UBA1-CDK16: A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism (preprint)

RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16, a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.

Assessment of the impact of the Vaccine Pass Policy on COVID-19 vaccine hesitancy and uptake among Chinese adults in Hong Kong (preprint)

Background: Recognising the importance of attaining high vaccine coverage to mitigate the COVID-19 impact, a Vaccine Pass scheme was implemented during and after the first large Omicron wave in Hong Kong in early 2022 requiring three doses by June 2022. We evaluated the impact of the Vaccine Pass policy on vaccine uptake in adults. Methods: We analyzed patterns in vaccine uptake and hesitancy using local data from the population vaccine registry and 32 cross-sectional surveys conducted from October 2021 to December 2022. We examined the association of Vaccine Pass phases with vaccine uptake, taking into account covariables including self-risk perception, perceived self-efficacy in preventing COVID-19 and trust in government in pandemic control as well as physical distancing measures and demographics. Findings: The uptake of primary series and third doses was significantly associated with stages of Vaccine Pass implementation, and other statistically significant drivers included age group, chronic condition, higher perceived personal susceptibility to COVID-19, higher trust in government, and higher educational attainment. Older adults ([≥]65y) were less likely to be vaccinated against COVID-19, compared to adults aged 18-44 years. Interpretation: Vaccine uptake in older adults was observed to have increased by a greater extent after the policy announcement and implementation, which occurred during and after a large Omicron wave with high mortality in older ages in early 2022. Since the policy withdrawal the uptake of further booster doses has been very low in all ages. Improving voluntary booster uptake in older adults should be prioritized.

Inpatient Antibacterial Drug Prescribing for Patients with COVID-19 in Hong Kong (preprint)

Background: Hong Kong experienced four epidemic waves caused by the ancestral strain of SARS-CoV-2 in 2020-2021 and a large Omicron wave in 2022. Few studies have assessed antibacterial drug prescribing for COVID-19 inpatients throughout the pandemic. Objectives: To describe inpatient antibacterial drug prescribing for COVID-19 patients throughout the pandemic and to determine factors associated with their prescription. Methods: This cohort study used electronic health records of COVID-19 cases admitted to public hospitals in Hong Kong from 21 January 2020 to 30 September 2022. We assessed the prevalence and rates of inpatient antibacterial drug use, using days of therapy/1000 patient days (DOT/1000PD), and examined the association of baseline factors and disease severity with receipt of an inpatient antibacterial drug prescription. Results: Among 65,810 inpatients, 54.0% were prescribed antibacterial drugs at a rate of 550.5 DOT/1000PD. Antibacterial use was lowest during wave 4 (28.0%; 246.9 DOT/1000PD), peaked in early wave 5 (64.6%; 661.2 DOT/1000PD), and then modestly declined in late wave 5 (43.2%; 464.1 DOT/1000PD) starting on 23 May 2022. Older age, increased disease severity, and residing in an elderly care home were strongly associated with increased odds of prescription, while receiving [≥] 2 doses of COVID-19 vaccines and pre-admission use of coronavirus antivirals were associated with lower odds. Conclusions: The rate of inpatient antibacterial prescribing initially declined during the pandemic, but increased during the Omicron wave when hospital capacity was overwhelmed. Despite the availability of COVID-19 vaccines and antiviral drugs, antibacterial drug use among COVID-19 inpatients remained high into late 2022.

Comparison of control and transmission of COVID-19 across epidemic waves in Hong Kong: an observational study (preprint)

Background: Hong Kong contained COVID-19 for two years, but experienced a large epidemic of Omicron BA.2 in early 2022 and endemic transmission of Omicron subvariants thereafter. Methods: We examined the use and impact of pandemic controls in Hong Kong by analysing data on more than 1.7 million confirmed COVID-19 cases and characterizing non-pharmaceutical and pharmaceutical interventions implemented from January 2020 through to 30 December 2022. We estimated the daily effective reproductive number (Rt) to track changes in transmissibility and effectiveness of community-based measures against infection over time. We examined the temporal changes of pharmaceutical interventions, mortality rate and case-fatality risks (CFRs), particularly among older adults. Findings: Hong Kong experienced four local epidemic waves predominated by the ancestral strain in 2020 and early 2021 and prevented multiple SARS-CoV-2 variants from spreading in the community before 2022. Strict travel-related, case-based, and community-based measures were increasingly tightened in Hong Kong over the first two years of the pandemic. However, even very stringent measures were unable to contain the spread of Omicron BA.2 in Hong Kong. Despite high overall vaccination uptake (>70% with at least two doses), high mortality was observed during the Omicron BA.2 wave due to lower vaccine coverage (42%) among adults [≥]65 years of age. Increases in antiviral usage and vaccination uptake over time through 2022 was associated with decreased case fatality risks. Interpretation: Integrated strict measures were able to reduce importation risks and interrupt local transmission to contain COVID-19 transmission and disease burden while awaiting vaccine development and rollout. Increasing coverage of pharmaceutical interventions among high-risk groups reduced infection-related mortality and mitigated the adverse health impact of the pandemic.

Global seasonal activities of respiratory syncytial virus before the COVID-19 pandemic: a systematic review (preprint)

Background: Varied seasonal patterns of respiratory syncytial virus (RSV) have been reported worldwide. We aimed to review the patterns of RSV activity globally before the COVID-19 pandemic and to explore factors potentially associated with RSV seasonality. Methods: We conducted a systematic review on articles identified in PubMed reporting RSV seasonality based on data collected before 1 January 2020. Information on the timing of the start, peak, and end of an RSV season, study location, study period, and details in study methods were extracted. RSV seasonal patterns were examined by geographic location, calendar month, analytic method and meteorological factors including temperature and absolute humidity. Correlation and regression analyses were conducted to explore the relationship between RSV seasonality and study methods and characteristics of study locations. Results: RSV seasons were reported in 209 articles published in 1973-2023 for 317 locations in 77 countries. Variations were identified in types of data, data collection and analytical methods across the studies. Regular RSV seasons were similarly reported in countries in temperate regions, with highly variable seasons identified in subtropical and tropical countries. Durations of RSV seasons were relatively longer in subtropical and tropical regions than from temperate regions. Longer durations of RSV seasons were associated with a higher daily average mean temperature and daily average mean absolute humidity. Conclusions: The global seasonal patterns of RSV provided important information for optimizing interventions against RSV infection. Heterogeneity in study methods highlighted the importance of developing and applying standardized approaches in RSV surveillance and data reporting.

Emergency Medical Services Scheduling During the Outbreak of Epidemics Via Improved Artifificial Bee Colony Algorithms (preprint)

This study investigates a novel emergency medical services scheduling problem (EMSSP) to address the outbreak of epidemics like COVID-19. The objective is to determine an optimal scheduling scheme to minimize the emergency service time for nucleic acid testing (NAT) and achieve rapid epidemic disruption. For the problem, we fifirst formulate the EMSSP into a mixed-integer linear programming (MILP) and analyze its complexity is NP-hard. However, due to the NP-hardness of the problem, existing optimization software such as CPLEX is diffiffifficult to solve large-scale problems in an acceptable time.To effiffifficiently address the EMSSP, we design two effffective improved artifificial bee colony algorithms (IABC) based on explored problem properties. Then, numerical experiments on a real-life case and randomly generated large-scale instances with up to 100 demand points are conducted. Finally, computational results show that the IABC algorithms can obtain a better scheduling scheme than CPLEX and two state-of-the-art evolutionary algorithms in only 16 seconds for large-scale instances, which helps decision-makers deal with the outbreak of epidemics in a short time.

Intrinsic and effective severity of COVID-19 cases infected with the ancestral strain and Omicron BA.2 variant in Hong Kong (preprint)

Background: Understanding severity of infections with SARS-CoV-2 and its variants is crucial to inform public health measures. Here we used COVID-19 patient data from Hong Kong to characterise the severity profile of COVID-19 and to examine factors associated with fatality of infection. Methods: Time-varying and age-specific effective severity measured by case-hospitalization risk and hospitalization risk was estimated with all individual COVID-19 case data collected in Hong Kong from 23 January 2020 through to 26 October 2022 over six epidemic waves, in comparison with estimates of influenza A(H1N1)pdm09 during the 2009 pandemic. The intrinsic severity of Omicron BA.2 was compared with the estimate for the ancestral strain with the data from unvaccinated patients without previous infections. Factors potentially associated with the fatality risk of hospitalized Omicron patients were also examined. Results: With 32,222 COVID-19 hospitalizations and 9,669 deaths confirmed over 6 epidemic waves in Hong Kong, the time-varying hospitalization fatality risk dramatically increased from below 10% before the largest fifth wave of Omicron BA.2, to 41% during the peak of the fifth wave when hospital resources were severely constrained. The age-specific fatality risk in unvaccinated hospitalized Omicron cases was comparable to the estimates for unvaccinated cases with the ancestral strain. During epidemics predominated by Omicron BA.2, the highest fatality risk was amongst unvaccinated patients aged [≥]80 years and the risk was inversely associated with the number of vaccination doses received. Conclusions: Omicron has comparable intrinsic severity to the ancestral Wuhan strain although the effective severity is substantially lower in Omicron cases due to vaccination. With a moderate-to-high coverage of vaccination, hospitalized COVID-19 patients caused by Omicron subvariants appeared to have similar age-specific risks of fatality to patients hospitalized with influenza A(H1N1)pdm09.

Characterizing human collective behaviours of COVID-19 in Hong Kong (preprint)

People are likely to engage in collective behaviour online during extreme events, such as the COVID-19 crisis, to express their awareness, actions and concerns. Hong Kong has implemented stringent public health and social measures (PHSMs) to curb COVID-19 epidemic waves since the first COVID-19 case was confirmed on 22 January 2020. People are likely to engage in collective behaviour online during extreme events, such as the COVID-19 crisis, to express their awareness, actions and concerns. Here, we offer a framework to evaluate interactions among individuals emotions, perception, and online behaviours in Hong Kong during the first two waves (February to June 2020) and found a strong correlation between online behaviours of Google search and the real-time reproduction numbers. To validate the model output of risk perception, we conducted 10 rounds of cross-sectional telephone surveys from February 1 through June 20 in 2020 to quantify risk perception levels over time. Compared with the survey results, the estimates of the risk perception of individuals using our network-based mechanistic model capture 80% of the trend of people risk perception (individuals who worried about being infected) during the studied period. We may need to reinvigorate the public by engaging people as part of the solution to live their lives with reduced risk.

Viral shedding among symptomatic COVID-19 cases infected with the ancestral strain and Omicron BA.2 (preprint)

Assessment of viral kinetics of SARS-CoV-2 may inform host immune responses to and transmission potential of the virus. We analyzed longitudinal data of RT-PCR tests conducted for symptomatic COVID-19 patients at confirmation and during hospital isolation in Hong Kong during three major epidemic waves, and modeled the temporal trajectories of viral burden in these patients. Our analysis demonstrated that a longer duration of viral shedding appeared in more severe and older cases. Vaccinated individuals with a breakthrough infection of Omicron BA.2 exhibited a lower viral burden than non-vaccinated Omicron cases in early days following onset and a shorter duration of viral shedding particularly in more recently vaccinated patients. The viral kinetics characterized in our study provided insight into further studies on host immune responses to SARS-CoV-2 infection, prognosis of COVID-19 patients as well as possible protective mechanisms of vaccination against infection and severe outcomes.

Residential clustering of COVID-19 cases and efficiency of building-wide compulsory testing notices as a transmission control measure in Hong Kong (preprint)

Background: Despite relatively few reports of residential case clusters of COVID-19, building-wide compulsory testing notices on residential apartment blocks are frequently applied in Hong Kong with the aim of identifying cases and reducing transmission. Methods: We aimed to describe the frequency of residential case clusters and the efficiency of compulsory testing notices in identifying cases. The residences of locally infected COVID-19 cases in Hong Kong were grouped to quantify the number of cases per residence. Buildings targeted in compulsory testing notices were matched with the residence of cases to estimate the number of cases identified. Results: We found that most of the residential buildings (4246/7688, 55.2%) with a confirmed COVID-19 case had only one reported case. In the fourth and the fifth epidemic wave in Hong Kong, we estimated that compulsory testing notices detected 29 cases (95% confidence interval: 26, 32) and 46 cases (44, 48) from every 100 buildings tested (each with hundreds of residents), respectively. Approximately 13% of the daily reported cases were identified through compulsory testing notices. Conclusions: Compulsory testing notices can be an essential method when attempting to maintain local elimination (zero covid) and most impactful early in an epidemic when the benefit remains of stemming a new wave. Compulsory testing therefore appears to be a relatively inefficient control measure in response to sustained community transmission in the community.

Nanobodies for the treatment of SARS-CoV-2 in animals: a meta-analysis (preprint)

This meta-analysis aimed to find the effect of variable domain of heavy-chain antibodies (VHHs) for the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in animals. The databases of the PubMed, China National Knowledge Infrastructure (CNKI), Wan fang data, Cochrane Library, and Embase were searched for articles published before August 2022 on the protective effects of VHHs in animals. The articles retrieved were screened using inclusion and exclusion criteria. The data were analyzed using Review Manager 5.4. Six articles were selected from 667 articles based on the inclusion and exclusion criteria in VHHs. A forest plot showed that VHHs could offer protection against SARS-CoV-2 infection in animals [Mantel-Haenszel (MH) = 172.94, 95% confidence interval (CI) = (43.96, 678.42), P < 0.00001]. There was almost no heterogeneity in this study (I2 = 0). A funnel plot showed that the bias of the data analysis was small. This is a special meta-analysis proved that VHHs could treat and prevent SARS-CoV-2 in animals.

Factors and optimizations of healthcare workers' perception in alternative care facilities

Background Diverse measures have been carried out worldwide to establish Alternative Care Facilities (ACFs) for different ends, such as receiving, curing or isolating patients, aiming to cope with tremendous shock in the urban medical system during the early passage of the COVID-19 epidemic. Healthcare workers always felt anxious and stressed during multiple major public health emergencies in medical facilities. Some active measures to improve healthcare workers' perceptions, such as temporary training, workflow improvement, and supplementary facilities, were proved insufficient in several past public health emergencies. Therefore, this study aims to analyze the contributing factors of the healthcare workers' perceptions of the ACFs in this pandemic, which can help find an innovative path to ensure their health, well-being and work efficiency. Method This paper conducted semi-structured in-depth interviews with the world's first batch of healthcare workers who have worked in ACFs through a qualitative study based on Grounded Theory. The healthcare workers interviewed from Heilongjiang, Shandong, Fujian, and Hubei provinces, have worked in one of the four different ACFs built in Wuhan. The results are obtained through the three-level codes and analyses of the interview recordings. Results The factors affecting the perception of healthcare workers in ACFs during the epidemic situation can be summarized into five major categories: individual characteristics, organization management, facilities and equipment, space design, and internal environment. The five major categories affecting the composition of perception can be further divided into endogenous and exogenous factors, which jointly affect the perception of healthcare workers in ACFs. Among them, individual characteristics belong to endogenous factors, which are the primary conditions, while other categories belong to exogenous factors, which are the decisive conditions. Conclusion This paper clarifies factors affecting the perception of healthcare workers in ACFs and analyzes the mechanism of each factor. It is posited that the passive strategies are a promising solution to protect healthcare workers' health, improve their work efficiency, and help reduce the operation stress of ACFs. We should train multidisciplinary professionals for future healthcare and enhance collaborations between healthcare workers and engineers. To sum up, this paper broadens new horizons for future research on the optimization of ACFs and finds new paths for alleviating healthcare workers' adverse perceptions of ACFs.

Insights into COVID-19 epidemiology and control from temporal changes in serial interval distributions in Hong Kong (preprint)

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to predict the effective reproductive number "Rt", a measure of transmissibility. However, serial interval distributions may change as an epidemic progresses rather than remaining constant. Here we show that serial intervals in Hong Kong varied over time, closely associated with the temporal variation in COVID-19 case profiles and public health and social measures that were implemented in response to surges in community transmission. Quantification of the variation over time in serial intervals led to improved estimation of Rt, and provided additional insights into the impact of public health measures on transmission of infections. One-Sentence SummaryReal-time estimates of serial interval distributions can improve assessment of COVID-19 transmission dynamics and control.

An observational study on imported COVID-19 cases in Hong Kong during mandatory on-arrival hotel quarantine (preprint)

Background: Hong Kong has enforced stringent travel restrictions particularly for inbound travellers since the emergence of SARS-CoV-2. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: We conducted a retrospective cohort study to summarise the characteristics of cases classified as imported cases that were detected on or soon after arrival into Hong Kong from 13 November 2020 through to 31 January 2022, when all arriving persons were required to quarantine in a hotel or a designated quarantine facility. We analysed individual demographics, and clinical information including symptoms and disease severity, virus variants, and Ct values. Results: There were 2269 imported COVID-19 cases aged 0-85 years identified in Hong Kong. Almost half (48.6%) of the imported cases were detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than cases infected with the ancestral strain and other variants (12 days; p<0.001) while lower Ct values at isolation were observed in cases infected with Omicron than the ancestral strain or other variants. No Omicron cases were detected beyond 14 days after arrival, and the cases (n=58, 2.6%) detected after 14 days of quarantine more frequently presented without symptoms at isolation and had a higher RT-PCR Ct-value during isolation. At least some of these cases were post-arrival infections. Conclusions: Testing inbound travellers at arrival and during on-arrival quarantine can detect imported cases early although it may not be sufficient to prevent all introductions of COVID-19 into the community. Public health measures should be adjusted in responses to the emergence of new variants of SARS-CoV-2 based on the epidemiologic evidence from continuous surveillance.

Inferring time-varying generation time, serial interval and incubation period distributions for COVID-19 (preprint)

The generation time distribution, reflecting the time between successive infections in transmission chains, is a key epidemiological parameter for describing COVID-19 transmission dynamics. However, because exact infection times are rarely known, it is often approximated by the serial interval distribution. This approximation holds under the assumption that infectors and infectees share the same incubation period distribution, which may not always be true. We investigated incubation period and serial interval distributions in data on 2989 confirmed cases in China in January-February 2020, and developed an inferential framework to estimate the generation time distribution that accounts for variation over time due to changes in epidemiology, sampling biases and public health and social measures. We identified substantial reductions over time in the serial interval and generation time distributions. Our proposed method provides more reliable estimation of the temporal variation in the generation time distribution, improving assessment of transmission dynamics.

Inferring time-varying generation time, serial interval and incubation period distributions for COVID-19 (preprint)

Background The generation time distribution, reflecting the time between successive infections in transmission chains, is one of the fundamental epidemiological parameters for describing COVID-19 transmission dynamics. However, because exact infection times are rarely known, it is often approximated by the serial interval distribution, reflecting the time between illness onsets of infector and infectee. This approximation holds under the assumption that infectors and infectees share the same incubation period distribution, which may not always be true. Methods We analyzed data on observed incubation period and serial interval distributions in China, during January and February 2020, under different sampling approaches, and developed an inferential framework to estimate the generation time distribution that accounts for variation over time due to changes in epidemiology, sampling biases and public health and social measures. Results We analyzed data on a total of 2989 confirmed cases for COVID-19 during January 1 to February 29, 2020 in Mainland China. During the study period, the empirical forward serial interval decreased from a mean of 8.90 days to 2.68 days. The estimated mean backward incubation period of infectors increased from 3.77 days to 9.61 days, and the mean forward incubation period of infectees also increased from 5.39 days to 7.21 days. The estimated mean forward generation time decreased from 7.27 days (95% confidence interval: 6.42, 8.07) to 4.21 days (95% confidence interval: 3.70, 4.74) days by January 29. We used simulations to examine the sensitivity of our modelling approach to a number of assumptions and alternative dynamics. Conclusions The proposed method can provide more reliable estimation of the temporal variation in the generation time distribution, enabling proper assessment of transmission dynamics.