Local magnetic delivery of adeno-associated virus AAV2(quad Y-F)-mediated BDNF gene therapy restores hearing after noise injury.

Moderate noise exposure may cause acute loss of cochlear synapses without affecting the cochlear hair cells and hearing threshold; thus, it remains "hidden" to standard clinical tests. This cochlear synaptopathy is one of the main pathologies of noise-induced hearing loss (NIHL). There is no effective treatment for NIHL, mainly because of the lack of a proper drug-delivery technique. We hypothesized that local magnetic delivery of gene therapy into the inner ear could be beneficial for NIHL. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) and a recombinant adeno-associated virus (AAV) vector (AAV2(quad Y-F)) to deliver brain-derived neurotrophic factor (BDNF) gene therapy into the rat inner ear via minimally invasive magnetic targeting. We found that the magnetic targeting effectively accumulates and distributes the SPION-tagged AAV2(quad Y-F)-BDNF vector into the inner ear. We also found that AAV2(quad Y-F) efficiently transfects cochlear hair cells and enhances BDNF gene expression. Enhanced BDNF gene expression substantially recovers noise-induced BDNF gene downregulation, auditory brainstem response (ABR) wave I amplitude reduction, and synapse loss. These results suggest that magnetic targeting of AAV2(quad Y-F)-mediated BDNF gene therapy could reverse cochlear synaptopathy after NIHL.

Evaluating the impact of efpeglenatide on cardiometabolic and safety outcomes in individuals with diabetes: a systematic review and meta-analysis.

Background: Efpeglenatide, a novel GLP-1 receptor agonist, has shown promise in improving glycemic control and inducing weight loss in individuals with type 2 diabetes (T2DM). This meta-analysis assessed its therapeutic potential and safety profile. Methods: A literature search was conducted on PubMed, SCOPUS, and Cochrane Central from inception until September 2023. We selected patients with T2DM and identified and compared those receiving efpeglenatide to placebo. Outcomes assessed included fasting plasma glucose (FPG), HbA1c, body weight, BMI, and cardiometabolic parameters. Data were analyzed using a random-effects model, with results presented as mean differences (MD) for continuous outcomes and risk ratios (RR) for safety analysis, along with their respective 95% confidence intervals. Quality assessment was conducted using the Cochrane risk of bias tool. Results: We included 11 studies in our analysis. Efpeglenatide demonstrated significant reductions in FPG (MD = -1.53 mmol/L, 95% CI = [-2.86, -0.66], p < 0.01), HbA1c (MD = -0.84, 95% CI= [-1.08, -0.60], p < 0.01), body weight (MD = -2.24 kg, 95% CI = [-4.20, -2.00], p < 0.01), and BMI (MD = -1.61 kg/m2, 95% CI= [-2.12, -1.09], p < 0.01). However, efpeglenatide was associated with a moderate increase in the risk of gastrointestinal adverse events, nausea, diarrhea, and vomiting. There was a non-significant elevated risk of hypoglycemia. Conclusions: Efpeglenatide significantly improves glycemic outcomes and promotes weight loss in individuals with diabetes. However, it is associated with moderate adverse effects related to the gastrointestinal system. Thus, further trials are warranted to comprehensively assess its safety and efficacy to derive a robust conclusion. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-024-01409-3.

Impact of complete versus culprit-only revascularization on major adverse cardiovascular event in diverse subpopulations.

Background: Myocardial infarction management relies on pharmaceuticals and interventions like percutaneous coronary intervention (PCI). While complete PCI has shown noninferiority to culprit-only PCI, its impact on major adverse cardiovascular events (MACE) outcomes in multiple subpopulations has been unknown.Methods: A systematic literature search (from January 2000 to May 2024) identified four relevant randomized controlled trials involving ST-segment elevation myocardial infarction patients. Data analysis employed a random-effects model with inverse variance weighting.Results: MACE risk was significantly lower in males than females undergoing complete PCI compared with culprit-only PCI (hazard ratio: 0.52; 95% CI: 0.39-0.68; p < 0.01; I2 = 53%). Furthermore, complete PCI significantly lowered the risk of MACE outcomes in patients without diabetes and in patients under the 65-year age limit in comparison to culprit-only PCI.Conclusion: Complete PCI reduces MACE risk in male, nondiabetic ST-segment elevation myocardial infarction patients under 65 with multivessel coronary artery disease, necessitating further investigation into outcome differences among different subpopulations.

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Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss.

Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t = 0) were given mannitol at either t = 0, t = 6 or t = 0,6 h. Another group of rats were treated with cisplatin with mannitol at 0 h and NAC/STS with and without mannitol at 6 h. Concurrent mannitol (t = 0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t = 6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t = 0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t = 6) was better than NAC/STS (t = 6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t = 6 h reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t = 0 h), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.