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This paper presents a case study on condition monitoring of power generators at offshore wind turbines. Two fault detection models are proposed for detecting sudden changes in the sensed value of metallic debris at the generator. The first model uses an exponentially weighted moving average, while the second monitors first-order derivatives using a fixed threshold. This is expected to improve the maintenance activities by avoiding late or early part replacement. The economic impact of the proposed approach is also provided with a realistic depiction of the cost structure associated with the corresponding maintenance plan. While the specifics of the case study are supported by real-life data, considering the prevalence of the use of generators not only in offshore wind turbines but also in other production environments, we believe the case study covered in this paper can be used as a blueprint for similar studies in other applications. • Large scale condition monitoring demonstrates economic benefits. • Case study from real wind turbine population with economic impact assessment. • Sensor for monitoring fault mode results in lead time for maintenance planning. • Sensitivity analysis assesses results despite downtime and power price uncertainty. [ABSTRACT FROM AUTHOR]

Background The purpose of the study was to quantify the association between body weight and health by estimating the expected lifetime with and without diabetes (diabetes-free life expectancy) at age 30 and 65. In addition, the diabetes-free life expectancy was stratified by educational level. Methods Life tables by sex, level of education and obese/not obese were constructed using nationwide register data and self-reported data on body weight and height and diabetes from the Danish National Health Survey in 2021. Diabetes-free life expectancies were estimated by Sullivan's method. Results The difference in life expectancy between not obese 30-year-old men with a long and a short education was 5.7 years. For not obese women, the difference was 4.1 years. For obese men and women, the difference in life expectancy at age 30 was 7.0 and 5.2 years. Women could expect more years without and fewer years with diabetes than men regardless of body weight and educational level. Diabetes-free life expectancy differed by 6.9 years between not obese 30-year-old men with a short and a long education and by 7.7 years for obese men with a short and a long education. For women, the differences were 5.9 and 6.6 years. Conclusion The results demonstrate an association of obesity and educational level with life expectancy and diabetes-free life expectancy. There is a need for preventive efforts to reduce educational inequality in life expectancy and diabetes-free life expectancy. Structural intervention will particularly benefit overweight people with short education. [ABSTRACT FROM AUTHOR]

Maintaining nanoparticle properties when scaling up a chemical synthesis is challenging due to the complex interplay between reducing agents and precursors. A sonochemical synthesis route does not require the addition of reducing agents as they are instead being continuously generated in-situ by ultrasonic cavitation throughout the reactor volume. To optimize the sonochemical synthesis of nanoparticles, understanding the role of radical scavengers is paramount. In this work we demonstrate that optimum scavenger concentrations exist at which the rate of Ag-nanoparticle formation is maximized. Titanyl dosimetry experiments were used in conjunction with Ag-nanoparticle formation rates to determine these optimum scavenger concentrations. It was found that more hydrophobic scavengers require lower optimum concentrations with 1-butanol < 2-propanol < ethanol < methanol < ethylene glycol. However, the optimum concentration is shifted by an order of magnitude towards higher concentrations when pyrolytic decomposition products contribute to the reduction. The reduction rate is also enhanced considerably. [ABSTRACT FROM AUTHOR]

Reducing the amount of noble metals in catalysts for electrochemical conversion devices is paramount if these devices are to be commercialized. Taking advantage of the high degree of particle property control displayed by the sonochemical method, we set out to synthesize Cu@Pt bimetallic nanocatalysts in an effort to improve the mass activity towards the hydrogen evolution reaction. At least 17 times higher mass activity was found for the carbon supported Cu@Pt bimetallic nanocatalyst (737 mA mg−1, E = − 20   m V) compared to carbon supported Pt nanocatalysts prepared with the same ultrasound conditions (44 mA mg−1, E = − 20   m V). The synthesis was found to proceed with the sonochemical formation of Cu and Cu2O nanoparticles with the addition of PtCl4 leading to galvanic displacement of the Cu-nanoparticles and the formation of a Pt-shell around the Cu-core. [ABSTRACT FROM AUTHOR]

Large scale production of electrocatalysts for electrochemical energy conversion devices such as proton exchange membrane fuel cells must be developed to reduce their cost. The current chemical reduction methods used for this synthesis suffer from problems with achieving similar particle properties such as particle size and catalytic activity when scaling up the volume or the precursor concentration. The continuous production of reducing agents through the sonochemical synthesis method could help maintain the reducing conditions (and also the particle properties) upon increasing the reactor volume. In this work we demonstrate that the reducing conditions of Pt-nanoparticles are indeed maintained when the reactor volume is increased from 200 mL to 800 mL. Similar particle sizes, 2.1(0.3) nm at 200 mL and 2.3(0.4) nm at 800 mL, and catalytic activities towards the oxygen reduction reaction (ORR) are maintained as well. The reducing conditions were assessed through TiOSO 4 dosimetry, sonochemiluminesence imaging, acoustic power measurements, and Pt(II) reduction rate measurements. Cyclic voltammetry, CO-stripping, hydrogen evolution measurements, ORR measurements, and electron microscopy were used to evaluate the catalytic activity and particle size. The similar particle properties displayed from the two reactor volumes suggest that the sonochemical synthesis of Pt-nanoparticles is suitable for large scale production. [ABSTRACT FROM AUTHOR]

In Chile, the budget for managing environmental liabilities such as abandoned tailings impoundments is limited. Using native and endemic plant species to remove heavy metals from tailings represents a low-cost alternative. Ex situ phytoremediation experiments were conducted over a period of seven months. The endemic species Lycium chilense and native species Haplopappus foliosus were used to remove copper and lead from mine tailings. The results indicate that both species can concentrate levels of Cu and Pb higher than the toxicity threshold in the roots and aerial parts, and present high removal efficiency for Cu higher than 50%. In both species, the concentrations of the target elements are higher in the roots than in the aerial parts. Haplopappus foliosus presents the best performance, accumulating higher concentrations of Cu and Pb than Lycium chilense, and presenting a bioconcentration of over one for Cu. [ABSTRACT FROM AUTHOR]

This study compares four models for industrial condition monitoring including a principal components analysis (PCA) approach and three deep learning models, one of which is a new, lightweight version of another. We also propose a simple attention mechanism for enchancing deep learning models with better predictions and feature importance. Two datasets are used, one simulated from the Tennessee Eastman Process, the other from two feedwater pumps at a Danish combined heat and power plant. Our final results show evidence in favour of the PCA-based approach as it has detection ability comparable to the deep learning approaches as well as faster training time, fewer hyperparameters, as well as robustness to changing operating conditions. We conclude the paper by putting into perspective the importance of building up complexity incrementally with a recommendation to start modelling with simpler and well-tested models before the adoption of more advanced, less transparent models. • A statistical model is compared with deep learning techniques for fault detection. • The principal components model's fault detection is as good as deep learning. • Deep learning method, ARGUELite, shows promise for single regime datasets. • A unique dataset from a power plant feedwater pump was used for model evaluation. [ABSTRACT FROM AUTHOR]

Optimizing the surface area of nanoparticles is key to achieving high catalytic activities for electrochemical energy conversion devices. In this work, the frequency range (200 kHz–500 kHz) for maximum sonochemical radical formation was investigated for the sonochemical synthesis of Pt-nanoparticles to assess whether an optimum frequency exists or if the entire range provides reproducible particle properties. Through physical and electrochemical characterization, it was found that the frequency dependent mechanical effects of ultrasound resulted in smaller, more open agglomerates at lower frequencies with agglomerate sizes of (238 ± 4) nm at 210 kHz compared to (274 ± 2) nm at 326 kHz, and electrochemical surface areas of (12.4 ± 0.9) m2g−1 at 210 kHz compared to (3.4 ± 0.5) m2g−1 at 326 kHz. However, the primary particle size (2.1 nm) and the catalytic activity towards hydrogen evolution, (19 ± 2) mV at 10mA cm2,remained unchanged over the entire frequency range. Highly reproducible Pt-nanoparticles are therefore easily attainable within a broad range of ultrasonic frequencies for the sonochemical synthesis route. [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary rehabilitation (PR) is a key standard treatment for people with chronic obstructive pulmonary disease (COPD) with documented effect on symptom relief, improved physical function, and quality of life. However, referral, uptake and adherence rates remain low. Pulmonary telerehabilitation (PTR) is a safe and effective alternative to conventional PR. This study explores associations, thoughts and attitudes towards PTR in patients with COPD who decline referral to outpatient hospital-based routine PR. Methods: A mixed-methods study with integration of survey data (n=84) and semi-structured interviews (n=9). Results: We found a significant association between belief of effect of PTR and willingness to participate. Increasing age was significantly associated with reduced odds of daily use of central processing unit (CPU) or tablet. One-third of the participants were undecided about potential participation in PTR. Qualitative findings highlight that participants perceived participating in PTR as more convenient and had preferences for individualized, supervised, and monitored rehabilitation. Conclusion: Those willing to participate in a PTR program believed in the benefits, were comfortable with technological devices, had preferences for exercising at home, and saw opportunities in the social setting. Future PTR programs should include monitoring, preferably managed by a familiar health care professional (HCP). [ABSTRACT FROM AUTHOR]

Background: Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Methods: GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing. Results: Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence. Conclusions: Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Methods: GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing. Results: Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence. Conclusions: Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH. [ABSTRACT FROM AUTHOR]

Background: The lack of classification by educational attainment in death and population exposure data at older ages is an important constraint for studying changes and patterns of mortality disparities by education in Denmark and Sweden. The missing educational distribution of population also restricts analyses aiming at estimating contributions of compositional change to the improvements in national longevity. This study proposes a transparent approach to solve the two methodological issues allowing to obtain robust education-specific mortality estimates and population weights. Methods: Using nonparametric approach, we redistribute the unknown cases and extrapolate the mortality curves of these sub-populations with the help of population-level data on an aggregate level from the Human Mortality Database. Results: We present reconstructed and harmonized education-specific abridged and complete life tables for Sweden and Denmark covering 5-year-long periods from 1991–1995 to 2011–2015. The newly estimated life tables are in good agreement with the national life tables and show plausible age- and education-specific patterns. The observed changes in life expectancy by education suggest about the widening longevity gap between the highest and lowest educated for males and females in both countries. Conclusions: The proposed simple and transparent method can be applied in similar country-specific cases showing large proportions of missing education or other socio-economic characteristics at older ages. [ABSTRACT FROM AUTHOR]

The organic matter content of marine sediments is often used to infer past changes in ocean conditions. However, the organic carbon pool preserved in coastal sediments is a complex mixture derived from different sources and may not reflect in situ processes. In this study, we combine taxonomic identification of reworked palynomorphs with pyrolysis organic geochemistry and reflected‐light organic petrographic microscopy to investigate the provenance, composition and preservation of organic matter in a marine sediment core retrieved from the NE Greenland shelf. Our study reveals continuous yet variable input of land‐derived organic carbon to the marine environment throughout the late Younger Dryas–Holocene, with the highest input of inert carbon in the late Younger Dryas. Although the sediments contain some recent marine palynomorphs, there is no other evidence of fresh marine organic carbon. In contrast, our results indicate that these shelf sediments represent a significant sink of recycled organic carbon. The results of pyrolysis geochemistry revealed that ~90% of the total organic carbon in the sediments is inert. The organic petrography analyses revealed that >70–84% of the organic carbon in the sediment core is terrigenous. Reworked dinoflagellate cysts showed a continuous provenance of Cretaceous land‐derived material, most likely from the nearby Clavering Island. Our study points to the importance of constraining the organic matter origin, composition and preservation in marine sediments to achieve more accurate palaeoenvironmental reconstructions based on organic proxies. [ABSTRACT FROM AUTHOR]

Introduction There is a substantial risk of developing stenosis and dysfunction in the arteriovenous fistula (AVF) in patients on hemodialysis (HD). Far infrared radiation (FIR) is a non-invasive local intervention with a potentially beneficial effect on AVF patency. The underlying mechanism is not clear. It was hypothesized that a single FIR treatment reduces factors of inflammation and promotes endothelial vasodilators in the AVF. Methods Forty HD patients with an AVF were included in an open-label intervention study. Patients were randomized to receive either FIR (FIR group) or no FIR (control group). Blood samples were drawn directly from the AVF and from a peripheral vein in the non-AVF arm before (T0) and 40 min after (T40) treatment during a HD session. The changes [median (interquartile range)] in circulating factors of inflammation, endothelial function and vasoreactivity during FIR were measured. Results In the AVF a single FIR treatment during dialysis resulted in a significantly diminished decrease in soluble vascular cell adhesion molecule, sVCAM [−31.6 (−54.3; 22.1) vs −89.9 (−121.6; −29.3), P  = .005] and soluble intercellular adhesion molecule, sICAM [−24.2 (−43.5; 25.3) vs −49 (−79.9; −11.6), P  = .02] compared with the control group. Other factors, such as interleukins, nitrite, nitrate and tumor necrosis factor 1, also declined during dialysis, but with no significant differences related to FIR in either the AVF or the non-AVF arm. Conclusion A single FIR treatment attenuated the decrease in sVCAM and sICAM in the AVF compared with a control group during HD. Findings do not support the hypothesis of a vaso-protective effect of FIR. The long-term effects of FIR on the AVF are unknown. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged as promising drug candidates for the treatment of nonalcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the long-acting FGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start of the study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion, PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogs for the treatment of NASH. NEW & NOTEWORTHY It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled the clinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model of NASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers and histological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued exploration of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Aim The aim of this study is to develop a reliable composite score based on simulator metrics to assess competency in virtual reality video-assisted thoracoscopic surgery lobectomy and explore the benefits of combining it with expert rater assessments. METHODS Standardized objective assessments (time, bleeding, economy of movement) and subjective expert rater assessments from 2 previous studies were combined. A linear mixed model including experience level, lobe and the number of previous simulated procedures was applied for the repeated measurements. Reliability for each of the 4 assessments was calculated using Cronbach's alpha. The Nelder–Mead numerical optimization algorithm was used for optimal weighting of scores. A pass–fail standard for the composite score was determined using the contrasting groups' method. RESULTS In total, 123 virtual reality video-assisted thoracoscopic surgery lobectomies were included. Across the 4 different assessments, there were significant effects (P  < 0.01) of experience, lobe, and simulator experience, but not for simulator attempts on bleeding (P  = 0.98). The left upper lobe was significantly more difficult compared to other lobes (P = 0.02). A maximum reliability of 0.92 could be achieved by combining the standardized simulator metrics with standardized expert rater scores. The pass/fail level for the composite score when including 1 expert rater was 0.33. CONCLUSIONS Combining simulator metrics with 1 or 2 raters increases reliability and can serve as a more objective method for assessing surgical trainees. The composite score may be used to implement a standardized and feasible simulation-based mastery training program in video-assisted thoracoscopic surgery lobectomy. [ABSTRACT FROM AUTHOR]

Non-invasive biomarkers of non-alcoholic fatty liver disease (NAFLD) supporting diagnosis and monitoring disease progression are urgently needed. The present study aimed to establish a bioinformatics pipeline capable of defining and validating NAFLD biomarker candidates based on paired hepatic global gene expression and plasma bioanalysis from individuals representing different stages of histologically confirmed NAFLD (no/mild, moderate, more advanced NAFLD). Liver secretome gene signatures were generated in a patient cohort of 26 severely obese individuals with the majority having no or mild fibrosis. To this end, global gene expression changes were compared between individuals with no/mild NAFLD and moderate/advanced NAFLD with subsequent filtering for candidate gene products with liver-selective expression and secretion. Four candidate genes, including LPA (lipoprotein A), IGFBP-1 (insulin-like growth factor-binding protein 1), SERPINF2 (serpin family F member 2) and MAT1A (methionine adenosyltransferase 1A), were differentially expressed in moderate/advanced NAFLD, which was confirmed in three independent RNA sequencing datasets from large, publicly available NAFLD studies. The corresponding gene products were quantified in plasma samples but could not discriminate among different grades of NAFLD based on NAFLD activity score. Conclusion: We demonstrate a novel approach based on the liver transcriptome allowing for identification of secreted hepatic gene products as potential circulating diagnostic biomarkers of NAFLD. Using this approach in larger NAFLD patient cohorts may yield potential circulating biomarkers for NAFLD severity. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) in insulin and insulin receptor genes may influence the interaction between the two molecules, as may anti-insulin antibodies (IAs), commonly found in patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) treated with exogenous insulin. We examined the impact of two SNPs in the human insulin gene (INS), rs3842752 and rs689, and two in the insulin receptor gene (INSR) rs2245649 and rs2229429, on disease susceptibility, glycaemic control, and IAs formation in 100 T1D patients and 101 T2D patients treated with insulin. 79 individuals without diabetes were typed as healthy controls. The minor alleles of rs3842752 and rs689 in INS protected against T1D (OR: 0.50, p = 0.01 and OR: 0.44; p = 0.002, respectively). The minor alleles of both rs2245649 and rs2229429 in INSR were risk factors for poor glycaemic control (HbA1c ≥ 80 mmol/mol) in T1D (OR: 5.35, p = 0.009 and OR: 3.10, p = 0.01, respectively). Surprisingly, the minor alleles of rs2245649 and rs2229429 in INSR associated strongly with the absence of IAs in T1D (OR = 0.28, p = 0.008 and OR = 0.30, p = 0.002, respectively). In conclusion, the minor alleles of the investigated INS SNPs protect against T1D, and the minor alleles of the investigated INSR SNPs are associated with poor glycaemic control and the absence of IAs in T1D. [ABSTRACT FROM AUTHOR]

Non‐alcoholic steatohepatitis (NASH) has emerged as a major challenge for public health because of high global prevalence and lack of evidence‐based therapies. Most animal models of NASH lack sufficient validation regarding disease progression and pharmacological treatment. The Gubra‐Amylin NASH (GAN) diet‐induced obese (DIO) mouse demonstrate clinical translatability with respect to disease etiology and hallmarks of NASH. This study aimed to evaluate disease progression and responsiveness to clinically effective interventions in GAN DIO‐NASH mice. Disease phenotyping was performed in male C57BL/6J mice fed the GAN diet high in fat, fructose, and cholesterol for 28–88 weeks. GAN DIO‐NASH mice with biopsy‐confirmed NASH and fibrosis received low‐caloric dietary intervention, semaglutide (30 nmol/kg/day, s.c.) or lanifibranor (30 mg/kg/day, p.o.) for 8 and 12 weeks, respectively. Within‐subject change in nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) and fibrosis stage was evaluated using automated deep learning‐based image analysis. GAN DIO‐NASH mice showed clear and reproducible progression in NASH, fibrosis stage, and tumor burden with high incidence of hepatocellular carcinoma. Consistent with clinical trial outcomes, semaglutide and lanifibranor improved NAS, whereas only lanifibranor induced regression in the fibrosis stage. Dietary intervention also demonstrated substantial benefits on metabolic outcomes and liver histology. Differential therapeutic efficacy of semaglutide, lanifibranor, and dietary intervention was supported by quantitative histology, RNA sequencing, and blood/liver biochemistry. In conclusion, the GAN DIO‐NASH mouse model recapitulates various histological stages of NASH and faithfully reproduces histological efficacy profiles of compounds in advanced clinical development for NASH. Collectively, these features highlight the utility of GAN DIO‐NASH mice in preclinical drug development. [ABSTRACT FROM AUTHOR]

Prolactin-releasing peptide (PrRP) is an endogenous neuropeptide involved in appetite regulation and energy homeostasis. PrRP binds with high affinity to G-protein coupled receptor 10 (GPR10) and with lesser activity towards the neuropeptide FF receptor type 2 (NPFF2R). The present study aimed to develop long-acting PrRP31 analogues with potent anti-obesity efficacy. A comprehensive series of C18 lipidated PrRP31 analogues was characterized in vitro and analogues with various GPR10 and NPFF2R activity profiles were profiled for bioavailability and metabolic effects following subcutaneous administration in diet-induced obese (DIO) mice. PrRP31 analogues acylated with a C18 lipid chain carrying a terminal acid (C18 diacid) were potent GPR10-selective agonists and weight-neutral in DIO mice. In contrast, acylation with aliphatic C18 lipid chain (C18) resulted in dual GPR10-NPFF2R co-agonists that suppressed food intake and promoted a robust weight loss in DIO mice, which was sustained for at least one week after last dosing. Rapid in vivo degradation of C18 PrRP31 analogues gave rise to circulating lipidated PrRP metabolites maintaining dual GPR10-NPFF2R agonist profile and long-acting anti-obesity efficacy in DIO mice. Combined GPR10 and NPFF2R activation may therefore be a critical mechanism for obtaining robust anti-obesity efficacy of PrRP31 analogues. [ABSTRACT FROM AUTHOR]

Hypertension is a critical comorbidity for progression of diabetic kidney disease (DKD). To facilitate the development of novel therapeutic interventions with the potential to control disease progression, there is a need to establish translational animal models that predict treatment effects in human DKD. The present study aimed to characterize renal disease and outcomes of standard of medical care in a model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) db/db mice. Five weeks after single AAV administration and 4 wk after UNx, female db/db UNx-ReninAAV mice received (PO, QD) vehicle, lisinopril (40 mg/kg), empagliflozin (20 mg/kg), or combination treatment for 12 wk (n = 17 mice/group). Untreated db/þ mice (n = 8) and vehicle-dosed db/db UNx-LacZAAV mice (n = 17) served as controls. End points included plasma, urine, and histomorphometric markers of kidney disease. Total glomerular numbers and individual glomerular volume were evaluated by whole kidney three-dimensional imaging analysis. db/db UNx-ReninAAV mice developed hallmarks of progressive DKD characterized by severe albuminuria, advanced glomerulosclerosis, and glomerular hypertrophy. Lisinopril significantly improved albuminuria, glomerulosclerosis, tubulointerstitial injury, and inflammation. Although empagliflozin alone had no therapeutic effect on renal endpoints, lisinopril and empagliflozin exerted synergistic effects on renal histological outcomes. In conclusion, the db/db UNx-ReninAAV mouse demonstrates good clinical translatability with respect to physiological and histological hallmarks of progressive DKD. The efficacy of standard of care to control hypertension and hyperglycemia provides a proof of concept for testing novel drug therapies in the model. [ABSTRACT FROM AUTHOR]