Pub Date : 2023-11-14DOI: 10.22541/au.169993686.63760519/v1
Yuanxiao Chi, Zhijun Wang, Liping Liang, Xin Qiu
Global placement roughly decides the location of units in the very large-scale integrated (VLSI) and fundamentally determines the quality of physical design. Thus, it’s desirable to find an efficient method to solve the global placement problem. Global placement solves the problem by minimizing the total half-perimeter wirelength (HPWL) under density constraints. However, the non-differentiability of HPWL prevents advanced gradient-based methods from being applied to global placement. Therefore, smooth wirelength models have been proposed to approximate HPWL. Among all the models, weighted-average wirelength (WAWL) performs the best. In this letter, we propose an improved self-adaptive weighted-average wirelength (SaWAWL) model to further fit the HPWL. Instead of setting a generic γ for all nets in the design, the new model enables each net to adaptively adjust their respective γ according to their real length, thus can better approximate HPWL to achieve higher-quality placement results. Based on the SaWAWL and the framework of DREAMPlace, a global placer is implemented. Experimental results show that HPWL on open-source benchmarks is reduced by up to 6.56% with an average of 3.74%, which proves that our model can achieve better performance than the current state-of-the-art WAWL.
{"title":"A Self-Adaptive weighted-average wire-length model for VLSI global placement","authors":"Yuanxiao Chi, Zhijun Wang, Liping Liang, Xin Qiu","doi":"10.22541/au.169993686.63760519/v1","DOIUrl":"https://doi.org/10.22541/au.169993686.63760519/v1","url":null,"abstract":"Global placement roughly decides the location of units in the very large-scale integrated (VLSI) and fundamentally determines the quality of physical design. Thus, it’s desirable to find an efficient method to solve the global placement problem. Global placement solves the problem by minimizing the total half-perimeter wirelength (HPWL) under density constraints. However, the non-differentiability of HPWL prevents advanced gradient-based methods from being applied to global placement. Therefore, smooth wirelength models have been proposed to approximate HPWL. Among all the models, weighted-average wirelength (WAWL) performs the best. In this letter, we propose an improved self-adaptive weighted-average wirelength (SaWAWL) model to further fit the HPWL. Instead of setting a generic γ for all nets in the design, the new model enables each net to adaptively adjust their respective γ according to their real length, thus can better approximate HPWL to achieve higher-quality placement results. Based on the SaWAWL and the framework of DREAMPlace, a global placer is implemented. Experimental results show that HPWL on open-source benchmarks is reduced by up to 6.56% with an average of 3.74%, which proves that our model can achieve better performance than the current state-of-the-art WAWL.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"21 19","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Due to their stationery nature, plants are exposed to a diverse range of biotic and abiotic stresses, of which heavy metals stress poses as one of the most detrimental abiotic stresses, targeting crucial and vital processes. Heavy metals instigate the over-production of reactive oxygen species (ROS), and in order to mitigate the adverse effects of ROS, plants induce multiple defence mechanisms. Besides the negative implications of overproduction of ROS, these molecules play a multitude of signaling roles in plants, acting as a central player in the complex signaling network of cells. One of the signaling mechanisms it is involved in is the mitogen-activated protein kinase (MAPK) cascade, a signaling pathway used to transduce extracellular stimuli into intracellular responses. Plant MAPKs have been implicated in signaling of stresses, phytohormones and cell cycle cues. However, the influence of various heavy metals on MAPKs activation has not been well documented. In this review, we will attempt to address and summarize several aspects related to various heavy metal-induced ROS signaling, how these signals activate the MAPK cascade and the downstream transcription factors that instigates the plants response to these heavy metals. Moreover, we will highlight a modern research methodology that could characterize the novel genes associated with MAPKs and their roles in heavy metal stress.
{"title":"Heavy Metal Stress and Mitogen Activated Kinase Transcription Factors in Plants: Exploring Heavy Metal-ROS Influences on Plant Signaling Pathways","authors":"Lee-Ann Niekerk, Arun Gokul, Gerhard Basson, Mihlali Badiwe, Mbukeni Nkomo, Ashwil Klein, Marshall Keyster","doi":"10.22541/au.169998555.59756936/v1","DOIUrl":"https://doi.org/10.22541/au.169998555.59756936/v1","url":null,"abstract":"Due to their stationery nature, plants are exposed to a diverse range of biotic and abiotic stresses, of which heavy metals stress poses as one of the most detrimental abiotic stresses, targeting crucial and vital processes. Heavy metals instigate the over-production of reactive oxygen species (ROS), and in order to mitigate the adverse effects of ROS, plants induce multiple defence mechanisms. Besides the negative implications of overproduction of ROS, these molecules play a multitude of signaling roles in plants, acting as a central player in the complex signaling network of cells. One of the signaling mechanisms it is involved in is the mitogen-activated protein kinase (MAPK) cascade, a signaling pathway used to transduce extracellular stimuli into intracellular responses. Plant MAPKs have been implicated in signaling of stresses, phytohormones and cell cycle cues. However, the influence of various heavy metals on MAPKs activation has not been well documented. In this review, we will attempt to address and summarize several aspects related to various heavy metal-induced ROS signaling, how these signals activate the MAPK cascade and the downstream transcription factors that instigates the plants response to these heavy metals. Moreover, we will highlight a modern research methodology that could characterize the novel genes associated with MAPKs and their roles in heavy metal stress.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"62 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-14DOI: 10.22541/au.169996530.07036487/v1
Guillermo Rodriguez-Nava, Vanessa El Kamari, Goar Egoryan, Hector Bonilla
{"title":"New-onset Sarcoidosis in a Patient with Long COVID","authors":"Guillermo Rodriguez-Nava, Vanessa El Kamari, Goar Egoryan, Hector Bonilla","doi":"10.22541/au.169996530.07036487/v1","DOIUrl":"https://doi.org/10.22541/au.169996530.07036487/v1","url":null,"abstract":"","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"51 17","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134901706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-14DOI: 10.22541/essoar.170000400.07669392/v1
J. Antonio Guzmán Q., Hendrik F. Hamann, G. Arturo Sanchez-Azofeifa
Clouds are critical to the biodiversity and function of Tropical Montane Cloud Forests (TMCF). These ecosystems provide vital services to humanity and are considered hotspots of endemism, given that the number of species is restricted to their microclimates. Cloudiness (e.g., the fraction of low-clouds) in these ecosystems is projected to decline owing to global warming, but recent temporal trends remain unclear. Here, we evaluated trends in low-cloud fractions (CF) and other Essential Climatic Variables (ECV) (e.g., surface temperature, pressure, soil moisture, and precipitation) for 521 sites worldwide with TMFCs from 1997 to 2020. Thus, we hypothesize that recent traces of global warming over the last few decades have led to decreases in low-cloud cover on TMCFs. The previous study was also evaluated globally and among biogeographic realms to identify regional trends. We computed trends by aggregating hourly observations from ERA5 reanalysis and CHIRPS into annual averages and then used linear regressions to calculate slopes (i.e., rate of change) (Δ, year). Our results suggest that CF trends at the TMCFs range between -64.7 ×10 and 51.4 ×10 CF year, revealing that 70% of the assessed sites have experienced reductions in CF. Declines in low-clouds in these ecosystems are 253% more severe than tropical landmasses when peak values of density distribution are compared (TMCFs: -7.8 ×10CF year; tropical landmasses -2.3 ×10 CF year). Despite this, CF trends tend to differ among biogeographic realms, as those TMCFs from the Neotropics and Indomalayan realms have the most pronounced declines. Decreases in CF were also associated with increases in surface temperature and pressure and decreases in soil moisture, revealing that the TMCF’s climate is changing to warmer environments. These climatic shifts may represent a fingerprint of global change on TMCFs, highlighting a current threat to species and essential ecosystem services that these ecosystems provide.
{"title":"Multi-decadal trends of low clouds at the Tropical Montane Cloud Forests ","authors":"J. Antonio Guzmán Q., Hendrik F. Hamann, G. Arturo Sanchez-Azofeifa","doi":"10.22541/essoar.170000400.07669392/v1","DOIUrl":"https://doi.org/10.22541/essoar.170000400.07669392/v1","url":null,"abstract":"Clouds are critical to the biodiversity and function of Tropical Montane Cloud Forests (TMCF). These ecosystems provide vital services to humanity and are considered hotspots of endemism, given that the number of species is restricted to their microclimates. Cloudiness (e.g., the fraction of low-clouds) in these ecosystems is projected to decline owing to global warming, but recent temporal trends remain unclear. Here, we evaluated trends in low-cloud fractions (CF) and other Essential Climatic Variables (ECV) (e.g., surface temperature, pressure, soil moisture, and precipitation) for 521 sites worldwide with TMFCs from 1997 to 2020. Thus, we hypothesize that recent traces of global warming over the last few decades have led to decreases in low-cloud cover on TMCFs. The previous study was also evaluated globally and among biogeographic realms to identify regional trends. We computed trends by aggregating hourly observations from ERA5 reanalysis and CHIRPS into annual averages and then used linear regressions to calculate slopes (i.e., rate of change) (Δ, year). Our results suggest that CF trends at the TMCFs range between -64.7 ×10 and 51.4 ×10 CF year, revealing that 70% of the assessed sites have experienced reductions in CF. Declines in low-clouds in these ecosystems are 253% more severe than tropical landmasses when peak values of density distribution are compared (TMCFs: -7.8 ×10CF year; tropical landmasses -2.3 ×10 CF year). Despite this, CF trends tend to differ among biogeographic realms, as those TMCFs from the Neotropics and Indomalayan realms have the most pronounced declines. Decreases in CF were also associated with increases in surface temperature and pressure and decreases in soil moisture, revealing that the TMCF’s climate is changing to warmer environments. These climatic shifts may represent a fingerprint of global change on TMCFs, highlighting a current threat to species and essential ecosystem services that these ecosystems provide.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"20 11","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134953760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-14DOI: 10.22541/essoar.170000348.85507974/v1
Min-Ken Hsieh, Chien-Ming Wu
This study develops an explainable variational autoencoder (VAE) framework to efficiently generate high-fidelity local circulation patterns in Taiwan, ensuring an accurate representation of the physical relationship between generated local circulation and upstream synoptic flow regimes. Large ensemble semi-realistic simulations were conducted using a high-resolution (2 km) model, TaiwanVVM, where critical characteristics of various synoptic flow regimes were carefully selected to focus on the effects of local circulation variations. The VAE was constructed to capture essential representations of local circulation scenarios associated with the lee vortices by training on the ensemble dataset. The VAE’s latent space effectively captures the synoptic flow regimes as controlling factors, aligning with the physical understanding of Taiwan’s local circulation dynamics. The critical transition of flow regimes under the influence of southeasterly synoptic flow regimes is also well represented in the VAE’s latent space.This indicates that the VAE can learn the nonlinear characteristics of the multiscale interactions involving the lee vortex. The latent space within VAE can serve as a reduced-order model for predicting local circulation using synoptic wind speed and direction. This explainable VAE ensures the accurate predictions of the nonlinear characteristics of multiscale interactions between synoptic flows and the local circulation induced by topography, thereby accelerating the assessments under various climate change scenarios.
{"title":"Developing an Explainable Variational Autoencoder (VAE) Framework for Accurate Representation of Local Circulation in Taiwan","authors":"Min-Ken Hsieh, Chien-Ming Wu","doi":"10.22541/essoar.170000348.85507974/v1","DOIUrl":"https://doi.org/10.22541/essoar.170000348.85507974/v1","url":null,"abstract":"This study develops an explainable variational autoencoder (VAE) framework to efficiently generate high-fidelity local circulation patterns in Taiwan, ensuring an accurate representation of the physical relationship between generated local circulation and upstream synoptic flow regimes. Large ensemble semi-realistic simulations were conducted using a high-resolution (2 km) model, TaiwanVVM, where critical characteristics of various synoptic flow regimes were carefully selected to focus on the effects of local circulation variations. The VAE was constructed to capture essential representations of local circulation scenarios associated with the lee vortices by training on the ensemble dataset. The VAE’s latent space effectively captures the synoptic flow regimes as controlling factors, aligning with the physical understanding of Taiwan’s local circulation dynamics. The critical transition of flow regimes under the influence of southeasterly synoptic flow regimes is also well represented in the VAE’s latent space.This indicates that the VAE can learn the nonlinear characteristics of the multiscale interactions involving the lee vortex. The latent space within VAE can serve as a reduced-order model for predicting local circulation using synoptic wind speed and direction. This explainable VAE ensures the accurate predictions of the nonlinear characteristics of multiscale interactions between synoptic flows and the local circulation induced by topography, thereby accelerating the assessments under various climate change scenarios.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"25 9","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134954204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Powder compression is essential in the storage and transportation processes. The compression characteristics of pulverized coal, rice husk and lignocellulose were compared under mechanical and gas pressurization respectively. The experimental results showed that the descending order of relative packing density was lignocellulose > rice husk > pulverized coal under mechanical pressurization, while an opposite trend was observed under gas pressurization. The effect of cohesion properties on compression results, such as inter-particle adhesion force and powder bed cohesion, was also investigated. For mechanical pressurization, the powder bed of cohesive biomass had higher void fraction, which was directly linked to larger relative packing density. On the contrary, gas permeated easily into the biomass powder bed, and the lower pressure drop decreased the compression capacity of gas pressurization. In addition, a model for predicting the relative packing density was proposed with an error of ± 5%.
{"title":"Comparative study on the compression characteristics under mechanical and gas pressurization","authors":"Shicheng Wang, Xiaolei Guo, Hui Zhang, Yunfei Yang, Haifeng Lu, Haifeng Liu","doi":"10.22541/au.169998699.97868680/v1","DOIUrl":"https://doi.org/10.22541/au.169998699.97868680/v1","url":null,"abstract":"Powder compression is essential in the storage and transportation processes. The compression characteristics of pulverized coal, rice husk and lignocellulose were compared under mechanical and gas pressurization respectively. The experimental results showed that the descending order of relative packing density was lignocellulose > rice husk > pulverized coal under mechanical pressurization, while an opposite trend was observed under gas pressurization. The effect of cohesion properties on compression results, such as inter-particle adhesion force and powder bed cohesion, was also investigated. For mechanical pressurization, the powder bed of cohesive biomass had higher void fraction, which was directly linked to larger relative packing density. On the contrary, gas permeated easily into the biomass powder bed, and the lower pressure drop decreased the compression capacity of gas pressurization. In addition, a model for predicting the relative packing density was proposed with an error of ± 5%.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"100 11","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134957623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-14DOI: 10.22541/essoar.170000026.63675767/v1
Peter J Haeussler, Adrian M Bender, Peter M Powers, Rich D Koehler, Daniel S Brothers
{"title":"Updating the Crustal Fault Model for the 2023 National Seismic Hazard Model for Alaska","authors":"Peter J Haeussler, Adrian M Bender, Peter M Powers, Rich D Koehler, Daniel S Brothers","doi":"10.22541/essoar.170000026.63675767/v1","DOIUrl":"https://doi.org/10.22541/essoar.170000026.63675767/v1","url":null,"abstract":"","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"7 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134954385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract Aim The U.S. Food and Drug Administration (FDA) has granted approval for the use of cyclin-dependent kinase 4 and 6 inhibitors (CDKIs) in the management of advanced and metastatic breast cancer. We evaluated the real-world data associated with safety in younger and older adults base on Adverse Event Reporting System (FAERS) database of the FDA. Methods We conducted disproportionality analysis to detect and compare CDKI-related adverse events (AEs) among the younger and older adults. Results The data used were from 3,851, 64,731, and 8,420 case reports on abemaciclib, palbociclib, and ribociclib, respectively Disproportionality analysis revealed 170, 397, and 626 AEs of abemaciclib, palbociclib, and ribociclib, respectively, in younger adults, and 113, 475, and 557 in older adults. The numbers of system organ classes for abemaciclib, palbociclib, and ribociclib were 27 each among younger adults, and 25, 27, and 27 among older adults. We found several expected AE signals same with drug instructions, such as diarrhea, neutropenia, and thromboembolic events. Furthermore, unexpected AE signals, such as campylobacter sepsis, enterococcal endocarditis, and atrioventricular block were identified. Conclusion Our results align with clinical observations, emphasizing possible AEs associated with CDKIs. It is essential to conduct future clinical research to confirm differences in CDKIs among younger and older individuals.
{"title":"Analysis of cyclin-dependent kinase 4 and 6 inhibitor adverse events in both younger and older adults using the FDA Adverse Event Reporting System database","authors":"Qiongtong Fang, Qiongyan Fang, Fuqiang Huang, Xinrong Wu, Huibin Zhao, Jiabi Liang, Yishen Chen, Cheng Li, Meirong Zhang, Wen-ji Luo","doi":"10.22541/au.169998501.11420287/v1","DOIUrl":"https://doi.org/10.22541/au.169998501.11420287/v1","url":null,"abstract":"Abstract Aim The U.S. Food and Drug Administration (FDA) has granted approval for the use of cyclin-dependent kinase 4 and 6 inhibitors (CDKIs) in the management of advanced and metastatic breast cancer. We evaluated the real-world data associated with safety in younger and older adults base on Adverse Event Reporting System (FAERS) database of the FDA. Methods We conducted disproportionality analysis to detect and compare CDKI-related adverse events (AEs) among the younger and older adults. Results The data used were from 3,851, 64,731, and 8,420 case reports on abemaciclib, palbociclib, and ribociclib, respectively Disproportionality analysis revealed 170, 397, and 626 AEs of abemaciclib, palbociclib, and ribociclib, respectively, in younger adults, and 113, 475, and 557 in older adults. The numbers of system organ classes for abemaciclib, palbociclib, and ribociclib were 27 each among younger adults, and 25, 27, and 27 among older adults. We found several expected AE signals same with drug instructions, such as diarrhea, neutropenia, and thromboembolic events. Furthermore, unexpected AE signals, such as campylobacter sepsis, enterococcal endocarditis, and atrioventricular block were identified. Conclusion Our results align with clinical observations, emphasizing possible AEs associated with CDKIs. It is essential to conduct future clinical research to confirm differences in CDKIs among younger and older individuals.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"8 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-14DOI: 10.22541/au.169994075.59042911/v1
Philip Ambery, Grzegorz Zajac, Joachim Almquist, Susanne Prothon, Carol Astbury, Mary Brown, Szilard Nemes, Joselyne Nsabimana, Karl Edman, Lisa Oberg, Matti Lepisto, Goran Endro, Suman Mitra, Graham Belfield, Christina Keen, Tim Heise
Aims Corticosteroids are the treatment of choice for many inflammatory diseases, but often lead to adverse effects, including hyperglycemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, a novel oral, non-steroidal, selective glucocorticoid receptor modulator, versus prednisolone in 46 patients with type 2 diabetes mellitus. Methods In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (Cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (Cohort 2); or placebo and prednisolone 5 mg daily (Cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycemic control was assessed after a standardized meal and with continuous glucose monitoring. Results A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions post-meal in Cohort 1 (glucose AUC0-4h -4.54%; 95% CI: -8.88, -0.01; p=0.049), but not in Cohort 2 (-5.77%; 95% CI: -20.92, 12.29; p=0.435). In Cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to Day 4 in insulin and glucagon secretion post-meal (p<0.001 and p=0.005, respectively), and change from baseline to Day 4 in GLP-1 response (p=0.022). Significant differences between AZD9567 and prednisolone for 24-hour glucose control were observed for both Cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; p<0.001), and Cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; p<0.001). Conclusions AZD9567 significantly reduced treatment-induced hyperglycemia compared with prednisolone.
{"title":"The effect of AZD9567 versus prednisolone on glycemic control in patients with Type 2 diabetes mellitus: Results from a Phase 2a clinical trial","authors":"Philip Ambery, Grzegorz Zajac, Joachim Almquist, Susanne Prothon, Carol Astbury, Mary Brown, Szilard Nemes, Joselyne Nsabimana, Karl Edman, Lisa Oberg, Matti Lepisto, Goran Endro, Suman Mitra, Graham Belfield, Christina Keen, Tim Heise","doi":"10.22541/au.169994075.59042911/v1","DOIUrl":"https://doi.org/10.22541/au.169994075.59042911/v1","url":null,"abstract":"Aims Corticosteroids are the treatment of choice for many inflammatory diseases, but often lead to adverse effects, including hyperglycemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, a novel oral, non-steroidal, selective glucocorticoid receptor modulator, versus prednisolone in 46 patients with type 2 diabetes mellitus. Methods In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (Cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (Cohort 2); or placebo and prednisolone 5 mg daily (Cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycemic control was assessed after a standardized meal and with continuous glucose monitoring. Results A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions post-meal in Cohort 1 (glucose AUC0-4h -4.54%; 95% CI: -8.88, -0.01; p=0.049), but not in Cohort 2 (-5.77%; 95% CI: -20.92, 12.29; p=0.435). In Cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to Day 4 in insulin and glucagon secretion post-meal (p<0.001 and p=0.005, respectively), and change from baseline to Day 4 in GLP-1 response (p=0.022). Significant differences between AZD9567 and prednisolone for 24-hour glucose control were observed for both Cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; p<0.001), and Cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; p<0.001). Conclusions AZD9567 significantly reduced treatment-induced hyperglycemia compared with prednisolone.","PeriodicalId":487619,"journal":{"name":"Authorea (Authorea)","volume":"23 21","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134991501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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