Clinical Applications of Pharmacogenomics of Warfarin

Ph.DDOCTOR OF PHILOSOPH

Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Impact of nitric oxide synthase 2 gene variant on risk of anti-tuberculosis drug- induced liver injury in the Malaysian population

Liver injury is a great threat associated with anti-tuberculosis (anti-TB) medication. Genetic variations in genes encoding drug-metabolising enzymes further enhance this threat. We aimed to explore genetic contributions by evaluating the impact of single nucleotide polymorphisms (SNPs) within the anti-tuberculosis (AT) metabolism pathway genes and within their respective chromosomes on anti-tuberculosis drug- induced liver injury (AT-DILI). Patients (n= 90) were recruited and 170 SNPs were genotyped using Illumina array and validated using Sanger Sequencing. The well-studied N-acetyltransferase 2 (NAT2*6) rs1799930 and cytochrome P450 2E1 (CYP2E1) C1/C1 were not significantly associated with AT-DILI in our cohort but nitric oxide synthase (NOS2A) rs11080344-C was found to be significantly higher in the cases than the controls (OR 2.73, 95% CI 1.12-6.64, P= 0.027). Association studies on all other SNPs within the anti-tuberculosis metabolism pathway genes and within their respective chromosomes also found no significant report. Our study suggests that genetic variation in NOS2A could influence the occurrence of AT-DILI

Mindfulness-based cognitive therapy v. group psychoeducation for people with generalised anxiety disorder: randomised controlled trial

Background: Research suggests that an 8-week mindfulness-based cognitive therapy (MBCT) course may be effective for generalised anxiety disorder (GAD). Aims: To compare changes in anxiety levels among participants with GAD randomly assigned to MBCT, cognitive–behavioural therapy-based psychoeducation and usual care. Method: In total, 182 participants with GAD were recruited (trial registration number: CUHK_CCT00267) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months. Primary outcomes were anxiety and worry levels. Results: Linear mixed models demonstrated significant group × time interaction (F(4,148) = 5.10, P = 0.001) effects for decreased anxiety for both the intervention groups relative to usual care. Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only. Conclusions: These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms

Effect of fertility health awareness strategies on fertility knowledge and childbearing in young married couples (FertStart): study protocol for an effectiveness-implementation hybrid type I multicentre three-arm parallel group open-label randomised clinical trial

Introduction Birth rates have been declining in many advanced societies including Singapore. We designed two interventions with vastly different resource requirements, which include fertility education, personalised fertility information and a behavioural change component targeting modifiable psychological constructs to modify fertility awareness and childbearing intentions. We aim to evaluate the effect of these two interventions on knowledge, attitudes and practice around childbearing compared with a control group among young married couples in Singapore and understand the implementation factors in the setting of an effectiveness-implementation hybrid type 1 three-arm randomised trial. Methods and analysis We will randomise 1200 young married couples to no intervention (control), Fertility Health Screening group (FHS) or Fertility Awareness Tools (FAT) in a 7:5:5 ratio. Couples in FHS will undergo an anti-Mullerian hormone test and semen analysis, a doctor’s consultation to explain the results and standardised reproductive counselling by a trained nurse. Couples in FAT will watch a standardised video, complete an adapted fertility status awareness (FertiSTAT) tool and receive an educational brochure. The attitudes, fertility knowledge and efforts to achieve pregnancy of all couples will be assessed at baseline and 6 months post-randomisation. Birth statistics will be tracked using administrative records at 2 and 3 years. The primary outcome is the change in the woman’s self-reported intended age at first birth between baseline and 6 months post-randomisation. In addition, implementation outcomes and cost-effectiveness of the two interventions will be assessed

miR-3099 promotes neurogenesis and inhibits astrogliogenesis during murine neural development

MicroRNA-3099 is highly expressed during neuronal differentiation and development of the central nervous system. Here we characterised the role of miR-3099 during neural differentiation and embryonic brain development using a stable and regulatable mouse embryonic stem cell culture system for miR-3099 expression and in utero electroporation of miR-3099 expression construct into E15.5 embryonic mouse brains. In the in vitro system, miR-3099 overexpression upregulated gene related to neuronal markers such as Tuj1, NeuN, Gat1, vGluT1 and vGluT2. In contrast, gene related to astrocyte markers (Gfap, S100β and Slc1a3) were suppressed upon overexpression of miR-3099. Furthermore, miR-3099 overexpression between E15.5 and E18.5 mouse embryonic brains led to disorganised neuronal migration potentially due to significantly decreased Gfap+ cells. Collectively, our results indicated that miR-3099 plays a role in modulating and regulating expression of key markers involved in neuronal differentiation. In silico analysis was also performed to identify miR-3099 homologues in the human genome, and candidates were validated by stem-loop RT-qPCR. Analysis of the miR-3099 seed sequence AGGCUA against human transcriptomes revealed that a potential miRNA, mds21 (Chr21:39186698-39186677) (GenBank accession ID: MK521584), was 100% identical to the miR-3099 seed sequence. Mds21 expression was observed and validated in various human cell lines (293FT, human Wharton's jelly and dental pulp mesenchymal stem cells, and MCF-7, MDA-MB-231, C-Sert, SW780, RT112, 5637, EJ28 and SH-SY5Y cells), with the highest levels detected in human mesenchymal stem cell lines. The analysis validated mds21 as a novel miRNA and a novel homologue of miR-3099 in the human genome

Age-Specific Associations of Usual Blood Pressure Variability With Cardiovascular Disease and Mortality: 10-Year Diabetes Mellitus Cohort Study.

Background The detrimental effects of increased variability in systolic blood pressure (SBP) on cardiovascular disease (CVD) and mortality risk in patients with diabetes mellitus remains unclear. This study evaluated age-specific association of usual SBP visit-to-visit variability with CVD and mortality in patients with type 2 diabetes mellitus. Methods and Results A retrospective cohort study investigated 155 982 patients with diabetes mellitus aged 45 to 84 years without CVD at baseline (2008-2010). Usual SBP variability was estimated using SBP SD obtained from a mixed-effects model. Age-specific associations (45-54, 55-64, 65-74, 75-84 years) between usual SBP variability, CVD, and mortality risk were assessed by Cox regression adjusted for patient characteristics. After a median follow-up of 9.7 years, 49 816 events (including 34 039 CVD events and 29 211 mortalities) were identified. Elevated SBP variability was independently, positively, and log-linearly associated with higher CVD and mortality risk among all age groups, with no evidence of any threshold effects. The excess CVD and mortality risk per 5 mm Hg increase in SBP variability within the 45 to 54 age group is >3 times higher than the 70 to 79 age group (hazard ratio, 1.66; 95% CI, 1.49-1.85 versus hazard ratio, 1.19; 95% CI, 1.15-1.23). The significant associations remained consistent among all subgroups. Patients with younger age had a higher association of SBP variability with event outcomes. Conclusions The findings suggest that SBP visit-to-visit variability was strongly associated with CVD and mortality with no evidence of a threshold effect in a population with diabetes mellitus. As well as controlling overall blood pressure levels, SBP visit-to-visit variability should be monitored and evaluated in routine practice, in particular for younger patients

Effectiveness of BNT162b2 and CoronaVac vaccinations against SARS-CoV-2 omicron infection in people aged 60 years or above: a case–control study

BACKGROUND: In view of limited evidence that specifically addresses vaccine effectiveness (VE) in the older population, this study aims to evaluate the real-world effectiveness of BNT162b2 and CoronaVac in older adults during the Omicron BA.2 outbreak. METHODS: This case-control study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Each case was matched with up to 10 controls by age, sex, index date and Charlson Comorbidity Index for the four outcomes (COVID-19 infection, COVID-19-related hospitalization, severe complications, and all-cause mortality) independently. Conditional logistic regression was conducted to evaluate VE of BNT162b2 and CoronaVac against COVID-19-related outcomes within 28 days after COVID-19 infection among participants stratified by age groups (60-79, ≥80 years old). RESULTS: A dose-response relationship between the number of vaccine doses received and protection against severe or fatal disease was observed. Highest VE (95% CI) against COVID-19 infection was observed in individuals aged ≥80 who received three doses of BNT162b2 [75.5% (73.1-77.7%)] or three doses of CoronaVac [53.9% (51.0-56.5%)] compared to those in the younger age group who received three doses of BNT162b2 [51.1% (49.9-52.4%)] or three doses of CoronaVac [2.0% (-0.1-4.1%)]. VE (95% CI) was higher for other outcomes, reaching 91.9% (89.4-93.8%) and 86.7% (84.3-88.8%) against COVID-19-related hospitalization; 85.8% (61.2-94.8%) and 89.8% (72.4-96.3%) against COVID-19-related severe complications; and 96.4% (92.9-98.2%) and 95.0% (92.1-96.8%) against COVID-19-related mortality after three doses of BNT162b2 and CoronaVac in older vaccine recipients, respectively. A similar dose-response relationship was established in younger vaccine recipients and after stratification by sex and Charlson Comorbidity Index. CONCLUSION: Both BNT162b2 and CoronaVac vaccination were effective in protecting older adults against COVID-19 infection and COVID-19-related severe outcomes amidst the Omicron BA.2 pandemic, and VE increased further with the third dose

Epidemiology and risk factors for Carbapenemase-Producing Enterobacteriaceae carriage in the hospital: a population-based nested case-control study

Objective: This study aims to study the epidemiology of Carbapenemase-producing Enterobacteriaceae (CPE) in Hong Kong. / Methods: This is a longitudinal population-based study reporting monthly CPE incidence rate and a nested case-control study for identifying risk factors for CPE carriage. The cases were patients with at least one CPE positive genotypic test, while the controls were randomly selected from the cohort with negative tests. Up to four controls per case were matched by sex, age group, and admission year-month. The independent risk factors were identified from a conditional logistic regression with potential covariates. / Results: From 1st January 2008 to 31st December 2019, 8,588 patients received CPE genotyping tests, and 2,353 had at least one positive result. Class B carbapenemase was the predominant enzyme in the samples (78.6%). The incidence rate increased from 0.04 in 2015 to 1.62 in 2019 per 10,000 person-year. In the nested case-control study, 1709 cases and 6664 controls were matched. Previous use of any beta-lactam antibiotics [Odds ratio:1.37 (1.22-1.53), p<.001] was found as an independent risk factor for carriage of CPE. / Conclusion: The carriage of CPE was found with an increasing trend in Hong Kong. Previous use of any beta-lactam antibiotics is a risk factor for CPE. / Summary: The incidence rate of Carbapenemase-producing Enterobacteriaceae is increasing in Hong Kong, with the predominant enzyme of class B carbapenemase. With multivariable conditional logistic regression, the previous use of any beta-lactam antibiotics was found as an independent risk factor for CPE carriage

Adverse events of special interest following the use of BNT162b2 in adolescents: a population-based retrospective cohort study

Accruing evidence suggests an increased risk of myocarditis in adolescents from messenger RNA COVID-19 vaccines. However, other potential adverse events remain under-researched. We conducted a retrospective cohort study of adolescents aged 12–18 with a territory-wide electronic healthcare database of the Hong Kong population linked with population-based vaccination records and supplemented with age- and sex-specific population numbers. Two age- and sex-matched retrospective cohorts were formed to observe 28 days following the first and second doses of BNT162b2 and estimate the age- and sex-adjusted incidence rate ratios between the vaccinated and unvaccinated. Thirty AESIs adapted from the World Health Organization’s Global Advisory Committee on Vaccine Safety were examined. Eventually, the first-dose cohort comprised 274,881 adolescents (50.25% received the first dose) and the second-dose cohort 237,964 (50.29% received the second dose). Ninety-four (34.2 per 100,000 persons) adolescents in the first-dose cohort and 130 (54.6 per 100,000 persons) in the second-dose cohort experienced ≥1 AESIs. There were no statistically significant differences in the risk of any AESI associated with BNT162b2 except myocarditis [first-dose cohort: incidence rate ratio (IRR) = 9.15, 95% confidence interval (CI) 1.14–73.16; second-dose cohort: IRR = 29.61, 95% CI 4.04–217.07] and sleeping disturbances/disorders after the second dose (IRR = 2.06, 95% CI 1.01–4.24). Sensitivity analysis showed that, with myocarditis excluded as AESIs, no significantly elevated risk of AESIs as a composite outcome associated with vaccination was observed (P = 0.195). To conclude, the overall absolute risk of AESIs was low with no evidence of an increased risk of AESIs except myocarditis and sleeping disturbances/disorders