Increased soluble HLA-DRB1in B-cell acute lymphoblastic leukaemia.

Soluble HLA (sHLA) are potential tumour markers released in order to counter immune surveillance. sHLA-class II is less known especially in acute lymphoblastic leukaemia (ALL). This study aimed to investigate soluble, surface and allelic expression of HLA Class II (sHLA-DR) in B-cell ALL patients and compare with soluble expression in normal individuals. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to measure soluble HLA-DRB1 in plasma. Flow cytometric analysis was performed to determine median fluorescence intensity in HLA-DR surface expression. HLA-DNA typing by polymerase chain reaction, sequence specific oligonucleotides, PCRSSO was performed to determine HLA-DRB1 type in ALL samples. Results showed sHLA-DRB1 (mean±SEM) was significantly increased (p=0.001) in plasma of ALL patients (0.260 ±0.057 µg/mL; n=30) compared to healthy controls (0.051 ± 0.007µg/mL; n=31) of Malay ethnicity. However, these levels did not correlate with percentage or median fluorescence intensity of HLA-DR expressed on leukemia blasts (CD19+CD34 ± CD45(lo)HLA-DR+) or in the normal B cell population (CD19+CD34- CD45(hi)HLA-DR+) of patients. No significant difference was observed in gender (male/female) or age (paediatric/adult). Only a trend in reduced sHLA was observed in patients carrying HLA-DR04. These results have to be validated with a larger number of samples.

Description of the COVID-19 epidemiology in Malaysia.

Introduction: Since the COVID-19 pandemic began, it has spread rapidly across the world and has resulted in recurrent outbreaks. This study aims to describe the COVID-19 epidemiology in terms of COVID-19 cases, deaths, ICU admissions, ventilator requirements, testing, incidence rate, death rate, case fatality rate (CFR) and test positivity rate for each outbreak from the beginning of the pandemic in 2020 till endemicity of COVID-19 in 2022 in Malaysia. Methods: Data was sourced from the GitHub repository and the Ministry of Health's official COVID-19 website. The study period was from the beginning of the outbreak in Malaysia, which began during Epidemiological Week (Ep Wk) 4 in 2020, to the last Ep Wk 18 in 2022. Data were aggregated by Ep Wk and analyzed in terms of COVID-19 cases, deaths, ICU admissions, ventilator requirements, testing, incidence rate, death rate, case fatality rate (CFR) and test positivity rate by years (2020 and 2022) and for each outbreak of COVID-19. Results: A total of 4,456,736 cases, 35,579 deaths and 58,906,954 COVID-19 tests were reported for the period from 2020 to 2022. The COVID-19 incidence rate, death rate, CFR and test positivity rate were reported at 1.085 and 0.009 per 1,000 populations, 0.80 and 7.57%, respectively, for the period from 2020 to 2022. Higher cases, deaths, testing, incidence/death rate, CFR and test positivity rates were reported in 2021 and during the Delta outbreak. This is evident by the highest number of COVID-19 cases, ICU admissions, ventilatory requirements and deaths observed during the Delta outbreak. Conclusion: The Delta outbreak was the most severe compared to other outbreaks in Malaysia's study period. In addition, this study provides evidence that outbreaks of COVID-19, which are caused by highly virulent and transmissible variants, tend to be more severe and devastating if these outbreaks are not controlled early on. Therefore, close monitoring of key epidemiological indicators, as reported in this study, is essential in the control and management of future COVID-19 outbreaks in Malaysia.

COVID-19 in Malaysia: Descriptive Epidemiologic Characteristics of the First Wave.

This study aimed to describe the characteristics of COVID-19 cases and close contacts during the first wave of COVID-19 in Malaysia (23 January 2020 to 26 February 2020), and to analyse the reasons why the outbreak did not continue to spread and lessons that can be learnt from this experience. Characteristics of the cases and close contacts, spatial spread, epidemiological link, and timeline of the cases were examined. An extended SEIR model was developed using several parameters such as the average number of contacts per day per case, the proportion of close contact traced per day and the mean daily rate at which infectious cases are isolated to determine the basic reproduction number (R0) and trajectory of cases. During the first wave, a total of 22 cases with 368 close contacts were traced, identified, tested, quarantine and isolated. Due to the effective and robust outbreak control measures put in place such as early case detection, active screening, extensive contact tracing, testing and prompt isolation/quarantine, the outbreak was successfully contained and controlled. The SEIR model estimated the R0 at 0.9 which further supports the decreasing disease dynamics and early termination of the outbreak. As a result, there was a 11-day gap (free of cases) between the first and second wave which indicates that the first wave was not linked to the second wave.

Modelling infectious diseases with herd immunity in a randomly mixed population.

The conventional susceptible-infectious-recovered (SIR) model tends to magnify the transmission dynamics of infectious diseases, and thus the estimated total infections and immunized population may be higher than the threshold required for infection control and eradication. The study developed a new SIR framework that allows the transmission rate of infectious diseases to decline along with the reduced risk of contact infection to overcome the limitations of the conventional SIR model. Two new SIR models were formulated to mimic the declining transmission rate of infectious diseases at different stages of transmission. Model A utilized the declining transmission rate along with the reduced risk of contact infection following infection, while Model B incorporated the declining transmission rate following recovery. Both new models and the conventional SIR model were then used to simulate an infectious disease with a basic reproduction number (r0) of 3.0 and a herd immunity threshold (HIT) of 0.667 with and without vaccination. Outcomes of simulations were assessed at the time when the total immunized population reached the level predicted by the HIT, and at the end of simulations. Further, all three models were used to simulate the transmission dynamics of seasonal influenza in the United States and disease burdens were projected and compared with estimates from the Centers for Disease Control and Prevention. For the simulated infectious disease, in the initial phase of the outbreak, all three models performed expectedly when the sizes of infectious and recovered populations were relatively small. As the infectious population increased, the conventional SIR model appeared to overestimate the infections even when the HIT was achieved in all scenarios with and without vaccination. For the same scenario, Model A appeared to attain the level predicted by the HIT and in comparison, Model B projected the infectious disease to be controlled at the level predicted by the HIT only at high vaccination rates. For infectious diseases with high r0, and at low vaccination rates, the level at which the infectious disease was controlled cannot be accurately predicted by the current theorem. Transmission dynamics of infectious diseases with herd immunity can be accurately modelled by allowing the transmission rate of infectious diseases to decline along with the reduction of contact infection risk after recovery or vaccination. Model B provides a credible framework for modelling infectious diseases with herd immunity in a randomly mixed population.

PICK-ing Malaysia's Epidemic Apart: Effectiveness of a Diverse COVID-19 Vaccine Portfolio.

Malaysia rolled out a diverse portfolio of predominantly three COVID-19 vaccines (AZD1222, BNT162b2, and CoronaVac) beginning 24 February 2021. We evaluated vaccine effectiveness with two methods, covering 1 April to 15 September 2021: (1) the screening method for COVID-19 (SARS-CoV-2) infection and symptomatic COVID-19; and (2) a retrospective cohort of confirmed COVID-19 cases for COVID-19 related ICU admission and death using logistic regression. The screening method estimated partial vaccination to be 48.8% effective (95% CI: 46.8, 50.7) against COVID-19 infection and 33.5% effective (95% CI: 31.6, 35.5) against symptomatic COVID-19. Full vaccination is estimated at 87.8% effective (95% CI: 85.8, 89.7) against COVID-19 infection and 85.4% effective (95% CI: 83.4, 87.3) against symptomatic COVID-19. Among the cohort of confirmed COVID-19 cases, partial vaccination with any of the three vaccines is estimated at 31.3% effective (95% CI: 28.5, 34.1) in preventing ICU admission, and 45.1% effective (95% CI: 42.6, 47.5) in preventing death. Full vaccination with any of the three vaccines is estimated at 79.1% effective (95% CI: 77.7, 80.4) in preventing ICU admission and 86.7% effective (95% CI: 85.7, 87.6) in preventing deaths. Our findings suggest that full vaccination with any of the three predominant vaccines (AZD1222, BNT162b2, and CoronaVac) in Malaysia has been highly effective in preventing COVID-19 infection, symptomatic COVID-19, COVID-19-related ICU admission, and death.

Modelling the Effectiveness of Epidemic Control Measures in Preventing the Transmission of COVID-19 in Malaysia.

Malaysia is currently facing an outbreak of COVID-19. We aim to present the first study in Malaysia to report the reproduction numbers and develop a mathematical model forecasting COVID-19 transmission by including isolation, quarantine, and movement control measures. We utilized a susceptible, exposed, infectious, and recovered (SEIR) model by incorporating isolation, quarantine, and movement control order (MCO) taken in Malaysia. The simulations were fitted into the Malaysian COVID-19 active case numbers, allowing approximation of parameters consisting of probability of transmission per contact (ß), average number of contacts per day per case (ζ), and proportion of close-contact traced per day (q). The effective reproduction number (Rt) was also determined through this model. Our model calibration estimated that (ß), (ζ), and (q) were 0.052, 25 persons, and 0.23, respectively. The (Rt) was estimated to be 1.68. MCO measures reduce the peak number of active COVID-19 cases by 99.1% and reduce (ζ) from 25 (pre-MCO) to 7 (during MCO). The flattening of the epidemic curve was also observed with the implementation of these control measures. We conclude that isolation, quarantine, and MCO measures are essential to break the transmission of COVID-19 in Malaysia.

Observational study on the current status of thalassaemia in Malaysia: a report from the Malaysian Thalassaemia Registry.

OBJECTIVE: Thalassaemia is the most common inherited blood disorder in Malaysia. This study aims to report the current status of thalassaemia in Malaysia and provide a comprehensive understanding of the disease through data obtained from the Malaysian Thalassaemia Registry. DESIGN: Data were extracted from the Malaysian Thalassaemia Registry, a web-based system accessible to enrolled users through www.mytalasemia.net.my. SETTING: The Malaysian Thalassaemia Registry data was recorded from reports obtained from 110 participating government and university hospitals in Malaysia. PARTICIPANTS: The patients were those attending the 110 participating hospitals for thalassaemia treatment. INTERVENTION: Data were collected from the Malaysian Thalassaemia Registry from 2007 until the fourth quarter of 2018. PRIMARY OUTCOME MEASURE: 7984 out of 8681 patients with thalassaemia registered in the Malaysian Thalassaemia Registry were reported alive. RESULTS: Majority of the patients were reported in the state of Sabah (22.72%); the largest age group affected was 5.0-24.9 years old (64.45%); the largest ethnic group involved was Malay (63.95%); and the major diagnosis was haemoglobin E/ß-thalassaemia (34.37%). From the 7984 patients, 56.73% were on regular blood transfusions and 61.72% were on chelation therapy. A small fraction (14.23%) has undergone splenectomy, while the percentage of patients with severe iron overload (serum ferritin ≥5000 µg/L) reduced over time. However, cardiac complications are still the main cause of death in patients with thalassaemia. CONCLUSION: Data gathered into the registry can be used to understand the progression of the disorder, to monitor iron overload management and to improve the outcomes of treatment, to enhance preventive strategies, reduce healthcare burden and improve the quality of life. Sustainability of the Malaysian Thalassaemia Registry is important for surveillance of thalassaemia management in the country and help the national health authorities to develop more effective policies.

Demographic, clinical and laboratory features of leptospirosis and dengue co-infection in Malaysia.

Purpose. In this study, we aim to describe and compare the demographical, clinical and laboratory features of leptospirosis and dengue co-infections (LDCI) against single leptospirosis infections in Malaysia.Methodology. Data of patients admitted to various hospitals in Malaysia from 2011 to 2015 diagnosed with leptospirosis in our laboratory were obtained from their admission records. Co-infection with dengue was determined by collecting dengue serology results. Multivariate analysis and multiple logistic regression were used to differentiate features between single leptospirosis infection and confirmed LDCI.Results/Key findings. Only 602 (29.11 %) out of 2068 leptospira-positive patients were concurrently tested for dengue during their admission in which 44 (7.31 %) patients had positive non-structural protein 1 (confirmed LDCI) while 140 (23.26 %) were positive for dengue IgM (probable LDCI) with the highest number of cases recorded in high-density suburban districts. Myalgia and arthralgia were the only significant distinguishing clinical feature of LDCI while significant laboratory features were thrombocytopenia and high levels of alanine and aspartate transaminases. Only thrombocytopenia displayed a predictive value for LDCI from analysis of multiple logistic regression. Death occurred in 19 (3.16 %) patients in this dataset studied but only three (0.50 %) were attributed to LDCI.Conclusion. There is a considerable prevalence of LDCI in this country of which overlapping demographic, clinical and laboratory presentations pose diagnostic and therapeutic challenges. Efforts to raise awareness regarding LDCI, better access to diagnostic services and further prospective studies are warranted.

ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers. METHODS: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls. RESULTS: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p < 0.01). All control cases remained unmethylated. CONCLUSION: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.

Increased soluble HLA-DRB1in B-cell acute lymphoblastic leukaemia

Soluble HLA (sHLA) are potential tumour markers released in order to counter immune surveillance. sHLA-class II is less known especially in acute lymphoblastic leukaemia (ALL). This study aimed to investigate soluble, surface and allelic expression of HLA Class II (sHLA-DR) in B-cell ALL patients and compare with soluble expression in normal individuals. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to measure soluble HLA-DRB1 in plasma. Flow cytometric analysis was performed to determine median fluorescence intensity in HLA-DR surface expression. HLA-DNA typing by polymerase chain reaction, sequence specific oligonucleotides, PCRSSO was performed to determine HLA-DRB1 type in ALL samples. Results showed sHLA-DRB1 (mean±SEM) was significantly increased (p=0.001) in plasma of ALL patients (0.260 ±0.057 μg/mL; n=30) compared to healthy controls (0.051 ± 0.007µg/mL; n=31) of Malay ethnicity. However, these levels did not correlate with percentage or median fluorescence intensity of HLA-DR expressed on leukemia blasts (CD19+CD34 ± CD45(lo)HLA-DR+) or in the normal B cell population (CD19+CD34- CD45(hi)HLA-DR+) of patients. No significant difference was observed in gender (male/female) or age (paediatric/adult). Only a trend in reduced sHLA was observed in patients carrying HLA-DR04. These results have to be validated with a larger number of samples.