Immunogenicity of COVID-19 vaccines and levels of SARS-CoV-2 neutralising antibody in the Bruneian population: Protocol for a national longitudinal study.

INTRODUCTION: Neutralising antibodies (NAbs) have been shown to be correlative of immune protection against SARS-CoV-2. We report the protocol for a national longitudinal study to assess and compare the level of NAbs generated in response to COVID-19 vaccines in Brunei Darussalam in adults 2-6 weeks post primary series (BBIBP-CorV, AZD1222, or mRNA-1273 vaccines) and their subsequent follow-up after administration of a third (booster-1) dose (BBIBP-CorV, mRNA-1273, or BNT162b2). METHODS AND ANALYSIS: Participant data will be extracted and processed from the national electronic health record system (Bru-HIMS) and the national mobile health application (BruHealth) into a research data platform. Eligible adults who have received their primary or booster vaccine will be invited using a stratified random sampling strategy based on age, gender and vaccine type (baseline target population, n=3000; 2-6 weeks post last dose). Blood serum will be isolated, and NAb levels assessed using the cPass surrogate virus neutralisation test. Baseline participants will then be screened for eligibility for subsequent longitudinal analysis. Those who have received a third dose will be followed up at 1, 3, 6, 9 and up to 12 months. NAb levels will be evaluated across the participant population according to vaccine platform/booster type, time since the last dose and correlated with demographic data. The study period is from December 2021 to January 2023 and aims to evaluate how NAb levels wane following a third vaccine dose across different vaccine platforms and determine the impact and rate of breakthrough infections. ETHICS AND DISSEMINATION: This study has been approved by the Medical and Ethical Research Committee of Ministry of Health, Brunei Darussalam. Individual NAb test results will be shared with each participant by text message. The findings from this study will help policy-makers in Brunei develop future vaccination strategies and establish regulations across multiple agencies.

Technology-assisted adaptive recruitment strategy for a large nation-wide COVID-19 vaccine immunogenicity study in Brunei.

A national study was conducted in Brunei to assess and compare the immunogenicity of the various brands of COVID-19 vaccines administered to the population as part of the National COVID-19 Vaccination Programme. Most of the population have had received at least 2 doses of BBIBP-CorV, AZD1222 or MRNA-1273 vaccines. Neutralising antibodies against SARS-CoV-2 induced by these vaccines will be analysed to infer population-level immune protection against COVID-19. During the 5-week recruitment period, 24,260 eligible individuals were invited to the study via SMS, out of which 2,712 participants were enrolled into the study. This paper describes the novel adaptive strategy used to recruit the study participants. Digital technology was leveraged to perform targeted online recruitment to circumvent the limitations of traditional recruitment methods. Technology also enabled stratified random selection of these eligible individuals who were stratified based on age, gender and vaccine brand. Data was extracted from the electronic health records, the national mobile health application and a third-party survey platform and integrated into a dedicated research platform called EVYDResearch. The instant availability and access to up-to-date data on EVYDResearch enabled the study team to meet weekly and adopt an adaptive recruitment strategy informed by behavioural science, where interventions could be quickly implemented to improve response rates. Some examples of these include incorporating nudge messaging into SMS invitations, involving the Minister of Health to make press announcements on this study, media coverage, setting up an enquiries hotline and reaching out to foreign language speaking expatriates of a local multinational company to participate in this study. Data integration from various data sources, real time information sharing and a strong teamwork led to good outcomes adaptable to the progress of recruitment, compared to the more time-consuming and static traditional recruitment methods.

A narrative review on the role of temperature and humidity in COVID-19: transmission, persistence, and epidemiological evidence

Since December 2019, the 2019 coronavirus disease (COVID-19) outbreak has become a global pandemic. Understanding the role of environmental conditions is important in impeding the spread of COVID-19. Given that airborne spread and contact transmission are considered the main pathways for the spread of COVID-19, this narrative review first summarized the role of temperature and humidity in the airborne trajectory of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Meanwhile, we reviewed the persistence of the virus in aerosols and on inert surfaces and summarized how the persistence of SARS-CoV-2 is affected by temperature and humidity. We also examined the existing epidemiological evidence and addressed the limitations of these epidemiological studies. Although uncertainty remains, more evidence may support the idea that high temperature is slightly and negatively associated with COVID-19 growth, while the conclusion for humidity is still conflicting. Nonetheless, the spread of COVID-19 appears to have been controlled primarily by government interventions rather than environmental factors.

Several major issues concerning the environmental transmission and risk prevention of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is the most serious infectious disease pandemic in the world in a century, and has had a serious impact on the health, safety, and social and economic development of all mankind. Since the earth entered the "Anthropocene", human activities have become the most important driving force of the evolution of the earth system. At the same time, the epidemic frequency of major human infectious diseases worldwide has been increasing, with more than 70% of novel diseases having zoonotic origins. The review of several major epidemics in human history shows that there is a common rule, i.e., changes in the natural environment have an important and profound impact on the occurrence and development of epidemics. Therefore, the impact of the natural environment on the current COVID-19 pandemic and its mechanisms have become scientific issues that need to be resolved urgently. From the perspective of the natural environment, this study systematically investigated several major issues concerning the environmental transmission and risk prevention of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). From a macroscopic temporal and spatial scale, the research focus on understand the impact of the destruction of the natural environment and global changes on the outbreak of infectious diseases; the threat of zoonotic diseases to human health; the regularity for virus diffusion, migration and mutation in environmental media; the mechanisms of virus transmission from animals and environmental media to humans; and environmental safety, secondary risk prevention and control of major epidemics. Suggestions were made for future key research directions and issues that need attention, with a view to providing a reference for the prevention and control of the global coronavirus disease 2019, and to improving the ability of response to major public health emergencies.

Effects of SARS-CoV-2 Infection During Late Pregnancy on Early Childhood Development: A Prospective Cohort Study.

Background: There is little direct or indirect evidence of the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on early childhood development. Methods: We conducted a prospective, observational cohort study in China from May 1 to October 31, 2020, that enrolled 135 mother-infant dyads: 57 dyads in the infection cohort and 78 in the non-infection cohort. Among all infants, 14.0% were preterm birth in the infection cohort and 6.4% in the non-infection cohort. Participants were followed by telephone interviews to collect demographic characteristics, medical records of coronavirus disease 2019, breastfeeding data, and early childhood development was assessed by the Age and Stage Questionnaire (ASQ-3) and Age and Stage Questionnaire Social-Emotional (ASQ:SE-2) Chinese versions at 3 months after childbirth. We used multivariable Poisson regression models to estimate the relative risk (RR) of SARS-CoV-2 infection. Multivariable linear regression models and a mediation model were used to test the direct and indirect associations between SARS-CoV-2 infection and the ASQ-3 score. This study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (No. IRB00006761-M2020127). Results: In the infection cohort, 13.6% of the children showed social-emotional developmental delay, and 13.5% showed overall developmental delay. The corresponding rates in the non-infection cohort were 23.4 and 8.1%. Compared with the non-infection cohort, SARS-CoV-2 infection during pregnancy did not increase the risk of social-emotional (RR = 0.87, 95% CI: 0.51-1.49) or overall (RR = 1.02, 95% CI: 0.60-1.73) developmental delay. The mediation model showed that SARS-CoV-2 infection indirectly affected the ASQ-3 score by increasing the length of mother-infant separation. Conclusions: SARS-CoV-2 during late pregnancy did not increase the risk of developmental delay of the offspring 3 months after delivery. However, SARS-CoV-2 may have indirect effects on early childhood development by increasing mother-infant separation.

Impact of Covid-19 in pregnancy on mother's psychological status and infant's neurobehavioral development: a longitudinal cohort study in China.

BACKGROUND: Evidence concerning the long-term impact of Covid-19 in pregnancy on mother's psychological disorder and infant's developmental delay is unknown. METHODS: This study is a longitudinal single-arm cohort study conducted in China between May 1 and July 31, 2020. Seventy-two pregnant patients with Covid-19 participated in follow-up surveys until 3 months after giving birth (57 cases) or having abortion (15 cases). We collected data from medical records regarding Covid-19, delivery or abortion, testing results of maternal and neonatal specimens, and questionnaires of quarantine, mother-baby separation, feeding, and measuring of mothers' mental disorders and infants' neurobehavioral disorders. RESULTS: All cases infected in the first trimester and 1/3 of cases infected in the second trimester had an abortion to terminate the pregnancy. 22.2% of pregnant patients were suffering from post-traumatic stress disorder or depression at 3 months after delivery or induced abortion. Among 57 live births, only one neonate was positive of nucleic acid testing for throat swab, but negative in repeated tests subsequently. The median duration of mother-baby separation was 35 days (interquartile range 16 to 52 days). After the termination of maternal quarantine, 49.1% of mothers chose to prolong the mother-baby separation (median 8 days; IQR 5 to 23 days). The breastfeeding rate was 8.8% at 1 week after birth, 19.3% at the age of 1 month, and 36.8% at the age of 3 months, respectively. The proportion of "monitoring" and "risk" in the social-emotional developmental domain at the age of 3 months was 22.7% and 63.6%, respectively. After the adjustment of preterm, neonatal sex, admitted to NICU, and the mother's Covid-19 condition, the negative associations were significantly identified (p < 0.05) between mother-baby separation days and three developmental domains: communication, gross motor, and personal-social. CONCLUSIONS: There is no definite evidence on vertical transmission of SARS-CoV-2. In addition to control infection risk, researchers and healthcare providers should pay more attention to maternal mental health and infant's feeding, closeness with parents, and early development.

Effects of the Lower Airway Secretions on Airway Opening Pressures and Suction Pressures in Critically Ill COVID-19 Patients: A Computational Simulation.

In patients with critically ill COVID-19 pneumonia, lower airways are filled with plenty of highly viscous exudates or mucus, leading to airway occlusion. The estimation of airway opening pressures and effective mucus clearance are therefore two issues that clinicians are most concerned about during mechanical ventilation. In this study we retrospectively analyzed respiratory data from 24 critically ill patients with COVID-19 who received invasive mechanical ventilation and recruitment maneuver at Jinyintan Hospital in Wuhan, China. Among 24 patients, the mean inspiratory plateau pressure was 52.4 ± 4.4 cmH2O (mean ± [SD]). Particularly, the capnograms presented an upward slope during the expiratory plateau, indicting the existence of airway obstruction. A computational model of airway opening was subsequently introduced to investigate possible fluid dynamic mechanisms for the extraordinarily high inspiratory plateau pressures among these patients. Our simulation results showed that the predicted airway opening pressures could be as high as 40-50 cmH2O and the suction pressure could exceed 20 kPa as the surface tension and viscosity of secretion simulants markedly increased, likely causing the closures of the distal airways. We concluded that, in some critically ill patients with COVID-19, limiting plateau pressure to 30 cmH2O may not guarantee the opening of airways due to the presence of highly viscous lower airway secretions, not to mention spontaneous inspiratory efforts. Active airway humidification and effective expectorant drugs are therefore strongly recommended during airway management.

Prolonged presence of viral nucleic acid in clinically recovered COVID-19 patients was not associated with effective infectiousness.

Prolonged presence of viral nucleic acid was reported in certain patients with coronavirus disease 2019 (COVID-19), with unclear clinical and epidemiological significance. We here described the clinical and epidemiological characteristics of 37 recovered COVID-19 patients with prolonged presence of viral RNA in Wuhan, China. For those who had been discharged and re-admitted, their close contacts outside the hospital were traced and evaluated. The median age of the 37 patients was 62 years (IQR 50, 68), and 24 (64.9%) were men. They had common or severe COVID-19. With prolonged positive RT-PCR, most patients were clinically stable, 29 (78.4%) denied any symptoms. A total of 431 PCR tests were carried out, with each patient at a median of 8 time points. The median time of PCR positivity to April 18 was 78 days (IQR 67.7, 84.5), and the longest 120 days. 22 of 37 patients had been discharged at a median of 44 days (IQR 22.3, 50) from disease onset, and 9 had lived with their families without personal protections for a total of 258 person-days and no secondary infection was identified through epidemiological investigation, nucleic acid and antibody screening. Infectiousness in COVID-19 patients with prolonged presence of viral nucleic acid should not solely be evaluated by RT-PCR. Those patients who have clinically recovered and whose disease course has exceeded four weeks were associated with very limited infectiousness. Reconsideration of disease control in such patients is needed.

The effects of chloroquine and hydroxychloroquine on ACE2 related coronavirus pathology and the cardiovascular system: An evidence based review

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health and there is currently no effective antiviral therapy. It has been suggested that Chloroquine (CQ) and hydroxychloroquine (HCQ), which were primarily employed as prophylaxis and treatment for malaria, could be used to treat COVID-19. CQ and HCQ may be potential inhibitors of SARS-CoV-2 entry into host cells, which is mediated via the angiotensin-converting enzyme 2 (ACE2), and may also inhibit subsequent intracellular processes which lead to COVID-19, including damage to the cardiovascular system. However, paradoxically, CQ and HCQ have also been reported to cause damage to the cardiovascular system. In this review, we provide a critical examination of the published evidence. CQ and HCQ could potentially be useful drugs in the treatment of COVID-19 and other ACE2 involved virus infections, but the antiviral effects of CQ and HCQ need to be tested in more well-designed clinical randomized studies and their actions on the cardiovascular system need to be further elucidated. However, even if it were to turn out that CQ and HCQ are not useful drugs in practice, further studies of their mechanism of action could be helpful in improving our understanding of COVID-19 pathology.

Liver damage at admission is an independent prognostic factor for COVID-19.

OBJECTIVE: Abnormal liver function is a common form of extra-pulmonary organ damage in patients with coronavirus disease 2019 (COVID-19). Patients with severe COVID-19 have a higher probability and progression of liver injury than those without severe disease. We aimed to evaluate the prognosis of liver injury in patients with COVID-19. METHODS: We retrospectively included 502 patients with laboratory-confirmed SARS-CoV-2 infection. Clinical features and survival of patients with and without liver injury were compared. Cox proportional hazards models were used to determine the variables that might have an effect on survival. RESULTS: Among the 502 patients enrolled, 301 patients had abnormal liver function with increased neutrophil count, C-reactive protein, creatinine, troponin I (TnI), D-dimer, lactose dehydrogenase and creatine kinase. Patients with abnormal liver functions had a higher mortality rate (28.9% vs 9.0%, P < 0.001), a higher ratio of male sex (65.1% vs 40.8%, P < 0.001) and a higher chance of developing systemic inflammatory response syndrome (53.5% vs 41.3%, P = 0.007). Among patients with abnormal liver functions, patients with grade 2 liver damage (with both abnormal alanine aminotransferase or aspartate aminotransferase levels and abnormal alkaline phosphatase or gamma-glutamyl transpeptidase levels) had a higher ratio of male patients, elevated neutrophil count, procalcitonin, D-dimer levels and mortality rate. Multivariate Cox regression analyses suggested that the grade of liver damage (hazard ratio: 1.377, 95% confidence interval: 1.000-1.896, P = 0.049) was an independent predictor of death. CONCLUSIONS: Patients with COVID-19 and abnormal liver functions have a higher mortality than those with normal liver functions. Liver damage is an independent prognostic factor of COVID-19.

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.

BACKGROUND: Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. METHODS: In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. FINDINGS: 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 µg/mL (18·42, 2·64-128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. INTERPRETATION: The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 µg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. FUNDING: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.

BACKGROUND: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. METHODS: In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020. FINDINGS: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure. INTERPRETATION: The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection. FUNDING: National Key R&D Program of China.

Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin ;European Heart Journal ;Oxford Academic

A 37-year-old male patient was admitted to hospital on 14 January 2020, with chest pain and dyspnoea for 3 days, accompanied by diarrhoea. His blood pressure decreased to 80/50 mmHg. X-ray chest film showed significant enlargement of the heart (Panel A: cardiothoracic ratio 0.70). Chest computed tomography (CT) examination indicated pulmonary infection, enlarged heart, and pleural effusion (Panels B and C). The electrocardiogram suspected ST-segment elevation acute myocardial infarction (III, AVF ST-segment elevation, Panels D and E), an emergency CT coronary angiography revealed no coronary stenosis. Markers of myocardial injury were significantly elevated. Troponin T was more than 10 000 ng/L. Creatine kinase isoenzyme CKMB 112.9 ng/L. Natriuretic peptide BNP was up to 21 025 ng/L. Echocardiography revealed an enlarged heart and a marked decrease in ventricular systolic function [left ventricle (end diastolic) dimension (LV) 58 mm, left atrium dimension (LA) 39 mm, right ventricle dimension (RV) 25 mm, right atrium dimension (RA) 48 mm, left ventricular ejection fraction (LVEF) 27%, trace 2 mm pericardial effusion]. Sputum was examined for 13 viral nucleic acids related to respiratory tract. Only the coronavirus nucleic acid test was positive. All of the other 12 nucleic acid tests were negative, including influenza A virus, adenovirus, bocavirus, rhinovirus, influenza A(H1N1) 2009, parainfluenza, chlamydia, partial pulmonary virus, influenza B virus, mycoplasma pneumoniae, influenza A virus H3N2, and respiratory syncytial virus. The diagnosis of this patient is coronavirus fulminant myocarditis with cardiogenic shock and pulmonary infection.