There is much interest in the tissue of origin of circulating DNA in plasma. Data generated using DNA methylation markers have suggested that hematopoietic cells of white cell lineages are important ...contributors to the circulating DNA pool. However, it is not known whether cells of the erythroid lineage would also release DNA into the plasma.
Using high-resolution methylation profiles of erythroblasts and other tissue types, 3 genomic loci were found to be hypomethylated in erythroblasts but hypermethylated in other cell types. We developed digital PCR assays for measuring erythroid DNA using the differentially methylated region for each locus.
Based on the methylation marker in the ferrochelatase gene, erythroid DNA represented a median of 30.1% of the plasma DNA of healthy subjects. In subjects with anemia of different etiologies, quantitative analysis of circulating erythroid DNA could reflect the erythropoietic activity in the bone marrow. For patients with reduced erythropoietic activity, as exemplified by aplastic anemia, the percentage of circulating erythroid DNA was decreased. For patients with increased but ineffective erythropoiesis, as exemplified by β-thalassemia major, the percentage was increased. In addition, the plasma concentration of erythroid DNA was found to correlate with treatment response in aplastic anemia and iron deficiency anemia. Plasma DNA analysis using digital PCR assays targeting the other 2 differentially methylated regions showed similar findings.
Erythroid DNA is a hitherto unrecognized major component of the circulating DNA pool and is a noninvasive biomarker for differential diagnosis and monitoring of anemia.
Objective
With increasing prevalence of childhood obesity worldwide, the incidence of pediatric‐onset type 2 diabetes (T2D) is also increasing in many countries. We aim to analyze the time trend and ...incidence of T2D in children in Hong Kong from 2008 to 2017, and to characterize clinical characteristics at diagnosis.
Methods
Data were retrieved from the Hong Kong Childhood Diabetes Registry. All children with T2D diagnosed at the age of less than 18 years from January 1, 2008 to December 31, 2017 and managed in the public health care system were included in this study.
Results
In the incident years of 2008–2017 period, 391 children were diagnosed with T2D. The crude incidence rate was 3.42 per 100,000 persons/year 95% confidence interval (CI) 3.08–3.76, which was much higher than that in last registry of 1.27 per 100,000 persons/year in 1997–2007 (P < 0.001).Most children (76%) were asymptomatic and were diagnosed by routine screening. At presentation, a significant proportion presented with co‐morbidities including fatty liver (37.9%), dyslipidaemia (35.3%), hypertension (22.5%), and microalbuminuria (12.8%).
Conclusions
The incidence of T2D in children has increased significantly in Hong Kong. Most of them were asymptomatic and picked up on routine health screening. Yet, comorbidities were commonly identified at diagnosis.
Globally, mortality rates of patients admitted to the intensive care unit (ICU) have decreased over the last two decades. However, evaluations of the temporal trends in the characteristics and ...outcomes of ICU patients in Asia are limited. The objective of this study was to describe the characteristics and risk adjusted outcomes of all patients admitted to publicly funded ICUs in Hong Kong over a 11-year period. The secondary objective was to validate the predictive performance of Acute Physiology And Chronic Health Evaluation (APACHE) IV for ICU patients in Hong Kong.
This was an 11-year population-based retrospective study of all patients admitted to adult general (mixed medical-surgical) intensive care units in Hong Kong public hospitals. ICU patients were identified from a population electronic health record database. Prospectively collected APACHE IV data and clinical outcomes were analysed.
From 1 April 2008 to 31 March 2019, there were a total of 133,858 adult ICU admissions in Hong Kong public hospitals. During this time, annual ICU admissions increased from 11,267 to 14,068, whilst hospital mortality decreased from 19.7 to 14.3%. The APACHE IV standard mortality ratio (SMR) decreased from 0.81 to 0.65 during the same period. Linear regression demonstrated that APACHE IV SMR changed by - 0.15 (95% CI - 0.18 to - 0.11) per year (Pearson's R = - 0.951, p < 0.001). Observed median ICU length of stay was shorter than that predicted by APACHE IV (1.98 vs. 4.77, p < 0.001). C-statistic for APACHE IV to predict hospital mortality was 0.889 (95% CI 0.887 to 0.891) whilst calibration was limited (Hosmer-Lemeshow test p < 0.001).
Despite relatively modest per capita health expenditure, and a small number of ICU beds per population, Hong Kong consistently provides a high-quality and efficient ICU service. Number of adult ICU admissions has increased, whilst adjusted mortality has decreased over the last decade. Although APACHE IV had good discrimination for hospital mortality, it overestimated hospital mortality of critically ill patients in Hong Kong.
To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region.
This study ...retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators.
A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%.
This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.
Abstract
Objectives
Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D). The aim of this study is to analyze the incidence, clinical characteristics, management ...and outcome of children presenting with DKA in new-onset T1D from 2008 to 2018 in Hong Kong.
Methods
Data was extracted from the Hong Kong Childhood Diabetes Registry. All subjects less than 18 years with newly diagnosed T1D from 1 January 2008 to 31 December 2018 managed in the public hospitals were included. Information on demographics, laboratory parameters, DKA-related complications and management were analyzed.
Results
In the study period, there were 556 children with newly diagnosed T1D in our registry and 43.3% presented with DKA. The crude incidence rate of new-onset T1D with DKA was 1.79 per 100,000 persons/year (CI: 1.56–2.04). Subjects presenting with DKA were younger (9.5 ± 4.5 vs. 10.5 ± 4.4, p=0.01) and had shorter duration of symptoms (4.2 ± 5.9 days vs. 10.6 ± 17.1 days, p<0.01). Regarding management, up to 12.4% were given insulin boluses and 82.6% were started on insulin infusion 1 h after fluid resuscitation. The rate of cerebral edema was 0.8% and there was no mortality.
Conclusions
Younger age and shorter duration of symptoms were associated with DKA in new-onset T1D. Despite availability of international guidelines, there was inconsistency in acute DKA management. These call for a need to raise public awareness on childhood diabetes as well as standardization of practice in management of pediatric DKA in Hong Kong.
Objective
The incidence of childhood‐onset type 1 diabetes (T1D) has been reported to be rising but there is also evidence that it has been attenuated in recent years. We described the time trends ...and the incidence of T1D in children in Hong Kong from 2008 to 2017 and compared with the previous local registry in 1997 to 2007.
Methods
Data were extracted from the Hong Kong Childhood Diabetes Registry, which was established in 2016. It consists of a retrospective registry (including all childhood diabetes diagnosed in 2008 to 2015) and a prospective registry (including all T1D children diagnosed from 2016 onwards). All T1D children diagnosed at the age of less than 18 years from 1 January 2008 to 31 December 2017 and managed in the public system were included in this study.
Results
For the incident years in the 2008 to 2017 period, a total of 498 children with T1D was identified. The crude incidence rate was 4.3 per 100 000 person/year (95% confidence interval 3.96‐4.72), which was much higher than the last registry of 2.2 per 100 000 persons/year. Using general linear model, the increment is statistically significant (P = .02). When compared to the last registry, the rate of increment had attenuated, with annual increment in crude incidence in the two periods for T1D <15 years changing from 4.3% to 3.5% (P = .02).
Conclusions
The incidence of T1D children increased significantly in the past two decades in Hong Kong, but the rate of increase had attenuated in recent years.
DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable ...expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the
(
) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing
mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of
and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent
silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.
Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures ...have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a , which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a K d of 1.3 μM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.
Tuberculosis (TB) is a preventable and curable disease, but mortality remains high among those who develop sepsis and critical illness from TB.
This was a population-based, multicentre retrospective ...cohort study of patients admitted to all 15 publicly funded Hong Kong adult intensive care units (ICUs) between 1 April 2008 and 31 March 2019. 940 adult critically ill patients with at least one positive
(MTB) culture were identified out of 133 858 ICU admissions. Generalised linear modelling was used to determine the impact of delay in TB treatment on hospital mortality. Trend of annual Acute Physiology and Chronic Health Evaluation (APACHE) IV-adjusted standardised mortality ratio (SMR) over the 11-year period was analysed by Mann-Kendall's trend test.
ICU and hospital mortality were 24.7% (232/940) and 41.1% (386/940), respectively. Of those who died in the ICU, 22.8% (53/232) never received antituberculosis drugs. SMR for ICU patients with TB remained unchanged over the study period (Kendall's τb=0.37, p=0.876). After adjustment for age, Charlson comorbidity index, APACHE IV, albumin, vasopressors, mechanical ventilation and renal replacement therapy, delayed TB treatment was directly associated with hospital mortality. In 302/940 (32.1%) of patients, TB could only be established from MTB cultures alone as Ziehl-Neelsen staining or PCR was either not performed or negative. Among this group, only 31.1% (94/302) had concurrent MTB PCR performed.
Survival of ICU patients with TB has not improved over the last decade and mortality remains high. Delay in TB treatment was associated with higher hospital mortality. Use of MTB PCR may improve diagnostic yield and facilitate early treatment.
PDF
