Influence of laser polishing on the material properties of aluminium L-PBF components

In this study, the influence of laser polishing on the microstructural and mechanical properties of additively manufactured aluminium AlSi10Mg Laser Powder Bed Fusion (L-PBF) parts is analysed. The investigation is carried out on a 5-axis laser cell equipped with 1D Scanner optics driven by a solid-state disc laser at a wavelength of 1030 nm. Laser polishing is performed with pulsed or continuous laser radiation on samples in the initial L-PBF state or after stress relief treatment in a furnace. The metallurgical investigation of the remelting zone with a depth of 101–237 µm revealed an unchanged and homogeneous chemical composition, with a coarsened α-phase and a changed grain structure. The hardness within the remelting zone is reduced to 102–104 HV 0.1 compared to 146 HV 0.1 at the L-PBF initial state. Below the remelting zone, within the heat affected zone, a reduced microhardness, which can reach a thickness up to 1.5 mm, occurs. Laser polishing results in a reduction in residual stresses and resulting distortions compared to the L-PBF initial state. Nevertheless, the re-solidification shrinkage of the polished surface layer introduces additional tensions, resulting in sample distortions well above ones remaining after a stress relieve heat treatment of the initial state. The mechanical properties, analysed on laser polished flat tensile specimens, revealed an increase in the ultimate elongation from 4.5% to 5.4–10.7% and a reduction in the tensile strength from 346 N/mm2 to 247–271 N/mm2 through laser polishing. Hence, the strength resulting from this is comparable to the initial L-PBF specimens after stress relieve heat treatment

Aging syndrome genes and premature coronary artery disease

BACKGROUND: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. METHODS: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan(® )probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. RESULTS: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. CONCLUSION: Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO

t4 Workshop Report: Integrated Testing Strategies (ITS) for Safety Assessment

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and “Good ITS Practices”.JRC.I.5-Systems Toxicolog

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

In-Situ XRD Study of Phase Transformation Kinetics in a Co-Cr-W-Alloy Manufactured by Laser Powder-Bed Fusion

The additive manufacturing process of laser powder-bed fusion (L-PBF) is an increasingly popular approach for patient-specific production of dental frameworks made from Co-Cr alloys. Macroscopically, frameworks produced in this way exhibit high anisotropy especially in Young’s modulus, and are missing standardized requirements. Microscopically, pronounced texture and high residual stresses are characteristic. To reduce resulting detrimental effects, the as-built (AB) parts are heat treated. Dependent on the treatment temperature, effects like the transformation of the γ-phase matrix in the AB condition to ϵ-phase, precipitation, stress relief, and grain growth were observed. While the existence of these processes was established in the past, little is known about their kinetics. To fill this gap, these effects were studied with in-situ X-ray diffraction (XRD) methods in isothermal heat treatments (HTs) at four different sample surface temperatures TS reaching from 650∘C to 900∘C. Furthermore, room temperature ex situ XRD and SEM/EDS measurements completed the analysis. An evaluation of the datasets, with single peak fitting and QXRD methods, yielded the following results. In the HTs below a certain threshold, a γ-to-ϵ transformation was observed in the sample bulk and close to the sample surface. In the latter case, evidence for a partially strain-induced transformation related to oxide formation was present. Above this threshold and possibly slightly below, σ- and Laves-phase precipitated. Additionally, peak profile evolutions hinted at a drop of inter- and intragranular stresses within the first 30 to 60 min. Therefore, an HT of about 30 to 60 min slightly above the threshold is proposed as optimal for reducing residual stresses while retaining a predominantly single-phased microstructure, possibly superior in corrosion properties and likewise in bio-compatibility

In-Situ XRD Study of Phase Transformation Kinetics in a Co-Cr-W-Alloy Manufactured by Laser Powder-Bed Fusion

The additive manufacturing process of laser powder-bed fusion (L-PBF) is an increasingly popular approach for patient-specific production of dental frameworks made from Co-Cr alloys. Macroscopically, frameworks produced in this way exhibit high anisotropy especially in Young’s modulus, and are missing standardized requirements. Microscopically, pronounced texture and high residual stresses are characteristic. To reduce resulting detrimental effects, the as-built (AB) parts are heat treated. Dependent on the treatment temperature, effects like the transformation of the γ-phase matrix in the AB condition to ϵ-phase, precipitation, stress relief, and grain growth were observed. While the existence of these processes was established in the past, little is known about their kinetics. To fill this gap, these effects were studied with in-situ X-ray diffraction (XRD) methods in isothermal heat treatments (HTs) at four different sample surface temperatures TS reaching from 650∘C to 900∘C. Furthermore, room temperature ex situ XRD and SEM/EDS measurements completed the analysis. An evaluation of the datasets, with single peak fitting and QXRD methods, yielded the following results. In the HTs below a certain threshold, a γ-to-ϵ transformation was observed in the sample bulk and close to the sample surface. In the latter case, evidence for a partially strain-induced transformation related to oxide formation was present. Above this threshold and possibly slightly below, σ- and Laves-phase precipitated. Additionally, peak profile evolutions hinted at a drop of inter- and intragranular stresses within the first 30 to 60 min. Therefore, an HT of about 30 to 60 min slightly above the threshold is proposed as optimal for reducing residual stresses while retaining a predominantly single-phased microstructure, possibly superior in corrosion properties and likewise in bio-compatibility