Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Comparison of diclofenac with tramadol, tizanidine or placebo in the treatment of acute low back pain and sciatica: multi-center randomized controlled trial.

BACKGROUND: Low back pain (LBP) is a leading cause of disability worldwide and has posed numerous health and socioeconomic challenges. This study compared whether nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with tramadol, tizanidine or placebo would be the best treatment regime to improve the Roland Morris Disability Questionnaire (RMDQ) scores at 1 week. METHODS: This was a multi-center, double-blind, randomized, and placebo-controlled trial including adult patients with acute LBP and sciatica in three emergency departments in Hong Kong. Patients were randomized to the receive tramadol 50 mg, tizanidine 2 mg, or placebo every 6 hours for 2 weeks in a 1:1:1 ratio. The RMDQ and other secondary outcomes were measured at baseline, Day 2, 7, 14, 21, and 28. Data were analyzed on an intention to treat basis. Crude and adjusted mean differences in the changes of RMDQ and NRS scores from baseline to Day 7 between tizanidine/tramadol and placebo were determined with 95% confidence intervals. RESULTS: Two hundred and ninety-one patients were analyzed with the mean age of 47.4 years and 57.7% were male. The primary outcome of mean difference in RMDQs on Day 7 (compared with baseline) was non-significant for tizanidine compared with placebo (adjusted mean difference - 0.56, 95% CI -2.48 to 1.37) and tramadol compared with placebo (adjusted mean difference - 0.85, 95% CI -2.80 to 1.10). Only 23.7% were fully compliant to the treatment allocated. Complier Average Causal Effect analysis also showed no difference in the primary outcome for the tizanidine and tramadol versus placebo. CONCLUSION: Among patients with acute LBP and sciatica presenting to the ED, adding tramadol or tizanidine to diclofenac did not improve functional recovery.

Characterizing superspreading potential of infectious disease: Decomposition of individual transmissibility.

In the context of infectious disease transmission, high heterogeneity in individual infectiousness indicates that a few index cases can generate large numbers of secondary cases, a phenomenon commonly known as superspreading. The potential of disease superspreading can be characterized by describing the distribution of secondary cases (of each seed case) as a negative binomial (NB) distribution with the dispersion parameter, k. Based on the feature of NB distribution, there must be a proportion of individuals with individual reproduction number of almost 0, which appears restricted and unrealistic. To overcome this limitation, we generalized the compound structure of a Poisson rate and included an additional parameter, and divided the reproduction number into independent and additive fixed and variable components. Then, the secondary cases followed a Delaporte distribution. We demonstrated that the Delaporte distribution was important for understanding the characteristics of disease transmission, which generated new insights distinct from the NB model. By using real-world dataset, the Delaporte distribution provides improvements in describing the distributions of COVID-19 and SARS cases compared to the NB distribution. The model selection yielded increasing statistical power with larger sample sizes as well as conservative type I error in detecting the improvement in fitting with the likelihood ratio (LR) test. Numerical simulation revealed that the control strategy-making process may benefit from monitoring the transmission characteristics under the Delaporte framework. Our findings highlighted that for the COVID-19 pandemic, population-wide interventions may control disease transmission on a general scale before recommending the high-risk-specific control strategies.

The non-pharmaceutical interventions may affect the advantage in transmission of mutated variants during epidemics: A conceptual model for COVID-19.

As the COVID-19 pandemic continues, genetic mutations in SARS-CoV-2 emerge, and some of them are found more contagious than the previously identified strains, acting as the major mechanism for many large-scale epidemics. The transmission advantage of mutated variants is widely believed as an innate biological feature that is difficult to be altered by artificial factors. In this study, we explore how non-pharmaceutical interventions (NPI) may affect transmission advantage. A two-strain compartmental epidemic model is proposed and simulated to investigate the biological mechanism of the relationships among different NPIs, the changes in transmissibility of each strain and transmission advantage. Although the NPIs are effective in flattening the epidemic curve, we demonstrate that NPIs probably lead to a decline in transmission advantage, which is likely to occur if the NPIs become intensive. Our findings uncover the mechanistic relationship between NPIs and transmission advantage dynamically, and highlight the important role of NPIs not only in controlling the intensity of epidemics but also in slowing or even containing the growth of the proportion of variants.

Excess deaths from Alzheimer's disease and Parkinson's disease during the COVID-19 pandemic in the USA.

BACKGROUND: COVID-19 pandemic has indirect impacts on patients with chronic medical conditions, which may increase mortality risks for various non-COVID-19 causes. This study updates excess death statistics for Alzheimer's disease (AD) and Parkinson's disease (PD) up to 2022 and evaluates their demographic and spatial disparities in the USA. METHODS: This is an ecological time-series analysis of AD and PD mortality in the USA from January 2018 to March 2022. Poisson log-linear regressions were utilised to fit the weekly death data. Excess deaths were calculated with the difference between the observed and expected deaths under a counterfactual scenario of pandemic absence. RESULTS: From March 2020 to March 2022, we observed 41,115 and 10,328 excess deaths for AD and PD, respectively. The largest percentage increases in excess AD and PD deaths were found in the initial pandemic wave. For people aged ≥85 years, excess mortalities of AD and PD (per million persons) were 3946.0 (95% confidence interval [CI]: 2954.3, 4892.3) and 624.3 (95% CI: 369.4, 862.5), which were about 23 and 9 times higher than those aged 55-84 years, respectively. Females had a three-time higher excess mortality of AD than males (182.6 vs. 67.7 per million persons). The non-Hispanic Black people experienced larger increases in AD or PD deaths (excess percentage: 31.8% for AD and 34.6% for PD) than the non-Hispanic White population (17.1% for AD and 14.7% for PD). CONCLUSION: Under the continuing threats of COVID-19, efforts should be made to optimise health care capacity for patients with AD and PD.

Evaluation of a package of risk-based pharmaceutical and lifestyle interventions in patients with hypertension and/or diabetes in rural China: A pragmatic cluster randomised controlled trial.

BACKGROUND: Primary prevention of cardiovascular disease (CVD) requires adequate control of hypertension and diabetes. We designed and implemented pharmaceutical and healthy lifestyle interventions for patients with diabetes and/or hypertension in rural primary care, and assessed their effectiveness at reducing severe CVD events. METHODS AND FINDINGS: We used a pragmatic, parallel group, 2-arm, controlled, superiority, cluster trial design. We randomised 67 township hospitals in Zhejiang Province, China, to intervention (34) or control (33). A total of 31,326 participants were recruited, with 15,380 in the intervention arm and 15,946 in the control arm. Participants had no known CVD and were either patients with hypertension and a 10-year CVD risk of 20% or higher, or patients with type 2 diabetes regardless of their CVD risk. The intervention included prescription of a standardised package of medicines, individual advice on lifestyle change, and adherence support. Control was usual hypertension and diabetes care. In both arms, as usual in China, most outpatient drug costs were out of pocket. The primary outcome was severe CVD events, including coronary heart disease and stroke, during 36 months of follow-up, as recorded by the CVD surveillance system. The study was implemented between December 2013 and May 2017. A total of 13,385 (87%) and 14,745 (92%) participated in the intervention and control arms, respectively. Their mean age was 64 years, 51% were women, and 90% were farmers. Of all participants, 64% were diagnosed with hypertension with or without diabetes, and 36% were diagnosed with diabetes only. All township hospitals and participants completed the 36-month follow-up. At 36 months, there were 762 and 874 severe CVD events in the intervention and control arms, respectively, yielding a non-significant effect on CVD incidence rate (1.92 and 2.01 per 100 person-years, respectively; crude incidence rate ratio = 0.90 [95% CI: 0.74, 1.08; P = 0.259]). We observed significant, but small, differences in the change from baseline to follow-up for systolic blood pressure (-1.44 mm Hg [95% CI: -2.26, -0.62; P < 0.001]) and diastolic blood pressure (-1.29 mm Hg [95% CI: -1.77, -0.80; P < 0.001]) in the intervention arm compared to the control arm. Self-reported adherence to recommended medicines was significantly higher in the intervention arm compared with the control arm at 36 months. No safety concerns were identified. Main study limitations include all participants being informed about their high CVD risk at baseline, non-blinding of participants, and the relatively short follow-up period available for judging potential changes in rates of CVD events. CONCLUSIONS: The comprehensive package of pharmaceutical and healthy lifestyle interventions did not reduce severe CVD events over 36 months. Improving health system factors such as universal coverage for the cost of essential medicines is required for successful risk-based CVD prevention programmes. TRIAL REGISTRATION: ISRCTN registry ISRCTN58988083.

Shrinkage in serial intervals across transmission generations of COVID-19.

One of the key epidemiological characteristics that shape the transmission of coronavirus disease 2019 (COVID-19) is the serial interval (SI). Although SI is commonly considered following a probability distribution at a population scale, recent studies reported a slight shrinkage (or contraction) of the mean of effective SI across transmission generations or over time. Here, we develop a likelihood-based statistical inference framework with truncation to explore the change in SI across transmission generations after adjusting the impacts of case isolation. The COVID-19 contact tracing surveillance data in Hong Kong are used for exemplification. We find that for COVID-19, the mean of individual SI is likely to shrink with a factor at 0.72 per generation (95%CI: 0.54, 0.96) as the transmission generation increases, where a threshold may exist as the lower boundary of this shrinking process. We speculate that one of the probable explanations for the shrinkage in SI might be an outcome due to the competition among multiple candidate infectors within the same case cluster. Thus, the nonpharmaceutical interventive strategies are crucially important to block the transmission chains, and mitigate the COVID-19 epidemic.

Modelling the association between COVID-19 transmissibility and D614G substitution in SARS-CoV-2 spike protein: using the surveillance data in California as an example.

BACKGROUND: The COVID-19 pandemic poses a serious threat to global health, and pathogenic mutations are a major challenge to disease control. We developed a statistical framework to explore the association between molecular-level mutation activity of SARS-CoV-2 and population-level disease transmissibility of COVID-19. METHODS: We estimated the instantaneous transmissibility of COVID-19 by using the time-varying reproduction number (Rt). The mutation activity in SARS-CoV-2 is quantified empirically depending on (i) the prevalence of emerged amino acid substitutions and (ii) the frequency of these substitutions in the whole sequence. Using the likelihood-based approach, a statistical framework is developed to examine the association between mutation activity and Rt. We adopted the COVID-19 surveillance data in California as an example for demonstration. RESULTS: We found a significant positive association between population-level COVID-19 transmissibility and the D614G substitution on the SARS-CoV-2 spike protein. We estimate that a per 0.01 increase in the prevalence of glycine (G) on codon 614 is positively associated with a 0.49% (95% CI: 0.39 to 0.59) increase in Rt, which explains 61% of the Rt variation after accounting for the control measures. We remark that the modeling framework can be extended to study other infectious pathogens. CONCLUSIONS: Our findings show a link between the molecular-level mutation activity of SARS-CoV-2 and population-level transmission of COVID-19 to provide further evidence for a positive association between the D614G substitution and Rt. Future studies exploring the mechanism between SARS-CoV-2 mutations and COVID-19 infectivity are warranted.

Inferencing superspreading potential using zero-truncated negative binomial model: exemplification with COVID-19.

BACKGROUND: In infectious disease transmission dynamics, the high heterogeneity in individual infectiousness indicates that few index cases generate large numbers of secondary cases, which is commonly known as superspreading events. The heterogeneity in transmission can be measured by describing the distribution of the number of secondary cases as a negative binomial (NB) distribution with dispersion parameter, k. However, such inference framework usually neglects the under-ascertainment of sporadic cases, which are those without known epidemiological link and considered as independent clusters of size one, and this may potentially bias the estimates. METHODS: In this study, we adopt a zero-truncated likelihood-based framework to estimate k. We evaluate the estimation performance by using stochastic simulations, and compare it with the baseline non-truncated version. We exemplify the analytical framework with three contact tracing datasets of COVID-19. RESULTS: We demonstrate that the estimation bias exists when the under-ascertainment of index cases with 0 secondary case occurs, and the zero-truncated inference overcomes this problem and yields a less biased estimator of k. We find that the k of COVID-19 is inferred at 0.32 (95%CI: 0.15, 0.64), which appears slightly smaller than many previous estimates. We provide the simulation codes applying the inference framework in this study. CONCLUSIONS: The zero-truncated framework is recommended for less biased transmission heterogeneity estimates. These findings highlight the importance of individual-specific case management strategies to mitigate COVID-19 pandemic by lowering the transmission risks of potential super-spreaders with priority.

Attach importance of the bootstrap t test against Student's t test in clinical epidemiology: a demonstrative comparison using COVID-19 as an example.

Student's t test is valid for statistical inference under the normality assumption or asymptotically. By contrast, although the bootstrap t test was proposed in 1993, it is seldom adopted in medical research. We aim to demonstrate that the bootstrap t test outperforms Student's t test under normality in data. Using random data samples from normal distributions, we evaluated the testing performance, in terms of true-positive rate (TPR) and false-positive rate and diagnostic abilities, in terms of the area under the curve (AUC), of the bootstrap t test and Student's t test. We explore the AUC of both tests with varying sample size and coefficient of variation. We compare the testing outcomes using the COVID-19 serial interval (SI) data in Shenzhen and Hong Kong, China, for demonstration. With fixed TPR, the bootstrap t test maintained the equivalent accuracy in TPR, but significantly improved the true-negative rate from the Student's t test. With varying TPR, the diagnostic ability of bootstrap t test outperformed or equivalently performed as Student's t test in terms of the AUC. The equivalent performances are possible but rarely occur in practice. We find that the bootstrap t test outperforms by successfully detecting the difference in COVID-19 SI, which is defined as the time interval between consecutive transmission generations, due to sex and non-pharmaceutical interventions against the Student's t test. We demonstrated that the bootstrap t test outperforms Student's t test, and it is recommended to replace Student's t test in medical data analysis regardless of sample size.

Real-time quantification of the transmission advantage associated with a single mutation in pathogen genomes: a case study on the D614G substitution of SARS-CoV-2.

BACKGROUND: The COVID-19 pandemic poses serious threats to global health, and the emerging mutation in SARS-CoV-2 genomes, e.g., the D614G substitution, is one of the major challenges of disease control. Characterizing the role of the mutation activities is of importance to understand how the evolution of pathogen shapes the epidemiological outcomes at population scale. METHODS: We developed a statistical framework to reconstruct variant-specific reproduction numbers and estimate transmission advantage associated with the mutation activities marked by single substitution empirically. Using likelihood-based approach, the model is exemplified with the COVID-19 surveillance data from January 1 to June 30, 2020 in California, USA. We explore the potential of this framework to generate early warning signals for detecting transmission advantage on a real-time basis. RESULTS: The modelling framework in this study links together the mutation activity at molecular scale and COVID-19 transmissibility at population scale. We find a significant transmission advantage of COVID-19 associated with the D614G substitution, which increases the infectivity by 54% (95%CI: 36, 72). For the early alarming potentials, the analytical framework is demonstrated to detect this transmission advantage, before the mutation reaches dominance, on a real-time basis. CONCLUSIONS: We reported an evidence of transmission advantage associated with D614G substitution, and highlighted the real-time estimating potentials of modelling framework.

A randomized controlled trial of different young child formulas on upper respiratory and gastrointestinal tract infections in Chinese toddlers.

BACKGROUND: Bioactive proteins and human milk oligosaccharides (HMOs), important ingredients in breast milk, that protect against infections are lacking in young child formula (YCF). This study investigated the effects of new YCFs on respiratory and gastrointestinal infections in toddlers. METHODS: Four hundred and sixty one healthy Chinese children aged 1-2.5 years were recruited in this randomized, controlled, double-blind, parallel-group clinical trial of different YCFs. They were randomly assigned to either standard milk formula (YCF-Ref) or one of three new YCFs containing bioactive proteins and/or the HMO 2'-fucosyllactose (2'-FL) and/or milk fat for six months. Primary outcomes were incidence of upper respiratory tract infection (URTI) and duration of gastrointestinal tract infections (GITI). RESULTS: There were no significant between-group differences in primary outcomes. For secondary outcomes, subjects receiving 2'-FL-supplemented YCF had longer URTI. Subjects receiving YCF supplemented with milk fat and intact bioactive proteins, and 2'-FL at levels found in breast milk, had more GITI episodes and shorter time to first GITI but similar effects on URTI duration than YCF-Ref recipients. No effects on URTI and GITI were observed in toddlers receiving YCF with bioactive proteins at lower levels than breast milk. Occurrence of adverse events and anthropometry were similar in all groups. CONCLUSIONS: All three YCFs supplemented with different combinations of intact bioactive proteins, 2'-FL, and milk fat are safe in toddlers. No difference is detected among YCFs on URTI incidence and GITI duration. Further studies are needed to verify these findings especially in infants who may benefit most from the immune-boosting effects of bioactive proteins and HMOs.

Electroacupuncture and splinting versus splinting alone to treat carpal tunnel syndrome: a randomized controlled trial.

BACKGROUND: The effectiveness of acupuncture for managing carpal tunnel syndrome is uncertain, particularly in patients already receiving conventional treatments (e.g., splinting). We aimed to assess the effects of electroacupuncture combined with splinting. METHODS: We conducted a randomized parallel-group assessor-blinded 2-arm trial on patients with clinically diagnosed primary carpal tunnel syndrome. The treatment group was offered 13 sessions of electroacupuncture over 17 weeks. The treatment and control groups both received continuous nocturnal wrist splinting. RESULTS: Of 181 participants randomly assigned to electroacupuncture combined with splinting (n = 90) or splinting alone (n = 91), 174 (96.1%) completed all follow-up. The electroacupuncture group showed greater improvements at 17 weeks in symptoms (primary outcome of Symptom Severity Scale score mean difference [MD] -0.20, 95% confidence interval [CI] -0.36 to -0.03), disability (Disability of Arm, Shoulder and Hand Questionnaire score MD -6.72, 95% CI -10.9 to -2.57), function (Functional Status Scale score MD -0.22, 95% CI -0.38 to -0.05), dexterity (time to complete blinded pick-up test MD -6.13 seconds, 95% CI -10.6 to -1.63) and maximal tip pinch strength (MD 1.17 lb, 95% CI 0.48 to 1.86). Differences between groups were small and clinically unimportant for reduction in pain (numerical rating scale -0.70, 95% CI -1.34 to -0.06), and not significant for sensation (first finger monofilament test -0.08 mm, 95% CI -0.22 to 0.06). INTERPRETATION: For patients with primary carpal tunnel syndrome, chronic mild to moderate symptoms and no indication for surgery, electroacupuncture produces small changes in symptoms, disability, function, dexterity and pinch strength when added to nocturnal splinting. TRIAL REGISTRATION: Chinese Clinical Trial Register no. ChiCTR-TRC-11001655 (www.chictr.org.cn/showprojen.aspx?proj=7890); subsequently deposited in the World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-TRC-11001655).

Transmission risks of Omicron BA.5 following inactivated COVID-19 vaccines among children and adolescents in China.

BACKGROUND: As SARS-CoV-2 Omicron variants circulating globally since 2022, assessing the transmission characteristics, and the protection of vaccines against emerging Omicron variants among children and adolescents are needed for guiding the control and vaccination policies. METHODS: We conducted a retrospective cohort study for SARS-CoV-2 infections and close contacts aged <18 years from an outbreak seeded by Omicron BA.5 variants. The secondary attack rate (SAR) was calculated and the protective effects of two doses of inactivated vaccine (mainly Sinopharm /BBIBP-CorV) within a year versus one dose or two doses above a year after vaccination against the transmission and infection of Omicron BA.5 were estimated. RESULTS: A total of 3442 all-age close contacts of 122 confirmed SARS-CoV-2 infections aged 0-17 years were included. The SAR was higher in the household setting and for individuals who received a one-dose inactivated vaccine or those who received a two-dose for more than one year, with estimates of 28.5% (95% credible interval [CrI]: 21.1, 37.7) and 55.3% (95% CrI: 24.4, 84.8), respectively. The second dose of inactivated vaccine conferred substantial protection against all infection and transmission of Omicron BA.5 variants within a year. CONCLUSIONS: Our findings support the rollout of the second dose of inactivated vaccine for children and adolescents during the Omciron BA.5 predominant epidemic phase. Given the continuous emergence of SARS-CoV-2 variants, monitoring the transmission risk and corresponding vaccine effectiveness against SARS-CoV-2 variants among children and adolescents is important to inform control strategy.

Children and adolescents have reported suffering less severe outcomes from the SARS-CoV-2 Omicron variant. However, the risk of transmission and vaccine effectiveness among this population group is not well studied. Here, we used contact tracing data that was collected during an Omicron BA.5 outbreak from Urumqi, China, before the exit of "zero-COVID" measures, to evaluate the spread of SARS-CoV-2 infection among those age under 18 years, and the effectiveness of inactivated vaccine regimens. Our findings indicate there is a high rate of transmission among children and adolescents in a household setting and receiving two doses of inactivated COVID-19 vaccination within a year was more effective than a single dose or two doses given more than a year apart. These findings highlight the importance of tracking transmission and vaccine effectiveness of novel SARS-CoV-2 variants in younger populations to inform control strategies.

The mechanism shaping the logistic growth of mutation proportion in epidemics at population scale.

Virus evolution is a common process of pathogen adaption to host population and environment. Frequently, a small but important fraction of virus mutations are reported to contribute to higher risks of host infection, which is one of the major determinants of infectious diseases outbreaks at population scale. The key mutations contributing to transmission advantage of a genetic variant often grow and reach fixation rapidly. Based on classic epidemiology theories of disease transmission, we proposed a mechanistic explanation of the process that between-host transmission advantage may shape the observed logistic curve of the mutation proportion in population. The logistic growth of mutation is further generalized by incorporating time-varying selective pressure to account for impacts of external factors on pathogen adaptiveness. The proposed model is implemented in real-world data of COVID-19 to capture the emerging trends and changing dynamics of the B.1.1.7 strains of SARS-CoV-2 in England. The model characterizes and establishes the underlying theoretical mechanism that shapes the logistic growth of mutation in population.

Temporal Patterns in the Evolutionary Genetic Distance of SARS-CoV-2 during the COVID-19 Pandemic.

During coronavirus disease 2019 (COVID-19) pandemic, the genetic mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred frequently. Some mutations in the spike protein are considered to promote transmissibility of the virus, while the mutation patterns in other proteins are less studied and may also be important in understanding the characteristics of SARS-CoV-2. We used the sequencing data of SARS-CoV-2 strains in California to investigate the time-varying patterns of the evolutionary genetic distance. The accumulative genetic distances were quantified across different time periods and in different viral proteins. The increasing trends of genetic distance were observed in spike protein (S protein), the RNA-dependent RNA polymerase (RdRp) region and nonstructural protein 3 (nsp3) of open reading frame 1 (ORF1), and nucleocapsid protein (N protein). The genetic distances in ORF3a, ORF8, and nsp2 of ORF1 started to diverge from their original variants after September 2020. By contrast, mutations in other proteins appeared transiently, and no evident increasing trend was observed in the genetic distance to the original variants. This study presents distinct patterns of the SARS-CoV-2 mutations across multiple proteins from the aspect of genetic distance. Future investigation shall be conducted to study the effects of accumulative mutations on epidemics characteristics.

Enabling Factors, Barriers, and Perceptions of Pneumococcal Vaccination Strategy Implementation: A Qualitative Study.

Invasive pneumococcal disease (IPD) is a leading cause of disability and mortality worldwide, particularly in the elderly population. With the implementation of the Government Vaccination Programme (GVP) and the Vaccination Subsidy Scheme (VSS), enabling factors and barriers in service provider scheme participation and vaccination uptake were examined in 32 interviews with doctors and 16 interviews with vaccine recipients. Interview data were analysed in NVivo 11.0 with reference to the Consolidated Framework for Implementation Research (CFIR) and the REAIM Framework to develop codes and themes. Barriers to pneumococcal vaccination uptake included concerns on vaccine efficacy and poor understanding of the disease and vaccine schemes, whilst service provider participation was hindered by ill-defined parameters for patient eligibility and time, location, and logistical constraints. Enabling factors to improve intervention implementation were involvement of the government and physicians to encourage participation, clarifying eligibility criteria, and improving individual knowledge of IPD and vaccination schemes. As participation rates in the GVP and VSS remains low in Hong Kong, efforts concentrating on health promotion strategies encouraging pneumococcal vaccination amongst the elderly population are recommended.

Suppression of influenza virus infection by rhinovirus interference - at the population, individual and cellular levels.

Background: Influenza virus (IV) and the rhinovirus (RV) are the two most common circulating respiratory viruses circulating. Natural viral interference has been suggested between them. The effect of such at the population level has been described in temperate region, while its effect at the individual and cellular levels warrants further validation. In this study, we described the respiratory virus epidemiology and the co-infection landscape in the hospitalized population and investigated the distinct molecular pathways involved in the inhibition of virus replication. Methods: Nasopharyngeal aspirates (NPAs) collected from patients during 2015 to 2019 were examined for the presence of respiratory viruses. The correlation of the monthly prevalence between all the tested respiratory viruses, the co-infection rate and the temporal interference of RV and IV were tested. The viral interference was validated in vitro by conducting sequential RV and IV infections in the well-differentiated primary human airway epithelial cells. The contributing molecular pathways were determined by transcriptome analysis. Findings: A total of 112,926 NPAs were evaluated, and the Enterovirus/RV was the most prevalent respiratory virus detected. The negative correlation between EV/RV and IVs prevalence was independent of age and meteorological factors. Compare with other viruses, EV/RV had a significantly lower incidence of co-infection with IVs. Prior exposure to RV inhibited the replication of IV species A, B and oseltamivir-resistance stain in vitro. RV uniquely downregulated genes related to processing of viral mRNA, ribosomal proteins, translation and influenza infection. Interpretation: Epidemiological surveillance and the sequential infection in vitro suggested viral interference between EV/RV and IV operates at the population, individual and cellular levels. Funding: This study was supported by the General Research Fund (Ref: 24107017 and 14103119 to RWYC) and the Chinese University Direct Grant for Research (Ref: 2019·073 to RWYC).

How Transportation Restriction Shapes the Relationship Between Ambient Nitrogen Dioxide and COVID-19 Transmissibility: An Exploratory Analysis.

Background: Several recent studies reported a positive (statistical) association between ambient nitrogen dioxide (NO2) and COVID-19 transmissibility. However, considering the intensive transportation restriction due to lockdown measures that would lead to declines in both ambient NO2 concentration and COVID-19 spread, the crude or insufficiently adjusted associations between NO2 and COVID-19 transmissibility might be confounded. This study aimed to investigate whether transportation restriction confounded, mediated, or modified the association between ambient NO2 and COVID-19 transmissibility. Methods: The time-varying reproduction number (Rt ) was calculated to quantify the instantaneous COVID-19 transmissibility in 31 Chinese cities from January 1, 2020, to February 29, 2020. For each city, we evaluated the relationships between ambient NO2, transportation restriction, and COVID-19 transmission under three scenarios, including simple linear regression, mediation analysis, and adjusting transportation restriction as a confounder. The statistical significance (p-value < 0.05) of the three scenarios in 31 cities was summarized. Results: We repeated the crude correlational analysis, and also found the significantly positive association between NO2 and COVID-19 transmissibility. We found that little evidence supported NO2 as a mediator between transportation restriction and COVID-19 transmissibility. The association between NO2 and COVID-19 transmissibility appears less likely after adjusting the effects of transportation restriction. Conclusions: Our findings suggest that the crude association between NO2 and COVID-19 transmissibility is likely confounded by the transportation restriction in the early COVID-19 outbreak. After adjusting the confounders, the association between NO2 and COVID-19 transmissibility appears unlikely. Further studies are warranted to validate the findings in other regions.

The changing patterns of COVID-19 transmissibility during the social unrest in the United States: A nationwide ecological study with a before-and-after comparison.

Nationwide mass social unrest has emerged in the US since May 25 and raised broad concerns about its impacts on the local COVID-19 epidemics. We compared the COVID-19 transmissibility between May 19-May 25 and May 29-June 4 for each state of the US. We found that social unrest is likely associated with the rebound of the COVID-19 transmissibility, which might raise difficulties in the pandemic control.