In-situ nitriding of Fe₂VAl during laser surface remelting to manipulate microstructure and crystalline defects

Tailoring the physical properties of complex materials for targeted applications requires optimizing the microstructure and crystalline defects that influence electrical and thermal transport and mechanical properties. Laser surface remelting can be used to modify the subsurface microstructure of bulk materials and hence manipulate their properties locally. Here, we introduce an approach to perform remelting in a reactive nitrogen atmosphere to form nitrides and induce segregation of nitrogen to structural defects. These defects arise from the fast solidification of the full-Heusler Fe2VAl compound that is a promising thermoelectric material. Advanced scanning electron microscopy, including electron channeling contrast imaging and three-dimensional electron backscatter diffraction, is complemented by atom probe tomography to study the distribution of crystalline defects and their local chemical composition. We reveal a high density of dislocations, which are stable due to their character as geometrically necessary dislocations. At these dislocations and low-angle grain boundaries, we observe segregation of nitrogen and vanadium, which can be enhanced by repeated remelting in nitrogen atmosphere. We propose that this approach can be generalized to other additive manufacturing processes to promote local segregation and precipitation states, thereby manipulating physical properties

Further insights from structural mass spectrometry into endocytosis adaptor protein assemblies

As a fundament in many biologically relevant processes, endocytosis in its different guises has been arousing interest for decades and still does so. This is true for the actual transport and its initiation alike. In clathrin-mediated endocytosis, a comparatively well understood endocytic pathway, a set of adaptor proteins bind specific lipids in the plasma membrane, subsequently assemble and thus form a crucial bridge from clathrin to actin for the ongoing process. These adaptor proteins are highly interesting themselves and the subject of this manuscript. Using many of the instruments that are available now in the mass spectrometry toolbox, we added some facets to the picture of how these minimal assemblies may look, how they form, and what influences the structure. Especially, lipids in the adaptor protein complexes result in reduced charging of a normal sized complex due to their specific binding position. The results further support our structural model of a double ring structure with interfacial lipids

Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis

<b>Background</b><p></p> It is assumed within the accumulated literature that children born of pregnant opioid dependent mothers have impaired neurobehavioral function as a consequence of chronic intrauterine opioid use.<p></p> <b>Methods</b><p></p> Quantitative and systematic review of the literature on the consequences of chronic maternal opioid use during pregnancy on neurobehavioral function of children was conducted using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched Cinahl, EMBASE, PsychINFO and MEDLINE between the periods of January 1995 to January 2012.<p></p> <b>Results</b><p></p> There were only 5 studies out of the 200 identified that quantitatively reported on neurobehavioral function of children after maternal opioid use during pregnancy. All 5 were case control studies with the number of exposed subjects within the studies ranging from 33–143 and 45–85 for the controls. This meta-analysis showed no significant impairments, at a non-conservative significance level of p < 0.05, for cognitive, psychomotor or observed behavioural outcomes for chronic intra-uterine exposed infants and pre-school children compared to non-exposed infants and children. However, all domains suggested a trend to poor outcomes in infants/children of opioid using mothers. The magnitude of all possible effects was small according to Cohen’s benchmark criteria.<p></p> <b>Conclusions</b><p></p> Chronic intra-uterine opioid exposed infants and pre-school children experienced no significant impairment in neurobehavioral outcomes when compared to non-exposed peers, although in all domains there was a trend to poorer outcomes. The findings of this review are limited by the small number of studies analysed, the heterogenous populations and small numbers within the individual studies. Longitudinal studies are needed to determine if any neuropsychological impairments appear after the age of 5 years and to help investigate further the role of environmental risk factors on the effect of ‘core’ phenotypes

Cellular dosimetry of [177Lu]Lu-DOTA-[Tyr3]octreotate radionuclide therapy: the impact of modeling assumptions on the correlation with in vitro cytotoxicity

Background: Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. Therefore, we have built a refined cellular dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. Methods: Time activity curves were measured and modeled for medium, membrane-bound, and internalized activity fractions over 6 days. Clonogenic survival assays were performed at various added activities (0.1–2.5 MBq/ml). 3D microscopy images (stained for cytoplasm, nucleus, and Golgi) were used as reference for developing polygonal meshes (PM) in 3DsMax to accurately render the cellular and organelle geometry. Absorbed doses to the nucleus per decay (S values) were calculated for 3 cellular morphologies: spheres (MIRDcell), truncated cone-shaped constructive solid geometry (CSG within MCNP6.1), and realistic PM models, using Geant4-10.03. The geometrical set-up of the clonogenic survival assays was modeled, including dynamic changes in proliferation, proximity variations, and cell death. The absorbed dose to the nucleus by the radioactive source cell (self-dose) and surrounding source cells (cross-dose) was calculated applying the MIRD formalism. Finally, the correlation between absorbed dose and survival fraction was fitted using a linear dose-response curve (high α/β or fast sub-lethal damage repair half-life) for different assumptions, related to cellular sha

White matter microstructure disruption in early stage amyloid pathology.

Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort. Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF‐AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract‐level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden. Results: Regression analyses showed a non‐linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC. Discussion: Early amyloid deposition is associated with changes in WM microstructure. The non‐linear relationship might reflect multiple stages of axonal damage

Attitudes towards chiropractic: an analysis of written comments from a survey of north american orthopaedic surgeons

<p>Abstract</p> <p>Background</p> <p>There is increasing interest by chiropractors in North America regarding integration into mainstream healthcare; however, there is limited information about attitudes towards the profession among conventional healthcare providers, including orthopaedic surgeons.</p> <p>Methods</p> <p>We administered a 43-item cross-sectional survey to 1000 Canadian and American orthopaedic surgeons that inquired about demographic variables and their attitudes towards chiropractic. Our survey included an option for respondants to include written comments, and our present analysis is restricted to these comments. Two reviewers, independantly and in duplicate, coded all written comments using thematic analysis.</p> <p>Results</p> <p>487 surgeons completed the survey (response rate 49%), and 174 provided written comments. Our analysis revealed 8 themes and 24 sub-themes represented in surgeons' comments. Reported themes were: variability amongst chiropractors (n = 55); concerns with chiropractic treatment (n = 54); areas where chiropractic is perceived as effective (n = 43); unethical behavior (n = 43); patient interaction (n = 36); the scientific basis of chiropractic (n = 26); personal experiences with chiropractic (n = 21); and chiropractic training (n = 18). Common sub-themes endorsed by surgeon's were diversity within the chiropractic profession as a barrier to increased interprofessional collaboration, endorsement for chiropractic treatment of musculoskeletal complaints, criticism for treatment of non-musculoskeletal complaints, and concern over whether chiropractic care was evidence-based.</p> <p>Conclusions</p> <p>Our analysis identified a number of issues that will have to be considered by the chiropractic profession as part of its efforts to further integrate chiropractic into mainstream healthcare.</p

Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with 111In-CP04 in medullary thyroid carcinoma patients

Introduction: From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methods: Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing do

Exploring the translational challenge for medical applications of ionising radiation and corresponding radiation protection research

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of Data and Materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Background: Medical applications of ionising radiation and associated radiation protection research often encounter long delays and inconsistent implementation when translated into clinical practice. A coordinated effort is needed to analyse the research needs for innovation transfer in radiation-based high-quality healthcare across Europe which can inform the development of an innovation transfer framework tailored for equitable implementation of radiation research at scale. Methods: Between March and September 2021 a Delphi methodology was employed to gain consensus on key translational challenges from a range of professional stakeholders. A total of three Delphi rounds were conducted using a series of electronic surveys comprised of open-ended and closed-type questions. The surveys were disseminated via the EURAMED Rocc-n-Roll consortium network and prominent medical societies in the field. Approximately 350 professionals were invited to participate. Participants’ level of agreement with each generated statement was captured using a 6-point Likert scale. Consensus was defined as median ≥4 with ≥60% of responses in the upper tertile of the scale. Additionally, the stability of responses across rounds was assessed. Results: In the first Delphi round a multidisciplinary panel of 20 generated 127 unique statements. The second and third Delphi rounds recruited a broader sample of 130 individuals to rate the extent to which they agreed with each statement as a key translational challenge. A total of 60 consensus statements resulted from the iterative Delphi process of which 55 demonstrated good stability. Ten statements were identified as high priority challenges with ≥80% of statement ratings either ‘Agree’ or ‘Strongly Agree’. Conclusion: A lack of interoperability between systems, insufficient resources, unsatisfactory education and training, and the need for greater public awareness surrounding the benefits, risks, and applications of ionising radiation were identified as principal translational challenges. These findings will help to inform a tailored innovation transfer framework for medical radiation research.European Commissio

Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours

Purpose: Peptide receptor radionuclide therapy using β-emitting radiolabelled somatostatin analogues like DOTA,Tyr3-octreotate shows beneficial results in patients suffering from somatostatin receptor overexpressing tumours. However, after high-dose therapy partial renal reabsorption of radiopeptides may lead to nephrotoxicity. Co-infusion of lysine/arginine lowers renal retention of these radiopeptides without affecting tumour uptake. Recently co-administration of Gelofusine has been described to have a comparable kidney-protecting effect in rats. In the present study optimal dosing of Gelofusine co-administration was studied in tumour-bearing rats. Methods: Doses of 40, 80, 120 or 160 mg/kg Gelofusine were co-injected with 15 μg DOTA,Tyr3-octreotate, labelled with 3 MBq111In for biodistribution (24 h post-injection, n=4 per group) and with 60 MBq111In for microSPECT imaging experiments at 3, 24 and 48 h post-injection. An additional group of rats received 80 mg/kg Gelofusine plus 400 mg/kg lysine co-injection. Biodistribution studies were performed both in older (475 g) and younger (300 g) rats, the latter bearing CA20948 tumours. Results: Co-injection of 40 mg/kg Gelofusine resulted in 40-50% reduction of renal uptake and retention of111In-DOTA,Tyr3-octreotate, whereas higher doses further increased the reduction to 50-60% in both groups of rats. Combining Gelofusine and lysine caused 70% reduction of renal uptake. The uptake of radiolabelled octreotate both in somatostatin receptor-expressing normal tissues and tumours was not affected by Gelofusine co-injection. Conclusion: In rats co-injection of 80 mg/kg Gelofusine resulted in maximum reduction of renal retention of111In-DOTA,Tyr3- octreotate, which was further improved when combined with lysine. Tumour uptake of radiolabelled octreotate was not affected, resulting in an increased tumour to kidney ratio