| 641. |
- Osinski, V., et al.
(författare)
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In vivo liposomal delivery of PPAR alpha/gamma dual agonist tesaglitazar in a model of obesity enriches macrophage targeting and limits liver and kidney drug effects
- 2020
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 10:2, s. 585-601
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Tidskriftsartikel (refereegranskat)abstract
- Macrophages are important regulators of obesity-associated inflammation and PPAR alpha and -gamma agonism in macrophages has anti-inflammatory effects. In this study, we tested the efficacy with which liposomal delivery could target the PPAR alpha/gamma dual agonist tesaglitazar to macrophages while reducing drug action in common sites of drug toxicity: the liver and kidney, and whether tesaglitazar had anti-inflammatory effects in an in vivo model of obesity-associated dysmetabolism. Methods: Male leptin-deficient (ob/ob) mice were administered tesaglitazar or vehicle for one week in a standard oral formulation or encapsulated in liposomes. Following the end of treatment, circulating metabolic parameters were measured and pro-inflammatory adipose tissue macrophage populations were quantified by flow cytometry. Cellular uptake of liposomes in tissues was assessed using immunofluorescence and a broad panel of cell subset markers by flow cytometry. Finally, PPAR alpha/gamma gene target expression levels in the liver, kidney, and sorted macrophages were quantified to determine levels of drug targeting to and drug action in these tissues and cells. Results: Administration of a standard oral formulation of tesaglitazar effectively treated symptoms of obesity-associated dysmetabolism and reduced the number of pro-inflammatory adipose tissue macrophages. Macrophages are the major cell type that took up liposomes with many other immune and stromal cell types taking up liposomes to a lesser extent. Liposome delivery of tesaglitazar did not have effects on inflammatory macrophages nor did it improve metabolic parameters to the extent of a standard oral formulation. Liposomal delivery did, however, attenuate effects on liver weight and liver and kidney expression of PPAR alpha and -gamma gene targets compared to oral delivery. Conclusions: These findings reveal for the first time that tesaglitazar has anti-inflammatory effects on adipose tissue macrophage populations in vivo. These data also suggest that while nanoparticle delivery reduced off-target effects, yet the lack of tesaglitazar actions in non-targeted cells such (as hepatocytes and adipocytes) and the uptake of drug-loaded liposomes in many other cell types, albeit to a lesser extent, may have impacted overall therapeutic efficacy. This fulsome analysis of cellular uptake of tesaglitazar-loaded liposomes provides important lessons for future studies of liposome drug delivery.
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| 642. |
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| 643. |
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| 644. |
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| 645. |
- Pemberton, J. S., et al.
(författare)
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CGM accuracy: Contrasting CE marking with the governmental controls of the USA (FDA) and Australia (TGA): A narrative review
- 2023
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 25:4, s. 916-939
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Tidskriftsartikel (refereegranskat)abstract
- The National Institute for Clinical Excellence updated guidance for continuous glucose monitoring (CGM) in 2022, recommending that CGM be available to all people living with type 1 diabetes. Manufacturers can trade in the UK with Conformite Europeenne (CE) marking without an initial national assessment. The regulatory process for CGM CE marking, in contrast to the Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) process, is described. Manufacturers operating in the UK provided clinical accuracy studies submitted for CE marking. Critical appraisal of the studies shows several CGM devices have CE marking for wide-ranging indications beyond available data, unlike FDA and TGA approval. The FDA and TGA use tighter controls, requiring comprehensive product-specific clinical data evaluation. In 2018, the FDA published the integrated CGM (iCGM) criteria permitting interoperability. Applying the iCGM criteria to clinical data provided by manufacturers trading in the UK identified several study protocols that minimized glucose variability, thereby improving CGM accuracy on all metrics. These results do not translate into real-life performance. Furthermore, for many CGM devices available in the UK, accuracy reported in the hypoglycaemic range is below iCGM standards, or measurement is absent. We offer a framework to evaluate CGM accuracy studies critically. The review concludes that FDA- and TGA-approved indications match the available clinical data, whereas CE marking indications can have discrepancies. The UK can bolster regulation with UK Conformity Assessed marking from January 2025. However, balanced regulation is needed to ensure innovation and timely technological access are not hindered.
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| 646. |
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| 647. |
- Perkins, Gavin D., et al.
(författare)
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Brain injury after cardiac arrest
- 2021
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Ingår i: The Lancet. - 0140-6736. ; 398:10307, s. 1269-1278
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Forskningsöversikt (refereegranskat)abstract
- As more people are surviving cardiac arrest, focus needs to shift towards improving neurological outcomes and quality of life in survivors. Brain injury after resuscitation, a common sequela following cardiac arrest, ranges in severity from mild impairment to devastating brain injury and brainstem death. Effective strategies to minimise brain injury after resuscitation include early intervention with cardiopulmonary resuscitation and defibrillation, restoration of normal physiology, and targeted temperature management. It is important to identify people who might have a poor outcome, to enable informed choices about continuation or withdrawal of life-sustaining treatments. Multimodal prediction guidelines seek to avoid premature withdrawal in those who might survive with a good neurological outcome, or prolonging treatment that might result in survival with severe disability. Approximately one in three admitted to intensive care will survive, many of whom will need intensive, tailored rehabilitation after discharge to have the best outcomes.
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| 648. |
- Petrov, Dmitry, et al.
(författare)
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Machine Learning for Large-Scale Quality Control of 3D Shape Models in Neuroimaging
- 2017
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Ingår i: Machine learning in medical imaging. MLMI (Workshop). - Cham : Springer International Publishing. ; 10541, s. 371-378
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Tidskriftsartikel (refereegranskat)abstract
- As very large studies of complex neuroimaging phenotypes become more common, human quality assessment of MRI-derived data remains one of the last major bottlenecks. Few attempts have so far been made to address this issue with machine learning. In this work, we optimize predictive models of quality for meshes representing deep brain structure shapes. We use standard vertex-wise and global shape features computed homologously across 19 cohorts and over 7500 human-rated subjects, training kernelized Support Vector Machine and Gradient Boosted Decision Trees classifiers to detect meshes of failing quality. Our models generalize across datasets and diseases, reducing human workload by 30-70%, or equivalently hundreds of human rater hours for datasets of comparable size, with recall rates approaching inter-rater reliability.
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| 649. |
- Pihl, E, et al.
(författare)
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Patient-reported outcomes after surgical and non-surgical treatment of proximal hamstring avulsions in middle-aged patients
- 2019
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Ingår i: BMJ open sport & exercise medicine. - : BMJ. - 2055-7647. ; 5:1, s. e000511-
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Tidskriftsartikel (refereegranskat)abstract
- In the literature on proximal hamstring avulsions, only two studies report the outcomes of non-surgically treated patients. Our objective was to compare subjective recovery after surgical and non-surgical treatment of proximal hamstring avulsions in a middle-aged cohort.MethodsWe included 47 patients (33 surgically and 14 non-surgically treated) with a mean (SD) age of 51 (±9) years in a retrospective cohort study. Follow-up time mean (SD) of 3.9 (±1.4) years. The outcome variables were the Lower Extremity Functional Scale (LEFS) and questions from the Proximal Hamstring Injury Questionnaire. Outcome variables were adjusted in regression models for gender, age, American Society of Anestesiologits (ASA) classification and MRI findings at diagnosis.ResultsThe baseline characteristics showed no differences except for the MRI result, in which the surgically treated group had a larger proportion of tendons retracted ≥ 2 cm. The mean LEFS score was 74 (SD±12) in the surgically treated cohort and 72 (SD±16) in the non-surgically treated cohort. This was also true after adjusting for confounders. The only difference in outcome at follow-up was the total hours performing physical activity per week, p=0.02; surgically treated patients reported 2.5 hours or more (5.2 vs 2.7).ConclusionThis study on middle-aged patients with proximal hamstring avulsions was unable to identify any difference in patient-reported outcome measures between surgically and non-surgically treated patients. The vast majority of patients treated surgically had complete proximal hamstring avulsions with ≥ 2 cm of retraction. We conclude that to obtain an evidence-based treatment algorithm for proximal hamstring avulsions studies of higher scientific level are needed.
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| 650. |
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