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.

The Impact of Medical Resources and Oral Antiviral Drugs on SARS-CoV-2 Mortality - Hong Kong SAR, China, 2022.

Introduction: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrates increased transmissibility compared to earlier strains, contributing to a significant number of fatalities in Hong Kong Special Administrative Region (HKSAR), China. Adequate medical resources and medications are essential in mitigating these deaths. This study evaluates the effects of supplementary resources from the Chinese mainland during the fifth wave of the pandemic in HKSAR. Methods: Vector autoregression (VAR) was employed to analyze data from the Oxford coronavirus disease 2019 (COVID-19) Government Response Tracker to assess the effectiveness of control measures during five waves of the pandemic in HKSAR. Additionally, a transmission dynamics model was created to investigate the influence of supplementary medical resources from the Chinese mainland and oral medications on mortality. Results: In the initial four waves, workplace closures, restrictions on public events, international travel bans, and shielding the elderly significantly influenced pandemic management. Contrarily, during the fifth wave, these measures showed no notable effects. When comparing a situation without extra medical resources or COVID-19 oral medication, there was a 17.7% decrease in COVID-19 fatalities with mainland medical resources and an additional 10.2% reduction with oral medications. Together, they contributed to a 26.6% decline in fatalities. Discussion: With the rapid spread of the virus, regional reallocation of medical resources may reduce mortality even when the local healthcare system is overstretched.

Radiofrequency ablation compared to surgery for thyroid nodules: A case for office based treatment.

Objective: We aim to evaluate the safety and effectiveness of radiofrequency ablation (RFA) for benign thyroid nodules by ENT surgeons and to compare it to conventional hemithyroidectomy in the public healthcare, operating theater contained setting. Methods: 50 patients who underwent a single session of RFA for symptomatic benign thyroid nodules in Prince of Wales Hospital and Tseung Kwan O Hospital in Hong Kong from 2020 to 2022 were evaluated. Objective outcomes including nodule volume, volume reduction rate (VRR) and complications were recorded. Subjective response in the form of a 0-10 point scale for patient symptoms including obstructive, cosmetic, pain and satisfaction scores were collected. Results: Significant reduction in mean VRR was found at 3, 6 and 12 months post treatment, accompanied by a significant reduction in the mean obstructive and cosmetic symptom scores. Comparing with conventional hemithyroidectomy, the RFA group had a significantly shorter mean procedure time and lower rate of complications. Estimated cost to patient for RFA was found to be less than half of that of hemithyroidectomy. Conclusion: RFA is a safe and effective treatment modality for benign thyroid nodules by ENT surgeons with advantages of being a scarless local anesthetic procedure with shorter procedure time, lower complication rate and lower cost to patient compared to hemithyroidectomy. In Hong Kong, where most of the population is treated in the public sector, there are limited resources, often with high caseload burden and long operation waiting times. Therefore, RFA is an office-based treatment that serves as a valuable alternative to hemithyroidectomy for benign nodules, especially in lower resource settings. Level of evidence: 3.

Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics.

INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

One-hour post-load plasma glucose level predicts future type 2 diabetes in a community-based study of Hong Kong Chinese workforce.

BACKGROUND: We compared performance of high 1-hour PG level, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in predicting type 2 diabetes in a longitudinal community-based cohort of Hong Kong Chinese. METHODS: Between 2001 and 2003, 472 adults aged 18-55 years without diabetes underwent 75-gram oral glucose tolerance test (OGTT). Between 2012 and 2014, progression to diabetes was ascertained by reviewing medical records or repeating OGTT and HbA1c. We defined high 1-hour PG as PG ≥ 8.6 mmol/L at 1-hour. RESULTS: In this cohort, 23.5% had normal glucose tolerance and high 1-hour PG, 10.0% had isolated IGT, 4.2% had isolated IFG. Over 12-year follow-up, 9.3% developed type 2 diabetes. In logistic regression, high 1-hour PG was associated with progression to type 2 diabetes with adjusted odds ratio (95% CI) of 4.20 (1.60, 12.40), independent of IFG, IGT and other clinical variables. Areas under ROC (95% CI) for type 2 diabetes were similar between 1-hour (0.84 [0.78, 0.89], 2-hour (0.79 [0.72, 0.86]) and fasting PG (0.79 [0.71, 0.86]). CONCLUSION: High 1-hour PG identified young Chinese with 5-fold increased risk of type 2 diabetes independent of other intermediate hyperglycaemia status and clinical factors. 1-hour PG is similar to fasting and 2-hour PG in predicting type 2 diabetes.

Global Seasonal Activities of Respiratory Syncytial Virus Before the Coronavirus Disease 2019 Pandemic: A Systematic Review.

Varied seasonal patterns of respiratory syncytial virus (RSV) have been reported worldwide. We conducted a systematic review on articles identified in PubMed reporting RSV seasonality based on data collected before 1 January 2020. RSV seasonal patterns were examined by geographic location, calendar month, analytic method, and meteorological factors including temperature and absolute humidity. Correlation and regression analyses were conducted to explore the relationship between RSV seasonality and study methods and characteristics of study locations. RSV seasons were reported in 209 articles published in 1973-2023 for 317 locations in 77 countries. Regular RSV seasons were similarly reported in countries in temperate regions, with highly variable seasons identified in subtropical and tropical countries. Longer durations of RSV seasons were associated with a higher daily average mean temperature and daily average mean absolute humidity. The global seasonal patterns of RSV provided important information for optimizing interventions against RSV infection.

Monogenic diabetes in a Chinese population with young-onset diabetes: A 17-year prospective follow-up study in Hong Kong.

AIMS: Asians have a high prevalence of young-onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young-onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. MATERIALS AND METHODS: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non-type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death were captured since enrolment (1995-2012) until 2019. RESULTS: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0-15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%-3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow-up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1-29.4] per 1000 person-years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8-18.9] per 1000 person-years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. CONCLUSIONS: In Chinese with young-onset non-type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes.

Associations of comorbid depression with cardiovascular-renal events and all-cause mortality accounting for patient reported outcomes in individuals with type 2 diabetes: a 6-year prospective analysis of the Hong Kong Diabetes Register.

Background: Psychosocial status and patient reported outcomes (PRO) [depression and health-related quality-of-life (HRQoL)] are major health determinants. We investigated the association between depression and clinical outcomes in Chinese patients with type 2 diabetes (T2D), adjusted for PRO. Methods: Using prospective data from Hong Kong Diabetes Register (2013-2019), we estimated the hazard-ratio (HR, 95%CI) of depression (validated Patient Health Questionnaire 9 (PHQ-9) score≥7) with incident cardiovascular disease (CVD), ischemic heart disease (IHD), chronic kidney disease (CKD: eGFR<60 ml/min/1.73m2) and all-cause mortality in 4525 Chinese patients with T2D adjusted for patient characteristics, renal function, medications, self-care and HRQoL domains (mobility, self-care, usual activities, pain/discomfort, anxiety/depression measured by EQ-5D-3L) in linear-regression models. Results: In this cohort without prior events [mean ± SD age:55.7 ± 10.6, 43.7% women, median (IQR) disease duration of 7.0 (2.0-13.0) years, HbA1c, 7.2% (6.6%-8.20%), 26.4% insulin-treated], 537(11.9%) patients had depressive symptoms and 1923 (42.5%) patients had some problems with HRQoL at baseline. After 5.6(IQR: 4.4-6.2) years, 141 patients (3.1%) died, 533(11.8%) developed CKD and 164(3.6%) developed CVD. In a fully-adjusted model (model 4) including self-care and HRQoL, the aHR of depression was 1.99 (95% confidence interval CI):1.25-3.18) for CVD, 2.29 (1.25-4.21) for IHD. Depression was associated with all-cause mortality in models 1-3 adjusted for demographics, clinical characteristics and self-care, but was attenuated after adjusting for HRQoL (model 4- 1.54; 95%CI: 0.91-2.60), though HR still indicated same direction with important magnitude. Patients who reported having regular exercise (3-4 times per week) had reduced aHR of CKD [0.61 (0.41-0.89)]. Item 4 of PHQ-9 (feeling tired, little energy) was independently associated with all-cause mortality with aHR of 1.66 (1.30-2.12). Conclusion: Depression exhibits significant association with CVD, IHD, and all-cause mortality in patients with diabetes, adjusting for their HRQoL and health behaviors. Despite the association between depression and all-cause mortality attenuated after adjusting for HRQoL, the effect size remains substantial. The feeling of tiredness or having little energy, as assessed by item Q4 of the PHQ-9 questionnaire, was found to be significantly associated with an increased risk of all-cause mortality after covariate adjustments. Our findings emphasize the importance of incorporating psychiatric evaluations into holistic diabetes management.

Clinical outcomes following discontinuation of metformin in patients with type 2 diabetes and advanced chronic kidney disease in Hong Kong: a territory-wide, retrospective cohort and target trial emulation study.

Background: Current labelling advises discontinuation of metformin when estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 due to increased risk of lactic acidosis. However, in real-world practice, the risk-benefit ratios remain uncertain. We examined the risk associations of discontinued-metformin use with cardiorenal and clinical outcomes in patients with type 2 diabetes (T2D) and advanced chronic kidney disease. Methods: In this territory-wide, retrospective cohort and target trial emulation study, we included Chinese patients attending the Hong Kong Hospital Authority (HA) and enrolled in the Risk-Assessment-and-Management-Programme-for-Diabetes-Mellitus (RAMP-DM) from 2002 to 2019. Patients were stratified by discontinuation of metformin within six months after reaching eGFR < 30 ml/min/1.73 m2 from January 1, 2002 to December 31, 2018, and followed up until December 31 2019. We excluded patients who had observational time <6 months from eGFR < 30 ml/min/1.73 m2, and had their eGFR measured during a hospitalisation episode due to acute kidney injury, or missing diagnosis date of diabetes. We compared the risk associations of metformin discontinuation with clinical outcomes. The primary outcomes were major adverse cardiovascular events (MACE), end-stage kidney disease (ESKD), cancer, and all-cause mortality. A Cox-model with time-dependent exposure and covariates was used to estimate the hazard ratio (HR) of outcomes in a propensity-score overlap-weighted cohort. The risk of occurrence of lactic acidosis (serum lactate > 5.0 mmol/L with a concomitant blood pH < 7.35 or ICD-9 codes of 276.2) in discontinued-metformin versus continued-metformin users was assessed in a separate register-based cohort. Findings: A total of 33,586 metformin users with new-onset eGFR < 30 ml/min/1.73 m2 were included in the study, 7500 (22.3%) of whom discontinued metformin within 6 months whereas 26,086 (77.7%) continued use of metformin. During a median follow-up of 3.8 (IQR: 2.2-6.1) years, 16.4% (5505/33,586), 30.1% (10,113/33,586), and 7.1% (2171/30,682) had incident MACE, ESKD, and cancer respectively, and 44.4% (14,917/33,586) died. Compared to continued-metformin use, discontinuation was associated with higher risk of MACE (weighted and adjusted HR = 1.40, 95% CI: 1.29-1.52), ESKD (HR = 1.52, 1.42-1.62), and death (HR = 1.22, 1.18-1.27). No association was observed for cancer (HR = 0.93, 0.85-1.01). Discontinued-metformin users had higher change in HbA1c change at 6-month of follow-up versus continued-metformin users (weighted mean HbA1c level change: 0.5% [0.4-0.6%] versus 0.2% [0.1-0.2]). In the separate register-based cohort (n = 3235), null association was observed between metformin use and risk of lactic acidosis (weighted HR = 0.94 [0.53-1.64]). Interpretation: Our results suggest that discontinuation of metformin in patients with T2D and chronic kidney disease may be associated with increased risk of cardiovascular-renal events. Use of metformin below eGFR of 30 ml/min/1.73 m2 may be associated with cardiovascular, renal, and mortality benefits that need to be weighed against the risk of lactic acidosis, but further research is needed to validate these findings. Funding: CUHK Impact Research Fellowship Scheme.

Integrative analysis reveals associations between oral microbiota dysbiosis and host genetic and epigenetic aberrations in oral cavity squamous cell carcinoma.

Dysbiosis of the human oral microbiota has been reported to be associated with oral cavity squamous cell carcinoma (OSCC) while the host-microbiota interactions with respect to the potential impact of pathogenic bacteria on host genomic and epigenomic abnormalities remain poorly studied. In this study, the mucosal bacterial community, host genome-wide transcriptome and DNA CpG methylation were simultaneously profiled in tumors and their adjacent normal tissues of OSCC patients. Significant enrichment in the relative abundance of seven bacteria species (Fusobacterium nucleatum, Treponema medium, Peptostreptococcus stomatis, Gemella morbillorum, Catonella morbi, Peptoanaerobacter yurli and Peptococcus simiae) were observed in OSCC tumor microenvironment. These tumor-enriched bacteria formed 254 positive correlations with 206 up-regulated host genes, mainly involving signaling pathways related to cell adhesion, migration and proliferation. Integrative analysis of bacteria-transcriptome and bacteria-methylation correlations identified at least 20 dysregulated host genes with inverted CpG methylation in their promoter regions associated with enrichment of bacterial pathogens, implying a potential of pathogenic bacteria to regulate gene expression, in part, through epigenetic alterations. An in vitro model further confirmed that Fusobacterium nucleatum might contribute to cellular invasion via crosstalk with E-cadherin/ß-catenin signaling, TNFα/NF-κB pathway and extracellular matrix remodeling by up-regulating SNAI2 gene, a key transcription factor of epithelial-mesenchymal transition (EMT). Our work using multi-omics approaches explored complex host-microbiota interactions and provided important insights into genetic and functional basis in OSCC tumorigenesis, which may serve as a precursor for hypothesis-driven study to better understand the causational relationship of pathogenic bacteria in this deadly cancer.

The functional role of L-fucose on dendritic cell function and polarization.

Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from melanoma- and breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.

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.

A retrospective cohort study of Paxlovid efficacy depending on treatment time in hospitalized COVID-19 patients.

Paxlovid, a SARS-CoV-2 antiviral, not only prevents severe illness but also curtails viral shedding, lowering transmission risks from treated patients. By fitting a mathematical model of within-host Omicron viral dynamics to electronic health records data from 208 hospitalized patients in Hong Kong, we estimate that Paxlovid can inhibit over 90% of viral replication. However, its effectiveness critically depends on the timing of treatment. If treatment is initiated three days after symptoms first appear, we estimate a 17% chance of a post-treatment viral rebound and a 12% (95% CI: 0-16%) reduction in overall infectiousness for non-rebound cases. Earlier treatment significantly elevates the risk of rebound without further reducing infectiousness, whereas starting beyond five days reduces its efficacy in curbing peak viral shedding. Among the 104 patients who received Paxlovid, 62% began treatment within an optimal three-to-five-day day window after symptoms appeared. Our findings indicate that broader global access to Paxlovid, coupled with appropriately timed treatment, can mitigate the severity and transmission of SARS-Cov-2.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

Comparison of ß-Cell Function and Insulin Sensitivity Between Normal-Weight and Obese Chinese With Young-Onset Type 2 Diabetes.

Normal-weight individuals with usual-onset type 2 diabetes have reduced ß-cell function and greater insulin sensitivity compared with their obese counterparts. The relative contribution of ß-cell dysfunction and insulin resistance to young-onset type 2 diabetes (YOD) among normal-weight individuals is not well established. In 44 individuals with YOD (24 with normal weight and 20 with obesity) and 24 healthy control individuals with normoglycemia (12 with normal weight and 12 with obesity), we conducted 2-h 12 mmol/L hyperglycemic clamps to measure acute (0-10 min) and steady-state (100-120 min) insulin and C-peptide responses, as well as insulin sensitivity index. Normal-weight individuals with YOD had lower acute insulin response, steady-state insulin and C-peptide responses, and a higher insulin sensitivity index compared with their obese counterparts with YOD. Compared with BMI-matched healthy control individuals, normal-weight individuals with YOD had lower acute and steady-state insulin and C-peptide responses but a similar insulin sensitivity index. The impairment of steady-state ß-cell response relative to healthy control individuals was more pronounced in normal-weight versus obese individuals with YOD. In conclusion, normal-weight Chinese with YOD exhibited worse ß-cell function but preserved insulin sensitivity relative to obese individuals with YOD and BMI-matched healthy individuals with normoglycemia. The selection of glucose-lowering therapy should account for pathophysiological differences underlying YOD between normal-weight and obese individuals.

Health impacts of new-onset diabetes in women post-gestational diabetes mellitus: Insights from Hong Kong's territory-wide data.

AIMS/INTRODUCTION: To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time-varying population attributable fraction was calculated. RESULTS: A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow-up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end-stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection-related hospitalization, and 1.8 (1.3, 2.4) for all-cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person-years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (-3.1%, 16.1%) of absolute number of CVD, ESKD, infection-related hospitalization, and all-cause mortality over 20 years after GDM, respectively. CONCLUSIONS: Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.

Association of COVID-19 vaccination with duration of hospitalization in older adults in Hong Kong.

INTRODUCTION: The association between COVID-19 vaccination and length of hospital stay may provide further insight into vaccination benefits, but few studies have investigated such associations in detail. We aimed to investigate the association between COVID-19 vaccination and length of hospital stay in COVID-19 patients during Omicron waves in Hong Kong, and explore potential predictors. METHODS: This retrospective cohort study was conducted on local patients aged ≥60 years who were admitted due to COVID-19 infection in Hong Kong in 2022, from 1 February to 22 November, and with 28 days of follow-up since admission. The exposure was either not vaccinated; or having received 2/3/4 doses of CoronaVac (Sinovac); or 2/3/4 doses of BNT162b2 (BioNTech/Fosun Pharma/Pfizer). Length of stay in hospital was the main outcome. Accelerated failure time models were used to quantify variation in hospital stay for vaccinated compared with unvaccinated patients, accounting for age, sex, comorbidity, type of vaccine and number of doses received, care home residence and admission timing; stratified by age groups and epidemic waves. RESULTS: This study included 32,398 patients aged 60 years and above for main analysis, their median (IQR) age was 79 (71-87) years, 53% were men, and 40% were unvaccinated. The patients were stratified by confirmation prior to or since 23 May 2022, resulting in a sample size of 15,803 and 16,595 in those two waves respectively. Vaccinated patients were found to have 13-39% shorter hospital stay compared to unvaccinated patients. More vaccine doses received were associated with shorter hospital stay, and BNT162b2 recipients had slightly shorter hospital stays than CoronaVac recipients. CONCLUSION: Vaccination was associated with reduced hospital stay in breakthrough infections. Increased vaccination uptake in older adults may improve hospital bed turnover and public health outcomes especially during large community epidemics.

Trends in all-cause and cause-specific mortality in older adults with and without diabetes: A territory-wide analysis in one million older adults in Hong Kong.

AIMS: Direct comparisons of population-level trends in all-cause and cause-specific mortalities among older adults with and without diabetes are lacking. METHODS: We performed a territory-wide analysis of 1,142,000 unique older adults aged ≥ 65 years (31.7 % with diabetes) with at least one attendance in the Hong Kong Hospital Authority in 2014-2018. We used Joinpoint regression to describe trends of age- and sex-standardised all-cause and cause-specific mortalities (cardiovascular disease [CVD], cancer, and non-CVD and non-cancer) in older adults with and without diabetes. RESULTS: All-cause mortality decreased in older adults with (average annual percent change [AAPC] = -1.6, 95 % confidence interval [-2.7, -0.4]) and without (AAPC = -3.1 [-4.2, -2.1]) diabetes. Largest declines were seen for CVD-cause mortalities for people with and without diabetes (AAPC = -5.5 [-6.8, -4.1] vs AAPC = -5.8 [-8.6, -2.9], respectively). Cancer-cause mortalities were similar in both groups with no change. Men with diabetes showed less favourable improvements. An increasing mortality trend was seen only in the 65-69 age-group regardless of diabetes status. CONCLUSIONS: Mortality continued to decline in older adults with and without diabetes, mainly driven by a decline in CVD deaths, with no narrowing of the mortality gap. Our findings call for continued actions to address excess mortalities especially in older men with diabetes and younger older adults.

Joint analysis of vaccination effectiveness and antiviral drug effectiveness for COVID-19: a causal inference approach.

OBJECTIVES: This study aims to estimate the causal effects of oral antivirals and vaccinations in the prevention of all-cause mortality and progression to severe COVID-19 in an integrative setting with both antivirals and vaccinations considered as interventions. METHODS: We identified hospitalized adult patients (i.e. aged 18 or above) in Hong Kong with confirmed SARS-CoV-2 infection between March 16, 2022, and December 31, 2022. An inverse probability-weighted (IPW) Andersen-Gill model with time-dependent predictors was used to address immortal time bias and produce causal estimates for the protection effects of oral antivirals and vaccinations against severe COVID-19. RESULTS: Given prescription is made within 5 days of confirmed infection, nirmatrelvir-ritonavir is more effective in providing protection against all-cause mortality and development into severe COVID-19 than molnupiravir. There was no significant difference between CoronaVac and Comirnaty in the effectiveness of reducing all-cause mortality and progression to severe COVID-19. CONCLUSIONS: The use of oral antivirals and vaccinations causes lower risks of all-cause mortality and progression to severe COVID-19 for hospitalized SARS-CoV-2 patients.