In some countries including Singapore, biologic therapies are not routinely available. Instead, oral corticosteroid (OCS) is commonly used for severe asthma management, which could lead to substantial adverse health events. To estimate the multimorbidity costs in asthma patients from a multi-ethnic Asian population. We examined national health administrative data (2012-2019) from Singapore. Direct medical costs were summed from costs of hospitalisation, emergency department (ED), specialist care, and public primary care. Prescription data were not available but formed part of public primary care costs. We measured cost per patient-year (PY) in 2023 Singaporean dollars (SGD$1 = US$0.76 = ₤0.60 = €0.69). We performed propensity-score matching on asthma and non-asthma patients, and applied generalised linear models to estimate total and excess costs due to asthma, OCS-related comorbidities, and other comorbidity groups. We identified 19,979 paediatric and 48,237 adult asthma patients (48.2% males, 50.4% Chinese, 13.9% Indian, 26.8% Malay), and matched equal number of non-asthma patients. Paediatric and adult asthma patients respectively incurred $816.3/PY (95% CI: $803.0/PY-$829.5/PY) and $1855.9/PY (95% CI: $1845.0/PY-$1871.0/PY) in total costs. The average ($1610.9/PY [95% CI: $1599.5/PY-$1621.3/PY]) was thrice of non-asthma patients' ($530.4/PY). Excess costs (mean = $927.2/PY) were driven by asthma ($403.0/PY), OCS-related comorbidities ($104.0/PY), other metabolic disease ($116.4/PY), circulatory diseases ($112.9/PY) and non-asthma respiratory conditions ($107.4/PY). All excess cost components increased steadily over the 8-year study period. The burden of asthma multimorbidity in Singapore is severe, with a considerable fraction attributable to OCS-related comorbidities. Policies should aim to reduce excess OCS use and enhance integrated multimorbidity management.

Novel inhibitors of aldosterone synthase (CYP11B2) hold promise as treatments for cardiorenal conditions including chronic kidney disease, heart failure, and hypertension. The inadequacy of rodent models and the failure of recombinant systems to reliably recapitulate the properties of the native human enzyme have hindered research in this area. Thus, we developed in vitro and in vivo models based on nonhuman primates. This approach led to the discovery of vicadrostat (BI 690517), an inhibitor with an in vitro IC50 of 19 nM against human aldosterone synthase, 250-fold selective against the highly homologous cortisol synthase (CYP11B1), and with drug-like chemical and pharmacokinetic properties. In an acute in vivo model in cynomolgus monkeys, vicadrostat displayed an IC50 against aldosterone production of 25 nM, with >2000-fold selectivity against synthesis of cortisol. The pharmacodynamic effects of repeated administration were determined in cynomolgus using doses estimated to mimic a likely therapeutic intervention in humans. Vicadrostat significantly lowered plasma aldosterone, with no effect on cortisol. Effects on precursor steroids were observed, with little effect on electrolytes. Importantly, a clear difference between dosing regimens emerged, indicating that once daily dosing (partial-day coverage) resulted in a sustained effect, whereas dosing twice daily (full-day coverage) induced a counteractive increase in aldosterone synthesis that resulted in a loss of effect on overall daily aldosterone levels. These studies were key to the design of early clinical trials with vicadrostat and illustrate the value of establishing a physiologically relevant pharmacodynamic model in reducing the scope of necessary human investigation. SIGNIFICANCE STATEMENT: The standard of care for chronic kidney disease is inadequate to prevent gradual loss of renal function in many patients. Here, the study describes key preclinical studies with the novel aldosterone synthase inhibitor vicadrostat that were instrumental in the design of early clinical studies and provide insight into predicted and unpredicted pharmacodynamic effects. These observations will inform further development of vicadrostat and related drugs for the treatment of kidney disease and other metabolic disease-related morbidities.

Anorexia nervosa (AN) is a severe, potentially life-threatening psychiatric disorder characterized by an intense fear of weight gain, a distorted body perception and an extern food restriction leading to an abnormally low body weight. In AN patients, malnutrition is often associated with hepatic cytolysis. A growing body of evidence support an association between AN and auto-immunity. In this exploratory study, we revealed for the first-time the presence of autoantibodies targeting hypoxia-inducible factor 1 alpha (HIF1a) in AN. We evidenced the presence of autoantibodies against HIF1a in 22% of AN patients, which were absent in patients with other metabolic disease as type-I diabetes or in healthy subjects. In addition, we found that HIF1a autoantibodies was associated with hepatic cytolysis in 80% of AN patients and that their levels significantly correlated with those of ALT (alanine aminotransferase). In-vitro experiments demonstrated that HIF1a autoantibodies induced hepatocyte lysis, suggesting a potential link between these autoantibodies and liver dysfunction in AN patients. Altogether, our data reveal an implication of HIF1a autoantibodies in AN with hepatic cytolysis. Future investigation will explore their potential as a diagnostic or a prognostic marker in AN, but also other diseases since dysregulated hypoxia pathway has been implicated in other pathologic conditions.

The central carbon energy metabolism, which is crucial to the metabolic pathway in almost all living organisms and in the regulation of responses to various kinds of stress. Most of serious metabolic disorders in basic life activities of life are attributed to energy metabolism disorders. Metabolic dysfunction-associated fatty liver disease (MAFLD) and other metabolic disease are usually accompanied with the disturbance of energy metabolism. Maintaining energy homeostasis is crucial for overall health and even survival. To date, there is no systematic study on energy metabolites profile of MAFLD. In this study, we established a method for the simultaneous quantification of 31 endogenous metabolites involved three pathways in the tricarboxylic acid (TCA) cycle, glycolysis and oxidative phosphorylation metabolic pathway by using the UPLC-MS/MS system. This present method offers significant advantages including simple and fast preparation of a wide range of mice and human biological samples and was successfully validated with satisfactory linearity, sensitivity, accuracy, precision, matrix effects, recovery and stability. Target metabolomics analysis was performed in different tissues and organs of mice and the substantial metabolic disparity among mice and human was demonstrated, further verifying the applicability and reliability of our method. Multivariate statistical analysis approach was conducted on 31 variables in human and mice serum samples. Based on VIP> 1, P value< 0.05, seven differential metabolites were screened out for MAFLD in human and mice. ROC analysis indicated that the seven potential markers provided a good diagnostic efficiency for MAFLD. The method demonstrated a simple and promising strategy to rapidly determine the energy metabolism status in mice and human, which can provide valuable results for mechanistic studies. This work provides metabolomic information for the study of metabolic diseases and analytical methodologies for clinical target analysis and efficacy evaluation related to energy metabolism in medical institutions.

Estimated glucose disposal rate (eGDR) is a novel insulin resistance (IR) assessment surrogate. Although it has shown promising potential in other metabolic disease studies, no research has yet explored its relationship with osteoarthritis (OA). Therefore, this study aims to investigate the association between eGDR and OA in a cross-sectional observational cohort. Data utilized in this cross-sectional study were drawn from the National Health and Nutrition Examination Survey (NHANES). Logistic regression models were used to evaluate the association between eGDR and OA, stratified analysis was applied to assess the stability of the results. A total of 19,040 participants were included in the study, including 2,001 OA patients and 17,039 non-OA participants with an age distribution ranging from 20 to 85 years. The fully adjusted logistic regression model shows that eGDR were less likely associated with OA compared to those with non-OA (OR = 0.879, 95% CI = 0.846-0.914, P < 0.001). By dispersing the eGDR into quartiles, the correlation between eGDR and OA remained significant (P for trend < 0.0001). This study suggests that eGDR is independently associated with OA, with lower eGDR values being linked to a higher risk of OA. Not applicable.