METHODOLOGY: We conducted a population-based, matched case-control study in Malaysia to estimate the marginal vaccine effectiveness (mVE) of homologous and heterologous BNT162b2 and CoronaVac booster vaccination against COVID-19 related intensive care unit (ICU) admission and death in Delta-predominant and Omicron-predominant periods.
RESULTS: Receipt of a booster vaccination - either homologous or heterologous for CoronaVac, and homologous for BNT162b2 - demonstrated mVE estimates of at least 70% against ICU admission and at least 80% against death, compared to BNT162b2 primary vaccination, in both periods. Overall, the mVE estimates were 10-20 percentage points lower in the Omicron-predominant period than in the Delta-predominant period.
CONCLUSIONS: Our study reaffirms that the administration of booster vaccination increases protection against severe COVID-19 outcomes for BNT162b2 and CoronaVac primary vaccination recipients.
METHODOLOGY: A qualitative, semi-structured interview, followed by a quantitative, questionnaire-based study, was carried out at the Shifa International Hospital (SIH; Islamabad, Pakistan). Discharge summaries of patients aged ≥ 60 years were collected to assess the prevalence of polypharmacy at SIH.
RESULTS: Discharge summaries of n = 350 patients were collected; 60.2% (n = 211) had comorbid conditions, and the co-occurrence of diabetes and hypertension were the most common. 37.8% (n = 132) were taking 8 or more medications. Eight (n = 8) hospital pharmacists participated in the qualitative study, and 4 major themes were identified in their perceptions regarding prescribing cascades. Fifty-two (n = 52) pharmacists were recruited in the quantitative phase. 86.5% (n = 45) of the participants reported long standing illness/chronic conditions; 67.3% (n = 35) noted the presence of comorbidities as a high risk, while 90.3% (n = 47) noted multiple prescribers, and 75.0% (n = 39) identified the ageing population as important risks factors for polypharmacy.
CONCLUSIONS: The current research may inform the role and responsibilities of hospital pharmacists in outpatient and inpatient departments, and in interprofessional care teams, in preventing and minimizing prescribing cascades.
METHODS: We conducted a single-center cross-sectional case-control study on the CTP changes of 31 patients presenting with acute seizures of different etiologies, and compared them with 31 patients of acute cortical stroke patients (n = 31) as the control.
RESULTS: 58.1% had increased time to peak (TTP) in the seizure group. None of the patients with acute stroke had reduced TTP compared to 25.8% in the seizure group. The majority of patients in the seizure group had normal to reduced relative cerebral blood flow (rCBF) (38.7% and 35.5%, respectively). 35.5% and 38.7% of the patients presenting with acute seizures had normal and reduced relative cerebral blood volume (rCBV), respectively. The association between the perfusion parameters and etiology of seizures, presence of underlying epilepsy, or presence of postictal neurological deficits was not statistically significant. The seizure group had cortical ribbon (51.6%), holo-hemispheric (32.3%), multi-lobar (9.7%), and normal (6.5%) CT perfusion patterns. In conclusion, our study shows that the majority of the patients of the acute seizure group had normal to hypoperfusion patterns. Seizure-related perfusion changes did not conform to expected vascular territories, and cortical ribbon pattern was found to be predominant in our study.
SIGNIFICANCE: There is cerebral hypoperfusion or normal perfusion in most patients presenting with acute seizures. Seizure-related perfusion changes are not limited to arterial vascular territories.
METHODS: A systematic search was conducted in September 2024 across multiple databases. Randomized controlled trials (RCTs) evaluating GLP-1 RAs for OSA in adults with a body mass index (BMI) ≥30 kg/m2 were included. The primary outcomes were changes in the apnea-hypopnea index (AHI) and overall adverse events. Meta-analyses were performed using a random-effects model.
RESULTS: Three RCTs were included in the analysis. Pooled results showed that GLP-1 RA treatment significantly reduced AHI compared to placebo, with a weighted mean difference (WMD) of -16.6 events per hour (95 % confidence interval [CI]: -27.9 to -5.3). However, GLP-1 RAs were associated with a higher frequency of adverse events, with an odds ratio (OR) of 1.62 (95 % CI: 1.16 to 2.24) compared to placebo.
CONCLUSION: GLP-1 RAs effectively reduce OSA severity, offering a promising alternative for individuals with OSA and elevated body weight. However, the increased risk of side effects must be considered. Further long-term studies are needed to confirm the sustained benefits and safety of GLP-1 RAs in OSA management.
METHODS: A de novo 4-state partitioned survival model was developed to compare lifetime cost and outcomes of 2 care models operationalized in R. The disease progression was based on independent survival modeling of relevant Kaplan-Meier data. The healthcare and out-of-pocket costs were drawn from the local setting. The quality of life was measured using the EQ5D5L and the time trade-off valuation of health-state vignettes that match the states in the model. Probabilistic and deterministic sensitivity analyses were conducted to test the uncertainty around the model results.
RESULTS: The lifetime incremental quality-adjusted life years were 4.1 years (95% CI, 2.37-5.68). Incremental costs were estimated to be $9.5 million (95% CI, 9.0 million-10.0 million), which primarily consists of drug costs (99%). The incremental costs per quality-adjusted life year were estimated to be approximately $2.4 million (95% CI, 1.7 million-3.8 million). Sensitivity analyses showed that the key drivers of incremental cost-effectiveness ratio were quality of life in the preprogression state and differential discounting approach, besides the acquisition cost of enzyme replacement therapy of idursulfase.
CONCLUSIONS: The incremental cost-effectiveness ratios were beyond any conventionally used cost-effectiveness threshold in all cases. At the current price, there is a significant discrepancy between the therapy's funding decision and the cost-effectiveness assessment as a basis for guiding healthcare prioritization in Malaysia.
METHODS: A nested case-control analysis was conducted on 3160 eligible participants with renal profile data from The Malaysian Cohort project. CKD status was determined by estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Multiple logistic regression analysis using the likelihood ratio method were used to identify the factors and their interaction with CKD.
RESULTS: This study suggested five factors associated with CKD: gender, ethnicity, physical activity, atherogenic plasma index (AIP), and systolic blood pressure. There was an interaction between AIP and gender, with increased odds of CKD among men with high AIP.
CONCLUSIONS: As CKD is mainly asymptomatic until it is in the later stages, these five factors serve as valuable tools for predicting CKD and enhancing the identification of at-risk individuals, particularly among men with elevated Atherogenic Index of Plasma (AIP). Future studies should focus on using these factors, especially in preventing new CKD cases and their progression.
METHODS: A deep intronic gene panel was designed to identify deep intronic variants. SSOs were then developed and validated in vitro using minigene assay and induced hepatocytes, and target engagement was verified in vivo by hydrodynamic tail vein injection of minigenes and SSOs.
RESULTS: With the Deep Intronic-Gene Panel and RNA analysis, we identified a novel SLC25A13 c.469-2922G>T variant that promotes the inclusion of a premature stop codon-containing pseudo-exon, SLC25A13-PE5, thereby causing CD. By a stepwise rational SSO design approach, we identified potent candidates inhibiting SLC25A13-PE5 at EC50 <2nM in vitro. Upon conjugating the SSOs with N-acetylgalactosamine (GalNAc), they were validated to rescue normal protein expression and restore ureagenesis and ammonia clearance, key urea cycle functions, in patient-derived induced hepatocytes. In vivo on-target efficacy of the clinical GalNAc-SSO candidate, in the absence of acute toxicity and inflammation, was observed in a mouse model with exogenous hepatic minigene expression.
CONCLUSIONS: Our data validates a platform to redefine molecular diagnosis of urea cycle disorders and provides a proof-of-concept for precision therapy of CD patients whose only effective treatment is liver transplantation.
IMPACT & IMPLICATIONS: Deep intronic variants are common causes of genetic diseases that are commonly neglected. In this study, we demonstrate an integrated precision diagnostic and therapeutic approach for UCD. Specifically, we focus on CD, going from the discovery of a novel splice variant in the SLC25A13 gene with our novel UCD Deep Intronic-Gene Panel, to the development and in vivo validation of an efficacious SSO candidate for the pathogenic splice variant. We envision the possibility of extrapolating this pipeline to the diagnosis and development of treatments for other rare genetic diseases.