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

Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3 methyl-picolinic acid

Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-κ2 N,O)2(1,10-phenanthroline-κ2 N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)2(phen)]·5H2O. The trans-configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G-quadruplex with human tolemeric sequence 5′-AG3(T2AG3)3-3′, can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line

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

Herpes zoster related hospitalization after inactivated (CoronaVac) and mRNA (BNT162b2) SARS-CoV-2 vaccination: A self-controlled case series and nested case-control study

BACKGROUND: Stimulation of immunity by vaccination may elicit adverse events. There is currently inconclusive evidence on the relationship between herpes zoster related hospitalization and COVID-19 vaccination. This study aimed to evaluate the effect of inactivated virus (CoronaVac, Sinovac) and mRNA (BNT162b2, BioNTech/Fosun Pharma) COVID-19 vaccine on the risk of herpes zoster related hospitalization. METHODS: Self-controlled case series (SCCS) analysis was conducted using the data from the electronic health records in Hospital Authority and COVID-19 vaccination records in the Department of Health in Hong Kong. We conducted the SCCS analysis including patients with a first primary diagnosis of herpes zoster in the hospital inpatient setting between February 23 and July 31, 2021. A confirmatory analysis by nested case-control method was also conducted. Each herpes zoster case was randomly matched with ten controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Conditional Poisson regression and logistic regression models were used to assess the potential excess rates of herpes zoster after vaccination. FINDINGS: From February 23 to July 31, 2021, a total of 16 and 27 patients were identified with a first primary hospital diagnosis of herpes zoster within 28 days after CoronaVac and BNT162b2 vaccinations. The incidence of herpes zoster was 7.9 (95% Confidence interval [CI]: 5.2–11.5) for CoronaVac and 7.1 (95% CI: 4.1–11.5) for BNT162b2 per 1,000,000 doses administered. In SCCS analysis, CoronaVac vaccination was associated with significantly higher risk of herpes zoster within 14 days after first dose (adjusted incidence rate ratio [aIRR]=2.67, 95% CI: 1.08–6.59) but not in other periods afterwards compared to the baseline period. Regarding BNT162b2 vaccination, a significantly increased risk of herpes zoster was observed after first dose up to 14 days after second dose (0-13 days after first dose: aIRR=5.23, 95% CI: 1.61–17.03; 14–27 days after first dose: aIRR=5.82, 95% CI: 1.62–20.91; 0-13 days after second dose: aIRR=5.14, 95% CI: 1.29–20.47). Using these relative rates, we estimated that there has been an excess of approximately 5 and 7 cases of hospitalization as a result of herpes zoster after every 1,000,000 doses of CoronaVac and BNT162b2 vaccination, respectively. The findings in the nested case control analysis showed similar results. INTERPRETATION: We identified an increased risk of herpes zoster related hospitalization after CoronaVac and BNT162b2 vaccinations. However, the absolute risks of such adverse event after CoronaVac and BNT162b2 vaccinations were very low. In locations where COVID-19 is prevalent, the protective effects on COVID-19 from vaccinations will greatly outweigh the potential side effects of vaccination. FUNDING: The project was funded by Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref. No.COVID19F01). FTTL (Francisco Tsz Tsun Lai) and ICKW (Ian Chi Kei Wong)’s posts were partly funded by D(2)4H; hence this work was partly supported by AIR@InnoHK administered by Innovation and Technology Commission

Association between the risk of seizure and COVID-19 vaccinations: A self-controlled case-series study

OBJECTIVE: The risk of seizure following BNT162b2 and CoronaVac vaccinations has been sparsely investigated. This study aimed to evaluate this association. METHOD: Patients who had their first seizure-related hospitalization between February 23, 2021 and January 31, 2022 were identified in Hong Kong. All seizure episodes happening on the day of vaccination (day 0) were excluded since clinicians validated that most of the cases on day 0 were syncopal episodes. Within-individual comparison using a modified self-controlled case series analysis was applied to estimate the incidence rate ratio (IRR) with 95% confidence intervals (CI) of seizure using conditional Poisson regression. RESULTS: We identified 1656 individuals who had their first seizure-related hospitalization (BNT162b2: 426; CoronaVac: 263; unvaccinated: 967) within the observation period. The incidence of seizure was 1.04 (95% CI: 0.80-1.33) and 1.11 (95% CI: 0.80-1.50) per 100,000 doses of BNT162b2 and CoronaVac administered respectively. 16 and 17 individuals received second dose after having first seizure within 28 days after first dose of BNT162b2 and CoronaVac vaccinations, respectively. None had recurrent seizures after the second dose. There was no increased risk during day 1-6 after the first (BNT162b2: IRR=1.39, 95% CI=0.75-2.58; CoronaVac: IRR=1.19, 95% CI=0.50-2.83) and second doses (BNT162b2: IRR=1.36, 95% CI 0.72-2.57; CoronaVac: IRR=0.71, 95% CI=0.22-2.30) of vaccinations. During 7-13, 14-20- and 21-27-days post-vaccination, no association was observed for both vaccines. SIGNIFICANCE: The findings demonstrated no increased risk of seizure following BNT162b2 and CoronaVac vaccinations. Future studies will be warranted to evaluate the risk of seizure following COVID-19 vaccinations in different populations with subsequent doses to ensure the generalizability

Maritime threat response

This report was prepared by Systems Engineering and Analysis Cohort Nine (SEA-9) Maritime Threat Response, (MTR) team members.Background: The 2006 Naval Postgraduate School (NPS) Cross-Campus Integrated Study, titled “Maritime Threat Response” involved the combined effort of 7 NPS Systems Engineering students, 7 Singaporean Temasek Defense Systems Institute (TDSI) students, 12 students from the Total Ship Systems Engineering (TSSE) curriculum, and numerous NPS faculty members from different NPS departments. After receiving tasking provided by the Wayne E. Meyer Institute of Systems Engineering at NPS in support of the Office of the Assistant Secretary of Defense for Homeland Defense, the study examined ways to validate intelligence and respond to maritime terrorist attacks against United States coastal harbors and ports. Through assessment of likely harbors and waterways to base the study upon, the San Francisco Bay was selected as a representative test-bed for the integrated study. The NPS Systems Engineering and Analysis Cohort 9 (SEA-9) Maritime Threat Response (MTR) team, in conjunction with the TDSI students, used the Systems Engineering Lifecycle Process (SELP) [shown in Figure ES-1, p. xxiii ] as a systems engineering framework to conduct the multi-disciplinary study. While not actually fabricating any hardware, such a process was well-suited for tailoring to the team’s research efforts and project focus. The SELP was an iterative process used to bound and scope the MTR problem, determine needs, requirements, functions, and to design architecture alternatives to satisfy stakeholder needs and desires. The SoS approach taken [shown in Figure ES-2, p. xxiv ]enabled the team to apply a systematic approach to problem definition, needs analysis, requirements, analysis, functional analysis, and then architecture development and assessment.In the twenty-first century, the threat of asymmetric warfare in the form of terrorism is one of the most likely direct threats to the United States homeland. It has been recognized that perhaps the key element in protecting the continental United States from terrorist threats is obtaining intelligence of impending attacks in advance. Enormous amounts of resources are currently allocated to obtaining and parsing such intelligence. However, it remains a difficult problem to deal with such attacks once intelligence is obtained. In this context, the Maritime Threat Response Project has applied Systems Engineering processes to propose different cost-effective System of Systems (SoS) architecture solutions to surface-based terrorist threats emanating from the maritime domain. The project applied a five-year time horizon to provide near-term solutions to the prospective decision makers and take maximum advantage of commercial off-the-shelf (COTS) solutions and emphasize new Concepts of Operations (CONOPS) for existing systems. Results provided insight into requirements for interagency interactions in support of Maritime Security and demonstrated the criticality of timely and accurate intelligence in support of counterterror operations.This report was prepared for the Office of the Assistant Secretary of Defense for Homeland DefenseApproved for public release; distribution is unlimited

Novel 2-benzoyl-6-(2,3- dimethoxybenzylidene)-cyclohexenol confers selectivity toward human MLH1 defective cancer cells through synthetic lethality

DNA mismatch repair (MMR) deficiency has been associated with a higher risk of developing colorectal, endometrial, and ovarian cancer, and confers resistance in conventional chemotherapy. In addition to the lack of treatment options that work efficaciously on these MMR-deficient cancer patients, there is a great need to discover new drug leads for this purpose. In this study, we screened through a library of commercial and semisynthetic natural compounds to identify potential synthetic lethal drugs that may selectively target MLH1 mutants using MLH1 isogenic colorectal cancer cell lines and various cancer cell lines with known MLH1 status. We identified a novel diarylpentanoid analogue, 2-benzoyl-6-(2,3-dimethoxybenzylidene)-cyclohexenol, coded as AS13, that demonstrated selective toxicity toward MLH1-deficient cancer cells. Subsequent analysis suggested AS13 induced elevated levels of oxidative stress, resulting in DNA damage where only the proficient MLH1 cells were able to be repaired and hence escaping cellular death. While AS13 is modest in potency and selectivity, this discovery has the potential to lead to further drug development that may offer better treatment options for cancer patients with MLH1 deficiency