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Abstract Currently there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2 infection. This target trial emulation study aims to address this gap by evaluating the use of nirmatrelvir/ritonavir in non-hospitalized paediatric patients aged 12–17 years with SARS-CoV-2 Omicron variant infection. Among paediatric patients diagnosed between 16th March 2022 and 5th February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or COVID-19 diagnosis. Primary outcome was 28 day all-cause mortality or all-cause hospitalization, while secondary outcomes were 28 day in-hospital disease progression, 28 day COVID-19-specific hospitalization, multisystem inflammatory syndrome in children (MIS-C), acute liver injury, acute renal failure, and acute respiratory distress syndrome. Overall, 49,378 eligible paediatric patients were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28 day all-cause hospitalization (absolute risk reduction = 0.23%, 95%CI = 0.19%–0.31%; relative risk = 0.66, 95%CI = 0.56–0.71). No events of mortality, in-hospital disease progression, or adverse clinical outcomes were observed among nirmatrelvir/ritonavir users. The findings confirmed the effectiveness of nirmatrelvir/ritonavir in reducing all-cause hospitalization risk among non-hospitalized pediatric patients with SARS-CoV-2 Omicron variant infection.

Abstract Cross-reactive antibodies with Fc receptor (FcR) effector functions may mitigate pandemic virus impact in the absence of neutralizing antibodies. In this exploratory study, we use serum from a randomized placebo-controlled trial of seasonal trivalent influenza vaccination in children (NCT00792051) conducted at the onset of the 2009 H1N1 pandemic (pH1N1) and monitored for infection. We found that seasonal vaccination increases pH1N1 specific antibodies and FcR effector functions. Furthermore, prospective baseline antibody profiles after seasonal vaccination, prior to pH1N1 infection, show that unvaccinated uninfected children have elevated ADCC effector function, FcγR3a and FcγR2a binding antibodies to multiple pH1N1 proteins, past seasonal and avian (H5, H7 and H9) strains. Whereas, children that became pH1N1 infected after seasonal vaccination have antibodies focussed to seasonal strains without FcR functions, and greater aggregated HA-specific profiles for IgM and IgG3. Modeling to predict infection susceptibility, ranked baseline hemagglutination antibody inhibition as the highest contributor to lack of pH1N1 infection, in combination with features that include pH1-IgG1, H1-stem responses and FcR binding to seasonal vaccine and pH1 proteins. Thus, seasonal vaccination can have benefits against pandemic influenza viruses, and some children already have broadly reactive antibodies with Fc potential without vaccination and may be considered ‘elite influenza controllers’.

Background: Hong Kong enforced stringent travel restrictions during the COVID-19 pandemic. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: Retrospective cohort study summarising the characteristics of imported cases detected in Hong Kong between 13 November 2020 and 31 January 2022, when compulsory quarantine was implemented. Findings: A total of 2269 imported COVID-19 cases aged 0–85 years were identified, of which 48.6 % detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than in ancestral strain and other variants cases (12 days; p

Summary: Background: The UN warns that Myanmar faces the ‘triple crises’ of mass conflict, uncontrolled COVID-19, and economic collapse. Therefore, we aimed to assess the population mental health burden, healthcare needs, and the associated risk factors in Myanmar. Methods: We established a nationwide random sample and recruited 1038 adults via random digit dialling from July 3–Aug 9, 2021, during the ongoing conflict since Feb 1, 2021, and surge in SARS-CoV-2 infections. Probable post-traumatic stress disorder (PTSD) was assessed using the PTSD Checklist—Civilian Version. Probable depression and anxiety were assessed using the Patient Health Questionnaire-2 and the Generalized Anxiety Disorder-2. We calculated population attributable fractions for probable mental disorders using multivariable logistic regression models. Based on the mental health burden and healthcare-seeking patterns, we projected the need for mental health services. Findings: During the ‘triple crises’, a third of adults in Myanmar (34.9%, 95% CI 32.0–37.7) reported a probable mental disorder. Prevalence of probable PTSD, depression, and anxiety were 8.1% (6.6–9.7), 14.3% (12.0–16.6), and 22.2% (19.7–24.7), respectively. We estimated that up to 79.9% (43.8–97.9) of probable PTSD was attributable to political stress. This corresponds to 2.1 million (1.1–3.2 million) fewer adults with probable PTSD if political stress was removed from the population. The mental health burden could translate into roughly 5.9 million adults seeking mental health services. Interpretation: The mental health burden in Myanmar is substantial, and population mental health might only be restored when the three crises have ended. An accelerated peace process is critical to protecting Myanmar’s population mental health. Funding: This research was supported the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU 17606122) and the Michele Tansella Award.

Abstract Reports of symptomatic rebound and/or test re-positivity among COVID-19 patients following the standard five-day treatment course of nirmatrelvir/ritonavir have sparked debates regarding optimal treatment timing and dosage. It is unclear whether initiating nirmatrelvir/ritonavir immediately after symptom onset would improve clinical outcomes and/or lead to post-treatment viral burden rebound due to inadequate viral clearance during treatment. Here we show that, by emulating a randomized target trial using real-world electronic medical record data from all 87,070 adult users of nirmatrelvir/ritonavir in Hong Kong between 16th March 2022 and 15th January 2023, early initiation of nirmatrelvir/ritonavir treatment (0 to 1 days after symptom onset or diagnosis) significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction [ARR]: 1.50% (95% confidence interval 1.17-1.80%); relative risk [RR]: 0.77 (0.73, 0.82)), but may be associated with a significant elevated risk of viral burden rebound (ARR: −1.08% (−1.55%, −0.46%)), although the latter estimates were associated with high uncertainty due to limited sample sizes. As such, patients should continue to initiate nirmatrelvir/ritonavir early after symptom onset or diagnosis to better protect against the more serious outcomes of hospitalization and mortality.

Abstract Background With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear. This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics. Methods A drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong’s “Children of 1997” birth cohort (n = 3443, aged ~ 17.6 years). Safety outcomes (n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. Positive control outcomes were cholesterol markers from the “Children of 1997” birth cohort and coronary artery disease from Biobank Japan. Results Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta [95% CI], − 1.06 [− 1.52 to − 0.60]; PCSK9: − 0.93 [− 1.56 to − 0.31]) and had the expected effect on the positive control outcomes. After correcting for multiple comparisons (p-value

Summary: Background: Despite the early demonstrated safety and effectiveness of COVID-19 vaccines in children, uptake was slow throughout the pandemic and remains low globally. Understanding vaccine refusal could provide insights to improving vaccine uptake in future pandemics. Methods: In a population-wide registry of all COVID-19 paediatric vaccination appointments, we used interrupted time series analysis to evaluate the impact of public policies. In a population-based cohort of adults, we used population attributable fractions to assess the individual and joint contributions of potential determinants to paediatric COVID-19 vaccination, and used mediation analysis to identify modifiable mediators between political views and paediatric vaccination. Findings: School vaccination requirements were associated with an increase in vaccination appointments by 278.7% (95% CI 85.3–673.9) in adolescents aged 12–17 and 112.8% (27.6–255.0) in children aged 5–11. Government-mandated vaccine pass, required for entry into restaurants, shopping malls and supermarkets, was associated with increased vaccination appointments by 108.7% (26.6–244.0) in adolescents. The following four determinants may explain 82.5% (63.5–100.0) of the reasons why children were unvaccinated: familial political views, vaccine hesitancy for children, mistrust in doctors and academics, and vaccine misconceptions. The influence of political views may be mitigated since 95.9% (76.4–100.0) of its association with vaccine reluctance for adolescents was mediated by modifiable factors such as mistrust in health authorities and low vaccine confidence. Interpretation: School vaccination requirements and vaccine passes were associated with increased vaccine uptake. Clinicians should recognise that factors beyond health, such as political views, can influence paediatric vaccine uptake to a significant extent. Nonetheless, such influences could be mitigated by targeted interventions and public policies. Funding: Hong Kong Jockey Club Charities Trust, Research Grants Council, University Grants Committee, and Health Bureau.

Summary: 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. We reflected on pandemic preparedness and responses by assessing COVID-19 transmission and associated disease burden in the context of implementation of various public health and social measures (PHSMs). 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 the temporal changes 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. Funding: Health and Medical Research Fund.

Abstract Hong Kong experienced a surge of Omicron BA.2 infections in early 2022, resulting in one of the highest per-capita death rates of COVID-19. The outbreak occurred in a dense population with low immunity towards natural SARS-CoV-2 infection, high vaccine hesitancy in vulnerable populations, comprehensive disease surveillance and the capacity for stringent public health and social measures (PHSMs). By analyzing genome sequences and epidemiological data, we reconstructed the epidemic trajectory of BA.2 wave and found that the initial BA.2 community transmission emerged from cross-infection within hotel quarantine. The rapid implementation of PHSMs suppressed early epidemic growth but the effective reproduction number (R e ) increased again during the Spring festival in early February and remained around 1 until early April. Independent estimates of point prevalence and incidence using phylodynamics also showed extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. Discordant inferences based on genomic and epidemiological data underscore the need for research to improve near real-time epidemic growth estimates by combining multiple disparate data sources to better inform outbreak response policy.

Abstract In randomized controlled trials of influenza vaccination, 550 children received trivalent-inactivated influenza vaccine, permitting us to explore relationship between vaccine response and host single nucleotide polymorphisms (SNPs) in 23 candidate genes with adjustment of multiple testing. For host SNPs in TLR7–1817G/T (rs5741880), genotype GT was associated with lower odds (OR: 0.22, 95% CI: 0.09, 0.53) of have post-vaccination hemagglutination-inhibiting (HAI) titers ≥40, compared with genotype GG and TT combined under the over-dominant model. For host SNPs in TLR8–129G/C (rs3764879), genotype GT was associated with lower odds (OR: 0.47; 95% CI: 0.28, 0.80) of have post vaccination HAI titers ≥40 compared with genotype GG and AA combined under the over-dominant model. Our results could contribute to the development of better vaccines that may offer improved protection to all recipients.

Hand, foot and mouth disease, caused by enterovirus A71 (EV-A71) infection, is common in children in China. Here, the authors estimate EV-A71 incidence and seroprevalence using data from two longitudinal cohorts and find that, despite high infection rates, a large proportion of children under 6 are susceptible.

Abstract Background The protective effect of T cell-mediated immunity against influenza virus infections in natural settings remains unclear, especially in seasonal epidemics. Methods To explore the potential of such protection, we analyzed the blood samples collected longitudinally in a community-based study and covered the first wave of pandemic H1N1 (pH1N1), two subsequent pH1N1 epidemics, and three seasonal H3N2 influenza A epidemics (H3N2) for which we measured pre-existing influenza virus-specific CD4 and CD8 T cell responses by intracellular IFN-γ staining assay for 965 whole blood samples. Results Based on logistic regression, we found that higher pre-existing influenza virus-specific CD4 and CD8 T cell responses were associated with lower infection odds for corresponding subtypes. Every fold increase in H3N2-specific CD4 and CD8 T cells was associated with 28% (95% CI 8%, 44%) and 26% (95% CI 8%, 41%) lower H3N2 infection odds, respectively. Every fold increase in pre-existing seasonal H1N1 influenza A virus (sH1N1)-specific CD4 and CD8 T cells was associated with 28% (95% CI 11%, 41%) and 22% (95% CI 8%, 33%) lower pH1N1 infection odds, respectively. We observed the same associations for individuals with pre-epidemic hemagglutination inhibition (HAI) titers < 40. There was no correlation between pre-existing influenza virus-specific CD4 and CD8 T cell response and HAI titer. Conclusions We demonstrated homosubtypic and cross-strain protection against influenza infections was associated with T cell response, especially CD4 T cell response. These protections were independent of the protection associated with HAI titer. Therefore, T cell response could be an assessment of individual and population immunity for future epidemics and pandemics, in addition to using HAI titer.

Background: Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city. Methods: We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist–hip ratio (WHR) in Hong Kong’s population-representative ‘Children of 1997’ birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity risk n ≤ 7119, WHR n = 5691) and ~17.6 years (n = 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n = 308) and CpG by CpG analysis (n = 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. Results: At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR. Conclusions: These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings. Funding: This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.

Our analysis of data collected from multiple epidemics in Hong Kong indicated a shorter serial interval and generation time of infections with the SARS-CoV-2 Omicron variant. The age-specific case-fatality risk for Omicron BA.2.2 case-patients without complete primary vaccination was comparable to that of persons infected with ancestral strains in earlier waves.

Abstract COVID-19 has imposed a very substantial direct threat to the physical health of those infected, although the corollary impact on mental health may be even more burdensome. Here we focus on assessing the mental health impact of COVID-19 and of other epidemics in the community. We searched five electronic databases until December 9, 2020, for all peer-reviewed original studies reporting any prevalence or correlates of mental disorders in the general population following novel epidemics in English, Chinese or Portuguese. We synthesised prevalence estimates from probability samples during COVID-19 and past epidemics. The meta-analytical effect size was the prevalence of relevant outcomes, estimated via random-effects model. I 2 statistics, Doi plots and the LFK index were used to examine heterogeneity and publication bias. This study is pre-registered with PROSPERO, CRD42020179105. We identified 255 eligible studies from 50 countries on: COVID-19 (n = 247 studies), severe acute respiratory syndrome (SARS; n = 5), Ebola virus disease (n = 2), and 1918 influenza (n = 1). During COVID-19, we estimated the point prevalence for probable anxiety (20.7%, 95% CI 12.9–29.7), probable depression (18.1%, 13.0–23.9), and psychological distress (13.0%, 0–34.1). Correlates for poorer mental health include female sex, lower income, pre-existing medical conditions, perceived risk of infection, exhibiting COVID-19-like symptoms, social media use, financial stress, and loneliness. Public trust in authorities, availability of accurate information, adoption of preventive measures and social support were associated with less morbidity. The mental health consequences of COVID-19 and other epidemics could be comparable to major disasters and armed conflicts. The considerable heterogeneity in our analysis indicates that more random samples are needed. Health-care professionals should be vigilant of the psychological toll of epidemics, including among those who have not been infected.

The time-varying effective reproductive number (Rt) is useful for monitoring transmission of infections such as COVID-19, but reporting delays impact case count-based estimation methods. Here, the authors demonstrate and validate a method for estimation of Rt based on viral load data from Hong Kong that does not require accurate daily counts.

Serological classification of influenza infection has classically been based on a four-fold or higher increase in antibody levels, but this approach may not be optimal. Here, the authors develop a Bayesian model to improve identification of infections in serological samples by accounting for individual antibody dynamics.

We report surveillance conducted in 217 pestiferous rodents in Hong Kong for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We did not detect SARS-CoV-2 RNA but identified 1 seropositive rodent, suggesting exposure to a virus antigenically similar to SARS-CoV-2. Potential exposure of urban rodents to SARS-CoV-2 cannot be ruled out.

Hong Kong has used an elimination strategy to control SARS-CoV-2 with stringent measures including traveller quarantine. Here, the authors show that the majority of community-acquired cases until January 2021 resulted from three importations, and that increased transmission followed prolonged periods of restrictions, likely due to adherence fatigue.

Summary: Background: Hong Kong followed a strict COVID-19 elimination strategy in 2020. We estimated the impact of the COVID-19 pandemic responses on all-cause and cause-specific hospitalizations and deaths in 2020. Methods: Interrupted time-series analysis using negative binomial regression accounting for seasonality and long-term trend was used on weekly 2010–2020 data to estimate the change in hospitalization risk and excess mortality occurring both within and out of hospitals. Findings: In 2020, as compared to a 2010–2019 baseline, we observed an overall reduction in all-cause hospitalizations, and a concurrent increase in deaths. The overall hospitalization reduction (per 100,000 population) was 4809 (95% CI: 4692, 4926) in 2020, with respiratory diseases (632, 95% CI: 607, 658) and cardiovascular diseases (275, 95% CI: 264, 286) contributing most. The overall excess mortality (per 100,000 population) was 25 (95% CI: 23, 27) in 2020, mostly among individuals with pre-existing cardiovascular diseases (12, 95% CI: 11, 13). A reduction in excess in-hospital mortality (−10 per 100,000, 95% CI: −12, −8) was accompanied by an increase in excess out-of-hospital mortality (32, 95% CI: 29, 34). Interpretation: The COVID-19 pandemic might have caused indirect impact on population morbidity and mortality likely through changed healthcare seeking particularly in youngest and oldest individuals and those with cardiovascular diseases. Better healthcare planning is needed during public health emergencies with disruptions in healthcare services. Funding: Health and Medical Research Fund, Collaborative Research Fund, AIR@InnoHK and RGC Senior Research Fellow Scheme, Hong Kong.

The performance of gargling for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase (RT)-PCR testing has not been previously reviewed. This review systematically assessed the performance of saline and water gargling for SARS-CoV-2 RT-PCR testing in the settings of diagnosing and monitoring viral shedding. We included original studies comparing the performance of gargling and (oropharyngeal–)nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing. Studies conducted in either suspected individuals or confirmed cases were included and analysed separately. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were examined using random-effects models. Gargles achieved a high overall sensitivity (91%), specificity (97%), PPV (95%) and NPV (91%) for SARS-CoV-2 RT-PCR testing. Studies using saline gargle and water gargle have an overall sensitivity of 97% and 86%, respectively. The sensitivity values were largely maintained for saline and water gargling on stratified analysis, for both diagnosis (96% and 92%) and viral shedding monitoring (98% and 78%). A higher sensitivity was also reported by studies using sterile saline (100%), a smaller amount of gargling solution (92% versus 87%) and a longer gargling duration (95% versus 86%). Our results supported the use of gargling as a sampling approach for SARS-CoV-2 RT-PCR testing, which achieved a high sensitivity for both diagnosis and viral shedding monitoring purposes. Further investigation on the comparative performance of different gargling mediums is needed to draw a definitive conclusion.

Controlling transmission in restaurants is an important component of public health and social measures for coronavirus disease. We examined the effects of restaurant measures in Hong Kong. Our findings indicate that shortening operating hours did not have an effect on time-varying effective reproduction number when capacity was already reduced.

Kenji Shibuya and coauthors discuss the potential contribution of East Asian countries to global health in the light of COVID-19.

Digital proxies of human mobility can be used to monitor social distancing, and therefore have potential to infer COVID-19 dynamics. Here, the authors integrate travel card data from Hong Kong into a transmission model and show that it can be used to track transmissibility in near real-time.

Summary: Background: In view of emerging variants of concern (VOCs), we aimed to evaluate the impact of various allocation strategies of COVID-19 vaccines and antiviral such that the pandemic exit strategy could be tailored to risks and preferences of jurisdictions in the East Asia and Pacific region (EAP) to improve its efficiency and effectiveness. Methods: Vaccine efficacies were estimated from the titre distributions of 50% plaque reduction neutralization test (PRNT50), assuming that PRNT50 titres of primary vaccination decreased by 2-10 folds due to antibody waning and emergence of VOCs, and an additional dose of vaccine would increase PRNT50 titres by 3- or 9-fold. We then used an existing SARS-CoV-2 transmission model to assess the outcomes of vaccine allocation strategies with and without the use of antivirals for symptomatic patients in Japan, Hong Kong, and Vietnam. Findings: Increasing primary vaccination coverage was the most important contributing factor in reducing the total and peak number of COVID-19 hospitalisations, especially when population vaccine coverage or vaccine uptake among older adults was low. Providing antivirals to 50% of symptomatic infections only further reduced total and peak hospitalisations by 10-13%. The effectiveness of an additional dose of vaccine was highly dependent on the immune escape potential of VOCs and antibody waning, but less dependent on the boosting efficacy of the additional dose. Interpretation: Increasing primary vaccination coverage should be prioritised in the design of allocation strategies of COVID-19 vaccines and antivirals against emerging VOCs, such as Omicron, in the EAP region. Heterologous vaccination with any available vaccine as the additional dose could be considered when planning pandemic exit strategies tailored to the circumstances of EAP jurisdictions. Funding: Health and Medical Research Fund, General Research Fund, AIR@InnoHK

COVID-19 disease models have aided policymakers in low-and middle-income countries (LMICs) with many critical decisions. Many challenges remain surrounding their use, from inappropriate model selection and adoption, inadequate and untimely reporting of evidence, to the lack of iterative stakeholder engagement in policy formulation and deliberation. These issues can contribute to the misuse of models and hinder effective policy implementation. Without guidance on how to address such challenges, the true potential of such models may not be realised. The COVID-19 Multi-Model Comparison Collaboration (CMCC) was formed to address this gap. CMCC is a global collaboration between decision-makers from LMICs, modellers and researchers, and development partners. To understand the limitations of existing COVID-19 disease models (primarily from high income countries) and how they could be adequately support decision-making in LMICs, a desk review of modelling experience during the COVID-19 and past disease outbreaks, two online surveys, and regular online consultations were held among the collaborators. Three key recommendations from CMCC include: A ‘fitness-for-purpose’ flowchart, a tool that concurrently walks policymakers (or their advisors) and modellers through a model selection and development process. The flowchart is organised around the following: policy aims, modelling feasibility, model implementation, model reporting commitment. Holmdahl and Buckee (2020) A ‘reporting standards trajectory’, which includes three gradually increasing standard of reports, ‘minimum’, ‘acceptable’, and ‘ideal’, and seeks collaboration from funders, modellers, and decision-makers to enhance the quality of reports over time and accountability of researchers. Malla et al. (2018) A framework for “collaborative modelling for effective policy implementation and evaluation” which extends the definition of stakeholders to funders, ground-level implementers, public, and other researchers, and outlines how each can contribute to modelling. We advocate for standardisation of modelling processes and adoption of country-owned model through iterative stakeholder participation and discuss how they can enhance trust, accountability, and public ownership to decisions.

The current Syrian conflict is considered a major humanitarian crisis. Here, the authors show a decline in population well-being with the onset of the conflict, and show how this decline compares to other populations experiencing wars, civil unrest or natural disasters.

The associations between absolute vs. relative income at the household or neighborhood level and cardiovascular disease (CVD) risk remain understudied in the Chinese context. Further, it is unclear whether stress biomarkers, such as cortisol, are on the pathway from income to CVD risk. We examined the associations of absolute and relative income with CVD risk observationally, as well as the mediating role of cortisol, and validated the role of cortisol using Mendelian Randomization (MR) in Hong Kong Chinese. Within Hong Kong's FAMILY Cohort, associations of absolute and relative income at both the individual and neighborhood levels with CVD risk [body mass index (BMI), body fat percentage, systolic blood pressure, diastolic blood pressure, self-reported CVD and self-reported diabetes] were examined using multilevel logistic or linear models (n = 17,607), the mediating role of cortisol using the mediation analysis (n = 1,562), and associations of genetically predicted cortisol with CVD risk using the multiplicative generalized method of moments (MGMMs) or two-stage least squares regression (n = 1,562). In our cross-sectional observational analysis, relative household income deprivation (per 1 SD, equivalent to USD 128 difference in Yitzhaki index) was associated with higher systolic blood pressure (0.47 mmHg, 95% CI 0.30–0.64), but lower BMI (−0.07 kg/m2, 95% CI −0.11 to −0.04), independent of absolute income. Neighborhood income inequality was generally unrelated to CVD and its risk factors, nor was absolute income at the household or neighborhood level. Cortisol did not clearly mediate the association of relative household income deprivation with systolic blood pressure. Using MR, cortisol was unrelated to CVD risk. Based on our findings, relative household income deprivation was not consistently associated with cardiovascular health in Hong Kong Chinese, nor were neighborhood income inequality and absolute income, highlighting the context-specific ways in which relative and absolute income are linked to CVD risk.

Background Hypertension is a leading preventable risk factor of chronic disease and all-cause mortality. Housing is a fundamental social determinant of health. Yet, little is known about the impacts of liveable residential space and density on hypertension. Methods and findings This retrospective observational study (median follow-up of 2.2 years) leveraged the FAMILY Cohort, a large territory-wide cohort in Hong Kong, Special Administrative Region, People’s Republic of China to quantify associations of objectively measured liveable space and residential density with blood pressure outcomes among adults aged ≥16 years. Blood pressure outcomes comprised diastolic blood pressure (DBP), systolic blood pressure (SBP), mean arterial pressure (MAP), and hypertension. Liveable space was measured as residential floor area, and density was assessed using the number of residential units per building block and neighborhood residential unit density within predefined catchments. Multivariable regression models examined associations of liveable floor area and residential density with prevalent and incident hypertension. We investigated effect modifications by age, sex, income, employment status, and housing type. Propensity score matching was further employed to match a subset of participants who moved to smaller residences at follow-up with equivalent controls who did not move, and generalized linear models examined the impact of moving to smaller residences upon blood pressure outcomes. Our fully adjusted models of prevalent hypertension outcomes comprised 30,439 participants at baseline, while 13,895 participants were available for incident models at follow-up. We found that each interquartile range (IQR) increment in liveable floor area was associated with lower DBP (beta [β] = −0.269 mm Hg, 95% confidence interval [CI]: −0.419 to −0.118, p < 0.001), SBP (β = −0.317 mm Hg, −0.551 to −0.084, p = 0.008), MAP (β = −0.285 mm Hg, −0.451 to −0.119 with p < 0.001), and prevalent hypertension (odds ratio [OR] = 0.955, 0.918 to 0.993, p = 0.022) at baseline. Each IQR increment in residential units per building block was associated with higher DBP (β = 0.477 mm Hg, 0.212 to 0.742, p = Conclusions We disentangled the association of micro-, meso-, and macrolevel residential densities with hypertension and found that higher liveable floor area and neighborhood scale residential density were associated with lower odds of hypertension. These findings suggest adequate housing in the form of provisioning of sufficient liveable space and optimizing residential density at the building block, and neighborhood levels should be investigated as a potential population-wide preventive strategy for lowering hypertension and associated chronic diseases. In a cohort study, Dr. Chinmoy Sarkar and colleagues investigate the association between liveable residential space, residential density and hypertension in Hong Kong. Author summary Why was this study done? Hypertension is the leading preventable risk factor of cardiovascular disease (CVD) and all-cause mortality. The fundamental role of housing in shaping population health has been acknowledged by the World Health Organization (WHO) and the American Heart Association. However, scientific evidence with regard to the relationship of housing overcrowding and residential density with hypertension has been insufficient. What did the researchers do and find? We examined associations of objectively measured liveable space and multiscalar residential density with hypertension among adults employing 2 consecutive waves of a large territory-wide cohort in Hong Kong, Special Administrative Region, People’s Republic of China. At baseline, each interquartile range (IQR) increment in liveable floor area was associated with lower blood pressure and prevalent hypertension. At the block level, each IQR increase in residential units per building block was associated with higher blood pressure and prevalent hypertension. At a neighborhood level, higher residential density was associated with lower blood pressure and hypertension. Our longitudinal analysis found that each IQR increment in liveable floor area was associated with 9.1% lower odds of incident hypertension. Propensity-matched analysis found that in reference to participants who did not move, those relocating to residences of lower liveable floor area was associated with higher odds of hypertension. What do these findings mean? Provisioning adequate liveable space and optimizing density of residential units at building block and neighborhood levels may act as population-wide preventive strategies for lowering the burden of hypertension. The evidence can inform housing policy toward health-centric housing space allocation and densification while planning, designing, and retrofitting high-density cities of similar contexts.

Summary: Background: Since the emergence of the COVID-19 pandemic in late 2019, various public health and social measures (PHSMs) have been used to suppress and mitigate the spread of SARS-CoV-2. With mass vaccination programmes against COVID-19 being rolled out in many countries in early 2021, we aimed to evaluate to what extent travel restrictions and other PHSMs can be relaxed without exacerbating the local and global spread of COVID-19. Methods: We adapted an existing age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission dynamics that can be parameterised with country-specific age demographics and contact patterns to simulate the effect of vaccination and PHSM relaxation on transmission. We varied assumptions by age-specific susceptibility and infectiousness, vaccine uptake, contact patterns, and age structures. We used Hong Kong as a case study and assumed that, before vaccination, the population is completely susceptible to SARS-CoV-2 infection. We applied our model to 304 jurisdictions (27 countries and 277 sub-national administrative regions from eight countries). We assumed that PHSMs have suppressed the effective reproductive number (Re) to fall between 1·0 and 9·0 locally before the commencement of vaccination programmes. We evaluated the levels of PHSMs that should be maintained during the roll-out of COVID-19 vaccination to avoid a large local outbreak of COVID-19, with different assumptions about vaccine efficacy, vaccination coverage, and travel restrictions. We assumed that the maximum capacity of the health system, in terms of daily hospital admissions, is 0·005% of the population size. Findings: At vaccine efficacy of 0·80 in reducing susceptibility to SARS-CoV-2 infection, 0·50 in reducing SARS-CoV-2 infectivity, and 0·95 in reducing symptomatic COVID-19 diseases, vaccination coverage would have to be 100% for all individuals aged 30 or older to avoid an outbreak, when relaxing PHSMs, that would overload the local health-care system, assuming a pre-vaccination Re of 2·5. Testing and quarantine of at least 5 days would have to be maintained for inbound travellers to minimise the risk of reintroducing a local outbreak until high vaccination coverages are attained locally and overseas in most countries. Interpretation: Gradual relaxation of PHSMs should be carefully planned during the roll-out of vaccination programmes, and easing of travel restrictions weighed against risk of reintroducing outbreaks, to avoid overwhelming health systems and minimise deaths related to COVID-19. Funding: Health and Medical Research Fund and the General Research Fund.

Influenza vaccination is an important intervention to prevent influenza virus infection. Our previous analysis suggested that indirect protection is limited in an influenza B epidemic in Hong Kong. We further analyzed six influenza A epidemics to determine such potential. We applied a statistical model to estimate household transmission dynamics in the 3 influenza A(H3N2) and 3 pandemic influenza A(H1N1) epidemics. Then, we estimated the reduction in infection risk among unvaccinated household members when all children in households are vaccinated, with different assumptions on vaccine efficacy (VE). In the optimal scenario that VE was 70%, the reduction to the total probability of infection was only marginal, with relative probabilities ranged from 0.91–0.94 when all children in households were vaccinated because community was by far the main source of infection during the six epidemics in our study. The proportion of cases attributed to household transmission was 10% (95% CrI: 7%, 13%). Individual influenza vaccination is important even when other household members are vaccinated, given the degree of indirect protection is small.

Objectives Data linkage of cohort-based data and electronic health records (EHRs) has been practised in many countries, but in Hong Kong there is still a lack of such research. To expand the use of multisource data, we aimed to identify a feasible way of linking two cohorts with EHRs in Hong Kong.Methods Participants in the ‘Children of 1997’ birth cohort and the Chinese Early Development Instrument (CEDI) cohort were separated into several batches. The Hong Kong Identity Card Numbers (HKIDs) of each batch were then uploaded to the Hong Kong Clinical Data Analysis and Reporting System (CDARS) to retrieve EHRs. Within the same batch, each participant has a unique combination of date of birth and sex which can then be used for exact matching, as no HKID will be returned from CDARS. Raw data collected for the two cohorts were checked for the mismatched cases. After the matching, we conducted a simple descriptive analysis of attention deficit hyperactivity disorder (ADHD) information collected in the CEDI cohort via the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour Scale (SWAN) and EHRs.Results In total, 3473 and 910 HKIDs in the birth cohort and CEDI cohort were separated into 44 and 5 batches, respectively, and then submitted to the CDARS, with 100% and 97% being valid HKIDs respectively. The match rates were confirmed to be 100% and 99.75% after checking the cohort data. From our illustration using the ADHD information in the CEDI cohort, 36 (4.47%) individuals had ADHD–Combined score over the clinical cut-off in the SWAN survey, and 68 (8.31%) individuals had ADHD records in EHRs.Conclusions Using date of birth and sex as identifiable variables, we were able to link the cohort data and EHRs with high match rates. This method will assist in the generation of databases for future multidisciplinary research using both cohort data and EHRs.

BackgroundExisting predictive outcomes models for type 2 diabetes developed and validated in historical European populations may not be applicable for East Asian populations due to differences in the epidemiology and complications. Despite the continuum of risk across the spectrum of risk factor values, existing models are typically limited to diabetes alone and ignore the progression from prediabetes to diabetes. The objective of this study is to develop and externally validate a patient-level simulation model for prediabetes and type 2 diabetes in the East Asian population for predicting lifetime health outcomes.Methods and findingsWe developed a health outcomes model from a population-based cohort of individuals with prediabetes or type 2 diabetes: Hong Kong Clinical Management System (CMS, 97,628 participants) from 2006 to 2017. The Chinese Hong Kong Integrated Modeling and Evaluation (CHIME) simulation model comprises of 13 risk equations to predict mortality, micro- and macrovascular complications, and development of diabetes. Risk equations were derived using parametric proportional hazard models. External validation of the CHIME model was assessed in the China Health and Retirement Longitudinal Study (CHARLS, 4,567 participants) from 2011 to 2018 for mortality, ischemic heart disease, cerebrovascular disease, renal failure, cataract, and development of diabetes; and against 80 observed endpoints from 9 published trials using 100,000 simulated individuals per trial. The CHIME model was compared to United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS-OM2) and Risk Equations for Complications Of type 2 Diabetes (RECODe) by assessing model discrimination (C-statistics), calibration slope/intercept, root mean square percentage error (RMSPE), and R2. CHIME risk equations had C-statistics for discrimination from 0.636 to 0.813 internally and 0.702 to 0.770 externally for diabetes participants. Calibration slopes between deciles of expected and observed risk in CMS ranged from 0.680 to 1.333 for mortality, myocardial infarction, ischemic heart disease, retinopathy, neuropathy, ulcer of the skin, cataract, renal failure, and heart failure; 0.591 for peripheral vascular disease; 1.599 for cerebrovascular disease; and 2.247 for amputation; and in CHARLS outcomes from 0.709 to 1.035. CHIME had better discrimination and calibration than UKPDS-OM2 in CMS (C-statistics 0.548 to 0.772, slopes 0.130 to 3.846) and CHARLS (C-statistics 0.514 to 0.750, slopes -0.589 to 11.411); and small improvements in discrimination and better calibration than RECODe in CMS (C-statistics 0.615 to 0.793, slopes 0.138 to 1.514). Predictive error was smaller for CHIME in CMS (RSMPE 3.53% versus 10.82% for UKPDS-OM2 and 11.16% for RECODe) and CHARLS (RSMPE 4.49% versus 14.80% for UKPDS-OM2). Calibration performance of CHIME was generally better for trials with Asian participants (RMSPE 0.48% to 3.66%) than for non-Asian trials (RMPSE 0.81% to 8.50%). Main limitations include the limited number of outcomes recorded in the CHARLS cohort, and the generalizability of simulated cohorts derived from trial participants.ConclusionsOur study shows that the CHIME model is a new validated tool for predicting progression of diabetes and its outcomes, particularly among Chinese and East Asian populations that has been lacking thus far. The CHIME model can be used by health service planners and policy makers to develop population-level strategies, for example, setting HbA1c and lipid targets, to optimize health outcomes.

Protective immunity after influenza virus infection is poorly understood. Here, the authors quantify the dynamics of immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology, and find that the form and dynamics of protection differ between children and adults.

Background: Early-life air pollution exposure is associated with lung function in children and adolescents. However, whether the association of prenatal and early postnatal exposure to air pollution with lung function continues into adulthood remains unclear. Objective: To investigate the associations of early exposure to air pollution with lung function at ~17.5 years in a non-western developed setting with more concentrated air pollutants. Methods: We examined the associations of exposure to particular matter with an aerodynamic diameter of

Relevance of indirect protection of household members of vaccinees is unclear. Here, Tsang et al. quantify the direct and indirect protection of vaccination in a randomized controlled trial and show that benefits of individual vaccination remain important even when other household members are vaccinated.

Background: The timing of administration of agents and use of combination treatments in COVID-19 remain unclear. We assessed the effectiveness of therapeutics in cohorts in Hong Kong SAR and Anhui, China. Methods: We conducted propensity-score analysis of 4771 symptomatic patients from Hong Kong between 21st January and 6th December 2020, and 648 symptomatic patients from Anhui between 1st January and 27th February 2020. We censored all observations as at 13st December 2020. Time from hospital admission to discharge, and composite outcome of death, invasive mechanical ventilation or intensive care unit admission across 1) all therapeutic options including lopinavir-ritonavir, ribavirin, umifenovir, interferon-alpha-2b, interferon-beta-1b, corticosteroids, antibiotics, and Chinese medicines, and 2) four interferon-beta-1b combination treatment groups were investigated. Findings: Interferon-beta-1b was associated with an improved composite outcome (OR=0.55, 95%CI 0.38, 0.80) and earlier discharge (−8.8 days, 95%CI −9.7, −7.9) compared to those not administered interferon-beta-1b. Oral ribavirin initiated within 7 days from onset was associated with lower risk of the composite outcome in Hong Kong (OR=0.51, 95%CI 0.29, 0.90). Lopinavir-ritonavir, intravenous ribavirin, umifenovir, corticosteroids, interferon-alpha-2b, antibiotics or Chinese medicines failed to show consistent clinical benefit. Interferon-beta-1b co-administered with ribavirin was associated with improved composite outcome (OR=0.50, 95%CI 0.32, 0.78) and earlier discharge (−2.35 days, 95%CI −3.65, −1.06) compared to interferon-beta-1b monotherapy. Interpretation: Our findings support the early administration of interferon-beta-1b alone or in combination with oral ribavirin for COVID-19 patients. Funding: Hong Kong Health and Medical Research Fund; Hong Kong Innovation and Technology Commission; Chinese Fundamental Research Funds for the Central Universities.

Abstract Background Although routine vaccination of females before sexual debut against human papillomavirus (HPV) has been found to be cost-effective around the world, its cost-benefit has rarely been examined. We evaluate both the cost-effectiveness and cost-benefit of routine female adolescent nonavalent HPV vaccination in Hong Kong to guide its policy, and by extension that of mainland China, on HPV vaccination. One major obstacle is the lack of data on assortativity of sexual mixing. Such difficulty could be overcome by inferring sexual mixing parameters from HPV epidemiologic data. Methods We use an age-structured transmission model coupled with stochastic individual-based simulations to estimate the health and economic impact of routine nonavalent HPV vaccination for girls at age 12 on cervical cancer burden and consider vaccine uptake at 25%, 50%, and 75% with at least 20 years of vaccine protection. Bayesian inference was employed to parameterize the model using local data on HPV prevalence and cervical cancer incidence. We use the human capital approach in the cost-benefit analysis (CBA) and GDP per capita as the indicative willingness-to-pay threshold in the cost-effectiveness analysis (CEA). Finally, we estimate the threshold vaccine cost (TVC), which is the maximum cost for fully vaccinating one girl at which routine female adolescent nonavalent HPV vaccination is cost-beneficial or cost-effective. Results As vaccine uptake increased, TVC decreased (i.e., economically more stringent) in the CBA but increased in the CEA. When vaccine uptake was 75% and the vaccine provided only 20 years of protection, the TVC was US$444 ($373–506) and $689 ($646–734) in the CBA and CEA, respectively, increasing by approximately 2–4% if vaccine protection was assumed lifelong. TVC is likely to be far higher when non-cervical diseases are included. The inferred sexual mixing parameters suggest that sexual mixing in Hong Kong is highly assortative by both age and sexual activity level. Conclusions Routine HPV vaccination of 12-year-old females is highly likely to be cost-beneficial and cost-effective in Hong Kong. Inference of sexual mixing parameters from epidemiologic data of prevalent sexually transmitted diseases (i.e., HPV, chlamydia, etc.) is a potentially fruitful but largely untapped methodology for understanding sexual behaviors in the population.

Abstract Secular trends in blood pressure (BP) and body mass index (BMI) during childhood and adolescence are sentinels for the future population cardiovascular disease burden. We examined trends in BP z-score (ages 9–18 years from 1999 to 2014) and BMI z-score (ages 6–18 years from 1996 to 2014) in Hong Kong, China. Overall, BP z-score fell, systolic BP from 0.08 to −0.01 in girls and from 0.31 to 0.25 in boys. However, the trends were not consistent, for both sexes, systolic BP z-score was stable from 1999, decreased slightly from 2002 to 2005 and increased slightly to 2014, diastolic BP z-score decreased slightly from 1999 to 2004 and then remained stable to 2014. In contrast, BMI z-score rose from −0.15 to −0.01 in girls and from 0.14 to 0.34 in boys, mainly during 1997 to 2010. The upper tail of the systolic (except boys) and diastolic BP distribution shifted downwards, whereas the entire BMI distribution shifted upward. BP declined slightly whereas BMI rose in Hong Kong children and adolescents during the last 20 years, with systolic BP and BMI in boys above the reference. This warrants dual action in tackling rising BMI and identifying favorable determinants of BP, particularly targeting boys.