The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression.

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG~MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation.

Time Pattern of Presentation of Victims of High-Speed Passenger Ferry Mass Casualty Incidents to the Emergency Department.

OBJECTIVE: Mass Casualty Incidents (MCIs) involving high-speed passenger ferries (HSPFs) may result in the dual-wave phenomenon, in which the emergency department (ED) is overwhelmed by an initial wave of minor injuries, followed by a second wave of more seriously injured victims. This study aimed to characterize the time pattern of ED presentation of victims in such accidents in Hong Kong. METHODS: All HSPF MCIs from 2005 to 2015 were reviewed retrospectively, with the time interval from accident to ED registration determined for each victim. Multivariable linear regression was used to identify independent factors associated with the time of ED presentation after the accidents. RESULTS: Eight MCIs involving 492 victims were identified. Victims with an Injury Severity Score (ISS) ≥ 9 had a significantly shorter median time interval compared to those with minor injuries. An ISS ≥ 9 and evacuation by emergency service vessels were associated with a shorter delay in ED arrival, whereas ship sinking, accident at nighttime, and a longer linear distance between the accident and receiving ED were associated with a longer delay. CONCLUSION: The dual-wave phenomenon was not present in HSPF MCIs. Early communication is the key to ensure early resource mobilisation and a well-timed response.

What is the prevalence of anabolic-androgenic steroid use among women? A systematic review.

BACKGROUND AND AIM: Evidence suggests there has been an increase in anabolic-androgenic steroid (AAS) use among women, driven by the evolving landscape of women's participation in sport. However, the extent of use is unknown. This systematic review aimed to estimate the prevalence of women's AAS use. METHOD: We conducted a systematic review of peer-reviewed articles in English, focusing on AAS use among women aged 18 and above. We excluded grey literature and studies that measured doping through some form of analysis (e.g. urine or hair). Searched databases were MEDLINE, CINAHL, PsycINFO, SocINDEX, SPORTDiscus, Embase and Cochrane Library. Titles and abstracts for all articles were screened, followed by full-text assessment and data extraction of included articles by multiple authors for accuracy. The pooled prevalence of lifetime use was determined using a random effects model and the risk of bias was assessed using the Joanna Briggs Institute Prevalence Critical Appraisal Tool. RESULTS: Based on 18 studies, participant numbers averaged 669 per study (median = 189; range = 16 to 7051). The overall pooled AAS use prevalence was 4% (95% confidence interval [CI] = 2-9%) with high heterogeneity overall (I2 = 95%). In the subgroup analysis, AAS use prevalence was 16.8% (95% CI = 11.0-24.9%, I2 = 44%) in the bodybuilder subgroup, 4.4% (95% CI = 1.2-15.1%, I2 = 93%) in athletes/recreational gym user subgroup, and 1.4% (95% CI = 0.4-4.7%, I2 = 96%) in the general population/other subgroup. Meta-regression demonstrated significantly higher AAS use in bodybuilders compared with the other subgroup (P = 0.011). CONCLUSION: Anabolic-androgenic steroid use among women appears to be substantially higher among bodybuilders and athletes/recreational gym users than the general female population.

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.

Comparing 11 early warning scores and three shock indices in early sepsis prediction in the emergency department.

BACKGROUND: This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores (EWSs) and three shock indices in early sepsis prediction in the emergency department (ED). METHODS: We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong. The primary outcome was sepsis (Sepsis-3 definition) within 48 h of ED presentation. Using c-statistics and the DeLong test, we compared 11 EWSs, including the National Early Warning Score 2 (NEWS2), Modified Early Warning Score, and Worthing Physiological Scoring System (WPS), etc., and three shock indices (the shock index [SI], modified shock index [MSI], and diastolic shock index [DSI]), with Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) in predicting the primary outcome, intensive care unit admission, and mortality at different time points. RESULTS: We analyzed 601 patients, of whom 166 (27.6%) developed sepsis. NEWS2 had the highest point estimate (area under the receiver operating characteristic curve [AUROC] 0.75, 95%CI 0.70-0.79) and was significantly better than SIRS, qSOFA, other EWSs and shock indices, except WPS, at predicting the primary outcome. However, the pooled sensitivity and specificity of NEWS2 ≥ 5 for the prediction of sepsis were 0.45 (95%CI 0.37-0.52) and 0.88 (95%CI 0.85-0.91), respectively. The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point. CONCLUSION: NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

Higher risk of incident diabetes among patients with primary hyperparathyroidism.

OBJECTIVES: There is relatively scarce data regarding the association between primary hyperparathyroidism (PHPT) and incident diabetes in large population-based longitudinal studies. We aimed to evaluate the risk of incident diabetes in individuals with and without PHPT and investigate the association between serum calcium concentrations and the risk of incident diabetes in patients with PHPT. METHODS: We included 2749 PHPT patients and 13,745 age, sex and index year matched non-PHPT individuals during 2000-2019. We used Cox regression models to compare the risk of incident diabetes in individuals with and without PHPT, and the risk of incident diabetes in PHPT patients with serum calcium concentration above and below the median value. The association between serum calcium concentrations and the risk of incident diabetes was examined by restricted cubic spline analyses in patients with PHPT. RESULTS: During a median follow-up time of 5.17 years (IQR 2.17, 9.58), 433 patients (15.75%) with PHPT and 2110 individuals (15.35%) without PHPT developed diabetes, respectively. Patients with PHPT had a higher incidence rate of diabetes compared to non-PHPT individuals (27.60 [95% CI 25.00, 30.30] vs. 23.90 [95% CI 22.80, 24.90] per 1000 person-years, log-rank test p = .007]. Crude Cox regression model showed PHPT was associated with a 15% higher risk of incident diabetes (HR 1.15, 95%CI 1.04, 1.28). In patients with PHPT, a 44% higher risk of incident diabetes was found in patients with serum calcium concentrations above the median value (2.63 mmol/L), compared to those below the median value (HR 1.44, 95%CI 1.08, 1.90). Restricted cubic spline analyses confirmed a positive linear association between serum calcium concentrations and the risk of incident diabetes in those with PHPT (p-value for nonlinear = .751) CONCLUSIONS: Patients with PHPT had a higher risk of incident diabetes compared to non-PHPT individuals. A positive linear association was found between serum calcium concentrations and the risk of incident diabetes in patients with PHPT.

Predicting Efficacies of Fractional Doses of Vaccines by Using Neutralizing Antibody Levels: Systematic Review and Meta-Analysis.

Background: With the emergence of SARS-CoV-2 variants that have eluded immunity from vaccines and prior infections, vaccine shortages and vaccine effectiveness pose unprecedented challenges for governments in expanding booster vaccination programs. The fractionation of vaccine doses might be an effective strategy for helping society to face these challenges, as fractional doses may have efficacies comparable with those of the standard doses. Objective: This study aims to investigate the relationship between vaccine immunogenicity and protection and to project efficacies of fractional doses of vaccines for COVID-19 by using neutralizing antibody levels. Methods: In this study, we analyzed the relationship between in vitro neutralization levels and the observed efficacies against both asymptomatic infection and symptomatic infection, using data from 13 studies of 10 COVID-19 vaccines and from convalescent cohorts. We further projected efficacies for fractional doses, using neutralization as an intermediate variable, based on immunogenicity data from 51 studies included in our systematic review. Results: In comparisons with the convalescent level, vaccine efficacy against asymptomatic infection and symptomatic infection increased from 8.8% (95% CI 1.4%-16.1%) to 71.8% (95% CI 63%-80.7%) and from 33.6% (95% CI 23.6%-43.6%) to 98.6% (95% CI 97.6%-99.7%), respectively, as the mean neutralization level increased from 0.1 to 10 folds of the convalescent level. Additionally, mRNA vaccines provided the strongest protection, which decreased slowly for fractional dosing with dosages between 50% and 100% of the standard dose. We also observed that although vaccine efficacy increased with the mean neutralization level, the rate of this increase was slower for vaccine efficacy against asymptomatic infection than for vaccine efficacy against symptomatic infection. Conclusions: Our results are consistent with studies on immune protection from SARS-CoV-2 infection. Based on our study, we expect that fractional-dose vaccination could provide partial immunity against SARS-CoV-2 and its variants. Our findings provide a theoretical basis for the efficacy of fractional-dose vaccines, serving as reference evidence for implementing fractional dosing vaccine policies in areas facing vaccine shortages and thereby mitigating disease burden. Fractional-dose vaccination could be a viable vaccination strategy comparable to full-dose vaccination and deserves further exploration.

Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma.

BACKGROUND: Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy. METHODS: 84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC. RESULTS: Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts. CONCLUSIONS: Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

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.

Forecasting of influenza activity and associated hospital admission burden and estimating the impact of COVID-19 pandemic on 2019/20 winter season in Hong Kong.

Like other tropical and subtropical regions, influenza viruses can circulate year-round in Hong Kong. However, during the COVID-19 pandemic, there was a significant decrease in influenza activity. The objective of this study was to retrospectively forecast influenza activity during the year 2020 and assess the impact of COVID-19 public health social measures (PHSMs) on influenza activity and hospital admissions in Hong Kong. Using weekly surveillance data on influenza virus activity in Hong Kong from 2010 to 2019, we developed a statistical modeling framework to forecast influenza virus activity and associated hospital admissions. We conducted short-term forecasts (1-4 weeks ahead) and medium-term forecasts (1-13 weeks ahead) for the year 2020, assuming no PHSMs were implemented against COVID-19. We estimated the reduction in transmissibility, peak magnitude, attack rates, and influenza-associated hospitalization rate resulting from these PHSMs. For short-term forecasts, mean ambient ozone concentration and school holidays were found to contribute to better prediction performance, while absolute humidity and ozone concentration improved the accuracy of medium-term forecasts. We observed a maximum reduction of 44.6% (95% CI: 38.6% - 51.9%) in transmissibility, 75.5% (95% CI: 73.0% - 77.6%) in attack rate, 41.5% (95% CI: 13.9% - 55.7%) in peak magnitude, and 63.1% (95% CI: 59.3% - 66.3%) in cumulative influenza-associated hospitalizations during the winter-spring period of the 2019/2020 season in Hong Kong. The implementation of PHSMs to control COVID-19 had a substantial impact on influenza transmission and associated burden in Hong Kong. Incorporating information on factors influencing influenza transmission improved the accuracy of our predictions.

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.

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.

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.

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.

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.