bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase-field modeling of austenitic steels used in turbines
Authors: Rodriguez Salvador Valtierra , Greenwood Michael , Li Delin , Lévesque Jean-Benoît , Timoshevskii Vladimir , Paquet Daniel , Provatas Nikolas
Published: May 2023

The performance in hydro-electric turbine casting and repair requires understanding of how process parameters and chemistry selection affect solidification microstructures. The aim of this study is to provide a quantitative phase-field formulation for process-microstructure relationships that seeks to model stainless steels. We have developed a phase-field model to simulate austenitic stainless steel solidification under experimental thermal histories. To this end we look at a pseudo-binary approximations for numerical efficiency. The pseudo-binary formulation is underpinned by the alloying element equivalent value, a metallurgical tool used to analyze the microstructural impact of “minor” alloying elements in stainless steels. For model validation we develop thin wall casting experiments to measure the thermal history and chemistry controlled microstructure. The models incorporate a thermodynamic parameterization and are linked to a thermal-phase transformation model which represents the experimentally measured thermal history. The results display a good agreement with the primary branch spacing and cellular to dendritic transition of the casting experiments. These models and software provide the basis for future expansion to include more complex microstructures.
Multi-scale modeling of equiaxed dendritic solidification of Al-Cu at constant cooling rate
Authors: Boukellal A. K. , Založnik M. , Debierre J.-M.
Published: May 2023

To provide quantitative predictions, multiscale models of dendritic solidification (e.g., GEM, DNN, CAFE) need to be validated and require model parameters, which can be calculated by phase-field simulations. We report on a multiscale modeling of dendritic solidification in samples that are cooled homogeneously at a constant rate. We consider three Al-Cu alloys and samples from thin to bulk thickness. We investigate how the alloy composition, the distance between the equiaxed dendrites and the sample thickness influence the transient growth velocity of the primary tips. Using 3D phase-field simulations, we calculate the tip selection parameter based on the microsolvability theory. We show that the selection parameter depends principally on the ratio between the sample thickness and the smallest tip diffusion length during the transient growth (D/vm
, where vm
is the maximum tip velocity). The extracted tip selection parameters are then used as inputs for three-dimensional grain envelope model (GEM) simulations. The comparison between TIPF and GEM shows that the GEM can reproduce transient growth of interacting equiaxed dendrites during cooling and can account for sample confinement effects.
Investigation of silicon sublattice substitution within (Al,Si)3Zr intermetallics via DFT simulations
Authors: Castillo-Sánchez Juan-Ricardo , Gheribi Aïmen E. , Lafaye Paul , Salloum-Abou-Jaoude Georges , Harvey Jean-Philippe
Published: May 2023

Aluminum alloys commonly contain Si as an impurity or alloying element. The energetic behavior of Si within multiple compounds and solutions is incorporated inside thermochemical packages, such as FactSage. This tool allows determining the Si partitioning within complex multiphasic systems. Recent experimental research suggests that Si can be found within Al3Zr-based intermetallics. Nevertheless, current FactSage databases do not consider the potential substitution of Si within the Al3Zr-D023 solid solution. In this work, Si substitution within the (Al,Si)3Zr-D023 phase was investigated by means of first-principles calculations. Replacement of Al atoms by Si resulted in a negative enthalpy of mixing, indicating that Si substitution is energetically enabled. The density of states (DOS) for both a Si-diluted (Al,Si)3Zr and a non-Si-doped (Al3Zr) simulation cells were analyzed. It is shown that (even in dilution), Si significantly impacts the electronic structure of the Al3Zr-D023 structure. Specifically, the presence of Si localizes electrons in the p orbital of Al, and increases the DOS of the dxy, dxz
, and dyz
sub-orbitals of Zr at low energies. Thus, yielding a coupled effect that stabilizes the D023 intermetallic. These findings are a benchmark for the future integration of a Si-based end-member within the Al3Zr-D023 solid solution of FactSage databases.
High-performance GPU computing of phase-field lattice Boltzmann simulations for dendrite growth with natural convection
Authors: Takaki Tomohiro , Sakane Shinji , Suzuki Ryosuke
Published: May 2023

The effect of natural convection on dendrite morphology is investigated through three-dimensional large-scale phase-field lattice Boltzmann simulations using a block-structured adaptive mesh refinement scheme with the mother-leaf method in a parallel-GPU environment. The simulations confirmed that downward buoyancy enhances the growth of the primary and secondary arms, and upward buoyancy delays the growth of those arms. In addition, the effect of natural convection on the solidification morphologies gradually decreased as the primary arm tip reached the top of the computational domain and finally stopped. Furthermore, in the longer simulation under purely isothermal diffusive conditions, detachment of the secondary arms owing to curvature-driven fragmentation was observed. A large-scale non-isothermal dendrite growth simulation was also conducted, wherein it was observed that the tip growth rate of the primary arm was delayed, and the secondary arm spacing was larger than that in the isothermal condition.
Application of a meshless space-time adaptive approach to phase-field modelling of polycrystalline solidification
Authors: Dobravec T , Mavrič B , Šarler B
Published: May 2023

We have developed a 2-D numerical meshless adaptive approach for phase-field modelling of dendritic solidification. The quadtree-based approach decomposes the computational domain into quadtree sub-domains of different sizes. The algorithm generates uniformly-distributed computational nodes in each quadtree sub-domain. We apply the meshless radial basis function generated finite difference method and the forward Euler scheme to discretise governing equations in each computational node. The fixed ratio between the characteristic size and the node spacing of a quadtree sub-domain ensures space adaptivity. The adaptive time-stepping accelerates the calculations further. In the framework of previous research studies, we used the approach to solve quantitative phase-field models for single dendrite growth in pure melts and dilute binary alloys. In the present study, we upgrade the solution procedure for the modelling growth of multiple differently oriented dendrites. Along with the space-time adaptive approach, we apply non-linear preconditioning of the phase-field equation to increase computational efficiency. We investigate a novel numerical approach’s accuracy and computational efficiency by simulating the equiaxed dendrite growth from a dilute binary alloy.
Modelling of spatial distribution of segregations in large steel ingots by analysis of centimetric segregation maps
Authors: Gutman L , Kennedy J R , Boukellal A.K , Roch F , Marceaux dit Clément A , Založnik M , Zollinger J
Published: May 2023

Mesosegregation appears during the solidification of low-alloyed steels at the scale of a few grains. It causes chemically segregated bands in forgings manufactured from steel ingots. As this may affect the mechanical properties of the produced parts, it is crucial to understand the formation of such segregation patterns. While both microsegregation and macrosegregation are well understood and can be readily characterized, little is known about the formation of mesosegregation. In this paper we present a data analysis method to identify the characteristic scales and patterns of mesosegregation. Segregation was mapped on centimetric samples, using micro X-Ray fluorescence (µXRF). The fine sampling grid used reveals segregation patterns at different scales. To identify and distinguish the mesoscale segregation patterns from smaller and larger present patterns, a numerical data analysis technique based on spatial filtering was used. It can identify characteristic scales of mesosegregation patterns on 2D serial cut samples, leading to 3D reconstruction. This approach combined with simulation studies, will ultimately pave the way to a comprehensive understanding of the formation of mesosegregation.
Solidification path for rapid solidification – Application to multicomponent alloys for L-PBF
Authors: Martin Paul , Guillemot Gildas , Bellet Michel , Pichot François , Leriche Nicolas , Mayi Yaasin , Gandin Charles-André
Published: May 2023

Laser Powder Bed Fusion (L-PBF) is seen as a process of interest by aeronautical industry to develop new engine components. Nevertheless, the reliability and durability of parts produced by L-PBF depend on the possibility to suppress the occurrence of defects. Among them, hot cracking represents a key issue. These cracks are due to the liquid film remaining between grains at the end of the solidification stage combined with stresses and strains endured by the mushy domain. A microsegregation model providing relevant prediction of the solidification path during L-PBF is thus required for coupling with a thermomechanical analysis. As an answer to the industrial need, a new model is proposed and applied in cooling conditions encountered in L-PBF. It includes the initial solidification conditions and follows the phases, and their composition in the interdendritic liquid region to predict the brittle temperature range. Both dendrite tip growth model and kinetic phase diagram due to non-equilibrium interface phenomena are considered. Cross-diffusion of solute species in the liquid phase is accounted for, as well as thermodynamic coupling with CALPHAD. The model will be applied to IN718, a nickel-based superalloy widely used in the aeronautic industry.
Analysis of the melting and solidification process of aluminum in a mirror furnace using Fiber-Bragg-Grating and numerical models
Authors: Bauer Constantin , Erber Maximilian , Fuchs Georg , Brügge Tobias , Hartmann Christoph , Volk Wolfram
Published: May 2023

In the search of an adequate real time strain measurement method in aluminum casting, the use of Fiber-Bragg-Grating (FBG) is being investigated with great interest. In order to do so, the behaviour of glass fiber sensors in a liquid aluminium alloy at temperatures up to 750°C is experimentally analysed in a laboratory environment. For better process understanding a simulation of the fiber alloy composite is conducted. FBG is an optical measurement method, which uses engraved Bragg reflectors in a 125 µm in diameter thick glass fiber. This reflector transmits most of the wavelengths but only reflects one specific wavelength. This specific wavelength can be measured and changes due to the axial strain on the grating by the fluid alloy reaction and by the changes in temperature. Using a so-called mirror furnace, several experiments with the fiber alloy composite are evaluated. These measurements are also the basis for the further understanding of hot tearing. The data gathered during the measurement campaign - both numerical and experimental - is used to parameterize a simulation. As a result, the understanding of the fiber alloy composite behaviour is expanded and a digital twin is modeled with MATLAB’s partial differential equation toolbox.
Hot tear prediction in large sized high alloyed turbine steel parts - experimental based calibration of mechanical data and model validation
Authors: Klinkhammer J , Thorborg J , Bernhard M , Winkler J , Bernhard C , Hanus R , Tischler G
Published: May 2023

The main defects in heavy steel castings are related to hot tear formation during solidification. Depending on the steel grade, design, and local solidification conditions, it is possible to predict regions with higher risk of hot tear formation during the casting process. However, steels containing Boron show more complex crack and defect patterns compared to common steel casting alloys. The mechanisms behind the Boron induced hot tearing is investigated in this work to understand the influence of Boron enrichment during solidification and the influence on hot tearing. The experimental work includes the investigation of phase diagrams and the corresponding fractions of the solid and liquid phases depending on temperature using thermal analysis e.g. DSC and HT-LSCM. The hot tearing sensitivity and mechanical properties during solidification are obtained in the Submerged Split Chill Test, SSCT. In addition IMC-B 3-point bending tests are performed to determine high-temperature material properties in the solid state. The work is part of a research project where the final goal is to improve the hot tear predictions based on experimental work and carry out a benchmark simulation of a real sized casting and use it to show the agreement between the numerical results and extensive non-destructive testing from industrial observations.
Modelling hot distortion of inorganic bonded sand cores and application on complex 3D printed automotive cores
Authors: Thorborg J , Wendling J , Klinkhammer J , Heitzer M
Published: May 2023

Inorganic bonded sand cores are getting increasing attention in industry due to their environmental advantages, and they are now widely used for series production in automotive applications. The advantages of these binder systems are nevertheless associated with a greater sensitivity of the core quality in relation to the manufacturing and storage process before casting, which is also having a major impact on the core strength. This paper presents the current work in integrating the modelling of the binder decomposition and evaporation of binder water with the mechanical performance of partially hardened and dried sand cores. This allows a local description of mechanical properties, considering different behaviour in compression and tension which depends on temperature and different levels of moisture content through the core. Recent work has shown the importance of including creep effects in the numerical modelling of 3D Printed (3DP) inorganic sand cores. Measurements of the mechanical behaviour of 3DP cores compared to shot cores have shown some fundamental differences in strength due to different density and binder content. This has been investigated in detail in collaboration with a major automotive manufacturer and the application of the model extension was done on a complex water jacket core.
General thermomechanical model of FSW based on a characteristic temperature for deformation and heat transfer
Authors: Salazar Sofia , Rojas Diego , Mendez Patricio F , Tello Karem E
Published: May 2023

This paper presents a coupled model of heat transfer and plastic deformation in friction stir welding (FSW), accounting for the temperature profile in the substrate near the pin. This approach is analogous to the boundary layer analysis in fluid mechanics and is based on the methodology of scaling and calibration based on published data. A model focusing on common conditions in FSW, such as relatively slow translation and high rotation velocities, a thin shear layer and the influence of the shoulder on the maximum temperature was reformulated. This paper extends previous work by considering the heat flow into the pin and an improved criterion for determining the temperature at the edge of the shear layer. The results are a set of updated closed-form expressions for the maximum temperature, the thickness of the shear layer, the shear stress around the pin, torque and thermal effect of the shoulder, applicable to all metals. The predictions from this model are verified against a comprehensive database of published experiments. Applications of this model also include the accelerated determination of procedure variables and the generalization of maps of process limits.
Upgrading gold to green nanoparticles: applications in prostate cancer
Authors: Mitri Nadim , Rahme Kamil , Fracasso Giulio , Ghanem Esther
Published: May 2023

Green nanotechnology produces biocompatible gold nanoparticles (AuNPs) with intrinsic anti-microbial, anti-viral, and anti-tumour properties. Green AuNPs (g-AuNPs) are gaining a solid ground in prostate cancer (PC) nanotherapy. Hence, in this review, we summarise and compare data from studies published between 2015 and 2022 to highlight major biological compounds and outputs from in vitro and in vivo applications of green or biosynthesised AuNPs in PC theranostics. In fact, g-AuNPs can be easily generated with effective antiproliferative PC characteristics. Taken together, g-AuNPs exert various apoptosis-related mechanisms, such as reactive oxygen species (ROS) generation, cell cycle arrest, cytotoxicity, mitochondrial disruption, and anti-tumour immune cell activation, with additional successful delivery of the biological compounds in green materials. g-AuNPs could offer another modality for targeted cancer therapy using antibodies and targeting ligands to specifically recognise and destroy PC tumours. In conclusion, g-AuNPs applications drive forth sustainable nanotechnology while minimising ethical concerns and toxicity risks in clinical trials.
A review on TIG cladding of engineering material for improving their surface property
Authors: Biswas Kaushik , Sahoo Chinmaya Kumar
Published: May 2023

Different components used in industries like power plant, petrochemical, automobile are subjected to severe wear and corrosion due to high temperature and pressure environments. Therefore, it is necessary to improve those components’ wear and corrosion resistance properties. Different processes like laser cladding, CVD, PVD, and thermal spraying are widely used for upgrading surface properties of material. In recent days, it has been found that many researchers investigated the performance of tungsten inert gas (TIG) welding for cladding of superior material like ceramics, metal etc on different substrate materials. TIG cladding can fulfil the requirements of industries by developing a quality cladded layer with low cost and high productivity. This research paper has made an effort to compile the literature related to TIG cladding process for improving substrate properties. It has been observed that the superior materials like titanium carbide(TiC), silicon carbide(SiC), tungsten carbide(WC), cobalt-based alloys, and nickel-based alloys have been successfully cladded using TIG welding process. Researchers have also observed adequate improvement in properties like microhardness and wear resistance of different grades of steel substrate material, like 304, 316 stainless steel, 1010, and 1020 low-carbon steel. The process is also successfully utilized for cladding of superior material on nonferrous metals like Al, Ti alloy. The TIG clad quality and performance rely on different process parameters like current, scan speed, and shielding gas flow rate and also the properties of coating and substrate material.
Mechanical performance and failure modes of self-piercing riveted joints between AA6061 and solution-treated TC4 alloy
Authors: Huang Zhi-Chao , Lu Dao-Chun , Zhang Yong-Chao , Jiang Yu-Qiang , Lu Yan , Guo Yan-Wei
Published: May 2023

TC4 titanium alloy and AA6061 aluminum alloy are widely used in the transportation industry because of their excellent mechanical properties and lightweight. In this work, the TC4 titanium alloy was solution heat treated between 800 °C and 990 °C for 1 h, and water cooled to room temperature. The riveting and tensile tests at room temperature were conducted to evaluate the joint performance. The tensile strength and failure morphology were used to discuss the mechanical performance of joints. Solution heat treatment significantly improves the elongation, mechanical performance, and hardness of TC4 titanium alloy. Compared with the as-received material, the elongation of the treated TC4 titanium alloy is increased by 13% at the solution temperature of 900 °C, the tensile strength was added by 175 MPa at 930 °C, and the hardness was significantly increased. The optimal performance of the TC4 titanium alloy can be obtained at 930 °C. The tensile strength of the joint with the TC4 alloy solution heat treated at 930 °C is the highest of all joints. When the TC4 alloy was solution treated between 800 °C and 850 °C, the rivets were pulled from the AA6061. While at 900 °C and 930 °C, the AA6061 sheet was broken at the rivet. At 960 °C and 990 °C, the TC4 sheet was broken near the rivet. The crack size of TC4 titanium alloy gradually decreases from the rivet outward, and the crack spreads around the rivet. Severe friction can be found, which causes the peeling of the lower plate AA6061 alloy. The breaks of TC4 alloys were the plastic broken. The failure morphology of the TC4 alloy sheet is different under different solution heat treatment temperatures.
Impact of curing on the volumetric and mechanical properties of cold bitumen emulsion mix
Authors: Prasad Deepak , Suman Sanjeev Kumar
Published: May 2023

Cold bitumen emulsion mix (CBEM) is an emerging sustainable material for constructing the base or surface layer of flexible pavements, reducing energy consumption and global warming effects compared to hot mix asphalt. The main challenges associated with CBEM are low initial strength, moisture susceptibility, etc. This is primarily due to water encapsulation. The curing process allows the water to evaporate gradually over time, improving mechanical properties. This study investigates CBEM’s volumetric and mechanical properties under different curing conditions. CBEMs were prepared using low (50 blows) and high (75 blows) compaction efforts and cured at 25, 40, and 55 °C for 1 to 28 days. In volumetric characteristics, the air voids and voids in mineral aggregates decreased slightly with curing, while total binder volume decreased. Effective binder volume and voids filled with binder increased slightly, then decreased. The mechanical properties, i.e., Marshal Stability, Marshal Quotient, Indirect Tensile Strength (ITS), and Moisture Susceptibility parameters like the Indirect Tensile Strength Ratio (ITSR) and Retained Marshal Stability (RMS), were found to improve over time at each curing temperature. Using a high curing temperature further improved the mechanical characteristics of CBEM. The curing process was decelerated in case of CBEM prepared by high compactive efforts compared to CBEM prepared by low compactive efforts. The Michaelis-Menten model can be used to analyze moisture loss growth and the development of mechanical properties over time. The strength-maturity model can be developed by using ITS as strength parameters. There was a strong correlation between all mechanical characteristics and moisture loss.
Mapping confinement potentials and charge densities of interacting quantum systems using conditional generative adversarial networks
Authors: Pantis-Simut Calin-Andrei , Preda Amanda Teodora , Ion Lucian , Manolescu Andrei , Alexandru Nemnes George
Published: May 2023

Accurate and efficient tools for calculating the ground state properties of interacting quantum systems are essential in the design of nanoelectronic devices. The exact diagonalization method fully accounts for the Coulomb interaction beyond mean field approximations and it is regarded as the gold-standard for few electron systems. However, by increasing the number of instances to be solved, the computational costs become prohibitive and new approaches based on machine learning techniques can provide a significant reduction in computational time and resources, maintaining a reasonable accuracy. Here, we employ pix2pix, a general-purpose image-to-image translation method based on conditional generative adversarial network (cGAN), for predicting ground state densities from randomly generated confinement potentials. Other mappings were also investigated, like potentials to non-interacting densities and the translation from non-interacting to interacting densities. The architecture of the cGAN was optimized with respect to the internal parameters of the generator and discriminator. Moreover, the inverse problem of finding the confinement potential given the interacting density can also be approached by the pix2pix mapping, which is an important step in finding near-optimal solutions for confinement potentials.
Geodesic length and shifted weights in first-passage percolation
Authors: Krishnan Arjun , Rassoul-Agha Firas , Seppäläinen Timo
Published: May 2023

We study first-passage percolation through related optimization problems over paths of restricted length. The path length variable is in duality with a shift of the weights. This puts into a convex duality framework old observations about the convergence of the normalized Euclidean length of geodesics due to Hammersley and Welsh, Smythe and Wierman, and Kesten, and leads to new results about geodesic length and the regularity of the shape function as a function of the weight shift. For points far enough away from the origin, the ratio of the geodesic length and the

ℓ
1

\ell ^1

distance to the endpoint is uniformly bounded away from one. The shape function is a strictly concave function of the weight shift. Atoms of the weight distribution generate singularities, that is, points of nondifferentiability, in this function. We generalize to all distributions, directions and dimensions an old singularity result of Steele and Zhang for the planar Bernoulli case. When the weight distribution has two or more atoms, a dense set of shifts produces singularities. The results come from a combination of the convex duality, the shape theorems of the different first-passage optimization problems, and modification arguments.
Objective Analysis of Age-Related Changes in the Superficial Musculoaponeurotic System in Japanese Females Using Computed Tomography
Authors: Okuda Itsuko , Abe Katsuhiro , Yoshioka Naoki , Komemushi Takayoshi , Jinzaki Masahiro , Ohjimi Hiroyuki
Published: May 2023

Background

The superficial musculoaponeurotic system (SMAS) is an anatomical structure involved in facial aging.

Objectives

This study focused on SMAS thickness and aimed to establish age-related changes in SMAS thickness.

Methods

A total of 100 adult Japanese female participants (aged 20-79 years) were enrolled in the study. The participants were divided into 3 age groups: Y, M, and E, comprising 20 to 39, 40 to 59, and 60 to 79 years, respectively. Anatomical structures were used as landmarks to standardize the SMAS analysis sites. The SMAS in a fixed analysis area (FAA) was quantified using multi-detector computed tomography (MDCT), and the relationship between SMAS thickness and age, as well as BMI, was analyzed.

Results

In 96 participants (four were excluded due to imaging artifacts), a moderate yet significant negative correlation was found between the average (A)-SMAS thickness within the FAA and age. The A-SMAS thickness in groups M and E was significantly lower than that of group Y, and the mean value of group E was significantly lower than that of group M. SMAS thickness was greater in the young population. The SMAS gradually became thinner with aging. A statistically significant correlation was not found between SMAS thickness and BMI.

Conclusions

Using MDCT technology, age-related changes in SMAS were successfully analyzed. This highly objective analysis method corroborated the aesthetic surgical knowledge of the SMAS features related to facial aging. In clinical applications, our findings may help elucidate the mechanisms involved in facial aging.

Level of Evidence: 3
Structural diversification of fungal natural products by oxidative enzymes
Authors: Ozaki Taro
Published: May 2023

Ascomycota and basidiomycota fungi are prolific producers of biologically active natural products. Fungal natural products exhibit remarkable structural diversity and complexity, which are generated by the enzymes involved in their biosynthesis. After the formation of core skeletons, oxidative enzymes play a critical role in converting them into mature natural products. Besides simple oxidations, more complex transformations, such as multiple oxidations by single enzymes, oxidative cyclization, and skeletal rearrangement, are often observed. Those oxidative enzymes are of significant interest for the identification of new enzyme chemistry and have the potential to be biocatalysts for the synthesis of complex molecules. This review presents selected examples of unique oxidative transformations that have been found in the biosynthesis of fungal natural products. The development of strategies for refactoring the fungal biosynthetic pathways with an efficient genome-editing method is also introduced.
Integrating multiple traits for improving polygenic risk prediction in disease and pharmacogenomics GWAS
Authors: Zhai Song , Guo Bin , Wu Baolin , Mehrotra Devan V , Shen Judong
Published: May 2023

Polygenic risk score (PRS) has been recently developed for predicting complex traits and drug responses. It remains unknown whether multi-trait PRS (mtPRS) methods, by integrating information from multiple genetically correlated traits, can improve prediction accuracy and power for PRS analysis compared with single-trait PRS (stPRS) methods. In this paper, we first review commonly used mtPRS methods and find that they do not directly model the underlying genetic correlations among traits, which has been shown to be useful in guiding multi-trait association analysis in the literature. To overcome this limitation, we propose a mtPRS-PCA method to combine PRSs from multiple traits with weights obtained from performing principal component analysis (PCA) on the genetic correlation matrix. To accommodate various genetic architectures covering different effect directions, signal sparseness and across-trait correlation structures, we further propose an omnibus mtPRS method (mtPRS-O) by combining P values from mtPRS-PCA, mtPRS-ML (mtPRS based on machine learning) and stPRSs using Cauchy Combination Test. Our extensive simulation studies show that mtPRS-PCA outperforms other mtPRS methods in both disease and pharmacogenomics (PGx) genome-wide association studies (GWAS) contexts when traits are similarly correlated, with dense signal effects and in similar effect directions, and mtPRS-O is consistently superior to most other methods due to its robustness under various genetic architectures. We further apply mtPRS-PCA, mtPRS-O and other methods to PGx GWAS data from a randomized clinical trial in the cardiovascular domain and demonstrate performance improvement of mtPRS-PCA in both prediction accuracy and patient stratification as well as the robustness of mtPRS-O in PRS association test.
Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia
Authors: Canals Isaac , Comella-Bolla Andrea , Cepeda-Prado Efrain , Avaliani Natalia , Crowe James A , Oburoglu Leal , Bruzelius Andreas , King Naomi , Pajares María A , Pérez-Sala Dolores , Heuer Andreas , Rylander Ottosson Daniella , Soriano Jordi , Ahlenius Henrik
Published: May 2023

Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development.
Characteristics of amplitude of low-frequency fluctuations in the resting-state functional magnetic resonance imaging of alcohol-dependent patients with depression
Authors: Sun Fengwei , Yang Jihui , Liu Xiaoying , Huang Gengdi , Kong Zhi , Liu Yu , Zhu Yingmei , Peng Ying , Yang Mei , Jia Xiaojian
Published: May 2023

The high comorbidity of alcohol use disorder and depressive disorder is associated with poor patient prognosis. The mechanisms underlying this comorbidity, however, are largely unknown. By applying the amplitude of low-frequency fluctuations parameter in resting-state functional magnetic resonance imaging, this study investigated changes in the brain functioning of alcohol-dependent patients with and without depression. Alcohol-dependent patients (n = 48) and healthy controls (n = 31) were recruited. The alcohol-dependent patients were divided into those with and without depression, according to Patients Health Questionnaire-9 scores. Amplitude of low-frequency fluctuations in resting-state brain images were compared among the alcohol-dependent patients with depression, alcohol-dependent patients without depression, and healthy controls groups. We further examined associations between amplitude of low-frequency fluctuations alterations, alcohol-dependence severity, and depressive levels (assessed with scales). Compared with the healthy controls group, both alcohol groups showed amplitude of low-frequency fluctuations enhancement in the right cerebellum and amplitude of low-frequency fluctuations abatement in the posterior central gyrus. The alcohol-dependent patients with depression group had higher amplitude of low-frequency fluctuations in the right cerebellum than the alcohol-dependent patients without depression group. Additionally, we observed a positive correlation between amplitude of low-frequency fluctuations value and Patients Health Questionnaire-9 score in the right superior temporal gyrus in the alcohol-dependent patients with depression group. Alcohol-dependent subjects showed abnormally increased spontaneous neural activity in the right cerebellum, which was more significant in alcohol-dependent patients with depression. These findings may support a targeted intervention in this brain location for alcohol and depressive disorder comorbidity.
Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing's syndrome: results from a retrospective multicenter study
Authors: Detomas Mario , Ritzel Katrin , Nasi-Kordhishti Isabella , Schernthaner-Reiter Marie Helene , Losa Marco , Tröger Viola , Altieri Barbara , Kroiss Matthias , Kickuth Ralph , Fassnacht Martin , Micko Alexander , Honegger Jürgen , Reincke Martin , Deutschbein Timo
Published: May 2023

Objective

Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as the gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing's syndrome (ECS). However, published data on the diagnostic value of additional prolactin analysis are controversial. Thus, we evaluated the diagnostic performance of BIPSS with and without prolactin in a multicenter study.

Design and methods

Retrospective study in five European reference centers. Patients with overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of BIPSS with human corticotropin–releasing hormone stimulation were eligible. Cut-offs for the inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and the normalized ACTH:prolactin IPS:P ratio were calculated via receiver operator characteristic analyses (reference: CD).

Results

156 patients with BIPSS were identified. Of these, 120 patients (92 [77%] females; 106 [88%] CD, 14 [12%] ECS) had either histopathologically confirmed tumors or biochemical remission and/or adrenal insufficiency after surgery; only this subgroup was analyzed by ROC analysis. The optimal cut-offs for the ACTH IPS:P ratio were ≥1.9 at baseline (sensitivity 82.1% [95% CI, 73.2-88.6], specificity 85.7% [95% CI, 56.2-97.5], AUC 0.86) and ≥2.1 at 5 minutes post-CRH (sensitivity 91.3% [95% CI, 83.6-95.7], specificity 92.9% [95% CI, 64.1-99.6], AUC 0.96). A subgroup underwent additional prolactin analysis. An optimal cut-off of ≥1.4 was calculated for the normalized ACTH:prolactin IPS:P ratio (sensitivity 96.0% [95% CI, 77.7-99.9], specificity 100% [95% CI, 56.1-100], AUC 0.99).

Conclusion

Our study confirms the high accuracy of BIPSS in the differential diagnosis of ACTH-dependent Cushing's syndrome and suggests that the simultaneous measurement of prolactin might further improve the diagnostic performance of this test.
C18 A FISTULA BETWEEN LVOT AND LEFT ATRIUM: AN UNKNOWN ORIGIN
Authors: Cosimo R , Palomba C , Malvezzi Caracciolo D‘Aquino M , Scognamiglio G , Sperlongano S , Liccardo B , Golino P
Published: May 2023

History of presentation A 76–year–old woman presented to our EchoLab for worsening exertional dyspnea. Few weeks prior the patient underwent cardiological examination that showed heart failure with preserved ejection fraction (HFpEF) with bilateral pleuric effusion, severe mitralic regurgitation (MR), moderate tricuspid regurgitation (TR) with an estimated systolic pulmonary artery pressure (sPAP) of 50 mmHg and a mildly increased mean gradient on bioprothesic aortic valve (26 mmHg). Past medical history The patient had a medical history significant for arterial hypertension, hyperlipidemia, diabetes mellitus, permanent atrial fibrillation and HCV–related liver disease. She received double surgical aortic valve replacement in 2015 and 2019, the second procedure was complicated by intraoperatory stretching of mitral anterior leaflet and atrioventricular block treated with implantation of bicameral PMK. In the following weeks, the patient was admitted to hospital for exposure of the PMK generator pocket associated to catether cultures positivity for S. Aureus oxacilline–resistant, thus undergoing to device removal and positioning of a new PMK. Investigations The cardio–thoracic auscultation revealed a bilateral basal reduction of vesicular breath sounds, an apical sweet systolic murmur (suggestive of MR) and a systolic small aortic murmur best heard at the second intercostal space. The transthoracic echocardiography showed a blood flow apparently originating from interatrial septum heading towards the free left atrial wall. The Transoesophageal Echocardiography (TEE) with bubble test ruled out any interatrial communication. The 3D TEE acquisitions clarified that the shunt arose from the left ventricular outflow tract (LVOT), thus allowing the diagnosis of fistula between the LVOT and the left atrium. Follow–up and conclusions The patient underwent a procedure of percutaneous closure of the fistula. One month after this intervention, the patient presented to our department for the cardiological follow–up. We noticed that the closure had been successful with no left residual shunts and a reduction of the transprothesic mean aortic gradient (18 mmHg). This case report highlights the importance of the 3D echocardiography in order to settle uncertain diagnostics whereas the 2D echocardiography alone is not sufficient. Nevertheless, the diagnostic challenge that remains open is to understand whether the etiology of the fistula is iatrogenic or post–infectious.
C66 PRIMARY RESULTS FROM APOLLO–B, A PHASE 3 STUDY OF PATISIRAN IN PATIENTS WITH TRANSTHYRETIN–MEDIATED AMYLOIDOSIS WITH CARDIOMYOPATHY
Authors: Longhi S , Maurer M , Fontana M , Berk J , Gustafsson F , Simões M , Grogan M , Fernandes F , Gottlieb R , Kubanek M , Poulsen S , Damy T , Diemberger I , Tahara N , Yu W , Tang W , Obici L , González–Duarte A , Sekijima Y , White M , Yureneva E , Jay P , Vest J , Gillmore J
Published: May 2023

Introduction

Transthyretin–mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Patisiran, an IV RNAi therapeutic, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The safety and efficacy of patisiran in patients with wild–type or hereditary ATTR amyloidosis with cardiomyopathy (CM) is being investigated in the ongoing APOLLO–B study.

Methods

Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization or current clinical evidence of HF was required. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo.

Results

APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range), 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%. Baseline characteristics were consistent between patients on tafamidis at baseline (91/360 [25%]) and those who were not. Patisiran achieved a rapid and sustained reduction in serum TTR, irrespective of baseline tafamidis treatment. At M12, patisiran showed a significant benefit vs placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162) and KCCQ–OS (LS mean [SEM] change from baseline: patisiran, 0.300 [1.263]; placebo, –3.408 [1.277]; LS mean [SEM] difference: 3.709 [1.796]; p=0.0397). Consistent benefits with patisiran in 6–MWT and KCCQ–OS were observed across predefined patient subgroups. Time to first event of all–cause hospitalization, urgent HF visit, or death directionally favored patisiran vs placebo (HR [95% CI], 0.839 [0.557, 1.263]), as did all–cause mortality (HR [95% CI], 0.355 [0.110, 1.138]), but all composite outcomes endpoints did not achieve statistical significance over 12 months. Patisiran was well tolerated; most AEs were mild or moderate in severity, and there were no cardiac safety concerns.

Conclusions

Benefits at 12 months were observed with patisiran vs placebo in functional capacity, and health status and quality of life, in patients with ATTR amyloidosis with CM. The efficacy and safety of patisiran continues to be studied in the APOLLO–B open–label extension.
C78 SPONTANEOUS CORONARY ARTERY DISSECTION: THE ROLE OF CORONARY CT ANGIOGRAPHY IN THE FOLLOW–UP MANAGEMENT
Authors: Savo M , Dellino C , Continisio S , Montonati C , Mattesi G , Cozza E , Amato F , Galzerano D , Tarantini G , De Conti G , Motta R , Iliceto S , Pergola V
Published: May 2023

Background

Spontaneous coronary artery dissection (SCAD) is one of the causes of acute coronary syndrome, myocardial infarction (MI) and sudden death. Although the gold standard for diagnosis is invasive coronary angiography, Coronary Computed Tomography Angiography (CCTA) is a new useful tool for the diagnosis and follow–up (FU). Treatment could involve a conservative or an invasive approach with percutaneous coronary intervention (PCI) or coronary artery bypass grafting. AIMS: 1) analyze the clinical and CCTA features at baseline of patients with SCAD; 2) evaluate the clinical and anatomic patients outcome with conservative or invasive treatment; 3) evaluate in patients treated with the conservative approach the clinical and anatomic features of those dismissed with single (SAPT) or double (DAPT) antiplatelet therapy.

Methods

Clinical and anatomic data of 57 patients with SCAD, followed up with CCTA enrolled retrospectively between 2010 ad 2022, were collected at baseline and at the FU. The clinical endpoints evaluated were: all causes mortality, hospitalization for cardiovascular cause, SCAD or PCI ex–novo and MI. The anatomic endpoints were: patency of coronary artery and/or stents and length dissection changing from baseline.

Results

46 (80,7%) patients underwent a conservative treatment and 11 (19,3%) under PCI. Patients treated with PCI were more smokers (45,5% vs 15,2%; p=0,042), had peripherical arteriopathy (18,2% vs 0%; p=0,034), higher troponin peak (40425,8 vs 13436; p=0,011) and lower ejection fraction (51,4±11,0 vs 57,1±7,6; p=0,050). Moreover the PCI population had a significant involvement of more than one coronary artery (72,7% vs 6,5%; p<0,001), of the proximal tracts of the coronary arteries (22,8% vs 13 %; p=0,001) and of the truncus communis (45,4% vs 0%; p<0,001). At the FU, there were no statistical differences for clinical and anatomic endpoints between the two groups (p>0,05). Among patients treated with conservative therapy, there was a more significant recurrence of SCAD in those treated with DAPT than in those treated with SAPT (33,3% vs 5,9%; p=0,033).

Conclusions

Patients with SCAD managed with PCI have more cardiovascular risk factors, a major myocardial infarction extension and a more complex coronary arteries involvement; conservative management is comparable to the PCI treatment for the clinical and anatomic endpoints evaluated. DAPT at discharge is associated with a higher rate of SCAD recurrence at FU.
P23 A STRANGE CASE OF CERVICALGIA
Authors: Carlà A , Palazzolo M , Ruggiero A
Published: May 2023

65–year–old patient with a history of Type 2 Diabetes Mellitus on oral hypoglycaemic therapy, hypercholesterolemia, previous diagnosis of non–secreting K–chain micronodular myeloma undergone heterologous marrow transplantation. From January 2022, he presented persistent mild–moderate neck pain and feverish episodes, therefore he started empiric antibiotic therapy at home. Since June 2022, he complained a worsening of the neck pain partially controlled by non–steroidal anti–inflammatories. Magnetic resonance imaging was therefore performed which highlighted findings consistent with spondylitis of probable infectious nature and subsequent start of empiric antibiotic. A bone marrow biopsy was also performed which showed no recurrence of myelopathy. In July 2022 new feverish episode with shaking chills lasting about 3 days. In this circumstance he underwent a blood culture which resulted positive for the presence of Str. Bovis. In addition, a transthoracic echocardiogram was performed and showed evident floating serpiginous vegetation on the anterior mitral leaflet measuring approximately 1.2 cm x 2.5 cm with a mild mitral regurgitation. Targeted antibiotic therapy was set up and abdominal ultrasound and brain MRI were performed which excluded splenic and brain embolization. A close echocardiographic follow–up showed no reduction of the vegetation. So the patient underwent cardiac surgery in thoracotomy to remove the vegetation adhered to the anterior mitral flap in A2 on the atrial side (3 cm x 1.5 cm x 0.5 cm), and also removal of millimetric lesions on the posterior flap and abrasion of the implantation areas. The post–surgery clinical course passed without any complications, the patient remained stably afebrile with a progressive reduction of the inflammation indexes. Approximately 10 days post–surgery, the patient was then discharged with indications for echocardiographic follow–up.