4 research outputs found
Palmitate-Induced Vacuolar-Type H(+)-ATPase Inhibition Feeds Forward Into Insulin Resistance and Contractile Dysfunction
Dietary fat overconsumption leads to myocardial lipid accumulation through mechanisms that are incompletely resolved. Previously, we identified increased translocation of the fatty acid transporter CD36 from its endosomal storage compartment to the sarcolemma as the primary mechanism of excessive myocellular lipid import. Here, we show that increased CD36 translocation is caused by alkalinization of endosomes resulting from inhibition of proton pumping activity of vacuolar-type H+-ATPase (v-ATPase). Endosomal alkalinization was observed in hearts from rats fed a lard-based high-fat diet and in rodent and human cardiomyocytes upon palmitate overexposure, and appeared as an early lipid-induced event preceding the onset of insulin resistance. Either genetic or pharmacological inhibition of v-ATPase in cardiomyocytes exposed to low palmitate concentrations reduced insulin sensitivity and cardiomyocyte contractility, which was rescued by CD36 silencing. The mechanism of palmitate-induced v-ATPase inhibition involved its dissociation into two parts: the cytosolic V-1 and the integral membrane V-0 subcomplex. Interestingly, oleate also inhibits v-ATPase function, yielding triacylglycerol accumulation but not insulin resistance. In conclusion, lipid oversupply increases CD36-mediated lipid uptake that directly impairs v-ATPase function. This feeds forward to enhanced CD36 translocation and further increased lipid uptake. In the case of palmitate, its accelerated uptake ultimately precipitates into cardiac insulin resistance and contractile dysfunction
A discrete-choice experiment to assess treatment modality preferences of patients with depression
Aims: There is an increasing interest in understanding patients’ preferences in the area of healthcare decision-making to better match treatment with patients’ preferences and improve treatment uptake and adherence. The aim of this study was to elicit the preferences of patients with a depressive disorder regarding treatment modalities. Materials and methods: In a discrete-choice experiment, patients chose repetitively between two hypothetical depression treatments that varied in four treatment attributes: waiting time until the start of treatment, treatment intensity, level of digitalization, and group size. A Bayesian-efficient design was used to develop 12 choice sets, and patients’ preferences and preference variation was estimated using a random parameters logit model. Results: A total of 165 patients with depression completed the survey. Patients preferred short (over long) waiting times, face-to-face (over digital) treatment, individual (over group) treatment, and one session per week over two sessions per week or one session per 2 weeks. Patients disfavoured digital treatment and treatment in a large group. Waiting time and treatment intensity were substantially less important attributes to patients than face-to-face (vs digital) and group size. Significant variation in preferences was observed for each attribute, and sub-group analyses revealed that these differences were in part related to education. Limitations: The convenience sample over-represented the female and younger population, limiting generalizability. Limited information on background characteristics limited the possibilities to explore preference heterogeneity. Conclusion: This study demonstrated how different treatment components for depression affect patients’ preferences for those treatments. There is significant variation in treatment preferences, even after accounting for education. Incorporating individual patients’ preferences into treatment decisions could potentially lead to improved adherence of treatments for depressive disorders
A discrete-choice experiment to assess treatment modality preferences of patients with anxiety disorder
Aims: The aim of this study was to elicit the preference of patients with an anxiety disorder regarding treatment modalities. Understanding patients' preferences could help optimize treatment uptake and adherence to therapeutic interventions. Materials and methods: A discrete-choice experiment was used to elicit patients' preferences with regard to four treatment characteristics: waiting time until first treatment, intensity of treatment, face-to-face vs digital treatment, and group size. In 12 choice sets, participants were asked to choose between two treatment alternatives. A random parameters logit model was used to analyse the data. Results: A total of 126 participants, aged 18 years and older, currently or in the previous year in treatment for an anxiety disorder, completed the survey. Respondents preferred short (over long) waiting times, face-to-face (over digital) treatment, individual (over group) treatment and a treatment intensity of one session per week rather than two sessions per week or one session every two weeks. Waiting time and treatment intensity were substantially less important to patients than level of digitalization and group size. Heterogeneity in preference was significant for each attribute, and sub-group analyses revealed this was partly related to education level and age. Limitations: The convenience sample over-represented the female and younger population, limiting generalizability. Limited information on background characteristics limited the possibilities to explore preference heterogeneity. Conclusions: This study demonstrated how different treatment components for anxiety disorders affect patients' preferences for those treatments. There is significant variation in treatment preferences, even after accounting for age and education. Incorporating patients' preferences into treatment decisions could potentially lead to improved adherence of treatments for anxiety disorders