 participants. Most adverse events were grade 1 and disappeared shortly after injection. For phase 2 study, after randomisation, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive the placebo (adjuvant only). Reactogenicity was absent or mild in the majority of participants and of short duration (mean ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. In general, there humoral responses were similar among vaccine groups which reached their peaks at day 42 and declined afterward. At day 42, IgG levels of vaccine groups were 60·48 [CI95%: 51·12-71·55], 49·11 [41·26-58·46], 57·18 [48·4-67·5] compared to 7·10 [6·32-13·92] of convalescent samples. IgG levels reported here can be converted to WHO international standard binding antibody unit (BAU/ml) by multiplying them to a conversion factor of 21·8. Neutralising antibody titre of vaccine groups at day 42 were 89·2 [52·2-152·3], 80·0 [50·8-125.9] and 95·1 [63·1-143·6], compared to 55·1 [33·4-91·0] of the convalescent group. Interpretation: Up to day 90, Nanocovax was found to be safe, well tolerated, and induced robust immune responses. Funding: This work was funded by the Coalition for Epidemic Preparedness Innovations (CEPI), the Ministry of Science and Technology of Vietnam, and Nanogen Pharmaceutical Biotechnology JSC.

Evaluating natural product compound inhibitors of SARS-CoV-2 main protease and spike protein target by molecular docking approach

Spike protein plays a significant role in viral transmission, while main protease's role is in the replication of the virus. In this study, we screened in silico natural products compounds activity to inhibit two targets of spike proteins and main proteases. Our data were compared with hydroxychloroquine and X77, which have been demonstrated inhibitory activity of these targets, respectively. Our results showed that 12/59 compounds have a higher ability to inhibit main protease than X77 and 59/59 compounds have a higher ability to inhibit spike protein than hydroxychloroquine. Notably, four compounds with the most strongly inhibitory activity of main protease are amentoflavone, punigluconin, amarogentin, emblicanin A. We found seven compounds with the most powerful inhibitory ability of spike protein are amentoflavone, hesperidin, rutin, glycyrrhizin, myricitrin, puerarin, daidzein. Among these compounds, ADMET profile and Lipinski's rule of five criterion analysis suggested four compounds including amentoflavone, myricitrin, purerarin and daidzein have drug-likeness properties. Interestingly, amentoflavone is the natural compound with the highest inhibitory ability for main protease and spike protein, which may be further explored as anti-SARS-CoV-2 agents.

Genome-wide analysis of SARS-CoV-2 strains circulating in Vietnam: Understanding the nature of the epidemic and role of the D614G mutation.

Genome-wide analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains is essential to better understand infectivity and virulence and to track coronavirus disease 2019 (COVID-19) cases and outbreaks. We performed whole-genome sequencing of 27 SARS-CoV-2 strains isolated between January 2020 and April 2020. A total of 54 mutations in different genomic regions was found. The D614G mutation, first detected in March 2020, was identified in 18 strains and was more likely associated with a lower cycle threshold (<25) in real-time reverse-transcription polymerase chain reaction diagnostic tests than the original D614 (prevalence ratio = 2.75; 95% confidence interval, 1.19-6.38). The integration of sequencing and epidemiological data suggests that SARS-CoV-2 transmission in both quarantine areas and in the community in Vietnam occur at the beginning of the epidemic although the country implemented strict quarantine quite early, with strict contact tracing, and testing. These findings provide insights into the nature of the epidemic, as well as shape strategies for COVID-19 prevention and control in Vietnam.

Unified modelling of epidemics by coupled dynamics via Monte-Carlo Markov Chain algorithms (preprint)

To forecast the time dynamics of an epidemic, we propose a discrete stochastic model that unifies and generalizes previous approaches to the subject. Viewing a given population of individuals or groups of individuals with given health state attributes as living in and moving between the nodes of a graph, we use Monte-Carlo Markov Chain techniques to simulate the movements and health state changes of the individuals according to given probabilities of stay that have been preassigned to each of the nodes. We utilize this model to either capture and predict the future geographic evolution of an epidemic in time, or the evolution of an epidemic inside a heterogeneous population which is divided into homogeneous sub-populations, or, more generally, its evolution in a combination or superposition of the previous two contexts. We also prove that when the size of the population increases and a natural hypothesis is satisfied, the stochastic process associated to our model converges to a deterministic process. Indeed, when the length of the time step used in the discrete model converges to zero, in the limit this deterministic process is driven by a differential equation yielding the evolution of the expectation value of the number of infected as a function of time. In the second part of the paper, we apply our model to study the evolution of the Covid-19 epidemic. We deduce a decomposition of the function yielding the number of infectious individuals into "wavelets", which allows to trace in time the expectation value for the number of infections inside each sub-population. Within this framework, we also discuss possible causes for the occurrence of multiple epidemiological waves.

A novel hyperinflammation clinical risk tool, HI5-NEWS2, predicts mortality following early dexamethasone use in an observational cohort of hospitalised COVID-19 patients. (preprint)

BackgroundThe success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. MethodsBlood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FindingsOf 1265 patients, high risk of HI (high HI5-NEWS2) (n=367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n= 455, 36.0%). An intermediate risk group (n= 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p=0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p=0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p=0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p =0.31). InterpretationThe HI5-NEWS2 measured at COVID-19 diagnosis, strongly predicts mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention. FundingNo external funding.

A Novel Hyperinflammation Clinical Risk Tool, HI5-NEWS2, Predicts Mortality Following Early Dexamethasone Use in an Observational Cohort of Hospitalised COVID-19 Patients (preprint)

Background: The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19.Methods: Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status.Findings: Of 1265 patients, high risk of HI (high HI5-NEWS2) (n=367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n= 455, 36.0%). An intermediate risk group (n= 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p=0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.57, p=0.006). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p=0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p =0.31).Interpretation: The HI5-NEWS2 measured at COVID-19 diagnosis, strongly predicts mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention.Clinical Trial Registration Details: Clinicaltraisl.gov ID: NCT04903834Funding Information: No external funding.Declaration of Interests: None of the authors declare any conflicts of interest relevant to this work.Ethics Approval Statement: UK NHS ethical approval from Health and Care Research Wales, IRAS 286016. The study followed the principles of the Declaration of Helsinki and was approved by the National Research Ethics Service (Identification of Novel Factors Leading to Activated Macrophage Expansion in COVID19 and related conditions to guide targeted intervention, INFLAME COVID-19 Study, NRES 286016).

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

Clinical features, isolation, and complete genome sequence of severe acute respiratory syndrome coronavirus 2 from the first two patients in Vietnam.

In January 2020, we identified two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients in a familial cluster with one person coming from Wuhan, China. The complete genome sequences of two SARS-CoV-2 strains isolated from these patients were identical and 99.98% similar to strains isolated in Wuhan. This is genetically suggestive of human-to-human transmission of SARS-CoV-2 and indicates Wuhan as the most plausible origin of the early outbreak in Vietnam. The younger patient had a mild upper respiratory illness and a brief viral shedding, whereas the elderly with multi-morbidity had pneumonia, prolonged viral shedding, and residual lung damage. The evidence of nonsynonymous substitutions in the ORF1ab region of the viral sequence warrants further studies.

Percentage HScore confirms low incidence of secondary haemophagocytic lymphohistiocytosis in hospitalised COVID-19 patients (preprint)

Objective: It has been assumed that a significant proportion of COVID-19 patients show evidence of hyperinflammation of which secondary haemophagocytic lymphohistiocytosis (sHLH) is the most severe manifestation. To facilitate diagnosis of sHLH the HScore has been developed and validated. We set out to examine the prevalence of sHLH-like hyperinflammation in COVID-19. Methods: We retrospectively examined HScore parameters in 626 COVID-19 cases admitted to our institute of which 567 were suitable for analysis and compared these to a cohort of confirmed infection associated sHLH cases. To account for missing data, we calculated the maximum possible HScore of the recorded parameters (%HScore). Results: Early measurement of HScore parameters (day -1 to 4 from diagnosis) strongly predicted the %HScore over the course of the admission (p <0.0001). The retrospective cohort of sHLH showed significantly higher %HScores as compared to COVID-19 (median 73.47 vs 18.13 respectively, p <0.0001). The overall prevalence of individuals with an 80% probability of sHLH in our COVID-19 cohort was 1.59% on admission and only rose to 4.05% during the whole disease course. In the small cohort with scores suggestive of sHLH, there was no excess mortality compared with the whole cohort. %HScores were higher in younger patients (p<0.0001) and did not reliably predict outcome at any cut-off value (AUROC 0.533, p=0.211; OR 0.99). Conclusion: Surprisingly, these findings show that sHLH-type hyperinflammation is not prevalent in COVID-19, and %HScores do not predict outcome. Therefore, new algorithms are required to optimise case selection for clinical trials of targeted anti-inflammatory interventions.

Supplementing the National Early Warning Score (NEWS2) for anticipating early deterioration among patients with COVID-19 infection (preprint)

BackgroundThe National Early Warning Score (NEWS2) is currently recommended in the United Kingdom for risk stratification of COVID outcomes, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for severe COVID outcome and identify and validate a set of routinely-collected blood and physiological parameters taken at hospital admission to improve the score. MethodsTraining cohorts comprised 1276 patients admitted to Kings College Hospital NHS Foundation Trust with COVID-19 disease from 1st March to 30th April 2020. External validation cohorts included 5037 patients from four UK NHS Trusts (Guys and St Thomas Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID disease (transfer to intensive care unit or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. ResultsA baseline model of NEWS2 + age had poor-to-moderate discrimination for severe COVID infection at 14 days (AUC in training sample = 0.700; 95% CI: 0.680, 0.722; Brier score = 0.192; 95% CI: 0.186, 0.197). A supplemented model adding eight routinely-collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, CRP, estimated GFR, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI: 0.715, 0.757) and these improvements were replicated across five UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. ConclusionsNEWS2 score had poor-to-moderate discrimination for medium-term COVID outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID. KO_SCPLOWEYC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWMESSAGESC_SCPLOWO_LIThe National Early Warning Score (NEWS2), currently recommended for stratification of severe COVID-19 disease in the UK, showed poor-to-moderate discrimination for medium-term outcomes (14-day transfer to ICU or death) among COVID-19 patients. C_LIO_LIRisk stratification was improved by the addition of routinely-measured blood and physiological parameters routinely at hospital admission (supplemental oxygen, urea, oxygen saturation, CRP, estimated GFR, neutrophil count, neutrophil/lymphocyte ratio) which provided moderate improvements in a risk stratification model for 14-day ICU/death. C_LIO_LIThis improvement over NEWS2 alone was maintained across multiple hospital trusts but the model tended to be miscalibrated with risks of severe outcomes underestimated in most sites. C_LIO_LIWe benefited from existing pipelines for informatics at KCH such as CogStack that allowed rapid extraction and processing of electronic health records. This methodological approach provided rapid insights and allowed us to overcome the complications associated with slow data centralisation approaches. C_LI