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

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 < 0.001). Lower Ct values at isolation were observed in Omicron cases than in ancestral strain or other variants cases. No Omicron cases were detected beyond 14 days after arrival. Cases detected after 14 days of quarantine (n=58, 2.6 %) were more likely asymptomatic at isolation and had higher Ct value during isolation, some of them indicating re-positivity or post-arrival infections. Conclusions: Testing inbound travellers at arrival and during quarantine can detect imported cases early, but may not prevent all COVID-19 introductions into the community. Public health measures should be adapted in response to the emergence of SARS-CoV-2 variants based on evidence from ongoing surveillance.

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

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to infer the transmissibility (${R}_t$) of an epidemic. However, serial interval distributions may change as an epidemic progresses. We examined detailed contact tracing data on laboratory-confirmed cases of COVID-19 in Hong Kong during the five waves from January 2020 to July 2022. We reconstructed the transmission pairs and estimated time-varying effective serial interval distributions and factors associated with longer or shorter intervals. Finally, we assessed the biases in estimating transmissibility using constant serial interval distributions. We found clear temporal changes in mean serial interval estimates within each epidemic wave studied and across waves, with mean serial intervals ranged from 5.5 days (95% CrI: 4.4, 6.6) to 2.7 (95% CrI: 2.2, 3.2) days. The mean serial intervals shortened or lengthened over time, which were found to be closely associated with the temporal variation in COVID-19 case profiles and public health and social measures and could lead to the biases in predicting ${R}_t$. Accounting for the impact of these factors, the time-varying quantification of serial interval distributions could lead to improved estimation of ${R}_t$, and provide additional insights into the impact of public health measures on transmission.

Surgical Reconstruction of Elbow Extension in Spinal Cord Injury and Tetraplegia: A Systematic Review.

Purpose: Surgical reconstruction of elbow extension can help restore function in patients with tetraplegia and triceps paralysis because of spinal cord injury. Both posterior deltoid-to-triceps tendon transfer and transfer of the branch of the axillary nerve to the triceps motor branch of the radial nerve have been described for triceps reanimation. This systematic review aimed at reviewing current evidence in the two schools of surgery in terms of their outcome and complication profile. Methods: A systematic review was conducted using MEDLINE (1974-2023) and EMBASE (1946-2023) databases. The keyword terms "elbow extension," "triceps," "deltoid," "nerve transfer," "spinal cord injury," "tetraplegia," "quadriplegia," and "tetraplegic" were used in the initial search, which was supplemented with manual searches of the bibliographies of retrieved articles. Results: Twenty studies met our inclusion criteria, with 14 studies (229 limbs) on posterior deltoid-to-triceps tendon transfer, 5 studies (23 limbs) on axillary to radial nerve transfer, and 1 study (1 limb) on combined transfer. For the tendon transfer group, the majority of studies reported a median triceps power of grade 3, with a wide range of failure percentage to reach antigravity (0% to 87.5%). Common complications included gradual stretching of the musculotendinous unit, rupture of the tendon transferred, elbow contracture, and infection. For the nerve transfer group, the majority of studies also reported a median triceps power reaching grade 3. There were no reported complications or loss of power in donor action of shoulder abduction or external rotation. Conclusions: Transfer of the axillary nerve branch to the triceps motor branch of the radial nerve in tetraplegia shows promising results, with comparable triceps muscle power compared to traditional tendon transfer and a low incidence of complication. Type of Study/Level of Evidence: Systematic Review III.

Effectiveness of nirmatrelvir/ritonavir in children and adolescents aged 12-17 years following SARS-CoV-2 Omicron infection: A target trial emulation.

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.

Association of childhood food consumption and dietary pattern with cardiometabolic risk factors and metabolomics in late adolescence: prospective evidence from 'Children of 1997' birth cohort.

BACKGROUND: Healthy diet might protect against cardiometabolic diseases, but uncertainty exists about its definition and role in adolescence. METHOD: In a subset of Hong Kong's 'Children of 1997' birth cohort (n=2844 out of 8327), we prospectively examined sex-specific associations of food consumption and dietary pattern, proxied by the Global Diet Quality Score (GDQS) at~12.0 years, with cardiometabolic risk factors and metabolomics at~17.6 years. RESULT: Higher vegetable (-0.04 SD, 95% CIs: -0.09 to 0.00) and soy consumption (-0.05 SD, 95% CI: -0.09 to -0.01) were associated with lower waist-to-hip ratio. Higher fruit and vegetable consumption were associated with lower fasting glucose (p<0.05). Higher fish consumption was associated with 0.06 SD (95% CI: 0.01 to 0.10) high-density lipoprotein cholesterol and -0.07 SD (95% CI: -0.11 to -0.02) triglycerides. After correcting for multiple comparisons (p<0.001), higher fish, fruit and vegetable consumption were associated with higher fatty acid unsaturation, higher concentration and percentage of omega-3 and a lower ratio of omega-6/omega-3. At nominal significance (p<0.05), higher fish consumption was associated with lower very-low-density lipoprotein and triglycerides relevant metabolomics. Higher vegetable and fruit consumption were associated with lower glycolysis-related metabolomics. Lower sugar-sweetened beverages (SSBs) consumption was associated with lower branched-chain amino acids. Similar associations with adiposity and metabolomics biomarkers were observed for GDQS. CONCLUSIONS: Higher consumption of fruit, vegetables and fish and lower ice cream and SSBs consumption were associated with lower cardiometabolic risk in adolescents.

Abiotic degradations of legacy and novel flame retardants in environmental and food matrices - a review.

Flame retardants (FRs) are commonly added to commercial products to achieve flammability resistance. Since most of them are not chemically bonded to the materials, they could be leached to the environment during the production and disposal cycle. These FRs were categorised based on their chemical nature, including brominated, organophosphorus-, mineral- and nitrogen-based. This review summarised the abiotic degradation reactions of these four classes of FRs, with a focus on thermal and photodegradation reactions in environmental and food matrices. Only 24 papers have reported related information on abiotic degradation reactions that could be useful for predicting possible degradation pathways, and most focused on brominated FRs. Most studies also investigated the thermal degradation of FRs under high temperatures (>400 °C), which exceeds the normal cooking temperature at 100-300 °C. For photodegradation, studies have used up to five times the energy typically used in UV radiation during food processing. It is recommended that future studies investigate the fate of these FRs in foods under more realistic processing conditions, to provide a more comprehensive picture of the estimated consumption of FRs and their degradation products from foods, and facilitate a better risk assessment of the use of these novel FRs.

Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

Previous studies suggest that influenza virus infection may provide temporary non-specific immunity and hence lower the risk of non-influenza respiratory virus infection. In a randomized controlled trial of influenza vaccination, 1 330 children were followed-up in 2009-2011. Respiratory swabs were collected when they reported acute respiratory illness and tested against influenza and other respiratory viruses. We used Poisson regression to compare the incidence of non-influenza respiratory virus infection before and after influenza virus infection. Based on 52 children with influenza B virus infection, the incidence rate ratio (IRR) of non-influenza respiratory virus infection after influenza virus infection was 0.47 (95% confidence interval: 0.27-0.82) compared with before infection. Simulation suggested that this IRR was 0.87 if the temporary protection did not exist. We identified a decreased risk of non-influenza respiratory virus infection after influenza B virus infection in children. Further investigation is needed to determine if this decreased risk could be attributed to temporary non-specific immunity acquired from influenza virus infection.

Contribution of systemic factors on macular vessel density: a sex-specific population-based study.

PURPOSE: To evaluate the influence of systemic factors on macular vessel density in quantitative Optical Coherence Tomography Angiography (OCTA) by sex. STUDY DESIGN: A cross-sectional study. METHODS: A total of 2018 adults were recruited in this study. Participants were excluded (n=964) due to missing data, eye-related problems, or low OCTA scan quality. Macular vessel densities were measured with OCTA using split-spectrum amplitude decorrelation angiography algorithm. Only the data from the right eyes were selected for analysis. Multivariable linear regression analysis was performed to determine the associations between macular vessel density and obesity-related systemic factors in each gender group. RESULTS: The right eyes of 1054 participants (59.6% women) were enrolled. Men had significantly higher obesity parameters and associated risk factors. In multivariable linear regression analysis in men, older age and type 2 diabetes mellitus were independently associated with lower superficial retinal vessel density (ß = -0.37, p = 0.002; ß = -1.22, p = 0.03) and deep retinal vessel density, respectively (ß = -0.66, p < 0.001; ß = -1.76, p = 0.02); positive association was also observed between body mass index (BMI) and superficial retinal vessel density (ß = 0.56, p = 0.02). In women, only higher systolic blood pressure was independently associated with a lower deep retinal vessel density (ß = -0.50, p = 0.003). CONCLUSIONS: This large cross-sectional study shows that older age and type 2 diabetes mellitus are associated with lower superficial and deep retinal capillary vessel density in men. This may help clinicians better understand how systemic factors influence retinal vessel density in different genders and future studies can ascertain more potential sex differences.

Post-traumatic stress, depression, and anxiety during the 2021 Myanmar conflict: a nationwide population-based survey.

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.

Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children.

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'.

Tracking diarrhea viruses and mpox virus using the wastewater surveillance network in Hong Kong.

The wastewater surveillance network successfully established for COVID-19 showed great potential to monitor other infectious viruses, such as norovirus, rotavirus and mpox virus. In this study, we established and validated detection methods for these viruses in wastewater. We developed a supernatant-based method to detect RNA viruses from wastewater samples and applied it to the monthly diarrhea viruses (norovirus genogroup I & II, and rotavirus) surveillance in wastewater treatment plants (WWTPs) at a city-wide level for 16 months. Significant correlations were observed between the diarrhea viruses concentrations in wastewater and detection rates in faecal specimens by clinical surveillance. The highest norovirus concentration in wastewater was obtained in winter, consistent with the seasonal pattern of norovirus outbreak in Hong Kong. Additionally, we established a pellet-based method to monitor DNA viruses in wastewater and detected weak signals for mpox virus in wastewater from a WWTP serving approximately 16,700 people, when the first mpox patient in Hong Kong was admitted to the hospital within the catchment area. Genomic sequencing provided confirmatory evidence for the validity of the results. Our findings emphasized the efficacy of the wastewater surveillance network in WWTPs as a cost-effective tool to track the transmission trend of diarrhea viruses and to provide sensitive detection of novel emerging viruses such as mpox virus in low-prevalence areas. The developed methods and surveillance results provide confidence for establishing robust wastewater surveillance programs to control infectious diseases in the post-pandemic era.

Estimating the Epidemic Size of Superspreading Coronavirus Outbreaks in Real Time: Quantitative Study.

BACKGROUND: Novel coronaviruses have emerged and caused major epidemics and pandemics in the past 2 decades, including SARS-CoV-1, MERS-CoV, and SARS-CoV-2, which led to the current COVID-19 pandemic. These coronaviruses are marked by their potential to produce disproportionally large transmission clusters from superspreading events (SSEs). As prompt action is crucial to contain and mitigate SSEs, real-time epidemic size estimation could characterize the transmission heterogeneity and inform timely implementation of control measures. OBJECTIVE: This study aimed to estimate the epidemic size of SSEs to inform effective surveillance and rapid mitigation responses. METHODS: We developed a statistical framework based on back-calculation to estimate the epidemic size of ongoing coronavirus SSEs. We first validated the framework in simulated scenarios with the epidemiological characteristics of SARS, MERS, and COVID-19 SSEs. As case studies, we retrospectively applied the framework to the Amoy Gardens SARS outbreak in Hong Kong in 2003, a series of nosocomial MERS outbreaks in South Korea in 2015, and 2 COVID-19 outbreaks originating from restaurants in Hong Kong in 2020. RESULTS: The accuracy and precision of the estimation of epidemic size of SSEs improved with longer observation time; larger SSE size; and more accurate prior information about the epidemiological characteristics, such as the distribution of the incubation period and the distribution of the onset-to-confirmation delay. By retrospectively applying the framework, we found that the 95% credible interval of the estimates contained the true epidemic size after 37% of cases were reported in the Amoy Garden SARS SSE in Hong Kong, 41% to 62% of cases were observed in the 3 nosocomial MERS SSEs in South Korea, and 76% to 86% of cases were confirmed in the 2 COVID-19 SSEs in Hong Kong. CONCLUSIONS: Our framework can be readily integrated into coronavirus surveillance systems to enhance situation awareness of ongoing SSEs.

Early-life exposure to ambient air pollution with cardiovascular risk factors in adolescents: Findings from the "Children of 1997" Hong Kong birth cohort.

BACKGROUND: Long-term exposure to ambient air pollution is associated with cardiovascular disease (CVD) risk. Little is known about the impact of early-life exposure to air pollutants on CVD risk factors in late adolescence, which may track into adulthood. To clarify, we examined this question in a unique setting with high air pollution and a high level of economic development. METHODS: This study leveraged the "Children of 1997" Hong Kong birth cohort (N = 8327), including here 3350 participants. We estimated ambient air pollutant exposure including inhalable particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2) and nitrogen monoxide (NO) by growth phase (in utero, infancy, childhood) and overall based on residential address. Generalized linear regression was used to assess the associations of air pollutants exposure by growth phase and sex with CVD risk factors (fasting blood glucose, glycosylated hemoglobin, lipid profile, blood pressure, and body mass index) at 17.6 years. We also assessed whether associations varied by sex. RESULTS: Early life exposed had little association with glucose metabolism, blood pressure or body mass index, but after considering multiple comparisons early exposure to PM10 was associated with low density lipoprotein (LDL) in boys, with ß and 95 % confidence intervals (95 % CI) of 0.184 (0.069 to 0.298) mmol/l, 0.151 (0.056 to 0.248) mmol/l, and 0.157 (0.063 to 0.252) mmol/l by per interquartile range (IQR) increment of PM10 for in utero, infancy, and overall, respectively. No such associations were evident for girls, differences by sex were evident. CONCLUSIONS: Our study suggested sex-specific associations of early-life PM10 exposure with elevated LDL in adolescence, especially exposure in utero and infancy.

Nirmatrelvir/ritonavir use in pregnant women with SARS-CoV-2 Omicron infection: a target trial emulation.

To date, there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant persons. This target trial emulation study aimed to address this gap by evaluating the use of nirmatrelvir/ritonavir in nonhospitalized pregnant women with symptomatic SARS-CoV-2 Omicron variant infection. Among patients diagnosed between 16 March 2022 and 5 February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or coronavirus disease 2019 (COVID-19) diagnosis. Primary outcomes were maternal morbidity and mortality index (MMMI), all-cause maternal death and COVID-19-related hospitalization, while secondary outcomes were individual components of MMMI, preterm birth, stillbirth, neonatal death and cesarean section. One-to-ten propensity-score matching was conducted between nirmatrelvir/ritonavir users and nonusers, followed by cloning, censoring and weighting. Overall, 211 pregnant women on nirmatrelvir/ritonavir and 1,998 nonusers were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28-day MMMI risk (absolute risk reduction (ARR) = 1.47%, 95% confidence interval (CI) = 0.21-2.34%) but not 28-days COVID-19-related hospitalization (ARR = -0.09%, 95% CI = -1.08% to 0.71%). Nirmatrelvir/ritonavir treatment was also associated with reduced risks of cesarean section (ARR = 1.58%, 95% CI = 0.85-2.39%) and preterm birth (ARR = 2.70%, 95% CI = 0.98-5.31%). No events of maternal or neonatal death or stillbirth were recorded. The findings suggest that nirmatrelvir/ritonavir is an effective treatment in symptomatic pregnant women with SARS-CoV-2 Omicron variant infection.

Understanding paediatric COVID-19 vaccination during the pandemic: a prospective cohort and a population-based registry study.

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.

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

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.

Optimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation.

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.

Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug-target Mendelian randomization study.

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 < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid - 0.79 [- 1.25 to - 0.35]. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed. CONCLUSIONS: Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Larger studies were warranted to verify these findings. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics.