Transdermal Delivery of Pramipexole Using Microneedle Technology for the Potential Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.

Can natural language processing be effectively applied for audit data analysis in gynaecological oncology at a UK cancer centre?

BACKGROUND: The British Gynaecological Cancer Society (BGCS) has highlighted the disparity of ovarian cancer outcomes in the UK compared to other European countries. Therefore, cancer quality assurance audits and subspecialty training are important in improving the UK standard of care for these patients. The current workforce crisis afflicting the NHS creates difficulty in dedicating teams of clinicians to these audits. We present a single institution study to evaluate if NLP-generated code can improve the efficiency of ovarian cancer and subspeciality reaccreditations audits. We used the chat bot Google Bard to write Visual Basic Applications algorithms that utilise Excel files from electronic health records. METHODS: Primary ovarian cancer data from 2019 to 2022 was retrospectively collected from the Cambridge University Hospital electronic health records. The surgical subspecialty reaccreditation audit analysed the 2022 surgical database. A modular coding approach with Google Bard was applied to generate audit algorithms. The time to complete these current audits was compared against the 2016 ovarian cancer and 2020 subspeciality reaccreditation audits. RESULTS: The previous ovarian cancer audit conducted in 2016 required 3 clinicians for the 135 cases and data collection required 1800 min. Data analysis was completed in 300 min. The current ovarian cancer audit allocated 2 clinicians to the 600 surgical cases. Data collection was completed in 3120 min, 3360 min for code development and 720 min for testing. The 2020 subspecialty reaccreditation audit was completed in 360 min. The 2022 subspecialty reaccreditation audit was completed in 1680 min, with 960 min for code development, 240 for debugging and 480 min for testing. CONCLUSION: We have demonstrated that NLP-generated code can significantly increase the efficiency of surgical quality assurance audits by eliminating the need for manual data analysis. With the current trajectory of NLP development, increasingly complex algorithms can be developed with minimal programming knowledge.

Disruption of the Francisella noatunensis subsp. orientalis pdpA Gene Results in Virulence Attenuation and Protection in Zebrafish.

Several Francisella spp., including Francisella noatunensis, are regarded as important emerging pathogens of wild and farmed fish. However, very few studies have investigated the virulence factors that allow these bacterial species to be pathogenic in fish. The Francisella pathogenicity island (FPI) is a well-described, gene-dense region encoding major virulence factors for the genus Francisella. pdpA is a member of the pathogenicity-determining protein genes carried by the FPI that are implicated in the ability of the mammalian pathogen Francisella tularensis to escape and replicate in infected host cells. Using a sacB suicide approach, we generated pdpA knockouts to address the role of PdpA as a virulence factor for F. noatunensis. Because polarity can be an issue in gene-dense regions, we generated two different marker-based mutants in opposing polarity (the F. noatunensis subsp. orientalis ΔpdpA1 and ΔpdpA2 strains). Both mutants were attenuated (P < 0.0001) in zebrafish challenges and displayed impaired intracellular replication (P < 0.05) and cytotoxicity (P < 0.05), all of which could be restored to wild-type (WT) levels by complementation for the ΔpdpA1 mutant. Importantly, differences were found for bacterial burden and induction of acute-phase and proinflammatory genes for the F. noatunensis subsp. orientalis ΔpdpA1 and ΔpdpA2 mutants compared to the WT during acute infection. In addition, neither mutant resulted in significant histopathological changes. Finally, immunization with the F. noatunensis subsp. orientalis ΔpdpA1 mutant led to protection (P < 0.012) against an acute 40% lethal dose (LD40) challenge with WT F. noatunensis in the zebrafish model of infection. Taken together, the results from this study further demonstrate physiological similarities within the genus Francisella relative to their phylogenetic relationships and the utility of zebrafish for addressing virulence factors for the genus.