Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.     

Pre-COVID-19 Social Determinants of Health Among Mexican Migrants in Los Angeles and New York City and Their Increased Vulnerability to Unfavorable Health Outcomes During the COVID-19 Pandemic

Journal of Immigrant and Minority Health - COVID-19 has disproportionally affected underrepresented minorities (URM) and low-income immigrants in the United States. The aim of the study is to...     

The success of Australia’s ‘No Jab,No Pay’ policy at a local level; retrospective clinical audit of a single medical practice assessing incidence of catch-up vaccinations

Vaccination is a vital health care initiative to prevent individual and population infection. To increase vaccination rates the federal government implemented the ‘No Jab, No Pay’ policy, where eligibility for several government benefits required children to be fully vaccinated by removing ‘conscientious objections’ and expanding the age range of children whose families receive benefits. This study assesses the impact of this policy at a local area within a single medical practice community in NSW, Australia. A retrospective clinical audit was performed between 2012 and 2017 on a single general practice's vaccination records for children ≤19 years. Catch-up vaccinations were assessed based on age at vaccination. Incidence of catch-up vaccinations was assessed for each of four years before and two years after the implementation of the ‘No Jab, No Pay’ policy in January 2016, along with the age of children and vaccination(s) given. Catch-up vaccinations were assessed temporally either side of implementation of ‘No Jab, No Pay’. Comparing the average annual vaccination catch-up incidence rate of 6.2% pre-implementation (2012–2015), there was an increase to 9.2% in 2016 (p < .001) and 7.8% in 2017 (p = .027). Secondary outcome measurement of catch-up vaccination incidence rates before (2012–2015) and after (2016–2017) ‘No Jab, No Pay’ implementation showed statistically significant increases for children aged 8–11 years (3.2%–5.6%, p = .038), 12–15 years (7.5%–14.7%, p < .001) and 16–19 years (3.3%–10.2%, p < .001) along with a statistically significant reduction in children aged 1–3 years (11.4%–6.2%, p = .015). Also, catch-up rates for DTPa significantly increased after program implementation. This study demonstrates that the Australian federal government vaccination policy ‘No Jab, No Pay’ was coincident with an increase in catch-up vaccinations within a rural NSW community served by one medical practice, especially for older children.